# embeddings_queue

created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 823
encoding: FLOAT32
metadata:
{"title": "Neutralizing antibodies targeting a novel epitope on envelope protein exhibited broad protection against flavivirus without risk of disease enhancement", "chroma:document": "sequence of JEV epitope RCPTTGE and DENV/ZIKV epitope RCPTQGE.\nMethods Immune sera were generated by immunization with the peptides which were synthesized by using five \ncopies of RCPTTGE or RCPTQGE and named as JEV\u2011NTE and DV/ZV\u2011NTE. Immunogenicity and neutralizing abilities of \nJEV\u2011NTE or DV/ZV\u2011NTE\u2011immune sera against flavivirus were evaluated by ELISA and neutralization tests, respectively. \nProtective efficacy in vivo were determined by passive transfer the immune sera into JEV\u2011infected ICR or DENV\u2011 and \nZIKV\u2011challenged AG129 mice. In vitro and in vivo ADE assays were used to examine whether JEV\u2011NTE or DV/ZV\u2011NTE\u2011\nimmune sera would induce ADE.\nResults Passive immunization with JEV\u2011NTE\u2011immunized sera or DV/ZV\u2011NTE\u2011immunized sera could increase the \nsurvival rate or prolong the survival time in JEV\u2011challenged ICR mice and reduce the viremia levels significantly in \nDENV\u2011 or ZIKV\u2011infected AG129 mice. Furthermore, neither JEV \u2011NTE\u2011 nor DV/ZV\u2011NTE\u2011immune sera induced antibody\u2011\ndependent enhancement (ADE) as compared with the control mAb 4G2 both in vitro and in vivo.\nConclusions We showed for the first time that novel bc loop epitope RCPTQGE located on the amino acids 73 to 79 \nof DENV/ZIKV E protein could elicit cross\u2011neutralizing antibodies and reduced the viremia level in DENV\u2011 and ZIKV\u2011\nchallenged AG129 mice. Our results highlighted that the bc loop epitope could be a promising target for flavivirus \nvaccine development.\nKeywords Japanese encephalitis virus, Dengue virus, Zika virus, Flavivirus vaccine, Neutralizing epitope, Envelop \nprotein domain II\n*Correspondence:\nChing\u2011Len Liao\nchinglen@gmail.com\nFull list of author information is available at the end of the article"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 824
encoding: FLOAT32
metadata:
{"title": "The role of trained immunity in COVID-19: Lessons for the next pandemic", "chroma:document": "Since January 2020 Elsevier has created a COVID-19 resource centre with \nfree information in English and Mandarin on the novel coronavirus COVID-\n19. The COVID-19 resource centre is hosted on Elsevier Connect, the \ncompany's public news and information website. \n \nElsevier hereby grants permission to make all its COVID-19-related \nresearch that is available on the COVID-19 resource centre - including this \nresearch content - immediately available in PubMed Central and other \npublicly funded repositories, such as the WHO COVID database with rights \nfor unrestricted research re-use and analyses in any form or by any means \nwith acknowledgement of the original source. These permissions are \ngranted for free by Elsevier for as long as the COVID-19 resource centre \nremains active."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 825
encoding: FLOAT32
metadata:
{"title": "Familial hyperamylasaemia", "chroma:document": "Gut 1997; 40: 689-690\nFamilial hyperamylasaemia\nP M Cuckow, A Y Foo, A Jamal, M D Stringer\nAbstract\nA six year old boy underwent extensive\ninvestigation for recurrent abdominal pain\nand was found to have a persistently raised\nserum amylase. Endoscopic retrograde\ncholangiopancreatography\nwas\nnormal\nand macroamylasaemia\nwas\nexcluded.\nSerum amylase concentrations were found\nto be raised in other family members\nspanning three generations, all of whom\nwere\nasymptomatic.\nClearance\nstudies\nsuggested no evidence of a renal tubular\ndefect and serum lipase concentrations\nwere normal. This is the first report of\napparently familial hyperamylasaemia and\nthe mode of inheritance is consistent with\nan autosomal dominant pattern.\n(Gut 1997; 40: 689-690)\nKeywords: amylase, pancreatitis.\nAlthough a greatly raised serum amylase in a\npatient with abdominal pain is most often due\nto pancreatic disease, there are many recog-\nnised causes of a mildly raised concentration.'\nWe report a hitherto undescribed cause of\nhyperamylasaemia.\nMethods\nINDEX CASE\nIn 1993, a four year old white boy presented\nacutely with colicky periumbilical pain, leth-\nargy, anorexia, and vomiting. He had experi-\nenced\nseveral\nsimilar\nepisodes\nduring\nthe\n2.5 r\n2\n0)\n0\n35.\nE\nE\n1.5\n0\n0\n0\n0.5\no\nI\nr'V\nr'rmc\nr'm\nC ')C r)\n14\n14\nI-\nle\nd.\nit le\nl\n0\ne\nLO\nLO\nLO\nLO\nLO\nULO\nLO\nLO\nLO\nLO\nLO\nLO\na,\na,\na, Oa\nw\na,\na,\na,\no\n) aOa,\na,\na\na,\na,\na,\na,\na,\na,\na,\nac\na\na,\na,o\na, Oa\n< E * n < cn \u00b0 Z a\nX) u E < E n\n<\n0\u00b0 z a n u E < E:\n< w0\nz\u00b0 a\n-t\nDate\nFigure 1: Serial serum amylase concentrations for the index case. *Serum amylase is\nexpressed as the ratio of the measured value to the upper limit of the normal range.\nprevious year, each resolving after a few hours\nwith simple analgesics. Between episodes he\nwas well. As an infant he had been investigated\nfor poor weight gain, vomiting with occasional\nloose stools, and a persistent cough. Routine\nhaematology and biochemistry, liver and renal\nfunction\ntests,\nserum\nferritin\nand\nvitamin\nB12, thyroid function tests, urine and stool"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 826
encoding: FLOAT32
metadata:
{"title": "Familial hyperamylasaemia", "chroma:document": "microbiology, a sweat test, xylose absorption\ntest, chest radiography, and barium meal had\nbeen\nnormal.\nAt two\nyears\nhis\npersistent\nsymptoms prompted an upper gastrointestinal\nendoscopy and jejunal biopsy, which were\nnormal. Subsequently, his problems resolved\nand his growth became normal with height and\nweight increasing between the 10th and 25th\ncentiles.\nOn admission, he had a mild pyrexia with no\nsigns\nof an\nacute\nabdomen.\nRoutine\nin-\nvestigations were normal except for a slightly\nraised serum amylase of 168 Somogyi U/dl\n(normal range 40-160 U/dl). A plain abdomi-\nnal\nradiograph\nand\nultrasound\nscan\nwere\nnormal. A laparoscopy disclosed no pathology\nand a non-inflamed appendix was removed.\nSix\nweeks\nlater\nhe\nwas\nreadmitted\nwith\nrecurrent abdominal pain and a repeat serum\namylase was raised at 336 Somogyi U/dl but a\nrepeat\nabdominal\nultrasound\nscan\nagain\nshowed no abnormality. His pain settled and\noutpatient\ninvestigations\nincluding\na\nsmall\nbowel\nmeal,\nabdominal\ncomputed\ntomog-\nraphy,\nsweat\ntest,\nand DNA\nanalysis\nfor\ncommon cystic fibrosis gene mutations were all\nnormal. His serum amylase remained raised at\n226 Somogyi U/dl and he was referred to us for\nfurther investigation.\nDuring the next year he remained well but\nhis serum amylase was raised at 160 inter-\nnational units/l (normal range 19-95 IU/1). He\nhad a normal lipid profile, liver function tests,\nurine metabolic screen, faecal chymotrypsin,\nand faecal fat content. Endoscopic retrograde\ncholangiopancreatography\nshowed\nnormal\nductal anatomy with a normal pancreatico-\nbiliary junction. Macroamylasaemia was con-\nsidered likely after finding a normal urinary\namylase excretion (38 IU/4 h) in the presence\nof a persistently raised serum amylase (149 IU/\n1).2 Macroamylasaemia was\ndefinitively\nex-\ncluded by the absence of diffuse streaking in\nthe y-globulin region after electrophoretic sep-\naration on cellulose acetate.3 Autoantibodies,\nrheumatoid factor, and Ro and La antigens were\nnegative. Currently the child is well with normal"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 827
encoding: FLOAT32
metadata:
{"title": "Familial hyperamylasaemia", "chroma:document": "growth. He has had no further attacks of non-\nspecific abdominal pain. During a three year\nperiod,\nthe\npatient's\nserum\namylase\nwas\nestimated on multiple\noccasions by various\nstandard laboratory methods4 and was found to\nbe consistently raised (Fig 1).\nDepartment of\nPaediatric Surgery,\nLeeds General\nInfirmary,\nLeeds\nP M Cuckow\nM D Stringer\nDepartment of\nChemical Pathology,\nSt James' University\nHospital\nA Jamal\nDepartment of\nChemical Pathology,\nRoyal Free Hospital,\nLondon, UK\nA Y Foo\nCorrespondence to:\nMr M D Stringer,\nDepartment of Paediatric\nSurgery, Clarendon Wmg,\nLeeds General Infirmary,\nLeeds LS2 9NS.\nAccepted for publication\n23 January 1997\n689\n1"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 828
encoding: FLOAT32
metadata:
{"title": "Postnatal intestinal mucosa and gut microbial composition develop hand in hand: A mouse study", "chroma:document": "Original Article\nPostnatal intestinal mucosa and gut microbial\ncomposition develop hand in hand: A mouse study\nUday Pandey a,b, Palok Aich a,b,*\na School of Biological Sciences, National Institute of Science Education and Research (NISER), P.O. Jatni, Khurda,\nOdisha, India\nb Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India\na r t i c l e i n f o\nArticle history:\nReceived 14 October 2021\nAccepted 10 March 2022\nAvailable online 16 March 2022\nKeywords:\nGut barrier integrity\nIntestinal epithelial cells (IECs)\nGut microbiota\nPostnatal period\nAkkermansia muciniphila (A. mucini-\nphila)\nGoblet cells\na b s t r a c t\nBackground: During the early postnatal life, gut microbiota development experiences\ndynamic changes in their structural and functional composition. The postnatal period is\nthe critical window to develop a host defense mechanism. The maturation of intestinal\nmucosal barrier integrity is one of the essential defense mechanisms to prevent the entry\nof pathogens. However, the co-development of intestinal microbial colonization, formation\nof barrier integrity, and intestinal epithelial cell layer is not entirely understood.\nMethods: We studied the gut microbial composition and diversity using 16S rRNA marker\ngene-based sequencing in mice to understand postnatal age-dependent association ki-\nnetics between gut microbial and intestinal development. Next, we assessed the intestinal\ndevelopment by in vivo gut permeability assay, mRNA gene expression of different tight\njunction proteins and intestinal epithelial cell markers, goblet cells population, villus\nlength, and cecal IgA quanti\ufb01cation.\nResults: Our results showed a signi\ufb01cant shift in gut microbial structural and functional\ncomposition from postnatal day 14 onwards with early life Proteobacteria abundance.\nRelative abundance of Verrucomicrobia was maximum at postnatal day 14 and showed a\ngradual decrease over time. We also observed an age-dependent biphasic pattern in barrier"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 829
encoding: FLOAT32
metadata:
{"title": "Postnatal intestinal mucosa and gut microbial composition develop hand in hand: A mouse study", "chroma:document": "integrity improvement and differentiation of intestinal epithelial cells (IECs). A signi\ufb01cant\nimprovement in barrier integrity between days 1 and 7 showed the host factor contribu-\ntion, while that beyond day 14 revealed an association with changes in microbiota\ncomposition. Our temporal correlation analysis associated Bacteroidetes phylum with the\nmucosal barrier formation during postnatal development.\nConclusions: The present study revealed the importance and interplay of host factors and\nthe microbiome in gut development and intestinal mucosal homeostasis.\n* Corresponding author. School of Biological Sciences, National Institute of Science Education and Research (NISER), P.O. Jatni, Khurda\n752050, Odisha, India\nE-mail address: palok.aich@niser.ac.in (P. Aich).\nPeer review under responsibility of Chang Gung University.\nAvailable online at www.sciencedirect.com\nScienceDirect\nBiomedical Journal\njournal homepage: www.elsevier.com/locate/bj\nb i o m e d i c a l j o u r n a l 4 6 ( 2 0 2 3 ) 1 0 0 5 1 9\nhttps://doi.org/10.1016/j.bj.2022.03.004\n2319-4170/\u00a9 2022 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC\nBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 830
encoding: FLOAT32
metadata:
{"title": "Ecological drivers of sustained enzootic yellow fever virus transmission in Brazil, 2017\u00852021", "chroma:document": "RESEARCH ARTICLE\nEcological drivers of sustained enzootic yellow\nfever virus transmission in Brazil, 2017\u20132021\nNata\u00b4lia Ingrid Oliveira Silva1\u00a4\u2021, Gregory F. Albery2\u2021, Matheus Soares Arruda1\u262f, Gabriela\nFernanda Garcia Oliveira1\u262f, Tha\u0131\u00b4s Alkifeles Costa1, E\u00b4 rica Munhoz de Mello1,3, Gabriel\nDias Moreira1, Erik Vin\u0131\u00b4cius Reis1, Simone Agostinho da Silva3, Marlise Costa Silva3,\nMunique Guimar\u00e3es de Almeida3, Daniel J. Becker4, Colin J. Carlson2,5,\nNikos Vasilakis6,7,8, Kathryn A. Hanley9, Beta\u02c6nia Paiva DrumondID1*\n1 Department of Microbiology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, 2 Department\nof Biology, Georgetown University, Washington, DC, United States of America, 3 Laborato\u00b4rio de Zoonoses\u2014\nCentro de Controle de Zoonoses, Prefeitura de Belo Horizonte, Belo Horizonte, Minas Gerais, Brazil,\n4 Department of Biology, University of Oklahoma, Norman, Oklahoma, United States of America, 5 Center\nfor Global Health Science and Security, Georgetown University, Washington, D.C., United States of America,\n6 Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of\nAmerica, 7 Center for Vector-Borne and Zoonotic Diseases, The University of Texas Medical Branch,\nGalveston, Texas, United States of America, 8 Institute for Human Infection and Immunity, University of\nTexas Medical Branch, Galveston, Texas, United States of America, 9 Department of Biology, New Mexico\nState University, Las Cruces, New Mexico, United States of America\n\u262f These authors contributed equally to this work.\n\u00a4 Current address: Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA\n\u2021 These authors share first authorship on this work.\n* betaniadrumond@gmail.com, betaniadrumond@ufmg.br\nAbstract\nBeginning December 2016, sylvatic yellow fever (YF) outbreaks spread into southeastern\nBrazil, and Minas Gerais state experienced two sylvatic YF waves (2017 and 2018). Follow-\ning these massive YF waves, we screened 187 free-living non-human primate (NHPs) car-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 831
encoding: FLOAT32
metadata:
{"title": "Ecological drivers of sustained enzootic yellow fever virus transmission in Brazil, 2017\u00852021", "chroma:document": "casses collected throughout the state between January 2019 and June 2021 for YF virus\n(YFV) using RTqPCR. One sample belonging to a Callithrix, collected in June 2020, was\npositive for YFV. The viral strain belonged to the same lineage associated with 2017\u20132018\noutbreaks, showing the continued enzootic circulation of YFV in the state. Next, using data\nfrom 781 NHPs carcasses collected in 2017\u201318, we used generalized additive mixed mod-\nels (GAMMs) to identify the spatiotemporal and host-level drivers of YFV infection and inten-\nsity (an estimation of genomic viral load in the liver of infected NHP). Our GAMMs explained\n65% and 68% of variation in virus infection and intensity, respectively, and uncovered strong\ntemporal and spatial patterns for YFV infection and intensity. NHP infection was higher in\nthe eastern part of Minas Gerais state, where 2017\u20132018 outbreaks affecting humans and\nNHPs were concentrated. The odds of YFV infection were significantly lower in NHPs from\nurban areas than from urban-rural or rural areas, while infection intensity was significantly\nlower in NHPs from urban areas or the urban-rural interface relative to rural areas. Both YFV\ninfection and intensity were higher during the warm/rainy season compared to the cold/dry\nseason. The higher YFV intensity in NHPs in warm/rainy periods could be a result of higher\nexposure to vectors and/or higher virus titers in vectors during this time resulting in the deliv-\nery of a higher virus dose and higher viral replication levels within NHPs. Further studies are\nPLOS NEGLECTED TROPICAL DISEASES\nPLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0011407\nJune 5, 2023\n1 / 18\na1111111111\na1111111111\na1111111111\na1111111111\na1111111111\nOPEN ACCESS\nCitation: Silva NIO, Albery GF, Arruda MS, Oliveira\nGFG, Costa TA, de Mello E\u00b4M, et al. (2023)\nEcological drivers of sustained enzootic yellow\nfever virus transmission in Brazil, 2017\u20132021.\nPLoS Negl Trop Dis 17(6): e0011407. https://doi.\norg/10.1371/journal.pntd.0011407"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 832
encoding: FLOAT32
metadata:
{"title": "Ecological drivers of sustained enzootic yellow fever virus transmission in Brazil, 2017\u00852021", "chroma:document": "Editor: Eric H. Y. Lau, The University of Hong\nKong, CHINA\nReceived: October 20, 2022\nAccepted: May 22, 2023\nPublished: June 5, 2023\nCopyright: \u00a9 2023 Silva et al. This is an open\naccess article distributed under the terms of the\nCreative Commons Attribution License, which\npermits unrestricted use, distribution, and\nreproduction in any medium, provided the original\nauthor and source are credited.\nData Availability Statement: The authors confirm\nthat all data underlying the findings are fully\navailable without restriction. All relevant data are\nwithin the paper and its Supporting Information\nfiles.\nFunding: This study was funded by National\nInstitute of Allergy and Infectious Diseases (NIAID)\n(https://www.niaid.nih.gov/) through the CREID\nPilot Research Program 2021 (https://creid-\nnetwork.org/pilot-program) awarded to BPD by the\nCenters for Research in Emerging Infectious"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 833
encoding: FLOAT32
metadata:
{"title": "Reconsideration of interferon treatment for viral diseases: Lessons from SARS, MERS, and COVID-19", "chroma:document": "Since January 2020 Elsevier has created a COVID-19 resource centre with \nfree information in English and Mandarin on the novel coronavirus COVID-\n19. The COVID-19 resource centre is hosted on Elsevier Connect, the \ncompany's public news and information website. \n \nElsevier hereby grants permission to make all its COVID-19-related \nresearch that is available on the COVID-19 resource centre - including this \nresearch content - immediately available in PubMed Central and other \npublicly funded repositories, such as the WHO COVID database with rights \nfor unrestricted research re-use and analyses in any form or by any means \nwith acknowledgement of the original source. These permissions are \ngranted for free by Elsevier for as long as the COVID-19 resource centre \nremains active."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 834
encoding: FLOAT32
metadata:
{"title": "Psychophysical assessment of a patient with Tolosa-Hunt syndrome", "chroma:document": "Journal of Neurology, Neurosurgery, and Psychiatry 1983;46:576-578\nShort report\nPsychophysical assessment of a patient with\nTolosa-Hunt syndrome\nLESLEY J FALLOWFIELD, JOHN E REES\nFrom the Laboratory of Experimental Psychology Sussex University, Falmer, and Hurstwood Park\nNeurological Centre, Haywards Heath, Sussex, UK\nSUMMARY\nPatients may complain of impaired vision and yet exhibit no abnormalities when tested\nwith conventional tests of visual acuity. Some sensitive psychophysical tests used by psychologists\nand neurophysiologists to examine the function of the normal visual system are beginning to gain\nrecognition as useful tools in clinical situations. They are particularly sensitive indicators of\ndamage to the visual pathways. The results are presented of one such application which character-\nises the visual defects of a patient with a suspected diagnosis of Tolosa-Hunt Syndrome.\nClinical History\nIn 1979 the patient, aged 51 years, presented with a history\nof 2 episodes of pain in and around the left orbit and upper\ngum. Diagnosis was thought to be an unusual presentation\nof migrainous neuralgia. By January 1980 there had been\ntwo further episodes of painful ophthalmoplegia with dip-\nlopia. This pain was predominantly peri-orbital and there\nwas 3rd and 6th cranial nerve paresis and ptosis on the left\nside. His visual fields were full and Snellen acuity was nor-\nmal. A carotid angiogram showed narrowing of the entire\nintracavernous section of the left carotid artery, and eleva-\ntion of the syphon. The CT scan (fig 1) shows a mass lesion\nin the left orbital apex surrounding the optic nerve, and\ninvolvement of the superior orbital fissure. Full blood\ncount, ESR, urea, electrolytes, protein electrophoresis\nwere\nall\nnormal.\nPredisone\ntreatment\nresolved\nthe\nheadache and improved the ocular pareses.\nA diagnosis of Tolosa-Hunt syndrome' was confirmed at\nthe Moorfields Eye Hospital. By May 1981 there was no\ndiplopia, although the patient still complained of transient"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 835
encoding: FLOAT32
metadata:
{"title": "Psychophysical assessment of a patient with Tolosa-Hunt syndrome", "chroma:document": "lack of clarity in the left eye. Central field analysis now\nshowed a left para-central scotoma despite a visual acuity\nof 6/5. Steroid treatment had been stopped and the CT\nscan was now normal. Visual evoked responses to checker-\nboard pattern reversal showed a delay across the left visual\npathway with a major P2 potential at 124 ms. The right\nside had a normal latency at 109ms. The patient continued\nAddress for reprint requests: Lesley J Fallowfield, Laboratory of\nExperimental Psychology, Sussex University, Brighton BN1 2QG,\nUK.\nReceived 6 October 1982 and in revised form 13 January 1983\nAccepted 26 January 1983\nFig 1\nCT scan showing high attenuation area in orbital\napex taken 18 February 1980.\nto complain of poor vision in the left eye when psychophys-\nical measurements were made in June 1981.\nMeasurement of contrast sensitivity.\nThe limits of normal spatial vision can be character-\nised by measuring the contrast sensitivity to sinusoi-\ndal gratings of different spatial frequency. Periodic\nexchange of the dark and light bars produces a flick-\nering grating. Different flicker-rates or temporal\nfrequencies produce specific changes in the shape of\nthe spatial contrast sensitivity curve as can be seen in\n576"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 836
encoding: FLOAT32
metadata:
{"title": "Loss of Motor Cortical Inputs to the Red Nucleus after CNS Disorders in Nonhuman Primates", "chroma:document": "Development/Plasticity/Repair\nLoss of Motor Cortical Inputs to the Red Nucleus after CNS\nDisorders in Nonhuman Primates\nSimon Borgognon1,2,3 and Eric M. Rouiller2\n1Center for the Neural Basis of Cognition, Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, 2Department of\nNeurosciences and Movement Sciences, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland, and\n3Center for Neuroprosthetics and Brain Mind Institute, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne, CH-1015 Lausanne, Switzerland\nThe premotor (PM) and primary motor (M1) cortical areas broadcast voluntary motor commands through multiple neuronal\npathways, including the corticorubral projection that reaches the red nucleus (RN). However, the respective contribution of\nM1 and PM to corticorubral projections as well as changes induced by motor disorders or injuries are not known in nonhu-\nman primates. Here, we quantified the density and topography of axonal endings of the corticorubral pathway in RN in\nintact monkeys, as well as in monkeys subjected to either cervical spinal cord injury (SCI), Parkinson\u2019s disease (PD)-like\nsymptoms or primary motor cortex injury (MCI). Twenty adult macaque monkeys of either sex were injected with the biotin-\nylated dextran amine anterograde tracer either in PM or in M1. We developed a semiautomated algorithm to reliably detect\nand count axonal boutons within the magnocellular and parvocellular (pRN) subdivisions of RN. In intact monkeys, PM and\nM1 preferentially target the medial part of the ipsilateral pRN, reflecting its somatotopic organization. Projection of PM to\nthe ipsilateral pRN is denser than that of M1, matching previous observations for the corticotectal, corticoreticular, and corti-\ncosubthalamic projections (Fregosi et al., 2018, 2019; Borgognon et al., 2020). In all three types of motor disorders, there"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 837
encoding: FLOAT32
metadata:
{"title": "Loss of Motor Cortical Inputs to the Red Nucleus after CNS Disorders in Nonhuman Primates", "chroma:document": "was a uniform and strong decrease (near loss) of the corticorubral projections from PM and M1. The RN may contribute to\nfunctional recovery after SCI, PD, and MCI, by reducing direct cortical influence. This reduction possibly privileges direct\naccess to the final output motor system, via emphasis on the direct corticospinal projection.\nKey words: motor disorders; plasticity; premotor cortex; primary motor cortex; primate; red nucleus\nSignificance Statement\nWe measured the corticorubral projection density arising from the PM or the M1 cortices in adult macaques. The premotor\ncortex sent denser corticorubral projections than the primary motor cortex, as previously observed for the corticotectal, corti-\ncoreticular, and corticosubthalamic projections. The premotor cortex may thus exert more influence than primary motor cor-\ntex onto subcortical structures. We next asked whether the corticorubral motor projections undergo lesion-dependent\nplasticity after either cervical spinal cord injury, Parkinson\u2019s disease-like symptoms, or primary motor cortex lesion. In all\nthree types of pathology, there was a strong decrease of the corticorubral motor projection density, suggesting that the red nu-\ncleus may contribute to functional recovery after such motor system disorders based on a reduced direct cortical influence.\nIntroduction\nThe multiple motor cortical areas in primates broadcast com-\nmands through parallel neuronal pathways to generate and coor-\ndinate voluntary movements (Luppino and Rizzolatti, 2000; Dum\nand Strick, 2002; Rouiller, 2012). These routes reach multiple\nregions of the CNS including subcortical relays, the brainstem,\nand the spinal cord. These projections are specifically organized\ndepending on their origin and their targets (Lemon, 2008). For\ninstance, in intact macaques, the premotor cortex (PM) sends\ndenser projections to the subthalamic nucleus (Borgognon et\nal., 2020), the superior colliculus (Fregosi and Rouiller, 2017),\nand the reticular formation (Fregosi et al., 2017) than the pri-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 838
encoding: FLOAT32
metadata:
{"title": "Loss of Motor Cortical Inputs to the Red Nucleus after CNS Disorders in Nonhuman Primates", "chroma:document": "mary motor cortex (M1). After motor disorders, these projec-\ntions undergo unique regional plasticity that depends on the\nReceived Oct. 17, 2022; revised Dec. 14, 2022; accepted Jan. 13, 2023.\nAuthor contributions: S.B. and E.M.R. designed research; S.B. and E.M.R. performed research; S.B. analyzed\ndata; S.B. and E.M.R. wrote the paper.\nThis work was supported by Swiss National Science Foundation Grants 110005, 132465, 144990, 149643,\nSinergia CRSII3_160696, Sinergia Prometheus CRSI33_125408 (E.M.R.), and 210986 (S.B.) and the Swiss\nPrimate Competence Center for Research. We thank Prof. Joceylne Bloch, Prof. Patrick Freund, Dr. Jean-\nFran\u00e7ois Brunet, Dr. Simon Badoud, and Dr. Eric Schmidlin for surgical assistance; Prof. Martin Schwab, Prof.\nJoceylne Bloch, Prof. Patrick Freund, Dr. Anis Mir, Dr. Thierry Wannier, Dr. Eric Schmidlin, Dr. Marie-Laure\nBeaud, Dr. Alexander Wyss, Dr. Shahid Bashir, Dr. Adjia Hamadjida, Dr. Aderraouf Belhaj-Sa\u00eff, Dr. M\u00e9lanie\nKaeser, Dr. Julie Savidan, Dr. Anne-Dominique Gindrat, Dr. Yu Liu, Dr. Michela Fregosi, Dr. Simon Badoud,\nAlessandro Contestabile, and J\u00e9r\u00f4me Cottet for contributions to experimental sessions and elaborations of\nexperimental protocols; Laurent Bossy, Jacques Maillard, Bernard Bapst, Bernard Morandi and Joseph\nCorpataux for animal care assistance; Christine Roulin, V\u00e9ronique Moret, and Christiane Marti for tissue processing;\nFelix Meyenhofer for technical microscopical assistance; and Dr. Erinn M. Grigsby for proofreading.\nThe authors declare no competing financial interests.\nCorrespondence should be addressed to Simon Borgognon at simon.borgo@pitt.edu.\nhttps://doi.org/10.1523/JNEUROSCI.1942-22.2023\nCopyright \u00a9 2023 the authors\n1682 \u2022 The Journal of Neuroscience, March 8, 2023 \u2022 43(10):1682\u20131691"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 839
encoding: FLOAT32
metadata:
{"title": "Spatio-Temporal Characterization of Brain Inflammation in a Non-human Primate Stroke Model Mimicking Endovascular Thrombectomy", "chroma:document": "Vol.:(0123456789)\n1 3\nNeurotherapeutics (2023) 20:789\u2013802 \nhttps://doi.org/10.1007/s13311-023-01368-2\nORIGINAL ARTICLE\nSpatio\u2011Temporal Characterization of\u00a0Brain Inflammation \nin\u00a0a\u00a0Non\u2011human Primate Stroke Model Mimicking Endovascular \nThrombectomy\nGuillaume\u00a0Becker1 \u00a0\u00b7 Justine\u00a0Debatisse1\u00a0\u00b7 Margaux\u00a0Rivi\u00e8re1\u00a0\u00b7 Claire\u00a0Crola\u00a0Da\u00a0Silva1\u00a0\u00b7 Maude\u00a0Beaudoin\u2011Gobert2\u00a0\u00b7 \nOmer\u00a0Eker3,4\u00a0\u00b7 Oc\u00e9ane\u00a0Wateau5\u00a0\u00b7 Tae\u00a0Hee\u00a0Cho1,4\u00a0\u00b7 Marl\u00e8ne\u00a0Wiart1\u00a0\u00b7 L\u00e9on\u00a0Tremblay6\u00a0\u00b7 Nicolas\u00a0Costes7\u00a0\u00b7 \nIn\u00e8s\u00a0M\u00e9rida7\u00a0\u00b7 J\u00e9r\u00f4me\u00a0Redout\u00e97\u00a0\u00b7 Christelle\u00a0L\u00e9on1\u00a0\u00b7 Jean\u2011Baptiste\u00a0Langlois7\u00a0\u00b7 Didier\u00a0Le\u00a0Bars4,7\u00a0\u00b7 Sophie\u00a0Lancelot4,7\u00a0\u00b7 \nNorbert\u00a0Nighoghossian1,4\u00a0\u00b7 Laura\u00a0Mechtouff1,4\u00a0\u00b7 Emmanuelle\u00a0Canet\u2011Soulas1\nAccepted: 13 March 2023 / Published online: 28 March 2023 \n\u00a9 The Author(s) 2023\nAbstract\nReperfusion therapies in acute ischemic stroke have demonstrated their efficacy in promoting clinical recovery. However, \nischemia/reperfusion injury and related inflammation remain a major challenge in patient clinical management. We evaluated \nthe spatio-temporal evolution of inflammation using sequential clinical  [11C]PK11195 PET-MRI in a non-human primate \n(NHP) stroke model mimicking endovascular thrombectomy (EVT) with a neuroprotective cyclosporine A (CsA) treat-\nment. The NHP underwent a 110-min transient endovascular middle cerebral artery occlusion. We acquired  [11C]PK11195 \ndynamic PET-MR imaging at baseline, 7 and 30\u00a0days after intervention. Individual voxel-wise analysis was performed \nthanks to a baseline scan database. We quantified  [11C]PK11195 in anatomical regions and in lesioned areas defined on per-\nocclusion MR diffusion-weighted imaging and perfusion  [15O2]H2OPET imaging.  [11C]PK11195 parametric maps showed \na clear uptake overlapping the lesion core at D7, which further increased at D30. Voxel-wise analysis identified individuals \nwith significant inflammation at D30, with voxels located within the most severe diffusion reduction area during occlusion,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 840
encoding: FLOAT32
metadata:
{"title": "Spatio-Temporal Characterization of Brain Inflammation in a Non-human Primate Stroke Model Mimicking Endovascular Thrombectomy", "chroma:document": "mainly in the putamen. The quantitative analysis revealed that thalamic inflammation lasted until D30 and was significantly \nreduced in the CsA-treated group compared to the placebo. In conclusion, we showed that chronic inflammation matched \nADC decrease at occlusion time, a region exposed to an initial burst of damage-associated molecular patterns, in an NHP \nstroke model mimicking EVT. We described secondary thalamic inflammation and the protective effect of CsA in this region. \nWe propose that major ADC drop in the putamen during occlusion may identify individuals who could benefit from early \npersonalized treatment targeting inflammation.\nKeywords Stroke\u00a0\u00b7 Inflammation\u00a0\u00b7 Endovascular thrombectomy\u00a0\u00b7 PET-MRI\u00a0\u00b7 TSPO\nAbbreviations\nADC \n Apparent diffusion coefficient\nAIS \n Acute ischemic stroke\nBBB \n Blood-brain barrier\nCBF \n Cerebral blood flow\nCIR \n Cerebral ischemia reperfusion\nCsA \n Cyclosporine A\nDAMPs \n Damage-associated molecular patterns\nDCE \n Dynamic contrast enhancement\nDSC-MRI  Dynamic susceptibility contrast MRI\nDVR \n Distribution volume ratio\nDWI \n Diffusion-weighted imaging\n * Guillaume Becker \n \nguillaume.becker@univ-lyon1.fr\n1 \nCarMeN Laboratory, INRAE U1397, INSERM U1060, \nGroupement Hospitalier Est, University Claude Bernard \nLyon 1, 59 Boulevard Pinel, 69500\u00a0Lyon,\u00a0Bron, France\n2 \nLyon Neuroscience Research Center, UMR5295, INSERM \nU1028, CNRS, Universit\u00e9 Claude Bernard Lyon 1, Lyon, \nFrance\n3 \nUMR-5220, CREATIS, CNRS, INSERM U1206, Universit\u00e9 \nLyon 1, INSA Lyon, Villeurbanne, France\n4 \nHospices\u00a0Civils\u00a0de\u00a0Lyon,\u00a0Lyon, France\n5 \nCynbiose SAS, Lyon, France\n6 \nCognitive Neuroscience Center, CNRS UMR5229, \nUniversit\u00e9 Claude Bernard Lyon 1, Lyon, France\n7 \nCERMEP, Lyon, France"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 841
encoding: FLOAT32
metadata:
{"title": "Opioid Use, Gut Dysbiosis, Inflammation, and the Nervous System", "chroma:document": "Opioid Use, Gut Dysbiosis, Inflammation, and the Nervous \nSystem\nRicha Jalodia1, Yaa Fosuah Abu1,2, Mark Ryan Oppenheimer1, Bridget Herlihy1, Jingjing \nMeng1, Irina Chupikova1, Junyi Tao1, Nillu Ghosh1, Rajib Kumar Dutta1, Udhghatri \nKolli1, Yan Yan1, Eridania Valdes1, Madhulika Sharma1, Umakant Sharma1, Shamsudheen \nMoidunny1, Sabita Roy1\n1 Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA\n2 Department of Microbiology and Immunology, University of Miami Miller School of Medicine, \nMiami, FL 33136, USA\nAbstract\nOpioid use disorder (OUD) is defined as the chronic use or misuse of prescribed or illicitly \nobtained opioids and is characterized by clinically significant impairment. The etiology of OUD is \nmultifactorial as it is influenced by genetics, environmental factors, stress response and behavior. \nGiven the profound role of the gut microbiome in health and disease states, in recent years \nthere has been a growing interest to explore interactions between the gut microbiome and the \ncentral nervous system as a causal link and potential therapeutic source for OUD. This review \ndescribes the role of the gut microbiome and opioid-induced immunopathological disturbances at \nthe gut epithelial surface, which collectively contribute to OUD and perpetuate the vicious cycle of \naddiction and relapse.\nKeywords\nOpioids; OUD; Microbiome; Gut-brain axis; Enteric nervous system\nIntroduction\nAccording to the 2019 National Survey on Drug Use and Health, non-medical opioid use in \nthe Unites States is estimated at 2.3% among adolescents (age 12\u201317), 5.3% among young \nadults (age 18\u201325), and 3.6% among adults (age \u2265 26) with the rates of opioid use being \nsignificantly higher than that of any other illicit drug (SAMSHA 2020). Consequently, this \nhas resulted in the rise of OUD and a concomitant increase in drug-related overdoses, with \nincreased morbidity and mortality among patients. Additionally, the opioid crisis poses a"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 842
encoding: FLOAT32
metadata:
{"title": "Opioid Use, Gut Dysbiosis, Inflammation, and the Nervous System", "chroma:document": "huge economic burden, partly attributable to higher direct medical costs for patients (Ghate \net al. 2010) and indirect costs due to loss of productivity (Reinhart et al. 2018).\n\u2709 Umakant Sharma usharma@med.miami.edu, Shamsudheen Moidunny sxm1464@med.miami.edu, Sabita Roy \nsabita.roy@miami.edu. \nConflict of Interest All authors declare that they have no conflict of interest in this manuscript.\nHHS Public Access\nAuthor manuscript\nJ Neuroimmune Pharmacol. Author manuscript; available in PMC 2023 June 17.\nPublished in final edited form as:\nJ Neuroimmune Pharmacol. 2022 June ; 17(1-2): 76\u201393. doi:10.1007/s11481-021-10046-z.\nAuthor Manuscript\nAuthor Manuscript\nAuthor Manuscript\nAuthor Manuscript"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 843
encoding: FLOAT32
metadata:
{"title": "The spontaneous immortalization probability of mammalian cell culture strains, as their proliferative capacity, correlates with species body mass, not longevity", "chroma:document": "Original Article\nThe spontaneous immortalization probability of\nmammalian cell culture strains, as their\nproliferative capacity, correlates with species body\nmass, not longevity\nMatteo Perillo a,*, Angela Punzo a, Cristiana Caliceti a, Christian Sell b,\nAntonello Lorenzini a\na Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy\nb Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA\na r t i c l e i n f o\nArticle history:\nReceived 17 March 2023\nAccepted 29 April 2023\nAvailable online 5 May 2023\nKeywords:\nCell culture immortalization\nReplicative senescence\nLongevity\nBody mass\nPartial correlation\nPhylogenetic regression\na b s t r a c t\nBackground: The Peto's paradox consists in the observation that individuals from long-lived\nand large animal species do not experience a higher cancer incidence, despite being\nexposed for longer time to the possibility of accumulating mutations and having more\ntarget cells exposed to the phenomenon. The existence of this paradox has been recently\ncon\ufb01rmed (Vincze et al., 2022). Concurrently, robust evidence has been published that\nlongevity involves a convergent evolution of cellular mechanisms that prevent the accu-\nmulation of mutations (Cagan et al., 2022). It remains unclear which cellular mechanisms\nare critical to allow the evolution of a large body mass while keeping cancer at bay.\nMethods: Adding to existing data linking cellular replicative potential and species body\nmass (Lorenzini et al., 2005), we have grown a total of 84 skin \ufb01broblast cell strains from 40\ndonors of 17 mammalian species and analyzed their Hay\ufb02ick's limit, i.e., their senescent\nplateau, and eventual spontaneous immortalization escape. The correlation of immortal-\nization and replicative capacity of the species with their longevity, body mass and meta-\nbolism has been assessed through phylogenetic multiple linear regression (MLR).\nResults: The immortalization probability is negatively related to species body mass. The"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 844
encoding: FLOAT32
metadata:
{"title": "The spontaneous immortalization probability of mammalian cell culture strains, as their proliferative capacity, correlates with species body mass, not longevity", "chroma:document": "new evaluation and additional data about replicative potential strengthen our previous\nobservation, con\ufb01rming that stable and extended proliferation is strongly correlated with\nthe evolution of a large body mass rather than lifespan.\nConclusion: The relation between immortalization and body mass suggests a need to evolve\nstringent mechanisms that control genetic stability during the evolution of a large body\nmass.\n* Corresponding author. Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Zamboni, 33, Bologna 40126,\nItaly.\nE-mail address: matteo.perillo2@unibo.it (M. Perillo).\nPeer review under responsibility of Chang Gung University.\nAvailable online at www.sciencedirect.com\nScienceDirect\nBiomedical Journal\njournal homepage: www.elsevier.com/locate/bj\nb i o m e d i c a l j o u r n a l 4 6 ( 2 0 2 3 ) 1 0 0 5 9 6\nhttps://doi.org/10.1016/j.bj.2023.100596\n2319-4170/\u00a9 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC\nBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 845
encoding: FLOAT32
metadata:
{"title": "Our sense of direction: progress, controversies and challenges", "chroma:document": "Our sense of direction: progress, controversies and challenges\nKathleen E Cullen1, Jeffrey S Taube2\n1Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, Maryland, \nUSA.\n2Department of Psychological & Brain Sciences, Dartmouth College, Hanover, New Hampshire, \nUSA.\nAbstract\nIn this Perspective, we evaluate current progress in understanding how the brain encodes our sense \nof direction, within the context of parallel work focused on how early vestibular pathways encode \nself-motion. In particular, we discuss how these systems work together and provide evidence that \nthey involve common mechanisms. We first consider the classic view of the head direction cell \nand results of recent experiments in rodents and primates indicating that inputs to these neurons \nencode multimodal information during self-motion, such as proprioceptive and motor efference \ncopy signals, including gaze-related information. We also consider the paradox that, while the \nhead-direction network is generally assumed to generate a fixed representation of perceived \ndirectional heading, this computation would need to be dynamically updated when the relationship \nbetween voluntary motor command and its sensory consequences changes. Such situations include \nnavigation in virtual reality and head-restricted conditions, since the natural relationship between \nvisual and extravisual cues is altered.\nSense of direction versus a self-motion-detection system\nOur ability to keep track of where we are going relative to where we have been requires \nknowledge of our ongoing location and orientation. In everyday life, this ability, or sense \nof direction, depends on the integration of both visual and nonvisual cues, including \nvestibular and proprioceptive information. The visual system provides retinal image-motion \n(optic flow) cues, which have long been known to provide a powerful sense of motion \nthrough an otherwise stationary environment1. In addition, extravisual cues make important"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 846
encoding: FLOAT32
metadata:
{"title": "Our sense of direction: progress, controversies and challenges", "chroma:document": "contributions to navigation and are thought to contribute to path integration or dead \nreckoning (Box 1) in the absence of visual cues (for review see refs. 2,3). Notably, \ninformation sent to the brain by the vestibular nerve allows the estimation of head \ndisplacement (both linear and angular) in the absence of visual cues4\u20138. Further, during \nlocomotion, proprioceptive and/or motor-related signals also contribute significantly to the \nestimation of self-motion. For example, estimates of distance traveled and self-velocity are \nReprints and permissions information is available online at http://www.nature.com/reprints/index.html.\nCorrespondence should be addressed to K.E.C. (kathleen.cullen@jhu.edu) or J.S.T. (jeffrey.taube@dartmouth.edu). \nCOMPETING FINANCIAL INTERESTS\nThe authors declare no competing financial interests.\nHHS Public Access\nAuthor manuscript\nNat Neurosci. Author manuscript; available in PMC 2023 June 19.\nPublished in final edited form as:\nNat Neurosci. 2017 October 26; 20(11): 1465\u20131473. doi:10.1038/nn.4658.\nAuthor Manuscript\nAuthor Manuscript\nAuthor Manuscript\nAuthor Manuscript"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 847
encoding: FLOAT32
metadata:
{"title": "m Effect of Selective Lesions of Nucleus Accumbens -Opioid Receptor-Expressing Cells on Heroin Self-Administration in Oprm1-Cre Male and Female Rats: A Study with Novel Knock-in Rats", "chroma:document": "Systems/Circuits\nEffect of Selective Lesions of Nucleus Accumbens m-Opioid\nReceptor-Expressing Cells on Heroin Self-Administration in\nMale and Female Rats: A Study with Novel Oprm1-Cre\nKnock-in Rats\nJennifer M. Bossert,1 Carlos A. Mejias-Aponte,1\nThomas Saunders,2 Lindsay Altidor,1 Michael Emery,2\nIda Fredriksson,1 Ashley Batista,1 Sarah M. Claypool,1 Kiera E. Caldwell,1 David J. Reiner,1 Jonathan J. Chow,1\nMatthew Foltz,2\nVivek Kumar,2 Audrey Seasholtz,2 Elizabeth Hughes,2 Wanda Filipiak,2\nBrandon K. Harvey,1\nChristopher T. Richie,1 Francois Vautier,1 Juan L. Gomez,1\nMichael Michaelides,1 Brigitte L. Kieffer,3\nStanley J. Watson,2 Huda Akil,2 and\nYavin Shaham1\n1Intramural Research Program, National Institute on Drug Abuse\u2013National Institutes of Health, Baltimore, Maryland, 21224, 2University of\nMichigan, Ann Arbor, Michigan, 48104, and 3University of Strasbourg\u2013Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U1114, Strasbourg,\nFrance, 67084\nThe brain m-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs.\nHowever, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known\nbecause of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in\ntransgenic rat that provides cell type-specific genetic access to MOR-expressing cells. After performing anatomic\nand behavioral validation experiments, we used the Oprm1-Cre knock-in rats to study the involvement of NAc MOR-\nexpressing cells in heroin self-administration in male and female rats. Using RNAscope, autoradiography, and FISH\nchain reaction (HCR-FISH), we found no differences in Oprm1 expression in NAc, dorsal striatum, and dorsal hip-\npocampus, or MOR receptor density (except dorsal striatum) or function between Oprm1-Cre knock-in rats and\nwildtype littermates. HCR-FISH assay showed that iCre is highly coexpressed with Oprm1 (95%-98%). There were no"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 848
encoding: FLOAT32
metadata:
{"title": "m Effect of Selective Lesions of Nucleus Accumbens -Opioid Receptor-Expressing Cells on Heroin Self-Administration in Oprm1-Cre Male and Female Rats: A Study with Novel Knock-in Rats", "chroma:document": "genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-\nrelated behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing\ncells. We found that the lesions decreased acquisition of heroin self-administration in male Oprm1-Cre rats and had\na stronger inhibitory effect on the effort to self-administer heroin in female Oprm1-Cre rats. The validation of an\nOprm1-Cre knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of\nopioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study indi-\ncates that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in male and\nfemale rats.\nKey words: mu opioid receptor; knockin; CRISPR; heroin self-administration; pain; caspase 3 lesion\nReceived Nov. 2, 2022; revised Dec. 29, 2022; accepted Jan. 18, 2023.\nAuthor contributions: J.M.B., C.A.M.-A., T.S., V.K., A.S., B.K.H., C.T.R., J.L.G., M.M., B.L.K., S.J.W., H.A., and Y.S.\ndesigned research; J.M.B., C.A.M.-A., T.S., L.A., M.E., I.F., A.B., S.M.C., K.E.C., D.J.R., M.F., V.K., E.H., W.F., C.T.R., J.L.G.,\nand M.M. performed research; J.M.B., C.A.M.-A., L.A., M.E., A.B., K.E.C., J.J.C., M.F., V.K., E.H., W.F., J.L.G., M.M., and Y.S.\nanalyzed data; J.M.B. and Y.S. wrote the first draft of the paper; J.M.B., C.A.M.-A., T.S., M.E., I.F., A.B., S.M.C., K.E.C.,\nD.J.R., J.J.C., M.F., V.K., A.S., E.H., W.F., B.K.H., C.T.R., F.V., J.L.G., M.M., B.L.K., S.J.W., H.A., and Y.S. edited the paper;\nT.S. and F.V. contributed unpublished reagents/analytic tools.\nThe work was supported by Intramural Research Program of National Institute on Drug Abuse ZIA-DA000434-\n22 and ZIA-DA000069; and National Institute on Drug Abuse U01DA043098, ONR 00014-19-1-2149, and HDRF to\nH.A. and S.J.W. The rats bred at National Institute on Drug Abuse were registered with the Rat Genome"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 849
encoding: FLOAT32
metadata:
{"title": "m Effect of Selective Lesions of Nucleus Accumbens -Opioid Receptor-Expressing Cells on Heroin Self-Administration in Oprm1-Cre Male and Female Rats: A Study with Novel Knock-in Rats", "chroma:document": "Database (RGD #155641245) and deposited at the Rat Resource and Research Center (RRRC #975).\nC.A. Mejias-Aponte\u2019s present address: Intramural Research Program, National Eye Institute-National\nInstitutes of Health, Bethesda, Maryland.\nThe authors declare no competing financial interests.\nCorrespondence should be addressed to Jennifer M. Bossert at jennifer.bossert@nih.gov or Yavin Shaham\nat yavin.shaham@nih.gov.\nhttps://doi.org/10.1523/JNEUROSCI.2049-22.2023\nCopyright \u00a9 2023 the authors\n1692 \u2022 The Journal of Neuroscience, March 8, 2023 \u2022 43(10):1692\u20131713"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 850
encoding: FLOAT32
metadata:
{"title": "The use of new CRISPR tools in cardiovascular research and medicine", "chroma:document": "The use of new CRISPR tools in cardiovascular research and \nmedicine\nMasataka Nishiga1, Chun Liu1, Lei S. Qi2, Joseph C. Wu1,3\n1Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.\n2Departments of Bioengineering and Chemical & Systems Biology and ChEM-H, Stanford \nUniversity School of Medicine, Stanford, CA, USA.\n3Division of Cardiovascular Medicine, Department of Medicine and Department of Radiology, \nStanford University School of Medicine, Stanford, CA, USA.\nAbstract\nMany novel CRISPR-based genome editing tools, with a wide variety of applications, have been \ndeveloped in the past few years. The original CRISPR/Cas9 (clustered regularly interspaced \nshort palindromic repeats/CRISPR-associated protein 9) system was developed as a tool to alter \ngenomic sequences within living organisms in a simple way. However, the functions of new \nCRISPR tools are not limited to conventional genome editing mediated by nonhomologous end-\njoining or homology-directed repair, but expand into gene-expression control, epigenome editing, \nsingle nucleotide editing, RNA editing and live-cell imaging. Furthermore, genetic perturbation \nscreening by multiplexing guide RNAs is gaining popularity as a method of identifying causative \ngenes and pathways in an unbiased manner. New CRISPR tools can also be applied to ex vivo \nor in vivo therapeutic genome editing for the treatment of conditions such as hyperlipidaemia. \nIn this Review, we first provide an overview of the diverse new CRISPR tools that have been \ndeveloped to date. Second, we summarize how these new CRISPR tools are being used to study \nbiological processes and disease mechanisms in cardiovascular research and medicine. Finally, we \ndiscuss the prospect of therapeutic genome editing by CRISPR tools to cure genetic cardiovascular \ndiseases.\nIntroduction\nThe development of genome editing technology has revolutionized biomedical research, \nparticularly since the introduction of the CRISPR/Cas9 (clustered regularly interspaced"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 851
encoding: FLOAT32
metadata:
{"title": "The use of new CRISPR tools in cardiovascular research and medicine", "chroma:document": "short palindromic repeats/CRISPR-associated protein 9) method. This system was initially \ndiscovered as part of the immune response in bacteria1, and was then applied to eukaryotic \ngenome editing2\u20134. The simplicity of the CRISPR/Cas9 system has made genome editing \nmore accessible and easier than with traditional DNA-editing techniques. As a genome \nediting tool, the system consists of two basic components \u2014 an endonuclease Cas9, which \njoewu@stanford.edu (JCW), mnishiga@stanford.edu (MN). \nCompeting interest statement\nThe authors declare no competing interests.\nHHS Public Access\nAuthor manuscript\nNat Rev Cardiol. Author manuscript; available in PMC 2023 June 21.\nPublished in final edited form as:\nNat Rev Cardiol. 2022 August ; 19(8): 505\u2013521. doi:10.1038/s41569-021-00669-3.\nAuthor Manuscript\nAuthor Manuscript\nAuthor Manuscript\nAuthor Manuscript"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 852
encoding: FLOAT32
metadata:
{"title": "Viral vector delivered immunogen focuses HIV-1 antibody specificity and increases durability of the circulating antibody recall response", "chroma:document": "RESEARCH ARTICLE\nViral vector delivered immunogen focuses\nHIV-1 antibody specificity and increases\ndurability of the circulating antibody recall\nresponse\nLaTonya D. WilliamsID1,2,3\u262f*, Xiaoying Shen2,3\u262f, Sheetal S. Sawant1,2,3, Siriwat Akapirat4,\nLindsay C. Dahora1,2,3,5, Matthew Zirui Tay1,2,3,6, Sherry Stanfield-Oakley1,2,3,\nSaintedym Wills1,2,3,5, Derrick Goodman1,2,3, DeAnna Tenney1,2,3, Rachel L. Spreng1,2,3,\nLu Zhang1,2,3, Nicole L. Yates1,2,3, David C. Montefiori2,3, Michael A. Eller7,8\u00a4a,\nDavid Easterhoff3,9\u00a4b, Thomas J. Hope10, Supachai Rerks-Ngarm11,\nPunnee Pittisuttithum12, Sorachai Nitayaphan12, Jean-Louis Excler7\u00a4c, Jerome H. Kim7\u00a4c,\nNelson L. Michael7, Merlin L. Robb7,8, Robert J. O\u2019Connell4, Nicos Karasavvas4\u00a4d\u00a4e,\nSandhya Vasan7,8, Guido Ferrari1,2,3,6\u2021, Georgia D. TomarasID1,2,3,5,6\u2021*, RV305 study team\u00b6\n1 Center for Human Systems Immunology, Duke University School of Medicine, Durham, North Carolina,\nUnited States of America, 2 Department of Surgery, Duke University School of Medicine, Durham, North\nCarolina, United States of America, 3 Duke Human Vaccine Institute, Duke University School of Medicine,\nDurham, North Carolina, United States of America, 4 Department of Retrovirology, US Army Medical\nDirectorate, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, 5 Department of\nImmunology, Duke University School of Medicine, Durham, North Carolina, United States of America,\n6 Department of Molecular Genetics Microbiology, Duke University School of Medicine, Durham, North\nCarolina, United States of America, 7 US Military HIV Research Program, Walter Reed Army Institute of\nResearch, Silver Spring, Maryland, United States of America, 8 Henry M. Jackson Foundation for the\nAdvancement of Military Medicine, Bethesda, Maryland, United States of America, 9 Department of\nMedicine, Duke University School of Medicine, Durham, North Carolina, United States of America,\n10 Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 853
encoding: FLOAT32
metadata:
{"title": "Viral vector delivered immunogen focuses HIV-1 antibody specificity and increases durability of the circulating antibody recall response", "chroma:document": "Chicago, Illinois, United States of America, 11 Thai Ministry of Public Health, Nonthaburi, Thailand, 12 Royal\nThai Army Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand\n\u262f These authors contributed equally to this work.\n\u00a4a Current address: Vaccine Translational Research Branch, National Institute of Allergy and Infectious\nDiseases, National Institutes of Health, Rockville, Maryland, United States of America\n\u00a4b Current address: Moderna Therapeutics, Cambridge, Massachusetts, United States of America\n\u00a4c Current address: International Vaccine Institute, Seoul, Republic of Korea\n\u00a4d Current address: Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda,\nMaryland, United States of America\n\u00a4e Current address: Diagnostics and Countermeasures Branch, Walter Reed Army Institute of Research,\nSilver Spring, Maryland, United States of America\n\u2021 These authors are joint senior authors on this work.\n\u00b6 RV305 study team members are listed in the Acknowledgements\n* latonya.williams@duke.edu (LDW); gdt@duke.edu (GDT)\nAbstract\nThe modestly efficacious HIV-1 vaccine regimen (RV144) conferred 31% vaccine efficacy\nat 3 years following the four-shot immunization series, coupled with rapid waning of putative\nimmune correlates of decreased infection risk. New strategies to increase magnitude and\ndurability of protective immunity are critically needed. The RV305 HIV-1 clinical trial evalu-\nated the immunological impact of a follow-up boost of HIV-1-uninfected RV144 recipients\nafter 6\u20138 years with RV144 immunogens (ALVAC-HIV alone, AIDSVAX B/E gp120 alone,\nPLOS PATHOGENS\nPLOS Pathogens | https://doi.org/10.1371/journal.ppat.1011359\nMay 31, 2023\n1 / 46\na1111111111\na1111111111\na1111111111\na1111111111\na1111111111\nOPEN ACCESS\nCitation: Williams LD, Shen X, Sawant SS, Akapirat\nS, Dahora LC, Tay MZ, et al. (2023) Viral vector\ndelivered immunogen focuses HIV-1 antibody\nspecificity and increases durability of the circulating\nantibody recall response. PLoS Pathog 19(5):"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 854
encoding: FLOAT32
metadata:
{"title": "Viral vector delivered immunogen focuses HIV-1 antibody specificity and increases durability of the circulating antibody recall response", "chroma:document": "e1011359. https://doi.org/10.1371/journal.\nppat.1011359\nEditor: Daniel C. Douek, Vaccine Research Center,\nUNITED STATES\nReceived: November 30, 2022\nAccepted: April 14, 2023\nPublished: May 31, 2023\nCopyright: This is an open access article, free of all\ncopyright, and may be freely reproduced,\ndistributed, transmitted, modified, built upon, or\notherwise used by anyone for any lawful purpose.\nThe work is made available under the Creative\nCommons CC0 public domain dedication.\nData Availability Statement: All relevant data are\nwithin the manuscript and its Supporting\nInformation files.\nFunding: This work was supported by the Bill and\nMelinda Gates Foundation (https://www.\ngatesfoundation.org/) Collaboration for AIDS\nVaccine Discovery grants (OPP1033098 [Dr.\nBarton F. Haynes (P.I).], OPP1032144 [D.C.M.]),\nHenry M. Jackson Foundation (https://www.hjf.org/\n) for the Advancement of Military Science"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 855
encoding: FLOAT32
metadata:
{"title": "Lack of Toxicity in Nonhuman Primates Receiving Clinically Relevant Doses of an AAV9U7snRNA Vector Designed to Induce DMD Exon 2 Skipping", "chroma:document": "RESEARCH ARTICLES\nLack of Toxicity in Nonhuman Primates Receiving Clinically\nRelevant Doses of an AAV9.U7snRNA Vector Designed\nto Induce DMD Exon 2 Skipping\nLiubov V. Gushchina,1 Emma C. Frair,1 Natalie Rohan,1 Adrienne J. Bradley,1 Tabatha R. Simmons,1\nHemantkumar D. Chavan,2 Hsin-Jung Chou,3 Michelle Eggers,3 Megan A. Waldrop,1,4\nNicolas Wein,1,4 and Kevin M. Flanigan1,4,5,*\n1The Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, and the Departments of 4Pediatrics and 5Neurology, The Ohio State\nUniversity, Columbus, Ohio, USA.\n2Charles River Laboratories, Wilmington, Massachusetts, USA.\n3Audentes Therapeutics, San Francisco, California, USA.\nTherapeutic exon skipping as a treatment for Duchenne muscular dystrophy (DMD) has largely concentrated on the\ndelivery of antisense oligomers to treat out-of-frame exon deletions. Here we report on the preclinical development of an\nadeno-associated virus (AAV)-encapsidated viral vector containing four copies of the noncoding U7 small nuclear RNA\n(U7snRNA), each targeted to either the splice donor or the splice acceptor sites of DMD exon 2. We have previously\nshown that delivery of this vector (scAAV9.U7.ACCA) to the Dup2 mouse model results in expression of full-length\ndystrophin from wild-type DMD mRNA, as well as an internal ribosome entry site (IRES)-driven isoform translated only\nin the absence of exon 2 (deletion exon 2 [Del2] mRNA). Here we present the data from a rigorous dose escalation\ntoxicity study in nonhuman primates, encompassing two doses (3 \u00b7 1013 and 8 \u00b7 1013 vg/kg) and two time points (3 and\n6 months postinjection). No evidence for signi\ufb01cant toxicity was seen by biochemical, histopathologic, or clinical\nmeasures, providing evidence for safety that led to initiation of a \ufb01rst-in-human clinical trial.\nKeywords: Duchenne muscular dystrophy, adeno-associated virus, noncoding U7snRNA\nINTRODUCTION\nTHERAPEUTIC RESTORATION OF an open reading frame by\nselectively excluding exons from a mature mRNA tran-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 856
encoding: FLOAT32
metadata:
{"title": "Lack of Toxicity in Nonhuman Primates Receiving Clinically Relevant Doses of an AAV9U7snRNA Vector Designed to Induce DMD Exon 2 Skipping", "chroma:document": "script, or exon skipping, is an approach that is already in\nclinical use for a subset of patients with Duchenne mus-\ncular dystrophy (DMD).1 Currently approved therapies\nuse repeated intravenous infusions of antisense oligomers\ncomplementary to target exons of interest adjacent to out-\nof-frame exon deletions, restoring an open mRNA reading\nframe and allowing translation of internally deleted but\npartially functional proteins. An alternative viral vector-\nbased approach uses a noncoding U7snRNA modi\ufb01ed with\na terminal sequence targeting exon. As a result, the single-\nstranded U7snRNA, stabilized by interaction with the\nSmOpt protein, binds to the pre-mRNA, resulting in\nthe exclusion of this exon.2\u20137 This approach is likely to\nbe advantageous in that expression of U7snRNA from the\nadeno-associated virus (AAV) genome and subsequent\nexon skipping is long-standing,8 which may allow a single\ntreatment rather than weekly infusions.\nWe have developed such a viral vector carrying se-\nquences targeting exon 2 within a self-complementary (sc)\nAAV genome. Our vector, scAAV9.U7.ACCA, carries\nfour copies of U7snRNA, with two directed toward the\nsplice acceptor sequence (sequence A) and two targeting\nthe splice donor sequence (sequence C) encapsidated\nwithin AAV9. In silico analysis has shown these sequen-\nces to be speci\ufb01c to the intron/exon junctions for human\nexon 2, and the targeted sequences are 100% identical\nbetween human and nonhuman primates (NHPs). We have\ndeveloped this vector intending to initially target not out-\nof-frame deletions, but instead single-exon duplications\nin the DMD gene. In contrast to the case with deletions,\nskipping of one of the two duplicated exons would restore\n*Correspondence: Dr. Kevin M. Flanigan, The Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, 700 Children\u2019s Drive, Columbus,\nOH 43205, USA. E-mail: kevin.\ufb02anigan@nationwidechildrens.org"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 857
encoding: FLOAT32
metadata:
{"title": "Lack of Toxicity in Nonhuman Primates Receiving Clinically Relevant Doses of an AAV9U7snRNA Vector Designed to Induce DMD Exon 2 Skipping", "chroma:document": "\u00aa Liubov V. Gushchina et al., 2021; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License [CC-BY]\n(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n882 j\nHUMAN GENE THERAPY, VOLUME 32, NUMBERS 17\u201318\nDOI: 10.1089/hum.2020.286\nMary Ann Liebert, Inc."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 858
encoding: FLOAT32
metadata:
{"title": "Concentration and reactivity of the sulphydryl population the membrane of intact erythrocytes in patients with rheumatoid arthritis", "chroma:document": "Annals ofthe Rheumatic Diseases 1990; 49: 668-671\nConcentration and reactivity of the sulphydryl\ngroup population on the membrane of intact\nerythrocytes in patients with rheumatoid arthritis\nC Chilles, M Mulheron, F M McCrae, J Reglinksi, W E Smith, M Brzeski, R D Sturrock\nAbstract\nThe\nsulphydryl\npopulation\non\nerythrocyte\nmembrane is shown to vary as a function of the\nnutritional status of the cell. When an assay\nbased on reaction with Eliman's reagent and\ncontrolled conditions were used the mean values\n(SEM) for the sulphydryl population on the\nmembranes of normal erythrocytes incubated\novernight in the presence and absence ofglucose\nwere found to be 3-29 (0.27) and 2 56 (0.25)\nmillion sulphydryl functions per cell respect-\nively. Under identical conditions rheumatoid\nerythrocytes incubated\nin the presence and\nabsence\nof glucose were found\nto have\na\nsignificantly lower sulphydryl population-1-54\n(0.08) and 1-15 (0.08) million respectively.\nThe predominant concentrations ofsulphydryl\ngroups on the membrane are found at sites on\nthe transmembrane proteins and, in particular,\non the hexose transport protein. By influencing\nthe nutritional status of the cells significant\ndifferences in activity between the normal and\ndiseased state have been identified and these\nmay have a role in the aetiology of rheumatoid\narthritis by altering the response of cells to\noxidative stress.\nDepartment of Pure and\nApplied Chemistry,\n295 Cathedral St,\nStrathelyde University,\nGlasgow GI 1XL, UK\nC Chilles\nM Mulberon\nF McCrae\nJ Reglinski\nW E Smith\nCentre for Rheumatic\nDiseases and University\nDepartment of Medicine,\nGlasgow Royal Infirmary,\nGlasgow G4 OSF, UK\nM Brzeski\nR D Sturrock\nCorrespondence to:\nDr Reglinski\nAccepted for publication\n23 October 1989\n*-As a direct result of the ionic\nstrength of the medium used\nin this study the molar\nextinction coefficient of\nEllman's anion was found to\nbe lower than the published\nvalue of 14 150 cm2/mol at\n412 nm.9\nPlasma\nsulphydryl\ngroup\nconcentrations\nare"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 859
encoding: FLOAT32
metadata:
{"title": "Concentration and reactivity of the sulphydryl population the membrane of intact erythrocytes in patients with rheumatoid arthritis", "chroma:document": "are\nknown to be low in rheumatoid arthritis and to\nbe\nraised\nto\nsome\nextent\nduring\ntreatment\nwith penicillamine' and gold compounds.2 The\nsulphydryl\ngroup\nconcentration\ncan\nbe\nsub-\ndivided into fast or reactive thiol and slow or\ncomparatively unreactive thiol. It is mainly the fast\nthiol which is affected during treatment.3 Both\ngold compounds\nand\npenicillamine would\nbe\nexpected to react with the available thiols in vivo.\nDuring treatment with these compounds, however,\nalteration in the plasma thiol concentration tends\nto be slow and follows signs ofclinical improvement\nrather than rises in plasma gold or penicillamine\nconcentrations. Thus the change is likely to follow\namelioration of disease activity rather than cause\nit.\nThe intracellular\nthiol concentration (mainly\nglutathione) increases within the first few weeks of\ntreatment in patients who subsequently improve.4\nWe have noted that during treatment with sodium\naurothiomalate most of the gold present in the red\ncell is in the membrane rather than the cytosol,\nparticularly in non-smokers,5 6 and that in the in\nvitro experiments with penicillamine some peni-\ncillamine crossed the membrane but much of it\nwas absorbed or reacted causing changes in cellular\nfunction.7 8\nLikely sites for these therapeutic agents to react\non the membrane are the available exofacial thiols,\nand in this preliminary study we have investigated\nthe question of how such groups are altered in\nrheumatoid arthritis. This initial study was carried\nout with patients who were not being treated\nwith disease modifying agents as these drugs\nmay further affect the thiol status of the cell\nmembrane.5-7\nMaterials and methods\nAll reagents used in this study were commercially\nobtained unless otherwise stated. Whole blood was\ncollected in heparinised anticoagulant tubes from\n10 healthy normal volunteers and 10 patients with\nclassical or definite rheumatoid arthritis as defined\nby the American Rheumatism Association criteria.\nThe\nlatter were not\nreceiving any prescribed\nsecond line or cytotoxic drugs."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 860
encoding: FLOAT32
metadata:
{"title": "Concentration and reactivity of the sulphydryl population the membrane of intact erythrocytes in patients with rheumatoid arthritis", "chroma:document": "Samples were centrifuged at 3000 rpm for 10\nminutes and the supernatant fluid and the buffy\nwhite coat removed by suction. The resulting cells\nwere washed three times in 0-125 M Na2HPO4;\n0 15 M NaCl buffer (adjusted to pH 7-4 with\nconcentrated\nhydrochloric\nacid).\nThe\nsamples\nwere divided into two roughly equal volumes and\nstored in buffer and buffer/glucose (5 mM) over-\nnight at 4\u00b0C in sealed containers (about 16 hours)\nto produce glucose depleted and activated cells.\nAfter this the cells were washed with their respec-\ntive media: phosphate/saline, with or without 5\nmM glucose. The supernatants were carefully\nchecked for lysis by eye and by spectrophotometry\n(k= 541 nm). Lysed samples were discarded.\nThe number of cells in a given volume of pellet\nwere counted, and 0 5 ml was transferred to a\nsterile container with 8-5 ml of the respective\nbuffers and 1-0 ml of 10-3 M Ellman's solution.\nThe container was gently mixed and allowed to\nreact for 30 minutes. The suspensions were then\ncentrifuged (3000 rpm for 10 minutes), the super-\nnatant removed, and the visible spectrum (600-\n350 nm) recorded. The concentration of Ellman's\nanion was calculated using Beer's law (molar\nabsorbance Emax for ES\n13600 cm2/mol, 412\nnm, and used in the equation below to give the\ntotal number of thiols present on the surface of the\nmembrane.\nTotal number of thiols\npresent on the\nerythrocyte membrane\n[ES - I x volumex Avogadro's No\nnumber of cellsx 1000\nwhere [ES-\nis the concentration of ElIman's\nanion in solution calculated using Beer's law.\nThe change in sulphydryl group concentration\non the membranes of depleted cells as a result of\nglucose addition is monitored by adding sugar to a\ndepleted erythrocyte suspension and then sampl-\ning at specific time intervals before addition of\nEllman's reagent.\nResults and Discussion\nElIman's reagent (ESSE) is an accepted method of\nassaying biological fluids'1'2 and membranes'3 14\n668"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 861
encoding: FLOAT32
metadata:
{"title": "Specificity of rheumatoid factors in relation the disease in rheumatoid arthritis", "chroma:document": "Annals ofthe Rheumatic Diseases 1990; 49: 757-762\nSpecificity of rheumatoid factors in relation to the\ndisease state in rheumatoid arthritis\nM G Jones, M E Shipley, J P Hearn, F C Hay\nAbstract\nRheumatoid factors found in patients with\nrheumatoid arthritis react with human IgG\nand with IgG from some other species. The\nlevels of rheumatoid factor give some indi-\ncation of prognosis, albeit a rather poor one in\nthis highly variable disease. The high degree\nofvariability may, in part, be due to differences\nin the fine specificity of the rheumatoid factor\nin each individual patient, leading to differ-\nences in the types ofimmune complex formed.\nTo study this hypothesis the fine specificity of\nrheumatoid factors of the IgM, IgA, and IgG\nclasses for IgG from human, baboon, orang-\nutan, macaque, owl monkey, gorilla, marmo-\nset, cow, pig, sheep, goat, horse, mouse, and\nchicken was examined. Differential reactivity\nfor these species was found and associations\nbetween the presence of rheumatoid factor\nand the development of moderate or severe\nerosions.\nImmunology Departnent,\nSt George's Hospital\nMedical School,\nCranmer Terrace,\nTooting, London\nSW17 ORE\nM G Jones\nF C Hay\nDepartments of\nImmunology and\nRheumatology Research,\nUniversity College and\nMiddlesex School of\nMedicine, Arthur Stanley\nHouse, 40-50 Tottenham\nStreet, London WIP 9PG\nM E Shipley\nMRC/AFRC\nComparative Physiology\nResearch Group,\nInstitute of Zoology,\nRegent's Park,\nLondon NW1 4RY\nCorrespondence to:\nDr Jones.\nAccepted for publication\n20 November 1989\nRheumatoid factors bind to normal human IgG\nand IgG from many different species.' It is long\nestablished\nthat\nraised\nlevels\nof such\nanti-\nglobulins\nare\nassociated\nwith\nrheumatoid\narthritis and that this antiglobulin activity is\nfound in IgM, IgA, and IgG classes.2 The\ndegree of binding of rheumatoid factor to IgG of\ndifferent\nspecies\nis\ncontroversial,\nas\nis\nthe\nclinical significance of the spectrum of such\npolyspecific rheumatoid factor activity. Some\nhave shown that rheumatoid factors binding"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 862
encoding: FLOAT32
metadata:
{"title": "Specificity of rheumatoid factors in relation the disease in rheumatoid arthritis", "chroma:document": "with rabbit IgG are more specific for rheumatoid\narthritis than are those reactive with human\nIgG.3 4 In contrast, others suggest that human\nrather than rabbit IgG is a better discriminator\nbetween patients with rheumatoid arthritis and\ncontrols.5 It has been shown that rheumatoid\nfactor binding to human IgG has similar bind-\ning activity with the primate rhesus monkey\nIgG, but lower binding with non-primate rabbit,\nhorse, sheep, and cow.6\nThe aim of this study was to examine the fine\nspecificity of rheumatoid factors in each of the\nthree main classes, IgM, IgA, and IgG, and to\ncompare these results with various measures of\ndisease process and outcome (particularly degree\nof erosiveness and presence of extra-articular\nmanifestations) to see if any can be linked to a\nparticular isotype or specificity of rheumatoid\nfactor. The specificities were measured with a\npanel of IgGs from a variety of primate and non-\nprimate species and their relation\nto disease\nactivity at the time of drawing the blood was\nestablished. To discover whether the pattern of\nreactivity with\nthe panel of IgGs had any\npredictive value stored sera from patients with\nrheumatoid arthritis were studied and the results\ncompared with\ntheir outcome\nat long term\nfollow up.\nMaterials and methods\nIgG PREPARATION\nIgG from\nvarious\nspecies\nwas\npurified\nby\npassing the serum over a DEAE-cellulose column\nand eluting with a gradient ofincreasing molarity\nof 0-017 M to 0-5 M phosphate buffer pH 8-0.\nSOLID PHASE RADIOIMMUNOASSAY\nNinety six well, flexible plates were coated with\n100\n1t of a\n10\n[ig/ml protein\nsolution\nin\nphosphate buffered saline (PBS) pH 7-2 and\nincubated for one hour at 37\u00b0C and overnight at\n4\u00b0C. Unbound proteins were removed by three\nwashes with cold PBS.\nSerum (1 1d) was added to each well with 100\n1t 0 05 M TRIS HCI pH 8-0 containing 0 05%\nTween 20 (TRIS HCI Tween), and incubated\nfor one hour at 37\u00b0C (serum dilution 1:100).\nThe plates were then washed three times with\ncold TRIS HCI Tween.\nDepending on the class of rheumatoid factor\nbeing"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 863
encoding: FLOAT32
metadata:
{"title": "Specificity of rheumatoid factors in relation the disease in rheumatoid arthritis", "chroma:document": "being\ndetected,\n100\n1t\nof\n5\n,tg/ml\nrabbit\nantihuman IgM, IgA, or Fd of IgG in TRIS\nHCI Tween were added and incubated for one\nhour at 37\u00b0C. The plates were then washed\nthree times with cold TRIS HCI Tween. A final\nlayer of 1 ,ug 1251 labelled goat antirabbit IgG\nwas added in 100\n,tl TRIS HC1 Tween and\nincubated for one hour at 37\u00b0C. The plates were\nwashed three times with cold TRIS HC1 Tween\nand counted in a gammacounter.\nSOLID PHASE CAPTURE ASSAY\nNinety six well, flexible plates were coated with\n100 [tl of a 10 [tg/ml protein solution in PBS and\nincubated for one hour at 37\u00b0C and overnight at\n4\u00b0C. Unbound proteins were removed with\nthree washes of cold PBS.\nSerum (1 ,ul) was added to each well with 100\n,ul TRIS HC1 Tween and incubated for one hour\nat 37\u00b0C (serum dilution 1:100). The plates were\nthen washed three times with cold TRIS HCI\nTween.\nOne hundred\nmicrolitres of 5\n,tg/ml\n1251\naggregated IgG was added in TRIS HC1 Tween\nand incubated for four hours at 37\u00b0C. The plates\nwere washed three times with cold TRIS HCI\nTween and counted in a gammacounter.\n757"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 864
encoding: FLOAT32
metadata:
{"title": "Long-Term Fertility Function Sequelae in Young Male Cancer Survivors", "chroma:document": "INTRODUCTION\nThe incidence of malignant tumors in Japanese \nyoung men is 86.2 in 100,000 adolescents and young \nadults, affecting approximately 7,600 people per year [1]. \nKatanoda et al [2] investigated the incidence of malig-\nnant disease among young people in Japan from 2009 \nto 2011. Per million population, there were 120.2 aged \n0\u201314 years, 130.5 aged 15\u201319 years, 229.0 aged 20\u201329 \nyears, and 537.3 males aged 30\u201339 years. This data was \nsimilar to that of the United States and World data \n(World Health Organization) [2]. As in other developed \ncountries, advances in treatment have significantly \nimproved outcomes for young patients with cancer. For \nadvanced testicular cancer, the 3-year survival rates for \ngood-, intermediate-, and poor-risk patients are 94.7%, \nReceived: May 17, 2022  Revised: Aug 30, 2022  Accepted: Sep 22, 2022  Published online Jan 1, 2023\nCorrespondence to: Yasushi Yumura  \n https://orcid.org/0000-0003-0909-478X\nReproduction Center, Yokohama City University Medical Center, Urafune-cho 4-57, Minami-ku, Yokohama, Kanagawa 232-0024, Japan.\nTel: +81-45-261-5656, Fax: 81-45-253-1962, E-mail: yumura@yokohama-cu.ac.jp\nCopyright \u00a9 2023 Korean Society for Sexual Medicine and Andrology\nLong-Term Fertility Function Sequelae in Young \nMale Cancer Survivors\nYasushi Yumura , Teppei Takeshima , Mitsuru Komeya , Jurii Karibe, Shinnosuke Kuroda ,  \nTomoki Saito\nReproduction Center, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan\nWith advances in cancer treatment, such as cytotoxic chemotherapy and radiotherapy, grave new sequelae of treatment have \nemerged for young cancer survivors. One sequela that cannot be overlooked is male infertility, with reportedly 15% to 30% \nof cancer survivors losing their fertility potential. Cytotoxic therapy influences spermatogenesis at least temporarily, and in \nsome cases, permanently. The degree of spermatogenesis impairment depends on the combination of drugs used, their cumu-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 865
encoding: FLOAT32
metadata:
{"title": "Long-Term Fertility Function Sequelae in Young Male Cancer Survivors", "chroma:document": "lative dose, and the level of radiation. The American Society of Clinical Oncology has created an index to classify the risks to \nfertility based on treatment. Medical professionals currently use this risk classification in fertility preservation (FP) programs. \nFP programs are currently being promoted to prevent spermatogenesis failure resulting from cancer treatment. For patients \nwho are able to ejaculate and whose semen contains sperm, the semen (sperm) is cryopreserved. Moreover, for patients who \nlack the ability to ejaculate, those with azoospermia or severe oligozoospermia, and those who have not attained puberty (i.e., \nspermatogenesis has not begun), testicular biopsy is performed to collect the sperm or germ cells and cryopreserve them. This \nmethod of culturing germ cells to differentiate the sperm has been successful in some animal models, but not in humans. FP \nhas recently gained popularity; however, some oncologists and medical professionals involved in cancer treatment still lack \nadequate knowledge of these procedures. This hinders the dissemination of information to patients and the execution of FP. \nInformation sharing and collaboration between reproductive medicine specialists and oncologists is extremely important for \nthe development of FP. In Japan, the network of clinics and hospitals that support FP is expanding across prefectures.\nKeywords: \nKeywords: Cancer; Chemotherapy; Fertility preservation; Male infertility; Radiotherapy; Sperm cryopreservation\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) \nwhich permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nReview Article\npISSN: 2287-4208 / eISSN: 2287-4690\nWorld J Mens Health 2023 Apr 41(2): 255-271\nhttps://doi.org/10.5534/wjmh.220102\nMale reproductive health and infertility"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 866
encoding: FLOAT32
metadata:
{"title": "Towards a Multi-Omics of Male Infertility", "chroma:document": "INTRODUCTION\nInfertility is a problem affecting one in six couples, \nwhich is approximately 15% of the population wishing \nto start a family. In 30% of infertile couples, the male \nfactor is a major cause [1,2]. A man is considered in-\nfertile if he is not able to induce a pregnancy after at \nleast 12 months of regular intercourse without contra-\nception [3]. In 30% to 45% of infertile men, the cause of \nthe abnormal semen parameters is not identified (idio-\npathic male infertility) [4]. The term idiopathic is used \nonly if defined causes of male infertility can be exclud-\ned, such as: sperm autoimmunity, sexual and/or ejacu-\nlatory dysfunction, cryptorchidism, acquired testicular \nReceived: Sep 14, 2022   Accepted: Oct 15, 2022   Published online Jan 4, 2023\nCorrespondence to: Tanja Kunej  \n https://orcid.org/0000-0002-0465-1762\nDepartment of Animal Science, Biotechnical Faculty, University of Ljubljana, Dom\u017eale 1230, Slovenia.\nTel: +386-13203890, Fax: +386-17241005, E-mail: tanja.kunej@bf.uni-lj.si\n*These authors contributed equally to this work as co-first authors.\nCopyright \u00a9 2023 Korean Society for Sexual Medicine and Andrology\nTowards a Multi-Omics of Male Infertility\nAna Ogrinc Wagner* , Aleksander Turk* , Tanja Kunej\nDepartment of Animal Science, Biotechnical Faculty, University of Ljubljana, Dom\u017eale, Slovenia\nInfertility is a common problem affecting one in six couples and in 30% of infertile couples, the male factor is a major cause. \nA large number of genes are involved in spermatogenesis and a significant proportion of male infertility phenotypes are of \ngenetic origin. Studies on infertility have so far primarily focused on chromosomal abnormalities and sequence variants in \nprotein-coding genes and have identified a large number of disease-associated genes. However, it has been shown that a \nmultitude of factors across various omics levels also contribute to infertility phenotypes. The complexity of male infertility has"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 867
encoding: FLOAT32
metadata:
{"title": "Towards a Multi-Omics of Male Infertility", "chroma:document": "led to the understanding that an integrated, multi-omics analysis may be optimal for unravelling this disease. While there is a \nvast array of different factors across omics levels associated with infertility, the present review focuses on known factors from \nthe genomics, epigenomics, transcriptomics, proteomics, metabolomics, glycomics, lipidomics, miRNomics, and integrated \nomics levels. These include: repeat expansions in AR, POLG, ATXN1, DMPK, and SHBG, multiple SNPs, copy number vari-\nants in the AZF region, disregulated miRNAs, altered H3K9 methylation, differential MTHFR, MEG3, PEG1, and LIT1 meth-\nylation, altered protamine ratios and protein hypo/hyperphosphorylation. This integrative review presents a step towards a \nmulti-omics approach to understanding the complex etiology of male infertility. Currently only a few genetic factors, namely \nchromosomal abnormalities and Y chromosome microdeletions, are routinely tested in infertile men undergoing intracyto-\nplasmic sperm injection. A multi-omics approach to understanding infertility phenotypes may yield a more holistic view of \nthe disease and contribute to the development of improved screening methods and treatment options. Therefore, beside dis-\ncovering as of yet unknown genetic causes of infertility, integrating multiple fields of study could yield valuable contributions \nto the understanding of disease development. Future multi-omics studies will enable to synthesise fragmented information \nand facilitate biomarker discovery and treatments in male infertility.\nKeywords: \nKeywords: DNA methylation; Epigenetics; Expression; Male infertility; Multi-omics; Non-coding RNAs (ncRNAs)\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) \nwhich permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nReview Article\npISSN: 2287-4208 / eISSN: 2287-4690"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 868
encoding: FLOAT32
metadata:
{"title": "Towards a Multi-Omics of Male Infertility", "chroma:document": "World J Mens Health 2023 Apr 41(2): 272-288\nhttps://doi.org/10.5534/wjmh.220186\nMale reproductive health and infertility"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 869
encoding: FLOAT32
metadata:
{"title": "Immunoadsorbent plasmapheresis for patient with antiphospholipid syndrome during", "chroma:document": "Annals ofthe Rheumatic Diseases 1992; 51: 399-401\nImmunoadsorbent plasmapheresis for a patient with\nantiphospholipid syndrome during pregnancy\nS Kobayashi, N Tamura, H Tsuda, C Mokuno, H Hashimoto, S Hirose\nAbstract\nThe case of a 34 year old woman with\nsystemic lupus erythematosus with a history\nof three previous recurrent abortions and\nlupus anticoagulant and anticardiolipin anti-\nbodies is reported. Immunoadsorbent plasma-\npheresis with a dextran sulphate column was\nused to remove lupus anticoagulant,\nanti-\ncardiolipin antibodies, and antibodies to DNA\nduring her fourth pregnancy in combination\nwith low doses of aspirin and prednisolone.\nAlthough\nduring\nthe\ncourse\nof treatment\nprednisolone was transiently increased to 30\nmg/day owing to an asymptomatic increase of\nlupus anticoagulant and anticardiolipin anti-\nbodies, the\nlevels of lupus anticoagulant,\nanticardiolipin antibodies, and antibodies to\nDNA were decreased by immunoadsorbent\nplasmapheresis and a baby girl was delivered\nsuccessfully by caesarean section. Therefore,\nimmunoadsorbent plasmapheresis with dex-\ntran sulphate seems to reduce the risk of\nrecurrent abortion in patients with the anti-\nphospholipid syndrome.\nDepartment of\nRheumatology,\nJuntendo University\nSchool of Medicine,\nTokyo,\nJapan\nS Kobayashi\nN Tamura\nH Tsuda\nC Mokuno\nH Hashimoto\nS Hirose\nCorrespondence to:\nDr Hiroshi Hashimoto,\nDepartment ofRheumatology,\nJuntendo University,\nSchool of Medicine,\n2-1-1 Hongo,\nBunkyo-ku,\nTokyo 113,\nJapan.\nAccepted for publication\n16 April 1991\nLupus anticoagulant and anticardiolipin anti-\nbodies are high risk factors for repeated abortion\nand intrauterine death.'13 These factors have\nbeen\nassociated\nwith\narterial\nor\nvenous\nthrombosis,\nor\nboth.\nLupus\nanticoagulant\ninterferes\nat\nthe\nlevel\nof the prothrombin\nactivation complex of the clotting cascade4 and\nmay interfere with the production ofprostacyclin\nby the vessel wall and other tissues, including\nthe myometrium, during pregnancy.5\nIt was noted that treatment with high dose"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 870
encoding: FLOAT32
metadata:
{"title": "Immunoadsorbent plasmapheresis for patient with antiphospholipid syndrome during", "chroma:document": "prednisolone (40-60 mg/day) in combination\nwith aspirin (75 mg/day) improved fetal survival\nin pregnant women with lupus anticoagulant\nand poor obstetric history.' 6 Such treatment\nfor several months sometimes causes serious\nmaternal adverse reactions, however, and the\neffect of high dose prednisolone on the fetus is\nunknown. In addition, therapeutic benefits are\nnot always obtained and, therefore, alternative\ntreatments should be evaluated.\nRecently, treatment with immunoadsorbent\nplasmapheresis using a dextran sulphate column\nwas introduced for patients with systemic lupus\nerythematosus to remove antibodies to DNA,7\nand we found that anticardiolipin antibodies\nand lupus anticoagulant bind with dextran\nsulphate by anionic charge.8 Here, we would\nlike to report the case of a patient with systemic\nlupus erythematosus with lupus anticoagulant,\nanticardiolipin antibodies, and recurrent spon-\ntaneous abortion who was treated witir the new\napproach of immunoadsorbent\nduring pregnancy.\nplasmapheresis\nMaterials and methods\nPLASMA SEPARATOR AND ADSORBENT COLUMN\nAs a plasma separator, hollow fibre membrane\nfilters of polysulphone with an average pore size\nof 0-2 ,tm and effective surface area of 0-5 m2\n(SF 05; Kanegafuchi Chemical Industry, Tokyo,\nJapan), were used together with Liposorber LA\n40 (Kanegafuchi Chemical Industry), in which\ndextran sulphate cellulose beads (350 ml) were\npacked and used as the sorbent gel for lupus\nanticoagulant, anticardiolipin antibodies, and\nantibodies to DNA.\nPROCEDURE FOR PLASMAPHERESIS\nBlood was withdrawn at a rate of 50 ml/min\nby a peristaltic pump through a double lumen\ncatheter inserted into the femoral vein. Plasma\nwas separated at a speed of 20 ml/min and\npassed through the Liposorber in a downward\nflow. The filtrate was infused into the patient\nwith the portion rich in blood cells. The total\nextracorporeal\ncirculation volume was about\n400 ml. For anticoagulant, nafamostat mesilate9\n(FUT-175; Torni Co, Tokyo, Japan) was used at\nan initial dose of 20 mg and then continuously"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 871
encoding: FLOAT32
metadata:
{"title": "Immunoadsorbent plasmapheresis for patient with antiphospholipid syndrome during", "chroma:document": "infused at a rate of 20 mg/h. In this patient one\nlitre of plasma was treated for each procedure.\nThis procedure was carried out two to three\ntimes a week. Nafamostat mesilate, with a half\nlife of eight minutes, prolongs activated partial\nthromboplastin time (APTT), and therefore\nAPTT, anticardiolipin antibodies, and lupus\nanticoagulant were measured before plasma-\npheresis and one day after treatment.\nMEASUREMENT OF LUPUS ANTICOAGULANT,\nAPTT, ANTICARDIOLIPIN ANTIBODIES, AND\nANTIBODIES TO DNA\nThe APTT was assessed in our laboratory.\nAutomated APTT reagent10 (General Diagnos-\ntics, Morris Plains, NJ, USA) which contained\nrabbit brain cephalin and colloidal silica was\nused, and all assays were performed on a Coag-\nA-Mate/Single Channel (General Diagnostics).\nThe normal range for APTT is 26-40 seconds\n(mean (2SD)). The sample containing lupus\nanticoagulant showed a prolonged APTT, which\nwas not corrected by adding normal plasma.\nAnticardiolipin antibodies were measured by\nenzyme linked immunosorbent assay (ELISA)\nas described.\" The results were expressed as\nunits, each unit equivalent to one standard\ndeviation above the mean of results for 100\nserum samples from apparently healthy blood\n399"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 872
encoding: FLOAT32
metadata:
{"title": "Animal models for osteoarthritis: problems and", "chroma:document": "Annals of the Rheumatic Diseases 1994; 53: 406-420\nREVIEW\nAnimal models for osteoarthritis:\nprocesses, problems and prospects\nKenneth P H Pritzker\nModel systems are systems that are used to\nsimplify complex phenomena and to under-\nstand otherwise elusive processes.' An animal\nmodel for human disease can be defined as\na homogenous\nset\nof animals which have\nan inherited,\nnaturally acquired, or experi-\nmentally induced biological process, amenable\nto scientific investigation, that in one or more\nrespects resembles the disease in humans.2 3\nElusive and complex as a precise under-\nstanding may be, virtually all definitions of\nosteoarthritis express the disease as transient\nand progressive\nstructural changes\nin\njoint\ntissues,\nprincipally\narticular\ncartilage,\nsub-\nchondral bone, synovium, and synovial fluid.4\nArticular cartilage oedema,\nfibrillation, and\nerosion accompanied\nby\nchondrocyte\npro-\nliferation and decreased\nstaining of matrix\nproteoglycans, subchondral bone thickening,\ndeformation of the articular surface, osteo-\nphyte formation, synovial intimal cell hyper-\nplasia, and synovial fibrosis are some of the\nstandard\nfeatures\nassociated\nwith\nosteo-\narthritis. These changes result from a poorly\nunderstood but very large series of functional\nevents which may occur over a large fraction\nof the life of each affected individual. Bio-\nchemical, cell or organ culture models can\nprovide information and insight concerning\nthe mechanisms for functional events within\ncartilage, bone or synovium or selected cells\nwithin these tissues. These ex vivo models,\ninherently more highly controlled than animal\nmodels,\nare most useful for understanding\nshort\nterm\nbiological\nevents,\nand\nevents\nisolated from the physiological influences of\nadjacent structures and general metabolism.\nAs yet, ex vivo models cannot simulate the\nstructural changes which occur in joint tissues\nin\nanimals\nover months\nto\nyears.\nHence,\nanimal models for osteoarthritis are required to\nstudy how the complex structural changes in\ntissues\nevolve"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 873
encoding: FLOAT32
metadata:
{"title": "Animal models for osteoarthritis: problems and", "chroma:document": "evolve\nover time, spontaneously\nor\nfollowing experimental injury, and to deter-\nmine how constitutive, environmental or bio-\nmechanical risk factors4 may initiate, promote,\nor otherwise regulate these changes (table 1).\nAnimal models are also needed to show how\ntherapeutic strategies may ameliorate, resolve\nor prevent osteoarthritis.6 8\nThe decision\nto use\na particular animal\nmodel to study osteoarthritis is governed by\ncriteria\nof relevance,\nappropriateness,\nand\navailability.3 9 10\nRelevance\nrefers\nto\nthe\ncomparability of the phenomenon studied in\nanimals to the corresponding process in human\ndisease. Animals with characteristics similar to\nTable I\nOsteoarthritis: constitutional and eznvironmiiental\nfactors\nConstitutional factors\n*\nGenetics\n*\nAge\n*\nSex, Parity\n*\nHormone and metabolic factors\n*\nSocial rank\nEnvironmental factors\n*\nNutrition\n*\nExercise\n*\nDrugs\nBiomechanical forces\n*\nJoint instability\n*\nDisplaced joint loads\n*\nJoint overloading\nhuman disease as well as animals with features\nthat differ in a known specific manner from\nhuman\nosteoarthritis may\nprovide\nrelevant\nmodels. Appropriateness refers first to the need\nto use animals rather than simpler models to\ninvestigate the process in question and second\nto the specific criteria that make one set of\nanimals more appropriate than others for the\nexperimental goals and objectives. Simplicity,\npredictability\nin\nreproducing\ncircumscribed\naspects of the disease, as well as the capacity\nto induce new insight, are appropriate factors\nwhen\nanimal models\nare\nconsidered.9\nFor\nexample, to test drug effects on an animal\nmodel, simplicity and predictability are para-\nmount whereas to understand pathogenesis, a\nmore complex model that more closely mimics\nhuman\ndisease may be more\nappropriate.\nAvailability criteria refers to practical factors\nsuch\nas\nadequacy\nof animal\nsupply,\nthe\npresence of controls, the ease of handling and\nenvironmental maintenance, as well as costs\n(table 2).\nTable 2\nAnimal models for osteoarthritis: availability\ncriteria\n0\n0\n0\nS0\n0\nS0\n0\n0\nS"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 874
encoding: FLOAT32
metadata:
{"title": "Animal models for osteoarthritis: problems and", "chroma:document": "S0\n0\n0\nS\nGenetic homogeneity or heterogeneity\nAvailability and homogeneity of nutrition and exercise\nhistory\nLife span of animal, time span of disease, age of onset\nDisease frequency\nAvailability of matched control population\nAnatomical and physiological attributes\nQuantitative\n*\nJoint tissues sufficient for studies\n*\nAdequate access to synovial fluid\nQualitative\n*\nResemblance to human tissues\n*\nWeight bearing vs non weight bearing joints\nAvailability of experimental techniques for model\nSupply of animals-standardisation\nEase of handling\nAccess of model to experimental manipulation\n*\nDrugs\n*\nPhysical intervention\nPrevious research in model (background knowledge,\npeer acceptance)\nCosts\nConnective Tissue\nResearch Group,\nMount Sinai Hospital,\nToronto, and\nDepartments of\nPathology and\nSurgery,\nUniversity ofToronto,\nToronto, Canada\nK P H Pritzker\nCorrespondence to:\nDr K P H Pritzker,\nDepartment of Pathology,\nMount Sinai Hospital,\n600 University Avenue,\nToronto, Ontario,\nCanada M5G IX5\n406"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 875
encoding: FLOAT32
metadata:
{"title": "Reconstitution of the alternative pathway of complement by plasma infusions given patient with SLE-like syndrome associated with hereditary C3 dysfunction", "chroma:document": "Annals of the Rheumatic Diseases 1994; 53: 691-694\nCONCISE REPORTS\nReconstitution of the alternative pathway of\ncomplement by plasma infusions given to a patient\nwith an SLE-like syndrome associated with a\nhereditary C3 dysfunction\nBo Nilsson, Ulf R Nilsson, Alex Karlsson-Parra, Gunilla Sjolin-Forsberg, Roger Hallgren\nAbstract\nObjective-To reconstitute a dysfunctional\nform ofcomplement factor C3 in a patient\nwith\na\nsystemic\nlupus\nerythematosus\n(SLE) -like syndrome.\nMethods-The\npropositus\nwas\ntreated\nwith plasma infusions during five sessions\nover a period of eight months.\nResults-The\nalternative\npathway\nwas\nreconstituted\nto\nnormal\nlevels\nfor\napproximately two to three days after each\ninfusion. C3 fragments were incorporated\ninto previously detected deposits of IgG\nand IgM at the dermal-epidermal junction\nand the immune complex levels gradually\ndecreased during the whole treatment\nperiod.\nConclusion-The reconstitution appears\nto result in the solubilisation of tissue\nimmune\ncomplexes\nand\na\nsubsequent\ntransportation to the fixed macrophage\nsystem.\n(Ann Rheum Dis 1994; 53: 691-694)\ndysfunctional\nC3\nin\nthis\nautoimmune\ncondition.\nPatient and methods\nCASE REPORT\nThe patient received plasma from her husband,\nwho had plasmapheresis before each session.\nBoth the patient and her husband were 0\nRhesus positive. The husband had not received\nblood transfusions or any other blood products\nwhich reduced the possibility that he was\nimmunised against leukocyte antigens. In vitro\nanalyses confirmed that the plasma contained\nno such antibodies (agglutination and cyto-\ntoxic assays). The plasma was always given\nthrough a leukocyte depletion filter to avoid\nadverse reactions and immunisations against\nleukocyte antigens. The study was approved by\nthe Ethical Committee of the Medical Faculty,\nUppsala\nUniversity. The patient gave\nher\ninformed consent to participate in the study.\nThe plasma treatment was performed during\nfive periods (table).\nUniversity Hospital,\nUppsala, Sweden\nDepartment of Clinical\nImmunology and\nTransfusion Medicine"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 876
encoding: FLOAT32
metadata:
{"title": "Reconstitution of the alternative pathway of complement by plasma infusions given patient with SLE-like syndrome associated with hereditary C3 dysfunction", "chroma:document": "B Nilsson\nU R Nilsson\nA Karlsson-Parra\nDepartment of\nInternal Medicine,\nSection of\nRheumatology\nR Hallgren\nDepartment of\nDermatology\nG Sj6lin-Forsberg\nCorrespondence to:\nDr Bo Nilsson,\nDepartment of Clinical\nImmunology and\nTransfusion Medicine,\nUniversity Hospital,\n751 85 Uppsala, Sweden.\nAccepted for publication\n11 May 1994\nThe strong association between deficiencies of\nthe complement system and the occurrence of\nimmune\ncomplex\nassociated\ninflammatory\nconditions\nsuch\nas\nsystemic\nlupus\nerythe-\nmatosus (SLE),lA\nemphasises the important\nrole of complement in immune complex (IC)\nmetabolism.\nWe recently reported of a patient with an\nSLE-like syndrome which was associated with\na dysfunction of C3.5 The propositus suffered\nfrom fatigue, swollen fingers, arthralgia and\nRaynaud's\nsyndrome\ncombined\nwith\nthe\npresence of anti-centromere antibodies. The\ndysfunction was a result of a double deficiency\nwith a null allele originating from the father\nand one allele for the dysfunctional C3 from\nthe mother. The haemolytic function by the\nalternative pathway (APW) was shown to be\ncompletely eliminated while the CPW function\nwas reduced by 75%. The reason for this was\nthat the dysfunctional C3, especially in the\nAPW, was not cleaved into C3a and C3b due\nto an inability of the C3 to interact properly\nwith the convertases.\nWe report the results of repeated plasma\ninfusions into the C3 dysfunctional patient\nin\nan\nattempt\nto\nclarify\nthe\nrole\nof the\nSession 1\nThe first dose was taken well but six hours after\nthe second dose the patient developed fever,\nnausea and diarrhoea which continued until\nthe next day. There was also transient mild\nhaematuria\n(1+)\nand\nproteinuria\n(1+). A\nCoombs\ntest showed no erythrocyte-bound\nIgG or C3d before or after the transfusions.\nSESSIONS 2-5\nA minute inflammatory reaction was observed\nafter the second, third and fourth treatment\nperiod in that the fingers were more swollen\nand the arthralgia was worse.\nThe\ntreatment\nduring\nthe\neight month\nperiod resulted in no obvious clinical improve-\nment\nof the"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 877
encoding: FLOAT32
metadata:
{"title": "Reconstitution of the alternative pathway of complement by plasma infusions given patient with SLE-like syndrome associated with hereditary C3 dysfunction", "chroma:document": "of the\npropositus\nclinical\ncondition\nexcept\nthat\nthe\npatient's\nRaynaud's\nphe-\nnomena seemed\nto disappear. The disease\nactivity assessed by the SLE Disease Activity\nIndex (SLEDAI)6 remained at the same level\nbefore and after the treatment period (score 6).\nHowever, the patient has subjectively improved\nand\nthe\nfatigue\nhas\nvanished.\nBefore\nthe\ntreatment the propositus was unable to work\nfor five years but she has now returned to her\nprevious occupation as a physiotherapist.\n691"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 878
encoding: FLOAT32
metadata:
{"title": "Osteoarthritis and magnetic imaging: potential and problems", "chroma:document": "Annals of the Rheumatic Diseases 1995; 54: 237-243\nREVIEW\nOsteoarthritis and magnetic resonance imaging:\npotential and problems\nC W Hutton, W Vennart\nMagnetic resonance imaging (MRI) is in its\ninfancy.\nDespite widespread\nclinical\nappli-\ncations it has enormous unrealised potential.\nUnlike\nall\nother imaging\nmodalities,\nit\nis\nintrinsically a varied technology that has to be\nengineered\nfor\neach\nproblem\ninvestigated.\nPresent imaging using whole body systems\nlacks specificity and resolution, but this should\neventually be overcome using\ntailor made\ndedicated\nequipment\nsuch\nas\nspecialised\nsurface coils and targeted gradient coils. MRI\noffers\npotential\nfor\nin\nvivo\nnon-invasive\nmeasurement and imaging that may revol-\nutionise the understanding of osteoarthritis\n(OA). Currently, there are no known physio-\nlogical hazards associated with the magnetic\nfield and gradient strengths used in routine\nMRI systems, and there\nis no other non-\ninvasive method that allows repeat imaging of\nspecific aspects of the joint without the use of\nionising radiation and hence promises insight\ninto the interactions between the\ndifferent\nstructures or the processes that are involved in\njoint physiology and pathology. Understanding\nthe potential ofMRI to investigate OA requires\nan insight into the physics of the technique.\nMount Gould Hospital,\nPlymouth, United\nKingdom\nC W Hutton\nDepartment of\nPhysics, University of\nExeter, Exeter, United\nKingdom\nW Vennart\nAccepted for publication\n10 October 1994\nBasic physics ofMRI\nNuclear\nmagnetic\nresonance\n(NMR)\nwas\ndeveloped as a method for studying the atomic\nnucleus\nand\nchemical\ncomposition\nof\nmaterials.' 2 With the development of methods\nof localising nuclear signals, it was extended to\nimaging.' MRI\nis primarily concerned with\nmapping the distribution of protons within\nhydrogen atoms.4 When protons, which spin\non their axes and possess a magnetic moment,\nare immersed in a homogeneous magnetic field\n(B.)\nthey\nprecess\naround\nthe\nfield\nwith\norientations allowed by quantum mechanics"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 879
encoding: FLOAT32
metadata:
{"title": "Osteoarthritis and magnetic imaging: potential and problems", "chroma:document": "that are parallel and anti-parallel to the field\ncorresponding to low and high energy states.\nThe frequency of the precession is given by\nwo = -yB0, where -y is the ratio of the magnetic\nmoment\nof\nthe\nnucleus\nto\nits\nangular\nmomentum.\nThe\nmajority\nof\ncommercial\nimaging systems operate in the range of values\nof Bo= 0-5-1-5 Tesla (T), the corresponding\nproton precessional frequencies being 20-60\nMHz.\nIf the protons are exposed to a pulse of\nradiofrequency radiation in a plane perpen-\ndicular\nto\nB.,\nthey\nare\ndisplaced\nfrom\nequilibrium and precess around B0 in the plane\nof the\nradiofrequency\nradiation.\nAfter\nthe\nradiofrequency\npulse\nis\nswitched\noff,\nthe\nprotons return to equilibrium with a process\nthat involves the dephasing of the spinning\nprotons relative to each other, and one that\nrestores the equilibrium of low and high energy\nstates. The former process, spin-spin relax-\nation, is determined by a constant, T2; the\nlatter, spin-lattice relaxation, by a constant,\nTI. Both TI and T2 vary and depend on a set\nof parameters such as tissue composition, field\nstrength, and temperature. As the spinning\nprotons\nrelax\nback\nto\nequilibrium,\ntheir\nassociated magnetisations vary in time and\nspace. This can induce a current in a coil of\nwire wound round the sample. To derive data\nfor MRI experiments, this signal is amplified\nand\nits\namplitude,\nfrequency\nand\nphase\nmeasured. Figure 1 illustrates this process.\nThe\nproton\nprecessional\nfrequency\n(the\nLarmor equation)\nis influenced by different\nchemical\nenvironments\nwhich\nproduce\na\nshielding effect on the proton, such that the\nLarmor equation becomes w = -yBO(I -8); B. is\nthe applied field and 8 is a shielding factor. The\nshielding factor gives information about the\nchemical composition of the material and is the\nbasis of magnetic resonance spectroscopy.\nThe position of the protons giving rise to the\nMRI\nsignal can be\nidentified by applying\nmagnetic field gradients across the sample.\nThe gradient causes the resonant frequency to\nvary with spatial position according to the\nt\nt\n,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 880
encoding: FLOAT32
metadata:
{"title": "Osteoarthritis and magnetic imaging: potential and problems", "chroma:document": "t\nt\n,\nhigh energy\n(b)\nequilibrium\ni\ni i\ni low energy\nI\nI\nI\nT1\n(c)\nt\n*I\n++\n+\nJR\nRF excitation\nR\ne\n(d)\n'\nv\nC>\nt t\n*.ld\nRFemission\n(a)\nFigure 1\n(a) Water protons spinning and precessing in\nequilibrium in a static magnetic field B0; protons are\nquantum particles-just afew more than half will precess\nwith thefield (low energy state) and slightly less against the\nfield (high energy state). (b) This equilibrium distribution\ncan be represented diagramatically as two energy levels with\nmore protons in the lower level (t) than the upper level (1).\n(c) Application ofa burst ofradiofrequency (RF) radiation\nto the system excites a net number ofprotonsfrom the low to\nthe high energy state. (d) When the RF is removed the spins\nreturn to equilibrium by emiting RF radiation\nthis is\ndetected in the MRI investigation.\n237"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 881
encoding: FLOAT32
metadata:
{"title": "Antigen recognition by T-cells and its suppression", "chroma:document": "Ann. rheum. Dis. (1971), 30, 565\nAntigen recognition by T-cells\nand its suppression\nSignificance and origin of rosette-forming cells\nJEAN-FRANtOIS BACH\nHopital Necker, Paris\nAntigen recognition\nis one of the most debated\naspects of the immune response and its mechanism\nis central to most theories of antibody formation.\nThe clonal selection theory of Bumet (1959), which\nseems to be widely accepted at the moment, holds\nthat lymphocyte clones are already in existence at\nbirth, each bearing receptors specific for one antigen.\nRecent studies have shown that three cell popula-\ntions are involved in immune responses, at least for\nsome antigens:\n(1) Macrophages;\n(2) Thymus-dependent (T) lymphocytes;\n(3) Bone-marrow-dependent (B) lymphocytes.\nThe existence and mechanism of co-operation of\nthese three cell types are still matters of discussion.\nOne of the most debated points, and one which will\ninterest us here, is the specificity at T and B-cell\nlevels.\nSeveral techniques have been proposed for study-\ning antigen binding by lymphoid cells, the most\nfrequently used being bacterial adherence,\nauto-\nradiography of cells having bound isotope-labelled\nantigens and, especially, immunocytoadherence (the\nrosette test), which was described by Nota, Liaco-\npoulos-Briot, Stiffel, and Biozzi (1964) and Zaalberg\n(1964) and developed by Biozzi, Stiffel, Mouton,\nBouthillier, and Decreusefond (1968). This antigen\nrecognition in vitro has been shown to be a model of\nrecognition in vivo. In other words, cells which bind\nantigens in vitro are the same as those which bind\nantigens in vivo, this being the first step in antigen\nrecognition (Bach, Muller, and Dardenne, 1970).\nAntigen binding can be prevented in several ways,\nincluding removal of antigen, neutralization of the\nreceptors responsible for the binding and membrane\nmodification making the receptors unavailable for\nantigen.\nThe Clones\nThe clonal selection theory of Burnet (1959)\nis\nsupported by the fact that antibody-forming cells (as"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 882
encoding: FLOAT32
metadata:
{"title": "Antigen recognition by T-cells and its suppression", "chroma:document": "studied by the local haemolysis in gel technique) are\nrestricted in specificity, class, and allotype (Dubiski\nand Fradette, 1966). One particular plaque-forming\ncell generally produces antibodies of one class, one\nallotype, one specificity, and one affinity, with a few\nexceptions (Makela and Cross, 1970; Liacopoulos,\n1971). While this is suggestive of clonal populations\nof lymphocytes, direct proof of the existence of\nclones before immunization is needed to support the\nclonal selection theory. Such direct proof has been\nafforded by a number of workers who have been able\nto remove one clone of a given specificity from a\npopulation of normal lymphoid cells, leaving them\nunresponsive to the particular antigen. Three main\nmethods have been applied for this purpose: cell\nretention on antigen-coated columns, specific killing\nby\nisotope-labelled\nantigens,\nand\nremoval\nof\nrosette-forming cells by centrifugation on gradient.\nThe first experiments were those of Wigzell (1970),\nshowing that it was possible to deplete a cell popula-\ntion of its antigen-sensitive lymphocytes by passing\nthe cells down an antigen-coated column. Cells with\nhigh affinity are retained more easily than cells with\nlow\naffinity. The retention\nis\ninhibited by the\npresence of free antigen in the column. These experi-\nments were done primarily with immune cells but\nhave also been performed with normal cells. This\nsystem works for both thymus-dependent antigens\n(e.g. serum albumin), against which the immune\nresponse needs the presence of the thymus, and for\nthymus-independent antigens (e.g. polyvinyl pyroly-\ndone). The experiments of Truffa-Bachi and Wofsy\n(1970), using a different type of antigen-coated\ncolumn, have confirmed those of Wigzell (1970) and\nLecture given at the VII European Rheumatology Congress, Brighton, June, 1971."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 883
encoding: FLOAT32
metadata:
{"title": "Asparagine protects pericentral hepatocytes during acute liver injury", "chroma:document": "The Journal of Clinical Investigation   \nR E S E A R C H  A R T I C L E\n1\nIntroduction\nThe liver is a highly structured tissue where oxygen-rich blood \nenters the hepatic lobule at peripheral portal triads and drains \nout through the central vein (reviewed in ref. 1). As blood flows, \noxygen, nutrients, and hormones are taken up and metabolized \nby hepatocytes that actively shape their microenvironment and \ncreate a gradient along the lobular axis. In turn, this gradient, \ntogether with local morphogens, shapes the cellular identity and \nsubsequent functional heterogeneity of cells within the lobule. \nConsequently, hepatic metabolic functions are nonuniformly dis-\ntributed along the lobular axis, a phenomenon called liver zona-\ntion (reviewed in ref. 1). Energy-demanding functions, such as \nprotein synthesis and secretion or de novo glucose production, are \nassigned to the periportal layers, where oxygen from arterial blood \nis abundant. Mid-lobular hepatocytes, on the other hand, special-\nize in the secretion of iron-regulating hormones, whereas pericen-\ntral hepatocytes preferentially engage in xenobiotic metabolism, \nbile acid biosynthesis, and glycolysis (reviewed in ref. 2).\nAcute liver failure, characterized by sudden and severe hepat-\nic injury, is a life-threatening condition (3). Drug-induced hepato-\ntoxicity is the leading cause of acute liver failure in North Amer-\nican and European countries (3). Liver transplantation remains \nthe most effective treatment for acute liver failure, but the lack \nof donor organs limits its availability. The survival rate of acute \nliver failure has stagnated in recent years, and novel treatment \noptions are urgently needed to improve the overall outcome of \npatients (4, 5). Liver zonation also has a role in this process, as it \ncan explain zonated damage during acute liver injury. The zonat-\ned nature of xenobiotic metabolism, for instance, is responsible \nfor the observed pericentral damage upon drug overdose. This is"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 884
encoding: FLOAT32
metadata:
{"title": "Asparagine protects pericentral hepatocytes during acute liver injury", "chroma:document": "due to the accumulation of toxic intermediates in the hepatocytes \nexpressing the detoxification enzymes, including cytochrome \nP450 2E1 (CYP2E1) and cytochrome P450 1A2 (CYP1A2) (6, 7), \nand is exemplified in the carbon tetrachloride (CCl4) murine mod-\nel of liver injury (8, 9). Although molecular CCl4 is not toxic, hep-\natotoxicity develops following its metabolic activation by CYP2E1 \nenzymes and the formation of the highly reactive trichloromethyl \n(CCl3) radicals. This highly reactive metabolite triggers oxidative \ndamage to proteins, DNA, and lipids in pericentral CYP2E1-posi-\ntive hepatocytes and culminates in liver injury and cell death (10).\nHepatic glutamine metabolism represents another highly \nzonated process where glutamine synthesis occurs through the \ncatalytic action of glutamate-ammonia ligase (GLUL, also known \nas glutamine synthetase, [GS]), an enzyme whose expression is \nconfined to a layer of hepatocytes surrounding the central veins, \nknown as scavenger cells (reviewed in ref. 11). While glutamine \nsynthesis from glutamate appears to be an efficient and required \nmechanism to capture ammonia (12), the fate of glutamine synthe-\nsized at high rates in the pericentral zone is unclear. In this study, \nwe demonstrate that a pericentral enzyme, asparagine synthe-\ntase (ASNS), colocalizes with GLUL and converts its main prod-\nuct, glutamine, into asparagine. We show that during acute liver \ninjury, pericentrally expressed ASNS is highly induced through \nthe enhanced recruitment of the nuclear receptor liver receptor \nhomolog 1 (LRH-1; NR5A2) to its promoter region. This transcrip-\ntional process is part of a noncanonical adaptive mechanism to \nThe nonessential amino acid asparagine can only be synthesized de novo by the enzymatic activity of asparagine synthetase \n(ASNS). While ASNS and asparagine have been implicated in the response to numerous metabolic stressors in cultured cells,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 885
encoding: FLOAT32
metadata:
{"title": "Asparagine protects pericentral hepatocytes during acute liver injury", "chroma:document": "the in vivo relevance of this enzyme in stress-related pathways remains unexplored. Here, we found ASNS to be expressed \nin pericentral hepatocytes, a population of hepatic cells specialized in xenobiotic detoxification. ASNS expression was \nstrongly enhanced in 2 models of acute liver injury: carbon tetrachloride (CCl4) and acetaminophen. We found that mice \nwith hepatocyte-specific Asns deletion were more prone to pericentral liver damage than their control littermates after \ntoxin exposure. This phenotype could be reverted by i.v. administration of asparagine. Unexpectedly, the stress-induced \nupregulation of ASNS involved an ATF4-independent, noncanonical pathway mediated by the nuclear receptor, liver receptor \nhomolog 1 (LRH-1; NR5A2). Altogether, our data indicate that the induction of the asparagine-producing enzyme ASNS acts as \nan adaptive mechanism to constrain the necrotic wave that follows toxin administration and provide proof of concept that i.v. \ndelivery of asparagine can dampen hepatotoxin-induced pericentral hepatocellular death.\nAsparagine protects pericentral hepatocytes during \nacute liver injury\nYu Sun, Hadrien Demagny, Adrien Faure, Francesca Pontanari, Antoine Jalil, Nadia Bresciani, Ece Yildiz, Melanie Korbelius, \nAlessia Perino, and Kristina Schoonjans\nInstitute of Bioengineering, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne, Lausanne, Switzerland.\nAuthorship note: YS and HD contributed equally to this work.\nCopyright: \u00a9 2023, Sun et al. This is an open access article published under the terms \nof the Creative Commons Attribution 4.0 International License.\nConflict of interest: The authors have declared that no conflict of interest exists.\nSubmitted: July 12, 2022; Accepted: January 27, 2023; Published: April 3, 2023.\nReference information: J Clin Invest. 2023;133(7):e163508. \nhttps://doi.org/10.1172/JCI163508."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 886
encoding: FLOAT32
metadata:
{"title": "Sex-based differences in autoimmune diseases", "chroma:document": "Monographic section\n205\nSex-based differences  \nin autoimmune diseases\nElena Ortona1, Marina Pierdominici1, Angela Maselli2, Caterina Veroni1, Francesca Aloisi1 \nand Yehuda Shoenfeld3\n1Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanit\u00e0, Rome, Italy \n2Dipartimento del Farmaco, Istituto Superiore di Sanit\u00e0, Rome, Italy \n3Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center (affiliated to Tel-Aviv University), \nTel-Hashomer, Israel\nAnn Ist Super Sanit\u00e0 2016 | Vol. 52, No. 2: 205-212\nDOI: 10.4415/ANN_16_02_12\nINTRODUCTION\nAutoimmune diseases include more than 80 chronic \ndisorders that affect nearly 5% of the population in \nWestern countries. They are characterized by an exag-\ngerated immune response leading to damage and dys-\nfunction of specific or multiple organs and tissues. The \naetiology of autoimmune diseases is still unknown, but \nthe available evidence points to an interaction between \ngenetic, environmental and life style factors in disease \ndevelopment. Autoimmune diseases are typically more \nprevalent in women than in men and are considered \nthe fourth leading cause of disability for women [1]. \nThe strongest sex bias is observed in Sjogren\u2019s syn-\ndrome, systemic lupus erythematosus (SLE), autoim-\nmune thyroid disease and scleroderma where the ratio \nof women to men is 7:1-10:1. In rheumatoid arthritis \n(RA), multiple sclerosis (MS) and myasthenia gravis, \nthe female to male ratio is 2:1-3:1, while there is little \nor no sex bias in inflammatory bowel diseases and type \n1 diabetes [2-4]. Symptom severity, disease course, re-\nsponse to therapy and overall survival may also differ \nbetween males and females with autoimmune diseases. \nIn general, women mount stronger humoral and cellu-\nlar immune responses than men and this is believed to \nhave an effect on the different susceptibility to develop \nautoimmune diseases. The main factors affecting the \ndifferences between female and male immune systems \nare the sex hormones, the presence of two X chromo-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 887
encoding: FLOAT32
metadata:
{"title": "Sex-based differences in autoimmune diseases", "chroma:document": "somes versus one X and one Y chromosome, and the \ndifferent response to environmental factors, such as \nmicrobial exposure and diet [5]. Sociological differenc-\nes between genders may also affect the development of \nautoimmunity. However, the discussion of this topic is \nbeyond the scope of this article and readers can refer \nto recent reviews [6]. Here, we briefly review the role \nof sex-related factors in autoimmunity and then high-\nlight key discoveries and controversies on the role of \nsexual dimorphism in three paradigmatic autoimmune \ndiseases: SLE, RA and MS.\nSEX HORMONES IN AUTOIMMUNITY\nDue to the presence of hormone receptors on im-\nmune cells [7], sex hormones, such as estrogens, pro-\ngesterone, androgens and prolactin, can influence \ndifferent aspects of immune system function and po-\ntentially affect the risk, activity and progression of au-\ntoimmune diseases. Generally, estrogens, in particular \n17-\u03b2 estradiol (E2) and prolactin, act as enhancers at \nleast of humoral immunity, and testosterone and pro-\ngesterone as natural immunosuppressants [3]. Sex hor-\nmones have different effects depending not only on the \nconcentration but also on the type of target cell and \nthe receptor subtype expressed on a given cell type. At \nperiovulatory to pregnancy levels [8], E2 has mainly \nanti-inflammatory effects, by inhibiting production and \nsignaling of pro-inflammatory cytokines, such as tumor \nAddress for correspondence: Marina Pierdominici, Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanit\u00e0, Viale Regina Elena \n299, 00161 Rome, Italy. E-mail: marina.pierdominici@iss.it.\nKey words\n\u2022\u2002 sex \n\u2022\u2002 autoimmunity \n\u2022\u2002  systemic lupus \nerythematosus \n\u2022\u2002 rheumatoid arthritis \n\u2022\u2002 multiple sclerosis\nAbstract\nAutoimmune diseases are characterized by an exaggerated immune response leading to \ndamage and dysfunction of specific or multiple organs and tissues. Most autoimmune \ndiseases are more prevalent in women than in men. Symptom severity, disease course,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 888
encoding: FLOAT32
metadata:
{"title": "Sex-based differences in autoimmune diseases", "chroma:document": "response to therapy and overall survival may also differ between males and females with \nautoimmune diseases. Sex hormones have a crucial role in this sex bias, with estrogens \nbeing potent stimulators of autoimmunity and androgens playing a protective role. Accu-\nmulating evidence indicates that genetic, epigenetic and environmental factors may also \ncontribute to sex-related differences in risk and clinical course of autoimmune diseases. \nIn this review, we discuss possible mechanisms for sex specific differences in autoimmu-\nnity with a special focus on three paradigmatic diseases: systemic lupus erythematosus, \nrheumatoid arthritis, and multiple sclerosis."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 889
encoding: FLOAT32
metadata:
{"title": "The gut signals to AGRP-expressing cells of the pituitary to control glucose homeostasis", "chroma:document": "The Journal of Clinical Investigation   \nR E S E A R C H  A R T I C L E\n1\nIntroduction\nThe hypothalamic AGRP/NPY neuron is well known to be orexi-\ngenic (1, 2), opposing the action of its counterpart, the hypothalamic \nanorexigenic POMC neuron (3, 4). However, constitutive absence \nof AGRP or NPY has little or no impact on feeding or body weight \ngain on normal chow (5). Only mice with adult ablation of AGRP/\nNPY neurons show hypophagia (6, 7), indicating that developmen-\ntal compensation occurs to normalize food intake in the absence \nof either orexigenic peptide. We have shown that the constitutive \nabsence of AGRP does have effects on glucose homeostasis and the \nreproductive system (8, 9). Agrp-KO mice have improved glucose \ntolerance if they are obese genetically as a result of leptin signaling \ndeficiency. Agrp-KO females also have earlier puberty onset, while \nob/ob Agrp-KO females are fertile. In addition, mammary gland \ndevelopment is restored in ob/ob Agrp-KO females. These were sur-\nprising results since severe hypoleptinemia is associated with infer-\ntility and failure to undergo puberty (10\u201312).\nWe have previously described a gut-to-brain axis (13, 14) that \ncomprises meal-associated bile acid secretion and FGF15/19 \nsignaling which regulates the expression and activity of AGRP- \nexpressing cells. This signaling pathway could constitute a physi-\nological role for AGRP in glucose homeostasis. This pathway may \nalso be relevant to bariatric surgery (15), wherein procedures result \nin altered bile flow, increased FGF19 concentrations, and improved \nglucose control, sometimes with remission of preexisting type 2 dia-\nbetes mellitus (16, 17). In this report, while searching for potential \nsites of regulation within the Agrp upstream regulatory region, we \nfound that public databases had identified multiple AGRP mRNA \nvariants. The mouse Agrp gene has 3 widely separated transcription \nstart sites that result in 3 different transcripts (AGRP-A, AGRP-B,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 890
encoding: FLOAT32
metadata:
{"title": "The gut signals to AGRP-expressing cells of the pituitary to control glucose homeostasis", "chroma:document": "and AGRP-C), which differ in their 5\u2032-untranslated regions (5\u2032-\nUTRs), implying the existence of 3 different promoters/enhancers \nand varying modes of regulation for each of the transcript variants. \nIn addition, the cell type specificities of these promoters/enhancers \nare likely to be different. We show that the AGRP-B mRNA variant is \nsuppressed by bile acids but remains unaffected by fasting. In con-\ntrast, the AGRP-A variant, the most proximal variant, is regulated \nby fasting but remains unaffected by bile acid treatment. Previous-\nly, we had shown that bile acids and FGF19 both affected glucose \nmetabolism by improving insulin sensitivity and glucose-stimu-\nlated insulin secretion (GSIS) in lean mice on normal chow, DIO \n(diet-induced obesity) mice, and obese leptin-deficient (ob/ob) mice \n(13, 14). This improved glucose metabolism is dependent on FGFR1 \nsignaling in AGRP-expressing cells as well as downstream MC4R \n(13), since Cre-mediated deletion of Fgfr1 in AGRP-expressing cells \nabolished the glucose homeostatic response to taurocholate.\nIn order to determine whether AGRP-B\u2013expressing cells are \ninvolved in glucose homeostasis, we generated a knockin/knock-\nout allele of the mouse Agrp gene that expresses FLP recombinase \nfrom the Agrp-B promoter, Agrp-B-FLP. Using the Agrp-B-FLP \nallele in combination with an FLP-dependent tdTomato reporter as \na lineage tracker, we found that the Agrp-B promoter is expressed \nin endocrine, non-neuronal cells of the pars tuberalis, colocalizing \nGlucose homeostasis can be improved after bariatric surgery, which alters bile flow and stimulates gut hormone \nsecretion, particularly FGF15/19. FGFR1 expression in AGRP-expressing cells is required for bile acids\u2019 ability to improve \nglucose control. We show that the mouse Agrp gene has 3 promoter/enhancer regions that direct transcription of each \nof their own AGRP transcripts. One of these Agrp promoters/enhancers, Agrp-B, is regulated by bile acids. We generated"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 891
encoding: FLOAT32
metadata:
{"title": "The gut signals to AGRP-expressing cells of the pituitary to control glucose homeostasis", "chroma:document": "an Agrp-B knockin FLP/knockout allele. AGRP-B\u2013expressing cells are found in endocrine cells of the pars tuberalis and \ncoexpress diacylglycerol lipase B \u2014 an endocannabinoid biosynthetic enzyme \u2014 distinct from pars tuberalis thyrotropes. \nAGRP-B expression is also found in the folliculostellate cells of the pituitary\u2019s anterior lobe. Mice without AGRP-B were \nprotected from glucose intolerance induced by high-fat feeding but not from excess weight gain. Chemogenetic inhibition \nof AGRP-B cells improved glucose tolerance by enhancing glucose-stimulated insulin secretion. Inhibition of the AGRP-B \ncells also caused weight loss. The improved glucose tolerance and reduced body weight persisted up to 6 weeks after \ncessation of the DREADD-mediated inhibition, suggesting the presence of a biological switch for glucose homeostasis \nthat is regulated by long-term stability of food availability.\nThe gut signals to AGRP-expressing cells  \nof the pituitary to control glucose homeostasis\nShun-Mei Liu,1 Bruno Ifebi,1 Fred Johnson,1 Alison Xu,1 Jacquelin Ho,1 Yunlei Yang,1,2 Gary Schwartz,1,2 Young Hwan Jo,1,3  \nand Streamson Chua Jr.1,2\n1Department of Medicine, 2Department of Neuroscience, and 3Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, New York, USA.\nConflict of interest: The authors have declared that no conflict of interest exists.\nCopyright: \u00a9 2023, Liu et al. This is an open access article published under the terms \nof the Creative Commons Attribution 4.0 International License.\nSubmitted: August 3, 2022; Accepted: February 7, 2023; Published: April 3, 2023.\nReference information: J Clin Invest. 2023;133(7):e164185. \nhttps://doi.org/10.1172/JCI164185."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 892
encoding: FLOAT32
metadata:
{"title": "Fc-rosette inhibition by hypocomplemen- taemic systemic lupus erythematosus", "chroma:document": "Ann. rheum. Dis. (1976), 35, 415\nFc-rosette inhibition by hypocomplemen-\ntaemic systemic lupus erythematosus sera\nTADAO MORITO, KIYOAKI TANIMOTO, YOSHIMI HASHIMOTO,\nYOSHIHIKO HORIUCHI, AND TAKEO JUJI*\nFrom the Department ofInternal Medicine and Physical Therapy, and Department of Transfusion,* School of\nMedicine, University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan\nMorito, T., Tanimoto, K., Hashimoto, Y., Horiuchi, Y., and Juji, T. (1976). Annals of\nthe Rheumatic Diseases, 35, 415-421. Fc-rosette inhibition by hypocomplementaemic\nsystemic lupus erythematosus sera. Human red cells sensitized with one of the Rh\nantisera (Ripley) form rosettes (Fc-rosette) with human B lymphocytes and the rosettes\nare well inhibited by aggregated human IgG. Since sera of hypocomplementaemic\npatients with systemic lupus erythematosus (SLE) have frequently been reported to\ncontain immune complexes, they were used for the inhibition of Fc-rosette formation\nin this study.\nThe results of Fc-rosette inhibition rates of the sera were inversely correlated with the\nserum CH,0 levels. When the sera were separated into top, middle, and bottom fractions\nby ultracentrifugation, the bottom fractions showed more effective inhibitions than the\nothers. Similarly, the strongest inhibition was found in the void volume of the serum\nseparated by Sephadex G200 gel filtration. Reduction and alkylation of IgG resulted\nin the loss of reactivity with Fc receptor of B lymphocytes, and the rosette inhibiting\nactivities of the SLE sera were markedly reduced after reduction and alkylation. Some of\nanti-HLA sera were inhibitory for the Fc-rosette formation, while the tested sera did\nnot contain anti-HLA activity assessed by the microcytotoxicity test. These results\nindicated that circulating immune complexes contained in the sera inhibit the rosette\nformation, and that the Fc-rosette inhibition test is a simple and relatively sensitive\nmethod for the detection of circulating immune complexes."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 893
encoding: FLOAT32
metadata:
{"title": "Fc-rosette inhibition by hypocomplemen- taemic systemic lupus erythematosus", "chroma:document": "Antinuclear antibody activities of the sera were tested by the indirect immuno-\nfluorescent method; however, clear correlations were not obtained between Fc-rosette\ninhibition rates and staining patterns of antinuclear antibodies. On the other hand,\nthe positive groups of LE-test exhibited slightly greater inhibition rates of the rosette\nthan the negative groups.\nA previous report (Morito and others, 1976) showed\nthat Fc-receptors mainly on human B lymphocytes\nare detected by the rosette formation (Fc-rosette)\nusing the human red cells sensitized with one of the\nRh-antisera (Ripley), and that the Fc-rosette\nis\nstrongly inhibited by aggregated human IgG. This\nsuggested that circulating immune complexes\nin\nsystemic lupus erythematosus (SLE) sera will inhibit\nthe Fc-rosette formation when the complexes contain\naggregated IgG. In the present study it was found\nthat all the tested hypocomplementaemic SLE sera\ninhibited the Fc-rosette formation. Analysis of the\nsera suggested that the inhibition was caused mainly\nby the immune complexes present in the sera.\nAccepted for publication February 11, 1976.\nCorrespondence to Dr. K. Tanimoto.\nMaterials and methods\nSLE SERA\nEleven sera from patients with SLE who fit the criteria of\nthe American Rheumatism Association (Cohen and\nothers, 1971) were used after heat inactivation at 56\u00b0C\nfor 30 minutes for the inhibition of Fc-rosette formation.\nSerum CH50 levels of these sera were < 20 units. 7 normal\nhuman sera and 8 normocomplementaemic SLE sera\nwere used as controls.\nPREPARATION OF AGGREGATED HUMAN IgG\nHuman Cohn Fraction II (purchased from Midori Juji,\nTokyo) was used as human IgG, and 10 mg/ml diluted\nin 0-15 mol/l phosphate-buffered saline, pH 7 4, were\nheat aggregated at 63'C for 20 minutes. Under this\ncondition, IgG showed moderate\nturbidity\nbut\nno"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 894
encoding: FLOAT32
metadata:
{"title": "Rubella virus and rheumatoid arthritis", "chroma:document": "Annals of the Rheumatic Diseases, 1977, 36, 3-12\nRubella virus and rheumatoid arthritis\nHELENA HART AND B. P. MARMION\nFrom the Department ofBacteriology, Edinburgh University Medical School, Teviot Place, Edinburgh EH8 9AG\nsumMARY\nA collection of synovial fibroblasts from 19 patients with rheumatoid arthritis (RA) and\n12 patients with osteoarthrosis or other non-RA disease has been examined for rubella virus antigens\nby immunofluorescence and radioimmunoassay with negative results. Eluates of synovial membrane\nprepared under conditions likely to dissociate antigen-antibody complexes have shown no rubella\nantibody. A serological survey of RA patients and those with other forms of arthritis has shown no\ndifferences in the frequency\nor levels of rubella haemagglutination-inhibiting antibody. These\nresults provide little support for various hypotheses that a persistent infection with rubella virus\nunderlies or initiates the rheumatoid process.\nThe\nphenomenon\nof\npersistent\ninfection\nwith\nrubella virus is familiar from the congenital rubella\nsyndrome and from some patients with a variety of\nsubacute\nsclerosing\npanencephalitis\n(Townsend\net al., 1975; Weil et al., 1975), and also from persis-\ntent infection of cultured cells in vitro. The tendency,\ntaken with the observation of a self-limiting synovitis\nas an occasional complication of acute rubella, lends\nattraction to a hypothesis that a persistent infection\nof synovial cells with rubella virus might be the\nultimate antigenic stimulus in juvenile (JRA) or\nadult rheumatoid arthritis (RA).\nTo\ntest\nthis\nhypothesis\nnumerous\nworkers\nhave compared the frequency, or mean titre, of\nrubella antibody in rheumatoid patients with that\nin control groups of healthy persons, or patients\nsuffering from other forms of arthritis (Chandler\net al., 1971; Laitinen et al., 1972; Simsarian et al.,\n1970; Deinard et al., 1974). These studies have gener-\nally failed to show a difference except for those\ndescribed by Patterson et al., (1973 and personal"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 895
encoding: FLOAT32
metadata:
{"title": "Rubella virus and rheumatoid arthritis", "chroma:document": "communication) and Deinard et al. (1974). Other\nworkers have examined antibody from RA synovial\nfluid cryoprecipitates, or eluates from RA synovial\nmembranes without, however,\ndetecting\nstriking\namounts of rubella antibody (Cremer et al., 1974;\nZvaifler, 1973).\nHowever, the resolution of rubella virus infection\nmay be protracted in some rheumatoid patients.\nThus Ogra,\net al.\n(1975) observed a prolonged\ninfection with rubella virus in some JRA patients,\nAccepted for publication 27 April, 1976\nCorrespondence to Professor B. P. Marmion\n3\nas judged by high and persistent levels of IgM and\nIgG antibody to rubella virus and the demonstration\nof rubella antigen by immunofluorescence in smears\nof synovial fluid cells. These effects may be related\nto the higher prevalence ofhistocompatibility antigen\nHLA-B27 in JRA patients (Racheleksfy et al., 1974),\nwith its postulated immunological implications.\nAn association of persistent rubella infection and\nadult RA appears to be much less common. A\nserologically documented case of rubella arthritis\nprogressing to, or associated with, classical adult\nRA was described by Martenis et al. (1968), who\nmentioned\nother\npatients.\nMore\nrecently,\nin\nEdinburgh, a 26-year-old woman has been observed\nwho had an illness resembling rubella and subse-\nquently developed classical RA with positive latex\nand SSCT tests and a raised erythrocyte sedimenta-\ntion rate. A raised titre (1/2048-1/4096) of rubella\nantibody by haemagglutination-inhibition in both\nthe IgG and IgM fractions of her serum was de-\ntected early in the illness. The rheumatoid state\npersisted for 18 months after onset of symptoms\nwhen there was a resolution of the symptoms and\nsigns accompanied by a fall in the level of IgM\nrubella antibody (Duthie et al., unpublished).\nOther investigators have approached the problem\nby trying to show rubella virions or other gene pro-\nducts, or interference by rubella virus, in RA synovial\ncells, usually fibroblasts. Thus Grayzel and Beck\n(1970), Smith and Hamerman (1969), and Ford and"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 896
encoding: FLOAT32
metadata:
{"title": "Rubella virus and rheumatoid arthritis", "chroma:document": "Oh (1965) found that RA synovial fibroblasts were\nmore resistant to infection with rubella or Newcastle\ndisease viruses than non-RA fibroblasts. This was\nconstrued as an\nintrinsic\nviral interference,\nbut"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 897
encoding: FLOAT32
metadata:
{"title": "Is persisting antigen responsible for the chronicity of experimental allergic arthritis?", "chroma:document": "Annals of the Rheumatic Diseases, 1977, 36, 34-38\nIs persisting antigen responsible for the chronicity\nof experimental allergic arthritis?\nA. FOX AND L. E. GLYNN\nFrom the MRC Rheumatism Unit, Canadian Red Cross Memorial Hospital, Taplow, Maidenhead, Berkshire\nSL6 OHN\nSUMMARY\nAnimals were injected intra-articularly with antigen after prior immunization with that\nantigen in Freund's incomplete adjuvant in order to precipitate immune complexes in the surfaces\nof menisci, ligaments, and cartilage. On reimmunization with antigen in Freund's complete adjuvant\n10 weeks later, generally an arthritis limited to the intercondylar fossa developed; but on intra-\narticular injection of antigen a second time a widespread arthritis developed in that joint. Thus\nimmune deviation had not occurred and animals were in an immunological condition such as to be\ncapable of developing widespread arthritis given the correct intra-articular stimulus. It is concluded\nthat antigen, persisting as immune complexes, plays no part in maintaining widespread monarthritis,\npresumably owing to its inability to participate in a delayed hypersensitivity reaction as a result of\nsequestration.\nExperimental allergic arthritis (EAA) is a chronic\ndisease which histologically resembles rheumatoid\narthritis. It is produced in rabbits by immunizing\nthem with a soluble antigen in Freund's complete\nadjuvant (FCA) and then injecting the antigen intra-\narticularly. The substitution of Freund's incomplete\nadjuvant (FIA) for FCA results only in an acute\ninflammation\non\njoint\nchallenge\nwith\nantigen\n(Dumonde and Glynn, 1962; Consden et al., 1971).\nIt has been shown that in EAA antigen persists as\nimmune complexes in the superficial layers of men-\nisci, ligaments, and cartilage (Cooke et al., 1972; Hol-\nlister and Mannik, 1974) (but not in synovial fluid:\nBelovic and Kinsella, 1973; or synovium: Doble et\nal., 1973), and it was suggested that slow release of\nantigen from them continuously activates comple-\nment which in turn causes the persisting inflamma-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 898
encoding: FLOAT32
metadata:
{"title": "Is persisting antigen responsible for the chronicity of experimental allergic arthritis?", "chroma:document": "tion. However, it has also been shown that immune\ncomplexes persist in similar locations in similar\namounts in thejoints ofanimals injected with antigen\nafter prior immunization with that antigen in FIA.\nSince these joints recover completely within a few\nweeks from the induced arthritis, it was concluded\nthat\nsomething\nmore\nthan\nimmune\ncomplexes\nactivating complement is required (Fox and Glynn,\n1975).\nAccepted for publication April 30, 1976\nCorrespondence to Mr. A. Fox\nIt was therefore suggested that slow release of\nantigen from complexes could continuously activate\na delayed hypersensitivity (DHS) reaction. The need\nfor a DHS reaction to antigen which is demonstrably\nnot produced on immunization with antigen\nin\nFIA but requires FCA (Audibert et al., 1976), has\nbeen stressed (Glynn, 1968). In addition the pro-\nduction of a macrophage migration inhibition factor\n(MIF) by cultures of synovia from EAA joints\nsuggests a continuing DHS reaction (Stastny, et al.,\n1973). Also injection of MIF into joints results in\narthritis (Andreis et al., 1974).\nWe present evidence that if animals are immunized\nwith antigen in FIA and then injected intra-articularly\nwith that antigen in order to precipitate complexes\nin collagenous surfaces, on reimmunization with\nantigen in FCA 10 weeks later they do not develop\na widespread chronic\narthritis although a mild\ninflammation does develop which is restricted to the\nintercondylar\nfossa.\nHowever,\non\nintra-articular\nreinjection of antigen unequivocal\narthritis does\ndevelop throughout\nthe joint, showing that this\nimmunization schedule does not induce immune\ndeviation and that the animals are in an immuno-\nlogical condition to develop arthritis given the correct\nintra-articular stimulus. We conclude that antigen\npersisting as immune complexes is not involved in\nmaintaining widespread arthritis, presumably as a\nresult of inability to participate in a DHS reaction.\n34"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 899
encoding: FLOAT32
metadata:
{"title": "Cerebral mechanisms operating in the and absence of inflammatory pain", "chroma:document": "Annals ofthe Rheumatic Diseases 1996; 55: 411-420\nREVIEW: PAIN\nSeries editor: Bruce L Kidd\nCerebral mechanisms operating in the presence\nand absence of inflammatory pain\nAnthony K P Jones, Stuart W G Derbyshire\nDuring episodes ofinflammatory arthritic pain,\nthe brain has the task of integrating new\ninformation from receptors of muscle, tendon,\nand skin afferents with nociceptive information\nfrom the joint capsule and, possibly, peri-\narticular bone. This integration will incorpor-\nate motivational, affective, discriminative, at-\ntentional, and motor responses that may result\nin changes of behaviour and modification of\ncentral nervous system (CNS) processing of\npain. It is as yet unclear what the nature of this\nCNS modification may be, and suggested\ninfluences\non\npain\nrelated\naffective-motor\nresponses or the inflammatory process itself\nremain largely speculative.\nIt is likely to be some time before we begin\nto have a proper understanding of the complex\nintegrated\nprocesses\nthat\noperate\nduring\narthritic pain and other chronic pains. How-\never, we are now able to measure aspects of\nthose processes in terms of measurement of\nbehavioural and cerebral responses to pain.\nThese measurements are providing early clues\nto the possible underlying CNS mechanisms\nand their relation to changes\nin\naffective-\nmotivational behaviour. This paper will review\nthe normal brain mechanisms of the conscious\nappreciation of pain, together with working\nhypotheses for how these mechanisms\nare\naltered during inflammatory and other types of\nclinical pain syndromes.\nHuman Physiology and\nPain Research\nLaboratory,\nManchester University\nRheumatic Diseases\nCentre, Clinical\nSciences Building,\nHope Hospital,\nSalford M6 8HD,\nUnited Kingdom\nA K P Jones\nS W G Derbyshire\nCorrespondence to:\nDr Jones.\nAccepted for publication\n14 March 1996\nNormal mechanisms: anatomy and\nphysiology\nIt is perhaps surprising that there should still\nbe debate about which areas of the brain might\nbe involved\nin the processing of such\nan"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 900
encoding: FLOAT32
metadata:
{"title": "Cerebral mechanisms operating in the and absence of inflammatory pain", "chroma:document": "an\nimportant and commonplace sensation as pain.\nThis has come about largely because of the\nunderstanding of pain as an experience involv-\ning sensory, cognitive-evaluative, and affective-\nmotivational components' which defies simple\nexplanations\ninvolving\npain\ncentres'\nand\nspecific pathways.2\nWhatever areas of the brain are involved in\npain processing, integration of the different\ncomponents\nmust be accommodated.\nThis\nimplies that there is unlikely to be any final\ncommon area of the brain that processes pain.\nIndeed, it is perhaps the search for a single\ndominant 'pain centre' that has done more to\nimpair our understanding of the functional\nanatomy of pain than anything else. Parallel\nprocessing of the conscious appreciation of\nprimary sensations such as vision and touch3\nare now well documented, and it would be\nsurprising if such parallel processing did not\nalso exist for non-primary sensations such as\npain. There is now growing evidence that pain\nis processed by a network or 'matrix' of struc-\ntures in the brain (fig 1), some components of\nwhich could be considered to comprise parallel\nbut integrated processing.\nNEUROANATOMY OF NOCICEPTION IN ANIMALS\nStudying pain in animals presents an insoluble\nproblem. Human beings can\ncall out and\nexpress their pain in ways that are commonly\nunderstandable\nto other members of their\nspecies; unfortunately, there is no equivalent\nframe of reference when dealing with animals.\nIncreased\nblood\npressure,\nmovements\nof\nwithdrawal, dilatation of the pupil, increased\ndepth of ventilation, attacking the source of\nnoxious stimulation, and cries may be common\nto all mammals in the face of seemingly 'pain-\nful' stimulation, but all such responses can be\nelicited\nafter the cerebral cortex has been\ndestroyed, in the probable absence of any\nsubjective experience. Furthermore, the sub-\njective experiences of an animal, if it has any,\nmay be totally different from those of humans.\nFor these reasons, human interpretation of\nwhat is observed in another species cannot be"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 901
encoding: FLOAT32
metadata:
{"title": "Cerebral mechanisms operating in the and absence of inflammatory pain", "chroma:document": "by extrapolation from human experience.\nThis is not to suggest that all 'pain' research\nin animals is valueless: the common ancestry\nbetween humans and animals suggests that\nsome of the underlying biological processes\ninvolved in human pain experience are likely to\nbe shared with other animals. A distinction is\ntherefore drawn between 'nociception' and\npain-which\nshould\nnot\nbe\nused\ninter-\nchangeably-the term nociception being used\nto refer to the biological response of receptors\nin tissue to potentially damaging stimuli such\nas intense heat or cold, chemical irritation, or\nintense pressure. The study ofnociceptive pain\navoids the fact that pain in man can occur\nwithout any evident nociceptor activation, as in\nperipheral and central deafferentation pain,\nand may also occur without any evidence of\nspinothalamic tract activation, as in psycho-\ngenic pain.\nThe spinothalamic tract has been demon-\nstrated to be 'both necessary and sufficient' for\nnociception in most species studied.4 It pro-\nvides the major direct nociceptive input from\nthe spinal cord to the thalamus. As a conse-\nquence, the spinothalamic tract ascending in\nthe anterolateral cord is widely considered as\nthe 'pain pathway'.\n41"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 902
encoding: FLOAT32
metadata:
{"title": "Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants", "chroma:document": "The Journal of Clinical Investigation   \nR E S E A R C H  A R T I C L E\n1\nIntroduction\nSince the start of the pandemic in December 2019, the severe acute \nrespiratory syndrome coronavirus 2 (SARS-CoV-2) virus has led to \nover 660 million cases of coronavirus disease 2019 (COVID-19) \nand over 6.5 million deaths globally. Although the rapid develop-\nment and distribution of vaccines and therapeutics have curbed \nthe effect of COVID-19 to a large extent, the emergence of cir-\nculating variants of concern (VOCs) continues to represent a \nmajor threat due to the potential for further immune evasion \nand enhanced pathogenicity. The D614G variant was the earliest \nvariant to emerge and became universally prevalent thereafter. \nCompared with WT, the D614G variant exhibited increased trans-\nmissibility rather than increased pathogenicity and was therefore \nunlikely to reduce efficacy of vaccines in clinical trials (1). Between \nthe emergence of D614G to October of 2021, 4 additional signif-\nicant VOCs evolved worldwide, including Alpha, Beta, Gamma, \nand Delta. Among these variants, Delta became a serious global \nthreat because of its transmissibility, increased disease severity, \nThe rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants has emphasized \nthe need to identify antibodies with broad neutralizing capabilities to inform future monoclonal therapies and vaccination \nstrategies. Herein, we identified S728-1157, a broadly neutralizing antibody (bnAb) targeting the receptor-binding site (RBS) \nthat was derived from an individual previously infected with WT SARS-CoV-2 prior to the spread of variants of concern \n(VOCs). S728-1157 demonstrated broad cross-neutralization of all dominant variants, including D614G, Beta, Delta, Kappa, \nMu, and Omicron (BA.1/BA.2/BA.2.75/BA.4/BA.5/BL.1/XBB). Furthermore, S728-1157 protected hamsters against in vivo \nchallenges with WT, Delta, and BA.1 viruses. Structural analysis showed that this antibody targets a class 1/RBS-A epitope"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 903
encoding: FLOAT32
metadata:
{"title": "Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants", "chroma:document": "in the receptor binding domain via multiple hydrophobic and polar interactions with its heavy chain complementarity \ndetermining region 3 (CDR-H3), in addition to common motifs in CDR-H1/CDR-H2 of class 1/RBS-A antibodies. Importantly, \nthis epitope was more readily accessible in the open and prefusion state, or in the hexaproline (6P)-stabilized spike \nconstructs, as compared with diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential and may \ninform target-driven vaccine designs against future SARS-CoV-2 variants.\nSite of vulnerability on SARS-CoV-2 spike induces \nbroadly protective antibody against antigenically \ndistinct Omicron subvariants\nSiriruk Changrob,1 Peter J. Halfmann,2 Hejun Liu,3 Jonathan L. Torres,3 Joshua J.C. McGrath,1 Gabriel Ozorowski,3 Lei Li,1  \nG. Dewey Wilbanks,1 Makoto Kuroda,2 Tadashi Maemura,2 Min Huang,1 Nai-Ying Zheng,1 Hannah L. Turner,3 Steven A. Erickson,4 \nYanbin Fu,1 Atsuhiro Yasuhara,1 Gagandeep Singh,5,6 Brian Monahan,6,7 Jacob Mauldin,6,7 Komal Srivastava,6,7 Viviana Simon,5,6,7,8,9 \nFlorian Krammer,5,6,7 D. Noah Sather,10,11,12 Andrew B. Ward,3 Ian A. Wilson,3,13 Yoshihiro Kawaoka,2,14,15,16 and Patrick C. Wilson1\n1Drukier Institute for Children\u2019s Health, Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA. 2Influenza Research Institute, Department of Pathobiological Sciences, School of \nVeterinary Medicine, University of Wisconsin\u2013Madison, Madison, Wisconsin, USA. 3Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA. \n4University of Chicago Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA. 5Department of Pathology, Molecular and Cell Based Medicine, 6Department of Microbiology, 7Center for \nVaccine Research and Pandemic Preparedness, 8The Global Health and Emerging Pathogens Institute, and 9Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 904
encoding: FLOAT32
metadata:
{"title": "Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants", "chroma:document": "New York, New York, USA. 10Center for Global Infectious Disease Research, Seattle Children\u2019s Research Institute, Seattle, Washington, USA. 11Department of Pediatrics and 12Department of Global Health, \nUniversity of Washington, Seattle, Washington, USA. 13The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA. 14Division of Virology, Department of Microbiology \nand Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 15The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, \nJapan. 16Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), University of Tokyo, Tokyo, Japan.\n \n Related Commentary: https://doi.org/10.1172/JCI168080\nAuthorship note: SC, PJH, HL, and JLT contributed equally to this work.\nConflict of interest: The University of Chicago has filed a patent application on No-\nvember 11, 2021, relating to anti-SARS-CoV-2 antibodies with PCW and SC as inventors \n(application number PCT/US22/79916). Some of the mAbs in this study are being \nconsidered for the development of therapeutic antibodies. The Icahn School of Med-\nicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological \nassays (U.S. provisional application numbers: 62/994,252; 63/018,457; 63/020,503; and \n63/024,436) and NDV-based SARS-CoV-2 vaccines (U.S. provisional application number: \n63/251,020), which list FK as a coinventor. VS is listed on the serological assay patent \napplication as a coinventor. Mount Sinai founded a company, Kantaro, to market sero-\nlogical tests for SARS-CoV-2. FK has consulted for Merck and Pfizer, before 2020, and is \ncurrently consulting for Pfizer, Seqirus, Third Rock Ventures and Avimex. The Krammer \nlaboratory is also collaborating with Pfizer on animal models of SARS-CoV-2.\nCopyright: \u00a9 2023, Changrob et al. This is an open access article published under the \nterms of the Creative Commons Attribution 4.0 International License."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 905
encoding: FLOAT32
metadata:
{"title": "Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants", "chroma:document": "Submitted: November 2, 2022; Accepted: February 28, 2023; Published: April 17, 2023.\nReference information: J Clin Invest. 2023;133(8):e166844. \nhttps://doi.org/10.1172/JCI166844."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 906
encoding: FLOAT32
metadata:
{"title": "A cell-free antigen processing system informs HIV-1 epitope selection and vaccine design", "chroma:document": "ARTICLE\nA cell-free antigen processing system informs HIV-1\nepitope selection and vaccine design\nSrona Sengupta1,2,8\ue840, Josephine Zhang1*\ue840, Madison C. Reed1*\ue840, Jeanna Yu1*\ue840, Aeryon Kim3\ue840, Tatiana N. Boronina4\ue840, Nathan L. Board1\ue840,\nJames O. Wrabl5\ue840, Kevin Shenderov1\ue840, Robin A. Welsh2\ue840, Weiming Yang2\ue840, Andrew E. Timmons1\ue840, Rebecca Hoh6\ue840, Robert N. Cole4\ue840,\nSteven G. Deeks6\ue840, Janet D. Siliciano1\ue840, Robert F. Siliciano1,7\ue840, and Scheherazade Sadegh-Nasseri2\ue840\nDistinct CD4+ T cell epitopes have been associated with spontaneous control of HIV-1 replication, but analysis of antigen-\ndependent factors that influence epitope selection is lacking. To examine these factors, we used a cell-free antigen processing\nsystem that incorporates soluble HLA-DR (DR1), HLA-DM (DM), cathepsins, and full-length protein antigens for epitope\nidentification by LC-MS/MS. HIV-1 Gag, Pol, Env, Vif, Tat, Rev, and Nef were examined using this system. We identified 35\nnovel epitopes, including glycopeptides. Epitopes from smaller HIV-1 proteins mapped to regions of low protein stability and\nhigher solvent accessibility. HIV-1 antigens associated with limited CD4+ T cell responses were processed efficiently, while\nsome protective epitopes were inefficiently processed. 55% of epitopes obtained from cell-free processing induced memory\nCD4+ T cell responses in HIV-1+ donors, including eight of 19 novel epitopes tested. Thus, an in vitro processing system utilizing\nthe components of Class II processing reveals factors influencing epitope selection of HIV-1 and represents an approach to\nunderstanding epitope selection from non\u2013HIV-1 antigens.\nIntroduction\nCD4+ T cells connect the humoral- and cell-mediated arms of the\nimmune system, both of which are vital for vaccine responses\nagainst chronic viral infections. Elegant analyses of CD4+ T cell\nresponses to HIV-1 by Walker and colleagues have provided\ninsights into protective HLA-DR alleles and viral epitopes asso-\nciated with control of viral replication. The breadth and magni-"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 907
encoding: FLOAT32
metadata:
{"title": "A cell-free antigen processing system informs HIV-1 epitope selection and vaccine design", "chroma:document": "tude of Gag-specific CD4+ T cell responses are associated with\nanti-Env neutralizing antibodies (Ranasinghe et al., 2015) and\ninversely correlated with viral load (Laher et al., 2017; Ranasinghe\net al., 2012; Ranasinghe et al., 2013). Three CD4+ T cell epitopes in\nGag are associated with spontaneous viral control (Ranasinghe\net al., 2012, 2013). However, it remains unclear why few in-\ndividuals develop these protective responses and whether this is\ninfluenced by antigen-processing mechanisms.\nThe antigen-processing pathway for major histocompatibility\ncomplex Class II (MHC-II)\u2013restricted CD4+ T cell epitopes begins\nwith the endocytosis of exogenous antigens or autophagy of\nintracellular contents (Unanue et al., 2016). Full-length protein\nantigens bind to MHC-II molecules in the late endosomal MHC-II\ncompartment (MIIC) of professional APCs, with subsequent\ncleavage/trimming of the exposed protein around the bound\nregion (Kim et al., 2014). Epitope selection by MHC-II is facili-\ntated by chaperones HLA-DM (DM) and HLA-DO. DM recognizes\nstructurally flexible conformations of peptide:MHC-II (pMHC-\nII) complexes (Chou and Sadegh-Nasseri, 2000) due to partially\nfilled or unfilled P1 pockets in the peptide binding groove\n(Anders et al., 2011; Chou and Sadegh-Nasseri, 2000) and in-\nduces dissociation of poorly bound peptides such as the class II\u2013\nassociated invariant chain (CLIP). The resulting open MHC-II\ngroove is peptide-receptive and can rapidly scan for the best fit-\nting sequences (Chou and Sadegh-Nasseri, 2000; Natarajan et al.,\n1999; Rabinowitz et al., 1998), generating tightly formed pMHC-II\ncomplexes that are no longer recognized by DM (Narayan et al.,\n2007, 2009) and that would likely have a longer half-life on the\nsurface of APCs (Nelson et al., 1994). DO works cooperatively with\nDM to promote its function in B cells, where it is primarily ex-\npressed (Poluektov et al., 2013; Welsh et al., 2019, 2020).\nCD4+ T cell epitopes are often defined using overlapping"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 908
encoding: FLOAT32
metadata:
{"title": "A cell-free antigen processing system informs HIV-1 epitope selection and vaccine design", "chroma:document": "synthetic peptides. While this approach provides a broad survey\nof the T cell epitopes within proteins of interest, it does not\n.............................................................................................................................................................................\n1Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA;\n2Department of Pathology, Johns Hopkins University School of Medicine,\nBaltimore, MD, USA;\n3Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA, USA;\n4Department of\nBiological Chemistry, Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, MD, USA;\n5Department of Biology, Johns\nHopkins University, Baltimore, MD, USA;\n6Department of Medicine, University of California, San Francisco, San Francisco, CA, USA;\n7Howard Hughes Medical Institute,\nBaltimore, MD, USA;\n8The Graduate Program in Immunology and Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.\n*J. Zhang, M.C. Reed, and J. Yu contributed equally to this paper. Correspondence to Scheherazade Sadegh-Nasseri: ssadegh@jhmi.edu; Robert F. Siliciano: rsiliciano@\njhmi.edu.\n\u00a9 2023 Sengupta et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/\n4.0/).\nRockefeller University Press\nhttps://doi.org/10.1084/jem.20221654\n1 of 24\nJ. Exp. Med. 2023 Vol. 220 No. 7\ne20221654"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 909
encoding: FLOAT32
metadata:
{"title": "Amniotic fluid macrophages and the antenatal diagnosis of anencephaly and spina bifida", "chroma:document": "Journal of Medical Genetics (1975).\n12, 135.\nAmniotic fluid macrophages and the antenatal\ndiagnosis of anencephaly and spina bifida\nGRANT R. SUTHERLAND,* D. J. H. BROCK, and J. B. SCRIMGEOUR\nDepartment of Pathology, Royal Hospital for Sick Children and University of Edinburgh, and the\nDepartments of Human Genetics and Obstetrics and Gynaecology, University of Edinburgh\nSummary.\nThe macrophage content of amniotic fluid has been measured and\nthe upper limit of normal on an arbitrary scale is 41.\nAmongst 65 amniotic fluids\ncollected for antenatal diagnostic studies before 22 weeks' gestation there were eight\nwhich had macrophage counts ranging from 82 to 6226, three of these were shown\nto have anencephaly and two spina bifida.\nThe reasons for three apparently false\npositives are as yet undetermined.\nRhesus iso-immunized amniotic fluids were\nfound to have macrophage counts of up to 276 and a possible explanation for this is\nconsidered.\nIt is argued that an elevated amniotic fluid macrophage count may\nindicate a CNS defect or possibly other fetal abnormality.\nThe finding by Sutherland, Brock, and Scrim-\ngeour (1973) of large numbers of macrophages in\nthe amniotic fluid from two cases ofanencephaly has\nbeen used by Nelson, Ruttiman, and Brock (1974)\nto make the antenatal diagnosis of a further case.\nThe macrophage content of spina bifida and anen-\ncephalic amniotic fluids has been quantitated and\ncompared with that from normal pregnancies.\nMaterials and methods\nAmniotic fluids were obtained by amniocentesis for\nantenatal chromosome studies, a-fetoprotein estimation,\nduring the management of Rhesus iso-immunized preg-\nnancies and at induction of labour in cases where the\nfetus was known to have anencephaly.\nAmniotic fluid cultures were established as previously\ndescribed (Sutherland, Grace, and Bain, 1973).\nThe\nculture vessel was a 50 mm Petri dish which contained\nfive or six 6 x 22 mm glass coverslips.\nThe culture\nmedium was Ham's F10 supplemented with 30% fetal\ncalf serum.\nThe day after cultures had been set up"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 910
encoding: FLOAT32
metadata:
{"title": "Amniotic fluid macrophages and the antenatal diagnosis of anencephaly and spina bifida", "chroma:document": "(usually about 20 hours later) one of the coverslips was\naseptically removed from the Petri dish, washed well in\nphosphate buffered saline, fixed with methanol, stained\nwith Giemsa, and mounted on a slide.\nThe number of\nglass adherent cells in 10 low power fields ( x 100) were\ncounted and this number was adjusted to relate to 10 ml\nof amniotic fluid, ie, if the cells from 5 ml of amniotic\nfluid had been inoculated into the Petri dish then the\nnumber was multiplied by two.\nThe resultant macro-\nphage count (glass adherent cells/10 low power fields/\n10 ml of amniotic fluid) has been used to compare dif-\nferent samples of amniotic fluid.\nAmniotic fluid a-\nfetoprotein was measured according to Brock and Sut-\ncliffe (1972).\nResults\nThe macrophage counts for the 94 fluids studied\nare shown in Fig. 1.\nAll the fluids classed as 'nor-\nmal' had low macrophage counts (range 0-41), and\nthere was no reason to suspect fetal CNS abnor-\nmality either because the infant had been delivered\nor because the amniotic fluid a-fetoprotein levels\nwere not elevated.\nFour amniotic fluids from cases\nof hydramnios of unknown aetiology had macro-\nphage counts within the normal range.\nA number\nof samples of amniotic fluid showing different de-\ngrees of blood staining had normal macrophage\ncounts.\nRhesus iso-immunized amniotic fluids had\nhighly variable macrophage counts ranging up to\n276.\nWhere serial samples were obtained from\nthese pregnancies the macrophage counts tended to\ndecrease as gestation progressed.\nDetails of the cases with anencephaly or spina\nbifida are shown in Table I.\nIn all except one of\nthese fluids the macrophage count was elevated,\n135\nReceived 21 June 1974.\n* Present address and reprint requests to: Cytogenetics Unit,\nDepartment of Pathology, The Adelaide Children's Hospital, North\nAdelaide 5006, Australia."}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 911
encoding: FLOAT32
metadata:
{"title": "Review article Cell membrane receptors for serological reagents", "chroma:document": "Review article\nJournal of Medical Genetics (1975).\n12, 174.\nCell membrane receptors for serological reagents\nG. W. G. BIRD\nWest Midlands Regional Blood Transfusion Service, Vincent Drive, Edgbaston, Birmingham B15 2SG\nMany useful genetic markers are cell surface struc-\ntures.\nFurthermore, the cell surface is intimately\ninvolved in cellular immunity, and often in humoral\nimmunity.\nIt is therefore important, both in gene-\ntics and immunogenetics, to understand cell surface\nstructure.\nAlthough the cell membrane has been actively\nstudied for many years, progress in this field is\nunderstandably slow.\nIt is generally agreed that\nthe cell membrane is fundamentally a phospholipid\nbilayer with inner and outer hydrophilic areas and a\ncentral hydrophobic region.\nBesides lipids, the\nmembrane contains proteins and carbohydrates; the\ncarbohydrates occur as glycolipids or glycoproteins.\nWhereas the protein and lipid portions of the cell\nmembrane occupy the plane of the membrane, the\ncarbohydrate chains of the glycolipid and glycopro-\ntein components of the cell membrane project out-\nwards, so that their N-terminal ends are exposed\nabove\nthe\nmembrane\nsurface.\nRecent\nwork,\nchiefly by Singer and Nicolson (1972) and Nicolson\n(1973), on the structural organization ofmembranes,\nin terms of the thermodynamics of macromolecular\nsystems, has led to the conclusion that the cell mem-\nbrane is a mosaic ofalternating globular proteins and\nphospholipid units, in which the phospholipid units\nrepresent the bricks and the globular protein the\nmortar (Fig. 1).\nThe mosaic structure is dynamic\nrather than static, with considerable lateral move-\nment of the phospholipid and protein components.\nDifferent membrane components move laterally in\nthe plane of the membrane at different rates, de-\npending on restraints applied from outside or inside\nthe cell.\nThe movement may account for certain\napparent changes on the cell surface, such as the\nappearance of 'new' HL-A specificities on cultured\ncells (Mackintosh, Hardy, and Aviet, 1971), or for"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 912
encoding: FLOAT32
metadata:
{"title": "Review article Cell membrane receptors for serological reagents", "chroma:document": "changes observed after treatment of intact cells by\nReceived 26 June 1974.\nenzymes.\nIndeed, it has been suggested (Singer\nand Nicolson, 1972) that after proteolysis or malig-\nnant transformation, agglutinin-binding sites diffuse\nand aggregate in clusters (Fig. 2).\nThis might\nexplain, for example, the very strong agglutination\nof papain-treated A2\ncells by the virtually A1-\nspecific agglutinin obtained from the seeds of Doli-\nchos biflorus.\nAlthough this lateral movement may\nsometimes affect the 'display' of surface compo-\nnents, molecular orientation is generally maintained.\nCeli surface carbohydrates\nWe know more about the structure of erythro-\ncytes than about any other cells, and more about\nthose antigens which are carbohydrate than those\nwhich are lipid, protein, or lipoprotein.\nThere are only seven monosaccharide components\nof the human red cell membrane (Winzler, 1969):\ngalactose, mannose, fucose, glucose, acetylgalactos-\namine, acetylglucosamine and N-acetylneuraminic\n(sialic) acid.\nAll human erythrocyte membrane\ncarbohydrate chains are therefore combinations of\nthese seven sugars, and differ from one another in\nthe serial arrangement of the sugar components, and\nthe nature of the chemical linkages between them.\nThere are therefore structural similarities in recep-\ntor sites for various serological reagents, so that it is\nnot surprising that they crossreact; what is surpris-\ning therefore is that many reagents are very highly\nspecific.\nThe ABH and Lewis systems\nThe ABH and Lewis blood group antigenic de-\nterminants are the carbohydrate moieties of glyco-\nproteins or glycolipids.\nPart of the work which led\nto the elucidation of ABH and Lewis structure was\ndone, not on red cells, but on blood group specific\nsubstances present in soluble form in certain body\nfluids,\neg,\nsaliva\nof secretors, pseudomucinous\n174"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 913
encoding: FLOAT32
metadata:
{"title": "45,X Turner's syndrome in monozygotic twin sisters", "chroma:document": "Journal of Medical Genetics (1975).\n12, 390.\n45,X Turner's syndrome in monozygotic twin sisters\nG. PESCIA,* P. E. FERRIER, D. WYSS-HUTIN, and D. KLEIN\nDepartment of Pediatrics and Genetics, University of Geneva, Switzerland\nSummary.\nA 7-year-old girl was admitted to the hospital for anaemia, secon-\ndary to intestinal blood loss (melaena).\nShe was found to have 45,X Turner's\nsyndrome.\nHer identical twin sister also had Turner's syndrome with a 45,X\nchromosome complement.\nAccording\nto various\ncriteria the probability of\nmonozygosity was 0.9905.\nAlthough the incidence of twinning is greater than\nusual in families of patients with Turner's syndrome, affected cases have only\nbeen observed in twin sisters on six occasions.\nIt seems therefore that the 45,X\nchromosome complement itself is not a factor predisposing to twinning, but that\nin some families, a factor is at play, which causes either twinning or the 45,X\naneuploidy, or both.\nTurner (1938) in his original publication reported\nthat one of his patients with the triad 'infantilism,\npterygium colli and cubitus valgus' had a normal\ntwin sister.\nSince Turner's original paper, the\nassociation of Turner's syndrome and twinning in\nthe same family has been recorded on 28 occasions.\nThe purpose of the present paper is to report the\ncase of two monozygotic sisters with non-mosaic\n45,X Turner's syndrome.\nCase reports\nThe proposita, the second born twin, a 7-year-old-\ngirl, was admitted to our paediatric service for investiga-\ntion of hypochromic anaemia due to recurrent melaena.\nFamily history was negative for consanguinity, small\nstature, sterility, or anaemia.\nTwinning has occurred\non two occasions on the matemal side (see pedigree,\nFig. 1).\nPregnancy was complicated by protracted vomiting\nduring the first 4 months, and by a threatened abortion at\n3 months.\nDelivery occurred on 15 June 1966, in the\nestimated 30th week of gestation.\nV.1 weighed 1950 g\nat birth, and V.2 (propositus) 1720 g.\nPlacenta was\nunique.\nThe mother was 22 years old and the father 23."}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 914
encoding: FLOAT32
metadata:
{"title": "45,X Turner's syndrome in monozygotic twin sisters", "chroma:document": "The neonatal period was uneventful.\nPsychomotor\ndevelopment of both twins was slow, they walked at 18\nmonths, and began to speak only at 4 years.\nLongi-\ntudinal growth was regular but slower than that of other\nchildren.\nV.2 experienced her first episode of melaena, followed\nby palor and fatigue, at the age of 4 years.\nA second\nepisode occurred at the age of 6 years, and a third, at the\nage of 7 years, prompted the hospital admission.\nV.1\nnever experienced any gastrointestinal bleeding.\nOn physical examination (Fig. 2), the proposita (V.2)\nwas a shy, slightly retarded (2 years retardation) 7 year-\nold girl.\nHeight was 117 cm (10th to 25th centile) and\nweight 2400 g (50th centile).\nSkin was pale, with several\npigmented naevi on the trunk and a few areas of hyper-\npigmentation on the\nextremities.\nPalpebral\nfissures\nwere slanted downwards, and a divergent squint was\n(fO\nTwins\nOI\n(9 3\nMonozyqotic twins\nMiscarriage\nII\n/\nProposita\n0\n45,X Turner's\nsyndrome\nIII\nIIIv\n1943\n944\nV\nFIG. 1.\nFamily pedigree.\nReceived 4 November 1974.\n* Present address: Clinique Universitaire de PNdiatrie, 30 bd. de la\nCluse, 121 1-Geneva 4, Switzerland.\n390"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 915
encoding: FLOAT32
metadata:
{"title": "Aspects of pre-eclamptic toxaemia of pregnancy, consanguinity, and twinning in Ankara", "chroma:document": "Journal of Medical Genetics (1976).\n13, 1-8.\nAspects of pre-eclamptic toxaemia of pregnancy,\nconsanguinity, and twinning in Ankara\nALAN C. STEVENSON,* BURHAN SAYj,t SEDAT USTAOGLU4, and\nZIYA DURMUSt\nSummary.\nIt appears that women classed as having pre-eclamptic toxaemia\nare less frequently consanguineous with their husbands than all other mothers and\nin particular those mothers classed as having pregnancies complicated by chronic\nhypertensive disease.\nSearch revealed no evidence for possible biases which could\nhave simulated such findings.\nFurther evidence is advanced suggesting that, though pre-eclamptic toxaemia is\nmore common in all types of twin pregnancies than in single births, it is more com-\nmon where the twins are dizygous than where they are monozygous.\nIt is pointed out that both these findings would be expected ifthere was a contri-\nbution to the aetiology of pre-eclamptic toxaemia by maternal/fetal immunological\nincompatibility.\nHowever, if such a mechanism exists it is not always determined\nat the same gene locus.\nStarting in 1971 a special study was made of all\nwomen\ndelivered\nin the Dogum Evi Hospital,\nAnkara.\nFrom data accumulated after the first\n5286 mothers who had been delivered, Stevenson\net al (1971) concluded that the proportion of women\nwho had pre-eclamptic toxaemia who were related\nto their husbands was significantly less than in the\nother patients.\nBy early 1973, 23 416 mothers with single preg-\nnancies and 271 with twin pregnancies had been\nstudied.\nBasic\ninformation\nconcerning\nthese\npatients is set out in Table I.\nRecords in respect of\n58 of the patients with single pregnancies were in-\ncomplete in respect of one or more of the variables\npresented in subsequent tables, so these forms were\nignored and the total in subsequent tables is 23 358.\nTen women (none classified as having pre-eclamptic\ntoxaemia) were identified as having been admitted\nfor two pregnancies during the period of the study.\nThe data from both admissions have been included.\nReceived 16 December 1974."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 916
encoding: FLOAT32
metadata:
{"title": "Aspects of pre-eclamptic toxaemia of pregnancy, consanguinity, and twinning in Ankara", "chroma:document": "* MRC Population Genetics Unit, Old Road, Headington, Oxford.\nPresent address: Southern District-Highland Health Board, Old\nLaboratories, Royal Northern Infirmary, Inverness IV3 5SF.\nt Department of Paediatrics, the Hacettepe University, Ankara,\nTurkey.\nt Dogum Evi Hospital, Ankara, Turkey.\nTABLE I\nOUTLINE OF DATA\nSingle births\nMales\n12455\nFemales\n10 961\nTotal (births)\n23 416\nTwin births\nMM pairs\n80\nMF pairs\n112\nFF pairs\n79\nTotal (pregnancies)\n271\nTotal (births)\n542\nGrand total (pregnancies)\n23 687\nGrand total (births)\n23 958\nFrequency of 'true' pre-eclamptic toxaemia per 1000 total\nbirths\n2.4\nStillbirth rate per 1000 total births\n19.3\nLive births-died before leaving hospital per 1000 total\nbirths\n17.0\n'Perinatal' mortality per 1000 total births\n36.3\nProportion of mothers in relationship with their husbands:\n16\n132 (fi-st cousins one removed)\n2.8%\n164 or less (second cousins or less) 0.8%\nAny consanguinity\n17.0%\n* These coefficients are really those of the offspring of such\nmarTiages, but as a convenience (with many precedents!) they are\napplied in this and other Tables to the marriages.\n1"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 917
encoding: FLOAT32
metadata:
{"title": "Blood and other polymorphisms in multiple sclerosis", "chroma:document": "Journal of Medical Genetics (1976).\n13, 30-33.\nBlood groups and other polymorphisms\nin multiple sclerosis\nJ. L. MacDONALD, D. F. ROBERTS, D. A. SHAW, and M. SAUNDERS\nDepartment of Human Genetics, and the Department of Neurology, University of Newcastle upon Tyne\nSummary.\nA comparative study was made of blood groups and other poly-\nmorphic systems in 136 patients with multiple sclerosis in the Newcastle area.\nThe\nmajority of systems showed no difference from normal frequencies, but differences\nin the ABO and rhesus systems are suggested.\nThe demonstration of an association of multiple\nsclerosis\nwith\nthe\nhistocompatibility\nantigens,\nHL-A 3 of the LA series, and HL-A 7 and W-18 of\nthe FOUR series (Arnason et al, 1972; Naito et al,\n1972;\nBertrams,\nKuwert,\nand\nLiedtke,\n1972;\nJersild et al, 1973; Smeraldi, 1973), has reopened the\nquestion of genetic susceptibility to the disease, and\nin particular whether patients represent a subsection\nof the population that is genetically identifiable.\nIt appears worth while, therefore, to re-examine the\nassociation of the disease with blood groups, which\nhas remained controversial throughout the 10 years\nsince it was first suggested (McAlpine, Lumsden,\nand Acheson, 1965).\nThis paper reports a com-\nparison of 8 blood group and 5 other polymorphic\nsystems in multiple sclerosis patients in the New-\ncastle area of the north-east of England.\nSubjects and methods\nThe subjects were 136 multiple sclerosis patients, diag-\nnosed and accepted as such in the Neurology Department\nof the Royal Victoria Infirmary, Newcastle.\nNone of\nthe patients was included in the earlier series of Simpson\net al (1965) as they had all presented after that date.\nFrom each patient a blood and saliva specimen was\nobtained.\nThe blood specimens were tested by standard\nserological procedures with the following antisera: anti\nA, Al, B, A+B, C, c, D, E, e, M, N, S, s, K, k, P, Jka,\nFya.\nThe salivas were tested with anti-H lectin and\nwhere necessary with A and B antisera for secretor\nstatus."}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 918
encoding: FLOAT32
metadata:
{"title": "Blood and other polymorphisms in multiple sclerosis", "chroma:document": "status.\nFor identification of the various isoenzymes, horizontal\nstarch gel electrophoresis was performed, using gels of\n9% BDH hydrolysed starch.\nAdenylate kinase was\nexamined by the method of Fildes and Harris (1966), acid\nReceived 28 January 1975.\n30\nphosphatase by the discontinuous buffer system as given\nby Hopkinson, Spencer, and Harris (1964), and phospho-\nglucomutase was typed using double the molar con-\ncentration of all ingredients of the buffer given by\nSpencer, Hopkinson, and Harris\n(1964)\nat pH\n7.4.\nHaptoglobin was typed using the discontinuous buffer\nsystem of Poulik and Smithies (1957) at 450 volts for 3 to\n4 hours in a cold room at 40 C, and staining with\nbenzidene to visualize the phenotypes.\nComparative figures were obtained in two ways.\nThe\nfirst\nseries\n(referred to\nas the population\nseries)\nis\nderived from the frequencies regarded as normal for\nthe population.\nFor the ABO and red cell enzyme\nsystems, frequencies specific to the north of England\nare available (Papiha and Roberts, 1976), and for hapto-\nglobins (Kopec, 1970; Papiha, 1973).\nFor the other\nblood groups, however,\nthe MN,\nSs, rhesus,\nKell,\nDuffy, Kidd, and secretor frequencies were taken from\nRace and Sanger (1968, pages 91, 92, 180, 267, 332,\n348, and 294, respectively), and the P frequencies from\nMourant (1954, page 366, line 1).\nSuch comparative\ndata are not entirely satisfactory,\nfirst because they\nignore the possible existence of local genetic variation in\nthe populations of Britain; and secondly because there\nmay be some laboratory variation in technique.\nBoth of\nthese could promote differences between our observed\nand the 'expected' frequencies.\nTo overcome these two\npossible objections, as a second control series, specimens\nwere\ntaken from\n136\nindividuals\nwithout\nmultiple\nsclerosis and tested at the same time by the same pro-\ncedures in this laboratory.\nThese controls included 98\nindividuals with minimal dermatoses attending the out-\npatient clinics of the dermatology department, and 38"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 919
encoding: FLOAT32
metadata:
{"title": "Blood and other polymorphisms in multiple sclerosis", "chroma:document": "normal parents of a series of healthy children.\nResults\nIn Table I are set out the results on the multiple\nsclerosis\npatients, compared\nwith\nthe numbers\nexpected\nin\neach\nsystem from\nthe\npopulation"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 920
encoding: FLOAT32
metadata:
{"title": "Review article Genetic markers in atherosclerosis: A review*", "chroma:document": "Review article\nJournal of Medical Genetics (1976).\n13, 81-90.\nGenetic markers in atherosclerosis: A review*\nNEWTON E. MORTON\nPopulation Genetics Laboratory, University of Hawaii, Honolulu\nSummary.\nThere is a growing number of lipoprotein markers recognized by\nimmunological, electrophoretic, and other biochemical methods, and a beginning\nhas been made on studying their modes of inheritance and linkage relations.\nSuggestive but inconclusive evidence of a relation between the cerumen polymor-\nphism and arteriosclerosis has been published.\nAssociations of the ABO blood\ngroups with cardiovascular disease and serum lipid levels have been established,\nbut the exact relation to lipoproteins and atherosclerosis remains to be determined.\nThe subject of genetic markers in atherosclerosis\nis at the intersection of genetics, medicine, epide-\nmiology, immunology, and biochemistry.\nThe ob-\nservations are scattered, sometimes preliminary or\nconflicting, and any review must soon be obsolete.\nRecognizing these limitations, I shall discuss the\npresent state of our knowledge on antigenic poly-\nmorphisms of lipoproteins (Ag, Lp, and Ld), the\ncontroversial evidence of a relation between Lp and\nthe HL-A locus, the cerumen polymorphism (W),\nelectrophoretic variants of lipoproteins,\navailable\nevidence on linkage of lipoprotein markers, and\nassociations of the ABO blood groups with cardio-\nvascular diseases and lipoproteins.\nCitation in this\nreview does not imply credence, and my comments\nin the last section are deliberately speculative.\nAntigenic polymorphisms\nThree genetic polymorphisms of ,B-lipoprotein\nhave been reported on the basis of the Ouchterlony\nmethod of double diffusion in agar gel.\nAllison\nand Blumberg (1961)\ndiscovered\nin\na multiply\ntransfused patient (C. de B.) an antiserum which\nthey attributed\nto\na polymorphic factor Ag( +),\nlater designated Ag(a).\nSubsequently, Hirschfeld\n(1963) showed that anti-Ag(a) is a mixture of three\nspecificities, anti-Ag(al), anti-Ag(x), and anti-Ag(z),\nwhich behave as a factor-union system."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 921
encoding: FLOAT32
metadata:
{"title": "Review article Genetic markers in atherosclerosis: A review*", "chroma:document": "A fourth\ndeterminant, Ag(y), is antithetical to Ag(x).\nSix\n* This work has been supported by\ngrants HL\n16774 and\nGM17173 of the U.S. National Institutes of Health.\nThe author is\nindebted to Drs K. Berg, J. Hirschfeld, L. Beckman, D. C. Shreffler,\nand F. Vogel for helpful comments on a first draft of this paper.\n81\nTABLE I\nAG CHROMOSOME FREQUENCIES IN SWEDEN\n(after Hirschfeld and Rittner, 1969)\nChromosome\nxa|Lz\nxal\nx\nya z\nyal\ny\nFrequency\n0.0048\n0.1935\n0.0249\n0.1549\n0.1010\n0.5210\nTABLE II\nGENE FREQUENCIES DEFINED BY x,y FACTORS OF\nAg SYSTEM\n(after Giblett, 1969)\nAlleles\nCaucasoid\nNegroid\nMongoloid\n(N = 248)\n(N = 54)\n(N = 1205)\nAgx\n0.23\n0.69\n0.73\nAgY\n0.77\n0.31\n0.27\nalleles appear to account for the population fre-\nquencies and segregation in families (Table I). The\nAg(z) factor is apparently a subtype of a,, since\nchromosomes xz and yz have not been observed.\nAll reported alleles have either the x or y factor, but\nnot both.\nFrom limited gene frequency data, Agx\nis the common allele in Africa and Asia, while Ag3\npredominates in Europe (Table II).\nThe symbol Ag has been suggested for all ,6-\nlipoprotein antigens detected by isoimmunization\n(Buitler,\n1967).\nPatients\nwith\nthalassaemia\nare\nespecially good producers of antiserum, perhaps\nbecause of the associated splenomegaly (Blumberg\net al, 1964).\nThe relation of many of these antisera\nto the Ag system defined by a,, x, y, and z is unclear\n(Hirschfeld,\n1972).\nDausset et al (1968) report\n1\nI\n---"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 922
encoding: FLOAT32
metadata:
{"title": "Review Article The mucopolysaccharidoses", "chroma:document": "Review Article\nJournal of Medical Genetics (1976).\n13, 169-181.\nThe mucopolysaccharidoses\nC. A. PENNOCK and I. C. BARNES\nFrom the Department of Child Health, Bristol University; and the Department of Chemical Pathology,\nBristol Royal Infirmary\nThe group of inherited disorders referred to as\nthe mucopolysaccharidoses, of which Hurler's syn-\ndrome is the best known example, have been ex-\npertly reviewed and classified by McKusick in 1965,\n1969, and reclassified in 1972.\nThe most recent\nclassification (Table I) resulted from observations\non skin fibroblasts made by Neufeld and her col-\nleagues during their studies on the basic biochemical\ndefects in the mucopolysaccharidoses.\nAs a result\nof this work, and research by other groups, the\nactual enzyme defects in all the conditions shown in\nTable I have been identified, and this has made the\nantenatal diagnosis of these disorders a real possi-\nbility.\nThese exciting developments which have\noccurred during the past four years are reviewed in\nthe following paragraphs.\nMucopolysaccharide (glycosaminoglycan)\nstructure and nomenclature\nMucopolysaccharides\nare\nthe\nmajor\nchemical\npolymers of the ground substance and connective\ntissue (in association with collagen, reticulin, and\nelastin).\nThe reports published in the past are\noften confusing since the terms mucopolysaccharide,\nmucoprotein, mucin, mucus, and glycoprotein have\nbeen used synonymously, but the position has been\nclarified by Jeanloz (1960) who introduced the term\nglycosaminoglycan (GAG).\nThis more clearly de-\nfines the chemical nature of the mucopolysaccha-\nrides (GAGs) as being high molecular weight poly-\nmers of repeating dimers of an amino sugar usually\nlinked to a hexuronic acid.\nThe amino sugar is\neither glucosamine or galactosamine, both of which\nare usually either acetylated or sulphated at the\namino group, and both of which may also be sul-\nphated either at carbon 4 or carbon 6 of the hexose\nring.\nThe hexuronic acid is either glucuronic acid\n(that is, glucose with a carboxyl group at carbon 5),"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 923
encoding: FLOAT32
metadata:
{"title": "Review Article The mucopolysaccharidoses", "chroma:document": "or iduronic acid (the C-5 epimer of glucuronic acid).\nSeveral GAG chains of similar molecular weight\nmay be linked through a short neutral carbohydrate\nlinkage (usually galactose-galactose-xylose) to a pro-\ntein core via a serine (or threonine) residue.\nFull details of the chemistry of these polymers\nhave been given in a review by Muir (1969) and are\nsummarized in Table II.\nExcretion of glycosaminoglycans\nThe term mucopolysaccharidosis was first sug-\ngested by Brante in 1952 after finding that the liver\nof two patients with Hurler's syndrome contained an\nexcess of chondroitin sulphate B (dermatan sul-\nphate), a designation that was made permanent by\nthe demonstration of excess mucopolysacchariduria\nby Dorfman and Lorincz in 1957, and confirmed by\nMeyer and his colleagues in 1958.\nThe study of\nurinary GAG excretion patterns gave the first indi-\ncations of the biochemical pathogenesis of the muco-\npolysaccharidoses, and contributed greatly to our\npresent understanding of the underlying defects.\n169\n(a) Normal GAG excretion.\nThe first sug-\ngestion that GAGs might be present in normal urine\nis thought to have been made by Moerner in 1895\nwho isolated a sulphated polysaccharide, which was\nprobably\nchondroitin\nsulphate\n(McGale,\n1969).\nThis finding was subsequently confirmed by Astrup\n(1947) and Kerby (1954) who isolated an alchohol-\ninsoluble metachromatic material which was identi-\nfied as chondroitin sulphate by DiFerrante and Rich\nin 1956.\nThe latter subsequently showed that the\nmain GAGs excreted in normal urine are chon-\ndroitin-4-sulphate\nand\nchondroitin-6-sulphate,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 924
encoding: FLOAT32
metadata:
{"title": "Annotation Risks of miscarriage after amniocentesis", "chroma:document": "Annotation\nJournal of Medical Genetics (1976).\n13, 351.\nRisks of miscarriage after amniocentesis\nC. O. CARTER\nFrom MRC Clinical Genetics Unit, Institute of Child Health, 30 Guilford Street, London WCIN IEH\nAn encouraging summary report has been re-\nleased by the U.S. Department of Health, Education\nand Welfare on the safety of amniocentesis and was\npresented at the American Academy of Pediatrics\nmeeting in Washington in October 1975.\nThe re-\nport was discussed by Dr Milunsky in 30 October\nissue of New EnglandJournal of Medicine.\nThe collaborative study from 9 centres compared\nthe outcome of pregnancy in 1040 women under-\ngoing the procedure and in 992\ncontrols.\nAn\nattempt was made to match the controls for mater-\nnal age, parity, race, religion, socioeconomic status\nand other features.\nThe most serious discrepancy\nin matching is that 53.4% of the amniocentesis\ngroup and only 34.9% of the controls were over the\nage of 35 years.\nThe follow-up included neonatal\nand one-year examinations of the children who were\nthe outcome of these pregnancies.\nThe most important finding was that fetal loss\n(spontaneous abortion and stillbirth) for the amnio-\ncentesis group was 3.5% (36 cases) and for the con-\ntrol group 3.2% (32 cases) a statistically insignificant\ndifference.\nFurther no significant difference was\nnoted in the instance of congenital malformations,\nnot detected by amniocentesis, neonatal illness, or\ndevelopment at 1 year of age.\nData are not given\non the incidence of Rhesus sensitization in the two\ngroups.\nThe overall accuracy of this screening\nprocedure is said to be 99%.\nNevertheless two\nnegative misdiagnoses\nare reported, two infants\nborn with Down's syndrome after they had been\nfound to be normal on prenatal screening, and one\npositive misdiagnosis, galactosaemia in a child who\nat birth was found to be normal.\nFetal sex was in-\ncorrectly assigned in three instances.\nThe findings\nare to be published in full in a monograph from the\nNational Institute of Child Health and Human\nDevelopment."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 925
encoding: FLOAT32
metadata:
{"title": "Annotation Risks of miscarriage after amniocentesis", "chroma:document": "It should be emphasized that these are the results\nof one, presumably selected, group of centres.\nIn\nthese centres, at least Dr Milunsky estimates, the\nrisk of abortion as a result of amniocentesis is pro-\nbably not more than 0.5%.\nThe findings of the\nMRC trial have not been published yet, but are\nawaited with interest.\n351"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 926
encoding: FLOAT32
metadata:
{"title": "Case Reports", "chroma:document": "Case Reports\nJournal of Medical Genetics (1976).\n13, 400-412.\nAntenatal diagnosis of trisomy 13\nwith unexpected increase in alpha-\nfeto protein\nSummary.\nA\n24-year-old\nwoman\nwho had previously given birth to an\ninfant with Down's syndrome was shown\nby chromosomal analysis of the liquor\namnii\nto be carrying\nan infant with\ntrisomy\nD.\nRoutine\nexamination\nof\nserum\nand\nliquor\nalpha-feto\nprotein\n(AFP) in the antenatal period showed\nunexpected high\nlevels of both,\ncon-\nsistent with a neural tube defect.\nThe\nfetus, however, did not have evidence of\na neural tube defect but had scalp defects\nwhich were presumed to have allowed\nthe leakage of AFP from the fetus into\nthe liquor amnii and hence into the\nmaternal serum.\nCase report\nThis 24-year-old woman had her first infant, a female,\nwith classical Down's syndrome, in 1971.\nAt that time\nshe was 20 years old and her husband 24 years old.\nThe\ninfant's karyotype was 46, XX +21 and mother and\nfather had normal karyotypes.\nA second pregnancy in\n1972\nwas\nterminated\nat nine weeks\non\npsychiatric\ngrounds.\nShe became pregnant for the third time in\nSeptember 1974 and was referred for amniocentesis on\n15 January 1975.\nShe was in good\ngeneral\nhealth.\nHer blood group was Rhesus positive and she had no\nhistory of hepatitis\nor thyroid\ndisease.\nSubsequent\nscreening for thyroid antibodies was negative, and her\nserum complement was normal as were her immuno-\nglobulins.\nThere was no family history of aneuploidy\nin her relatives or in those of her husband.\nLiquor amnii was obtained without difficulty and\nunexpectedly showed an increased AFP level of 70 ug/ml\n(radioimmunoassay technique; normal upper limits 40\nto 45 ,g/ml).\nA simultaneous check at another labora-\ntory by\na\ndifferent method\n(single\nradial immuno-\ndiffusion)\nconfirmed\nthe\nraised\nlevel.\nCytogenetic\nstudies on the liquor specimen showed the presence of a\nfetus with trisomy D abnormality.\nThe mother was\ntherefore offered termination, and this was performed at\n20 weeks' gestation.\nA further specimen of liquor ob-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 927
encoding: FLOAT32
metadata:
{"title": "Case Reports", "chroma:document": "tained before induction, and while the fetus was still alive,\nshowed that the AFP was still raised, 68 jug/ml in the\nliquor; 187 ng/ml in the serum.\nNecropsy\nExternal features.\nThe fetus was female, weighing\n240 g (Fig.\n1).\nAt the vertex of the skull there was an\narea of translucent, very thin skin, approximately 3 x 1\ncm, the histological appearance of which is shown in\nFig. 2.\nThere was a similar smaller defect near the posterior\nfontanelle.\nThere was micrognathia, low set ears, a\ncleft palate, and polydactyly.\nCNS.\nThe brain weighed 40 g and showed no gross\nabnormality.\nThe\noptic and\nolfactory\nnerves\nwere\nnormal.\nThorax.\nThere\nwas\nanomalous\nvenous\ndrainage\nwith a small high ventricular septal defect.\nAbdomen.\nA Meckel's diverticulum was present.\nThe uterus was bicomuate with a single cervix.\nThe\nright umbilical artery was absent.\nAll other organs\nappeared normal on macroscopical and microscopical\nexamination.\nThe position of the scalp defects and their character-\nistics were similar to those previously described\nin\ninfants with trisomy 13.\nSubsequent fibroblast culture\nfrom the fetus confirmed trisomy 13.\nOne month after\n00o"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 928
encoding: FLOAT32
metadata:
{"title": "Pyloric stenosis in the Oxford Record Linkage Study Area", "chroma:document": "journal of Medical Genetics (1976).\n13, 439-448.\nPyloric stenosis in the\nOxford Record Linkage Study Area\nPHILIPPA ADELSTEIN and JEAN FEDRICK\nFrom the Unit of Clinical Epidemiology, Department of the Regius Professor of Medicine, University of Oxford\nSummary.\nThe files of the Oxford Record Linkage Study were employed to\nidentify 220 infants presenting with infantile hypertrophic pyloric stenosis (IHPS)\nin the 6-year period 1966 to 1971.\nInformation on these infants was obtained from\nbirth certificates and maternity notes.\nThe overall incidence was 2.5 per 1000 live-\nbirths.\nThere was a distinct seasonal variation, with highest incidence to infants\nborn in the third quarter of the year as well as variation in incidence with area: the\ncities had much lower rates of IHPS than the adjacent rural or small urban areas.\nIt was shown that the rates in the south and east ofthe area studied were far greater\nthan in the north and west.\nIn the present study there was no excess of primiparae, the peak maternal age\ngroup was 20 to 24; there was a slight excess of parents of social classes I and II;\nand a significant association with mothers who were Rhesus negative.\nThe rate of\nIHPS among sibs was 85 per 1000.\nThough there was the usual correlation with\nthe male sex (M: F ratio = 5.5: 1), there was no variation with birthweight and only\namong the females was an association found with prolonged gestation.\nThere\nappeared to be an inverse relation between gestation and age on admission to\nhospital.\nThe disease of infantile hypertrophic pyloric\nstenosis (IHPS) has become so amenable to present\nmethods of treatment that there have been relatively\nfew studies designed to elucidate the causes of the\ndisorder.\nOne of the major drawbacks to any study\nof this kind is that the condition generally manifests\nitself after discharge from maternity hospital. Thus\nany information on factors connected with the rele-\nvant pregnancy and social background must either\nbe obtained from retrospective inquiry ofthe mother"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 929
encoding: FLOAT32
metadata:
{"title": "Pyloric stenosis in the Oxford Record Linkage Study Area", "chroma:document": "or from a procedure oflinking with the records from\nthe relevant maternity hospital or domiciliary mid-\nwife.\nThe problem, too, of obtaining an unbiased\ncontrol population can often be extremely time con-\nsuming.\nThe present study has the advantage of\nemploying the data banks of the Oxford Record\nLinkage Study and in a sense may be considered to\nbe prospective.\nPyloric stenosis had been described in the medical\nreports of the 18th century (Blair, 1717; Weber,\nReceived 26 January 1976.\n1758; Armstrong, 1777), but was first recognized as\na clinical syndrome after a description of 5 cases by\nHirschsprung (1888) in Copenhagen.\nAt the turn of\nthe century several types of surgical procedure were\nattempted with varying degrees of success, until in\n1912 Rammstedt developed a very simple procedure\nwhich has remained one of the most satisfactory\nsurgical operations to this day, with an extremely\nlow associated mortality.\nNevertheless there are a\nfew paediatricians who still prefer management by\nmedical means.\nThe\nincidence\nwithin\nthe\nBritish\nIsles\nhas\ngenerally been reported as of the order of 2 to 3 per\n1000 livebirths (Table I).\nThe only other European\nareas recorded as having incidences ofover 1 per 1000\nareGothenburgin Sweden and BudapestinHungary.\nThe rate in the southern countries of Europe is ap-\nparently very low.\nThe one study from Malta\n(Cachia and Fenech, 1966) suggested that the rate\nthere was as high as 0.9 because of the inter-\nmingling of races resulting from the presence of\nBritish servicemen on the island.\nIn the middle-\n'39"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 930
encoding: FLOAT32
metadata:
{"title": "Heterozygote advantage for the phenylketonuria allele", "chroma:document": "Journal of Medical Genetics, 1977, 14, 20-24\nHeterozygote advantage for the\nphenylketonuria allele\nLETTEN FEGERSTEN SAUGSTAD\nVestheimgt. 6, Oslo 2, Norway\nSUMMARY\nMean weight at birth of unaffected (normal homozygous and PKU heterozygous)\noffspring of parents heterozygous for the phenylketonuria (PKU) allele averages significantly\nabove that of Norwegian neonates, with no significant difference in mean age of mothers or in mean\nparity. It approaches the optimal birthweight-that which confers the minimum overall mortality\nin the pre-, peri-, and postnatal periods. This near-optimal birthweight together with the possibly\nhigher effective fertility observed in PKU heterozygous couples (at least in those who married\nbefore 1940), has apparently more than outweighed the disadvantages of the allelele in PKU\nhomozygous offspring as shown, for example, in an excessive number of pre- and perinatal deaths\namong the total offspring of PKU heterozygotes, to say nothing of the PKU survivors who, often,\nused to die young. The two effects-fertility and viability-apparently both contribute in the same\ndirection, to give a biological fitness in excess of 1 for the heterozygote. This heterozygote advantage\npresumably explains the presence of the allele at frequencies above those to be expected from the\nsimple replacement of a homozygously-lethal allele by mutation alone.\nThe prevalence at birth of recessive disorders\nis\naffected inter alia by changes in inbreeding level and\nby any\nselective advantage\nin the heterozygous\ncarrier. Heterozygote advantage has been observed\nin man in sickle-cell anaemia and possibly in some\nother disorders (see Motulsky,\n1974; Stuart and\nBurdon, 1974).\nEvidence is presented for the view that heterozy-\ngosity for the phenylketonuria (PKU) allele is ad-\nvantageous in parents by rendering their unaffected\noffspring more viable at birth, thereby improving the\nchance of survival of the allele.\nMaterial and methods\nThe mortality rate (incorporating the stillbirth rate)"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 931
encoding: FLOAT32
metadata:
{"title": "Heterozygote advantage for the phenylketonuria allele", "chroma:document": "for infants before 1 month of age is lowest among\nthose with birthweights at a point somewhat above\nthe mean (Karn and Penrose, 1951; Fraccaro, 1955;\nRantakallio, 1968). This is also the case in regard to\nall\nbirths\nin Norway\n1967-1968\n(Bjerkedal and\nBakketeig, 1972). There, the rate is lowest for birth-\nweights in the neighbourhood of 4500 g (males), or\n4000 g (females): while the average birthweight was\n3512 g for males and 3391 g for females (Table 1).\nReceived for publication 12 March 1976\nThe chances for further survival to\n1 year of age\nappeared to be best for neonates of either sex that\nhad a weight at birth of approximately 4500 g.\nWeights at birth of children with PKU born in\nNorway between 1940 and 1973 and of their non-\nPKU sibs were investigated, using the information in\nthe maternity hospitals (Saugstad, 1972). Controls\nwere all births in Norway between January 1967 and\nJanuary 1969 from the Medical Registration of\nBirths (T. Bjerkedal, 1973, personal communication),\nwhich is based on forms completed on the ninth day\nof life.\nThe number of pregnancies (including abortions\nand pre- and perinatal deaths) of the heterozygous\nmothers with PKU offspring were also investigated\nand compared with a control series of 230 non-\nprimiparous women, of unknown heterozygosity for\nPKU, consecutively admitted for delivery in Oslo in\n1967. In addition, the numbers of liveborn offspring\nin 36 families with PKU offspring born in Norway\nbefore 1940 were investigated (Saugstad,\n1975a).\nThe late Asbjorn F0lling kindly supplied information\non 22 of the 36 families diagnosed by him in 1932 to\n1938 inclusive (F0lling et al., 1944). The remaining 14\nof the 36 families were investigated by the present\nauthor 1968 to 1971, when the reproductive histories\n20"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 932
encoding: FLOAT32
metadata:
{"title": "Partial trisomy 7p associated with familial 7p;22q translocation", "chroma:document": "Journal ofMedical Genetics, 1977, 14, 258-261\nPartial trisomy 7p associated with familial 7p;22q\ntranslocation\nLINDA M. LARSON, WALTER A. WASDAHL, AND SYED M. JALAL\nFrom the Department ofPathology, The Medical School; University ofNorth Dakota, and the Department of\nBiology, University ofNorth Dakota, Grand Forks, North Dakota, U.S.A.\nSUMMARY\nA newly described partial trisomy of the short arm of chromosome number 7 is reported\nin a familial translocation between 7 and 22. The unbalanced translocation was found in one family\nmember, the propositus, and the balanced form in 5 other members. The possibility of this trans-\nlocation being a rare telomeric attachment previously undescribed in humans is discussed. Prominent\nclinical features include general mental and motor retardation, microbrachycephaly, and cardiac and\noral abnormalities.\nThe advent of various banding techniques, parti-\ncularly G banding, has enabled the accurate identi-\nfication of several minute structural alterations in the\nlast few years. Described here is onesuch case inwhich\na small portion of the short arm of number 7 was\ntranslocated to the long arm of chromosome number\n22. This is one of the first reported cases involving\npartial trisomy of the short arm of chromosome 7.\nFamilial studies of this condition have shown 5\nbalanced carriers and\n1\naffected individual in 3\ngenerations. The propositus was a 15-month-old boy\nwith general mental and motor retardation. Physical\nabnormalities\nincluded high\npalate,\nsplit\nuvula,\nmicrobrachycephaly,\nand\nincreased\ntransillumi-\nnation of the frontal area of the skull.\nCase reports\nCASE IV.1\nThe propositus (Fig. 1) was the product of the first\npregnancy of an 18-year-old mother and a 22-year-\nold father who were not related. At birth he weighed\n2951 g and was 47 cm in length.\nAt 2 months of age a grade 2 systolic murmur was\nheard at the apex of the heart and it was noted that he\nhad low set ears and a small mandible. At 15 months\nof age he was referred.for chromosomal analysis"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 933
encoding: FLOAT32
metadata:
{"title": "Partial trisomy 7p associated with familial 7p;22q translocation", "chroma:document": "because of his very retarded mental and motor\ndevelopment and congenital heart abnormalities.\nAt this time physical examination showed weight\nand height in the third centile and head circumference\nin less than the third centile. Appetite and weight\nReceived for publication 17 August 1976\nwere poor from birth and he tired easily. His diet had\nbeen mostly milk and few solids. There was increased\nperspiration around the head and neck. He did not\nsmile, roll over, sit up, pull up, or stand but was able\nto move his hand to his mouth. Other abnormalities\nincluded high broad palate,\nspilt\nuvula, micro-\nbrachycephaly, and increased transillumination of\nthe frontal area of the skull. Heart abnormalities at\nthis time revealed a normal first sound and a second\nsound that was\nsplit, with accentuation of the\npulmonary closure. There was a grade 3/6 ejection\nmurmur along the upper left sternal border trans-\nmitted into the lungs and a third heart sound along\nthe left sternal border followed by a grade 3 diastolic\nmurmur.\nElectrocardiogram and echocardiogram revealed a\ncomplete form of atrioventricular canal and evidence\nof right ventricular hypertrophy without left ventri-\ncular hypertrophy. Radiographs showed an enlarged\nthymus and heart. An EMI scan showed hypoplasia\nor atrophy of the brain with a dilated ventricular\nsystem and enlarged subarachnoid spaces.\nResults of laboratory tests for sweat chloride, total\nthyroxine, and serum calcium were normal. Exami-\nnation of urine was negative. Haemoglobin was 10-5\ng/dl and cellular morphology of peripheral blood\nshowed hypochromia and microcytosis, suggestive\nof chronic iron deficiency anaemia.\nCASE iii.3\nThe father of the propositus was phenotypically\nnormal and in general good health. He was a high\nschool graduate and self-employed farmer.\n258"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 934
encoding: FLOAT32
metadata:
{"title": "Annotation Mendelian inheritance or transmissible ag4 lesson of Kuru and the Australia antigen", "chroma:document": "Journal of Medical\nAnnotation\nMendelian inheritance or transmissible ag4\nlesson of Kuru and the Australia antigen\nPETER S. HARPER\nFrom the Department ofMedicine, Welsh National School of Medicine, Heath Park, Cardiff\nThe award of the 1976 Nobel prize in medicine to the\ndiscoverers of two major forms of transmissible\ndisease-Kuru and the Australia antigen in relation\nto hepatitis-might seem at first sight to be unrelated\nto medical genetics. Yet not only was one of the\nlaureates, Baruch S. Blumberg, trained as a geneticist,\nand the Australia antigen originally believed to be a\ngenetically determined serum protein system, but\nKuru itself and some other non-tropical encephalo-\npathies, now known to have a related aetiology,\nwere originally considered to have a hereditary basis.\nThe development of concepts in these two parallel\nfields is of great interest in its own right, but for medi-\ncal geneticists it is ofparticularrelevance, since it raises\na number of questions which may have much wider\nsignificance. May other disorders now thought to be\ngenetically determined prove in reality to be infectious\ndiseases? May transmissible agents be closely in-\nvolved in determining the action of specific genes in\nproducing disease? It is worth looking critically at\nsome of the conditions where Mendelian inheritance\nhas been assumed to be the basis for familial aggre-\ngation in the light of what has happened to our ideas\non the aetiology of Kuru and the Australia antigen.\nKuru\nThe fascinating story of the discovery and epidemio-\nlogical documentation of Kuru, and the steps which\nled to the suspicion and elucidation ofa transmissible\nviral agent as its basis, have been lucidly told in a\nseries of publications by Gajdusek and his colleagues\nover the past 20 years (Gajdusek and Zigas, 1957,\n1959; Gajdusek et al., 1966; Gajdusek, 1973, 1977).\nThe points of special interest to us here are threefold.\nWhy was a hereditary basis ofthe disorder considered\npossible initially? Why was this explanation found"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 935
encoding: FLOAT32
metadata:
{"title": "Annotation Mendelian inheritance or transmissible ag4 lesson of Kuru and the Australia antigen", "chroma:document": "inadequate, and an infective agent suspected? Is\nthere indeed a hereditary basis for susceptibility to\nthe disease ?\nKuru, a subacute, progressive, and invariably fatal\nReceived for publication 9 May 1977\nneurological degeneration, is and appears always to\nhave been confined to a localised area of the New\nGuinea highlands, occupied by the Fore people.\nGajdusek and Zigas\nfirst\ndescribed\nthe\nclinical\nfeatures in 1957, and\nit was soon clear that the\ndisease was unique both clinically and epidemiolo-\ngically.\nA genetic basis for Kuru was proposed on the basis\nof its restriction to a particular tribal group and\nnotable familial aggregation, with vertical trans-\nmission from generation to generation. Gajdusek\nand Zigas' original paper concludes:\n'The peculiar sex and age distribution of cases, the\nhigh familial prevalence in a closely intermarried\ncommunity, the phenomenon of anticipation (with\ncases occurring in an earlier age in the second\ngeneration) and occasional\nfamily histories\nin\nwhich several siblings had died of the disease on\nreaching approximately the same age, along with\nthe type of clinical picture that the disease presents\nall support the suspicion that strong genetic factors\nare operating in the pathogenesis. . .'\nGajdusek and Zigas (1957).\nThe genetic basis of Kuru was elaborated by Gaj-\ndusek and Zigas (1959) and by Bennett et al. (1959)\nand postulated an autosomal gene, fully penetrant\nin the heterozygous female, but rarely in the male\nunless present in homozygous state. Affected children\nwere considered to be homozygotes. Closer study,\nhowever, showed discrepancies which were hard to\nreconcile with Mendelian inheritance: though the\nKuru region was a sharply localised one the inhabi-\ntants\nwere\nheterogeneous,\nshowing\nno\nspecial\nlinguistic or physical differences from adjacent areas\nfree of the disease; furthermore the disease was of\nrelatively recent occurrence in the area, having shown\na rapid spread over a period of half a century, and\nsubsequently an equally dramatic decline, too rapid"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 936
encoding: FLOAT32
metadata:
{"title": "Annotation Mendelian inheritance or transmissible ag4 lesson of Kuru and the Australia antigen", "chroma:document": "to be explained on a purely genetic basis. The sex\nratio, though equal in children, showed a distinct\nfemale preponderance\nin adults, while in adults\nconjugal cases were frequent.\n389"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 937
encoding: FLOAT32
metadata:
{"title": "A 'new' syndrome of mental retardation with characteristic facies and brachyphalangy", "chroma:document": "Journal ofMedical Genetics, 1977, 14, 430-437\nA 'new' syndrome of mental retardation with\ncharacteristic facies and brachyphalangy\nALASDAIR G. W. HUNTER, PHYLLIS\nJ. McALPINE, NOREEN L. RUDD,\nAND F. CLARKE FRASER\nFrom the Division of Genetics, Department ofPediatrics, University ofManitoba and Health Sciences\nCentre, Winnipeg, Manitoba; the Department ofGenetics, Hospitalfor Sick Children, Toronto, Ontario; and\nthe Department ofMedical Genetics, The Montreal Children's Hospital, Montreal, Quebec, Canada\nSUMMARY\nThis paper describes 6 individuals, occurring in 3 generations of a single family, who were\naffected by a distinct syndrome which included: retardation and microcephaly; a small oval face with\nalmond-shaped eyes, droopy eyelids, a small nose, and small downturned mouth; minor acral skeletal\nanomalies, and short stature. Craniosynostosis, heart defects, and limited elbow extension were seen\nless frequently. Expression was variable and parents who were in the direct vertical line of trans-\nmission of the syndrome showed few, if any, overt signs of the disease. However, the metacarpal/\nphalangeal profile of the parents showed a similar pattern to that seen in the affected individuals, and\nit is suggested that this profile may be the most sensitive indicator of carrier status.\nIt is important to distinguish, within the hetero-\ngeneous category of 'mental retardation', those cases\nwith specific syndromes, so that the families con-\ncerned can be advised more accurately about the\nprognosis, both medical and genetic. This paper\ndescribes a new familial syndrome appearing in 6\nindividuals over 3 generations, whose major features\ninclude: retardation of varying severity, a charac-\nteristic facies, and minor acral skeletal anomalies with\na characteristic pattern of phalangeal shortness. The\ndistribution of this syndrome in this kindred\nis\nReceived for publication 7 March 1977\ncompatible with autosomal dominant inheritance\nwith reduced penetrance.\nFamily history\nThe family was of British extraction, and was"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 938
encoding: FLOAT32
metadata:
{"title": "A 'new' syndrome of mental retardation with characteristic facies and brachyphalangy", "chroma:document": "ascertained independently through a girl in Montreal\n(Fig. 1, V.14), and a boy in Toronto (Fig. 1, V.1) who\nwas studied as part of a project on craniosynostosis\n(Family 9, Hunter and Rudd, 1977). The probands\nwere third cousins. There was considerable variation\nin severity of expression of the syndrome among the\nsix retarded individuals, and all parents of affected\npersons were of normal intelligence.\nII\nIII\nIV\nV\nVI\nFig. 1\nPedigree offamily\n430\nI"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 939
encoding: FLOAT32
metadata:
{"title": "Linkage studies Van syndromel", "chroma:document": "Journal ofMedical Genetics, 1978, 15, 217-218\nLinkage studies in Van der Woude syndromel\nJOHN RUSSELL EASTMAN, DAVID BIXLER, AND VICTOR ESCOBAR\nFrom the Departments ofOral-Facial Genetics and Medical Genetics, Indiana University School ofMedicine,\nIndianapolis, Indiana 46202, U.SA.\nSUMMARY\nA newly ascertained kindred segregating Van der Woude syndrome through four\ngenerations is described. Linkage studies using the methods of Ott (1974) were carried out using 19\nmarker loci.\nVan der Woude syndrome has 3 primary manifes-\ntations: (a) bilateral lower lip pits, (b) cleft lip with or\nwithout palate, or (c) isolated cleft palate (Van der\nWoude, 1954; Cervenka et al., 1967). The disease\nentity segregates as an autosomal dominant trait with\n70 to 80% penetrance (Van der Woude, 1954; Gorlin\nand Pindborg, 1964; Cervenka et al., 1967). Variable\ngene expression was shown by Cervenka et al. (1967)\nwho observed\nlip\npits\nin 69.6% of obligate gene\ncarriers but facial clefts in only 36% of the cases.\nCongenital absence of second premolars has also been\nreported in association with Van der Woude syndrome\n(Schneider,\n1973). A\nsingle\npreviously\npublished\nlinkage study involving this syndrome observed no\nlinkage with 13 marker loci. Unfortunately no lod\nscores were published (Schneider, 1973).\nIn the present study, linkage analysis was perfor-\nmed on a previously unreported family in which Van\nder Woude syndrome was segregating.\nSubjects and methods\nA phenotypic\ndescription of each family member\nexamined is given in the Fig. Blood group pheno-\ntyping\nin\nthis family involved the ABO, Rhesus,\nMNSs, Kidd, Kell, Duffy, and P traits. Haptoglobin\nwas determined from serum. Erythrocytes were used\nin\ndetermining\nphosphoglucomutase,\nacid\nphos-\nphatase,\n6-phosphogluconate\ndehydrogenase,\nand\nadenosine deaminase. Parotid saliva was used to deter-\nmine amylase1, PA, PB, PR, and DB phenotypes. The\namylase2 phenotype was obtained from urine and the\nability to taste phenylthiocarbamide (PTC) was also\nevaluated\nwith\nPTC\nsolutions\nto\nvarying\ncon-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 940
encoding: FLOAT32
metadata:
{"title": "Linkage studies Van syndromel", "chroma:document": "con-\ncentrations.\n'This is publication number 77-12 from the Department of Medical Genetics\nand was supported in part by the Human Genetics Center Grant PHS GM\n21054 and the Oral-Facial Genetics Training Grant T22 DE 00007.\nReceived for publication 23 August 1977\nTable\nLod scoresfor linkage with Van der Woude\nsyndrome: male andfemale scores combined\n0o10\n0.20\n0.30\n0.40\n050\nABO\n-0 19\n0-04\n0.07\n0.03\n0 00\nRh\n0-84\n0-52\n0-26\n0.06\n0-00\nMNS\n-1-16\n-0-63\n-0-30\n-0-11\n0-00\nKidd\n0-22\n0-13\n0-07\n0-02\n0-00\nKell\n-0-03\n-003\n-0-03\n-0-02\n0-00\nDuffy\n0-03\n0-14\n0-13\n0-07\n0.00\np\n-0-12\n-0-05\n-0-01\n0-00\n0-00\nHp\n0-41\n0-29\n0-18\n0.08\n0-00\nPGM,\n-0-56\n-0-24\n-0.11\n-0.04\n0-00\nACP\n0-30\n0.20\n0-11\n0-04\n0-00\n6GPD\n0.01\n0-00\n0-00\n0-00\n0.00\nADA\n0.01\n0-01\n0-00\n0.00\n0.00\nAMY,\n0.00\n0-00\n0-00\n0.00\n0-00\nPA\n0.05\n0.07\n0.04\n0.01\n0-00\nPB\n0.00\n0-00\n0-00\n0-00\n0-00\nPR\n0-10\n0.19\n0-13\n0-05\n0.00\nDB\n0-29\n0.23\n0-16\n0.08\n0.00\nAMY2\n0.01\n0.01\n0.00\n0.00\n0.00\nPTC\n0-31\n0.22\n0-13\n0-06\n0-00\nComputation of the likelihood and lod scores for\nvarious recombination fractions was done by com-\nputer analysis for each of the marker loci using a\nrecently\navailable\nprogramme\n(Ott,\n1974)\nwhich\ncomputes the likelihood of linkage recursively,\nas\nproposed by Elston and Stewart (1971), starting with\nthe more recent generation and working back into the\npedigree.\nResults\nThe lod scores for various recombination fractions are\ngiven for each locus analysed in the Table.\nDiscussion\nThe results indicate that close linkage of Van der\nWoude syndrome with any of the tested marker loci is\nunlikely. Because of the small number of individuals\ninvolved in the present study further investigations of\n217"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 941
encoding: FLOAT32
metadata:
{"title": "Linkage analysis dominant acrocephalosyndactyly 1", "chroma:document": "Journal ofMedical Genetics, 1978, 15, 292-293\nLinkage analysis in dominant\nacrocephalosyndactyly 1\nJOHN RUSSELL EASTMAN, VICTOR ESCOBAR, AND DAVID BIXLER\nFrom The Departments ofOral-Facial Genetics and Medical Genetics, Indiana University School ofMedicine,\nIndianapolis, Indiana 46202, USA\nSUMMARY\nLinkage analysis was performed on a previously reported family in which multiple\ndominantly inherited acrocephalosyndactyly syndromes were present. An underlying axiom of linkage\nanalysis is that the trait analysed be monogenic. This prerequisite was presumptively established in the\nsingle kindred analysed because acrocephalosyndactyly was observed in multiple cases in multiple\ngenerations.\nThe acrocephalosyndactylies (ACS) are a clinically\nsimilar\ngroup\nof disorders\nmanifesting\npremature\ncraniosynostosis and varying degrees of brachydac-\ntyly and syndactyly (McKusick, 1975; Gorlin et al.,\n1976). McKusick (1975) most recently listed 4 types\nof ACS, Pfeiffer, Apert, Chotzen, and Vogt, all of\nwhich are dominantly inherited. The distinctness of\nthese categories has, however, been questioned by 2\nlines\nof evidence.\nFirstly,\nit\nhas\nbeen\nsuggested\n(Degenhardt, 1950) that Pfeiffer and Apert syndromes\ninvolve the same gene defect based upon close clinical\nsimilarity. That this is a viable possibility is shown by\nEscobar and Bixler (1977a,b), who documented Apert,\nPfeiffer,\nand\ntransitional\nphenotypes\nin\nmultiple\ngenerations of a single family. Additionally, 2 other\nfamilies have been reported in which multiple ACS\ntypes have been found in the same family (Robinow\nand Sorauf 1975; Jackson et al., 1976). Secondly,\nEscobar and Bixler (1977a) have recently reported a\nunique\nmetacarpophalangeal\npattern\nprofile which\ndiscriminates\n2 ACS types (Pfeiffer and Chotzen)\nfrom normal individuals, but not from each other.\nAlthough most investigators consider the dominan-\ntly\ninherited ACS syndromes\nto be the result of\ndifferent (though possibly\nallelic) genes, the above\nevidence raises a second possibility; this being that the"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 942
encoding: FLOAT32
metadata:
{"title": "Linkage analysis dominant acrocephalosyndactyly 1", "chroma:document": "multiple ACS phenotypes are the result of a single\ngene with a highly variable expression. This hypothesis\nis testable by performing linkage analysis on infor-\nmative families, that is, those previously mentioned\nwhich show multiple ACS types segregating within a\nsingle kindred. This paper gives the results of such an\n'This is publication number 77-50 from the Department of Medical Genetics,\nand was supported in part by the Human Genetics Center Grant PHS GM\n21054, and the Oral-Facial Genetics Training Grant T22 DE 00007.\nReceived for publication 23 August 1977\nanalysis performed on the family previously charac-\nterised both phenotypically and radiographically by\nEscobar and Bixler (1977a,b).\nMethods and materials\nThe family involved\nin this analysis\n(Fig.\n1) was\nascertained in the Department of Medical Genetics\nthrough\na\nproband\ndiagnosed\nas\nhaving\nPfeiffer\nsyndrome.\nDetailed\nphenotypic\nfindings\nfor\neach\nfamily\nmember\nhave\nbeen\npreviously\npublished\n(Escobar and Bixler, 1977b).\nThe marker loci employed in this analysis included\n7 blood groups: ABO, Rhesus, MNSs, Kidd, Kell,\nDuffy, and P traits. Three other traits were hapto-\nglobin, determined from serum, and the red blood cell\nenzymes phosphoglucomutase and acid phosphatase.\nComputation of the likelihood and lod scores for\nvarious recombination fractions was done for each of\nprogramme (Ott, 1974). This programme computes\nthe likelihood of linkage recursively,\nas proposed\nby\nElston and\nStewart\n(1971),\nstarting\nwith\nthe\nmore recent generation and working back into the\npedigree.\nResults\nThe lod scores for various recombination fractions are\ngiven in the Table for each locus analysed.\nDiscussion\nThe\nresults shown\nin the Table indicate that the\nhypothesised single gene resulting in the dominantly\n292"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 943
encoding: FLOAT32
metadata:
{"title": "X-Y translocation in retarded phenotypic male", "chroma:document": "Journal ofMedical Genetics, 1978, 15, 466-474\nX-Y translocation in a retarded phenotypic\nmale\nClinical, cytogenetic, biochemical, and serogenetic studies\nRENtE BERNSTEIN, JOAN WAGNER, JOY ISDALE, G. T. NURSE, A. B. LANE,\nAND TREFOR JENKINS\nFrom the Department ofHuman Genetics, School ofPathology, The South African Institutefor Medical\nResearch and University ofthe Witwatersrand, Johannesburg; and the Departments ofPaediatrics and\nRadiology, University ofthe Witwatersrand, Johannesburg\nSUMMARY\nCytogenetic studies on a mentally retarded boy revealed an X-Y translocation, karyotype\n46,X,t(X;Y)(p22;ql 1). Only 5 other such cases have been reported and these were all females. The\nunequivocal male phenotype suggested non-random inactivation of the normal maternally derived X\nchromosome, and that the non-inactivated X-Y translocation chromosome included the locus for male\ndetermination. Confirmation of this was provided by unassociated X and Y chromatin in interphase\ncells, as well as by reverse banding after BrdU incorporation and autoradiography of metaphase\nchromosomes. There was anomalous Xg blood group inheritance in the proband, indicating possible\nlocalisation of the Xg locus to the terminal portion of the X short arm. Linkage of Xg and a form of\nX-linked mental retardation is suggested. Close linkage of the Xg locus with the loci for aPgalactos-\nidase, phosphoglycerate kinase, G-6-PD, and MPS II was excluded.\nCytologically\nidentifiable\ntranslocation\nof\nthe Y\nchromosome to the X chromosome has been reported\nvery rarely (Khudr et al., 1973; Borgaonkar et al.,\n1974; Van den Berghe et al., 1977). In all instances\nwhere there was no free-lying Y chromosome, the\npatients were phenotypic females. Two XX males with\npresumptive morphological evidence of a Y to X\ntranslocation have also been documented (Madan and\nWalker, 1974; Wachtel et al., 1976).\nWe wish to report the investigation of a mentally\nretarded child with a morphologically identified X-Y\ntranslocation and an unequivocally male phenotype.\nThis\npatient\nafforded"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 944
encoding: FLOAT32
metadata:
{"title": "X-Y translocation in retarded phenotypic male", "chroma:document": "afforded\na valuable\nopportunity\nfor\nstudying the pattern ofX inactivation in such cases, as\nwell as the location of the male determining genes of\nthe Y chromosome, and the linkage of genes possibly\nlocated on the distal portion of the short arm of the X\nchromosome, including the Xg locus.\nCase report\nThe proband was first referred at the age of 4 years for\ninvestigation of severe mental retardation associated\nReceived for publication 23 January 1978\nwith\nskeletal\nabnormalities\nand short\nstature. He\nweighed 2.3 kg at birth, and was delivered normally at\nterm after a pregnancy uneventful except for a slight\nshow of blood at 16 weeks. The mother gave no\nhistory of stillbirths or miscarriages at any time, or of\ninfection, drug ingestion, or irradiation during preg-\nnancy. She had an ovarian cyst removed 3 months\nbefore conception. The parents were unrelated and of\nnormal intelligence. The father was aged 26 and the\nmother 23 years at the time of birth of the proband,\nwho was 3 years younger than his phenotypically\nnormal\nbrother.\nThe\nfamily\nhistory\nwas\nnon-\ncontributory, except that the father's sister was said to\nhave\na\nson\nsuffering from hyperactivity,\nslurred\nspeech, and incoordination of eye movements. The\nfather's height was 165 cm and his parents and sister\nwere also short in stature.\nLimitation of elbow movements was noted in the\nproband shortly after birth. His physical and mental\ndevelopment was slow and all his milestones were\ndelayed. He first smiled and lifted his head between 4\nand 6 months old, never crawled, presumably because\nof his upper limb abnormalities, and first walked un-\nassisted when nearly 4 years old. At 5 he still was not\n466"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 945
encoding: FLOAT32
metadata:
{"title": "Pain-related evoked potentials in cortical reflex myoclonus", "chroma:document": "Journal of Neurology, Neurosurgery, and Psychiatry 1990;53:44-48\nPain-related somatosensory evoked potentials in\ncortical reflex myoclonus\nRyusuke Kakigi, Hiroshi Shibasaki, Ryuji Neshige, Akio Ikeda, Kousuke Mamiya,\nYasuo Kuroda\nAbstract\nTo elucidate the sensitivity to pain stimuli\nin\npatients with\ncortical\nreflex myo-\nclonus,\npain-related\nsomatosensory\nevoked potentials (pain SEPs) following\nCO2 laser stimulation and conventional\nelectrically-stimulated\nSEPs\n(electric\nSEPs) were compared in four patients\nwith cortical reflex myoclonus. The P25\npeak of electric SEPs was considerably\nenhanced but the P320 potential of pain\nSEPs was of normal amplitude in all\npatients. After medication, myoclonus\nwas reduced and the amplitude ofP25 was\ndecreased, but P320 showed no change. In\nour previous study of the scalp distribu-\ntion in normal subjects, a subcortical site,\nprobably the thalamus, was considered to\nbe the generator source of P320. Because\nmost pain stimuli do not reach the cortex,\npatients with cortical reflex myoclonus\nare not sensitive to pain stimuli and P320\nin pain SEPs is not enhanced.\nDepartment of\nInternal Medicine,\nSaga Medical School,\nNabeshima,\nSaga City 840-01,\nJapan\nR Kakigi\nH Shibasaki*\nR Neshige\nA Ikeda,\nK Mamiya,\nY Kuroda\n*Present address: National\nInstitute of Neuroscience,\nNational Centre of\nNeurology and Psychiatry,\nKodaira City, Tokyo 187,\nJapan\nCorrespondence to:\nDr Ryusuke Kakigi,\nDepartment of Internal\nMedicine,\nSaga Medical School,\nNabeshima, Saga City,\n840-01, Japan\nReceived 31 March 1989.\nAccepted 10 July 1989\nThere is a general concept that cortical reflex\nmyoclonus'\nis\ninduced\nmainly\nby\nmuscle\nstretch, touch or pressure.25 This is compatible\nwith the facts\nthat\ncortical components of\nelectrically-stimulated somatosensory evoked\npotentials (electric SEPs), which are generated\nin the sensorimotor cortex as a result of as-\ncending signals mediated through large mye-\nlinated\nfibres,\nare\nconsiderably\nenhanced\n(\"giant\") in most patients with cortical reflex\nmyoclonus.`'0\nThese\npatients"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 946
encoding: FLOAT32
metadata:
{"title": "Pain-related evoked potentials in cortical reflex myoclonus", "chroma:document": "patients\nmight\nbe\nsensitive to pain stimulation as well, but by\nusing a pin or needle,\nit is difficult to give\n\"pure\" pain stimuli without causing excitation\nof cutaneous mechanoreceptors. A low power\nand long wavelength CO2 laser beam induces\npain or heat sensation when applied to the skin.\nRecently, we have investigated pain-related\nSEPs (pain SEPs) by CO2 laser stimulation,\nand as a result of various studies involving\nischaemic or anaesthetic conditions in normal\nsubjects, its ascending signals were considered\nto be mediated through Ab fibres. \" Bromm and\nTreede using the microneurogram reached a\nsimilar conclusion.'2\nThe object ofthis investigation was therefore\nto elucidate the degree of sensitivity to pain\nstimuli in cortical reflex myoclonus by analys-\ning pain SEPs.\nMaterials and methods\nFour patients with cortical reflex myoclonus,\none with Ramsay Hunt syndrome, one with\nsialidosis type 2, and 2 with unclassified pro-\ngressive myoclonic\nepilepsy, were\nselected\naccording to the following three criteria;9 (1)\nthe amplitude of the P25, the initial cortical\npositive potential recorded at or around the\nsomatosensory hand area of the scalp following\nstimulation of the median nerve at the wrist,\nwas larger than the mean + 2 SD for normal\nsubjects. (2) An enhanced long-loop reflex (C\nreflex'3) recorded even at rest (without volun-\ntary contraction ofthe corresponding muscles),\nand (3) the presence of cortical spikes pre-\nceding spontaneous myoclonic jerks using the\njerk-locked back averaging method.78\"4 The\npatients' profiles are summarised in table 1. No\nneurological\ndysfunction\nother\nthan myo-\nclonus, cerebellar ataxia or generalised convul-\nsion was found. Thirty normal subjects (10\nfemales and 20 males, mean age 46 years, range\n18 to 75) were also studied. All subjects gave\ninformed consent.\nIn addition to using the conventional pin-\nprick method, pain sense was also evaluated by\na specially made dolorimeter using a CO2 laser\nbeam,\nto determine\nthe\nexact strength of"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 947
encoding: FLOAT32
metadata:
{"title": "Pain-related evoked potentials in cortical reflex myoclonus", "chroma:document": "stimulus. Laser wavelength was 10 6 im, and\nthe diameter of the irradiated beam was ap-\nproximately 2 mm. The stimulus was applied\nto the dorsum of the hand, with increasing\npower, once every 3 seconds. Subjects were\nrequested to tell the examiner each time they\nfelt mild touch (pre-pain threshold) and dis-\ntinct sharp pain\n\"like\na pin-prick\"\n(pain\nthreshold). As the intensity above 20 5 mJ/mm2\nwas suspected to cause skin erythema, maxi-\nmum power was set to that level. The test was\nrepeated at least three times and the lowest\nthreshold was adopted.\nThe electric stimulus was a constant voltage\nsquare-wave pulse of0 2 ms duration delivered\nto the left median nerve at the wrist. The\nstimulus intensity was sufficient to produce a\ndefinite twitch of the thumb.\nStimulus\nintensity\nof approximately\n17-\n20 mj/mm2 elicited sharp pain that subjects\ntolerated without any discomfort and felt \"like\na pin-prick\". Stimulus duration was 10 ms.\nTo avoid habituation, irradiated sites were\nchanged slightly from stimulus to stimulus. A\nred helium-neon laser was combined with the\nCO2 laser to indicate the irradiated area. The\ntemporal delay between laser stimulation and\nthe onset of averaging was less than 1 ms. The\ndetailed\nmethods\nwere\ndescribed\nin\nour\nprevious study.\"\n44"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 948
encoding: FLOAT32
metadata:
{"title": "Saccadic function in spasmodic", "chroma:document": "Journal ofNeurology, Neurosurgery, and Psychiatry 1990;53:496-501\nSaccadic function in spasmodic torticollis\nR Stell, A M Bronstein, M Gresty, D Buckwell, C D Marsden\nAbstract\nTwelve patients with idiopathic\nspas-\nmodic torticollis were compared with 19\nnormal controls on tests of saccadic eye\nmovements thought to depend upon nor-\nmal basal ganglia function. The patients\nwere able to make random, predictive,\nremembered, and self-paced saccades\nequally as well as control subjects. This\nsuggests that those parts of the basal\nganglia which may be damaged in spas-\nmodic\ntorticollis,\nare\nseparate\nfrom\npathways\nresponsible\nfor\nthe normal\ninitiation and execution of saccades.\nMedical Research\nCouncil Neuro-otology\nUnit, Institute of\nNeurology, National\nHospital, Queen\nSquare, London\nR Stell\nA M Bronstein\nM Gresty\nD Buckwell\nUniversity\nDepartment of\nClinical Neurology,\nInstitute of Neurology,\nNational Hospital,\nQueen Square,\nLondon\nC D Marsden\nCorrespondence to:\nDr Rick Stell\nMRC Neuro-otology Unit,\nInstitute of Neurology,\nNational Hospital for\nNervous Diseases,\nQueen Square,\nLondon WC1N 3BG,\nUnited Kingdom.\nReceived 14 July 1989\nand in revised form\n11 October 1989.\nAccepted 3 November 1989\nThe cause and pathophysiology of idiopathic\nspasmodic torticollis, the most common form\nof focal dystonia, is unknown. It is assumed to\nbe a disease of the basal ganglia by inference\nas occasionally it is produced by lesions in this\nregion of the brain.' To date there have been\nvery few reports of abnormalities in ocular\nmotor function in torticollis. These have dealt\nmainly\nwith\nasymmetries\nin\nvestibular\nresponses\non caloric and rotational\ntests.2 3\nWhilst no gross abnormalities of oculomotor\nfunction have been recognised,\nthere have\nbeen no studies specifically focusing on the\nsaccadic subsystems requiring the integrity of\nthe basal ganglia for their production.\nThe saccadic ocular motor system utilises a\nnumber\nof\npathways\nsubserving\nspecific\nfunctions, namely predictive and remembered\nsaccades,\nas well\nas\nsaccades\nto voluntary"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 949
encoding: FLOAT32
metadata:
{"title": "Saccadic function in spasmodic", "chroma:document": "visual and novel visual targets. In sub-human\nprimates,\npathways\ntraversing\nthe\nbasal\nganglia are important for the generation of\npredictive\nand\nremembered\nsaccades.4\nIn\nhumans,\nthe\nanalysis\nof\npredictive\nand\nremembered saccades in diseases of the basal\nganglia,\nsuch\nas\nParkinson's\ndisease,\nhas\nconfirmed the presence of specific deficits in\nthis saccadic subsystem.56\nWe report the results of tests of saccadic\nfunction known to be sensitive to basal ganglia\ndisease in a group of patients with idiopathic\ntorticollis and compare them to a group of\nage-matched normal subjects.\nPatients and methods\nTwelve\npatients\nwith\nisolated\nspasmodic\ntorticollis producing pure horizontal rotation\nof the head were studied (table 1). Patients with\nisolated rotation were chosen because we were\ninterested in right-left asymmetries of saccadic\nfunction; if such an asymmetry were present it\nwould be most likely manifested in patients\nwith a lateralised disoider of motor control.\nThe direction of torticoilis referred to the side\nto which the chin was displaced. There were 11\nfemales and one male, with a mean age of 50-6\nyears (range 29-63). The mean disease dura-\ntion was 9 6 years (range 1-25). Seven patients\nhad rotation of the chin to the left and five to\nthe\nright. Three patients were not taking\nmedication at the time of the study, four were\ntaking benzhexol (Artane), three were taking\ndiazepam, one lorazepam and one mianserin.\nAll had been on the stated medications for at\nleast six months without any change in dosage.\nAll patients had previously received at least one\nset of injections of botulinum toxin into the\nappropriate neck muscles, and some had been\ntreated at regular intervals for up to two years.\nThe patients were compared to a group of 19\nnormal controls; seven females and 12 males\nwith a mean age of 43 years (range 30-65).\nEye movements were recorded with DC\nelectronystagmography\n(ENG)\nonto\npaper\nwith an ink-jet polygraph (Mingograph) and\nrecordings\nwere\nthen\nanalysed\nby\nhand."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 950
encoding: FLOAT32
metadata:
{"title": "Saccadic function in spasmodic", "chroma:document": "by\nhand.\nElectrodes were placed near the inner and outer\ncanthi of each eye and a reference ground\nelectrode was placed onto the forehead. The\nsubject's head was supported by a head rest. In\naddition, a binaural head clamp was used in\npatients who\ncould\nnot keep\ntheir heads\nstraight voluntarily. The recordings were made\nwith the head directed to face the screen and\nwith eyes in the primary gaze position.\nSaccadic eye movements were made to a\ntarget projected onto a screen 1-3 metres from\nthe patient by a video projector. The target, a\n10 pixel diameter spot of light subtending an\nangle of 1-30, was generated using a graphics\ngenerator controlled by\na micro-computer.\nThe computer generated each of the target\ndisplacement sequences, each sequence being\naccessed by selection from an on screen menu.\nAn analogue signal of target displacement was\ntransformed to the paper recorder by a digital\nto\nanalogue\nconverter,\nso\nthat\nlatency\nmeasurements could be made directly from the\nrecording.\nThe parameters of saccadic function exam-\nined were: random saccades, hidden predictive\nsaccades,\npredictive\nsaccades,\nremembered\nsaccades, and self-paced saccades. The target\nmoved in a square wave step fashion across the\nscreen in the horizontal plane for each of the\nexperimental conditions. Subjects and controls\nperformed all of the following experiments in\none session. Each experimental paradigm was\nseparated by a rest period ofapproximately two\nminutes.\n496"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 951
encoding: FLOAT32
metadata:
{"title": "Vermal infarct with pursuit eye movement disorders", "chroma:document": "Journal of Neurology, Neurosurgery, and Psychiatry 1990;53:519-521\nSHORT REPORT\nVermal infarct with pursuit eye movement\ndisorders\nCharles Pierrot-Deseilligny, Pierre Amarenco, Etienne Roullet, Rene Marteau\nAbstract\nSevere deficits of foveal smooth pursuit\nand optokinetic nystagmus in all direc-\ntions\nwere\nelectro-oculographically\nrecorded in an 80 year old woman. Mag-\nnetic resonance imaging (MRI) showed\nan infarct involving the postero-inferior\npart of the vermis (lobules VI to X) and\na portion of the left cerebellar hemi-\nsphere, with apparent preservation of\nthe flocculus and the brainstem. The role\nof the vermal lesion in these pursuit eye\nmovement disorders is discussed.\nIt has recently been shown that, besides the\nflocculus, the posterior part of the vermis\n(especially lobules VI and VII) is involved in\nthe control of pursuit eye movements in the\nmonkey.'2 Our case reports for the first time a\nrecent ischaemic lesion of the posterior vermis\nand eye movement recordings, suggesting that\nthis cerebellar structure is also involved in the\ncontrol of pursuit eye movements in humans.\nService de Neurologie,\nHopital Saint-Antoine\nand Unite INSERM\n289, Hopital de la\nSalpetriere, Paris,\nFrance\nC Pierrot-Deseilligny\nP Amarenco\nE Roullet\nR Marteau\nCorrespondence to:\nDr C Pierrot-Deseilligny,\nH6pital de la Salpetriere, 47\nboulevard de l'Hopital,\n75651 Paris cedex 13, France\nReceived 14 June 1989\nand in revised form\n22 September 1989.\nAccepted 30 October 1989\nCase report\nAn 80 year old woman experienced sudden\nvertigo,\nwith\nunsteadiness,\nvomiting,\npos-\nterior headache, without auditory symptoms.\nFor the previous five years she had received\ntreatment for high blood pressure. On admis-\nsion her blood pressure was 160/80 mm Hg,\nher pulse rate was irregular at 1 15 per minute.\nThere was no drowsiness. Vertigo increased\non change of head posture. Finger-to-nose\nand rapid alternating movements of the left\nupper limb were ataxic. Both eyes and head\nwere tonically deviated leftwards. However,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 952
encoding: FLOAT32
metadata:
{"title": "Vermal infarct with pursuit eye movement disorders", "chroma:document": "oculocephalic movement allowed both eyes to\novercome this tonic deviation and reach the\nextreme right position. Cranial nerves were\nunaffected. There were no sensory or motor\ndeficits, all tendon reflexes were normal and\nplantar\nresponses\nflexor.\nThe\nelectrocar-\ndiogram showed atrial fibrillation. CT scan\nperformed\non\nthe\nday\nof admission\nwas\nnormal. In particular, there was no hydro-\ncephalus,\nwhich\nsuggested\nthat\nthere\nwas\nno\ncompression\nof the\nbrainstem\nby\nthe\ncerebellum.\nMRI performed four days later showed an\ninfarct in the territory of the left posterior and\ninferior cerebellar artery, mainly the territory\nof its medial branch.3 All the inferior part of\nthe vermis was affected (lobules VI to X),\nnamely the clivus, the folium, the tuber, the\npyramis, the uvula and the nodulus (fig 1).\nThe inferior part of the left cerebellar hemi-\nsphere was also damaged. The flocculus, the\ndifferent cerebellar peduncles and the brain-\nstem were apparently spared. Moreover, the\nbrainstem did .not appear to be compressed.\nThere was only slight diffuse atrophy in the\ncerebral hemispheres, without hydrocephalus.\nThe posterior headache lasted one day, ver-\ntigo and left lateropulsion on walking cleared\nup within several days and the\nleft tonic\nocular\ndeviation\nprogressively\ndisappeared\nwithin ten days.\nOculographic study\nEye\nmovements\nwere\nrecorded\non\nthe\neleventh day after the onset of the symptoms,\nwhile the patient was fully alert, cooperative\nand attentive. She was not taking any other\nmedication than acetyl-salycylic acid. Direct-\ncurrent electro-oculography (EOG) was used,\nfor each eye separately, in darkness, with the\nhead immobilised. There was no nystagmus\nwhen the patient looked straight ahead or in\nthe extreme positions. With eyes open, there\nwas no tonic deviation, but with eyes closed\nthere was a left conjugate eye deviation.\nHorizontal eye movements Saccades to com-\nmand and visually guided saccades had nor-\nmal latency, velocity and amplitude (fig 2A).\nIn particular, no dysmetria was observed,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 953
encoding: FLOAT32
metadata:
{"title": "Vermal infarct with pursuit eye movement disorders", "chroma:document": "whatever the position of the visual target (at\n5\u00b0, 150, 250 and 350 away from the midline)\nand\ndirection\nof saccades\n(left,\nright,\nor\nreturns to the midline).\nFoveal pursuit of a small luminous target\nmoving sinusoidally at peak-to-peak ampli-\ntude of 500 was largely saccadic in both direc-\ntions (fig 2B). Both catch-up saccades and\nsmooth portions were larger leftwards than\nrightwards but smooth eye movement veloci-\nties were similar in both directions. Smooth\nmovement gains (ratio of peak eye velocity to\npeak stimulus velocity) were low, bilaterally,\ncompared to an age-matched control group,\nfor the two frequencies of stimulation used\n(table). These gains were less than the lower\nlimit of the normal range (control mean-2\nSD).\nOptokinetic nystagmus (OKN) was elicited\nusing alternating black and white stripes mov-\ning at 30\u00b0/s across a screen covering 60\u00b0 of the\nvisual field. It was severely impaired (fig 2C),\n519"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 954
encoding: FLOAT32
metadata:
{"title": "The effects of baclofen and cholinergic drugs upbeat and downbeat", "chroma:document": "Journal of Neurology, Neurosurgery, and Psychiatry 1991;54:627-632\nThe effects of baclofen and cholinergic drugs on\nupbeat and downbeat nystagmus\nMarianne Dieterich, Andreas Straube, Thomas Brandt, Walter Paulus, Ulrich Buttner\nAbstract\nThe GABAergic drug baclofen and the\ncholinergic\ndrug\nphysostigmine\nwere\nadministered\nto\npatients\nwith upbeat\nand\ndownbeat\nnystagmus.\nBaclofen\n(orally, 5 mg three times daily) reduced\nnystagmus slow phase velocity and dis-\ntressing oscillopsia by 25-75% in four out\nof five patients (two upbeat nystagmus;\ntwo downbeat\nnystagmus).\nPhysostig-\nmine (1 mg single intravenous injection)\nincreased nystagmus in five additional\npatients with downbeat (1) or positional\ndownbeat nystagmus (4) for a duration\nof 15-20 minutes. The different interac-\ntions of baclofen and physostigmine on\nneurotransmission\nsubserving\nvertical\nvestibulo-ocular reflex could account for\nthese effects. The response to baclofen\nappears to be a GABA-B-ergic effect with\naugmentation\nof\nthe\nphysiological\ninhibitory\ninfluence\nof the\nvestibulo-\ncerebellum\non\nthe\nvestibular\nnuclei.\nSimilarly\nbaclofen\nhas\nan\ninhibitory\neffect on the velocity storage mechanism.\nCholinergic\naction\nmay\ncause\nthe\nincrement of nystagmus by physostig-\nmine.\nLittle\nis known about neurotransmitters\ninvolved, although pathways for upward and\ndownward VOR have been identified. Clinical\nevidence suggests cholinergic and gabaergic\ntransmission.\nCholinergic drugs (physostig-\nmine)\ncounteract\na\nhyperactive\nhorizontal\nVOR and disturbed fixation suppression of\ncaloric nystagmus in familial ataxia\" \" and\ncerebellar\ndegeneration. 6\nAnticholinergic\ndrugs (scopolamine or trihexiphenidyl) sup-\npress\nacquired\npendular\nnystagmus\nand\npalatal\nmyoclonus. 7 The GABA-B-agonist\nbaclofen effectively suppresses periodic and\nnon-periodic alternating nystagmus.'20\nIn this report, we describe the effects of\nbaclofen (GABA-B-agonist) and physostig-\nmine (cholinergic drug) in 10 patients with\nacquired\nupbeat\n(2),\ndownbeat\n(4),\nor\npositional downbeat nystagmus\n(4). In one"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 955
encoding: FLOAT32
metadata:
{"title": "The effects of baclofen and cholinergic drugs upbeat and downbeat", "chroma:document": "(patient 6), the effect of the anticholinergic\ndrug biperiden, which was injected 10 min-\nutes after physostigmine injection, was tested.\nIt was found that baclofen inhibits upbeat and\ndownbeat nystagmus in some patients and this\nhas obvious clinical relevance. Physostigmine\non the other hand, appeared to change the\ncondition for the worse.\nDepartment of\nNeurology, Klinikum\nGrosshadern,\nUniversity of Munich,\nMunich, Germany\nM Dieterich\nA Straube\nT Brandt\nW Paulus\nU Buttner\nCorrespondence to:\nDr Dieterich, Neurologische\nKlinik, Klinikum\nGrosshadern, Ludwig-\nMaximilians Universitat,\nMarchioninistrasse 15,\nD 8000 Munich 70,\nGermany\nReceived 19 July 1990\nand in revised form\n25 October 1990.\nAccepted 15 November 1990\nUpbeat\nand\ndownbeat\nnystagmus\nin\nthe\nprimary position of gaze, with concomitant\noscillopsia, reflect an imbalance of vertical ves-\ntibulo-ocular reflex tone in the pitch plane.'\nBoth\nare\nmodulated\nby\notolithic\ninput.23\nAlternatively,\nan imbalance of the\nvertical\nsmooth pursuit system for downbeat nystag-\nmus4 has been proposed. However, features of\nthe syndrome such\nas fore-aft postural ins-\ntability2 cannot be explained with this hypo-\nthesis.\nThe pathways for upward- and downward-\nvestibulo-ocular reflexes (VOR), from the ves-\ntibular nuclei\nto the oculomotor nuclei, are\npartially\nseparated.5\nThe\nvertical VOR\nis\nunder the influence of the cerebellum, mainly\nthe vestibulo-cerebellum which projects on to\nthe vestibular nuclei.6 Upbeat nystagmus may\nbe induced by disrupting the upward VOR\npathways within the brachium conjunctivum7\nor within structures of the caudal brainstem,\nsuch as perihypoglossal nuclei89 and the ven-\ntral\ntegmental\npathway,'0\nwhich\nmodulate\nVOR. The downbeat nystagmus syndrome, as\ndemonstrated in monkeys, is caused by lesions\nof either the floor of the fourth ventricle bet-\nween\nthe\nvestibular\nnuclei\"\nor\nthe\nfloc-\nculus. 12\n1\nPatients and methods\nData for patients 1-10 are listed in table 1.\nPatients 7-10 showed slight downbeat nys-\ntagmus, with Frenzel's glasses, in the upright"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 956
encoding: FLOAT32
metadata:
{"title": "The effects of baclofen and cholinergic drugs upbeat and downbeat", "chroma:document": "position of the head and positional downbeat\nnystagmus in the head hanging position. After\nphysostigmine\napplication\n(1 mg),\nthe\nincreased downbeat nystagmus was recorded\nin the upright position with the eyes closed.\nThere was no history of previous drug treat-\nment in these patients.\nTwo healthy male subjects (aged 34 and 29\nyears\nrespectively)\nwere\nused\nas\ncontrols.\nTheir eye movements were recorded with\nelectro-oculography (EOG) before and after\nthe intravenous injection of 1 mg physostig-\nmine.\nHorizontal and vertical eye position was\nrecorded\nseparately\nby DC-EOG\nwith\na\nresolution of 1 degree. The linearity of DC-\nEOG for recording vertical eye movements\nwas\n+ 30\ndegrees. The bandwidth of the\nrecording\nsystem\nwas\n0-30 Hz.\nEOG\nmeasurements\nof\nvertical\neye\nmovements\ncontaminated by lid artifacts were dismissed.\nEye movements and stimuli were stored on a\nsix channel tape recorder and printed on a\nthermoprinter.\nDuring recordings,\nthe subject\nsat\nin\na\n627"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 957
encoding: FLOAT32
metadata:
{"title": "Saccade deficits after unilateral lesion affecting the superior colliculus", "chroma:document": "Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:1106-1109\nSHORT REPORT\nSaccade deficits after a unilateral lesion affecting\nthe superior colliculus\nC Pierrot-Deseilligny, A Rosa, K Masmoudi, S Rivaud, B Gaymard\nAbstract\nA\n70\nyear\nold\npatient with a small\nhaematoma largely restricted to the area\nof\nthe\nright\nsuperior\nand\ninferior\ncolliculi\nis\nreported. Eye movements\nwere electro-oculographically recorded\n17 and 80 days after the onset of the\nhaematoma. At the first examination,\nlatency\nof\nlateral\nreflexive\nvisually-\nguided saccades was asymmetrical, both\nin the gap task (central fixation point\nswitched off200 ms before the onset ofthe\nlateral target) and in the overlap task\n(central\nfixation\npoint\nremaining\nswitched on). Furthermore, latency of\nleftward saccades in the overlap task\nwas increased, and accuracy of these\nsaccades was impaired, at both examina-\ntions. In the immobility task (fixation\nstraight\nahead\nwhile\nlateral\ntargets\nsuddenly\noccurred) and\nin\nthe\nanti-\nsaccade task (saccade made away from\nthe lateral target), the percentages of\nerrors (saccades made\nto the target)\nwere high at the first examination, and\nnoticeably lower at the second. These\nresults\nsuggest\nthat\nthe\nsuperior\ncolliculus plays an important role both\nin\nthe\ntriggering\nand\ninhibition\nof\nreflexive visually-guided saccades.\nService de Neurologie\nand Unit6 INSERM\n289, H6pital de la\nSalpetri&re, Paris, and\nService de Neurologie,\nH6pital Nord, Amiens,\nFrance\nC Pierrot-Deseilligny\nA Rosa\nK Masmoudi\nS Rivaud\nB Gaymard\nCorrespondence to:\nDr Pierrot-Deseilligny,\nService de Neurologie,\nH6pital de la Salpetriire,\n47 Bd de l'H6pital,\n75651 Paris Cedex 13,\nFrance.\nReceived 17 December 1990\nand in revised form\n19 March 1991.\nAccepted 5 April 1991\nThe triggering of all types of saccades appears\nto be performed by two suprareticular struc-\ntures, the superior colliculus (SC) and the\nfrontal eye field (FEF), which both project\ndirectly\non\nto\nthe\nbrainstem\npremotor\nreticular formations.'2 In the normal\nstate,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 958
encoding: FLOAT32
metadata:
{"title": "Saccade deficits after unilateral lesion affecting the superior colliculus", "chroma:document": "state,\nhowever, the degree of involvement of each of\nthese two parallel pathways is different depen-\nding upon the types of saccade to be perfor-\nmed. Lesion studies in the monkey suggest\nthat the SC plays an important role in the\ncontrol of reflexive visually-guided saccades.\"\nTo date, only one patient with an isolated SC\nlesion has been studied with saccade record-\nimgs:'\nspontaneous\nsaccades\nand\nreflexive\nvisually-guided\nsaccades\nwere\nimpaired.\nThere was also a limited lesion affecting the\nSC\nin\nour\npatient. Eye\nmovements\nwere\nelectrooculographically recorded using four\ndifferent paradigms, which tested both the\nexcitatory\nand\ninhibitory\nmechanisms\ninvolved during the\ninitiation of reflexive\nvisually-guided saccades. The results lead to a\nbetter understanding of the role of the SC in\nthe initiation of these saccades.\nCase report\nA 70 year old diabetic man, treated with\noral medicines for 10 years, was admitted to\nhospital\nfor\nheadache\nand\na\nslight\nleft\nhemiparesis, which began the day before. He\nalso complained of intermittent slight vertical\ndiplopia,\noccurring\nin\ndownward\ngaze.\nNeurological\nexamination\non\nadmission\nshowed only a cerebellar syndrome in his\nright arm. There was no obvious ocular motor\nparesis, and convergence and pupillary reac-\ntions were normal. His blood pressure was\n220/100 mm Hg. A CT performed on the day\nof admission, and an MRI performed 17 days\nlater, showed\na\nlesion\naffecting\nthe\nright\nsuperior and inferior colliculi and possibly the\nright brachium conjunctivum suggestive of a\nsmall haematoma (fig A, B, C). The headache\nlasted three days. Eye movements were recor-\nded twice, 17 days and 80 days after the onset.\nDuring\nthese\ntwo\nrecording\nsessions\nthe\npatient was alert and cooperative. His vertical\ndiplopia still occurred occasionally in down-\nward gaze, being due to a slight paresis of the\nleft superior oblique muscle (Lancaster test).\nThere was no diplopia when the eyes moved\nhorizontally\nin\nthe\ndifferent\nsaccade\nparadigms. Visual attention was tested in the\nfirst\nrecording\nsession,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 959
encoding: FLOAT32
metadata:
{"title": "Saccade deficits after unilateral lesion affecting the superior colliculus", "chroma:document": "session,\naccording\nto\na\nprocedure previously described;7 there was no\nvisual neglect. A second MRI was performed\nthe day before the second recording session,\nshowing a small cicatricial lesion affecting the\nright superior and inferior colliculi (fig D).\nEye movement recordings\nEye movements were recorded by\ndirect-\ncurrent\nelectro-oculography\n(EOG)\nin\ncomplete darkness with four electrodes (two\nhorizontal temporal, and two vertical on one\neye). The head was immobilised by a head-\nrest with\na\nrestraining mechanism\nat the\ntemples.\nFour\nsaccade\nparadigms\nwere\nstudied.\nThe overlap task tested the triggering of\nreflexive visually-guided saccades. A central\nfixation point was switched on throughout the\ntask. The subject was instructed to fix this\npoint, and to look as quickly as possible at a\nlateral target, suddenly occurring 250 away\nfrom the central point, either right or left,\n1106"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 960
encoding: FLOAT32
metadata:
{"title": "Association of atrophy of the medial temporal lobe with reduced blood flow in the posterior parietotemporal in patients with clinical and pathological diagnosis ofAlzheimer's disease", "chroma:document": "Journal ofNeurology, Neurosurgery, and Psychiatry 1992;55:190-194\nAssociation of atrophy of the medial temporal lobe\nwith reduced blood flow in the posterior\nparietotemporal cortex in patients with a clinical\nand pathological diagnosis of Alzheimer's disease\nK A Jobst, A D Smith, C S Barker, A Wear, E M King, A Smith, P A Anslow,\nA J Molyneux, B J Shepstone, N Soper, K A Holmes, J R Robinson, R A Hope,\nC Oppenheimer, K Brockbank, B McDonald\nRadcliffe Infirmary,\nOxford OX2 6HE\nUniversity\nDepartment of\nClinical Neurology\nK A Jobst\nA Wear\nE M King\nA Smith\nUniversity\nDepartment of\nPharmacology\nA D Smith\nDepartment of\nNeuroradiology\nC S Barker\nP A Anslow\nA J Molyneux\nDepartment of\nNeuropathology\nB McDonald\nUniversity\nDepartment of\nNuclear Medicine,\nJohn Radcliffe\nHospital, Oxford\nB J Shepstone\nN Soper\nK A Holmes\nLittlemore Hospital,\nOxford\nJ R Robinson\nK Brockbank\nUniversity\nDepartment of\nPsychiatry,\nWarneford Hospital,\nOxford\nR A Hope\nC Oppenheimer\nReceived 11 March 1991 and\nin revised form 10 June 1991.\nAccepted 18 July 1991\nAbstract\nA combination of medial temporal lobe\natrophy,\nshown\nby\ncomputed\ntomo-\ngraphy, and reduced blood flow in the\nparietotemporal cortex, shown by single\nphoton emission tomography, was found\nin 86% (44151) of patients with a clinical\ndiagnosis of senile dementia of the Alz-\nheimer type (SDAT). The same combina-\ntion ofchanges was found in four out of 10\npatients\nwith\nother\nclinical\ntypes\nof\ndementia and in two out of 18 with no\nevidence of cognitive deficit. Of the 12\npatients who died, 10 fulfilled histopatho-\nlogical criteria for Alzheimer's disease,\nnine ofthem having a clinical diagnosis of\nSDAT, and one a clinical diagnosis of\nmulti-infarct dementia. All 10 patients\nwith histopathologically diagnosed Alz-\nheimer's disease had shown a combina-\ntion ofhippocampal atrophy and reduced\nparietotemporal blood flow in life. In 10\npatients (nine with SDAT) out of 12 in\nwhom\nthe\nhippocampal\natrophy\nwas\nmore noticeable on one side of the brain\nthan on the other the parietotemporal"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 961
encoding: FLOAT32
metadata:
{"title": "Association of atrophy of the medial temporal lobe with reduced blood flow in the posterior parietotemporal in patients with clinical and pathological diagnosis ofAlzheimer's disease", "chroma:document": "perfusion deficit was also asymmetrical,\nbeing greater on the side showing more\nhippocampal atrophy. These results sug-\ngest that the combination of atrophy of\nthe hippocampal formation and reduced\nbloodflowin the parietotemporal region is\na feature of dementia of the Alzheimer\ntype and that the functional change in the\nparietotemporal region might be related\nto the loss ofthe projection neurons in the\nparahippocampal gyrus that innervate\nthis region of the neocortex.\nCT has shown that many patients with a\nclinical diagnosis of senile dementia of the\nAlzheimer\ntype\n(SDAT)\ndisplay\nmore\nappreciable cerebral atrophy than expected for\ntheir age.' Functional changes in the brains of\ndemented patients have been found by meth-\nods that show cerebral blood flow, or uptake of\nglucose, oxygen\nor radioligands:\nthe most\nfrequent finding is a functional deficit in the\nposterior parietal and temporal lobes ofthe cor-\ntex.2\"\nSingle photon emission tomography\n(SPET) has recently been used to show that the\nfunctional deficits in the posterior parietal and\nlateral temporal lobes are related to the degree\nof cognitive decline,\"8 but such findings are\ndifficult to reconcile with neuropathological\nstudies showing that the most severely affected\nparts of the brain in Alzheimer's disease are in\nthe medial lobe, mainly the amygdala, the\nhippocampal formation and adjacent parahip-\npocampal gyrus.>'3 Atrophy of these areas can\nbe revealed in life by CT studies in which the\nscan angle is adjusted to give a clearer view of\nthe medial temporal lobe, and such studies in\npatients with a clinical diagnosis ofAlzheimer's\ndisease have, indeed, shown severe damage to\nstructures in the medial temporal lobe.'\"\"6\nHowever, atrophy of the medial temporal lobe\nis also found in other conditions-notably,\nepilepsy and hypoxia,'7 schizophrenia,'8 and\namnesia'9-and so is not unique to dementia of\nthe Alzheimer's type.\nIn none of the CT and SPET studies des-\ncribed above were the two procedures carried\nout in the same patients. The purpose of our"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 962
encoding: FLOAT32
metadata:
{"title": "Association of atrophy of the medial temporal lobe with reduced blood flow in the posterior parietotemporal in patients with clinical and pathological diagnosis ofAlzheimer's disease", "chroma:document": "report is to describe CT studies ofthe temporal\nlobe and SPET studies of perfusion of the\ncortex in the same group of patients. We\nwished to see whether there was any relation\nbetween atrophy of the medial temporal lobe\nand a perfusion deficit in the parietotemporal\ncortex and, if so, whether such a relation was\nassociated with Alzheimer's disease defined\nclinically and, when possible, by histopatho-\nlogical criteria. Preliminary findings have been\nreported.20\nPatients and methods\nPatients were recruited,\nafter having been\ngiven a full explanation of the study protocol,\nfrom general practitioners and hospital based\nservices, with some subjects entering them-\nselves. Ethical approval for the study was\nobtained\nfrom\nboth\nthe\nCentral\nOxford\nResearch and the Psychiatric Sector Research\nethics committees. Informed consent was ob-\ntained from those without cognitive deficit, and\nfor those with a significant deficit it was given by\na close relative. Subjects were referred with\nvarying degrees of mental deterioration and\nmemory loss, many for detailed screening with\na view to making a diagnosis. Diagnoses were\nmade according to DSM-III-R criteria. Drug\ntreatment remained unchanged during screen-\ning.\n190"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 963
encoding: FLOAT32
metadata:
{"title": "Age influences magnitude but duration of response to levodopa", "chroma:document": "Journal of Neurology, Neurosurgery, and Psychiatry 1993;56:65-68\nAbstract\nFollowing an all-night fast, 45 patients\nwith Parkinson's disease were examined\nusing certain motor items present in the\nUnited Parkinson's Disease Rating Scale.\nAll were given a single tablet of carbidopa\n25 mg and levodopa 250 mg and re-exam-\nined 90 minutes later. In addition to this\nevaluation, 23 of these patients underwent\nfurther scoring over a 4-hour period. A\nsignificant negative correlation was found\nbetween age and one important aspect of\ndrug-derived\nbenefit:\nmagnitude\nof\nresponse. In contrast, age had no appar-\nent influence on duration of benefit from\nthe\ndrug.\nAlthough\nbaseline\n(fasting)\nscores were predictably correlated with\nduration\nof\ndisease,\nmagnitude\nof\nresponse was not adversely influenced by\nthis variable. Not all Parkinsonian signs\nwere equally influenced by age. Whereas\nthe poor response ofgait and bradykinesia\nappeared to be dependent on age, no such\neffect was noted on rest tremor scores.\nThe data indicate that in patients with\nParkinson's disease treated long term,\nfactors associated with age rather than\nduration of disease may have a stronger\nadverse\ninfluence\non\nmagnitude\nof\nresponse to levodopa.\n(J Neurol Neurosurg Psychiatry 1993;56:65-68)\nDepartment of\nNeurology, Boston\nUniversity School of\nMedicine, Boston,\nMassachusetts, United\nStates, Department of\nNeurology, Boston\nVeterans\nAdministration\nMedical Center,\nBoston,\nMassachusetts, United\nStates\nR Durso\nK Isaac\nL Perry\nM Saint-Hilaire\nR G Feldman\nCorrespondence to:\nRaymon Durso, Department\nof Neurology, Boston\nVeterans Administration\nMedical Center, 150 South\nHuntington Avenue, Boston,\nMA 02130, United States.\nReceived 17 July 1991\nand in revised form\n3 February 1992 and\n28 April 1992.\nAccepted 2 May 1992\nA well-documented finding regarding limita-\ntions of levodopa use in Parkinson's disease is\nthe observation that treatment is most effica-\ncious during the early years of therapy and\nthat, later, many patients experience a sig-\nnificant decline\nin the"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 964
encoding: FLOAT32
metadata:
{"title": "Age influences magnitude but duration of response to levodopa", "chroma:document": "in the\neffectiveness of the\ndrug.' 2 Two\nfactors\nthat\ncharacterise\nthis\ndecline\nare,\nfirstly,\na\nshorter\nduration\nof\nresponse and, secondly, an inability to main-\ntain the same quality of improvement. The\nreduction\nin\nthe\nduration\nof response\nto\nlevodopa is clinically manifested as wearing\noff, end-of-dose deterioration or the on-off\nphenomenon. There is considerable agreement\nthat these limitations in duration of benefit are,\nat least in part, related to disease progression\n(that\nis,\na continuing loss of cells\nin the\nnigra).36 In this regard, a diminished capacity\nof nigral terminals to synthesize and store\ndopamine, or both,78 may play an important\nrole. There is less consensus about factors that\nmay limit the magnitude of the response to\nlevodopa. Using data obtained from patients\nparticipating in pharmacological studies at the\n65\nBoston Veterans Administration Medical Cen-\nter and University Hospital, we analysed the\nduration and magnitude of response to levo-\ndopa in relation to several potential factors that\nmight influence its efficacy. This opportunity\nwas\navailable\nbecause\nall\nparticipants had\nreceived\nthe same dose of carbidopa and\nlevodopa without concomitant administration\nof other medications and all had been scored\nusing motor items\npresent\nin\nthe United\nParkinson's Disease Rating Scale (UPDRS).\nPatients and methods\nExamination scores from 45 patients (39 males\nand\nsix females)\nwith Parkinson's\ndisease,\nhaving participated in either of two pharmaco-\nlogical studies, were analysed with regard to\ntheir age at the time of study; their age at time\nof disease onset; the duration of the disease\nand the daily levodopa dose. The duration\nof levodopa\ntherapy\nwas\nnot\nspecifically\naddressed as essentially it was identical to the\nduration of disease in our patient population.\nThe diagnosis of Parkinson's disease had been\nagreed upon by\nat\nleast two\nneurologists\nexperienced in movement disorders and all\npatients exposed\nto levodopa had demon-\nstrated sustained, significant benefit from the"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 965
encoding: FLOAT32
metadata:
{"title": "Age influences magnitude but duration of response to levodopa", "chroma:document": "drug. Individuals with pyramidal, cerebellar or\nprominent autonomic signs were excluded, to\nminimise inclusion of the diagnosis of multi-\nsystems degeneration. Prior approval for these\nprojects had been given by the Research and\nDevelopment Human Studies Subcommittees\nof both the Boston Veterans Administration\nMedical Center and the Boston University\nHospital.\nThe\ntwo\npharmacological\nstudies\nfrom\nwhich subjects were evaluated employed iden-\ntical methodologies except for frequency of\nobservations following carbidopa and levodopa\nadministration.\nOne\npatient\ngroup\n(22\npatients) was scored immediately preceding\nadministration of carbidopa and levodopa and\n90 minutes after. The other group (23 patients\nunderwent multiple examinations immediately\nbefore and 30, 60, 90, 120, 180, 240 minutes\nafter administration. No single patient partici-\npated in both studies. On the day of investiga-\ntion, patients were fasted and all medications\nwithheld from midnight. Studies were con-\nducted in both outpatient and inpatient set-\ntings. At 9am subjects were evaluated using\nmotor examination\nitems\nin\nthe UPDRS.\nThese\nexaminations\nwere\nalso\nvideotaped.\nScoring was done by either one of two inves-\ntigators (RD or KI). A separate analysis of the\nAge influences magnitude but not duration of\nresponse to levodopa\nRaymon Durso, Kathryn Isaac, Linda Perry, Marie Saint-Hilaire, Robert G Feldman"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 966
encoding: FLOAT32
metadata:
{"title": "Severe psychiatric disturbance and abnormalities of the callosum: review and series", "chroma:document": "J7ournal of Neurology, Neurosurgery, and Psychiatry 1993;56:85-93\nSevere psychiatric disturbance and abnormalities\nof the corpus callosum: review and case series\nAnthony S David, Alisa Wacharasindhu, W Alwyn Lishman\nAbstract\nThe association between developmental\ndefects of the corpus callosum and major\npsychiatric disturbance is discussed with\na review of published cases. Seven new\ncases are presented, of which four had\nclear psychotic symptoms, two receiving a\ndiagnosis\nof\nschizophrenia.\nOf\nthe\nremainder, one had a developmental dis-\norder\naffecting\nsocial\ninteraction\nand\nspeech which could be classed as Asper-\nger's syndrome, one had a personality\ndisorder with depressive and conversion\nsymptoms, and the last was an adolescent\nboy with severe behavioural problems.\nThe difficulties in determining the precise\nrelevance of the\ncallosal anomalies\nto\nthese clinical manifestations are discussed\nespecially since the prevalence of such\nanomalies in the population is uncertain.\n(y Neurol Neurosurg Psychiatry 1993;56:85-93)\nDepartment of\nPsychological\nMedicine, Institute of\nPsychiatry and King's\nCollege Hospital,\nLondon, UK\nA S David\nA Wacharasindhu\nSection of\nNeuropsychiatry,\nInstitute of Psychiatry,\nLondon, UK\nW A Iishman\nCorrespondence to:\nDr David, Department of\nPsychological Medicine,\nKing's College Hospital,\nDenmark Hill, London SE5\n9RS, UK\nReceived 18 December 1991\nand in revised form\n3 April 1992.\nAccepted 13 April 1992\nThe corpus callosum (CC) contains the largest\nnerve fibre tract in the human brain, connect-\ning the cerebral hemispheres with one another.\nIt is estimated to contain nearly 200 million\nfibres. The CC together with the anterior and\nhippocampal commissures form the forebrain\ncommissures. The tract develops intimately in\nassociation with the fornix, hippocampal com-\nmissure, hippocampal formation, septum pel-\nlucidum and cingulate cortex, beginning to\nform shortly after the anterior commissure.\nDetails of the anatomy and embryology of\nthe CC have been well described.''\nAbnormal"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 967
encoding: FLOAT32
metadata:
{"title": "Severe psychiatric disturbance and abnormalities of the callosum: review and series", "chroma:document": "Abnormal\nmorphologies of the CC can be classified into\nacquired\nand\ncongenital\ndefects.\nAcquired\nchanges\ncan\nresult from\ntrauma,\ntumours,\nhydrocephalus, vascular accidents and white\nmatter diseases.' Complete agenesis is a rare\ndevelopmental anomaly of unknown cause and\nis associated with a wide variety of genetic\ndefects,\nin particular trisomies of chromo-\nsomes, 8, 13 and 18.67 Agenesis has also been\nconsidered a marker of intrauterine metabolic\nupsets such\nas hyperglycinaemia,8 and may\nresult from insults such as intrauterine infec-\ntions and exposure to toxins.3\n-\nThe partial\nforms of agenesis usually affect the posterior\nportions and are presumed to reflect the action\nof pathogenic influences occurring after the\ninitial development of the commissures, that is,\nafter the sixteenth week of gestation.\nAgenesis is frequently accompanied by other\ndevelopmental defects. These encompass com-\nmon midline abnormalities (for example, cleft\npalate),\nalthough\nother\nocular\nand\nspinal\nabnormalities\nmay\noccur.6 The\nassociated\nbrain anomalies which have been reported\ninclude interhemispheric\ncysts with hydro-\ncephalus (Dandy-Walker malformation), lipo-\nmas of the CC or interhemispheric fissure,\ninvariably\nassociated\nwith\npartial\nagenesis,\nabsence of the inferior cerebellar vermis, and\ndisorders of neuronal migration.\"2 The cingu-\nlate gyrus is invariably abnormal and limbic\nstructures may also be affected.\nThe main function of the CC\nis\ninter-\nhemispheric\nintegration:\nconnecting\ncorre-\nsponding regions of the cerebral cortex in the\ntwo\nhemispheres.\nCrudely,\nit\nserves\nas\na\nconduit\nfor\ntransfer\nof\nsensory\ninforma-\ntion,'3-15 although the precise nature of the\ninformation transferred and its overall influ-\nence on the activity of the hemispheres is a\ntopic of continued research and speculation.'6\nIt has been noted repeatedly that in agenesis of\nthe CC there is an absence of most aspects of\nthe disconnection symptoms which affect sub-\njects who have had\nsurgical separation of\nthe\ncommissures-the\n\"split-brain\nopera-\ntion\".\" 1"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 968
encoding: FLOAT32
metadata:
{"title": "Severe psychiatric disturbance and abnormalities of the callosum: review and series", "chroma:document": "tion\".\" 1\nThis has been attributed to the\npresence of alternative pathways connecting\nthe hemispheres such as the anterior com-\nmissure, which\nis frequently\nintact despite\ncallosal\nagenesis,\nor\nsubcortical\nchannels.\nOther compensatory mechanisms may also\nplay a part such as the duplication of those\nspecialised functions which are usually dis-\ntributed asymmetrically between the hemi-\nspheres, such as speech. Nevertheless, some\nfailures of interhemispheric communication\nhave been noted such as reduced transfer of\nmaze learning from one hand to another,'9\nimpaired matching of visual patterns between\nthe right and left visual fields20 and reduced\ntransfer of incongruent word\nstimuli\nin\na\ncolour naming task,2' (but see22).\nThe prevalence of callosal agenesis is diffi-\ncult to quantify. Widely varying estimates in the\nliterature, ranging from 0 004% to 2-64%,\nreflect the different study populations (tables 1\nand 2). Thus paediatric neurology services will\ngive higher rates than necropsy studies of\nunselected members of the population. Sim-\nilarly, the rates of associated abnormalities and\nclinical problems reflect the setting in which\ncases are evaluated. All that can be stated is\nthat\ncertain presentations, namely learning\ndisability\nand\nepilepsy\nare\nrather\ncom-\nmon,3 17 30\nthe\nlatter\nusually\nestimated\nat\naround 40%. Despite most cases coming to\nlight because of the need\nto investigate\na\nmanifest neurological syndrome, many series\n85"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 969
encoding: FLOAT32
metadata:
{"title": "Ideomotor apraxia without aphasia and aphasia without apraxia: the anatomical for double dissociation", "chroma:document": "26ournal of Neurology, Neurosurgery, and Psychiatry 1993;56:286-289\nIdeomotor apraxia without aphasia and aphasia\nwithout apraxia: the anatomical support for a\ndouble dissociation\nCostanza Papagno, Sergio Della Sala, Anna Basso\nAbstract\nThis study aimed to verify the existence of\na\ndouble\naphasialapraxia\ndissociation.\nApraxic\npatients\nwithout\naphasia and\naphasic\npatients without apraxia were\nincluded in a consecutive series ofpatients\nwith cortical or subcortical CT docu-\nmented vascular lesions in the left hemi-\nsphere. Of 699 patients, 10 were found to\nbe apraxic but not aphasic and 149 aphasic\nbut not apraxic. These findings indicate an\naphasialapraxia double dissociation. This\nsuggests that praxis and language make\nuse of two different, partly overlapping\nnetworks.\n(J Neurol Neurosurg Psychiatry 1993;56:286-289)\nMRC Applied\nPsychology Unit,\nCambridge, UK\nC Papagno\nDepartment of\nNeurophysiology, S\nPaolo Hospital, Milan\nand Neuropsychology\nUnit, Clinica del\nLavoro Foundation,\nMedical Center of\nVeruno, Italy\nS Della Sala\nIstituto di Clinica\nNeurologica, Milan\nUniversity, Milan,\nItaly\nA Basso\nCorrespondence to:\nDr Papagno, Presidio\nOspedaliero, via Verdi 2,\n20038 Seregno, Milano,\nItaly\nReceived 6 June 1991\nand in final revised form\n29 June 1991\nAccepted\n10 July 1992\nThe term \"apraxia\" encompasses various dis-\norders affecting the purposeful execution of\ndeliberate\nmovements\nwhich\ncannot\nbe\nexplained by elementary motor-sensory defi-\ncits, perceptual and comprehension impair-\nment\nor\nsevere\nmental\ndeterioration.\nIdeomotor apraxia\nis\na form of apraxia in\nwhich the implementation of the gesture in a\nprecise motor programme\nis disrupted.\nIn\nright handed subjects ideomotor apraxia\nis\nassociated with lesions in the left hemisphere2 3\nwhich is also dominant for language and has\ntherefore often been associated with aphasia.\nAjuriaguerra\net\nal 4 reported\nthat 90%\nof\npatients with ideomotor apraxia also had apha-\nsia.\nConversely\n32\nof 60\n(53%)\naphasic\npatients5 were also apraxic.\nThe\nassociation\nbetween\naphasia\nand"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 970
encoding: FLOAT32
metadata:
{"title": "Ideomotor apraxia without aphasia and aphasia without apraxia: the anatomical for double dissociation", "chroma:document": "and\napraxia is often due to the encroachment of the\nlesion upon contiguous\nstructures, differen-\ntially\nspecialised\nfor language and\npraxis.'\nAphasia has often been reported in the absence\nof apraxia5 which supports this theory. The\nopposite pattern (apraxia without aphasia) has\nrarely been reported.\nLiepmann6 (quoted by Ajuriaguerra et al 4)\nreported 7 non-aphasic patients with poorly\nspecified disturbances of praxis, 6 of whom\nhad right hemiplegia and therefore presumably\na left-hemisphere lesion. Recently, Goodglass\nand Kaplan7 reported 5 mildly apraxic though\nnon-aphasic patients with left brain damage,\nHeilman et al8 reported a non-aphasic, right\nhanded man who was examined three months\nafter\na left-hemisphere\nstroke who showed\nideomotor apraxia and agraphia, and Selnes et\nae\ndescribed\na patient with transient fluent\naphasia with an auditory comprehension defi-\ncit and persistent apraxia and dysgraphia three\nyears after frontoparietal ischaemia. Selnes et\nallo described an 81 year old right handed\nman, affected by myasthenia gravis who, one\nmonth after a massive left-hemisphere stroke,\nshowed marked limb apraxia coupled with\ndyscalculia, right neglect, anosognosia, agra-\nphia but no aphasia, except for mild dysno-\nmia.\nOne apraxic patient out of 40 non-aphasic\nsubjects with left brain damage was reported\nby De Renzi et al.5 Agostoni et al\" described a\npatient (case 5) who sustained an ischaemic\nlesion of the internal capsule and caudate\nnucleus, and was not aphasic. To find support\nfor the notion of dissociability between aphasia\nand apraxia, Kertesz et al'3 studied a series of\n143 patients who had sustained a cortical or\nsubcortical stroke of the left-hemisphere and\nwho had been examined at least three months\nafterwards. In 2 severe and 7 moderate aphasic\npatients, praxis was spared and in one case of\nmild aphasia, praxis was moderate. Kertesz et\nall3 did not observe apraxia in non-aphasic\npatients. Junque et all4 reported a right handed\npatient who had ideomotor apraxia but not"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 971
encoding: FLOAT32
metadata:
{"title": "Ideomotor apraxia without aphasia and aphasia without apraxia: the anatomical for double dissociation", "chroma:document": "aphasia, after a massive left-hemisphere infarc-\ntion. Recently Della Sala et all' reported a\npatient (case 29) with apraxia and without\naphasia in a series of patients with left hemi-\nsphere subcortical lesions.\nIn this study we aimed to verify the existence\nof a double dissociation between aphasia and\napraxia. For this purpose we systematically\nsearched for apraxic non-aphasic subjects and\nvice versa in a consecutive series of patients\nwith cortical or subcortical left-hemisphere\nvascular lesions.\nMaterial and methods\nSubjects\nAmong the patients examined at the Aphasia\nUnit at Milan University between 1979 and\n1988,\nwe\nselected\nthe\n699\nright\nhanded\npatients with CT documented vascular lesion\nin the left-hemisphere (CT without enhance-\nment performed\nat least\n15 days after the\nstroke).\nNeuropsychological investigation\nAll subjects had the following neuropsycho-\nlogical examination at different intervals after\nstroke:\n1) Ideomotor apraxia\nA 24 item test for ideomotor apraxia, which\nconsists of half nonsymbolic and half symbolic\nmovements, half requiring the holding of a\nstatic position and half the execution of motor\n286"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 972
encoding: FLOAT32
metadata:
{"title": "Peripheral neuropathy the presenting feature of tyrosinaemia I and effectively treated with inhibitor of 4-hydroxyphenylpyruvate dioxygenase", "chroma:document": "Journal ofNeurology, Neurosurgery, and Psychiatry 1993;56: 1129-1132\nLESSON OF THE MONTH\nPeripheral neuropathy as the presenting feature of\ntyrosinaemia type I and effectively treated with an\ninhibitor of 4-hydroxyphenylpyruvate dioxygenase\nT C Gibbs, J Payan, E M Brett, S Lindstedt, E Holme, P T Clayton\nAbstract\nA 21 month old girl presented with a\nshort history of frequent falls and a right\nsided foot drop. She went on to suffer\nrecurrent episodes of distal weakness in\nher arms and legs with hyporeflexia.\nElectrophysiological studies were consis-\ntent with inflammatory\ndemyelinating\npolyradiculoneuropathy (IDP) and treat-\nment with corticosteroids appeared to\nlead to an improvement. However, the\ndevelopment ofhypertension, evidence of\ntubulopathy, and hepatomegaly led to re-\nevaluation. A diagnosis of type I tyrosi-\nnaemia was made, based on increased\nurinary excretion of succinylacetone and\ndecreased\nactivity\nof fiumarylacetoac-\netase in her cultured skin fibroblasts. A\nlow tyrosine diet did not prevent life-\nthreatening exacerbations of neuropathy\nbut intravenous haemarginate appeared\nto aid her recovery from one exacerba-\ntion.\nAn\nimmediate\nimprovement\nin\nstrength was seen after starting treat-\nment with 2-(2-nitro-4-trifluoro-methyl-\nbenzoyl)-1,3-cyclohexanedione\n(NTBC),\nan inhibitor of 4-hydroxy-phenylpyru-\nvate\ndioxygenase.\nA\nliver\ntransplant\nwas performed but the patient died of\nimmediate postoperative complications.\nTyrosinaemia needs to be considered in a\nchild with recurrent peripheral neur-\nopathy because (i) the signs of liver dis-\nease and renal tubular dysfunction may\nbe subtle;\n(ii) acute exacerbations may\nbe life threatening; (iii) specific forms of\ntreatment are available.\n(7 Neurol Neurosurg Psychiatry 1993;56:1129-1132)\nTyrosinaemia type I (McKusick no 276700)\nusually presents with symptoms attributable\nto hepatic or renal tubular dysfunction, or\nboth.'\nTyrosinaemia\ncan\nbe\ndetected by\nneonatal amino acid screening,2 or by more\nspecific screening procedures based on the\naccumulation\nof"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 973
encoding: FLOAT32
metadata:
{"title": "Peripheral neuropathy the presenting feature of tyrosinaemia I and effectively treated with inhibitor of 4-hydroxyphenylpyruvate dioxygenase", "chroma:document": "of\nsuccinylacetone\nor\nits\neffects.34 Succinylacetone, which accumulates\nin this disorder, is a potent inhibitor of por-\nphobilinogen synthase and patients usually\nshow increased urinary excretion of 5-amino-\nlaevulinic acid (&-ALA).\nNeurological crises resembling acute por-\nphyria have been well described in children\nwith tyrosinaemia,'7 but we are only aware of\none case in which a neurological symptom\n(ataxia) was\nthe presenting\nfeature.8 This\nreport describes a patient with tyrosinaemia\ntype I in whom recurrent weakness due to a\nperipheral\nneuropathy was\nthe\npresenting\nsymptom. A number of different forms of\ntreatment were attempted and the results are\npresented.\nCase report\nOur\npatient was\nthe\nfirst\nchild born\nto\nunrelated Asian parents. There was no family\nhistory\nof\nneurological\ndisease.\nNeonatal\nscreening excluded hyperphenylalaninaemia\nand hypothyroidism but the methods used\nwere not capable of picking up tyrosinaemia.\nThe patient had started walking at 16 months\nand was apparently well until 21 months of\nage. At about this time her parents noticed\nshe tended to fall over and had a right-sided\nfoot drop.\nAt 26, 29, and 32 months, she had an\nacute illness characterised by a fever, irritabil-\nity, leg pains, a right-sided limp, and colicky\nright iliac fossa pain. Examination revealed\ndistal weakness in her arms and legs, bilateral\nfoot drop, and decreased reflexes with absent\nankle jerks. Nerve conduction studies were\nperformed at 30 and 33 months (see below).\nA diagnosis of a chronic relapsing form of\npolyneuropathy was made because of the\nnature and variability of the results of motor\nconduction studies and the persisting normal-\nity of sensory conduction. High dose daily\noral corticosteroids led to an improvement in\nher symptoms. Any attempt to reduce the\ndose of prednisolone to less than 17-5 mg per\nday over the next 18 months led to exacerba-\ntion of her symptoms. The response to treat-\nment was gratifying but certain features of the\ncase remained unexplained as indicated in"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 974
encoding: FLOAT32
metadata:
{"title": "Peripheral neuropathy the presenting feature of tyrosinaemia I and effectively treated with inhibitor of 4-hydroxyphenylpyruvate dioxygenase", "chroma:document": "table 1 (26 months, 29 months).\nAt 3-5 years the patient was noted to have\ndeveloped palmar erythema. She was cushin-\ngoid,\nhypertensive\n(170/120),\nand\nhad\nstopped growing. Examination revealed clini-\ncal cardiomegaly and echocardiography con-\nfirmed biventricular hypertrophy. A firm liver\nedge was palpable 2-5 cm below the costal\nmargin. She had a wide-based\ngait,\ndistal\nmuscle weakness with areflexia, and flexor\nHospital for Sick\nChildren, Great\nOrmond Street,\nLondon WClH 3JH\nMedical Professorial\nUnit\nT C Gibbs\nP T Clayton\nDepartment of\nNeurology\nJ Payan\nE M Brett\nDepartment of\nClinical Chemistry,\nGothenburg\nUniversity, Sahlgren's\nHospital, Sweden\nS Lindstedt\nE Holme\nCorrespondence to:\nDr P Clayton.\nReceived 26 October 1992\nand in final revised form\n18 February 1993.\nAccepted 26 February 1993\n1129"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 975
encoding: FLOAT32
metadata:
{"title": "after ischaemic stroke: metabolic study", "chroma:document": "9'ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:990-996\nMotor recovery after acute ischaemic stroke: a\nmetabolic study\nV Di Piero, F M Chollet, P MacCarthy, G L Lenzi, R S J Frackowiak\nAbstract\nThe metabolic changes occurring after\nischaemic stroke were measured to inves-\ntigate the functional anatomy of clinical\nmotor recovery. Positron emission tomog-\nraphy (PET) and the\nsteady-state\n15O\ntechnique was used to compare resting\nrelative\nmetabolic\ndistributions\nat\nthe\nonset of functional deficit with those fol-\nlowing recovery. Ten patients were studied\nwith repeat scans. Motor recovery was\nassociated\nin\nsome\npatients\nwith\nan\nincrease of relative oxygen metabolism in\nanatomical structures normally involved\nin motor function in the affected hemi-\nsphere, particularly in the cortical motor\nareas. In those patients without such met-\nabolic changes in the cortex of the dis-\neased hemisphere, relative increases in\ncortical metabolism in the contralateral\nhemisphere were associated with better\nmotor recovery than in patients with no\nrelative\ncortical metabolic\nincrease\nin\neither hemisphere. There was no correla-\ntion between the degree of improvement\nin motor function and the severity of\nmotor deficit at onset, the size and site of\nthe lesion and the metabolic changes in\nthe infarcted zone. No particular pattern\nof global metabolic changes was observed\nafter recovery. Thus different relative pat-\nterns of metabolic recovery were seen in\npatients with different lesions and evi-\ndence was found for the participation of\ncontralateral structures in the recovery\nprocess in some patients.\n(7 Neurol Neurosurg Psychiatry 1992;55:990-996)\nA demonstrably effective therapeutic approach\nto acute cerebral ischaemia has\nstill to be\ndefined. This is partly due to an incomplete\nunderstanding of the mechanisms leading to\nischaemic\ncell death and partly to an even\ngreater ignorance about the mechanisms of\nfunctional recovery following cerebral infarc-\ntion. Research in the area of functional rehabil-\nitation\nis\ndoubly"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 976
encoding: FLOAT32
metadata:
{"title": "after ischaemic stroke: metabolic study", "chroma:document": "is\ndoubly\ndifficult\nbecause\nof the\nmultiple variables that affect outcome and the\ndifficulty of selecting homogeneous patient\npopulations with respect to mechanism and\nextent of infarction.1 Methods of selecting\ngroups of patients that might benefit from\nintensive rehabilitation treatment and what\nforms,\nif any, such treatment should\ntake\nremain to be defined. One step would be the\nestablishment\nof the\nfunctional\nanatomical\nbasis for such recovery. The investigation of\nsuch aspects of human functional recovery has\nbeen mainly\nclinical and pathological with\nattention directed principally at the ischaemic\nlesion. The results have been contradictory.25\nCerebral blood flow (CBF) has been the\nprincipal\nfunctional\nparameter\ninvestigated\nwith the development of functional neuroim-\naging techniques. However, in the acute phase\nof stroke there is profound mismatch between\ncerebral\nmetabolism\nand\nblood\nflow\nwith\nvarious degrees of relative or absolute hyper-\naemia, -' which means that CBF does not\nreflect cerebral function in the early phase of\ninjury. The mismatch is responsible for the low\nprognostic value of CBF unless the measure-\nment is made within a very few hours of onset\nof the acute ischaemia.9\"-1 Positron emission\ntomography (PET) can be used to measure\nhuman brain metabolism in vivo thus provid-\ning more direct evidence of cerebral function\nin the acute phase of stroke.\nThe aim of our study was to evaluate the\nmetabolic changes occurring after ischaemic\nstroke in the acute and recovered phase and to\ninvestigate correlations with clinical recovery\nof motor function.\nMaterials and methods\nWe studied 5 male and 5 female patients, mean\n(SD) age 54-3\n(8 7) years, presenting with\nmotor dysfunction due\nto\nacute ischaemic\ninfarction in a cerebral hemisphere. Comatose\npatients or those suffering from other neuro-\nlogical conditions were excluded. The study\nhad the approval of the Hammersmith Hospi-\ntal ethics committee and the Administration of\nRadioactive Substances Advisory Committee"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 977
encoding: FLOAT32
metadata:
{"title": "after ischaemic stroke: metabolic study", "chroma:document": "of the Department of Health, UK. Written\ninformed consent was obtained in each case\nfrom the patient or the nearest relative. All but\none patient (case 8-table 1) had no history of\ncerebrovascular\ndisease.\nClinical\nevaluation\nincluded a full neurological examination, an\nassessment ofmotor function using the motric-\nity index (MI) of Demeurisse et al, 2 of general\nfunction using the Barthel\nscale,'3\na Mini\nMental State test'4 and a formal neuropsycho-\nlogical evaluation. The MI is a published scale\nbased upon\nthe MRC\ngrading of muscle\nstrength,\nespecially\ndesigned\nto\nevaluate\n\"patients' progress in motor recovery ... and\ncorrelations with other clinical data\".'2 The\nscale reflects motor performance using three\nmovements\nin each limb with appropriate\nweighting to give a 0-100 scale, with 100\nrepresenting normality. Scores from 0 to 32\nMRC Cyclotron Unit,\nHanmersmith\nHospital, London, UK\nV Di Piero*\nR S J Frackowiak\nF M Chollett\nCattedra di\nNeuropatologia e\nPsicopatologia,*\nDipartimento di\nScienze Neurologiche,\nUniversita degli Studi\n\"La Sapienza\", Rome,\nItaly\nG L Lenzi\nService de\nNeurologie,t HBpital\nPurpan, Toulouse,\nFrance\nDepartment of\nRadiology,\nHammersmith\nHospital, London, UK\nP MacCarthy\nCorrespondence to:\nProfessor Frackowiak, MRC\nCyclotron Unit,\nHammersmith Hospital, 150\nDucane Road, Lond6n W12\nOHS, UK\nReceived 13 February 1991\nand in final revised form\n31 October 1991.\nAccepted 14 December\n1991\n990"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 978
encoding: FLOAT32
metadata:
{"title": "Hysteria following brain injury", "chroma:document": "06ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:1046-1053\nHysteria following brain injury\nPeter Eames\nAbstract\nOf 167 patients referred to a unit treating\nsevere behaviour disorders after brain\ninjury, 54 showed clinical features closely\nresembling those of gross hysteria as des-\ncribed by Charcot. Close correlation was\nfound with very diffuse insults (hypoxia\nand hypoglycaemia), but not with severity\nof injury or with family or personal his-\ntory of hysterical or other psychiatric\ndisorder. The findings may have implica-\ntions for the understanding of the nature\nof hysteria.\n(7 Neurol Neurosurg Psychiatry 1992;55:1046-1053)\nBurden Neurological\nHospital, Bristol BS16\nlQT\nP Eames\nCorrespondence to:\nP Eames\nReceived 13 February 1991\nand in revised form\n24 December 1991.\nAccepted 24 February 1992\n\"Hysteria\" is a difficult term, partly because it\nembraces several distinct ideas. The complex-\nity is well illustrated byVeith' and in two recent\nmulti-author books.23 In addition to the diffi-\nculties of characterising the central idea of\nhysteria, problems arise from the fact that a\nrange of disorders is subsumed. Four semi-\nseparable syndromes may be identified: hyster-\nical personality disorder, Briquet's syndrome\nor \"the stable syndrome of hysteria,\"4 the\nmore focal presentations of dissociation still\nusually referred to as \"conversion hysteria,\"\nand what might be\ncalled \"Charcot's\nsyn-\ndrome\" or \"gross hysteria.\" Charcot described\na large number of individuals, mainly but not\nexclusively inpatients, who for much if not all\nof the time showed a wide and varying range of\nusually\ngross disturbances\nof function and\nbehaviour that could not be explained on a\nbasis of demonstrable pathology of the central\nnervous system and were thus considered to be\n\"simulations.\"5 It was his view, however, that\nthese simulations were compulsive rather than\nvoluntary, and were the result of an as yet\nunrecognised kind of organic brain disturb-\nance.\nIn\na\nprivate\nhospital\nunit\nspecifically\ndesigned\nfor\ntreating\npatients\nwith"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 979
encoding: FLOAT32
metadata:
{"title": "Hysteria following brain injury", "chroma:document": "with\nsevere\nbehaviour disorders following brain injury,6 it\nis the routine practice\nto make systematic\nobservations and ratings ofbehaviours,7 and all\nobservations\nare pooled and discussed\nreg-\nularly by the whole treatment team. As a result,\na particular patient with severe hypoxic brain\ninjury from an anaesthetic accident (see below)\nwas ultimately recognised to be presenting a\nwide\narray\nof\nbehaviours\nthat\ncould\nbe\nexplained only on a basis of gross hysteria. (It\nwas interesting that\nit took several months\nbefore the team suddenly realised the nature of\nthese disturbances. In retrospect it seemed that\nthe emotive aspects of severe brain injury of\nthis kind had elicited what amounted to a\nmental set against accurate identification ofthe\nproblem.)\nCase history\nCase A\nAt the age of 26, A, a female schoolteacher,\nunderwent\nplanned\ncholecystectomy.\nThe\noperation went well, but during the immediate\nrecovery period she became cyanosed. Urgent\ninvestigation revealed that the lines supplying\nnitrous oxide and oxygen had been reversed on\nthe other side of the wall of the theatre. With\nappropriate treatment cardiorespiratory func-\ntion soon became normal, but she remained\nunconscious for some days, emerging very\ngradually, and continuing to seem confused for\nmany months. It became apparent that she was\ncortically blind, with gross disturbance of eye\nmovements, and there was a diffuse movement\ndisorder with dystonic quadriparesis, and later,\nmild choreoathetosis. She soon became disin-\nhibited in talk and behaviour, and required\nconstant supervision. She began to produce an\nalmost continuous stream of \"empty\" phrases\n(\"Nurse, darling, I'm hungry, I'm thirsty, I\nwant to go to the toilet, nurse.\n. .\").\nA succession of \"special\" nurses all devel-\noped the habit of responding to each of these\nutterances in a reassuring manner. She grad-\nually regained mobility (though this was awk-\nward and hampered by her visual deficit) and\nalso control of bowel and bladder. Several\nattempts at formal rehabilitation were blocked"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 980
encoding: FLOAT32
metadata:
{"title": "Hysteria following brain injury", "chroma:document": "by her disordered behaviour.\nWhen case A was seen some two and a half\nyears after the injury constant utterances inter-\nfered with all activities, although she was able\nto cooperate with physical examination\nto\nsome extent. There was no apparent response\nto visual stimuli, though for most of the time\nshe kept her eyes closed. Eye movements were\nseverely disrupted, with searching nystagmus.\nSpeech was slightly dysarthric and often tele-\ngrammatic. There was no paresis, but most\nmovements were dyspraxic, and there was\nplastic rigidity of all limbs; slight choreoathe-\ntotic movements were seen at rest and on\neffort. Reflexes were normal. CT had shown\nmild diffuse cortical atrophy and moderately\nenlarged ventricles, but an electroencephalo-\ngram was normal.\nShe was admitted to a single room in a\ngeneral psychiatric unit and had one to one\nnursing. It was thought she had considerable\npotential for further rehabilitation if the behav-\niour disorder could be overcome. The constant\n1046"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 981
encoding: FLOAT32
metadata:
{"title": "Propriospinal myoclonus in multiple sclerosis", "chroma:document": "16ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:1086-1088\nSHORT REPORT\nPropriospinal myoclonus in multiple sclerosis\nR Kapoor, P Brown, P D Thompson, D H Miller\nAbstract\nThe clinical and electrophysiological fea-\ntures of segmental myoclonus affecting\nthe right arm and upper trunk are des-\ncribed in a patient with multiple sclerosis.\nElectrophysiological\nstudies\nsuggested\nthat the myoclonus was propagated from a\ngenerator site in the cervical cord, where\nlesions were found using MRI. The spread\nof electromyographic\nactivity\nin\neach\nmyoclonic jerk was slow and variable.\nThese findings are characteristic of pro-\npriospinal myoclonus, which has not been\nassociated with multiple\nsclerosis pre-\nviously.\n(7 Neurol Neurosurg Psychiatry 1992;55: 1086-1088)\nUniversity\nDepartment of\nClinical Neurology,\nNational Hospital for\nNeurology and\nNeurosurgery, Queen\nSquare, London, UK\nR Kapoor\nP Brown\nP D Thompson\nD H Miller\nCorrespondence to:\nDr Kapoor\nReceived 18 November\n1991.\nAccepted 23 January 1992\nThe types of myoclonus that arise from various\ngenerator sites in the nervous system can be\ndistinguished\non\nclinical and\nneurophysio-\nlogical grounds.\nIn cortical myoclonus,\nfor\nexample, discharges in the sensorimotor cortex\nare conducted rapidly in the pyramidal tracts,'\nleading to focal or multifocal jerks. In myoclo-\nnus of brainstem origin, reticular firing causes\nmore generalised axial jerks due to rostral and\ncaudal\nspread\nof\nactivity\nin\nreticulospinal\npathways.2 3\nIn\ncontrast,\nspinal myoclonus\ntends to be focal and segmental, with little\nspread of activity from spinal generator sites,\nwhich\nproduce\njerks\nof longer\nand\nmore\nvariable duration than those of supraspinal\norigin.' 5\nRecently, an additional form of spinal myo-\nclonus has been described in which a spinal\ngenerator\nrecruits\naxial muscles\nvia\nslowly\nconducting propriospinal pathways to produce\nextensive jerks of the trunk.6 Whereas segmen-\ntal spinal myoclonus can occur with numerous\ndisorders\nincluding multiple\nsclerosis,5\nfew"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 982
encoding: FLOAT32
metadata:
{"title": "Propriospinal myoclonus in multiple sclerosis", "chroma:document": "few\ncases of propriospinal myoclonus have been\ndescribed. In one, a cervical cord lesion was\npresent, but lesions were not found in the\nothers.6We now report a patient with multiple\nsclerosis\nin whom propriospinal myoclonus\nwas documented\nand\nin whom\nassociated\nlesions of the cervical cord were found on\nMRI.\nCase report\nA right handed white woman developed right\noptic neuritis when aged 23 years. The follow-\ning year there was an episode of left optic\nneuritis. She then noted a fine postural tremor\n(which responded to propranolol), together\nwith irregular, involuntary jerking of the right\nshoulder and arm, and sometimes of the leg.\nThis could be preceded by a tingling sensation\nover the back of the neck. The muscle jerking\npersisted, and when aged 25 years she also\ndeveloped Lhermitte's symptom and altered\nsensation over the left side of her face. This\nprogressed over four weeks to include urinary\nurgency, an unsteady gait and finally a burning\ndiscomfort of the right leg. There was no\nadditional past or family history of neuro-\nlogical disease, she was otherwise asympto-\nmatic and took no regular medications.\nAt this point the general and state examina-\ntion were normal. The corrected visual acuities\nwere 6/6 on the right and 6/9 on the left, with\nimpaired colour perception on the left (9 of 13\nIshihara plates were identified). There were\nbilateral, paracentral scotomata and both op-\ntic discs were pale. A\nleft relative afferent\npupillary defect and convergence nystagmus\naffecting only the left eye were noted. Spino-\nthalamic sensation was impaired in the first\nand second divisions of the left fifth cranial\nnerve, but the corneal reflexes and remaining\ncranial nerves were normal.\nIn the limbs, there were spontaneous, irregu-\nlar jerks of the right shoulder and arm leading\nto elevation and abduction of the right shoul-\nder associated sometimes with a grunt. They\nwere preceded by a tingling sensation over the\nneck but could not be suppressed voluntarily.\nSimilar jerks were elicited by taps to the right"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 983
encoding: FLOAT32
metadata:
{"title": "Propriospinal myoclonus in multiple sclerosis", "chroma:document": "shoulder and by pinprick over the proximal\nright arm. More violent jerks spread to involve\ntrunk and hip flexion on the right. Limb tone\nand coordination were normal but there was\nmild pyramidal weakness of the left leg. The\ntendon\nreflexes\nwere\nuniformly\nbrisk,\nthe\nabdominal reflexes present and the left plantar\nresponse\nwas\nextensor.\nSensory\ntesting\nrevealed no\nobjective\nabnormalities\nin\nthe\nlimbs.\nInvestigations\nAll routine haematological and biochemical\ntests were normal. After the episode of left\noptic neuritis the auditory evoked potentials\nwere also normal, but the visual evoked poten-\ntials were delayed bilaterally (full field pattern\nevoked P100 latencies 125 ms on the right,\n131 ms\non\nthe\nleft). The CSF\ncontained\n0 58 g/l protein, glucose\n3-3 mmol/l\n(blood\nglucose 5*1 mmol/l) and 11 white blood cells/\nmm3\n(all\nmature\nlymphocytes).\nElectro-\n1086"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 984
encoding: FLOAT32
metadata:
{"title": "In vitro microglia models: the era of engineered cell microenvironments", "chroma:document": "NEURAL REGENERATION RESEARCH\uff5cVol 18\uff5cNo. 8\uff5cAugust 2023\uff5c1709\nNEURAL REGENERATION RESEARCH\nwww.nrronline.org\nPerspective\nIn vitro microglia models: the era of \nengineered cell microenvironments\nBackground: The most widely employed approach \nby cell biologists to performing in vitro cell culture \nassays is the one using 2D plastic culture ware \nsystems, which allows reproducibility and ease \nof use. Moreover, this method is cost-effective. \nHowever, in most cases, these flat surfaces lead \nto the formation of unrealistic 2D cell monolayers, \nwhich do not reproduce the complex configuration \ncharacteristics of native tissues in terms of \ndimensionality, rigidity, and topography. For this \nreason, a new generation of interdisciplinary \nscientists, working across microengineering and \ncell biology has started to develop engineered \ncell microenvironments (Huang et al., 2017) by \nemploying advanced materials and fabrication \napproaches (Fan et al., 2019) over the last two \ndecades. Depending on the level of resolution \nof the adopted manufacturing technique, the \ngeometrical features of these structures can \nreach micrometric or even sub-micrometric \ndimensions comparable to the ones of cellular \nsomas or cellular filopodia, therefore fostering \ncell-biomaterial interactions. The developed \nstructures are pivotal for a better investigation \nof fundamental mechanobiology (Lemma et \nal., 2019), the optimization of in vitro disease \nmodeling, drug/treatment screening (Gao et al., \n2021), and tissue engineering (Mani et al., 2022).\nAmong all tissues in our body, brain tissue is \none of the most complex. Several efforts have \nbeen made (Accardo et al., 2019) to create \nphysiologically relevant and biomimetic artificial \nniches that are able to efficiently host different \nneuronal and glial cell lineages. Among these, \nmicroglia are the resident macrophages of \nthe central nervous system and contribute to \nmaintaining the brain\u2019s homeostasis. In addition, \nthey have a vital role in tissue repair. Activation"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 985
encoding: FLOAT32
metadata:
{"title": "In vitro microglia models: the era of engineered cell microenvironments", "chroma:document": "and dysfunction of microglial cells are associated \nwith neurodegenerative diseases, such as \nAlzheimer\u2019s disease and Parkinson\u2019s disease. \nIn the human brain, four main phenotypes of \nmicroglia are reported, namely ramified, primed, \nreactive and amoeboid. The ramified or \u201cresting\u201d \nphenotype is the most abundant in the healthy \nbrain and features a cellular morphology with \nmultiple extensively ramified processes that \nprobe chemical or physical cues that indicate \nthe presence of a foreign body or cellular debris. \nMicroglia that display an amoeboid or \u201cactivated\u201d \nphenotype secrete pro-inflammatory mediators \nand neurotoxins, initiating a pro-inflammatory \nsignal cascade that results in phagocytosis, \namong other things. This amoeboid phenotype \nis characterized by a flat cellular morphology, a \nwide cell body, and few (i.e., less than three) or \nno branched primary processes. One of the main \nissues when primary microglia are isolated from \nthe brain and are seeded in 2D plastic culture \nware systems is that they display either round, \nglobular-like, or flat, amoeboid-like, morphologies \n(Figure 1A; Jeong et al., 2013). Although progress \nhas been made in the optimization of microglia \nAhmed Sharaf, Raissa Timmerman, Jeffrey Bajramovic, Angelo Accardo* \nemployed technique for the fabrication of cell \nscaffolds called electrospinning (Figure 1C-i), able \nto generate polymeric nanofibers using electric \nfields, was employed to assess the response \nof primary microglia (which have a higher pre-\nclinical relevance compared to the BV-2 cell line), \nisolated from Wistar rat pups (Pires et al., 2015), \nin presence of poly(trimethylene carbonate-co-\u03b5-\ncaprolactone) (P(TMC-CL)) fibers. A comparison \nbetween flat P(TMC-CL) films and P(TMC-CL) \nfibers showed that cells cultured on P(TMC-\nCL) films were larger and featured an increased \ncircularity compared to microglia cultured on \nfibers. This can be considered as an indication \nof a more pro-inflammatory profile. However,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 986
encoding: FLOAT32
metadata:
{"title": "In vitro microglia models: the era of engineered cell microenvironments", "chroma:document": "when media from the primary microglia culture \nwas introduced to astrocytes, astrogliosis was \nnot exacerbated, signifying that microglia were \nnot activated. Thus, it is important to mention \nthat the association between microglia activation \nstates and the display of distinct morphologies \nare not always linked. In another recent work, the \naddition of conditioned medium of BV-2 microglia \ngrown within 3D graphene foams obtained by \nchemical vapor deposition (Figure 1C-ii) promoted \nneurosphere formation, which was not observed \nwhen neurons were exposed to conditioned \nmedium from 2D cultured microglia, suggesting \npossible applications in the field of regenerative \nmedicine (Jiang et al., 2016).\nAll the above-mentioned studies employed \nmicroglia cell lines or primary microglia coming \nfrom rodent models. However, in order to have \nmore clinically relevant models for prospective in \nvitro disease modeling, drug-screening assays, or \neven neural tissue engineering purposes, it is of \nparamount importance to evaluate the behavior \nof microglia that are closer to human microglia. \nA recent advancement, making use of primary \nmicroglia isolated from adult rhesus macaques, \nreported for the first time how micro- and nano-\nmetric 2.5D and 3D structures, fabricated via \ntwo-photon polymerization, directly influenced \nprimary microglia morphology and branching \n(Figure 1C-iii and D; Sharaf et al., 2022). Two-\nphoton polymerization is a manufacturing \nin vitro culture conditions, e.g. the elimination of \nserum from the culture medium, in vitro microglia \nare still characterized by an activated phenotype \n(Bohlen et al., 2017; Timmerman et al., 2022). This \nlimits the potential of performing fundamental \nneuromechanobiology investigations, and of \ndeveloping in vitro disease models or in vitro \ndrug-screening studies that involve microglia. In \norder to overcome this limitation, research has \nbeen emerging over the last decade showing \nthat micro- and nano-engineering approaches"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 987
encoding: FLOAT32
metadata:
{"title": "In vitro microglia models: the era of engineered cell microenvironments", "chroma:document": "represent a powerful tool to create controlled and \nreproducible microenvironments able to guide the \nfate of microglia and to optimize current in vitro \nmicroglia models.\nEngineered microglia environments: The \nguidance of microglia morphology and phenotype \nvia engineered microenvironments can take place \nby exploiting four different parameters: substrate \ngeometry, topography (e.g., roughness), stiffness, \nand biochemical coating (Figure 1B). A decade \nago, excimer laser processing of thin hydrogenated \namorphous silicon films deposited by plasma-\nenhanced chemical vapor deposition on glass \nsubstrates already enabled the formation of silicon \nmicro and nano-structures (between 2 nm and 2.3 \n\u03bcm) resulting in substrates with various roughness \nwhich influenced the morphology of a murine \nmicroglial cell line (BV-2) (Persheyev et al., 2011). \nOn amorphous flat silicon, BV-2 cells tended to \nadopt a rounded morphology with flat protrusions \nwhereas in the presence of laser-processed \nsilicon micro- and nano-structures, these cells \ndisplayed a more elongated, bipolar shape. The \nmanufactured features are sensed by microglia via \nlamellipodia and filopodia in a process known as \nmechanosensing. More recently, another widely \nA\nB\nC\nD\nFigure 1 \uff5c Schematic representation of the various features of in vitro microenvironments, the processes used to \nfabricate them, and their effect on microglia.\n(A) Microglia phenotypes observed in vivo and in vitro. (B) Overview of the parameters of in vitro microglia \nengineered microenvironments and their interplay therein. (C) Examples of processes employed to fabricate in vitro \nengineered microglia microenvironments (i) electrospinning, (ii) chemical vapor deposition (CVD), and (iii) two-photon \npolymerization (2PP). (D) An example of the effect of engineered microenvironments where nanopillar arrays, providing \na topography and stiffness that resemble those of the native cell environment, fostered the expression of a ramified"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 988
encoding: FLOAT32
metadata:
{"title": "In vitro microglia models: the era of engineered cell microenvironments", "chroma:document": "phenotype in primate-derived microglia compared to the amoeboid one on flat surfaces. Created with BioRender.com."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 989
encoding: FLOAT32
metadata:
{"title": "New mutation Huntington's disease", "chroma:document": "Journal of Medical Genetics 1989, 26, 18-27\nNew mutation to Huntington's disease\nGERHARD WOLFF*, GUNTHER DEUSCHLt, THOMAS F WIENKER*,\nKONRAD HUMMEL:, KLAUS BENDER*, CARL H LUCKINGt,\nMARTIN SCHUMACHER\u00a7, JURG HAMMERII, AND GODEHARD OEPEN\u00b6\nFrom *Institut fur Humangenetik und Anthropologie, tNeurologische Klinik und Poliklinik, lInstitut fur\nBlutgruppenserologie,\n\u00a7Radiologische\nUniversitatsklinik,\nSektion Neuroradiologie, and\n\u00b6Psychiatrische\nKlinik und Poliklinik,\nUniversity of Freiburg\ni Br,\nFederal Republic of Germany; and IlInstitut fur\nMedizinische Genetik,\nUniversity of Zurich, Switzerland.\nSUMMARY\nWe report a large family with an isolated case of Huntington's disease (HD), which is\nprobably the result of a new mutation. The patient developed clinical signs typical of HD at the\nage of 36. The clinical course of the patient's disease is documented by several clinical admissions\nover a period of 14 years at present. The family history is strikingly negative with the parents\nhaving been clearly unaffected into their 80s and with 13 older and two younger, living, healthy\nsibs. Extensive testing of polymorphic markers (blood groups, red cell and serum proteins, HLA\nantigens) showed no indication of non-paternity, but rather gave strong support to the hypothesis\nthat the proband is a full sib. In addition, DNA typing for several RFLPs known to be closely\nlinked to the HD gene locus indicated that several clearly unaffected sibs share one or the other\nor both of the patient's haplotypes. This is further evidence in favour of the hypothesis of a\nnew mutation at the HD locus.\nThe posterior probability of a new mutation to HD in the patient exceeds 99%, even if an\na priori probability of non-paternity of 10% and a mutation rate of HD of 10-7 is assumed.\nHuntington's\ndisease\n(HD)\nis\nan\nautosomal\ndominantly inherited neurodegenerative\ndisorder\nwith a variable age at onset but full penetrance by\nold age. The defect causes specific neuronal loss,\nleading to progressive motor disturbance, psycho-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 990
encoding: FLOAT32
metadata:
{"title": "New mutation Huntington's disease", "chroma:document": "logical manifestations, and intellectual deteriora-\ntion.1 2 The mutation rate\nis among the lowest\nknown for human disorders,3 the estimated number\nof mutants per million\ngametes varying between\n013x 10-6 and 9 6x 10- .4\nCalculated\nmutation\nrates\nusing\nthe\n'direct'\nmethod, based on the proportion of cases without a\ndetectable family\nhistory,\nare\nclearly maximum\nestimates owing\nto\nthe\ninherent\ndifficulties\nin\ndefining a mutant case.5 6 Wendt and Drohm,7 in\ntheir study of 4024 HD patients, found no mutant\ncase after having tested for paternity by examining\nblood groups of all living unaffected parents and\nafter having excluded those cases where the parents\ndied before outliving their risk.\nIn a review of data on mutation rates to HD,\nShaw and Caro8 came to the conclusion that new\nReceived for publication 18 January 1988.\nRevised version accepted for publication 5 May 1988.\nmutants make up only around 0-1% or less of all\ncases.\nTwelve possible cases of new mutation to HD, in\nwhich the parents were living or died healthy at\nadvanced age, have been reported to date,5 9-19 but\nnone of them meets all of the criteria suggested by\nStevens and Parsonage16 to designate a case of a\nnew mutation: (1) clinical cardinal features in the\nproband and similarly affected offspring; (2) both\nparents having outlived most of their risk; (3) suffi-\ncient information about the health status of the\nparents; and (4) proof of paternity.\nNot surprisingly, there is no definite proof of a\nnew mutation in HD.\nIt seems impossible that a\nspecific case will meet all the postulated criteria.\nClinical symptoms being unspecific with a wide\ndifferential diagnosis,20-22 late onset, and the diffi-\nculty\nin\nmost sporadic\ncases\nof establishing\na\nconvincing negative family history, cause inherent\nproblems, which led Reed and Neel5 to the conclu-\nsion\nthat specific instances of mutation\nin\nthis\ndisorder will not be demonstrable.\nHowever, proving a new mutation in a sporadic\ncase may be of great importance to the family, that"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 991
encoding: FLOAT32
metadata:
{"title": "New mutation Huntington's disease", "chroma:document": "is, healthy relatives other than offspring who other-\n18"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 992
encoding: FLOAT32
metadata:
{"title": "Chronic and delayed neurological manifestations of persistent infections", "chroma:document": "CURRENT\nOPINION Chronic and delayed neurological manifestations of\npersistent infections\nDarshan Pandya and Tory P. Johnson\nPurpose of the review\nPersistent infections capable of causing central nervous system (CNS) complications months or years after\nthe initial infection represent a major public health concern. This concern is particularly relevant\nconsidering the ongoing coronavirus disease 2019 pandemic, where the long-term neurological effects are\nstill being recognized.\nRecent findings\nViral infections are a risk factor for the development of neurodegenerative diseases. In this paper, we\nprovide an in-depth exploration of the prevalent known and suspected persistent pathogens and their\nepidemiological and mechanistic links to later development of CNS disease. We examine the pathogenic\nmechanisms involved, including direct viral damage and indirect immune dysregulation, while also\naddressing the challenges associated with detecting persistent pathogens.\nSummary\nViral encephalitis has been closely associated with the later development of neurodegenerative diseases\nand persistent viral infections of the CNS can result in severe and debilitating symptoms. Further, persistent\ninfections may result in the development of autoreactive lymphocytes and autoimmune mediated tissue\ndamage. Diagnosis of persistent viral infections of the CNS remains challenging and treatment options are\nlimited. The development of additional testing modalities as well as novel antiviral agents and vaccines\nagainst these persistent infections remains a crucial research goal.\nKeywords\nautoimmune, encephalitis, neurological impairments, persistent infections, post-acute sequelae of SARS CoV-2\ninfection\nINTRODUCTION\nThe central nervous system (CNS) is comprised of\nlong-lived cells and is capable of modulating inflam-\nmatory processes [1] providing an ideal location in\nwhich pathogens can persist [2]. However, not all\npathogens require presence in the CNS to cause\nneurologic disease. Emerging evidence from the"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 993
encoding: FLOAT32
metadata:
{"title": "Chronic and delayed neurological manifestations of persistent infections", "chroma:document": "severe acute respiratory syndrome coronavirus 2\n(SARS-CoV-2) pandemic (COVID19) has reinforced\nthe concept that infections, irrespective of their\nanatomical location, can contribute to neurological\ndisease in both acute and late phases [3].\nDelayed onset of neurological issues due to\ninfections can occur months or years after the initial\ninfectious insult as highlighted by the recent strik-\ning finding that viral encephalitis is associated with\nsignificant risk of later development of dementia\n[4\n&&] and that vaccination against some viruses\ncan decrease the risk of developing dementia [5].\nHowever, several barriers exist in distinguishing if\nthe neurological symptoms are due to persistent\ninfectious agents or postinfectious inflammatory\nsequelae. First, persistent infections, especially those\nin the CNS, are often underdiagnosed as they are not\nreadily detected by conventional tests. Clinically,\nthese may account for a significant proportion of\nthe approximately 40\u201350% of cases of encephalitis\nthat have no identifiable cause [6\u20139]. Second,\nduring persistent infections there is ongoing inflam-\nmation which can mimic autoimmune or autoin-\nflammatory processes leading to misdiagnosis of\nSection of Infections of the Nervous System, National Institute of Neuro-\nlogical Disorders and Stroke, National Institutes of Health, Bethesda,\nMaryland, USA\nCorrespondence to Tory P. Johnson, Room 7C-120; Building 10, 10\nCenter Drive, Bethesda, MD 20892, USA. Tel: 301.827.9783;\ne-mail: tory.johnson@nih.gov\nCurr Opin Neurol 2023, 36:198\u2013206\nDOI:10.1097/WCO.0000000000001154\nWritten work prepared by employees of the Federal Government as part\nof their official duties is, under the U.S. Copyright Act, a \u201cwork of the\nUnited States Government\u201d for which copyright protection under Title\n17 of the United States Code is not available. As such, copyright does\nnot extend to the contributions of employees of the Federal Government.\nwww.co-neurology.com\nVolume 36 \u0001 Number 3 \u0001 June 2023\nREVIEW"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 994
encoding: FLOAT32
metadata:
{"title": "Fetal hydrops", "chroma:document": "91\nJ Med Genet 1992; 29: 91-97\nFetal hydrops\nP A Boyd, J W Keeling\nAbstract\nSeventy-two\nfetuses\nor\nneonates\nwith\nnon-immune\nhydrops\nwere\nexamined\nbetween 1983 and 1988. The commonest\nassociation was chromosome abnormal-\nity; 11 fetuses had a 45,X karyotype and 11\nautosomal trisomy. Chromosome abnor-\nmality was suspected in a further 20 on\nnecropsy findings but chromosome cul-\nture was not possible or unsuccessful. In\n11 cases there was histological evidence of\ninfection; seven babies had major struc-\ntural anomalies and six affected fetuses\nwere twins. In six (8%) the cause of hyd-\nrops was not determined compared with\neight (16%) of cases examined between\n1976 and 1982. Hydrops was diagnosed\nmore frequently while the fetus was alive,\nbefore 20 weeks' gestation, and associated\nwith chromosome anomaly than found\npreviously.\nDepartments of\nMedical Genetics,\nChurchill Hospital,\nHeadington, Oxford\nOX3 7LJ.\nP A Boyd\nDepartment of\nPaediatric Pathology,\nJohn Radcliffe\nMaternity Hospital,\nOxford.\nJ W Keeling*\n*Present address:\nDepartment of Paediatric\nPathology and\nCytogenetics, Royal\nHospital for Sick\nChildren, Edinburgh\nEH9 lLF.\nCorrespondence to\nDr Boyd.\nReceived 17 April 1991.\nAccepted 2 July 1991.\nEffective prevention of rhesus\ndisease has\nshifted the emphasis of the investigation of the\npregnancy complicated by fetal hydrops to-\nwards non-immunological causes.' The increas-\ning availability of obstetric ultrasound and its\nuse in the investigation of pregnancies which\nare 'large for dates' or have a clinical diagnosis\nof polyhydramnios has resulted in a larger\nproportion of cases of fetal hydrops being\ndiagnosed while the fetus is still alive. The\nmore frequent use of ultrasound for dating\npurposes\nin the second trimester, together\nwith opportunities for a detailed fetal anomaly\nscan around 20 weeks' gestation, means that\nmany hydropic fetuses are now recognised at\nan asymptomatic stage. This enables a wider\nrange of investigations to be undertaken. Elu-\ncidation of the underlying cause or association"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 995
encoding: FLOAT32
metadata:
{"title": "Fetal hydrops", "chroma:document": "of hydrops should be possible in\na larger\nproportion of cases.\nWe report our experience with fetal hydrops\nduring the last five years and compare gesta-\ntional age at diagnosis, method of diagnosis,\nand pathological findings in the hydropic fetus\nwith those examined in the same unit between\n1976 and 1982.2\nMaterial and methods\nCases of fetal hydrops from pregnancies which\nterminated in both the second and third tri-\nmesters were identified from the files of the\nDepartment\nof Paediatric\nPathology, John\nRadcliffe Maternity Hospital (JRH), Oxford.\nThese comprised fetuses from women who\nwere booked for delivery at that hospital and\nthose referred for pathological examination.\nReferral was often prompted by prenatal in-\nvestigations\nundertaken\nin\nOxford,\neither\nultrasound examination at the JRH or through\nthe Department of Medical Genetics.\nFetal hydrops was defined as generalised\nsubcutaneous oedema with an effusion in at\nleast one body cavity. After pathological ex-\namination each case was allotted to one of six\ngroups: proven chromosome anomaly, dys-\nmorphic features (two or more) suggestive of\nchromosome anomaly but without cytogenetic\ndiagnosis, infection, visceral anomaly, compli-\ncation\nof twin pregnancy, and\nidiopathic.\nClinical and pathological details were con-\nsidered first within each group and then the\ngroups were compared with each other. They\nwere finally compared with cases of fetal hyd-\nrops seen between 1976 and 1982.\nResults\nPertinent clinical details of each pregnancy\nand\nthe\nresults\nof\nprenatal\nultrasound\nexamination and chromosome culture are pre-\nsented in table 1, grouped according to patho-\nlogical findings in the fetus. A comparison\nbetween the groups is made in table 2 and\ngestational age at diagnosis, status at delivery,\nand pathological associations are compared\nwith cases reported previously in table 3.\nCHROMOSOME ANOMALY\nThe commonest association of fetal hydrops\nseen during the present study was chromo-\nsome anomaly. There were 22 such fetuses"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 996
encoding: FLOAT32
metadata:
{"title": "Fetal hydrops", "chroma:document": "(table 1). The hydropic state in all fetuses in\nthis group was identified by ultrasound scan.\nIn seven this was during a scan before amnio-\ncentesis. Amniocentesis was indicated because\nof advanced maternal age in six and for known\nmaternal balanced translocation in one case. In\n13 of the remaining 15 women, a hydropic\nfetus was identified on routine scan, and in two\nwomen a detailed scan was performed because\nof raised\nmaternal\nserum\nalphafetoprotein\nlevel and a history of intrauterine growth re-\ntardation, respectively.\nHalf of the fetuses with chromosome anom-\naly exhibited a 45,X karyotype. In 10 of the 11,\npostnuchal fluid accumulation was described\nin the scan report and two were already dead\nwhen the scan took place. Examination of these\nfetuses after delivery showed that 10 out of 11\nexhibited tubular hypoplasia of the distal aor-\ntic arch (Haa). In case 11, material was not\navailable for review. The only other cardiac\nanomaly was a persistent left superior vena\ncava (PLSVC). Three fetuses had horseshoe\nkidney and a further fetus had unilateral in-\ncomplete renal rotation, the renal pelvis facing\narteriorly.\nThree of five fetuses with trisomy 21 had\ncardiovascular\nmalformations.\nThese\nwere"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 997
encoding: FLOAT32
metadata:
{"title": "The morbid of the human chromosomal location of mutations causing disease", "chroma:document": "J Med Genet 1993; 30: 1-26\nREVIEW ARTICLE\nThe morbid anatomy of the human genome:\nchromosomal location of mutations causing\ndisease\nVictor A McKusick, Joanna S Amberger\nAbstract\nInformation is given in tabular form de-\nrived from a synopsis of the human gene\nmap which has been updated continu-\nously since 1973 as part of Mendelian\nInheritance\nin\nMan\nJohns\nHopkins\nUniversity Press, 10th ed, 1992) and of\nOMIM (Online Mendelian Inheritance in\nMan, available generally since 1987). The\npart of the synopsis reproduced here\nconsists of chromosome by chromosome\ngene lists of loci for which there are asso-\nciated disorders (table 1), a pictorial rep-\nresentation of this information (fig la-d),\nand an index of disorders for which the\ncausative mutations have been mapped\n(table 2).\nIn table 1, information on genes that\nhave been located to specific chromoso-\nmal positions and are also the site of\ndisease producing mutations is arranged\nby chromosome, starting with chromo-\nsome 1 and with the end of the short arm\nof the chromosome in each case.\nIn table 2 an alphabetised list of these\ndisorders and the chromosomal location\nof the mutation in each case are pro-\nvided. Both in the 'Disorder' field of table\n1 and in table 2, the numbers 1, 2, or 3 in\nparentheses after the name of the dis-\norder\nindicate\nthat\nits\nchromosomal\nlocation was determined by mapping of\nthe wildtype gene (1), by mapping of\nthe clinical phenotype\n(2), or by both\nstrategies (3).\n(J Med Genet 1993;30:1-26)\nThe fields in the listing by chromosome (table\n1) are as follows:\nLocation\n-\nthat\nis,\nchromosomal\nsite\n(p = short arm; q = long arm; numbers = band;\nter = end).\nSymbol - The symbol approved by\nthe\nNomenclature Committee of the Human Gene\nMapping Workshops and their successor orga-\nnisation is given first; alternative symbols are\nincluded.\nStatus\n-\nC = confirmed;\nP = provisional;\nL= 'in limbo' (that is, tentative or inconsis-\ntent). The 'in limbo' entries are not listed in\nfig 1.\nTitle - name of gene locus.\nMIM# - This is the number in McKusick's"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 998
encoding: FLOAT32
metadata:
{"title": "The morbid of the human chromosomal location of mutations causing disease", "chroma:document": "Mendelian Inheritance in Man, 10th ed (1992)\nand its continuously updated online version\nOMIM. (For historical reasons, the number\nmay sometimes indicate location of the entry in\nthe 'dominant catalogue' because the wildtype\ngene was characterised and mapped before the\nrecessive disorder resulting from mutation at\nthat site. The practice is to create only one\nentry in OMIM for each gene locus.)\nMethod of mapping\nA = in situ DNA-RNA or DNA-DNA anneal-\ning ('hybridisation'), for example, ribosomal\nRNA\ngenes\nto\nacrocentric\nchromosomes;\nkappa light chain genes to chromosome 2.\nAAS = deductions\nfrom\nthe\namino\nacid\nsequence of proteins,\nfor example, linkage\nof delta and beta globin loci from study of\nhemoglobin Lepore.\nC = chromosome\nmediated\ngene\ntransfer\n(CMGT), for example, cotransfer of galacto-\nkinase and thymidine kinase.\nCh = chromosomal\nchange\nassociated\nwith\nparticular phenotype and not proved to repre-\nsent linkage (Fc), deletion (D), or virus effect\n(V), for example, loss of 13q14 band in some\ncases of retinoblastoma.\nD = deletion or dosage mapping (concurrence\nof chromosomal deletion and phenotypic evid-\nence of hemizygosity), trisomy mapping (pres-\nence of three alleles in the case of a highly\npolymorphic locus), or gene dosage effects\n(correlation of trisomic state of part or all of a\nchromosome with 50% more gene product).\nIncludes\n'loss\nof\nheterozygosity'\n(loss\nof\nalleles) in malignancies. Examples: acid phos-\nphatase- 1\nto\nchromosome\n2;\nglutathione\nreductase to chromosome 8. Includes DNA\ndosage, for example, fibrinogen loci to 4q2.\nDosage mapping also includes coamplification\nin tumour cells.\nEM= exclusion mapping, that\nis, narrowing\nthe possible location of loci by exclusion of\nparts of the map by deletion mapping, extended\nto include negative lod scores from families\nwith marker chromosomes and negative lod\nscores with other assigned loci, for example,\nsupport for assignment of MNSs to 4q.\nCenter for Medical\nGenetics, The Johns\nHopkins University\nSchool of Medicine,\nBlalock Building,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 999
encoding: FLOAT32
metadata:
{"title": "The morbid of the human chromosomal location of mutations causing disease", "chroma:document": "Room 1007, 600 N\nWolfe Street,\nBaltimore, MD\n21287-4922, USA.\nV A McKinsick\nJ S Amberger\nCorrespondence to\nDr Amberger.\nReceived 12 October 1992.\nI"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1000
encoding: FLOAT32
metadata:
{"title": "Intracellular trafficking of HLA-E and its regulation", "chroma:document": "ARTICLE\nIntracellular trafficking of HLA-E and its regulation\nWanlin He1\ue840, Ester Gea-Mallorqu\u00b4\u01311\ue840, Huw Colin-York2\ue840, Marco Fritzsche2\ue840, Geraldine M. Gillespie1\ue840, Simon Brackenridge1\ue840,\nPersephone Borrow1\ue840, and Andrew J. McMichael1\ue840\nInterest in MHC-E\u2013restricted CD8+ T cell responses has been aroused by the discovery of their efficacy in controlling simian\nimmunodeficiency virus (SIV) infection in a vaccine model. The development of vaccines and immunotherapies utilizing human\nMHC-E (HLA-E)\u2013restricted CD8+ T cell response requires an understanding of the pathway(s) of HLA-E transport and antigen\npresentation, which have not been clearly defined previously. We show here that, unlike classical HLA class I, which rapidly\nexits the endoplasmic reticulum (ER) after synthesis, HLA-E is largely retained because of a limited supply of high-affinity\npeptides, with further fine-tuning by its cytoplasmic tail. Once at the cell surface, HLA-E is unstable and is rapidly\ninternalized. The cytoplasmic tail plays a crucial role in facilitating HLA-E internalization, which results in its enrichment in\nlate and recycling endosomes. Our data reveal distinctive transport patterns and delicate regulatory mechanisms of HLA-E,\nwhich help to explain its unusual immunological functions.\nIntroduction\nMHC-E is a highly conserved non-classical major histocom-\npatibility complex class I (MHC-I) molecule. Although HLA-E\n(human MHC-E) cell surface expression is universal, it is\nnormally low compared with classical HLA-Ia molecules\n(D\u2019Souza et al. 2019). The main function of HLA-E is to present\na highly conserved peptide VL9 (VMAPRTL/VV/L/FL), which\nis derived from the leader sequences of other HLA-I (HLA-A/\nB/C and G) molecules, to CD94/NKG2 receptors on natural\nkiller (NK) cells (Borrego et al., 1998; Braud et al., 1998a).\nThus, MHC-E regulates NK cell functions, a role that is con-\nserved across mammals.\nMHC-E can also present different pathogen-derived pep-\ntides to CD8+ T cells, though reports are scarce compared with"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1001
encoding: FLOAT32
metadata:
{"title": "Intracellular trafficking of HLA-E and its regulation", "chroma:document": "classical MHC-Ia molecules. HLA-E can activate CD8+ T cells\nthrough the presentation of Mycobacterium tuberculosis (Mtb)\npeptides (Heinzel et al., 2002). Among the 36 Mtb-derived\npeptides shown to bind to HLA-E, 11 are recognized by CD8+\nT cells (Joosten et al., 2010). The CD8+ T cells activated by\nthese peptides in Mtb infection exhibit HLA-E\u2013restricted cy-\ntotoxic activity against mycobacterium-infected cells (van\nMeijgaarden et al., 2015). HLA-E can also present Salmonella\ntyphi (S. typhi) peptides to CD8+ T cells and inhibit S. typhi\npathogenesis (Fresnay et al., 2016; Rudolph et al., 2019;\nSalerno-Gon\u00e7alves et al., 2004). A BZLF1 peptide derived from\nthe EBV can also bind to HLA-E and activate CD8+ T cells\n(Garc\u00b4\u0131a et al., 2002; Ulbrecht et al., 1998). HLA-E\u2013restricted\npresentation of human cytomegalovirus (HCMV) UL40-derived\npeptide, with an identical sequence to the human VL9 peptide,\ncan stimulate specific CD8+ T cells that effectively recognize and\nkill HCMV-infected cells (Mazzarino et al., 2005; Pietra et al.,\n2003). Recent studies of a simian immunodeficiency virus (SIV)\nvaccine that enabled 55% of rhesus macaques (RMs) to clear in-\nfection following an SIV challenge have sparked renewed interest\nin MHC-E (Hansen et al., 2011; Hansen et al., 2013; Hansen et al.,\n2016). This vaccine, vectored by a particular strain of rhesus cy-\ntomegalovirus (RhCMV68-1) with key gene deletions and en-\ngineered to express SIV genes, stimulates an MHC-E\u2013restricted\nCD8+ T cell response that is critical for the effective and long-\nlasting protection observed in vaccinated RMs (Hansen et al.,\n2016; Malouli et al., 2021).\nHLA-E\u2013bound pathogen-derived epitopes offer potential\nadvantages for vaccine-elicited CD8+ T cell responses. Many\npathogens downregulate surface HLA-Ia molecules to evade\nimmune recognition (Antoniou and Powis, 2008), which\nposes a significant challenge for vaccines targeting CD8+ T cell\nresponses. However, HLA-E is usually resistant to such\ndownregulation and is frequently upregulated, thus preserv-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1002
encoding: FLOAT32
metadata:
{"title": "Intracellular trafficking of HLA-E and its regulation", "chroma:document": "ing the HLA-E\u2013NKG2A axis, which enables pathogens to avoid\nNK cell\u2013mediated lysis (McMichael and Picker, 2017). This\nretained or augmented surface expression ensures the effi-\ncacy of HLA-E\u2013restricted CD8+ T cells if they can be elicited by\nvaccination. The typical low surface expression of HLA-E may\nprevent or limit natural HLA-E\u2013restricted T cell priming in\nmost infections, making prior immune escape unlikely and\nfacilitating the therapeutic application of HLA-E\u2013restricted\nT cells. There are only two dominant alleles of HLA-E that\n.............................................................................................................................................................................\n1Nuffield Department of Medicine, Center for Immuno-Oncology, University of Oxford, Oxford, UK;\n2Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.\nCorrespondence to Andrew J. McMichael: andrew.mcmichael@ndm.ox.ac.uk; Simon Brackenridge: simon.brackenridge@ndm.ox.ac.uk; Persephone Borrow:\npersephone.borrow@ndm.ox.ac.uk.\n\u00a9 2023 He et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).\nRockefeller University Press\nhttps://doi.org/10.1084/jem.20221941\n1 of 18\nJ. Exp. Med. 2023 Vol. 220 No. 8\ne20221941"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1003
encoding: FLOAT32
metadata:
{"title": "Linkage of internal minisatellite loci chromosome and exclusion of autosomal dominant retinitis pigmentosa proximal rhesus", "chroma:document": "1JMed Genet 1990; 27: 14-16\nLinkage of internal minisatellite loci on chromosome 1\nand exclusion of autosomal dominant retinitis\npigmentosa proximal to rhesus\nChris F Inglehearn, Surinder S Papiha, Marcelle Jay, Alan F Wright, Anthony T Moore,\nShomi S Bhattacharya\nAbstract\nWe report the exclusion of a locus for autosomal\ndominant\nretinitis\npigmentosa\nproximal\nto\nthe\nrhesus locus in a single large pedigree. In addition,\na\npreviously\nunreported\nlinkage\nis\ndescribed\nbetween\ntwo\nchromosome\n1\nmarkers,\nwhich\nconfirms that a highly variable minisateilite locus is\nplaced internally on chromosome 1.\nRetinitis pigmentosa is an inherited human disorder\ncharacterised by\nprogressive\ndegeneration\nof the\nretina, leading to loss of visual field, night blindness,\nand ultimately to complete loss of sight late in the\ndisease\nprocess.' There\nare X linked, autosomal\ndominant,\nand\nautosomal\nrecessive\nforms,\nwith\nphenotypic heterogeneity in all categories. Families\nfalling into the autosomal dominant retinitis pigmen-\ntosa (ADRP) category can be further subdivided on\nthe basis of age of onset, penetrance, and persistence\nof a measurable rod electroretinogram. 4 Several\nreports have suggested that an ADRP locus is linked\nto rhesus on chromosome lp, but with lod scores no\nhigher than 1-89 at a recombination fraction of 0-2 in\nmale meioses and 0 4 in female meioses.5-8 In one\nlarge Irish pedigree such a location has been excluded,\nconsistent with the hypothesis that phenotypic varia-\ntion in ADRP is the result of underlying genetic\nheterogeneity.9 We report linkage data using two\nDepartment of Human Genetics, University of Newcastle\nupon Tyne, 19 Claremont Place, Newcastle upon Tyne\nNE2 4AA.\nC F Inglehearn, S S Papiha, S S Bhattacharya\nMoorfields Eye Hospital, City Road, London.\nM Jay\nMRC Human Genetics Unit, Western General Hospital,\nEdinburgh.\nA F Wright\nAddenbrooke's Hospital, Hills Road, Cambridge.\nA T Moore\nCorrespondence to Dr S S Bhattacharya.\nReceived for publication\n11 August 1989."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1004
encoding: FLOAT32
metadata:
{"title": "Linkage of internal minisatellite loci chromosome and exclusion of autosomal dominant retinitis pigmentosa proximal rhesus", "chroma:document": "Revised version accepted for publication 8 September\n1989.\nVNTR probes derived from chromosome 1 in a single\nlarge family in which regional ADRP'\nhas been\ndiagnosed. One of these probes, YNZ2, obtained\nfrom Yusuku Nakamura, detects a moderately variable\nlocus, DIS57, with at least eight alleles'0 approxi-\nmately 11 cM proximal to rhesus on chromosome\nip.\"1 The other, known as pMSl, was donated by\nProfessor Alec Jeffreys and is a truly hypervariable\nsequence (at least 33 alleles, none of which attain a\nsignificant population frequency) detected by finger-\nprinting probe 33 15.12 This probe has been assigned\nto lp33-35 by in situ hybridisation,'3 but has as yet\nnot been genetically mapped.\nMaterials and methods\nGenomic DNA prepared from lymphocytes of subjects\nin family ADRP5 was digested at 65\u00b0C with TaqI, size\nfractionated on a 1% agarose gel, and capillary blotted\nonto nylon filters (Hybond N, Amersham). Filters\nwere prehybridised in 7% SDS and 0 5 mol/l sodium\nphosphate\nbuffer\nat 68\u00b0C\nfor\n30 minutes,\nthen\nhybridised in the same buffer overnight with 32p\nlabelled probes. Washes were at 65\u00b0C in 0- 1 x SSC and\n0-1% SDS.\nResults and discussion\nLymphocyte DNA from subjects in the pedigree\nshown in fig 1, known as ADRP5, were digested with\nTaqI, southern blotted, then probed first with pMSl\nand then with YNZ2. The lod scores obtained from\nanalysis of the results are shown in the table. When\ncalculating the lod scores for linkage between each\nprobe and ADRP, all subjects classed as unaffected,\nwho were either under the age of 25 or had not been\nseen by an ophthalmologist, were excluded. Large\nnegative lod scores betweenADRPand YNZ2 exclude a\nlocus for ADRP proximal to rhesus in this family.\nFurther experiments are under way in this laboratory\nto test this family with a suitable probe distal to\nrhesus, and also to analyse four other large ADRP\nfamilies, one cone-rod dystrophy pedigree, and one\nfamily with Sorsby's macular degeneration with these\n14"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1005
encoding: FLOAT32
metadata:
{"title": "Search for consanguinity within and families of patients with trichothiodystrophy associated with xeroderma pigmentosum", "chroma:document": "J Med Genet 1990; 27: 21-25\nSearch for consanguinity within and among families\nof patients with trichothiodystrophy associated with\nxeroderma pigmentosum\nFiorella Nuzzo, Gianna Zei, Miria Stefanini, Rita Colognola, Augusta Silvana Santachiara,\nPaola Lagomarsini, Stefano Marinoni, Laura Salvaneschi\nAbstract\nThe association of two rare hereditary disorders,\ntrichothiodystrophy\n(TTD)\nand\nxeroderma\npigmentosum (XP), was found in four patients from\nthree families, apparently unrelated but living in the\nsame\ngeographical\narea.\nIn\norder\nto\ntest\nthe\nhypothesis of a common ancestor, consanguinity\nwithin and among the families was checked using\nthree\ndifferent\napproaches:\nreconstruction\nof\ngenealogical trees, typing of blood markers, and\nsurname analysis.\nThe\nresults\nof the\nthree\ntypes\nof analyses\nstrengthen the hypothesis that, in at least two out of\nthe three families, the genetic defect determining\nthe TTD/XP phenotype is identical by descent, as a\nconsequence of remote inbreeding. This implies\nthat if two mutations are responsible for the two\ndiseases they are at linked loci or affect the same\ngene.\nThe hereditary disorders xeroderma pigmentosum\n(XP) and trichothiodystrophy (TTD) have both been\nfound to be present in patients showing clinical and\ncellular photosensitivity, typical of XP, in addition to\nclinical\ntraits of TTD\n(brittle hair with reduced\nsulphur content,\nichthyosis,\nphysical and mental\nretardation). '\nAt present, 19 photosensitive TTD patients have\nbeen\nreported; DNA\nrepair\nstudies\nhave\nbeen\nperformed\nin\ncells\nfrom\n10\npatients\nand\nIstituto di Genetica Biochimica ed Evoluzionistica, CNR,\nVia Abbiategrasso 207, 27100 Pavia, Italy.\nF Nuzzo, G Zei, M Stefanini, R Colognola, P Lagomarsini\nDipartimento di Genetica e Microbiologia 'A Buzzati-\nTraverso', Universita di Pavia, Italy.\nA S Santachiara\nIstituto per l'Infanzia, Trieste, Italy.\nS Marinoni\nCentro Trasfusionale AVIS, Pavia, Italy.\nL Salvaneschi\nCorrespondence to Dr Nuzzo.\ncomplementation analysis showed the presence of the"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1006
encoding: FLOAT32
metadata:
{"title": "Search for consanguinity within and families of patients with trichothiodystrophy associated with xeroderma pigmentosum", "chroma:document": "XP group D (XP-D) mutation in all of them.2 3\nXP\nand TTD\nare\nboth\nautosomal\nrecessive\ndisorders\nresulting\nfrom\nsingle\ngene\ndefects.\nHomozygote frequency is very low: XP occurs in 1\nout\nof\n250 000\nsubjects,\nthe\nXP-D\npatients\ncomprising\nabout\n10%\nof\nall\nthe\nXP\ncases\ninvestigated.4 5 The incidence of TTD is unknown; a\ntotal\nof\n81\npatients\n(with\nand\nwithout\nphotosensitivity) from 51 families has been reported\nsince 1963.2 Thus, the presence of the homozygous\nconditions for both mutations is a highly improbable\nevent\nand\nalternative\nexplanations\nshould\nbe\nconsidered for the occurrence of the complex XP-D/\nTTD phenotype.\nThe four patients described by Stefanini\net al,'\nbelonging to three families, apparently unrelated but\nliving\nin\nthe\nsame\ngeographical\narea,\noffer\nthe\nopportunity to investigate some genetic aspects, in\nparticular the identity of the defect.\nWe checked consanguinity within and among the\nthree families using different approaches, namely the\nreconstruction of genealogical\ntrees, the study of\nblood genetic markers, and the analysis of surnames.\nMaterials and methods\nThe families studied (families 1, 2, and 3) originated\nfrom, and currently live in, small towns no more than\n100 km apart, located in an area of about 1600 km2 in\nthe plain behind the Alps in north-east Italy (Veneto\nand Friuli-Venezia Giulia regions).\nData\nfor\nthe\nconstruction\nof\npedigrees\nand\nsurnames were obtained by direct interview and from\nregisters of births, marriages, and deaths and area\nstatistics. Data on consanguinity in these regions were\nobtained from the list of consanguineous marriages\navailable for the period 1911 to 1964 (Moroni and Zei,\nunpublished data).\nBlood samples were obtained from three patients\naffected by XP-D and TTD (one from family 1, two\nfrom family 2), from their parents, from the parents\nof a dead affected child (from family 3), and from\nrelatives in the three families. The subjects examined,\nthat is, 11 from family 1, 12 from family 2, and eight\nfrom family 3, are shown in fig 1."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1007
encoding: FLOAT32
metadata:
{"title": "Search for consanguinity within and families of patients with trichothiodystrophy associated with xeroderma pigmentosum", "chroma:document": "Received for publication 14 December 1988.\nRevised version accepted for publication 27 June 1989.\n21"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1008
encoding: FLOAT32
metadata:
{"title": "Original articles An exclusion of Marfan syndrome", "chroma:document": "J Med Genet 1990; 27: 73-77\nOriginal articles\nAn exclusion map of Marfan syndrome\nSusan H Blanton, Mansoor Sarfarazi, Hans Eiberg, Jacques de Groote, Peter A Farndon,\nMichael W Kilpatrick, Anne H Child, F Michael Pope, Leena Peltonen, Clair A Francomano,\nCatherine Boileau, Marion Keston, Petros Tsipouras\nAbstract\nThe combined genetic data between the Marfan\nsyndrome and 75 informative loci on 18 autosomes\nwere used to construct an exclusion map for this\ndisorder. Data are also presented for a further two\nunmapped markers. The most likely location of the\nMarfan syndrome gene is highlighted and all the\nunexcluded areas of the genome are displayed in a\ngraphical form. This exclusion map shows that\nalmost 75% of the genome has been excluded as a\nlikely location for the Marfan syndrome gene in\nDepartment\nof Pediatrics,\nUniversity\nof Connecticut\nHealth Center, Farmington, CT 06032, USA.\nS H Blanton*, M Sarfarazi, P Tsipouras\nInstitute of Medical Genetics, University of Copenhagen,\nDenmark.\nH Eiberg\nClinical Genetics Unit, Birmingham Maternity Hospital,\nBirmingham.\nJ de Groote, P A Farndon, M W Kilpatrick\nDepartment\nof\nCardiological\nSciences,\nSt\nGeorge's\nHospital Medical School, London.\nJ de Groote, A H Child\nClinical Research Centre, Harrow, Middlesex.\nJ de Groote, F M Pope\nLaboratory\nof Molecular\nGenetics,\nNational\nPublic\nHealth Institute, Helsinki, Finland.\nL Peltonen\nDivision of Medical Genetics, Johns Hopkins Medical\nSchool, Baltimore, MD, USA.\nC A Francomano\nUnite 73, INSERM, Paris, France.\nC Boileau\nClinical Genetics Service, Western General Hospital,\nEdinburgh.\nM Keston\nCorrespondence to Dr Sarfarazi.\n*Present address: Graduate School of Biomedical Sciences,\nUniversity of Texas Health\nSciences\nCenter,\nHouston,\nTX 77225, USA.\nReceived for publication 16 August 1989.\nRevised version accepted for publication 26 October 1989.\nthe majority of the families studied. Apart from\nchromosomes 8, 13, 21, and 22, for which no data\nwere\navailable, other regions not excluded yet"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1009
encoding: FLOAT32
metadata:
{"title": "Original articles An exclusion of Marfan syndrome", "chroma:document": "include Sp, 6p, 9p, 10p, 12p, 15, 17p, 18, and 20p.\nFuture linkage analysis using markers located in the\nhighlighted regions\nshould\nfacilitate\nthe\nidenti-\nfication of the site of the Marfan syndrome gene.\nMarfan\nsyndrome\n(MS)\nis\na\nserious\nheritable\ndisorder of connective tissue associated with signi-\nficant morbidity and mortality.' The mapping of the\ngene for MS will help significantly in our eventual\nunderstanding of its pathogenesis and, more impor-\ntantly, it will be essential in the design of a rational\ntherapy. Since 1976 a number of reports on linkage\nstudies in MS have appeared, none of which showed\nlinkage of MS to a marker.\nMore recently (June 1989) various groups involved\nin linkage analysis in MS were invited to participate in\nthe first International Genetic Linkage Workshop on\nMarfan syndrome. At the meeting it was agreed that\na significant advance towards the mapping of the gene\nwould be made by the pooling of all linkage data for\nMS to date. In particular, this would avoid unnecessary\nduplication of negative results and highlight those\nareas of the genome not yet studied.\nAs a result of this meeting a consortium of those\ninvolved with MS was formed. This paper presents a\nmore\ndetailed\nexclusion map\nfor MS\nbased on\npreviously published reports, and on the data provided\nby other members of the consortium; some of the\nindividual data sets are given in full in the other\npapers in this issue of the Journal.\nSource of linkage data\nThe linkage data presented here were compiled either\nduring\nthe\nfirst\nInternational Workshop by\nthe\ncollaborating consortium groups or were subsequently\nsent to us. In addition previously published data were\nincorporated. The pooled data on MS consist\nat\npresent of 77 markers on 18 autosomes. Seventy-five\nof these markers have been localised with various\ndegrees of confidence and the remaining two (APOH\nand C6) are still unmapped. These two markers have\nbeen excluded from our analysis. Three of the groups\n73"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1010
encoding: FLOAT32
metadata:
{"title": "Linkage data for Marfan syndrome and markers chromosomes and 11", "chroma:document": "8\nMed Genet 1990; 27: 82-85\nLinkage data for Marfan syndrome and markers on\nchromosomes\n1 and 11\nJacques de Groote, Peter A Farndon, Michael V Kilpatrick, Anne de Paepe,\nJ W Oorthuys,\nNorman C Nevin, Anne H Child, F Michael Pope\nAbstract\nSix large families with classical Marfan syndrome\nwere studied using markers on chromosomes 1 and\n11. Two of three families tested showed negative\nscores using DIS7 but a third family gave a positive\nscore (0.92) at 0=0*1. The other chromosome 1\nmarkers typed (MUCI, NGFB, DIS8) excluded\nclose linkage. Negative lod scores with two chromo-\nsome 11q22 markers (DIIS84, DIIS148) excluded\nat least 20 cM in this area (Z= <-2), which was\nchosen for study as two enzymes responsible for\ncoliagen degradation (coliagenase and stromelysin)\nare localised to this region.\nMarfan syndrome is a dominantly inherited connective\ntissue disorder affecting primarily the skeletal, ocular,\nand cardiovascular systems. The estimated prevalence\nis 6/100 000, with 25% of cases resulting from new\nDermatology Research Group, Clinical Research Centre,\nHarrow, Middlesex.\nJ de Groote, F M Pope\nClinical Genetics Unit, Birmingham Maternity Hospital,\nBirmingham.\nP A Farndon, M V Kilpatrick\nFacultair Centrum voor Medische Genetica, Universitair\nZiekenhuis, Gent, Belgium.\nA de Paepe\nKindergeneeskunde,\nAcademisch\nZiekenhuis\nbij\nde\nUniversiteit van Amsterdam, The Netherlands.\nJ W Oorthuys\nDepartment of Medical Genetics, Belfast City Hospital,\nBelfast.\nN C Nevin\nDepartment\nof\nCardiological\nSciences,\nSt\nGeorge's\nHospital Medical School, Cranmer Terrace, London\nSW17 ORE.\nA H Child\nCorrespondence to Dr Child.\nmutations.' The gene shows a high penetrance. The\ncondition is heterogeneous2 and shows great intra-\nfamilial variability of expression.\nA typical Marfan syndrome patient is characterised\nby an asthenic build, being unusually tall with a high\narched palate, long thin extremities, arachnodactyly,\nchest wall deformities (pectus carinatum, excavatum),\nscoliosis, and joint hypermobility. Common ocular"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1011
encoding: FLOAT32
metadata:
{"title": "Linkage data for Marfan syndrome and markers chromosomes and 11", "chroma:document": "abnormalities range from myopia to bilateral lens\ndislocation and retinal detachment. Eighty percent\nhave cardiovascular involvement ranging from mitral\nvalve prolapse to aortic root dilatation and aneurysm.\nMost of the premature deaths result from aortic\ndissection, although beta blocker therapy decreases\nthe rate of dilatation of the aortic root, while elective\nsurgical replacement prolongs life, with an 87% five\nyear postoperative survival rate.3\nThe primary defect of Marfan syndrome remains\nunknown, and no laboratory or prenatal diagnostic\ntest\nis available. Although many abnormalities of\nconnective tissue have been reported,\"7 none of the\nputative genes coding for major connective tissue\nfibrillar components has been found to be linked in\nfamily studies.812\nTo date, however, the following loci have been\nexcluded in the families studied: COLIAI, COLIA2,\nCOL2AI, COL3AI, COL6AI, COL6A2, COL6A3,\nand tentatively, elastin.\nIn\n1979, Mace's study of 17 families with\n19\nconventional markers yielded a maximum lod score of\n1F38 at 0=0-25 between the rhesus blood group locus\non chromosome 1 and Marfan syndrome.'3\nIn our present study, we report exclusion data for\nfour loci on chromosome 1 and two loci on chromo-\nsome\n11. Linkage studies were performed for six\nfamilies with classical Marfan syndrome, that\nis,\nmembers classically affected in at least two out of\nthree major systems (table 1) with a pedigree showing\nautosomal dominant inheritance.\nThe two main enzymes responsible for collagen\ndegradation are collagenase (localised to 1 1q21-q22. 1)\nand stromelysin ( l1q22.2-q22.3).14 It is possible that\nexcessive degradation of collagen (and other com-\nponents of connective tissue) could be the primary\ncause of Marfan syndrome. A regulatory gene for\ncollagenase or stromelysin or both becomes a new\nReceived for publication 8 September 1989.\nRevised version accepted for publication 30 October 1989.\n82"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1012
encoding: FLOAT32
metadata:
{"title": "Linkage analysis in Marfan syndrome", "chroma:document": "8J Med Genet 1990; 27: 86-90\nLinkage analysis in Marfan syndrome\nRobin C Schwartz, Susan H Blanton, Catherine A Hyde, Thomas R Sottile Jr, Louanne Hudgins,\nMansoor Sarfarazi, Petros Tsipouras\nAbstract\nWe have analysed 40 marker loci on 13 chromo-\nsomes for linkage with Marfan syndrome. None of\nthe loci was linked to the Marfan syndrome locus\nat 0=0.00. This study provides\na basis for an\nexclusion map and for further coliaboration\nin\nmapping of the locus.\nMarfan syndrome (MS) is an autosomal dominant\ndisorder of the connective tissue, characterised by\ncardiovascular,\nmusculoskeletal,\nocular,\nand\npul-\nmonary abnormalities. This condition is estimated to\nhave a prevalence of 4 to 6 per 100 000 persons and\nimparts\nsignificant\nmorbidity\nand\nmortality.' 2\nAlthough the clinical manifestations of this disorder\nhave been very well described,' to date there is only\none documented genetic defect in one family. This\nwas originally reported by Byers et al3 to be a small\npolypeptide insertion in the a2 chain of type\nI\ncollagen, and has recently been shown by Phillips et\na14 to be a single nucleotide change that results in a\nsubstitution of glutamine for arginine at position 618\nin the triple helical domain of the protein. However,\nthe causal relationship between\nthis finding and\nthe phenotype remains unclear. Despite numerous\nhistological,\nultrastructural,\nand\nbiochemical\ninvestigations 9 and genetic linkage studies using\nconventional protein and cell surface markers,'0 11 as\nwell as the candidate gene approach,'2-'7 the under-\nlying genetic basis of MS has eluded definition.\nFor this reason, we developed the strategy of using\nrestriction fragment length polymorphisms (RFLPs)\nthat are associated with random probes throughout\nthe genome to map the MS locus. We present the\nresults of our analysis of 10 three generation families\nhere.\nDepartment\nof Pediatrics,\nUniversity\nof Connecticut\nHealth Center, Farmington, CT 06032, USA.\nR C Schwartz, S H Blanton*, C A Hyde, T R Sottile Jr,\nL Hudgins, M Sarfarazi, P Tsipouras"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1013
encoding: FLOAT32
metadata:
{"title": "Linkage analysis in Marfan syndrome", "chroma:document": "Correspondence to Dr Tsipouras.\n*Present address: Graduate School of Biomedical Sciences,\nUniversity of Texas Health\nSciences Center, Houston,\nTX 77225, USA.\nReceived for publication 16 August 1989.\nRevised version accepted for publication 26 October 1989.\nMaterials and methods\nPEDIGREES\nTen three generation families with MS\nwere\nas-\ncertained, in which the proband had involvement\nof the cardiovascular, musculoskeletal, and ocular\nsystems. One of us (PT) personally examined 100\naffected and unaffected subjects included in\nthis\nstudy.\nThe\nclinical\nevaluation\nusually\nincluded\nanthropometric measurements, clinical examination,\na dilated slit lamp examination by an ophthalmologist,\nand an echocardiogram. The diagnosis of MS was\nmade if a subject had at least two major manifesta-\ntions and one minor manifestation, as described in\ntable 1, which summarises the clinical features of this\ncondition. The phenotype in all families was con-\nsistent with the above diagnostic criteria. Family 1\nlacked aortic dilatation but certain persons had mitral\nvalve prolapse. In family 6 the lenses were only mildly\nTable\nI\nMajor\nsyndrome.\nand minor manifestations of Marfan\nMajor\nMinor\nSystem\nfindings\nfindings\nOcular\nEctopia lentis\nMyopia\nRetinal detachment\nCardiovascular\nAortic regurgitation\nMitral valve prolapse\nAortic root diameter\n(clinically and on\ndilatation\nechocardiogram)\nMusculoskeletal\nKyphosis\nTall stature\nPectus deformity\nArachnodactyly\nUpper to lower\nJoint laxity\nsegment ratio at\nleast 2 SD below\nmean for age\nPulmonary\nPneumothorax\nTable 2\nStructure of MS pedigrees.\nPhase\nFamily\nNo of\nNo of\nPotential\nknown\nno\naffected\nunaffected\nmeioses\nmeioses\nMS1\n17\n11\n28\n19\nMS2\n3\n2\n5\n2\nMS3\n11\n8\n19\n4\nMS4\n6\n6\n12\n5\nMS6\n10\n4\n14\n7\nMS7\n5\n0\n4\n1\nMS8\n4\n1\n4\n1\nMS9\n3\n1\n3\n2\nMS1O\n14\n4\n18\n1\nMS11\n12\n5\n17\n15\nTotal\n85\n42\n124\n57\n86"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1014
encoding: FLOAT32
metadata:
{"title": "Alphafetoprotein in midtrimester Down's syndrome fetal", "chroma:document": "2\nMed Genet 1990; 27: 240-243\nAlphafetoprotein in midtrimester Down's syndrome\nfetal serum\nMary J Seller\nAbstract\nSerum alphafetoprotein was estimated in fetuses\nwith and without Down's syndrome or with other\nchromosome abnormalities from the 17th to the\n28th week of pregnancy. In normal fetuses, the AFP\nlevel declines steadily during this period. Before 20\nweeks, there was no difference in the serum AFP\nlevels of the three groups of fetuses. After 20 weeks,\nthe serum AFP level in cases of Down's syndrome\ndeclined more rapidly than normal. This was not\nobserved\nin\nfetuses\nwith\nother\nchromosome\nabnormalities.\nThis suggests that low maternal\nserum alphafetoprotein levels used for prenatal\nscreening for Down's syndrome in the early second\ntrimester cannot be explained by low levels in the\nDown's fetuses themselves.\nIt is now well established that midtrimester maternal\nserum alphafetoprotein (MSAFP) levels tend to be\nlower\nthan normal when\nthe\nfetus\nhas Down's\nsyndrome. 1-6 Some workers have found that the\namniotic fluid alphafetoprotein (AFAFP) levels are\nbelow the normal median in such cases too,2 58 while\nothers have found them to be normally distributed.\n'4\nThe mechanism for these low AFP levels in the\nmaternal serum, and possibly the amniotic fluid, is\nnot yet known, but one suggestion has been that\nDown's syndrome fetuses produce less AFP than\nnormal fetuses.9 My previous studyl'\nsuggested that\nthis is not so; consequently, I have examined this\npoint further by determining the serum AFP levels in\nmidtrimester\nfetuses\nwith\nand\nwithout\nDown's\nsyndrome.\nMaterials and methods\nFetal blood samples were obtained from two sources\nand the results were analysed separately. In one case,\nDivision of Medical and Molecular Genetics, United\nMedical and Dental Schools of Guy's and St Thomas's\nHospitals, Guy's Campus, London SEI 9RT.\nM J Seller\nReceived for publication 12 April 1989.\nRevised version accepted for publication\nI November 1989.\nfresh\nfetal\nblood was\nobtained\nby\npercutaneous"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1015
encoding: FLOAT32
metadata:
{"title": "Alphafetoprotein in midtrimester Down's syndrome fetal", "chroma:document": "umbilical cord sampling (cordocentesis) from the 18th\nto\n28th week\nof pregnancy\nfor\ndiagnostic\nfetal\nkaryotyping. In the other, postmortem blood samples\nwere obtained by cardiac puncture from\nfetuses\nreceived for postmortem examination after prosta-\nglandin termination of pregnancy, or after a mid-\ntrimester spontaneous abortion, between 17 and 26\nweeks of gestation.\nAfter either means of collection, the blood samples\nwere spun at 6000 rpm for 10 minutes. The serum was\ndiluted 1 in 200,\n1 in 100, or 1 in 50 with distilled\nwater according to gestational age, and the AFP level\nwas quantified by one dimensional crossed antigen-\nantibody electrophoresis (the rocket technique).\"\nCordocentesis\nsamples\nfrom\nfetuses\nwithout\nDown's syndrome were divided into two groups and\ntheir results were also analysed separately. Group 1\n(41 samples) comprised fetuses which were completely\nnormal, both chromosomally and developmentally.\nThese were derived from patients undergoing the\nprocedure for raised maternal age who presented too\nlate for amniocentesis, or where the amniotic cell\nculture had failed, or where the fetus was at risk for a\nblood disorder. Group 2 (49 samples) consisted of\nfetuses who were chromosomally normal but who had\na developmental defect, such as diaphragmatic hernia,\nhydrocephalus, congenital heart defect, or exomphalos,\nor there was an obstructive uropathy or Rhesus\nincompatibility.\nSamples were also received from\nfetuses with renal agenesis,\nascites, hydrops, and\nintrauterine\ngrowth\nretardation,\nbut\nthey\nwere\nexcluded from the study.\nAll postmortem specimens of fetuses with Down's\nsyndrome were derived from termination of preg-\nnancy after prenatal diagnosis. Seven fetuses without\nDown's syndrome also came from terminations: five\nhad a neural tube defect and two were normal. Serum\nAFP\nresults from\nthese were pooled with those\nobtained\nfrom\n16\nspontaneous\nabortions\nof\nan\napparently\nnormal\nfetus\n(group\n3).\nOnly\nthose\nabortuses that were fresh, showing no sign of early"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1016
encoding: FLOAT32
metadata:
{"title": "Alphafetoprotein in midtrimester Down's syndrome fetal", "chroma:document": "maceration, were selected for study, in an attempt to\nobtain a comparable group to those from terminations,\nwhere the fetuses were presumably alive up to the\ntime of the induction. Unfortunately, because of\ndepartmental\npolicy\nnot\nto perform chromosome\n240"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1017
encoding: FLOAT32
metadata:
{"title": "Cerebrocostomandibular syndrome in four sibs,", "chroma:document": "7\nMed Genet 1991; 28: 704-707\nCerebrocostomandibular syndrome in four sibs, two\npairs of twins\nVassiliki Drossou-Agakidou, Alexandros Andreou, Vassiliki Soubassi-Griva,\nMaria Pandouraki\nAbstract\nWe report four sibs, two pairs of twins, with\ncerebrocostomandibular syndrome (CCMS).\nThe family history was negative. All four\nbabies\nhad\nthe\ncharacteristic\nfeatures\nof\nCCMS, including Pierre-Robin anomalad and\nrib dysplasia. Cerebral involvement was evid-\nent in two of the patients who had suffered\nperinatal asphyxia. The presence of the syn-\ndrome in all four sibs together with the negat-\nive family history in previous generations is\nconsistent with Mendelian autosomal reces-\nsive inheritance with high penetrance.\nThe cerebrocostomandibular syndrome (CCMS) is\na rare dysmorphic syndrome\nfirst described by\nSmith et all in 1966. At least 34 cases of the syn-\ndrome have been reported to date.23 It is character-\nised primarily by defective costal development and\nfeatures of the Pierre-Robin anomalad.\"2 Cerebral\nmaldevelopment or malfunction is common among\nthe reported cases.2 We describe the syndrome in\nfour sibs, consisting of two pairs of twins. To our\nknowledge, this is the first report ofCCMS in twins.\nCase reports\nThe mother was a 23 year old primigravida at the\nbirth of the first pair of twins. The father was 28\nDepartment of Neonatology and Neonatal Intensive\nCare Unit, Aristotelian University of Thessaloniki,\nGreece.\nV Drossou-Agakidou, V Soubassi-Griva\nNeonatal Intensive Care Unit, Ippokration Hospital\nof Thessaloniki, Greece.\nA Andreou\nDepartment of Radiology, Ippokration Hospital of\nThessaloniki, Greece.\nM Pandouraki\nCorrespondence to Dr Drossou-Agakidou, 52 Neapoleos\nStreet, 54454 Thessaloniki, Greece.\nyears old and non-consanguineous. The parents\nwere clinically and radiologically normal and there\nwas no history of malformations in the family (fig 1)\nor of exposure to any known teratogenic agents\nduring the pregnancies. Prenatal ultrasound indic-\nated polyhydramnios in both pregnancies, but no"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1018
encoding: FLOAT32
metadata:
{"title": "Cerebrocostomandibular syndrome in four sibs,", "chroma:document": "malformations were detected. Both pairs of twins\nwere delivered by caesarian section at 38 weeks'\ngestation.\nCASES 1 AND 2 (II1i AND III-2)\nThe first pair of twins (cases 1 and 2), two boys, had\ntwo placentas and the same ABO and rhesus blood\ngroups, so that we cannot be certain about the\nzygosity. Both babies had low Apgar scores and\nrequired resuscitation. Endotracheal intubation was\nimpossible and they both received oxygen by face\nmask and ambu bag. Soon after birth they developed\nsevere respiratory distress which improved after the\ninsertion of nasopharyngeal tubes. Both babies had\nfeatures of the Pierre-Robin anomalad (severe mic-\nroretrognathia, glossoptosis, and cleft palate). The\nchest radiograph of case 1 showed a funnel shaped\nthorax with\n11 pairs of ribs (no 12th pair was\nidentified) and discontinuity of the posterior arcs of\nboth fifth ribs (fig 2). The chest radiograph of case 2\nwas similar with discontinuity of the right fifth rib\nonly (fig 3).\nBoth babies had clinical signs of mild postasphyx-\nial\nencephalopathy and\nfeeding\ndifficulties,\nfor\nwhich they needed gavage feeding. Case 1 was doing\nwell, breathing through the nasopharyngeal tube,\nuntil the 50th day of life, when he was found dead in\n1\n2\n3\n4\nReceived for publication 13 December 1990.\nRevised version accepted for publication 7 March 1991.\n704\nFigure 1\nFamily pedigree."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1019
encoding: FLOAT32
metadata:
{"title": "Cancer family syndrome: cytogenetic investigations, in vitro tetraploidy, and biomarker studies in large family", "chroma:document": "I MedGenet 1990; 27: 441-445\nCancer family syndrome: cytogenetic investigations, in\nvitro tetraploidy, and biomarker studies in a large\nfamily\nGinevra Guanti, Francesco Susca, Giuseppe Cristofaro, Maria Lucia Caruso, Serafina Massari,\nRosa Porsia, Alessandro Stella, Italo Giorgio\nAbstract\nFifty-five members of a family with the cancer\nfamily syndrome (CFS) were investigated for the\nfoliowing potential biomarkers for cancer prone-\nness: (1) cytogenetics of peripheral blood lympho-\ncytes and skin fibroblasts; (2) in vitro tetraploidy of\ndermal fibroblast monolayer cultures; (3) quantita-\ntive\nserum\nimmunoglobulin\ndeterminations;\n(4)\nstudy of genetic linkage with respect to eight blood\ngroup markers including Kidd.\nBiological specimens were\nobtained from\n14\npatients affected with cancer, 21 subjects at risk,\nand 20 healthy subjects. None of the markers\ntested in this family, in order to identify a biomarker\nfor the status of CFS gene carrier, was found to be\nuseful. Our search for linkage to other biological\nmarkers (DNA RFLPs and NK cells) is in progress.\nColon cancer is the second most common internal\nmalignancy. About 5 to 10% of all colon cancers have\nbeen estimated to occur in families with an inherited\nsusceptibility, as seen in Gardner's syndrome, familial\npolyposis\ncoli,\nTurcot's\nsyndrome,\nand\nLvnch's\nsyndrome\ntypes\nI and\nII.\nInvestigation\nof such\nfamilies may help us to understand the aetiology of\nmalignancy and help in selecting subjects at risk for\nmore intensive surveillance and earlier detection of\ntumours.\nWe report here the results of a series of genetic\nIstituto\ndi\nGenetica,\nUniversita\ndegli\nStudi,\nVia G\nAmendola 165/A, 70126 Bari, Italy.\nG Guanti. S Massari, R Porsia. A Stella\nIstituto Scientifico Gastroenterologico De Bellis, Castel-\nlana, Italy.\nF Susca, G Cristotaro, M L Caruso,\nI Giorgio\nCorrespondence to Dr Guanti.\nstudies on a large family with a hereditary predis-\nposition to non-polypotic colon cancer syndrome or\nLynch's syndrome type 11.1 Its main features include"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1020
encoding: FLOAT32
metadata:
{"title": "Cancer family syndrome: cytogenetic investigations, in vitro tetraploidy, and biomarker studies in large family", "chroma:document": "early age of onset of tumours, increased frequency of\nadenocarcinomas of the colon, mainly proximal loca-\ntion of colorectal tumours,\na high occurrence of\ngastric, endometrial, and multiple primary malignan-\ncies, and an autosomal dominant mode of inheritance\nof the susceptibility to colorectal and other neoplasias.\nPotential markers for cancer proneness,2 that is,\ncytogenetic\nstudies of peripheral lymphocytes,\nin\nvitro\ntetraploidy\nof dermal\nfibroblast monolayer\ncultures, quantitative serum immunoglobulin deter-\nminations, and red cell blood groups, were investigated\nin this study.\nMaterials and methods\nThe family was identified by one of us (GC) in 1985\nwhen a 26 year old subject reported that many\nrelatives\nhad\ncolon\ncancer.\nOnce informed,\nthe\nconsenting members of the family were interviewed\nand\nall available medical and other vital records\nreviewed. Retrospective clinical data were obtained\nfrom interviews with members of the fourth and fifth\ngenerations, who identified the names of members of\nthe first and second generations. Medical records and\npathology\ndocuments\nwere\nthen\nretrieved\nfrom\nphysicians as well as hospitals throughout the geo-\ngraphical catchment area where the majority of the\nfamily lived. The relative lack of population mobility\namong this kindred, coupled with availability of\nmedical records in the area, made possible clinical\nand pathological documentation on relatives with or\nwithout cancer. The same members were then offered\na clinical examination, gastroscopy and colonoscopy,\nand laboratory analyses. Several subjects accepted and\nwere evaluated accordingly. The diagnosis of persons\nin generation VII of the family was provisional\nbecause most of them were children under the age of\npuberty or under the age of risk. The pedigree is\nshown in the figure. The clinical phenotypes have\nbeen previously published.3\nIn order to investigate the possible existence of\nReceived for publication 9 October 1989.\nRevised version accepted for pbtilication\nI February\n1990.\n41"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1021
encoding: FLOAT32
metadata:
{"title": "Review article Cystic fibrosis screening and community genetics", "chroma:document": "J Med Genet 1990; 27: 475-479\nReview article\nCystic fibrosis screening and community genetics\nB Modell\nCystic fibrosis (CF), the commonest serious recessively\ninherited disease of Caucasians,\nis fast becoming\npreventable. The gene in which mutation can lead to\nCF, the cystic fibrosis transmembrane conductance\nregulator (CFTR), has recently been identified, and a\ndeletion of three DNA base pairs that removes a\nphenylalanine residue from position 508 of the protein\nproduct accounts for 60 to 80% ofCF mutations in the\nUK population.' This mutation can be detected by\nrelatively simple DNA methods.2 3 Consequently,\ngeneticists are now confronting an imminent need to\nset up\npopulation\nscreening\nfor CF\ncarriers,\na\nchallenge that, if appropriately seized, could greatly\nimprove the delivery of genetics services as a whole.\nAt present, clinical geneticists are mainly concerned\nwith diagnosis, counselling, and prenatal diagnosis for\nfamilies referred to them. Relatively few have yet\nbeen drawn into the issues of population screening\nand the outreach approach to the community that it\nentails. However, a recent report of the Royal College\nof Physicians (RCP)4 pointed out the existence of a\nrange\nof 'community\ngenetics\nservices',\nthat\nis,\npreventive\ngenetics\nservices\nbased on population\nscreening that are often delivered by obstetricians and\nothers,\nrather\nthan by\nclinical\ngeneticists.\nThey\ninclude (1) neonatal screening for phenylketonuria,\ncongenital hypothyroidism, and other disorders; (2)\nscreening in pregnancy for rhesus blood group and\nviral infections, maternal serum AFP screening, the\noffer of fetal karyotyping\nto older women,\nand\nmidtrimester ultrasound scanning for fetal anomalies;\n(3) population screening for carriers of haemoglobin\ndisorders or Tay-Sachs disease.\nThe RCP report noted many shortcomings in the\ndelivery of these services and proposed that they\nPerinatal Centre, Department of Obstetrics and Gynae-\ncology, UCH School of Medicine, 86-96 Chenies Mews,\nLondon WC1E 6HX, and Department of Public Health"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1022
encoding: FLOAT32
metadata:
{"title": "Review article Cystic fibrosis screening and community genetics", "chroma:document": "and Policy, London School of Hygiene and Tropical\nMedicine.\nB Modell\nshould be improved, not only by increased resource\nallocation\nbut\nalso\nby\nappropriate\nregional\nand\nnational organisation, public education and profes-\nsional training, and service monitoring.\nIncreased\ninvolvement\nof clinical\ngeneticists\nin delivery\nof\ncommunity genetics services was strongly recom-\nmended,\nespecially\nwith\nregard\nto\norganisation,\nmonitoring, information, and counselling. The new\ndevelopments in CF are likely to bring this about,\nsince\nclinical\ngeneticists\nwill\nnecessarily\nplay\na\nprominent\npart\nin organising national\nscreening,\nbecause of the large numbers and the DNA tech-\nnology involved. The time has come\nto plan\na\ncomprehensive prevention programme for CF, based\non a national policy and including laboratory services,\ninfrastructure\nfor\nscreening,\ninformation\nfor\nthe\npublic, education for health professionals, prenatal\ndiagnosis, and service monitoring.\nCarrier screening and prenatal diagnosis for\nrecessively inherited disorders\nIn dominant or X linked conditions, such as Hunting-\nton's chorea or haemophilia, the family history is the\nkey\nto\nidentifying\ncarriers,\nbut with\nrecessively\ninherited conditions, like cystic fibrosis or the haemo-\nglobin disorders, the issues of carrier screening are\nvery different.\n(1) The number of carriers vastly exceeds the\nnumber of affected children: about a hundred times\nmore CF carriers than patients are born annually.\nWhen carrier screening is possible and desirable, the\nlarge numbers imply that screening and counselling\nmust be integrated into primary health care.\n(2) Most affected\ninfants\nare born\nto couples\nwithout a family history. Population screening, when\nit is possible, is the only way to detect most carriers.\nFew of the carriers so detected will be familiar with\nthe major disease.\n(3) When prenatal diagnosis is possible but carriers\ncannot be detected, only the second affected birth to\nthe same couple can be avoided. For the past few"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1023
encoding: FLOAT32
metadata:
{"title": "Review article Cystic fibrosis screening and community genetics", "chroma:document": "years, this has been the situation with CF. Though\nsuch 'retrospective' prevention is very beneficial for\n475"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1024
encoding: FLOAT32
metadata:
{"title": "Exclusion of autosomal dominant polycystic kidney disease (ADPKD2) from 160 of chromosome", "chroma:document": "I Med Genet 1990; 27: 697-700\nExclusion of autosomal dominant polycystic kidney\ndisease type\nII (ADPKD2) from 160 cM of\nchromosome\n1\nShrawan Kumar, William J Kimberling, Patricia A Gabow, Yin Y Shugart, Sandra Pieke-Dahl\nAbstract\nAutosomal dominant polycystic kidney disease is a\nheritable disorder and recent studies have shown\ngenetic heterogeneity,\nwith some,\nbut not\nall,\nfamilies showing linkage with markers on chromo-\nsome 16p. Members of a large ADPKD family,\nunlinked to chromosome 16, have been typed for 12\nmarker loci located on both arms of chromosome 1.\nMultipoint analysis excluded ADPKD2 from the\nregion\nbetween DIS81 (pTHH33)\nand D1S67\n(pHHH106) on the long arm and between Rh and\nPGMI on the short arm. This excludes the disease\nlocus from about 61% of chromosome\n1.\nAutosomal\ndominant\npolycystic\nkidney\ndisease\n(ADPKD) is a systemic disorder characterised by\ncysts in the kidneys, liver, pancreas, and ovaries and\nby structural abnormalities in the gastrointestinal\ntract, vascular tree, and cardiac valves. ADPKD is\none of the most common genetic disorders, occurring\nwith a frequency of about 1:1000, and is responsible\nfor 8 to 9% of end stage renal disease in Europe and\nNorth America. 1-3\nOne gene responsible forADPKD has been localised\non the short arm ofchromosome 16 by virtue ofshowing\ntight linkage between the cluster of genes coding for\nthe a chain of haemoglobin4 and the gene for the\nenzyme\nphosphoglycolate\nphosphatase\n(PGP).5 6\nHowever, subsequent studies showed genetic hetero-\ngeneity in ADPKD with the observation of a lack of\nDepartment of Genetics, Center for Hereditary Com-\nmunication Disorders, Boys Town National Research\nHospital, 555 North 30th Street, Omaha, Nebraska 68131,\nUSA.\nS Kumar, W\nJ Kimberling, Y Y Shugart, S Pieke-Dahl\nDepartment of Medicine, University of Colorado Health\nSciences Center, Denver, Colorado 80262, USA.\nP A Gabow\nCorrespondence to Professor Kimberling.\nReceived for publication\n11 April 1990.\nAccepted for publication 9 May 1990."}


