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Do adipose-derived mesenchymal stem cells ameliorate STZ-induced pancreas damage in type 1 diabetes?	To investigate the possibility of adipose-derived mesenchymal stem cells (ADSC) in the treatment of type 1 diabetes (T1D). ADSC were isolated from the adipotic tissue of abdomen in Sprague-Dawley rats (4-6 week-old,female) and expanded in vitro. Cells were then identified by testing their phenotypes through flow cytometry. Balb/c mice (8 week-old, male) were divided into 3 groups: T1D group, ADSC group and control group. Streptozocin (50 mg/kg·d) were injected intraperitoneally into mice of T1D group and ADSC group for 5 consecutive days to establish the T1D model. In ADSC group, ADSC were injected intravenously on day 3 of STZ injection. In control group, only PBS was injected. Fasting blood glucose (FGB) level was examined once a week. At the end of the 4th week, animals were killed. The pathological changes of islet were showed by histochemistry through hematoxylin-eosin staining (HE staining). β cell insulin expression was detected by quantum dots immunofluorescence histochemistry. After ADSC administration, FGB levels decreased significantly from the second week. Whereas FGB levels in T1D group increased significantly and continuously during the experimental period. Moreover, ADSC effectively suppressed pancreatic islet damage induced by STZ and increased the expression of insulin protein in pancreatic β cells.	We conducted this pooled analysis to assess the prognostic value of pretreatment Quality of Life (QOL) assessments on overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Four hundred twenty patients with advanced NSCLC (stages IIIB with pleural effusion and IV) from six North Central Cancer Treatment Group trials were included in this study. QOL assessments included the single-item Uniscale (355 patients), Lung Cancer Symptom Scale (217 patients), and Functional Assessment of Cancer Therapy-Lung (197 patients). QOL scores were transformed to a 0 to 100 scale with higher scores representing better status and categorized using the sample median or clinically deficient score (CDS, <or=50 versus >50). Cox proportional hazards models stratified by study were used to evaluate the prognostic importance of QOL on OS alone and in the presence of other prognostic factors such as performance status, age, gender, body mass index, and laboratory parameters. Pretreatment QOL accessed by Uniscale was significantly associated with OS univariately (p < 0.0001). Uniscale (p < 0.0001; hazard ratio = 1.6 for the sample median and 2.0 for the CDS categorization) and body mass index were the only significant predictors of OS multivariately. The median survival of patients who had a Uniscale score less than or equal to the CDS (<or=50) was 5.7 versus 11.1 months for the >50 group; and 7.8 versus 13 months for the less than or equal to sample median (<or=83) group and >83 group, respectively. The Lung Cancer Symptom Scale and the Functional Assessment of Cancer Therapy-Lung total scores were not significant predictors of OS.
Is prevalence of asthma and allergic diseases in Croatian children increasing : survey study?	To estimate the prevalence of asthma, allergic rhinitis, and atopic dermatitis among school children in the region of Primorsko-goranska County in Croatia, and compare the results with data from other countries. The study was conducted during the 2001-2002 school year, in complete adherence to the Phase One protocol of the International Study of Asthma and Allergies in Childhood (ISAAC). The target population comprised two age groups (6-7 and 13-14 years) in the region of Primorsko-Goranska County in Croatia. Data were collected using standardized ISAAC written questionnaire and asthma video questionnaire. There were 1,634 participating children in the 6-7 age group (response rate 80.3%) and 2,194 participating children in the 13-14 age group (response rate 89.8%). Estimated 12-month prevalence rates of symptoms were: wheezing 9.7% and 8.4%, allergic rhinitis symptoms 16.9% and 17.5%, allergic rhinoconjunctivitis symptoms 5.6% and 6.7%, and atopic dermatitis symptoms 5.4% and 3.4%, for younger and older age group, respectively.	Leaks of the blood-brain barrier can be detected on postcontrast-enhanced T1-weighted MRIs. Although early disruptions of the blood-brain barrier appear to be an important risk factor for tissue plasminogen activator-related hemorrhages in rodents, little is known about their incidence and consequences in human stroke. This is a retrospective analysis of a prospectively collected stroke database over the past 6 years. In 52 patients, multimodal MRI (including diffusion-weighted, perfusion-weighted, and postcontrast-enhanced T1-weighted MRI to detect blood-brain barrier changes) had been performed immediately before systemic thrombolysis and in 48 patients within a median of 30 minutes (interquartile range: 30 to 60 minutes) after recombinant tissue plasminogen activator treatment. The incidence of symptomatic hemorrhage (SICH), defined as any parenchymal hemorrhage leading to deterioration in the patient's clinical condition, was related to several clinical and imaging variables, including early blood-brain barrier changes. Overall, SICH was detected in 9 (9%) patients and among these, 2 died. Although no blood-brain barrier changes were detectable before thrombolysis, 3 of 48 patients (6.25%) had a parenchymal gadolinium enhancement in the areas of initial infarction after tissue plasminogen activator treatment. All 3 patients developed SICHs at sites corresponding to the areas of enhancement. The presence of a parenchymal enhancement was significantly associated with SICH (P<0.01), whereas other clinical and imaging variables did not predict SICH in this series.
Does synovial fluid glycosaminoglycan concentration correlate with severity of chondropathy or predict progression of osteoarthritis in a canine cruciate deficiency model?	Considerable interest exists today in biochemical or immunochemical tests for monitoring the progression of osteoarthritis (OA). It has been suggested that measurements made on synovial fluid (SF) will more accurately reflect the magnitude of cartilage destruction in an index joint than those performed on serum. However, we have shown that the synovitis that occurs in OA affects the rate of protein clearance from the joint. We tested the hypothesis that if adjusted for clearance rate, the SF concentration of cartilage proteoglycans (PG) estimates severity of chondropathy and predicts progression of cartilage damage more accurately than if clearance is not taken into account. Clearance of radioiodinated serum albumin (RISA), a surrogate for the clearance of PG, was measured in 19 adult dogs at baseline and again 16 weeks and 32 weeks after anterior cruciate ligament transection (ACLT). Severity of chondropathy was determined arthroscopically after 16 weeks of instability and at postmortem 32 weeks after ACLT. Adjustment for the RISA clearance rate showed that the SF PG concentration markedly underestimated the quantity of PG released from the OA cartilage. Regardless of whether the concentration was adjusted for clearance, no correlation existed between the SF PG level and the severity of chondropathy. Further, the SF concentration of PG 16 weeks after ACLT failed to predict severity of cartilage damage at postmortem.	Previous research has demonstrated that chronic cigarette smoking and major depressive disorder (MDD) are each associated with cognitive decrements. Further, these conditions co-occur commonly, though mechanisms in the comorbid condition are poorly understood. There may be distinct, additive, or overlapping factors underlying comorbid cigarette smoking and MDD. The present study investigated the impact of smoking and MDD on executive function and emotion processing. Participants (N=198) were grouped by diagnostic category (MDD and healthy controls, HC) and smoking status (ever-smokers, ES and never-smokers, NS). Participants completed the Facial Emotion Perception Test (FEPT), a measure of emotional processing, and the parametric Go/No-go task (PGNG), a measure of executive function. FEPT performance was analyzed using ANCOVA with accuracy and reaction time as separate dependent variables. Repeated measures MANCOVA was conducted for PGNG with performance measure and task level as dependent variables. Analyses for each task included diagnostic and smoking group as independent variables, and gender was controlled for. Results for FEPT reveal that lower overall accuracy was found for ES relative to NS, though MDD did not differ from HC. Post-hoc analyses revealed that ES were poorer at identifying happy and sad, but not fearful or angry, faces. For PGNG, poorer performance was observed in MDD relative to HC in response time to Go targets, but there were no differences for ES and NS. Interaction of diagnosis and smoking group was not observed for performance on either task.
Does the Decline of Amylase Level of Pancreatic Juice After Pancreaticoduodenectomy predict Postoperative Pancreatic Fistula?	Postoperative pancreatic fistula (POPF) is a life-threatening complication after pancreaticoduodenectomy (PD). The aim of this study is to evaluate the significance of pancreatic amylase level of pancreatic juice for PF after PD. The subjects were 46 patients who underwent PD between January 2012 and August 2015 at Jikei University Hospital. We retrospectively investigated the relation between patient characteristics including pancreatic amylase level of pancreatic juice through the pancreatic drainage tube and the incidence of POPF (grade B or grade C according to the International Study Group on the Pancreatic Fistula) using univariate and multivariate analyses. The decline of pancreatic amylase level of pancreatic juice was evaluated by 1 - postoperative day 3/postoperative day 1 ratio. In univariate analysis, nonductal adenocarcinoma (P = 0.0252), soft pancreatic remnant (P = 0.0155), and decline of pancreatic amylase level of pancreatic juice ≥ 80% (P = 0.0010) were significant predictors of POPF. In multivariate analysis, decline of pancreatic amylase level of pancreatic juice of 80% or greater (P = 0.0192) was the only significant independent parameter.	Cohesion between sister chromatids is fundamental to ensure faithful chromosome segregation during mitosis and accurate repair of DNA damage postreplication. At the molecular level, cohesion establishment involves two defined events, a chromatin binding step and a chromatid entrapment event driven by posttranslational modifications on cohesin subunits. Here, we show that modification by the small ubiquitin-like protein (SUMO) is required for sister chromatid tethering after DNA damage. We find that all subunits of cohesin become SUMOylated upon exposure to DNA damaging agents or presence of a DNA double-strand break. We have mapped all lysine residues on cohesin's α-kleisin subunit Mcd1 (Scc1) where SUMO can conjugate. We demonstrate that Mcd1 SUMOylation-deficient alleles are still recruited to DSB-proximal regions but are defective in tethering sister chromatids and consequently fail to establish damage-induced cohesion both at DSBs and undamaged chromosomes. Moreover, we demonstrate that the bulk of Mcd1 SUMOylation in response to damage is carried out by the SUMO E3 ligase Nse2, a subunit of the related Smc5-Smc6 complex. SUMOylation occurs in cells with compromised Chk1 kinase activity, necessary for known posttranslational modifications on Mcd1, required for damage-induced cohesion.
Is lower-normal TSH associated with better metabolic risk factors : A cross-sectional study on Spanish men?	Subclinical thyroid conditions, defined by normal thyroxin (T4) but abnormal thyroid-stimulating hormone (TSH) levels, may be associated with cardiovascular and metabolic risk. More recently, TSH levels within the normal range have been suggested to be associated with metabolic syndrome and cardiovascular risk. This work studies the linearity of the relationship between metabolic syndrome and TSH across the euthyroid range. We studied 3533 male participants of the Aragon Workers' Health Study (AWHS) with normal TSH and free T4 levels, across quintiles of these variables, after adjusting for age, alcohol intake, and smoking. Compared with the lowest TSH quintile, the odds ratios for metabolic syndrome at the higher quintiles, which indicate lower thyroid function, were 1.34 (1.04, 1.73), 1.56 (1.21, 2.01), 1.57 (1.22, 2.03), and 1.71 (1.32, 2.21). The lowest free T4 quintile also showed an odds ratio of 1.49 (1.16, 1.90) with respect to the highest quintile. In addition, spline models showed departures from linearity: the risk of metabolic syndrome mostly increases at TSH values below the median (sample half-closest to subclinical hyperthyroidism). Interestingly, glucose also increases with TSH primarily below the median TSH, diastolic blood pressure shows similar changes across the entire TSH range, whereas body mass index, triglycerides, and high-density lipoprotein (HDL)-cholesterol change only at the highest normal TSH values, which are associated with lower free T4 concentration.	Aggressive periodontitis is characterized by rapid destruction of periodontal tissue caused by Aggregatibacter actinomycetemcomitans. Interleukin (IL)-1β is a proinflammatory cytokine, and its production is tightly regulated by inflammasome activation. Xylitol, an anticaries agent, is anti-inflammatory, but its effect on inflammasome activation has not been researched. This study investigates the effect of xylitol on inflammasome activation induced by A. actinomycetemcomitans. The differentiated THP-1 macrophages were stimulated by A. actinomycetemcomitans with or without xylitol and the expressions of IL-1β and inflammasome components were detected by real time PCR, ELISA, confocal microscopy and Immunoblot analysis. The effects of xylitol on the adhesion and invasion of A. actinomycetemcomitans to cells were measured by viable cell count. A. actinomycetemcomitans increased pro IL-1β synthesis and IL-1β secretion in a multiplicity of infection- and time-dependent manner. A. actinomycetemcomitans also stimulated caspase-1 activation. Among inflammasome components, apoptosis-associated speck-like protein containing a CARD (ASC) and absent in melanoma 2 (AIM2) proteins were upregulated by A. actinomycetemcomitans infection. When cells were pretreated with xylitol, proIL-1β and IL-1β production by A. actinomycetemcomitans infection was significantly decreased. Xylitol also inhibited ASC and AIM2 proteins and formation of ASC puncta. Furthermore, xylitol suppressed internalization of A. actinomycetemcomitans into differentiated THP-1 macrophages without affecting viability of A. actinomycetemcomitans within cells.
Is arterial wall thickness associated with prevalent cardiovascular disease in middle-aged adults . The Atherosclerosis Risk in Communities ( ARIC ) Study?	This study was done to assess the relationship between prevalent cardiovascular disease and arterial wall thickness in middle-aged US adults. The association of preexisting coronary heart disease, cerebrovascular disease, and peripheral vascular disease with carotid and popliteal intimal-medial thickness (IMT) (measured by B-mode ultrasound) was assessed in 13,870 black and white men and women, aged 45 to 64, during the Atherosclerosis Risk in Communities (ARIC) Study baseline examination (1987 through 1989). Prevalent disease was determined according to both participant self-report and measurements at the baseline examination (including electrocardiogram, fasting blood glucose, and medication use). Across four race and gender strata, mean carotid far wall IMT was consistently greater in participants with prevalent clinical cardiovascular disease than in disease-free subjects. Similarly, the prevalence of cardiovascular disease was consistently greater in participants with progressively thicker IMT. The greatest differences in carotid IMT associated with prevalent disease were observed for reported symptomatic peripheral vascular disease (0.09 to 0.22 mm greater IMT in the four race-gender groups).	Small cell lung cancer (SCLC) is an extremely aggressive disease, commonly displaying therapy-resistant relapse. We have previously identified neuroendocrine and epithelial phenotypes in SCLC tumours and the neuroendocrine marker, pro-opiomelanocortin (POMC), correlated with worse overall survival in patients. However, the effect of treatment on these phenotypes is not understood. The current study aimed to determine the effect of repeated irradiation treatment on SCLC cell phenotype, focussing on the neuroendocrine marker, POMC. Human SCLC cells (DMS 79) were established as subcutaneous xenograft tumours in CBA nude mice and then exposed to repeated 2Gy irradiation. In untreated animals, POMC in the blood closely mirrored tumour growth; an ideal characteristic for a circulating biomarker. Following repeated localised irradiation in vivo, circulating POMC decreased (p< 0.01), in parallel with a decrease in tumour size, but remained low even when the tumours re-established. The excised tumours displayed reduced and distinctly heterogeneous expression of POMC compared to untreated tumours. There was no difference in the epithelial marker, cytokeratin. However, there were significantly more N-cadherin positive cells in the irradiated tumours. To investigate the tumour response to irradiation, DMS79 cells were repeatedly irradiated in vitro and the surviving cells selected. POMC expression was reduced, while mesenchymal markers N-cadherin, β1-integrin, fibroblast-specific protein 1, β-catenin and Zeb1 expression were amplified in the more irradiation-primed cells. There were no consistent changes in epithelial marker expression. Cell morphology changed dramatically with repeatedly irradiated cells displaying a more elongated shape, suggesting a switch to a more mesenchymal phenotype.
Does carvacrol alleviate ischemia reperfusion injury by regulating the PI3K-Akt pathway in rats?	Liver ischemia reperfusion (I/R) injury is a common pathophysiological process in many clinical settings. Carvacrol, a food additive commonly used in essential oils, has displayed antimicrobials, antitumor and antidepressant-like activities. In the present study, we investigated the protective effects of carvacrol on I/R injury in the Wistar rat livers and an in vitro hypoxia/restoration (H/R) model. The hepatoportal vein, hepatic arterial and hepatic duct of Wistar rats were isolated and clamped for 30 min, followed by a 2 h reperfusion. Buffalo rat liver (BRL) cells were incubated under hypoxia for 4 h, followed normoxic conditions for 10 h to establish the H/R model in vitro. Liver injury was evaluated by measuring serum levels of alanine aminotransferase (ALT) and aspatate aminotransferase (AST), and hepatic levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondiadehyde (MDA), and hepatic histology and TUNEL staining. MTT assay, flow cytometric analysis and Hoechst 33258 staining were used to evaluate the proliferation and apoptosis of BRL cells in vitro. Protein expression was examined by Western Blot analysis. Carvacrol protected against I/R-induced liver damage, evidenced by significantly reducing the serum levels of ALT and AST, histological alterations and apoptosis of liver cells in I/R rats. Carvacrol exhibited anti-oxidative activity in the I/R rats, reflected by significantly reducing the activity of SOD and the content of MDA, and restoring the activity of CAT and the content of GSH, in I/R rats. In the in vitro assays, carvacrol restored the viability and inhibited the apoptosis of BRL cells, which were subjected to a mimic I/R injury induced by hypoxia. In the investigation on molecular mechanisms, carvacrol downregulated the expression of Bax and upregulated the expression of Bcl-2, thus inhibited the activation of caspase-3. Carvacrol was also shown to enhance the phosphorylation of Akt.	Sequential events of endometrial tumorigenesis can be studied by comparison of genetic lesions seen in normal, premalignant, and malignant tissues. The distribution of k-ras mutations in microsatellite stable and unstable premalignant lesions was studied to determine whether this gene is implicated in both tumorigenic pathways. K-ras mutations were analysed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing in matched endometrial normal, premalignant (atypical hyperplasias), and adenocarcinoma tissues from individual patients. Identification of precancers solely by their appearance as atypical endometrial hyperplasias is very subjective; therefore, in addition to histopathological assessment, we performed molecular testing (non-random X inactivation or clonal altered microsatellites) for an expected feature of precancers--that is, monoclonality. Equivalent K-ras mutation frequencies were seen in microsatellite stable (six of 33) and unstable (three of 23) cancers. In both types, K-ras mutation in monoclonal precancers usually corresponded to a change from normal to an equivocal (two of 12) or hyperplastic (10 of 12) histology. Divergent K-ras genotypes among multiple neoplastic tissues of individual patients (two of six patients) are exceptions explained either by multicentric premalignant disease, or acquisition of K-ras mutation late in neoplastic progression.
Does dexmedetomidine inhibit inducible nitric oxide synthase in lipopolysaccharide-stimulated microglia by suppression of extracellular signal-regulated kinase?	Dexmedetomidine (DEX) has been implicated in modulating the inflammatory response in central nervous system (CNS). However, the mechanism is still poorly understood. In this study, we evaluate the effects of DEX on lipopolysaccharide (LPS)-induced microglia activation and elucidate its possible signaling pathway involved in its anti-inflammatory effects. BV2 and primary microglia were pretreated with various concentrations of DEX (0·01, 0·1, 1, and 10 μM) and/or PD98059 for 1 hour, then microglia were incubated with LPS (1 μg/ml) for 24 hours. Nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression were measured by Griess reagent and real-time polymerase chain reaction. Furthermore, two intracellular signaling cascades including extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) were investigated by western blot analysis. Dexmedetomidine significantly attenuated LPS-induced NO production and iNOS expression in both BV2 cells and primary microglial cells. Lipopolysaccharide activated both ERK1/2 and JNK signal pathways; however, DEX exerted a specific inhibitory effect on ERK1/2 rather than JNK. Intriguingly, treatment of primary microglia and BV2 cells with DEX in combination with ERK1/2 inhibitor (PD98059) enhanced attenuation of LPS-induced NO production and iNOS expression.	The intertidal copepod Tigriopus californicus is a model for studying the process of genetic divergence in allopatry and for probing the nature of genetic changes that lead to reproductive isolation. Although previous studies have revealed a pattern of remarkably high levels of genetic divergence between the populations of this species at several spatial scales, it is not clear what types of historical processes are responsible. Particularly lacking are data that can yield insights into population history from the finest scales of geographic resolution. Sequence variation in both cytochrome b (CYTB, mtDNA) and the rieske iron-sulfur protein (RISP, nuclear) are examined at a fine scale within four different regions for populations of T. californicus. High levels of genetic divergence are seen for both genes at the broader scale, and genetic subdivision is apparent at nearly all scales in these populations for these two genes. Patterns of polymorphism and divergence in both CYTB and RISP suggest that selection may be leading to non-neutral evolution of these genes in several cases but a pervasive pattern of neither selection nor coadaptation is seen for these markers.
Does 5 mCi pretreatment scanning cause stunning when the ablative dose is administered within 72 hours?	To determine the stunning effect of a tracer dose of 5 mCi iodine-131. We retrospectively analyzed 145 patients who received the first ablative treatment at our service. Patients were divided according to disease status determined upon post-treatment scanning (101 patients with thyroid remnants and 44 with pulmonary metastases) and whole-body scanning before ablation (performed on 69 individuals). All patients with thyroid remnants were treated with an ablative dose of 100 mCi and those with metastases received 200 mCi. In patients with remnants only (n= 41) or metastases (n= 28) submitted to diagnostic scanning, uptake was found to be apparently increased in most patients cases (71 and 73%, respectively) 7 days after therapy, while reduced uptake (visual) was not observed in any patient. The efficacy of ablation was similar in the groups submitted or not to diagnostic scanning: 71 and 80% in patients without metastases (p= 0.28), respectively, and 43 and 50% in those with pulmonary involvement (p= 0.64).	Diabetes mellitus (DM) is a major risk factor for periodontal disease and affects various cellular functions. Periodontal ligament stem cells (PDLSCs) play an important role in periodontal tissue regeneration; however, the effect of hyperglycemia on PDLSCs is unclear. The aim of this study is to investigate whether hyperglycemia affects periodontal tissue regeneration, using human PDLSCs and high-glucose medium as a model of DM. PDLSCs were obtained from healthy adult human mandibular third molars. Cell proliferation, osteoblastic differentiation, and proinflammatory cytokine expression were investigated by culturing PDLSCs in media supplemented with four different glucose concentrations representative of control patients (5.5 mM), patients with postprandial or controlled DM (8.0 mM), and patients with uncontrolled DM (12.0 and 24.0 mM). The molecular effects of hyperglycemia on PDLSC physiology were examined with a focus on the nuclear factor (NF)-(κB signaling pathway. The involvement of NF-κB was investigated with a specific NF-κB inhibitor in PDLSCs under hyperglycemic conditions. High glucose levels inhibited PDLSC proliferation and differentiation into osteoblasts but induced NF-κB activation and subsequent interleukin (IL)-6 and IL-8 expression. Treatment with an NF-κB inhibitor rescued the defects in cell proliferation and osteoblastic differentiation and inhibited the IL-6 expression caused by the high-glucose environment.
Is familiar Papillary Thyroid Carcinoma in a Large Brazilian Family Associated with Succinate Dehydrogenase Defects?	Thyroid cancer is the most common endocrine gland malignancy. Advances in understanding the genetic basis for thyroid cancer revealed the potential involvement of several genes in the formation of thyroid tumors. Mutations in the gene coding for succinate dehydrogenase subtype B (SDHB) have been implicated in papillary thyroid cancer (PTC). Succinate dehydrogenase (SDH) is a heterotetrameric protein composed of four subunits, SDHA, SDHB, SDHC, and SDHD, and participates in both the electron transport chain and the tricarboxylic acid cycle. The aim of the study was to evaluate the association between variants in the SDHA, SDHB, SDHC, and SDHD genes and familiar PTC in a large Brazilian family. Four patients with PTC, 1 patient with PTC and gastrointestinal stromal tumor (GIST), 1 patient with GIST, and their relatives - several of them with different thyroid problems - from a large Brazilian family were screened for genetic variations of SDHx genes with the use of polymerase chain reaction-single-stranded conformational polymorphism and direct sequencing. Only one rare variation in SDHA was found in some of the family members, but not segregating with the disease. No other genetic variants of these genes were detected in the family members that presented with PTC and/or GIST.	Current conceptualizations of drug reinforcement assume that drug-taking behavior is a consequence of the contingent, temporal relationship between the behavior and drug reward. However, stimulant drugs also potentiate the rewarding effects of other reinforcers when administered noncontingently. These studies were designed to determine whether noncontingent nicotine enhances the reinforcing properties of a nonpharmacological reinforcer and whether this direct effect facilitates operant behavior within the context of a nicotine self-administration procedure. Rats self-administered nicotine or food, or received noncontingent nicotine, saline, or food either with or without a response-contingent, unconditioned reinforcing visual stimulus (VS). Noncontingent nicotine, whether delivered as discrete injections based on a pattern of self-administered nicotine or as a continuous infusion, increased response rates maintained by the VS. There were no significant differences in responding by animals that received contingent compared with noncontingent nicotine when a VS was available. This increase was not observed in the absence of the VS or as a consequence of noncontingent food delivery. Operant behavior was equally attenuated and reinstated by the removal and subsequent replacement of contingent and noncontingent nicotine. Nicotine supported self-administration in the absence of response-contingent, nicotine-paired stimuli; however, response rates were drastically reduced compared with nicotine self-administration with the VS.
Do increased interleukin-23/17 axis and C-reactive protein are associated with severity of acute pancreatitis in patients?	The interleukin (IL)-23/IL-17 axis plays an important role in various inflammatory conditions but its function in acute pancreatitis (AP) is not well understood. The present study investigated the relationship between serum levels of IL-23, IL-17, and C-reactive protein (CRP) in patients and the severity of AP. Eighty-five patients with AP were categorized into mild group, moderately severe group, and severe group according to the revised Atlanta classification, 2012. Serum levels of IL-23 and IL-17 were measured by enzyme-linked immunosorbent assay in patients 48 hours after admission. The CRP levels of patients were also measured on admission and 48 hours after admission. The serum levels of CRP of patients on admission and 48 hours after admission and levels of IL-23 and IL-17 of patients 48 hours after admission increased alone with the severity of AP, respectively (P < 0.01). The serum levels of IL-23 and IL-17 in the patients were correlated with CRP levels (r = 0.234, r = 0.552, P < 0.001, respectively).	Determining the ways in which personality traits interact with contextual determinants to shape social behavior remains an important area of empirical investigation. The specific personality trait of neuroticism has been related to characteristic negative emotionality and associated with heightened attention to negative, emotionally arousing environmental signals. However, the mechanisms by which this personality trait may shape social behavior remain largely unspecified. We employed eye tracking to investigate the relationship between characteristics of visual scanpaths in response to emotional facial expressions and individual differences in personality. We discovered that the amount of time spent looking at the eyes of fearful faces was positively related to neuroticism.
Does c-reactive protein increase with gestational age during pregnancy among Chinese women?	To examine the concentration of C-reactive protein (CRP) in relation to gestational weeks during pregnancy among Chinese women. From a randomized control trial of prenatal supplementation with folic acid, iron-folic acid, and multiple micronutrients in China, we examined 834 pregnant women with CRP measured initially between 5 and 20 weeks and at follow-up between 28 and 32 weeks gestation. We calculated and plotted CRP geometric means by gestational weeks. The same analysis was repeated for women who had normal pregnancies (624 women) by excluding women with stillbirth, preterm, small for gestational age, body mass index <18.5 kg/m(2) or >30 kg/m(2) at enrollment, and hypertension or anemia during pregnancy. We observed a significant positive trend between log-transformed CRP and gestational age from 5 to 20 weeks and from 28 to 32 weeks both in the full sample and in the subset of women who had normal pregnancies. CRP geometric mean was 0.81 mg/l at 5-7 weeks of gestation, 2.85 mg/l at 19-20 weeks of gestation, and 3.89 mg/l at 32 weeks of gestation. A similar increasing trend in the CRP median or percentage of elevated CRP were also observed.	Activation of extracellular signal-regulated kinase1/2 (ERK1/2) in dorsal horn of the spinal cord by peripheral inflammation is contributed to inflammatory pain hypersensitivity. Although electroacupuncture (EA) has been widely used to alleviate various kinds of pain, the underlying mechanism of EA analgesia requires further investigation. This study investigated the relationship between EA-induced analgesia and ERK signaling involved in pain hypersensitivity. The rats were randomly divided into control, model, EA and sham EA groups. Inflammatory pain model was induced by injecting of 100 μl Complete Freund's adjuvant (CFA) into the plantar surface of a hind paw. Rats in the EA group were treatment with EA (constant aquare wave, 2 Hz and 100 Hz alternating frequencies, intensities ranging from 1-2 mA) at 5.5 h, 24.5 h and 48.5 h. Paw withdrawal thresholds (PWTs) were measured before modeling and at 5 h, 6 h, 25 h and 49 h after CFA injection. Rats were killed and ipsilateral side of the lumbar spinal cords were harvested for detecting the expressions of p-ERK1/2, Elk1, COX-2, NK-1 and CREB by immunohistochemistry, real-time PCR, western blot analysis and EMSA. Finally, the analgesic effect of EA plus U0126, a MEK (ERK kinase) inhibitor, on CFA rats was examined. Inflammatory pain was induced in rats by hindpaw injection of CFA and significantly increased phospho-ERK1/2 positive cells and protein levels of p-ERK1/2 in the ipsilateral spinal cord dorsal horn (SCDH). CFA up-regulated of cyclooxygenase-2 (COX-2) mRNA and protein expression at 6 h after injection and neurokinin-1 receptor (NK-1) expression at 49 h post-injection, in the SCDH. EA, applied to Zusanli (ST36) and Kunlun (BL60), remarkably increased the pain thresholds of CFA injected rats, significantly suppressed ERK1/2 activation and COX-2 protein expression after a single treatment, and decreased NK-1 mRNA and protein expression at 49 h. EA decreased the DNA binding activity of cAMP response element binding protein (CREB), a downstream transcription factor of ERK1/2, at 49 h after CFA injection. Moreover, EA and U0126 synergistically inhibited CFA-induced allodynia.
Does tauroursodeoxycholic acid activate protein kinase C in isolated rat hepatocytes?	Ursodeoxycholic acid (UDCA) improves liver function in patients with chronic cholestatic liver diseases by an unknown mechanism. UDCA is conjugated to taurine in vivo, and tauroursodeoxycholic acid (TUDCA) is a potent hepatocellular Ca2+ agonist and stimulates biliary exocytosis and hepatocellular Ca2+ influx, both of which are defective in experimental cholestasis. Protein kinase C (PKC) mediates stimulation of exocytosis in the liver. The aim of this study was to determine the effects of TUDCA on PKC in isolated hepatocytes. The effect of TUDCA on the distribution of PKC isoenzymes within the hepatocyte was studied using immunoblotting and immunofluorescence techniques. In addition, the effect of TUDCA on the accummulation of sn-1,2-diacylglycerol (DAG), the intracellular activator of PKC, and hepatocellular PKC activity was studied using radioenzymatic techniques. Immunoblotting studies showed the presence of four isoenzymes (alpha, delta, epsilon, and zeta). The phorbol ester phorbol 12-myristate 13-acetate (1 mumol/L) induced translocation of alpha-PKC, delta-PKC, and epsilon-PKC from cytosol to a particulate membrane fraction, a key step for activation of PKC. TUDCA, but not taurocholic acid, selectively induced translocation of the alpha-PKC isoenzyme from cytosol to the membranes. In addition, TUDCA induced a significant increase in hepatocellular DAG mass and stimulated membrane-associated PKC activity.	Animal models suggest a genetic contribution to cerebral susceptibility to ischemia. Family history of stroke (FHxstroke) is a risk factor for ischemic stroke, but there is significant confounding by heritability of hypertension and other intermediate phenotypes, and it is uncertain whether genetic factors have a direct independent influence on cerebral susceptibility to ischemia in man. We related detailed FHxstroke to baseline characteristics and subsequent risk of stroke in 2 population-based incidence studies and a consecutive hospital-referred series of patients with recent transient ischemic attack (TIA). In none of the cohorts or the pooled data (757 patients; 5515 patient years follow-up; 200 ischemic strokes; 126 myocardial infarctions [MIs]) did FHxstroke predict ischemic stroke (odds ratio [OR], 0.87; 95% CI, 0.57 to 1.32). No associations were revealed by analyses stratified by age or hypertension in the proband, FHx(stroke) in parents versus siblings, number of affected relatives, or their age at stroke. FHxstroke was unrelated to presence of ischemic lesions on baseline computed tomography (OR, 0.96; 0.52 to 1.76) or risk of MI during follow-up. There was no bias attributable to any relationship between FHxstroke and risk factor control or medication.
Is not only type 2 diabetes but also prediabetes associated with portal inflammation and fibrosis in patients with non-alcoholic fatty liver disease?	Growing evidence suggests that not only type 2 diabetes (T2D) but also prediabetes (PD) is common in patients with non-alcoholic fatty liver disease (NAFLD). However, few data exist on how PD impacts the histological characteristics of NAFLD patients. In this exploratory study, we sought to investigate the associations of PD and T2D with the severity of the histological features in patients with NAFLD. The population consisted of 280 patients with biopsy-proven NAFLD. The associations of PD and T2D with the severity of histological features of NAFLD were analyzed using multiple logistic (or ordinal logistic) regression models after adjustment for confounding factors. PD and T2D was noted in 102 (36.4%) and 92 (32.8%) of patients, respectively. Of the 92 patients with T2D, ten (10.9%) were diagnosed de novo after the OGTT. PD and T2D were significantly associated with more severe portal inflammation (P<0.01); the adjusted odds ratios (ORs) of PD and T2D for having a higher grade of portal inflammation were 1.8 [95% CI, 1.1, 3.2] and 2.6 [95% CI, 1.3, 5.8]), respectively. A similar relationship was observed for liver fibrosis (P<0.001); specifically, the adjusted ORs of PD and T2D for having a higher grade of hepatic fibrosis were 2.4 [95% CI, 1.3, 3.7] and 3.8 [95% CI, 1.9, 6.1]), respectively.	To identify the risk factors for suboptimal response to GnRH agonist (GnRH-a) trigger and evaluate the effect of hCG on the outcome of patients with suboptimal response to GnRH-a. A retrospective data analysis. A tertiary-care academic medical center. A total of 8,092 women undergoing 8,970 IVF/intracytoplasmic sperm injection (ICSI) treatment cycles. All women underwent hMG + medroxyprogesterone acetate (MPA)/P treatment cycles during IVF/ICSI, which were triggered using a GnRH-a alone or in combination with hCG (1,000, 2,000, or 5,000 IU). Viable embryos were cryopreserved for later transfer. The rates of oocyte retrieval, mature oocytes, fertilization, and the number of oocytes retrieved, mature oocytes, and embryos frozen. In total, 2.71% (243/8,970) of patients exhibited a suboptimal response to GnRH-a. The suboptimal responders (LH ≤15 mIU/mL) had a significantly lower oocyte retrieval rate (48.16% vs. 68.26%), fewer mature oocytes (4.10 vs. 8.29), and fewer frozen embryos (2.32 vs. 3.54) than the appropriate responders. Basal LH levels served as the single most valuable marker for differentiating suboptimal responders with the areas under the receiver operating curve of 0.805. Administering dual trigger (GnRH-a and hCG 1,000, 2,000, 5,000 IU) significantly increased oocyte retrieval rates (60.04% vs. 48.16%; 68.13% vs. 48.16%; and 65.76% vs. 48.16%, respectively) in patients with a suboptimal response.
Is glycA , a biomarker of inflammatory glycoproteins , more closely related to the leptin/adiponectin ratio than to glucose tolerance status?	Plasma GlycA is a recently developed biomarker whose nuclear magnetic resonance signal originates from glycosylated acute-phase proteins. The aim of our study was to determine potential relationships between GlycA and adiposity, insulin resistance (HOMA(ir)), high sensitive C-reactive protein (hs-CRP), leptin, adiponectin, and the leptin/adiponectin ratio, and to test whether GlycA is elevated in subjects with impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM). Plasma GlycA, hs-CRP, leptin, adiponectin, the leptin/adiponectin ratio, and insulin resistance (HOMA(ir)) were measured in 103 fasting subjects (30 with normal fasting glucose, 25 with IFG and 48 with T2DM). In all subjects combined, plasma GlycA was correlated positively with body mass index (BMI), HOMA(ir), hs-CRP, leptin and the leptin/adiponectin ratio, and inversely with adiponectin (p < 0.05 to p < 0.001). GlycA did not significantly vary according to glucose tolerance category (p = 0.060). GlycA was related positively to the leptin/adiponectin ratio (p = 0.049), independent of BMI (p = 0.056) and HOMA(ir) (p = 0.50).	Decreased local availability of nitric oxide (NO) may mediate chronic vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Previous reports have shown that early treatment with NO prevents vasospasm in animals. We evaluated the efficacy of controlled-release polymers that contain the NO donor diethylenetriamine (DETA-NO) for the delayed treatment of vasospasm in a rabbit model of SAH. DETA-NO 20% (wt/wt) was incorporated into ethylene-vinyl acetate (EVAc) polymers. Animals (n = 52) were randomized to two experimental groups. In the first group (n = 32), animals received SAH and implantation of either 20% DETA-NO/EVAc polymer at a dose of 0.5 mg/kg of DETA-NO (n = 16) or empty EVAc polymer (n = 16). Polymers were implanted 24 (n = 16) or 48 hours (n = 16) after SAH. In the second group (n = 20), animals received SAH and implantation of either 20% DETA-NO/EVAc polymer at a dose of 1.3 mg/kg (n = 10) or empty EVAc (n = 10). Polymers were implanted 24 (n = 10) or 48 hours (n = 10) after SAH. An additional group (n = 16) underwent either sham operation (n = 6) or SAH only (n = 10). Animals were killed 3 days after hemorrhage, and the basilar arteries were processed for morphometric measurements. Results were analyzed using Student's t test. Treatment with 20% DETA-NO/EVAc polymers at a dose of 1.3 mg/kg significantly increased basilar artery lumen patency when administered at 24 (97 +/- 6% versus 73 +/- 10%; P = 0.0396) or 48 hours (94 +/- 6% versus 71 +/- 9%; P = 0.03) after SAH. Treatment with 20% DETA-NO/EVAc polymers at a dose of 0.5 mg/kg administered 48 hours after SAH significantly increased lumen patency (82 +/- 8% versus 68 +/- 12%; P = 0.03); a dose of 0.5 mg/kg, 24 hours after SAH, did not reach statistical significance (74 +/- 7% versus 65 +/- 9%; P = 0.16). The SAH-only group had a lumen patency of 67 +/- 12%.
Are beta-Catenin mutation and its nuclear localization confirmed to be frequent causes of Wnt signaling pathway activation in pilomatricomas?	beta-Catenin has been shown to play an important role in the formation of hair follicle-related tumors, including pilomatricomas. Several investigators have shown that beta-catenin gene mutation is observed in pilomatricomas. However, the relationship between the pattern of beta-catenin localization in the cell and beta-catenin gene mutation is still controversial. This work was performed to determine the frequency of beta-catenin nuclear localization in pilomatricoma, the relationship between the pattern of beta-catenin localization and beta-catenin mutation, and the involvement of APC mutation. Typical 32 pilomatricomas were examined for beta-catenin expression by immunostaining. Genomic DNA was extracted, amplified and sequenced from 23 pilomaticomas with nuclear beta-catenin staining and 4 pilomaticomas without nuclear beta-catenin staining. Mutations of beta-catenin gene were confirmed by subcloning assay and restriction endonuclease assay. Using immunostaining, we found that 81% (26/32) of pilomatricomas displayed nuclear beta-catenin staining in basophilic cells. Sequence analysis revealed that 61% (14/23) contained mutations in exon 3 of beta-catenin. However, no mutations were detected in 4 pilomaticomas without beta-catenin nuclear staining. Detected mutations were adjacent to or abolished well-known regulatory phosphorylation sites of beta-catenin. APC gene mutations were not detected in 27 pilomatricomas with/without beta-catenin nuclear staining.	Arterial stiffening and thickening and endothelial dysfunction may be associated with cognitive decline or white matter hyperintensities (WMH) independently of blood pressure level. We aimed to investigate, using an integrative approach, the relative contributions of structural and functional vascular factors to the degree of cognitive impairment (primary outcome) and the severity of WMH (secondary outcome) in elderly hypertensive patients with subjective memory complaints, a group prone to dementia. A prospective, dedicated, cross-sectional population of 198 elderly hypertensive patients (mean age 69.3+/-6.2 years) with subjective memory complaints underwent a full set of cognitive function assessments, brain MRI with semiquantification of WMH, carotid ultrasonography, carotid-femoral pulse wave velocity, brachial endothelial function, and plasma von Willebrand Factor measurements. After adjustment for the usual cardiovascular risk factors, increased arterial stiffness (as assessed by pulse wave velocity) was significantly and independently associated with memory impairment in men. The severity of WMH was independently associated with increased carotid intima media thickness and stiffness (as assessed by augmentation index) as well as with increased age and plasma levels of von Willebrand Factor, a biomarker of endothelial dysfunction.
Does furosemide improve renal recovery after hemofiltration for acute renal failure in critically ill patients : a double blind randomized controlled trial?	To study the potential beneficial role of furosemide in resolving renal failure after hemofiltration in mechanically ventilated critically ill patients. Single-center randomized, double blind, placebo-controlled study. A 13-bed mixed intensive care unit (ICU) in a teaching hospital. Patients who had been treated with continuous venovenous hemofiltration were included. After the end of continuous venovenous hemofiltration, the urine of the first 4 hours was collected for measuring creatinine clearance. Patients were subsequently randomized for furosemide (0.5 mg/kg/hr) or placebo by continuous infusion. To prevent hypovolemia, the rate of fluid infusion was adapted every hour and was set as the urinary production of the previous hour. End points were renal recovery (creatinine clearance more than 30 mL/min or stable serum creatinine without renal replacement therapy) in the ICU and in the hospital. Seventy-two patients were included and 71 were eligible for the analysis. The 36 furosemide-treated patients had a significantly increased urinary volume compared with the 35 placebo-treated patients (median 247 mL/hr (interquartile range [IQR] 774 mL/hr) vs. 117 mL/hr (IQR 158 mL/hr), p = 0.003) and greater sodium excretion (median 73 mmol/L (IQR 48) vs. 37 (IQR 48) mmol/L, p = 0.001). In the furosemide group 25 patients and in the placebo group 27 patients showed recovery of renal function at ICU discharge (p = 0.46). Two patients of the furosemide group needed long-term dialysis dependency (p = 0.23).	Recently, we have shown that intraplaque mast cell numbers are associated with atherosclerotic plaque vulnerability and with future cardiovascular events, which renders inhibition of mast cell activation of interest for future therapeutic interventions. However, the endogenous triggers that activate mast cells during the progression and destabilization of atherosclerotic lesions remain unidentified. Mast cells can be activated by immunoglobulins and in the present study, we aimed to establish whether specific immunoglobulins in plasma of patients scheduled for carotid endarterectomy were related to (activated) intraplaque mast cell numbers and plasma tryptase levels. In addition, the levels were related to other vulnerable plaque characteristics and baseline clinical data. OxLDL-IgG, total IgG and total IgE levels were measured in 135 patients who underwent carotid endarterectomy. No associations were observed between the tested plasma immunoglobulin levels and total mast cell numbers in atherosclerotic plaques. Furthermore, no associations were found between IgG levels and the following plaque characteristics: lipid core size, degree of calcification, number of macrophages or smooth muscle cells, amount of collagen and number of microvessels. Interestingly, statin use was negatively associated with plasma IgE and oxLDL-IgG levels.
Does elimination of laboratory ozone lead to a dramatic improvement in the reproducibility of microarray gene expression measurements?	Environmental ozone can rapidly degrade cyanine 5 (Cy5), a fluorescent dye commonly used in microarray gene expression studies. Cyanine 3 (Cy3) is much less affected by atmospheric ozone. Degradation of the Cy5 signal relative to the Cy3 signal in 2-color microarrays will adversely reduce the Cy5/Cy3 ratio resulting in unreliable microarray data. Ozone in central Arkansas typically ranges between approximately 22 ppb to approximately 46 ppb and can be as high as 60-100 ppb depending upon season, meteorological conditions, and time of day. These levels of ozone are common in many areas of the country during the summer. A carbon filter was installed in the laboratory air handling system to reduce ozone levels in the microarray laboratory. In addition, the airflow was balanced to prevent non-filtered air from entering the laboratory. These modifications reduced the ozone within the microarray laboratory to approximately 2-4 ppb. Data presented here document reductions in Cy5 signal on both in-house produced microarrays and commercial microarrays as a result of exposure to unfiltered air. Comparisons of identically hybridized microarrays exposed to either carbon-filtered or unfiltered air demonstrated the protective effect of carbon-filtration on microarray data as indicated by Cy5 and Cy3 intensities. LOWESS normalization of the data was not able to completely overcome the effect of ozone-induced reduction of Cy5 signal. Experiments were also conducted to examine the effects of high humidity on microarray quality. Modest, but significant, increases in Cy5 and Cy3 signal intensities were observed after 2 or 4 hours at 98-99% humidity compared to 42% humidity.	Tibial bones are shorter and less resistant to shear forces after treatment with doxorubicin, methotrexate, or cisplatin. We investigated the pattern of failure after shear loading of the proximal tibial growth plate in rats treated with these chemotherapeutic agents. Male Wistar rats from the age of 4 weeks were given doxorubicin intravenously at 15 mg/m2 body surface area (BSA), methotrexate 60 mg/m2 BSA, or cisplatin 7.5 mg/m2 BSA. There was one nontreated control group fed ad libitum an d a diet control group for each drug-treated group. At the age of 13 weeks the tibial bones were dissected. The proximal growth plate was shear loaded to failure in the posteroanterior direction. The pattern of failure through the growth plate was examined. In rats fed ad libitum the failure pattern ran mainly through the transitional zone between proliferating and hypertrophic chondrocytes, but the pattern of failure showed considerable variability. The pattern in rats treated with methotrexate or cisplatin and that in their diet controls were comparable. In rats treated with doxorubicin the fracture ran mainly through the trabecular zone.
Does chemotherapy affect the pattern of failure after shear loading of the proximal tibial growth plate?	Tibial bones are shorter and less resistant to shear forces after treatment with doxorubicin, methotrexate, or cisplatin. We investigated the pattern of failure after shear loading of the proximal tibial growth plate in rats treated with these chemotherapeutic agents. Male Wistar rats from the age of 4 weeks were given doxorubicin intravenously at 15 mg/m2 body surface area (BSA), methotrexate 60 mg/m2 BSA, or cisplatin 7.5 mg/m2 BSA. There was one nontreated control group fed ad libitum an d a diet control group for each drug-treated group. At the age of 13 weeks the tibial bones were dissected. The proximal growth plate was shear loaded to failure in the posteroanterior direction. The pattern of failure through the growth plate was examined. In rats fed ad libitum the failure pattern ran mainly through the transitional zone between proliferating and hypertrophic chondrocytes, but the pattern of failure showed considerable variability. The pattern in rats treated with methotrexate or cisplatin and that in their diet controls were comparable. In rats treated with doxorubicin the fracture ran mainly through the trabecular zone.	Environmental ozone can rapidly degrade cyanine 5 (Cy5), a fluorescent dye commonly used in microarray gene expression studies. Cyanine 3 (Cy3) is much less affected by atmospheric ozone. Degradation of the Cy5 signal relative to the Cy3 signal in 2-color microarrays will adversely reduce the Cy5/Cy3 ratio resulting in unreliable microarray data. Ozone in central Arkansas typically ranges between approximately 22 ppb to approximately 46 ppb and can be as high as 60-100 ppb depending upon season, meteorological conditions, and time of day. These levels of ozone are common in many areas of the country during the summer. A carbon filter was installed in the laboratory air handling system to reduce ozone levels in the microarray laboratory. In addition, the airflow was balanced to prevent non-filtered air from entering the laboratory. These modifications reduced the ozone within the microarray laboratory to approximately 2-4 ppb. Data presented here document reductions in Cy5 signal on both in-house produced microarrays and commercial microarrays as a result of exposure to unfiltered air. Comparisons of identically hybridized microarrays exposed to either carbon-filtered or unfiltered air demonstrated the protective effect of carbon-filtration on microarray data as indicated by Cy5 and Cy3 intensities. LOWESS normalization of the data was not able to completely overcome the effect of ozone-induced reduction of Cy5 signal. Experiments were also conducted to examine the effects of high humidity on microarray quality. Modest, but significant, increases in Cy5 and Cy3 signal intensities were observed after 2 or 4 hours at 98-99% humidity compared to 42% humidity.
Does chimeric DNA-RNA hammerhead ribozyme targeting transforming growth factor-beta1 mRNA ameliorate renal injury in hypertensive rats?	Transforming growth factor (TGF)-beta is a critical factor in the progression of renal injury, regardless of the primary etiology. Such injury is characterized by glomerular sclerosis and tubulointerstitial fibrosis. To develop a ribozyme-based therapy for progressive renal diseases, we examined the effects of chimeric DNA-RNA hammerhead ribozyme targeting TGF-beta1 mRNA on glomerulosclerosis in salt-loaded, stroke-prone spontaneously hypertensive rats (SHR-SP) and salt-sensitive Dahl (Dahl-S) rats. The chimeric DNA-RNA ribozyme to TGF-beta1 was delivered by polyethylenimine to cultured mesangial cells from SHR-SP in vitro and to glomeruli in SHR-SP in vivo. The chimeric ribozyme reduced expression of TGF-beta1 mRNA and protein, which was accompanied by inhibition of expression of extracellular matrix molecules such as fibronectin and collagen type I in mesangial cells from SHR-SP in vitro. One intraperitoneal injection of 200 microg of chimeric DNA-RNA ribozyme to TGF-beta1 in vivo markedly ameliorated thickening of capillary artery walls and glomerulosclerosis in salt-loaded SHR-SP and Dahl-S rats without a reduction in blood pressure. The chimeric ribozyme reduced expression of TGF-beta1 and connective tissue growth factor (CTGF) mRNAs in renal cortex in salt-loaded Dahl-S rats. Chimeric ribozyme to TGF-beta1 significantly reduced levels of protein in urine in the Dahl-S rats.	To test whether the chronic users of celecoxib, a selective cyclo-oxygenase-2 inhibitor, had less Helicobacter pylori-related intestinal metaplasia or if such users' intestinal metaplasia could be prone to disappear after H. pylori eradication. The study enrolled 150 chronic celecoxib users and 216 non-users who underwent pan-endoscopy to detect H. pylori infection and its related intestinal metaplasia. One hundred and three H. pylori-infected patients with intestinal metaplasia (43 chronic celecoxib users and 60 non-users) received anti-H. pylori therapy and completed the 12-month follow-up to survey the regression of intestinal metaplasia by mean intestinal metaplasia score. There were no differences in the prevalence of H. pylori-related intestinal metaplasia between the chronic celecoxib users and controls (P > 0.05). On the 12th month of follow-up, chronic celecoxib users had a lower mean intestinal metaplasia score (1.2 vs. 1.8, P < 0.005) and a higher regression rate of intestinal metaplasia (42% vs. 20%, P = 0.027) than non-users.
Is [ Islet isolation outcome influenced by pancreas preparation method ]?	Pancreatic islet transplantation is a treatment method for type I diabetes. Its outcome is influenced by numerous factors, islet quantity and function being important ones of them. was to estimate the influence of pancreas preparation method on the outcome of islet isolation in rat. 6 pancreata harvested from Lewis rats were used in this research. Pancreatic duct was cannulated and pancreas was injected with 1 mg/ml collagenase P solution (Sigma) and then excised. After cutting into smaller fragments, it was digested in collagenase P solution for 15-20 min. Enzyme activity was then stopped by adding dilution medium. Heterogenous cell suspension was centrifuged in density gradient (Gradisol) to isolate islets. Pancreatic islets were collected and islet equivalent was calculated. Islet purity degree was estimated as islet cells to all cells, including exocrine, ratio. Islet viability was estimated using propidium iodide and fluorescein diacetate staining. Photographic documentation was made. Proper islet morphology, highest number and viability was obtained when pancreas was excised properly (isolation 3 and 4).	Aspirin inhibits the cyclooxygenase-1 (COX-1) mediated thromboxane A2 synthesis. Despite COX-1 inhibition, in patients with coronary artery disease (CAD), platelets can be activated through other mechanisms, like activation by thrombin. At baseline in this cross-sectional substudy of the ASCET trial, 1001 stable CAD patients, all on single aspirin treatment, were classified by the PFA100® method, as having high on-aspirin residual platelet reactivity (RPR) or not. Markers of hypercoagulability, endothelial and platelet activation as related to RPR, were evaluated to explore the potential mechanisms behind high on-aspirin RPR. Altogether, 25.9% (n=259) of the patients were found to have high on-aspirin RPR. S-thromboxane B(2) levels were very low and did not differ between patients having high on-aspirin RPR or not. Patients with high on-aspirin RPR had significantly higher levels of von Willebrand Factor (vWF) (124 vs 100%, p<0.001, platelet count (236 vs 224 × 10(9)/l, p=0.008), total TFPI (68.4 vs 65.5 ng/ml, p=0.005) and ß-thromboglobulin (ß-TG) (33.3 vs 31.3 IU/ml, p=0.041) compared to patients with low on-aspirin RPR. No significant differences between the groups were observed in levels of endogenous thrombin generation (ETP), pro-thrombin fragment 1+2 (F1+2), D-dimer, soluble TF (sTF) or P-selectin (all p>0.05).
Is increases in physical activity as important as smoking cessation for reduction in total mortality in elderly men : 12 years of follow-up of the Oslo II study?	Physical activity (PA) at leisure by the elderly, and its relationship to cardiovascular (CV) and non-CV mortality, with and without competing risk, has been scarcely described. We determined the relationships between PA, smoking and 12-year CV, non-CV and all-cause mortality in elderly Oslo men screened for CV disease in 1972-1973 and 2000. Among 14,846 men born during 1923-1932 and participating in 1972-1973, there were 5738 participants in 2000. During the 12 years follow-up 2154 died. Cox regression modelling of mortality endpoints, with and without competing risk, was applied analysing PA variables hours per week of light or vigorous PA intensity and degree of PA at leisure. Comparisons of predictive ability between PA and smoking were done by receiver operating characteristics. Thirty minutes of PA per 6 days a week was associated with about 40% mortality risk reduction. There was a 5 years increased lifetime when comparing sedentary and moderate to vigorous physically active men. Associations to CV or non-CV mortality were slightly weakened, allowing competing risk. Conditional on the prevalence of smoking and PA, the degree of PA at leisure was almost as predictive as smoking with regard to the effects on mortality. Increase in PA was as beneficial as smoking cessation in reducing mortality.	It was recently reported that protein disulfide isomerase (PDI) stimulates factor X (FX) activation by factor VIIa (FVIIa) bound to soluble tissue factor (sTF) in a purified system and that PDI may be responsible for activating cellular tissue factor (TF) and switching it between its roles in blood coagulation and cellular signalling. This study further investigates the former effect of PDI. FX activations by FVIIa-sTF(1-219) were carried out in the presence of different forms of PDI, with annexin V or detergent present in the system and using various forms of FVIIa and FX. In addition, FVIIa-lipidated TF was used as the FX activator. Recombinant human PDI did not influence FX activation by FVIIa-sTF(1-219), whereas PDI purified from bovine liver enhanced the activation rate in a dose-dependent manner. The inclusion of annexin V or detergent abolished the stimulatory effect. Removal of the phospholipid-interactive gamma-carboxyglutamic acid (Gla)-containing domain from either FVIIa or FX obliterated the bovine PDI-induced enhancement of FX activation, as did the introduction of F4A or L8A mutation in FVIIa. The presence of 25 nM bovine PDI lowered the apparent K(m) for FX from far above 10 microM to 1-2 microM. No PDI effect was seen when FVIIa-lipidated TF was the FX activator.
Does increased glucocorticoid receptor beta alter steroid response in glucocorticoid-insensitive asthma?	Glucocorticoids (GCs) are highly effective in the treatment of asthma. However, some individuals have GC-insensitive asthma. To evaluate the functional response to steroids of bronchoalveolar lavage (BAL) cells from sites of airway inflammation from patients with GC-insensitive versus GC-sensitive asthma. As well, to attempt to define the functional role of glucocorticoid receptor (GCR)beta (a splicing variant, and dominant negative inhibitor of, the classic GCRalpha) in controlling GCRalpha nuclear translocation and transactivation at a molecular level. Fiberoptic bronchoscopy with collection of BAL fluid was performed on seven patients with GC-sensitive asthma and eight patients with GC-insensitive asthma. GCRalpha cellular shuttling in response to 10(-6) M dexamethasone treatment and GCRbeta expression were analyzed in BAL cells by immunofluorescence staining. The effects of overexpression and silencing of GCRbeta mRNA on GCRalpha function were assessed. Significantly reduced nuclear translocation of GCRalpha in response to steroids was found in BAL cells from patients with GC-insensitive asthma. BAL macrophages from patients with GC-insensitive asthma had significantly increased levels of cytoplasmic and nuclear GCRbeta. It was demonstrated that GCRalpha nuclear translocation and its transactivation properties were proportionately reduced by level of viral transduction of the GCRbeta gene into the DO-11.10 cell line. RNA silencing of GCRbeta mRNA in human BAL macrophages from patients with GC-insensitive asthma resulted in enhanced dexamethasone-induced GCRalpha transactivation.	Health-risk behaviours (HRB) increase the risk of disability and chronic diseases at an older age. This study aimed to compare Slovakia and the Netherlands regarding differences in the prevalence of HRB by neighbourhood and individual deprivation and to determine whether area differences could be explained by the socio-economic position (SEP) of the residents. We obtained data on non-institutionalized residents aged ≥ 65 years from the EU-FP7: EURO-URHIS 2 project from Slovak (N = 665, response rate 44.0%) and Dutch cities (N = 795, response rate 50.2%). HRB concerned daily smoking, binge drinking, physical activity, consumption of fruits and vegetables and body mass index. Area deprivation was measured by the neighbourhood unemployment rate. Individual SEP was measured by education and household income with financial strain. We used multilevel logistic regression. In Slovakia, no HRB was associated with either neighbourhood unemployment or individual SEP. The elderly in the Netherlands from the least favourable neighbourhoods were more likely to be daily smokers [odds ratio (OR) 2.32; 95% confidence interval (CI) 1.25, 4.30] and overweight (OR 1.84; 95% CI 1.24, 2.75) than residents from the most favourable ones. For the Dutch elderly the gradients varied per HRB and per individual-level SEP indicator. Individual SEP explained country differences in the association of area unemployment with smoking and lack of physical activity but not that with overweight.
Is red cell distribution width increased in patients with ascending aortic dilatation?	The prognostic importance of red cell distribution width (RDW) and neutrophil/lymphocyte ratio (NLR) in cardiovascular diseases has been shown. Ascending aortic dilatation (AAD) is a common cardiovascular disease and is associated with aortic wall inflammation and cystic degeneration. In this study, we aimed to investigate the relationship between serum levels of RDW, NLR and the presence of AAD. Two-hundred consecutive patients with AAD diagnosed by transthoracic echocardiography were prospectively recruited and were compared to 170 age-gender- matched subjects with normal aortic diameters. Complete blood counts (CBCs) were analyzed for hemoglobin, RDW and NLR counts, as well as mean corpuscular volume (MCV). If possible, results of CBC tests within the previous two years were also included and the averages were used. RDW [median 13.9, interquartile range (IQR) 1.40 vs. median 13.3, IQR 1.05%, p=0.01], NLR (median 2.04, IQR 1.09 vs. median 1.78, IQR 0.90, p=0.01) and high-sensitive C-reactive protein (hs-CRP) (median 0.60, IQR 0.80 vs. median 0.44, IQR 0.68 mg/L, p=0.01) levels were significantly higher in the AAD group compared to the control group. In univariate correlation analysis, ascending aortic diameters were correlated with RDW levels (r=0.31, p=0.01), NLR levels (r=0.15, p=0.01) and hs-CRP levels (r=0.12, p=0.03). In multivariate logistic regression analysis, increased levels of RDW and hs-CRP remained as the independent correlates of AAD in the study population. Receiver operating characteristic (ROC) curve analysis revealed that a RDW measurement higher than >13.8% predicted AAD with a sensitivity of 49.5% and a specificity of 82.8% (area under the curve [AUC] 0.681, p=0.01).	Spinal cord plasticity can be assessed in spinal rats using an instrumental learning paradigm in which subjects learn an instrumental response, hindlimb flexion, to minimize shock exposure. Prior exposure to uncontrollable intermittent stimulation blocks learning in spinal rats but has no effect if given before spinal transection, suggesting that supraspinal systems modulate nociceptive input to the spinal cord, rendering it less susceptible to the detrimental consequences of uncontrollable stimulation. The present study examines whether disrupting brain function with pentobarbital blocks descending inhibitory systems that normally modulate nociceptive input, making the spinal cord more sensitive to the adverse effect of uncontrollable intermittent stimulation. Male Sprague-Dawley rats received uncontrollable intermittent stimulation during pentobarbital anesthesia after (experiment 1) or before (experiment 2) spinal cord transection. They were then tested for instrumental learning at a later time point. Experiment 3 examined whether these manipulations affected nociceptive (thermal) thresholds. Experiment 1 showed that pentobarbital had no effect on the induction of the learning deficit after spinal cord transection. Experiment 2 showed that intact rats anesthetized during uncontrollable intermittent stimulation failed to learn when later transected and tested for instrumental learning. Experiment 3 found that uncontrollable intermittent stimulation induced an antinociception in intact subjects that was blocked by pentobarbital.
Does a novel three serum phospholipid panel differentiate normal individuals from those with prostate cancer?	The results of prostate specific antigen (PSA) and digital rectal examination (DRE) screenings lead to both under and over treatment of prostate cancer (PCa). As such, there is an urgent need for the identification and evaluation of new markers for early diagnosis and disease prognosis. Studies have shown a link between PCa, lipids and lipid metabolism. Therefore, the aim of this study was to examine the concentrations and distribution of serum lipids in patients with PCa as compared with serum from controls. Using Electrospray ionization mass spectrometry (ESI-MS/MS) lipid profiling, we analyzed serum phospholipids from age-matched subjects who were either newly diagnosed with PCa or healthy (normal). We found that cholester (CE), dihydrosphingomyelin (DSM), phosphatidylcholine (PC), egg phosphatidylcholine (ePC) and egg phosphatidylethanolamine (ePE) are the 5 major lipid groups that varied between normal and cancer serums. ePC 38:5, PC 40:3, and PC 42:4 represent the lipids species most prevalent in PCa as compared with normal serum. Further analysis revealed that serum ePC 38:5 ≥0.015 nmoles, PC 40.3 ≤0.001 nmoles and PC 42:4 ≤0.0001 nmoles correlated with the absence of PCa at 94% prediction. Conversely, serum ePC 38:5 ≤0.015 nmoles, PC 40:3 ≥0.001 nmoles, and PC 42:4 ≥0.0001 nmoles correlated with the presence of PCa.	Lung injury after cardiopulmonary bypass is a serious complication for infants with congenital heart disease and pulmonary hypertension. Excessive neutrophil sequestration in the lung occurring after reestablishment of pulmonary circulation implies that interaction between neutrophils and pulmonary endothelium is the major cause of lung injury. Thirty infants with either ventricular septal defect or atrioventricular septal defect and with pulmonary hypertension were enrolled in this study. We performed continuous pulmonary perfusion during total cardiopulmonary bypass on 16 patients (perfused group) and conventional cardiopulmonary bypass on 14 patients (control group). PaO2/FiO2 and neutrophil counts were assessed from immediately before surgery to 24 hours after termination of cardiopulmonary bypass. PaO2/FiO2 was higher in the perfused group than in the control group, and the difference was significant throughout the study period. Neutrophil counts decreased below prebypass values in both groups at 30 minutes after aortic unclamping, and the difference was significant in the control group but was not in the perfused group. Duration of postoperative ventilatory support was significantly less in the perfused group.
Does liver stiffness by transient elastography predict liver-related complications and mortality in patients with chronic liver disease?	Liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is a validated method for noninvasively staging liver fibrosis. Most hepatic complications occur in patients with advanced fibrosis. Our objective was to determine the ability of LSM by TE to predict hepatic complications and mortality in a large cohort of patients with chronic liver disease. In consecutive adults who underwent LSM by TE between July 2008 and June 2011, we used Cox regression to determine the independent association between liver stiffness and death or hepatic complications (decompensation, hepatocellular carcinoma, and liver transplantation). The performance of LSM to predict complications was determined using the c-statistic. Among 2,052 patients (median age 51 years, 65% with hepatitis B or C), 87 patients (4.2%) died or developed a hepatic complication during a median follow-up period of 15.6 months (interquartile range, 11.0-23.5 months). Patients with complications had higher median liver stiffness than those without complications (13.5 vs. 6.0 kPa; P<0.00005). The 2-year incidence rates of death or hepatic complications were 2.6%, 9%, 19%, and 34% in patients with liver stiffness <10, 10-19.9, 20-39.9, and ≥40 kPa, respectively (P<0.00005). After adjustment for potential confounders, liver stiffness by TE was an independent predictor of complications (hazard ratio [HR] 1.05 per kPa; 95% confidence interval [CI] 1.03-1.06). The c-statistic of liver-stiffness for predicting complications was 0.80 (95% CI 0.75-0.85). A liver stiffness below 20 kPa effectively excluded complications (specificity 93%, negative predictive value 97%); however, the positive predictive value of higher results was sub-optimal (20%).	Prions and amyloid-β (Aβ) oligomers trigger neurodegeneration by hijacking a poorly understood cellular signal mediated by the prion protein (PrP) at the plasma membrane. In early zebrafish embryos, PrP-1-dependent signals control cell-cell adhesion via a tyrosine phosphorylation-dependent mechanism. Here we report that the Src family kinases (SFKs) Fyn and Yes act downstream of PrP-1 to prevent the endocytosis and degradation of E-cadherin/β-catenin adhesion complexes in vivo. Accordingly, knockdown of PrP-1 or Fyn/Yes cause similar zebrafish gastrulation phenotypes, whereas Fyn/Yes expression rescues the PrP-1 knockdown phenotype. We also show that zebrafish and mouse PrPs positively regulate the activity of Src kinases and that these have an unexpected positive effect on E-cadherin-mediated cell adhesion. Interestingly, while PrP knockdown impairs β-catenin adhesive function, PrP overexpression enhances it, thereby antagonizing its nuclear, wnt-related signaling activity and disturbing embryonic dorsoventral specification. The ability of mouse PrP to influence these events in zebrafish embryos requires its neuroprotective, polybasic N-terminus but not its neurotoxicity-associated central region. Remarkably, human Aβ oligomers up-regulate the PrP-1/SFK/E-cadherin/β-catenin pathway in zebrafish embryonic cells, mimicking a PrP gain-of-function scenario.
Are the status of rheumatoid factor and anti-cyclic citrullinated peptide antibody associated with the effect of anti-TNFα agent treatment in patients with rheumatoid arthritis : a meta-analysis?	This meta-analysis was conducted to investigate whether the status of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody are associated with the clinical response to anti-tumor necrosis factor (TNF) alpha treatment in rheumatoid arthritis (RA). A systemic literature review was performed using the MEDLINE, SCOPUS, Cochrane Library, ISI Web of Knowledge, and Clinical Trials Register databases, and Hayden's criteria of quality assessment for prognostic studies were used to evaluate all of the studies. The correlation between the RF and anti-CCP antibody status with the treatment effect of anti-TNFα agents was analyzed separately using the Mantel Haenszel method. A fixed-effects model was used when there was no significant heterogeneity; otherwise, a random-effects model was applied. Publication bias was assessed using Egger's linear regression and a funnel plot. A total of 14 studies involving 5561 RA patients meeting the inclusion criteria were included. The overall analysis showed that the pooled relative risk for the predictive effects of the RF and anti-CCP antibody status on patient response to anti-TNFα agents was 0.98 (95% CI: 0.91-1.05, p=0.54) and 0.88 (95% CI: 0.76-1.03, p=0.11), respectively, with I(2) values of 43% (p=0.05) and 67% (p<0.01), respectively. Subgroup analyses of different anti-TNFα treatments (infliximab vs. etanercept vs. adalimumab vs. golimumab), response criteria (DAS28 vs. ACR20 vs. EULAR response), follow-up period (≥ 6 vs. <6 months), and ethnic group did not reveal a significant association for the status of RF and anti-CCP.	Age-related cataract (ARC) is the leading cause of visual impairment worldwide, and α-crystallin (CRYAA) is the predominant structural protein involved in the maintenance of lens clarity and refractive properties. We previously demonstrated that CRYAA genes undergo epigenetic repression in the lens epithelia in ARC. We further analyze the underlying mechanism in the current study. The transcription factor binding sites of the CpG island of CRYAA promoter were predicted by TESS website. An electrophoretic mobility shift assay (EMSA) was used to analyze the impact of the methylation of CpG sites on transcription factors. Human lens epithelial B-3 (HLE B-3) Cells were treated with demethylation agent zebularine in the concentrations of 0 (PBS as control), 10 μM, 20 μM, 50 μM, 100 μM and 200 μM, respectively. After treatment in the above concentrations for 24 h, 48 h and 72 h, respectively, CRYAA mRNA expression levels were detected by Quantitative Real-Time RT-PCR. The methylation of the CpG site of the CRYAA promoter decreased the DNA-binding capacity of transcription factor Sp1. Zebularine increased CRYAA expression in HLE B-3 Cells in a dose- dependent and time- dependent pattern.
Does severe and morbid obesity ( BMI ≥ 35 kg/m ( 2 ) ) increase surgical time and length of hospital stay in total knee arthroplasty surgery?	Certain aspects of total knee arthroplasty (TKA) in severely and morbidly obese (SMO) patients (BMI ≥ 35 kg/m(2)) remain controversial. This study aimed to assess the duration of TKA surgery and hospital stay in relation to patients' BMI. Three operative times during TKA surgery were recorded: tourniquet time, to determine surgical difficulty, total surgical time, to assess the difficulty of achieving anaesthesia, and time in the surgical area, to assess patient management in the surgical area. Length of hospital stay was also calculated. Data were collected prospectively from consecutive patients and were recorded in a database for retrospective analysis. Data were obtained from 922 consecutive patients undergoing TKA. The non-obese group comprised 418 patients (45.3%), obese group Class I 331 (36%), and the SMO group (Class II-III) 173 (18.7%). Mean tourniquet time was 53 min, mean total surgical time was 84 min, and mean time in the surgical area was 132 min. There were no differences according to BMI group. Median length hospital stay (LHS) was 6 days in all patients regardless of BMI. Factors that significantly prolonged LHS were ASA III-IV and pre-operative haemoglobin between 12 and 13 g/dl.	The liver contains a population of small bipotential facultative progenitor cells that reconstitute liver function when mature hepatocytes or cholangiocytes are unable to proliferate. Mesenchymal markers, including members of the forkhead transcription factor gene family, have been detected in hepatic progenitor cells. The winged helix transcription factor Foxl1 localizes to mesenchymal cells in the intestine; however, its expression in the liver has not been reported. We found that Foxl1 is expressed in rare cells in the normal liver but is dramatically induced in the livers of mice that have undergone bile duct ligation or were fed a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing or choline-deficient, ethionine-supplemented diet. In addition, we employed genetic lineage tracing using a Foxl1-Cre transgenic mouse crossed with the Rosa26R lacZ reporter line to demonstrate that Foxl1-Cre-expressing cells are present within the periportal region shortly after injury. These cells give rise to both hepatocytes [marked by hepatocyte nuclear factor 4 alpha (HNF-4alpha) expression] and cholangiocytes (marked by CK19 expression), indicating that these cells are derived from Foxl1-Cre-expressing cells. Foxl1-Cre-expressing cells are distinct from hepatic stellate cells, portal fibroblasts, and myofibroblasts, although they are located in close proximity to portal fibroblasts. These results demonstrate that the early Foxl1-Cre lineage cell gives rise to both cholangiocytes and hepatocytes after liver injury and suggest the potential for progenitor-portal fibroblast cell interactions.
Is conservation of the glucan phosphatase laforin linked to rates of molecular evolution and the glucan metabolism of the organism?	Lafora disease (LD) is a fatal autosomal recessive neurodegenerative disease. A hallmark of LD is cytoplasmic accumulation of insoluble glucans, called Lafora bodies (LBs). Mutations in the gene encoding the phosphatase laforin account for approximately 50% of LD cases, and this gene is conserved in all vertebrates. We recently demonstrated that laforin is the founding member of a unique class of phosphatases that dephosphorylate glucans. Herein, we identify laforin orthologs in a protist and two invertebrate genomes, and report that laforin is absent in the vast majority of protozoan genomes and it is lacking in all other invertebrate genomes sequenced to date. We biochemically characterized recombinant proteins from the sea anemone Nematostella vectensis and the amphioxus Branchiostoma floridae to demonstrate that they are laforin orthologs. We demonstrate that the laforin gene has a unique evolutionary lineage; it is conserved in all vertebrates, a subclass of protists that metabolize insoluble glucans resembling LBs, and two invertebrates. We analyzed the intron-exon boundaries of the laforin genes in each organism and determine, based on recently published reports describing rates of molecular evolution in Branchiostoma and Nematostella, that the conservation of laforin is linked to the molecular rate of evolution and the glucan metabolism of an organism.	To determine the effect of interleukin-2 (IL-2) therapy on immunologic and virologic responses in subjects with acute or recent HIV infection already receiving highly active antiretroviral therapy (HAART). The effect of IL-2 therapy on immunologic and virologic responses was studied in 21 acutely infected individuals who had been receiving HAART for 48 weeks following acute or recent HIV infection. Nine subjects receiving no therapy served as controls. Viral loads, as well as CD4 and CD8 cell counts were monitored and the CD8 cell non-cytotoxic anti-HIV response (CNAR) was measured. IL-2 therapy led to significant increases in CD4 cell numbers (P = 0.005) that were maintained for 6 months after discontinuation of the IL-2 treatment. No effect of IL-2 was observed on viral loads or the CD8 cell numbers as compared to subjects receiving HAART alone. CNAR activity was restored among subjects receiving HAART and IL-2 whereas CNAR declined among those receiving HAART alone and in untreated infected subjects. The percentage of HAART subjects with CD8 cells showing at least 50% suppression of HIV replication increased significantly following IL-2 therapy (P = 0.02) and persisted for 6 months.
Does physical exercise alleviate ER stress in obese humans through reduction in the expression and release of GRP78 chaperone?	Perturbation of the endoplasmic reticulum (ER) homeostasis has emerged as one of the prominent features of obesity and diabetes. This occurs when the adaptive unfolded protein response (UPR) fails to restore ER function in key metabolic tissues. We previously reported increased inflammation and impaired heat shock response (HSR) in obese human subjects that were restored by physical exercise. Here, we investigated the status of ER stress chaperone; glucose-regulated protein 78 (GRP78) and its downstream UPR pathways in human obese, and their modulation by a supervised 3-month physical exercise. Subcutaneous adipose tissue (SAT) and blood samples were collected from non-diabetic adult human lean (n=40) and obese (n=40, at baseline and after 3months of physical exercise). Transcriptomic profiling was used as a primary screen to identify differentially expressed genes and it was carried out on SAT samples using the UPR RT(2) Profiler PCR Array. Conventional RT-PCR, immunohistochemistry, immunofluorescence, Western blot and ELISA were used to validate the transcriptomic data. Correlation analyses with the physical, clinical and biochemical outcomes were performed using Pearson's rank correlation coefficient. Levels of GRP78 and its three downstream UPR arms; activating transcription factor-6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were increased in obese subjects. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects which correlated negatively with maximum oxygen uptake (VO2 Max) but positively with high-sensitivity C-reactive protein (hsCRP) and obesity indicators such as BMI, percentage body fat (PBF) and waist circumference. GRP78 increased secretion in obese was further confirmed in vitro using 3T3-L1 preadipocyte cells under ER stress. Finally, we showed that physical exercise significantly attenuated the expression and release of GRP78 with a concomitant reduction in the phosphorylation of IRE1α and eukaryotic initiation factor-2α (eIF2α).	It is recommended that dentists screen for dental anxiety (DA) so that fearful patients may be better managed. The main aim of this study was to determine what dentists are being taught in relation to DA as well as whether and how anxious patients are identified in the clinic. Two hundred and forty-six practising dentists (adjusted response rate = 40.1%), from a random sample of registered Australian dentists, completed a mailed questionnaire. Dentists estimated that high DA affected 23.3% of children and 19.4% of adults seen. Only 3.7% of dentists reported using a published scale for screening DA, with the most common reason being lack of awareness (56.5%). Approximately one-half of responding dentists directly asked their patients about DA and this was more common among younger dentists (χ(2) = 7.75, p = 0.021). There were few differences in DA screening by other practitioner or practice characteristics (p > 0.05). Only one-third of dentists had received undergraduate training related to DA and only 41.7% considered this to be 'good' or better. Almost 37% of respondents expressed an interest in future training opportunities.
Does interleukin 6 production during cardiac surgery correlate with increasing age?	Cardiac surgery produces a proinflammatory response characterized by cytokine production. Proinflammatory cytokines such as interleukin 6 (IL-6) may contribute to morbidity and mortality after cardiopulmonary bypass (CPB). Elderly patients undergoing CPB are at increased risk of morbidity and mortality. We hypothesized that patients aged >70 y produce more IL-6 during CPB. Twenty-three patients (ages 23-80) undergoing cardiac surgery had blood sampled from the ascending aorta and coronary sinus on initial cannulation for bypass, at 30 min of aortic cross-clamp time, on release of the aortic cross-clamp, and at 20 min after reperfusion. Group 1 patients (n = 8) were aged <60 y, group 2 patients (n = 7) were aged between 60 and 70 y, and group 3 patients (n = 8) were aged >70 y. Plasma levels of tumor necrosis factor-alpha, IL-1, and IL-6 were analyzed. The three groups did not differ with respect to preoperative ejection fraction, New York Heart Association classification, mean aortic cross-clamp time, or mean CPB time. IL-6 levels rose throughout myocardial ischemia and reperfusion in all three age groups. The increase in IL-6 during ischemia and reperfusion in the age group >70 was greater than the increase in younger patients. IL-6 was similar in the coronary sinus and the ascending aorta.	An oligonucleotide termed 'T-oligo' having sequence homology with telomere overhang has shown cytotoxicity in multiple cancers. We have demonstrated that T-oligo can induce apoptosis in androgen independent prostate cancer cell line DU-145. In this report, we evaluate the use of star-shaped tetraspermine (SSTS) for delivery of T-oligo. SSTS was synthesized from spermine and its intrinsic cytotoxicity towards DU-145 cells was compared with spermine and branched polyethyleneimine (bPEI). Atomistic molecular dynamic (MD) simulations were conducted to understand binding and complexation of spermine and SSTS with T-oligo. Complexation was also determined using gel electrophoresis and SYBR gold assay. Complexes were characterized for size, cellular uptake and antiproliferative effect. SSTS exhibited significantly lower toxicity than spermine and bPEI. Its affinity towards T-oligo was significantly higher than spermine as determined by experimental studies and confirmed by MD simulations and it formed stable complexes (TONPs) with T-oligo. TONPs facilitated cellular uptake and nuclear accumulation of T-oligo and their cytotoxic potential was observed at concentration several folds lower than that required for T-oligo alone.
Is the composition and differentiation potential of the duodenal intraepithelial innate lymphocyte compartment altered in coeliac disease?	Coeliac disease (CD), a gluten-induced enteropathy, alters the composition and function of duodenal intraepithelial T cells. The intestine also harbours four types of CD3-negative intraepithelial lymphocytes (IELs) with largely unknown function: CD56(-)CD127(-), CD56(-)CD127(+), CD56(+)CD127(-) and CD56(+)CD127(+). Here we aimed to gain insight into the potential function of these innate IELs in health and disease. We determined the phenotypes, relative abundance and differentiation potential of these innate IEL subsets in duodenal biopsies from controls and patients with CD or patients with refractory CD type II (RCDII). Hierarchical clustering analysis of the expression of 15 natural killer and T cell surface markers showed that innate IELs differed markedly from innate peripheral blood lymphocytes and divided innate IEL subsets into two main branches: a CD127(-) branch expressing high levels of interleukin (IL) 2/15Rβ but no IL-21R, and a CD127(+) branch with the opposite phenotype. While CD was characterised by the contraction of all four innate IEL subsets, a selective expansion of CD56(-)CD127(-) and CD56(-)CD127(+) innate IEL was detected in RCDII. In vitro, in the presence of IL-15, CD56(-)CD127(-) IEL from controls and patients with CD, but not from patients with RCDII, differentiated into functional natural killer and T cells, the latter largely dependent on notch-signalling. Furthermore, compared with non-coeliac controls, CD56(-)CD127(-) IEL from patients with CD expressed more intracellular CD3ε and CD3γ and gave more pronounced T cell differentiation.	We tested the hypothesis that the negative functional effects of cyclic GMP would be attenuated by cyclic AMP and this interaction would be reduced in pacing-induced failure of hypertrophic hearts. 8-Bromo-cGMP (2 microg/kg/min) was infused into a coronary artery in eight control, eight ventricular hypertrophy (HYP), and eight hypertrophic failure (HYP-FAIL) dogs. Then isoproterenol (0.1 microg/kg/min) was infused, followed by 8 Br-cGMP. Regional myocardial work (forceshortening/min), and O(2) consumption (VO(2)) (coronary blood flowO(2) extraction) were measured. Cyclic GMP levels were determined by radioimmunoassay. 8-Br-cGMP significantly decreased regional work from 3812 +/- 839 g*mm/min by 17% and VO(2) by 29% in control, but not in HYP (1073 +/- 182 by -10%, VO(2) by -16%) or HYP-FAIL (495 +/- 145 by -9%, VO(2) by 0%). Isoproterenol increased work by 43% and VO(2) by 48% in controls and in HYP (work by 54%, VO(2) by 39%), but not in HYP-FAIL (work by -28%, VO(2) by -5%). Subsequently, 8-Br-cGMP had no effect on work or VO(2) in control (-2%, -13%), HYP (-12%, -30%), or HYP-FAIL (+13%, +14%). Cyclic AMP levels were elevated by isoproterenol in control (381 +/- 115 versus 553 +/- 119 pmol/g) and HYP (313 +/- 55 versus 486 +/- 227), but not in HYP-FAIL (300 +/- 60 versus 284 +/- 126). After isoproterenol, 8-Br-cGMP further elevated cyclic AMP in control (687 +/- 122), but not in HYP or HYP-FAIL.
Does meconium microbiome analysis identify bacteria correlated with premature birth?	Preterm birth is the second leading cause of death in children under the age of five years worldwide, but the etiology of many cases remains enigmatic. The dogma that the fetus resides in a sterile environment is being challenged by recent findings and the question has arisen whether microbes that colonize the fetus may be related to preterm birth. It has been posited that meconium reflects the in-utero microbial environment. In this study, correlations between fetal intestinal bacteria from meconium and gestational age were examined in order to suggest underlying mechanisms that may contribute to preterm birth. Meconium from 52 infants ranging in gestational age from 23 to 41 weeks was collected, the DNA extracted, and 16S rRNA analysis performed. Resulting taxa of microbes were correlated to clinical variables and also compared to previous studies of amniotic fluid and other human microbiome niches. Increased detection of bacterial 16S rRNA in meconium of infants of <33 weeks gestational age was observed. Approximately 61·1% of reads sequenced were classified to genera that have been reported in amniotic fluid. Gestational age had the largest influence on microbial community structure (R = 0·161; p = 0·029), while mode of delivery (C-section versus vaginal delivery) had an effect as well (R = 0·100; p = 0·044). Enterobacter, Enterococcus, Lactobacillus, Photorhabdus, and Tannerella, were negatively correlated with gestational age and have been reported to incite inflammatory responses, suggesting a causative role in premature birth.	Impaired insulin sensitivity has been linked with chronic heart failure (CHF). Exercise has a beneficial effect on insulin sensitivity in healthy subjects. It is used also as an adjunctive therapy in patients with CHF. We studied the effect of randomized treatment with celiprolol, a vasodilating beta(1)-adrenoceptor antagonist, 200 mg once daily (n=20) or placebo (n=11) on serum lipid levels and insulin sensitivity in patients with CHF. In addition, all subjects participated in a 6-month exercise training protocol. Thirteen subjects in the celiprolol and eight subjects in the control group were on additional beta(1)-adrenoceptor antagonist as part of their tailored CHF therapy. Insulin sensitivity was determined using the hyperinsulinemic euglycemic clamp test (diabetic subjects excluded, n=11 for the celiprolol group and n=8 for the placebo group). Insulin sensitivity index (ISI) increased by 33% (P<0.05) in the celiprolol group and by 17% (NS) in the control group. The mean increase in the whole group was 20% [from 68.2+/-11.5 to 81.7+/-10.7 ml/min/kg (mU/l), P<0.05]. No change was found in the total cholesterol level. HDL cholesterol levels increased by 12% (from 0.98+/-0.05 to 1.10+/-0.05 mmol/l, P<0. 005), and HDL/total cholesterol and HDL/LDL cholesterol ratios by 15% and 16%, respectively (P<0.005). The increase in serum fasting HDL cholesterol level was greater in the celiprolol-treated group (P<0.05). At baseline ISI correlated with maximal oxygen uptake (r=0. 65, P<0.0001) and body mass index (r=-0.55, P<0.001). The change in ISI correlated weakly with the improvement in muscle exercise capacity (r=0.53, P<0.05).
Do silent polymorphisms in the RYR1 gene modify the phenotype of the p.4898 I > T pathogenic mutation in central core disease : a case report?	Central core disease is a congenital myopathy, characterized by presence of central core-like areas in muscle fibers. Patients have mild or moderate weakness, hypotonia and motor developmental delay. The disease is caused by mutations in the human ryanodine receptor gene (RYR1), which encodes a calcium-release channel. Since the RYR1 gene is huge, containing 106 exons, mutation screening has been limited to three 'hot spots', with particular attention to the C-terminal region. Recent next-generation sequencing methods are now identifying multiple numbers of variants in patients, in which interpretation and phenotype prevision is difficult. In a Brazilian Caucasian family, clinical, histopathological and molecular analysis identified a new case of central core disease in a 48-year female. Sanger sequencing of the C-terminal region of the RYR1 gene identified two different missense mutations: c.14256 A > C polymorphism in exon 98 and c.14693 T > C in exon 102, which have already been described as pathogenic. Trans-position of the 2 mutations was confirmed because patient's daughter, mother and sister carried only the exon 98's mutation, a synonymous variant that was subsequently found in the frequency of 013-0,05 of alleles. Further next generation sequencing study of the whole RYR1 gene in the patient revealed the presence of additional 5 common silent polymorphisms in homozygosis and 8 polymorphisms in heterozygosis.	Orostachys japonicus A. Berger (Crassulaceae) (OJ), well-known as Wa-song in Korea is a medicinal plant with immunoregulatory, anti-febrile, antidote, and anti-cancer activities. This study was aimed at evaluating the immunostimulatory effect of O. japonicus A. Berger and its possible mechanisms of action. To evaluate the effect of OJ aqueous extract on macrophage activity, we evaluated the modulation of macrophage activation state by observing structural (phagocytic activities) and the production of nitric oxide increase. The effect of OJ aqueous extract on RAW264.7 cell viability were assessed using Cell Counting Kit (CCK)-8 assay. HPLC analysis was performed to identify potential active compounds of this extract. The biological investigations indicated that OJ aqueous extract, among others, possessed the highest macrophage activation as indicated by NO production yield. The results showed that OJ aqueous extract exhibited antioxidant effects, which included scavenging activities against DPPH radicals. OJ aqueous extract increased the phagocytic activity of RAW 264.7 cells against IgG-opsonized red blood cells (RBC). The level of phosphorylated Syk kinase was increased in OJ aqueous extract-treated group as compared to control. Phosphorylation of PLC-γ was increased in the OJ aqueous extract-treated groups. Quercetin-3-O-rhamnose and kaempferol-3-O-rhamnose was detected in OJ aqueous extract by HPLC analysis.
Is depression associated with cardiac symptoms , mortality risk , and hospitalization among women with suspected coronary disease : the NHLBI-sponsored WISE study?	Depression is a robust predictor of cardiovascular risk. In this study, we examined the association between depression measured in terms of symptom severity and treatment history, cardiac symptom presentation, and clinical outcomes among a sample of women with suspected myocardial ischemia. Seven hundred fifty women with chest pain, mean age 53.4, completed a diagnostic protocol including depression measures, coronary angiogram, ischemia testing, and coronary disease risk factor assessment. Five hundred five participants also completed the Beck Depression Inventory. We further tracked participants over a mean 2.3-year period to evaluate subsequent cardiac events, hospitalization, and mortality. Depression treatment history and current symptom severity were differentially associated with cardiac symptoms and outcomes. Both measures were reliably associated with coronary artery disease (CAD) risk factors and more severe cardiac symptoms. Depression symptom severity was linked to an increased mortality risk over follow-up (RR = 1.05; 95% CI, 1.01-1.09), whereas depression treatment history predicted an increased risk of hospitalization (RR = 1.3; 95% CI, 1.02-1.6), less severe CAD from angiogram, and a reduced likelihood of a positive ischemia test.	Hyaluronan (HA) has a major role in regulating synovial fluid volume. This role depends on the synovium functioning as an ultrafilter that reflects HA during trans-synovial fluid drainage. Reflection boosts the HA concentration on the membrane surface, leading to osmotic retention of synovial fluid ("buffering"). In arthritic effusions, however, HA concentration and osmotic buffering are greatly reduced. We tested the hypothesis that reflection is reduced (escape increased) when the HA concentration falls below the molecular entanglement concentration (C). HA at 0.2 mg/ml (<C) or 1.5 mg/ml (>C) was infused continuously into rabbit knee joints to set up a steady trans-synovial filtration. Joint-derived lymph was sampled over 3 hours, and subsynovial fluid was sampled at the end of the 3-hour period. HA was quantified by high-performance liquid chromatography to evaluate the reflected fraction. C was determined by viscometry. Viscometry showed that 0.2 mg/ml HA was below C* and 1.5 mg/ml was above it. At 0.2 mg/ml, the mean +/- SEM HA reflected fraction was 0.66 +/- 0.04 (n = 7). At 1.5 mg/ml the reflection increased to 0.88 +/- 0.04 (n = 5) (P < 0.005). HA permeation increased almost 3-fold, from 12% to 34%, at the lower concentration.
Do surgery residency curriculum examination scores predict future American Board of Surgery in-training examination performance?	A protected block curriculum (PBC) with postcurriculum examinations for all surgical residents has been provided to assure coverage of core curricular topics. Biannual assessment of resident competency will soon be required by the Next Accreditation System. To identify opportunities for early medical knowledge assessment and interventions, we examined whether performance in postcurriculum multiple-choice examinations (PCEs) is predictive of performance in the American Board of Surgery In-Training Examination (ABSITE) and clinical service competency assessments. Retrospective single-institutional education research study. Academic general surgery residency program. A total of 49 surgical residents. Data for PGY1 and PGY2 residents participating in the 2008 to 2012 PBC are included. Each resident completed 6 PCEs during each year. The results of 6 examinations were correlated to percentage-correct ABSITE scores and clinical assessments based on the 6 Accreditation Council for Graduate Medical Education core competencies. Individual ABSITE performance was compared between PGY1 and PGY2. Statistical analysis included multivariate linear regression and bivariate Pearson correlations. A total of 49 residents completed the PGY1 PBC and 36 completed the PGY2 curriculum. Linear regression analysis of percentage-correct ABSITE and PCE scores demonstrated a statistically significant correlation between the PGY1 PCE 1 score and the subsequent PGY1 ABSITE score (p = 0.037, β = 0.299). Similarly, the PGY2 PCE 1 score predicted performance in the PGY2 ABSITE (p = 0.015, β = 0.383). The ABSITE scores correlated between PGY1 and PGY2 with statistical significance, r = 0.675, p = 0.001. Performance on the 6 Accreditation Council for Graduate Medical Education core competencies correlated between PGY1 and PGY2, r = 0.729, p = 0.001, but did not correlate with PCE scores during either years.	Much research effort has been focused on investigating new compounds derived from low-cost sources, such as natural products, for treating leishmaniasis. Oleuropein derived from numerous plants, particularly from the olive tree, Olea europaea L. (Oleaceae), is a biophenol with many biological activities. Our previous findings showed that oleuropein exhibits leishmanicidal effects against three Leishmania spp. in vitro, and minimizes the parasite burden in L. donovani-infected BALB/c mice. The aim of the present study is to investigate the possible mechanism(s) that mediate this leishmanicidal activity. We determined the efficacy of oleuropein in elevating ROS and NO production in L. donovani-infected J774A.1 macrophages and in explanted splenocytes and hepatocytes obtained from L. donovani-infected BALB/c mice. We also assessed the expression of genes that are related to inflammation, T-cell polarization and antioxidant defense, in splenocytes. Finally, we determined the ratios of specific IgG2a/IgG1 antibodies and DTH reactions in L. donovani-infected BALB/c mice treated with oleuropein. Oleuropein was able to elevate ROS production in both in vitro and in vivo models of visceral leishmaniasis and raised NO production in ex vivo cultures of splenocytes and hepatocytes. The extensive oxidative stress found in oleuropein-treated mice was obviated by the upregulation of the host's antioxidant enzyme (mGCLC) and the simultaneous downregulation of the corresponding enzyme of the parasite (LdGCLC). Moreover, oleuropein was able to mount a significant Th1 polarization characterized by the expression of immune genes (IL-12β, IL-10, TGF-β1, IFN-γ) and transcription factors (Tbx21 and GATA3). Moreover, this immunomodulatory effect was also correlated with an inhibitory effect on IL-1β gene expression, rather than with the expression of IL-1α, IL-1rn and TNF-α. Furthermore, oleuropein-treated BALB/c mice mounted a delayed-type hypersensitivity (DTH) response and an elevated Leishmania-specific IgG2a/IgG1 ratio that clearly demonstrated an in vivo protective mechanism.
Do activation conditions determine susceptibility of murine primary T-lymphocytes to retroviral infection?	Genetically modified T-lymphocytes are potential therapeutic agents for the treatment of various disorders. Successful retroviral infection of primary murine T-lymphocytes is a prerequisite to the study of adoptive cell therapies in a small animal model. The definition of factors controlling retroviral infection of T-lymphocytes would also be useful to better understand retroviral diseases. However, retroviral-mediated gene transfer into murine primary T-cells has remained elusive. In order to define the requirements for stable and efficient gene transfer in primary murine T-lymphocytes, we investigated factors capable of affecting retroviral infection. These include activation conditions (using mitogens or monoclonal antibodies), culture conditions (including media composition and cytokine addition), timing of viral exposure, retroviral receptor selection (ecotropic, amphotropic, or vesicular stomatitis virus G (VSV-G) glycoprotein receptor), and viral titer. We show that efficient gene transfer can be achieved in murine T-lymphocytes, provided that a number of favorable conditions are met, in particular optimized T-cell activation conditions, optimal timing of infection, adequate interleukin-2 concentration and T-cell density, and a high viral titer. On a particulate basis, we find that ecotropic particles are more effective than amphotropic or VSV-G-pseudotyped particles, and recommend the use of a specifically selected retroviral packaging cell line. CD4+ T-cells are equally or more infectible than CD8+ lymphocytes, depending on the activation conditions. The Th1 and Th2 subsets are comparably susceptible to retroviral infection, in contrast to what has been reported in some instances of human T-cell infection by human immunodeficiency virus (HIV).	This study was performed to examine the characteristics of indoor and outdoor falls in older patients and the factors related to severe injury in the emergency department (ED). In total, 26,515 patients fell indoors and 19,581 outdoors. The general and clinical characteristics were compared between the two groups and factors associated with severe injury following the falls were evaluated. Younger males fell more frequently outdoors than indoors. The common activities during outdoor falls were sports and leisure activities. Environmental hazards lead to more outdoor falls than indoor falls. Factors associated with severe injury after indoor falls were transport to the ED by public ambulance or from another medical facility rather than individual transportation, fall from stairs rather than fell over, and a head and neck injury rather than a lower extremity injury. Factors related to severe injury after outdoor falls were male sex, transport to the ED by public ambulance or from another medical facility or by another method rather than individual transportation, state employed, fall from stairs rather than fell over, head and neck or thorax or abdomen injury rather than a lower extremity injury.
Does preoperative administration of intravenous flurbiprofen axetil reduce postoperative pain for spinal fusion surgery?	The aim of the study was to investigate postoperative analgesia and the opioid-sparing effect of the preoperative administration of intravenous flurbiprofen axetil in patients undergoing spinal fusion surgery. Thirty-six patients were randomly allocated into one of three groups. Group A received preoperative flurbiprofen axetil, 1 mg x kg(-1). Group B received postoperative flurbiprofen axetil, 1 mg x kg(-1). Group C received a placebo. All groups were given a standardized anesthesia and intravenous morphine via a patient-controlled analgesia device for postoperative analgesia. The pain score was evaluated by a visual analog scale (VAS) at 0 (T(0)), 1 (T(1)), 2 (T(2)), 6 (T(3)), 12 (T(4)), and 24 (T(5)) h after surgery, and the morphine requirement was recorded during the study period. VAS in group A was significantly lower than that in group B at T(0) and T(1). VAS in group A was significantly lower than that in group C throughout the time course after surgery. Postoperative morphine consumption in group A was significantly lower than that in groups B and C at T(0) to T(3).	The blotchy mouse caused by mutations of ATP7A develops low blood copper and aortic aneurysm and rupture. Although the aortic pathologies are believed primarily due to congenital copper deficiencies in connective tissue, perinatal copper supplementation does not produce significant therapeutic effects, hinting additional mechanisms in the symptom development, such as an independent effect of the ATP7A mutations during adulthood. We investigated if bone marrow from blotchy mice contributes to these symptoms. For these experiments, bone marrow from blotchy mice (blotchy marrow group) and healthy littermate controls (control marrow group) was used to reconstitute recipient mice (irradiated male low-density lipoprotein receptor -/- mice), which were then infused with angiotensin II (1,000 ng/kg/min) for 4 weeks. By using Mann-Whitney U test, our results showed that there was no significant difference in the copper concentrations in plasma and hematopoietic cells between these 2 groups. And plasma level of triglycerides was significantly reduced in blotchy marrow group compared with that in control marrow group (P < 0.05), whereas there were no significant differences in cholesterol and phospholipids between these 2 groups. Furthermore, a bead-based multiplex immunoassay showed that macrophage inflammatory protein (MIP)-1β, monocyte chemotactic protein (MCP)-1, MCP-3, MCP-5, tissue inhibitor of metalloproteinases (TIMP)-1, and vascular endothelial growth factor (VEGF)-A production was significantly reduced in the plasma of blotchy marrow group compared with that in control marrow group (P < 0.05). More important, although angiotensin II infusion increased maximal external aortic diameters in thoracic and abdominal segments, there was no significant difference in the aortic diameters between these 2 groups. Furthermore, aortic ruptures, including transmural breaks of the elastic laminae in the abdominal segment and lethal rupture in the thoracic segment, were observed in blotchy marrow group but not in control marrow group; however, there was no significant difference in the incidence of aortic ruptures between these 2 groups (P = 0.10; Fisher's exact test).
Do microRNA gene polymorphisms and environmental factors increase patient susceptibility to hepatocellular carcinoma?	Micro RNAs (miRNAs) are small RNA fragments that naturally exist in the human body. Through various physiological mechanisms, miRNAs can generate different functions for regulating RNA protein levels and balancing abnormalities. Abnormal miRNA expression has been reported to be highly related to several diseases and cancers. Single-nucleotide polymorphisms (SNPs) in miRNAs have been reported to increase patient susceptibility and affect patient prognosis and survival. We adopted a case-control research design to verify the relationship between miRNAs and hepatocellular carcinoma. A total of 525 subjects, including 377 controls and 188 hepatocellular carcinoma patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR were used to analyze miRNA146a (rs2910164), miRNA149 (rs2292832), miRNA196 (rs11614913), and miRNA499 (rs3746444) genetic polymorphisms between the control group and the case group. The results indicate that people who carry the rs3746444 CT or CC genotypes may have a significantly increased susceptibility to hepatocellular carcinoma (adjusted odds ratio [AOR] = 2.84, 95% confidence interval [CI] = 1.88-4.30). In addition, when combined with environmental risk factors, such as smoking and alcohol consumption, interaction effects were observed between gene polymorphisms and environmental factors (odds ratio [OR] = 4.69, 95% CI = 2.52-8.70; AOR = 3.38, 95% CI = 1.68-6.80).	Hypoglycaemic sulphonylureas are thought to stimulate insulin release by binding to a sulphonylurea receptor, closing K(ATP) channels and inducing electrical activity. However, the fact that these drugs stimulate insulin release at high glucose concentrations where K(ATP) channels are closed suggests additional ionic actions. The aim of this study was to test the hypothesis that sulphonylureas influence the current of the glucose- and volume-regulated anion channel. Electrical and ion-channel activity were recorded in isolated rat beta cells using the patch-clamp technique. (86)Rb(+) efflux was measured using intact islets. Beta cell volume was measured using a video-imaging technique. In the absence of glucose, tolbutamide (100 micromol/l) transiently depolarised the cells. In the presence of glucose (5 mmol/l), tolbutamide evoked a sustained period of electrical activity, whilst at 10 mmol/l glucose, the drug evoked a pronounced 'silent' depolarisation. In the absence of glucose, tolbutamide inhibited (86)Rb(+) efflux. However, at 10 mmol/l glucose, tolbutamide induced a transient stimulation of efflux. Tolbutamide potentiated the whole-cell volume-regulated anion conductance in a glucose-dependent manner with an EC(50) of 85 micromol/l. In single channel recordings, tolbutamide increased the channel-open probability. Tolbutamide caused beta cell swelling in the presence of glucose, but not in its absence.
Is overweight in dogs , but not in cats , related to overweight in their owners?	To quantify the environmental component of aetiology of overweight and obesity by examining the relationship between the degree of overweight in dogs and cats and the degree of overweight in their owners. Cross-sectional study. Main outcome measures of the owners were weight, height (stature) and BMI. Of the animals, weight and divergence from ideal weight were measured by a veterinarian. Three veterinary clinics in Amsterdam, The Netherlands. Dogs and cats, together with their owners, who visited the veterinary clinic. Dogs and cats had to be older than 1 year, and their owners had to be at least 21 years old. After exclusion, there remained forty-seven pairs of dogs and their owners and thirty-six pairs of cats and their owners. We found a significant relationship between the degree of overweight of dogs and the BMI of their owners (r = 0.31). Correction for length of ownership, gender and age of the animal, and gender, age, education level and activity score of the owner did not materially affect this relationship. However, after correction for the amount of time the dog was being walked each day, this relationship disappeared. No significant relationship was found between the degree of overweight of cats and the BMI of their owners.	The pp125 focal adhesion kinase (FAK) plays a pivotal role in tumor cell signaling. FAK expression has been linked to tumor cell invasion and metastasis, but data on cervical cancer are inconclusive. Our goal was to investigate FAK expression in cervical cancer and to assess whether its expression correlates with prognosis. FAK expression was examined using immunohistochemistry with sections from 162 resected cervical cancer specimens. Kaplan-Meier survival curves were used to determine the significance of FAK expression in the prognosis of cervical cancer patients. Specific FAK expression was found in the tumor cells, whereas normal cervical epithelium showed barely any FAK expression. Of 162 invasive cervical cancer specimens, 55 (34%) revealed weak expression of FAK, whereas moderate and strong expression was found in 63 (39%) and 44 (27%) tumors, respectively. Patients with tumors expressing weak amounts of FAK were characterized by a significantly poorer overall survival compared with those with moderate and high intratumoral FAK expression (P = 0.002). Weak expression of FAK correlated with pelvic lymph node metastasis (P = 0.026) and recurrent disease (P = 0.013). Multivariate Cox regression analysis revealed decreased FAK expression and pelvic lymph node metastasis to be significant independent factors predictive of poor disease outcome (hazard ratio, 0.36; P = 0.005; hazard ratio, 2.38; P = 0.018, respectively).
Is pentraxin 3 reduced in bipolar disorder?	Immunologic abnormalities have been found in bipolar disorder but pentraxin 3, a marker of innate immunity, has not been studied in this population. Levels of pentraxin 3 were measured in individuals with bipolar disorder, schizophrenia, and non-psychiatric controls. Linear regression models were used to compare the pentraxin 3 levels in each of the psychiatric groups to that in the control group, adjusting for demographic and clinical variables. Logistic regression models were used to calculate the odds ratios associated with levels of pentraxin 3 which differed from specified levels of the control group. The sample consisted of 831 individuals: 256 with bipolar disorder, 309 with schizophrenia, and 266 without a psychiatric disorder. The levels of pentraxin 3 in the bipolar disorder, but not in the schizophrenia, group were significantly lower than those of controls, adjusting for age, gender, race, maternal education, smoking status, and body mass index (t = -3.78, p < 0.001). The individuals with bipolar disorder also had significantly increased odds of having low levels of pentraxin 3 relative to both the 10th and 25th percentile level of the controls and significantly decreased odds of having a level greater than the 75th and the 90th percentile level of the controls, adjusting for the same covariates.	A prospective radiographic analysis of deformity correction during the balloon kyphoplasty procedure. To determine the spontaneous reduction of the deformity in prone position, the subsequent deformity correction by the inflatable bone tamp, and the overall deformity correction after deposition of the cement. Fracture mobility has been shown to contribute to fracture reduction in vertebroplasty. Spontaneous reduction has not been taken into account in recently published series of balloon kyphoplasty, but it must be considered when performing vertebral augmentation and when reporting and interpreting the significance of vertebral height restoration. A consecutive series of 39 osteoporotic vertebral compression fractures were treated in 30 patients. Lateral radiographs were taken and analyzed at six different time points: 1) Preoperative standing. During the kyphoplasty procedure, four consecutive radiographs were obtained: 2) after placing the patient in prone position on the operation table, 3) after inflation of the bone tamp (IBT), 4) after deflation and removal of the IBT, and 5) after deposition of the cement. 6) Standing lateral radiographs were taken after the procedure. All fractures were analyzed for improvement in sagittal alignment (Cobb angle, kyphotic angle, sagittal index, vertebral height), complications, and reduction of pain (VAS). Placement of the patient in prone position displayed a significant spontaneous reduction in deformity of 6.5 degrees +/- 4.1 degrees Cobb angle. Inflation of the IBT demonstrated a further reduction of the fracture and a significant improvement of the Cobb angle of 3.4 degrees compared with baseline prone. After deflation and removal of the IBT and placement of the cement, no significant loss of fracture reduction was seen. Postoperative measurement of the Cobb angle by means of standing radiographs demonstrated a 3.1 degrees significant loss of reduction compared with the intraoperative measurement in prone position after cement application. Cement leaks occurred in 9 of 39 vertebral fractures. All patients subjectively reported immediate relief of their typical fracture pain. The VAS score significantly improved from 8.7 +/- 1.4 before surgery to 2.3 +/- 0.9.
Is myopia progression in Chinese children slower in summer than in winter?	To characterize seasonal variation in the myopic progression of Chinese children. Myopia progression data are presented for a total of 85 Chinese children, aged 6 to 12 years, with baseline myopia of -0.75 D to -3.50 D sphere and astigmatism ≤-1.50 D, who wore traditional single-vision spectacles in two clinical trials (trial A: n = 37, trial B: n = 48). Refractive error and axial length data were obtained at 6-month intervals using cycloplegic autorefraction and partial coherence interferometry, respectively. Progression rates for right eyes were defined for the first and second 6 months of the studies and classified in terms of "summer," "autumn," "winter," or "spring" based on the mid-point of the 6-month period between visits. The mean 6-month spherical equivalent progression was -0.31 ± 0.25 D for summer, -0.40 ± 0.27 D for autumn, -0.53 ± 0.29 D for winter, and -0.42 ± 0.20 D for spring (p < 0.001). Mean axial elongation was 0.17 ± 0.10 mm for summer, 0.24 ± 0.09 mm for autumn, 0.24 ± 0.09 mm for winter, and 0.15 ± 0.08 mm for spring (p < 0.001). Post hoc analysis indicated that data for summer and winter were different from each other at p < 0.05 for both myopia progression and axial elongation after adjusting for age.	Compounds generated during the routine storage of platelet concentrates may have deleterious effects on the transfusion recipient. Daily plasma samples from platelet concentrates, both apheresis platelets and those separated from whole blood, were obtained serially during routine storage. These plasma samples were assayed for their ability to prime the NADPH oxidase in isolated human neutrophils. Quantitative and qualitative analysis of the priming agents was completed by lipid extraction, high-pressure liquid chromatography separation, and gas chromatography/mass spectroscopy. Compounds were generated in both apheresis and whole-blood platelets that significantly primed the NADPH oxidase after 24 and 48 hours of storage, respectively. The priming activity was maximal by component outdate: 2.6-fold that of the buffer-treated control neutrophils (apheresis) and 3.9-fold that of the buffer-treated control neutrophils (whole blood). These agents were generated by cellular constituents, as stored plasma did not demonstrate such priming activity. Inhibition of this priming activity by WEB 2170, a specific platelet-activating factor receptor antagonist, suggested that the observed priming involved the platelet-activating factor receptor. A portion of the priming activity from platelet concentrates was organically extractable: 69 percent of that from apheresis platelets and 46 percent of that from whole-blood platelets. Further purification of the lipid's priming activity by normal-phase high-pressure liquid chromatography demonstrated a single peak of priming activity at the retention time of lysophosphatidylcholines. Because 46 percent of the priming activity from whole-blood platelets was chloroform insoluble and because it has been reported that interleukin 8 is generated during routine storage of whole-blood platelets, the effects of interleukin 8 on the NADPH oxidase were examined. Recombinant monocyte interleukin 8 rapidly primed the oxidase but was not inhibited by WEB 2170.
Is midline uterine defect size correlated with miscarriage of euploid embryos in recurrent cases?	To compare subsequent pregnancy outcomes after two or more miscarriages in patients with and without congenital uterine anomalies. Case-control study. Nagoya City University Hospital. A total of 42 patients with a bicornuate or septate uterus and 1528 with normal uteri. No surgery. The cumulative success rate for birth, abnormal chromosome karyotype rate in aborted concepti, and the predictive values of the height of the defect/length of the remaining uterine cavity ratio (D/C ratio). Of the total of 1676 patients, 54 (3.2%) had congenital uterine anomalies; 25 (59.5%) of the 42 patients with a bicornuate or septate uterus had a successful first pregnancy after examination, while this was the case for 1096 (71.7%) of the 1528 with normal uteri. There was no difference in the cumulative live-birth rate (78.0% and 85.5%) within the follow-up period. However, the rates for an abnormal chromosome karyotype in aborted concepti in cases with and without uterine anomalies were 15.4% (two of 13) and 57.5% (134 of 233), respectively, with the latter being significantly higher. The D/C ratio in the miscarriage group was also significantly greater than that for the live-birth group.	Apolipoprotein A-I (apoA-I), the major component of high-density lipoprotein (HDL), has been recently found to suppress inflammation. This study was to investigate the effects and potential mechanisms of apoA-I on the CD40/CD40 ligand (CD40L) proinflammatory signaling pathway. Human THP-1 macrophage-derived foam cells were treated with sCD40L alone or in the presence of apoA-I. Secretion of proinflammatory cytokines was performed by enzyme-linked immunosorbent assay(ELISA). The proteins and mRNA expression were examined by western-blot and real-time PCR analysis, respectly. Cholesterol efflux was assessed by liquid scintillation counting. Cholesterol depletion of macrophages was performed with methylated β-cyclodextrin. ApoA-I inhibits the inflammatory response stimulated by soluble CD40L (sCD40L) in macrophages. In addition, apoA-I inhibited the sCD40L-stimulated activation of nuclear factor-kB (NF-kB). The apoA-I-induced NF-kB deactivation was related to the decreased recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF-6), a crucial adapter protein for CD40 in macrophages, to lipid rafts after being treated by sCD40L. When interfering the expression of ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transporter for apoA-I in macrophages, it could significantly diminish the effect of apoA-I on the sCD40L-stimulated inflammatory response.
Does a MAP3k1 SNP predict survival of gastric cancer in a Chinese population?	Genome-wide association studies (GWAS) have demonstrated that the single nucleotide polymorphism (SNP) MAP3K1 rs889312 is a genetic susceptibility marker significantly associated with a risk of hormone-related tumors such as breast cancer. Considering steroid hormone-mediated signaling pathways have an important role in the progression of gastric cancer, we hypothesized that MAP3K1 rs889312 may be associated with survival outcomes in gastric cancer. The purpose of this study was to test this hypothesis. We genotyped MAP3K1 rs889312 using TaqMan in 884 gastric cancer patients who received subtotal or total gastrectomy. Kaplan-Meier survival analysis and Cox proportional hazard regression were used to analyze the association between MAP3K1 rs889312 genotypes and survival outcomes of gastric cancer. Our findings reveal that the rs889312 heterozygous AC genotype was significantly associated with an increased rate of mortality among patients with diffuse-type gastric cancer (log-rank P = 0.028 for AC versus AA/CC, hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 1.03-1.69), compared to those carrying the homozygous variant genotypes (AA/CC). Additionally, univariate and multivariate Cox regression analysis demonstrate that rs889312 polymorphism was an independent risk factor for poor survival in these patients.	Escalation in monocyte trafficking from the bone marrow into the brain may play a critical role in central nervous system injury and cognitive deterioration in patients with HIV infection. This study tested the hypothesis that the mean diffusivity is sensitive to marrow changes in HIV patients and that these quantitative imaging measurements correlate with the severity of dementia. The mean diffusivity (MD), determined for clival and calvarial marrow regions, was compared in 11 HIV-infected patients and 9 control subjects. The imaging measurements were also evaluated for relationships with dementia severity and markers of disease progression (CD4 and viral load in plasma). The MD was significantly reduced in both clival and calvarial marrow in HIV-infected patients (P =.006). Diffusion measurements for clival (P =.02) and for calvarial (P =.03) regions were significantly correlated with the severity of dementia.
Does nerve ultrasound depict peripheral nerve enlargement in patients with genetically distinct Charcot-Marie-Tooth disease?	To elucidate the ultrasound (US) features of peripheral nerves including nerve roots in patients with different types of Charcot-Marie-Tooth disease (CMT), and the association between US findings, clinical features and parameters of nerve conduction studies (NCS) in CMT1A. US of median, sural and great auricular nerves and the C6 nerve root was performed in patients with CMT1A (n=20), MPZ-associated CMT (n=3), NEFL-associated CMT (n=4), EGR2-associated CMT (n=1), ARHGEF10-associated CMT (n=1) and in controls (n=30). In patients with CMT1A, we analysed the correlations between US findings and the following parameters: age, CMT Neuropathy Score (CMTNS) and NCS indices of the median nerve. Cross-sectional areas (CSAs) of all the nerves were significantly increased in patients with CMT1A compared with that in controls. In MPZ-associated CMT, increased CSAs were found in the median nerve at wrist and in the great auricular nerve, whereas it was not increased in patients with NEFL-associated CMT. In patients with CMT1A, there was a positive correlation between CMTNS and the CSAs in the median nerves or great auricular nerves. In median nerves in patients with CMT1A, we found a negative correlation between the nerve conduction velocity and the CSA.	Although obesity is associated with gonadal dysfunction in the general population, gonadotoxic treatment might diminish the impact of obesity in childhood cancer survivors (CCS). The aim was to evaluate whether altered body composition is associated with gonadal dysfunction in male CCS, independent of gonadotoxic cancer treatment. Three hundred fifty-one male CCS were included. Median age at diagnosis was 5.9 years (0-17.8) and median age at follow-up 25.6 years (18.0-45.8). Total and non-SHBG-bound testosterone, sex hormone-binding globulin, inhibin B, and follicle-stimulating hormone (FSH) were studied. Potential determinants were BMI, waist circumference, waist-hip ratio, and body composition measures (dual energy X-ray absorptiometry). Non-SHBG-bound testosterone was significantly decreased in survivors with BMI ≥ 30 kg/m(2) (adjusted mean 9.1 nmol/L vs. 10.2 nmol/L, P = 0.015), high fat percentage (10.0 vs. 11.2, P = 0.004), and high waist circumference (>102 cm) (9.0 vs. 11.0, P = 0.020). Survivors with high fat percentage (≥25%) had significantly lower inhibin B/FSH ratios (inhibin B/FSH ratio: β -34%, P = 0.041).
Is hIV infection associated with an increased prevalence of coronary noncalcified plaque among participants with a coronary artery calcium score of zero : Multicenter AIDS Cohort Study ( MACS )?	HIV-infected individuals bear increased cardiovascular risk even in the absence of traditional cardiovascular risk factors. In the general population, coronary artery calcium (CAC) scanning is of value for cardiovascular risk stratification, but whether a CAC score of zero implies a low noncalcified coronary plaque burden in HIV-infected persons is unknown. We assessed the prevalence of noncalcified coronary plaque and compared noncalcified coronary plaque burden between HIV-infected and HIV-uninfected participants who had CAC scores of zero in the Multicenter AIDS Cohort Study (MACS) using coronary computed tomography (CT) angiography. HIV infection was associated with the presence of noncalcified coronary plaque among these men with CAC scores of zero. In a model adjusted only for age, race, centre, and pre- or post-2001 cohort, the prevalence ratio for the presence of noncalcified plaque was 1.27 (95% confidence interval 1.04-1.56; P = 0.02). After additionally adjusting for cardiovascular risk factors, HIV infection remained associated with the presence of noncalcified coronary plaque (prevalence ratio 1.31; 95% confidence interval 1.07-1.6; P = 0.01).	To investigate the toxicological mechanism of microcystin-LR (MCLR) on L-02 cells. L-02 cells was treated with MCLR at different concentrations and the subsequent changes such as cell proliferation (MTT assay), morphology, lactate dehydrogenase (LDH) leakage, apoptosis rate and apoptosis-related gene expression were examined. MTT assay showed that MCLR mildly inhibited the cell growth within the initial 24 h of treatment but enhanced the cell viability after that till 60 h in a time- and dose-dependent manner. LDH leakage underwent no marked changes in response to 48-hour MCLR treatment but increased upon prolonged treatment for 60 h, indicating the presence of oxidative damage. After a 48-h treatment with MCLR at 50 microg/ml, obvious apoptosis of L-02 cells occurred as manifested by cell rounding, detachment from the substrate, cell shrinkage and membrane blebbing. The apoptosis rates were rather low (between 22% and 29%) after treatment with MCLR at different concentrations for 36 h, and increased to as much as 80% after a 60-h treatment with 50 microg/ml MCLR. The expressions of p53 and bcl-2 increased in the cells after treatment with high-concentration MCLR, suggesting that MCLR up-regulated the expression levels of the two proteins.
Is siglec-10 associated with survival and natural killer cell dysfunction in hepatocellular carcinoma?	The interaction between Siglec-10 and its ligand, CD24, selectively represses tissue damage-caused immune responses. However, the nature of Siglec-10 and CD24 in human hepatocellular carcinoma (HCC) is still poorly defined. Hereon, the expression, function, and regulation of CD24 and Siglec-10 in HCC were investigated in the present study. Flow cytometry was performed to examine the expression of Siglec-10 in HCC tissues and adjacent non-tumor tissues of HCC patients. To further determine whether Siglec-10 expression is associated with the clinical characteristics and survival, conventional immunohistochemistry was performed in 96 HCC patients. Additionally, the role of Siglec-10 in the regulation of natural killer (NK) cell dysfunction was evaluated. Finally, CD24 expression in HCC was also assessed. Siglec-10 was expressed most on NK cells in HCC (40.7 ± 4.5%). Compared with surrounding non-tumor tissues, tumor tissues had higher Siglec-10 expression (31.0 ± 1.7% versus 40.7 ± 4.5%, n = 10, P < 0.05), and the expression was negatively associated with patient survival. Siglec-10(+)CD56(+) NK cells exhibited reduced effector function, as shown by decreased granules and cytokine expressions compared with Siglec-10(-)CD56(+) NK cells. Moreover, the number of CD24(+)CD45(-) cells in HCC tissues was higher than that in adjacent non-tumor tissues (9.4 ± 0.9% versus 3.1 ± 0.9%, n = 15, P < 0.05).	Determining the reasons people choose to study nursing may help educators and managers develop student-focussed and enticing nursing programmes. In Australia, little research has been undertaken with students entering nursing programmes and the reasons for their choice. The aim of this study was to determine why new students choose to enter nursing at university. A descriptive survey design. An urban university in Sydney, Australia. Undergraduate nursing students at the beginning of their first year of study. An open-ended question relating to the reasons for students' choice of a nursing programme was included in the survey. The transcribed textual data were content analysed for words related to the students' choice. The students' reasons for entering nursing programmes were both personal and career related, with personal being more dominant. The reasons to start nursing were: being able to help and care for people, job security, the ability to enter tertiary education and the enjoyment or love of nursing.
Do evaluation of sinus and atrioventricular nodes function in patients with vasovagal syncope?	Evaluation of sinus and atrioventricular nodes function as a potential factor responsible for prolonged bradycardia, asystole, or both in patients with cardioinhibitory and non-cardioinhibitory vasovagal syncope (VVS). The study included 258 patients (mean age = 47.7 +/- 17.2 years; range 18-62; 147 females) with a history of VVS. They were divided among four groups, according to results of head-up tilt test (HUTT). All patients underwent standard HUTT, carotid sinus massage (CSM), and rapid transesophageal atrial pacing for evaluation of total sinus node recovery time (SNRT), and corrected sinus node recovery time (CNRT), resting and intrinsic heart rate (IHR), and Wenckebach point (WP). Values of SNRT > 1,500 ms, CNRT > 525 ms, WP < 130 bpm, and CSM-induced pause >3 seconds were considered abnormal. SNRT, CNRT, and WP before and after pharmacological blockade, resting heart rate, and IHR did not differ significantly among the study groups. The prevalence of mild sinus node dysfunction (SND), decreased value of WP, and cardioinhibitory carotid sinus hypersensitivity was similar among all study groups.	Antibody-mediated rejection (ABMR) is dependent on complement activating donor-specific anti-HLA antibodies (DSA). This is commonly detected by C4d deposition in allografts. However, recent data define a C4d negative ABMR phenotype suggesting a role for complement-independent DSA injury, antibody-dependent cellular cytotoxicity (ADCC). Here, we established an in vitro ADCC model that identified human ADCC-activated genes using microarray analysis. We subsequently interrogated renal allograft biopsies from patients with ABMR and controls for mRNA expression of the ADCC-activated gene set. We identified 13 ADCC-activated genes. Six gene expression assays including 8 of the 13 genes (CCL3, CCL4/CCL4L1/CCL4L2, CD160, IFNG, NR4A3 and XCL1/XCL2) were analyzed in 127 kidney biopsies obtained from HLA-sensitized (HS), non-HS patients and control individuals. Most ADCC-activated genes showed significantly higher expression in the transplant samples compared to the controls (p<0.0005). The gene expression levels were significantly higher in HS and non-HS transplant patients who developed ABMR compared to those who did not (p=0.04-0.002). There was no difference in the gene expression levels between C4d positive and negative ABMR (p=0.26-0.99). Samples from high PRA (>80%) or positive DSA patients showed higher gene expression levels for the ADCC-activated genes compared to low PRA (<80%) and negative DSA patients (p=0.04-0.001).
Does indexed effective orifice area after mechanical aortic valve replacement affect left ventricular mass regression in elderly?	After aortic valve replacement, the effects of a small functional prosthesis on the extent and pattern of regression of left ventricular hypertrophy and on clinical outcomes may be less significant in older patients with low cardiac output requirements. The objective of this study was therefore to determine whether patient-prosthesis mismatch affects left ventricular mass regression in the elderly. The population studied was made up of 88 patients over 65 years of age with pure aortic stenosis who underwent mechanical aortic valve replacement. The effective orifice area index was calculated for each patient on the basis of the projected prosthesis in vivo effective orifice area. It was considered a continuous variable and influence of its entire range of values on the extent of left ventricular mass regression was analyzed in a multivariate prediction model. Even though, in the group with prosthesis-patient mismatch there was a trend for lower postoperative left ventricular mass index (115+/-24 g/m(2) vs 102+/-27 g/m(2), p=0.24) and postoperative peak trans-prosthetic gradients (32+/-9.8 mmHg vs 28.9+/-7.79 mmHg, p=0.35) these differences were not statistically significant. The prevalence of residual left ventricular hypertrophy at follow-up was 50% in the group with patient-prosthesis mismatch and 50% in the group without patient-prosthesis mismatch (p=0.83). In multivariate analysis the only factors associated with indexed left ventricular mass were the follow-up time (p=0.015, r(2)=0.22) and preoperative indexed left ventricular mass (p=0.0012, r(2)=0.11).	Low dose-rate radioimmunotherapy (RIT) using (125)I-labelled monoclonal antibodies ((125)I-mAbs) is associated with unexpected high cytotoxicity per Gy. We investigated whether this hypersensitivity was due to lack of detection of DNA damage by the targeted cells. DNA damage was measured with the alkaline comet assay, gamma-H2AX foci and the micronucleus test in p53(-/-) and p53(+/+) HCT116 cells exposed to increasing activities of internalizing anti-HER1 (125)I-mAbs or non-internalizing anti-CEA (125)I-mAbs. The expression of proteins involved in radiation response and progression of cells through the cycle were determined. Cell hypersensitivity to low absorbed doses of anti-CEA (125)I-mAbs was not due to defect in DNA damage detection, since ATM (ataxia telangiectasia mutated gene), gamma-H2AX, p53 and p21 were activated in RIT-treated HCT116 cells and G2/M cell cycle arrest was observed. Moreover, the alkaline comet assay showed that DNA breaks accumulated when cells were placed at 4°C during exposure but were repaired under standard RIT conditions (37°C), suggesting that lesions detected under alkaline conditions (mostly DNA single strand breaks and alkali-labile sites) are efficiently repaired in treated cells. The level of gamma-H2AX protein corroborated by the level of foci measured in nuclei of treated cells was shown to accumulate with time thereby suggesting the continuous presence of DNA double strand breaks. This was accompanied by the formation of micronuclei.
Does receipt of diabetes preventive services differ by insurance status at visit?	Lack of insurance is associated with suboptimal receipt of diabetes preventive care. One known reason for this is an access barrier to obtaining healthcare visits; however, little is known about whether insurance status is associated with differential rates of receipt of diabetes care during visits. To examine the association between health insurance and receipt of diabetes preventive care during an office visit. This retrospective cohort study used electronic health record and Medicaid data from 38 Oregon community health centers. Logistic regression was used to test the association between insurance and receipt of four diabetes services during an office visit among patients who were continuously uninsured (n=1,117); continuously insured (n=1,466); and discontinuously insured (n=336) in 2006-2007. Generalized estimating equations were used to account for within-patient correlation. Data were analyzed in 2013. Overall, continuously uninsured patients had lower odds of receiving services at visits when due, compared to those who were continuously insured (AOR=0.73, 95% CI=0.66, 0.80). Among the discontinuously insured, being uninsured at a visit was associated with lower odds of receipt of services due at that visit (AOR=0.77, 95% CI=0.64, 0.92) than being insured at a visit.	Although Kupffer cells (KCs) are capable of producing important growth-stimulating cytokines, their role in liver regeneration following partial hepatectomy (PH) remains poorly understood. In the present study liver regeneration was studied after KC-depletion by intravenous administration of liposome-encapsulated dichloromethylene-diphosphonate (C12MDP), a method known to physically eliminate KCs. Furthermore, splenectomy was performed one week prior to PH to exclude the effect of C12MDP-liposomes on macrophage populations in the spleen. KC-depletion was confirmed in cryostat liver sections stained with the monoclonal antibody ED2, a marker for resident tissue macrophages. Forty-eight hours after PH, the cumulative hepatocyte DNA synthesis, as determined in liver sections by the hepatocyte bromodeoxyuridine labeling index, was significantly decreased in KC-depleted rats when compared to control-rats. The weight of the remnant liver, expressed as a percentage of the initial liver weight, was significantly less at 96 h after PH in KC-depleted rats. KC-depletion abolished the hepatic interleukin-6 (IL-6) and interleukin-10 (IL-10) mRNA synthesis and decreased hepatic expression of tumor necrosis factor-alpha (TNF-alpha), hepatocyte growth factor (HGF) and transforming growth factor-beta1(TGF-beta1) mRNA after PH, as was assessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Moreover, at 4 h after PH the systemic release of IL-6 was significantly decreased in KC-depleted rats.
Is antibody immunity to the p53 oncogenic protein a prognostic indicator in ovarian cancer?	Presence of intratumoral T-cell infiltration has been linked to improved survival in ovarian cancer patients. We questioned whether antibody immunity specific for ovarian cancer tumor antigens would predict disease outcome. We evaluated humoral immune responses against ovarian cancer antigens p53, HER-2/neu, and topoisomerase IIalpha. Serum was collected from 104 women (median age, 59 years; range, 34 to 89 years) at the time of their initial definitive surgery for ovarian cancer. Serum was analyzed by enzyme-linked immunosorbent assay for antibodies to p53, HER-2/neu, and topoisomerase IIalpha proteins. Antibody immunity to tetanus toxoid was assessed as a control. The incidence of humoral immunity at the time of diagnosis to any of these three antigens was tabulated. For patients with advanced-stage disease (III/IV), correlation was made between the presence of tumor-specific immunity at the time of diagnosis and overall survival. Patients were followed for a median of 1.8 years. Multivariate analysis showed the presence of p53 antibodies to be an independent variable for prediction of overall survival in advanced-stage patients. Overall survival was significantly higher for patients with antibodies to p53 when compared with patients without p53 antibodies (P = .01). The median survival for p53 antibody-positive patients was 51 months (95% CI, 23.5 to 60.5 months) compared with 24 months (95% CI, 19.4 to 28.6 months) for patients without antibodies to p53.	Regular physical activity is an effective non-pharmacological therapy for prevention and control of hypertension. However, the underlying mechanisms are not fully understood. Accumulating evidence shows that the elevated vascular tone in hypertension is a consequence of the 'ion channel remodelling' that occurs during sustained high BP. The present study investigated the effects of aerobic exercise on the electrical remodelling of L-type Ca(2+) (Cav 1.2) and large-conductance Ca(2+) -activated K(+) (KCa 1.1) channels in mesenteric arteries (MAs) from spontaneously hypertensive rats (SHRs). SHRs and normotensive (Wistar-Kyoto) rats were subjected to aerobic training or kept sedentary, and vascular mechanical and functional properties were evaluated. Exercise did not affect the heart weight, but reduced the heart rate and body weight in SHR. In mesenteric arterial myocytes, exercise normalized the increased Cav 1.2 and KCa 1.1 current density in SHRs. Exercise also ameliorated the increased open probability and mean open time of the single KCa 1.1 channel in hypertension. The isometric contraction study revealed that both nifedipine (Cav 1.2 channel blocker) and NS11021 (KCa 1.1 channel activator) induced concentration-dependent vasorelaxation in MAs precontracted with noradrenaline. Exercise normalized the increased sensitivity of tissues to nifedipine and NS11021 in SHR. Furthermore, protein expression of the Cav 1.2 α1C -subunit together with the KCa 1.1 α- and β1-subunit was significantly increased in SHRs; and exercise ameliorated these molecular alterations in hypertension.
Does sterility testing of platelet concentrate prepared from deliberately infected blood donations?	In general the bacterial count in freshly donated blood is low and even lower in the corresponding platelet concentrates (PCs). By use of flow cytometry (FACS) for sterility testing, the reliability of early versus later sampling times was evaluated. Blood donations were spiked with various numbers of Staphylococcus epidermidis, Staphylococcus aureus, Bacillus cereus, and Klebsiella pneumoniae. The corresponding PCs were prepared by the buffy-coat method and stored at 22 degrees C. A 20-mL sample was collected from each PC directly after preparation and after 8 hours. Samples were stored at 35 degrees C. Sterility testing of both PCs and samples was by FACS analysis at different time points. All stored PCs were found positive by FACS analysis, with detection times ranging between 8 and 24 hours (K. pneumoniae, B. cereus), 8 and 91 hours (S. aureus), and 144 hours (S. epidermidis). In the samples incubated at 35 degrees C, bacteria were detected after 8 to 19 hours (K. pneumoniae, B. cereus), 8 to 67 hours (S. aureus), and 19 to 43 hours (S. epidermidis). Some of the samples did not contain bacteria.	Histone deacetylase inhibitors (HDACi) are a new class of promising anti-tumour agent inhibiting cell proliferation and survival in tumour cells with very low toxicity toward normal cells. Neuroblastoma (NB) is the second most common solid tumour in children still associated with poor outcome in higher stages and, thus NB strongly requires novel treatment modalities. We show here that the HDACi Sodium Butyrate (NaB), suberoylanilide hydroxamic acid (SAHA) and Trichostatin A (TSA) strongly reduce NB cells viability. The anti-tumour activity of these HDACi involved the induction of cell cycle arrest in the G2/M phase, followed by the activation of the intrinsic apoptotic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the activation of the pro-apoptotic proteins Bid and BimEL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-xL, RIP and survivin, that further enhanced the apoptotic signal. Interestingly, the activity of these apoptosis regulators was modulated by several different mechanisms, either by caspases dependent proteolytic cleavage or by degradation via the proteasome pathway. In addition, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells.
Does nitrite therapy improve left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling?	Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury. No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy. Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.	To investigate the effect of the percentage of free prostate-specific antigen (%fPSA) on future prostate cancer risk. We examined serum total PSA (tPSA) and %fPSA annually in a prostate cancer-screening cohort between July 2001 and June 2011. Men with tPSA >4.0 ng/mL or tPSA of 2.0-4.0 ng/mL with %fPSA ≤12% were screened as positive and were recommended to undergo a biopsy. The study population consisted of 6368 men, aged 40-79 years, who had tPSA ≤4.0 ng/mL at initial screening and who subsequently underwent 1 or more screenings. We calculated the cumulative risk and hazard ratio of prostate cancer stratified by the initial %fPSA groups as quartiles of prostate cancer patients. During a median follow-up of 36 months, 119 men were diagnosed with prostate cancer. The lowest quartile of %fPSA (<13.3%) was associated with a 21.2-fold higher risk of having prostate cancer compared with the highest quartile (>22.2%). For the subset with an initial tPSA ≤1.0 ng/mL, all men diagnosed with cancer had an initial %fPSA ≤33.3% (median). For the subset with tPSA >1.0 ng/mL, men with %fPSA ≤23.0% (median) had significantly higher risk for cancer than those with %fPSA >23.0% (P <.0001). Of the 114 men with prostate cancer in whom pathologic findings were available, 79 (69.3%) had a Gleason score ≥3 + 4 = 7.
Does radial forearm free tissue transfer reduce complications in salvage skull base surgery?	Patients who undergo skull base resection after prior surgery or radiation may be at high risk for complications when local flaps alone are used for reconstruction. To determine whether the complication rate could be reduced, fasciocutaneous free tissue transfer was used to reinforce the dural closure in patients who had prior skull base surgery or radiation. This study is a case series of 20 patients (14 males, 6 females, aged 8-79 years of age with a mean of 47.7 years) from 1997 to 2001 who had prior skull base surgery or radiation, and underwent salvage skull base resection without large volume defects. All patients had a radial forearm free tissue transfer to reinforce the dural closure. Six patients had an osseous component to the forearm flap to provide vascularized bone to the orbital rim. The overall local complication rate was 35%. Three patients (15%) had major complications including 1 case of meningitis, 1 case of cerebrospinal fluid leak, and 1 case of a flap requiring venous salvage. There were no flap failures, 1 idiopathic median nerve palsy, and no pathologic radius bone fractures.	Proprotein convertase subtilisin kexin type 9 (PCSK9) is a natural inhibitor of the low-density lipoprotein receptor, and its deficiency in humans results in low plasma LDL-cholesterol and protection against cardiovascular disease. We explored whether PCSK9 expression impacts postprandial triglyceridemia, another important cardiovascular risk factor. Real-time PCR and confocal microscopy were used to show that PCSK9 is expressed throughout the entire small intestine and in human enterocytes. On olive oil gavage, PCSK9-deficient mice showed a dramatically decreased postprandial triglyceridemia compared with their wild-type littermates. Lymph analysis revealed that intestinal TG output is not quantitatively modified by PCSK9 deletion. However, PCSK9-/- mice present with a significant reduction of lymphatic apoB secretion compared to PCSK9+/+ mice. Modulating PCSK9 expression in polarized CaCo-2 cells confirmed the relationship between PCSK9 and apoB secretion; PCSK9-/- mice consistently secrete larger TG-rich lipoprotein than wild-type littermates. Finally, kinetic studies showed that PCSK9-deficient mice have an increased ability to clear chylomicrons compared to wild-type littermates.
Do inotropes increase cardiac output or cerebral blood flow in preterm piglets?	The preterm newborn is at high risk of developing cardiovascular compromise during the first day of life and this is associated with increased risk of brain injury. Standard treatments are volume expansion and administration of inotropes, typically dopamine and/or dobutamine, but there is limited evidence that inotropes improve clinical outcomes. This study investigated the efficacy of dopamine and dobutamine for the treatment of cardiovascular compromise in the preterm newborn using a piglet model. Preterm and term piglets were assigned to either dopamine, dobutamine or control infusions. Heart rate, left ventricular contractility, cardiac output, blood pressure, and cerebral and regional blood flows were measured during baseline, low (10 µg/kg/h), and high (20 µg/kg/h) dose infusions. At baseline, preterm piglets had lower cardiac contractility, cardiac output, blood pressure, and cerebral blood flow compared to term piglets. The response of preterm piglets to either dopamine or dobutamine administration was less than in term piglets. In both preterm and term piglets, cardiac output and cerebral blood flow were unaltered by either inotrope.	Melanoma is a heterogeneous group of diseases with distinct sets of genetic changes. Recurrent and mutually exclusive C>T or CC>TT transition mutations were identified in the promoter region of the reverse transcriptase catalytic subunit of the telomerase gene (TERT) in melanoma recently, and it was suggested that they enhanced the expression of TERT gene and played important roles in the melanoma pathogenesis. These mono or di-nucleotide transitions were ultraviolet (UV)-signature mutations. In this study, polymerase chain reaction and direct sequencing of TERT promoter using formalin-fixed and paraffin-embedded tissue was performed to investigate whether these UV-signature mutations were also present in acral lentiginous melanoma. TERT promoter mutation was identified in only 2 of the 32 cases (6%) of acral lentiginous melanomas while it was identified in 3 of the 9 cases (33%) of non-acral cutaneous melanomas. The difference was statistically significant (p = 0.028).
Is neuronal cell death in a rat model for mesial temporal lobe epilepsy induced by the initial status epilepticus and not by later repeated spontaneous seizures?	To determine whether repeated seizures contribute to hippocampal sclerosis, we investigated whether cell loss in the (para) hippocampal region was related to the severity of chronic seizure activity in a rat model for temporal lobe epilepsy (TLE). Chronic epilepsy developed after status epilepticus (SE) that was electrically induced 3-5 months before. The presence of neuronal damage was assessed by using Fluoro-Jade and dUTP nick end-labeling (TUNEL) of brain sections counterstained with Nissl. We found a negative correlation between the numbers of surviving hilar cells and the duration of the SE (r = -0.66; p < 0.01). In the chronic phase, we could discriminate between rats with occasional seizures (0.15 +/- 0.05 seizures per day) without progression and rats with progressive seizure activity (8.9 +/- 2.8 seizures/day). In both groups, the number of TUNEL-positive cells in parahippocampal regions was similar and higher than in controls. In the hippocampal formation, this was not significantly different from controls. Fluoro-Jade staining showed essentially the same pattern at 1 week and no positive neurons in chronic epileptic rats.	Whether obesity affects surgical outcomes in patients with hepatocellular carcinoma (HCC) is controversial. Here we retrospectively evaluated the impact of obesity on outcomes in HCC patients after curative hepatectomy. Patients with Child-Pugh A liver function who underwent curative hepatectomy between 2006 and 2010 were categorized as obese (BMI ≥25 kg/m2, n = 68) and non-obese (<25 kg/m2, n = 242). To reduce interference from baseline differences between the two groups, propensity score-matched analysis was performed in the ratio 1:2 using a caliper width of 0.1. Surgical outcomes were compared for 61 obese and 115 non-obese patients. Obese patients had higher levels of albumin and aspartate aminotransferase, and more solitary tumors compared to the non-obese patients (all P<0.05). In the propensity-matched cohort, baseline characteristics did not differ between the two groups (all P>0.05). Obese and non-obese patients had comparable 30-day mortality (1.6% vs. 2.6%, P = 1.000), 90-day mortality (3.3% vs. 4.3%, P = 1.000), and incidence of postoperative complications (19.7% vs. 18.3%, P = 0.819). Overall survival at 1, 3, and 5 years was similar for obese patients (83.6%, 63.6%, 41.6%) as for non-obese patients (80.9%, 65.9%, 49.1%; P = 0.358). Disease-free survival at 1, 3, and 5 years was also similar for obese patients (71.5%, 36.3%, 24.3%) as for non-obese ones (60.2%, 43.7%, 27.7%; P = 0.969).
Is prehydration effective for rapid control of recalcitrant atopic dermatitis?	Skin care remains a key component in atopic dermatitis (AD) management; there are no data available guiding optimal bathing recommendations. This study aims to determine whether 15-minute to 20-minute baths followed by topical corticosteroid application (prehydration therapy) are effective for clearing moderate to severe AD. In the Oregon Health & Science University outpatient dermatology clinic, a retrospective review was done of the health records of patients with AD seen first between January 1, 2007, and December 31, 2011, who were then reevaluated within 1 to 3 weeks of starting the therapy. Qualifying patients underwent the prehydration regimen and were reevaluated. The primary outcome was therapeutic response using the Investigators' Global Assessment Scale. Secondary outcomes were measured using the dynamic Treatment Response Scale. Of 110 distinct electronic records, 35 patients were excluded. At the initial visit, 75 patients were evaluated with the Investigators' Global Assessment Scale. Forty-eight patients (64%) were severe, and 27 patients (36%) were moderate. All subjects began prehydration therapy followed by topical corticosteroid. At follow-up visit in 1 to 3 weeks when using the patient's or provider's assessment of treatment response, 59 patients (79%) had marked improvement, and 3 patients (4%) were clear.	The human GLB1 gene is known to give rise to two alternatively spliced mRNAs, which encode two different proteins: lysosomal beta-galactosidase (beta-gal) and elastin-binding protein (EBP). The beta-gal transcript includes the 16 exons of the GLB1 gene. In the EBP transcript, exons 3, 4 and 6 are skipped, while exon 5 has a different reading frame. However, little is known on how this alternative splicing is regulated. Cycloheximide treatment of HeLa cells and human fibroblasts revealed the presence of new transcripts that are otherwise degraded by nonsense-mediated decay (NMD). A minigene carrying the exons involved in the alternative splicing of GLB1 was constructed. Improving the acceptor-site scores of exons 3 or 4 increased the relative inclusion of these exons, but did not stop them being skipped in some transcripts. Overexpression of different SR proteins altered the relative proportion of the different transcripts produced by the minigene, indicating a possible mechanism for the regulation of the alternative splicing of GLB1. Finally, a comparison of this gene among different species was performed.
Does platelet-derived growth factor expression correlate with tumor grade and proliferative activity in human oligodendrogliomas?	For the last one and a half decade, it has been found that platelet-derived growth factor (PDGF) promotes glial tumor growth through autocrine and paracrine loops, by expression of PDGFalpha receptor (PDGFRalpha) on glioma cells and PDGFbeta receptor (PDGFRbeta) on proliferating endothelial cells. However, studies on oligodendrogliomas, correlating expression of PDGF and its receptor with tumor grade and proliferative activity, through MIB-1 labeling index (LI) are relatively few as compared to astroglial counterpart. Formalin-fixed paraffin-embedded tissues from 55 cases of oligodendrogliomas (34 World Health Organization [WHO] grade II and 21 WHO grade III tumors) were subjected to immunohistochemistry. MIB-1 LI was calculated, and a semiquantitative scoring system for expression of PDGF and PDGFRalpha was used. MIB-1 LI and PDGF expression increased with histologic grades of malignancy ("t" test, P < .001 and Mann Whitney test, U = 109, P < .001 respectively). The PDGF expression scores had a positive correlation with MIB-1 LI, irrespective of tumor grade (Pearson's correlation coefficient, r = 0.566; P < .001). However, there was no significant difference of PDGFRalpha expression between 2 grades of tumors.	Abnormal thoraco-abdominal motion may contribute to exercise limitation in patients with COPD. The current study aimed to assess how the thoraco-abdominal asynchrony in COPD patients correlates with exercise performance during the 6-minute walk test (6MWT). Eighty-eight COPD subjects (40 moderate and 48 severe) and 14 healthy controls were evaluated at rest and during the 6MWT for the magnitude of rib cage and abdominal motion and asynchrony between the two (phase angle) with respiratory inductive plethysmography. Compared to healthy control subjects, subjects with COPD had similar magnitude of rib cage and abdominal motion, but greater asynchrony at rest. During the 6MWT, subjects with COPD showed decreased rib cage motion and increased asynchrony. Rib cage excursion at 3 min after the beginning of the 6MWT was an independent predictor for the 6MWT distance (P < .001), in addition to age, percent of predicted FEV(1), and residual volume/total lung capacity. There was no correlation between rib cage excursion at 3 min and St George's Respiratory Questionnaire score.
Does monoclonal antibody against transforming growth factor Beta 1 influence liver regeneration after resection in large animal experiments?	Steatohepatitis is a type of histopathological liver injury that can be caused by chemotherapy [chemotherapy-associated steatohepatitis (CASH)] and can progress to liver fibrosis or cirrhosis. CASH impairs liver functions, including liver regeneration. Impaired liver regeneration reduces the number of patients who can undergo liver resection and reduces opportunities for curative therapies. Transforming growth factor-beta (TGFβ) is a potent mitotic inhibitor that participates during the last phase of liver regeneration. TGFβ has been studied as a potential solution to the development of liver fibrosis or hepatocellular carcinoma. The first aim of our study was to establish a large animal model of toxic liver injury and test the ability of a monoclonal antibody against TGFβ (MAB-TGFβ) to increase liver-regeneration capacity. The second aim was to evaluate the degree to which early preoperative administration of MAB-TGFβ influenced hepatic parenchyma regeneration following healthy liver resection in a swine experimental model. Toxic liver injury was induced by alcohol consumption and regular intraperitoneal administration of carbon tetrachloride (CCl4) to piglets for 10 weeks. After 10 weeks, the piglets underwent liver resection of the left lateral and left medial liver lobes. Twenty-four hours after liver resection, MAB-TGFβ was administered to the experimental group (10 piglets) and a physiological solution to the control group (10 piglets) through an implemented port-a-cath. In the second part of the study, either MAB-TGFβ or a saline solution control were administered at 12 and 4 days prior to resection of the right lobes of healthy liver (six experimental and 10 control group subjects). Observation and follow-up was performed throughout the entire experiment. Ultrasound and biochemical tests (for albumin, cholinesterase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, bilirubin, urea, creatinine and ammonia levels) were performed on postoperative days 1, 3, 7, 10 and 14. A histopathological examination was performed after sacrificing the animals on the 14th postoperative day. No significant differences were observed between groups when using ultrasound volumetry to assess the regenerative volume of the liver in both experiments. The only significant differences found when comparing biochemical parameters between groups were higher serum levels of both creatinine and γ-glutamyl transferase in the experimental group with preoperative administration of MAB-TGFβ. There were no differences in the histological analyses of hepatic lobule cross-sectional area nor in the proliferative index between animals receiving MAB-TGFβ and those treated with physiological saline solution before resection. Hepatocytic cross-sectional areas were larger in animals treated with physiological solution versus those treated with MAB-TGFβ on the operative day; however, these values were comparable between groups by 14 days following resection.	To analyze the KRT6A gene mutation and mutating patterns in a sporadic Chinese patient with Pachyonychia congenita (PC)-1 so as to provide a basis for gene diagnosis and genetic counseling of this disorder. Genomic DNA was extracted from whole blood by standard methods from a female patient with PC-1 and her parents, and from 50 normal, unrelated individuals. Primers for specific amplification of the structural KRT6A gene without co amplification of homologous genes were designed and synthesized. All exons of the gene and their flanking intronic sequences were amplified using polymerase chain reaction (PCR) and subjected to automatic DNA sequencing. The mutation was confirmed by Mbo I restriction digestion of the KRT6A-specific PCR products. Direct sequencing of the PCR products revealed a novel heterozygous missense mutation, I462S in the KRT6A gene, which resulted from T to G transversion at nucleotide 1385 (1385T > G) in exon 7 was detected in the patient. This mutation would result in the substitution of Isoleucine by Serine at codon 462 (I462S) located in the end 2B domain of keratin 6A. No such mutation was found in the patient's parents by sequencing of PCR products and this mutation was confirmed in the patient and excluded from both parents and 50 normal, unrelated controls by restriction analysis of PCR fragments using Mbo I enzyme.
Does alcohol withdrawal alleviate adipose tissue inflammation in patients with alcoholic liver disease?	Patients with alcoholic liver disease (ALD) display inflammation of the subcutaneous adipose tissue (SAT) which correlates with liver lesions. We examined macrophage markers and polarization in the SAT of alcoholic patients and adipokine expression according to liver inflammation; we studied the consequences of alcohol withdrawal. Forty-seven patients with ALD were prospectively included. SAT and blood samples were collected at inclusion and after 1 week of alcohol withdrawal. Pro-inflammatory cytokines/chemokines, inflammasome components and products, adipokine expression levels, macrophage markers and polarization in liver and SAT samples were assessed by RT-PCR arrays. mRNA expression level of chemokines (IL8, semaphorin 7A) correlated with hepatic steatosis in both liver and SAT. Liver expression of inflammasome components (IL1β, IL18, caspase-1) and SAT IL6 and CCL2 correlated with liver damage. In patients with mild ALD, 1 week of alcohol withdrawal was sufficient to decrease expression level of total macrophage markers in the adipose tissue, to orient adipose tissue macrophages (ATM) towards an anti-inflammatory M2 phenotype and to decrease the mRNA expression of cytokines/chemokines (IL18, CCL2, osteopontin, semaphorin 7A). In patients with severe ALD, 1 week of abstinence was also associated with an increase in CCL18 expression.	Using sonography, the bicornate and septate uterus as causes of failure of quinacrine sterilization (QS) are explored. Whether QS can be effectively performed on women with a bicornate or septate uterus is a question answered by a presentation of three such cases. Three cases presented were part of a prospective nonrandomized study of QS in 205 women requesting sterilization at the Family Planning Clinic, School of Medicine of the Federal University of Minas Gerais, Belo Horizonte, Brazil. Sonography was performed on all patients before, during and after QS. Quinacrine was packaged as seven pellets in a modified Copper-T IUD inserter (Sipharm, Sisseln, Switzerland). Each woman received the first transcervical insertion of 252 mg of quinacrine during the follicular phase of the menstrual cycle, usually immediately after menses. One month later, a second insertion was similarly performed. Patients were advised to use an alternate method of birth control for 12 weeks to allow time for scarring of the oviducts. A blood pregnancy test was done before the QS procedure. The diagnosis of a septate or bicornuate uterus was made by sonography in three of the 205 patients in the study. It was obvious that quinacrine had to be inserted into the two horns of such an anomalous uterus if the dissolved drug was to enter both fallopian tubes. Quinacrine dissolved into "lakes of quinacrine," and sonographically could be seen at the top of the uterine fundus. For this clinical trial of 205 patients, there were 546 woman-years of follow-up, and the Pearl index was 0.73 per 100 woman-years (95% confidence limits: 0.02, 1.4).
Does atrial natriuretic peptide suppress endothelin gene expression and proliferation in cardiac fibroblasts through a GATA4-dependent mechanism?	Atrial natriuretic peptide (ANP) is a hormone that has both antihypertrophic and antifibrotic properties in the heart. We hypothesized that myocyte-derived ANP inhibits endothelin (ET) gene expression in fibroblasts. We have investigated the mechanism(s) involved in the antiproliferative effect of ANP on cardiac fibroblasts in a cell culture model. We found that cardiac myocytes inhibited DNA synthesis in co-cultured cardiac fibroblasts as did treatment with the ET-1 antagonist BQ610. The effect of co-culture was reversed by antibody directed against ANP or the ANP receptor antagonist HS-142-1. ANP inhibited the expression of the ET-1 gene and ET-1 gene promoter activity in cultured fibroblasts. The site of the inhibition was localized to a GATA-binding site positioned between -132 and -135 upstream from the transcription start site. GATA4 expression was demonstrated in cardiac fibroblasts, GATA4 bound the ET-1 promoter both in vitro and in vivo, and siRNA-mediated knockdown of GATA4 inhibited ET-1 expression. ET-1 treatment resulted in increased levels of phospho-serine(105) GATA4 in cardiac fibroblasts and this induction was partially suppressed by co-treatment with ANP.	Pedicle subtraction osteotomy (PSO) is one of the surgical options for treating alignment disorders of the fused spine (due to post-surgical fusion or related to arthritis). It enables satisfactory sagittal realignment and improved function due to economic sagittal balance. The aim of this study was to analyze clinical and radiological results of PSO after a minimum follow-up of 2 years and demonstrate the benefit of sub-group analysis as a function of pelvic incidence (PI). A descriptive prospective single center study of 63 patients presenting with spinal global malalignment who underwent correction by PSO. Function was assessed by the Oswestry disability index (ODI), a visual analog scale of lumbar pain (VAS) and a SF-36 questionnaire. Radiographic analyses of pre- and post-operative pelvic-spinal parameters were performed on X-rays obtained by EOS(®) imaging after 3D modeling. Global analysis and analysis of sub-groups as a function of pelvic incidence were performed and the full balance integrated index (FBI) was calculated. this series showed a marked clinical improvement and significant progress of functional scores. Global post-operative radiological analysis showed a significant improvement in all pelvic and spinal parameters. The mean correction obtained after PSO was 31.7° ± 8.4°, hence global improvement of lumbar lordosis of 22°. The sagittal vertical angle (SVA) decreased from +9 cm before surgery to +4.3 cm after surgery. Sub-group analysis demonstrated greater improvement in pelvic tilt, sacral slope and spinal parameters of patients with a small or moderate pelvic incidence; all had an FBI index <10°. Most of the pelvic and spinal parameters of patients with a large pelvic incidence were insufficiently corrected and they had an FBI index >10°
Does dobutamine influence inflammatory pathways during human endotoxemia?	Catecholamines have anti-inflammatory and anticoagulant properties. Dobutamine is a synthetic catecholamine frequently used in patients with septic myocardial dysfunction. The objective was to determine whether a continuous infusion of dobutamine exerts immunomodulatory effects in healthy volunteers challenged with endotoxin. Prospective, open-label study. Clinical research unit of a university hospital. Sixteen male healthy volunteers. Volunteers received a constant infusion with dobutamine (10 microg.kg.min, n = 8) or physiologic saline (n = 8). All participants were challenged with a bolus injection of endotoxin prepared from Escherichia coli (4 ng/kg). Dobutamine infusion was commenced 1 hr before endotoxin challenge and was continued until 3 hrs thereafter. Dobutamine infusion was associated with an increase in mean arterial blood pressure (peak 122 +/- 5 mm Hg) and heart rate (peak 84 +/- 4 beats/min, both p < .05 vs. saline). Endotoxin injection induced the systemic release of cytokines (tumor necrosis factor-alpha, interleukins-6, -8, and -10) and secretory phospholipase A2, endothelial cell activation (increase in the plasma levels of soluble E-selectin and von Willebrand factor), activation of coagulation (increased plasma levels of soluble tissue factor, F1 + 2 prothrombin fragment, and thrombin-antithrombin complexes), and activation with subsequent inhibition of fibrinolysis (increased plasma concentrations of tissue-type plasminogen activator, plasminogen activator inhibitor type I, and plasmin-alpha2-antiplasmin complexes). None of these responses were influenced by dobutamine.	In individual patients with squamous cell carcinoma of the head and neck (SCCHN), established prognostic factors do not satisfactorily predict clinical outcome. Although the karyotype is an independent prognostic factor in certain hematologic malignancies and solid tumors, no data have been reported concerning the possible relationship between chromosomal abnormalities and clinical outcome in patients with SCCHN: In 116 cases of primary SCCHN, short term cultures were analyzed cytogenetically during 1987 through 1991, the karyotypes were divided into four groups: k1, normal (n = 35); k2, numeric changes only (n = 31); k3, simple structural abnormalities (n = 27); and k4, complex karyotypes (n = 23). The patients were followed for at least 18 months after diagnosis or until death. The 2-year survival rate was lower in the k4 subgroup (35%) than in the k1, k2, and k3 subgroups taken together (61%), both in the series as a whole (P = 0.02), and in the largest tumor site subgroup, laryngeal squamous cell carcinoma (n = 32), (P = 0.04). The most prevalent breakpoint was in chromosome band 11q13, occurring in 11 tumors, 10 of which belonged to the k4-subgroup. The 2-year survival rate was lower for patients with 11q13 rearrangements (20%) than for those without (60%), both in the series as a whole (P = 0.001), and in the k4-subgroup (P = 0.02).
Does chronic low vitamin intake potentiate cisplatin-induced intestinal epithelial cell apoptosis in WNIN rats?	To investigate if cisplatin alters vitamin status and if VR modulates cisplatin induced intestinal apoptosis and oxidative stress in Wistar/NIN (WNIN) male rats. Weanling, WNIN male rats (n = 12 per group) received adlibitum for 17 wk: control diet (20% protein) or the same with 50% vitamin restriction. They were then sub-divided into two groups of six rats each and administered cisplatin (2.61 mg/kg bodyweight) once a week for three wk or PBS (vehicle control). Intestinal epithelial cell (IEC) apoptosis was monitored by morphometry, Annexin-V binding, M30 cytodeath assay and DNA fragmentation. Structural and functional integrity of the villus were assessed by villus height/crypt depth ratio and activities of alkaline phosphatase, lys, ala-dipeptidyl amino-peptidase, respectively. To assess the probable mechanism(s) of altered apoptosis, oxidative stress parameters, caspase-3 activity, and expression of Bcl-2 and Bax were determined. Cisplatin per se decreased plasma vitamin levels and they were the lowest in VR animals treated with cisplatin. As expected VR increased only villus apoptosis, whereas cisplatin increased stem cell apoptosis in the crypt. However, cisplatin treatment of VR rats increased apoptosis both in villus and crypt regions and was associated with higher levels of TBARS, protein carbonyls and caspase-3 activity, but lower GSH concentrations. VR induced decrease in Bcl-2 expression was further lowered by cisplatin. Bax expression, unaffected by VR was increased on cisplatin treatment. Mucosal functional integrity was severely compromised in cisplatin treated VR-rats.	The benefits of intravenous tissue-plasminogen activator (tPA) in acute ischemic stroke are time-dependent. Emergency medical services (EMS) hospital prenotification of an incoming patient with potential stroke may provide a means of reducing evaluation and treatment times and improving treatment rates; yet, available data are limited. We examined 371 988 patients with acute ischemic stroke transported by EMS and enrolled in Get With The Guidelines-Stroke from April 1, 2003, to March 31, 2011. Prenotification occurred in 249 197 (67.0%) of EMS-transported patients. Among eligible patients arriving by 2 hours, patients with EMS prenotification were more likely to be treated with tPA within 3 hours (82.8% versus 79.2%, absolute difference +3.5%, P<0.0001, the National Institutes of Health Stroke Scale-documented cohort; 73.0% versus 64.0%, absolute difference +9.0%, P<0.0001, overall cohort). Patients with EMS prenotification had shorter door-to-imaging times (26 minutes versus 31 minutes, P<0.0001), shorter door-to-needle times (78 minutes versus 80 minutes, P<0.0001), and shorter symptom onset-to-needle times (141 minutes versus 145 minutes, P<0.0001). In multivariable and modified Poisson regression analyses accounting for the clustering of patients within hospitals, use of EMS prenotification was independently associated with greater likelihood of door-to-imaging times ≤25 minutes, door-to-needle times for tPA ≤60 minutes, onset-to-needle times ≤120 minutes, and tPA use within 3 hours.
Does rectocele repair improve evacuation and prolapse complaints independent of anorectal function and colonic transit time?	Evacuation disorders associated with a rectocele can be improved by rectocele repair. This study investigated whether anorectal function tests results change after rectocele repair. Fourteen patients with 2nd or 3rd degree rectocele and evacuation disorder were treated by posterior colporrhaphy and evaluated pre- and postoperatively (after 8 months, range 3-14) using questionnaires, anal manometry and endosonography, rectal barostat testing, and colonic transit time measurement with radio-opaque markers. Results from female controls were used for comparison. Preoperatively, rectocele patients had high maximal basal sphincter pressures, large sphincter lengths, and low maximal squeeze pressures, with an anal sphincter defect in seven and lower visceral sensitivity scores than in controls. Postprandial rectal responses (more than 10% decrease in postprandial volume after 1 h) were found in 3 of 14 patients compared to 2 of 11 parous and 9 of 11 nulliparous controls. After repair, a rectocele of 2nd degree was found in four patients. Questionnaire scores were significantly decreased for straining, evacuation disorder, manual support, and protrusion. Overall patient satisfaction with the operation scored 8.25 (range 3-10). Defecation frequencies and stool consistencies were unaltered. Anal pressures, rectal compliance-curves, visceral sensitivity, and colonic transit times were unaltered after the rectocele repair.	The population analysis of cardiovascular risk and non-risk genetic variation can help to identify adaptive or random demographic processes that shaped coronary incidence variation across geography. In this study, 114 single nucleotide polymorphisms and 17 tandem repeat polymorphisms from Nitric Oxide Synthases (NOS) regions were analyzed in 1686 individuals from 35 populations from Europe, North Africa, and the Middle East. NOS genes encode for key enzymes on nitric oxide availability, which is involved in several cardiovascular processes. These genetic variations were used to test for selection and to infer the population structure of NOS regions. Moreover, we tested whether the variation in the incidence of coronary events and in the levels of classical risk factors in 11 of these European populations could be explained by the population structure estimates. Our results supported, first, the absence of clear signs of selection for NOS genetic variants associated with cardiovascular diseases, and second, the presence of a continuous genetic pattern of variation across European and North African populations without a Mediterranean barrier for gene flow. Finally, population structure estimates from NOS regions are closely correlated with coronary event rates and classical risk parameters (explaining 39-98%) among European populations.
Does endoplasmic reticulum stress activate the hepatic activator protein 1 complex via mitogen activated protein kinase-dependent signaling pathways?	Endoplasmic reticulum (ER) stress is induced in many forms of chronic liver disease and may promote the development of hepatocellular carcinoma. The activator protein 1 (AP-1) complex is a transcription factor that promotes hepatic carcinogenesis in response to cellular stress. The aim of this study was to determine the role of ER stress in the regulation of the hepatic AP-1 complex. Human hepatocellular carcinoma (HepG2) cells and C57BL/6J mice were subjected to pharmacologic ER stress and the expression of AP-1-associated genes and proteins was assessed. To determine the role of MAPK signaling in ER stress-induced AP-1 activation, ER stress was induced in JNK- and ERK-inhibited HepG2 cells. Induction of ER stress promoted the activation of both Jun- and Fos-related genes and proteins of the AP-1 complex in HepG2 cells and murine liver. Inhibition of ERK phosphorylation in HepG2 cells completely prevented ER stress-induced activation of the fos-related components of AP-1 whereas activation of Jun-related components was only partially attenuated. Conversely, inhibition of JNK phosphorylation in HepG2 cells reduced ER stress-induced activation of Jun-related components but did not prevent activation of fos-related components.	Operation notes are an important part of medical records for clinical, academic and medicolegal reasons. This study audited the quality of operative note keeping for total knee replacements against the standards set by the British Orthopaedic Association (BOA). A prospective review of all patients undergoing total knee replacement at a district general hospital over 8 months. Data recorded were compared with those required by the BOA good-practice guidelines. Change in practice was implemented and the audit cycle completed. Data were statistically analysed. A total of 129 operation notes were reviewed. There was a significant improvement in the mean number of data points recorded from 9.6 to 13.1. The least well recorded data were diagnosis, description of findings, alignment and postoperative flexion range. All had a significant improvement except description of findings. The operating surgeon writing the note improved from 56% to 67%. Detailed postoperative instructions also improved in quality.

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