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15546136
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Interdependence of N-acetyl aspartate and high-energy phosphates in healthy human brain.
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Because cellular and extract data have suggested that N-acetylaspartate (NAA) reflects neuronal mitochondrial function, we evaluated the quantitative relationship between NAA, high-energy phosphates, and ADP levels in the hippocampus and occipital lobe of 15 healthy volunteers. The ADP levels are calculated using the creatine kinase equilibrium and quantified (31)P and total creatine measurements. Using high-field quantitative MR spectroscopic imaging, we find that NAA and ADP concentrations in the hippocampal body are 9.7 +/- 1.5mM and 35 +/- 8microM, respectively. In the occipital lobe, NAA and ADP are 11.9 +/- 1.9mM and 32 +/- 12microM, respectively. There is a statistically significant positive correlation between NAA and ADP, with R = +0.80, p < 2 x 10(-7)in the hippocampal body. In an adjacent hippocampal NAA voxel, the correlation between NAA and ADP had a R = +0.62, p < 3 x 10(-4), whereas, in the occipital lobe, R = +0.67, p < 5 x 10(-5). There was no significant relationship NAA and either ATP or phosphocreatine. This positive relationship of NAA with ADP suggests a directional process wherein energetics may modulate mitochondrial function.
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15546135
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High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group.
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High dose myeloablative chemotherapy ("megatherapy"), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma. In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative "megatherapy" was evaluated in a randomised, multi-centre trial. Between 1982 and 1985, 167 children with stages IV and III neuroblastoma (123 stage IV > 1 year old at diagnosis and 44 stage III and stage IV from 6 to 12 months old at diagnosis) were treated with oncovin, cisplatin, epipodophyllotoxin, and cyclophosphamide (OPEC) induction chemotherapy every 3 weeks. After surgical excision of primary tumour, the 90 patients (69% of the total) who achieved complete response (CR) or good partial response (GPR) were eligible for randomisation either to high dose melphalan (180 mg per square meter) with autologous bone marrow support or to no further treatment. Sixty-five (72%) of eligible children were actually randomised and 21 of these patients were surviving at time of this analysis, with median follow-up from randomisation of 14.3 years. Five year event-free survival (EFS) was 38% (95% confidence interval (CI) 21-54%) in the melphalan-treated group and 27% (95% CI 12-42%) in the "no-melphalan" group. This difference was not statistically significant (P = 0.08, log rank test) but for the 48 randomised stage IV patients aged >1 year at diagnosis outcome was significantly better in the melphalan-treated group-5 year EFS 33% versus 17% (P = 0.01, log rank test). In this trial, high dose melphalan improved the length of EFS and overall survival of children with stage IV neuroblastoma >1 year of age who achieved CR or GPR after OPEC induction therapy and surgery. Multi-agent myeloablative regimens are now widely used as consolidation therapy for children with stage IV disease and in those with other disease stages when the MYCN gene copy number in tumour cells is amplified. Because they are more toxic, complex, and costly these combination megatherapy regimens should be compared with single agent melphalan in randomised clinical trials.
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15546134
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Atypical protein kinase C-zeta modulates clonogenicity, motility, and secretion of proteolytic enzymes in murine mammary cells.
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In this paper, we investigated whether protein kinase C-zeta (PKC zeta), a member of the atypical PKC family, induces phenotypic alterations associated with malignant transformation and tumor progression in mammary cells. The stable overexpression of PKC zeta in immortalized mammary epithelial cells (NMuMG), activates the mitogenic extracellular signal-regulated kinase (ERK) pathway, enhanced clonal cell growth and exerts profound effects on proteases secretion. The effect on proteases expression seems to be specific for urokinase-type plasminogen activator and metalloproteinase-9 (MMP-9) because no modulation in MMP-2 and MMP-3 production could be detected. In addition, our experiments demonstrated that PKC zeta overexpression markedly altered the adhesive, spreading, and migratory abilities of NMuMG cells. The overexpression of this enzyme was not sufficient to confer an anchorage-independent growth capacity. An extensive mutational analysis of PKC zeta revealed that the effects observed in NMuMG cells were strictly dependent on the kinase (catalytic) domain of the enzyme. Taken together, these results suggest that in mammary cells PKC zeta modulates several of the critical events involved in tumor development and dissemination through the activation of mitogen activated protein kinase (MAPK)/ERK pathway.
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15546133
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Overlap bias in the case-crossover design, with application to air pollution exposures.
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The case-crossover design uses cases only, and compares exposures just prior to the event times to exposures at comparable control, or 'referent' times, in order to assess the effect of short-term exposure on the risk of a rare event. It has commonly been used to study the effect of air pollution on the risk of various adverse health events. Proper selection of referents is crucial, especially with air pollution exposures, which are shared, highly seasonal, and often have a long-term time trend. Hence, careful referent selection is important to control for time-varying confounders, and in order to ensure that the distribution of exposure is constant across referent times, a key assumption of this method. Yet the referent strategy is important for a more basic reason: the conditional logistic regression estimating equations commonly used are biased when referents are not chosen a priori and are functions of the observed event times. We call this bias in the estimating equations overlap bias. In this paper, we propose a new taxonomy of referent selection strategies in order to emphasize their statistical properties. We give a derivation of overlap bias, explore its magnitude, and consider how the bias depends on properties of the exposure series. We conclude that the bias is usually small, though highly unpredictable, and easily avoided.
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15546132
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Measurement error model for misclassified binary responses.
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The article considers regression models for binary response in a situation when the response is subject to classification error. It is also assumed that some of the covariates are unobservable, but measurements on its surrogates are available. Likelihood based analysis is developed to fit the model. A sensitivity analysis is also carried out through simulation to ascertain the effect of ignoring classification error and/or measurement error on the estimation of regression parameters. At the end, the methodology developed in this paper is illustrated through an example.
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15546130
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Factors affecting delivery of antiviral drugs to the brain.
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Although the CNS is in part protected from peripheral insults by the blood-brain barrier and the blood-cerebrospinal fluid barrier, a number of human viruses gain access to the brain, replicate within this organ, or sustain latent infection. The efficacy of antiviral drugs towards the cerebral viral load is often limited as both blood-brain interfaces impede their cerebral distribution. For polar compounds, the major factor restricting their entry lies in the tight junctions that occlude the paracellular pathway across these barriers. For compounds with more favourable lipid solubility properties, CNS penetration will be function of a number of physicochemical factors that include the degree of lipophilicity, size and ability to bind to protein or red blood cells, as well as other factors inherent to the vascular and choroidal systems, such as the local cerebral blood flow and the surface area available for exchange. In addition, influx and efflux transport systems, or metabolic processes active in both capillary endothelial cells and choroid plexus epithelial cells, can greatly change the bioavailability of a drug in one or several compartments of the CNS. The relative importance of these various factors with respect to the CNS delivery of the different classes of antiviral drugs is illustrated and discussed.
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15546131
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Non-empirical calculations of NMR indirect carbon-carbon coupling constants. Part 11--saturated carbocycles: a reference data set and a practical guide to structural elucidation.
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Carbon-carbon spin-spin coupling constants, J(C,C), calculated at the SOPPA level for 50 mono-, bi- and polycycloalkanes in 10 previous papers are put in order and discussed on unified grounds. Basic structural trends of J(C,C) established in the original publications are summarized and briefly outlined for the representative series. Many unknown couplings are predicted with high reliability, and this provides a good reference data set and a practical guide to the structural elucidation of saturated carbocycles by means of J(C,C) coupling constants.
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15546129
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Recombination in alphaherpesviruses.
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Within the Herpesviridae family, Alphaherpesvirinae is an extensive subfamily which contains numerous mammalian and avian viruses. Given the low rate of herpesvirus nucleotide substitution, recombination can be seen as an essential evolutionary driving force although it is likely underestimated. Recombination in alphaherpesviruses is intimately linked to DNA replication. Both viral and cellular proteins participate in this recombination-dependent replication. The presence of inverted repeats in the alphaherpesvirus genomes allows segment inversion as a consequence of specific recombination between repeated sequences during DNA replication. High molecular weight intermediates of replication, called concatemers, are the site of early recombination events. The analysis of concatemers from cells coinfected by two distinguishable alphaherpesviruses provides an efficient tool to study recombination without the bias introduced by invisible or non-viable recombinants, and by dominance of a virus over recombinants. Intraspecific recombination frequently occurs between strains of the same alphaherpesvirus species. Interspecific recombination depends on enough sequence similarity to enable recombination between distinct alphaherpesvirus species. The most important prerequisite for successful recombination is coinfection of the individual host by different virus strains or species. Consequently the following factors affecting the distribution of different viruses to shared target cells need to be considered: dose of inoculated virus, time interval between inoculation of the first and the second virus, distance between the marker mutations, genetic homology, virulence and latency. Recombination, by exchanging genomic segments, may modify the virulence of alphaherpesviruses. It must be carefully assessed for the biosafety of antiviral therapy, alphaherpesvirus-based vectors and live attenuated vaccines.
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15546128
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Reactivation of Epstein-Barr virus from latency.
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The general problem in cancer treatment centres on finding agents that specifically affect cancer cells without damaging normal cells. The differences between cancer cells and normal cells are usually very subtle but about 15% of all human cancers involve a virus infection, for example the Epstein-Barr virus associated cancers. In these cancers, every tumour cell carries the virus in a latent infection but the number of normal cells infected is very low. So a treatment that could somehow cause the elimination of EBV infected cells would be very specific for the cancer in such cases. One potential approach could involve finding ways to reactivate the latent virus in cancer cells into the early part of the lytic cycle, impeding cell proliferation, targeting chemotherapeutic agents to the cancer and causing the cancer cells to become targets for immune surveillance. This review considers the mechanisms by which EBV reactivation is controlled and discusses possible therapeutic approaches.
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15546127
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Measles as a potential oncolytic virus.
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The use of replicating viruses for cancer therapy is attracting increasing interest. Numerous viruses are now being considered as potential cancer therapeutics, including the vaccine strain of measles virus (MV). The attenuated strain of measles readily lyses transformed cells, whilst replication and lysis are limited in normal human cells. It has a number of features which make it highly suitable for further development as an oncolytic agent, among them stability and a long history of safety in human use. These features are being combined with its ready potential for genetic manipulations to generate recombinant MVs with desirable therapeutic attributes. This review summarises the pre-clinical studies of the oncolytic efficacy of MV to date. Promising developments in MV engineering--such as re-targeting MV entry to specific cell types and enhancing its utility as a therapeutic agent by expression of non-viral proteins--as well as outstanding issues, such as the role of anti-MV immunity, are highlighted.
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15546126
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Endothelin receptor expression in human lungs of newborns with congenital diaphragmatic hernia.
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Congenital diaphragmatic hernia (CDH) is a major cause of refractory respiratory failure in the neonatal period and is characterized by persistent pulmonary hypertension of the newborn (PPHN) and pulmonary hypoplasia. Endothelin-1 (ET-1) dysregulation may play a significant role in the pathophysiology of PPHN and ET-1 acts through binding to type A (ETA) and type B (ETB) receptors. Therefore, ETA and ETB receptor protein expression was studied using immunohistochemistry in 10 lung specimens obtained from newborns with CDH, and 4 normal lung specimens, in order to explore whether dysregulation of ETA and ETB expression contributes to PPHN. ETA and ETB mRNAs were then quantified using real-time RT-PCR in laser-microdissected pulmonary resistive arteries. In the lungs of newborns with CDH, immunohistochemistry of both ETA and ETB receptors demonstrated over-expression in the thickened media of pulmonary arteries. Using laser microdissection and real-time RT-PCR, higher levels of ETA and ETB mRNA were found in CDH pulmonary arteries than in controls: this increase was more pronounced for ETA mRNA. This study provides the first demonstration of ET-1 receptor dysregulation in association with structural alteration of pulmonary arteries in newborns with CDH and PPHN. This dysregulation preferentially affects the ETA receptor. These results suggest that dysregulation of ET-1 receptors may contribute to PPHN associated with CDH.
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15546125
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Posttranslational activation, site-directed mutation and phylogenetic analyses of the lysine biosynthesis enzymes alpha-aminoadipate reductase Lys1p (AAR) and the phosphopantetheinyl transferase Lys7p (PPTase) from Schizosaccharomyces pombe.
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Alpha-aminoadipate reductase (AAR), the signature enzyme for lysine biosynthesis in fungi, catalyses the conversion of alpha-aminoadipate to alpha-aminoadipate-semiadehyde in the presence of ATP and NADPH. In Saccharomyces cerevisiae and Candida albicans, the LYS2-encoded AAR is posttranslationally activated by CoA and the LYS5-encoded PPTase. The fission yeast Schizosaccharomyces pombe is evolutionarily highly diverged from S. cerevisiae and C. albicans. We report here several unusual activation characteristics of Sz. pombe Lys1p and Lys7p, isofunctional to Lys2p (AAR) and Lys5p (PPTase), respectively. Unlike the Lys2p from S. cerevisiae and C. albicans, the Sz. pombe Lys1p was active when expressed in E. coli and exhibited significant AAR activity without the addition of CoA or the Sz. pombe Lys7p intron free PPTase. Somewhat higher AAR activity was obtained with the addition of CoA and the Sz. pombe Lys7p PPTase. Substitution of G910A, S913T or S913A in the Sz. pombe Lys1p activation domain (IGGHSI) resulted in no AAR activity. Similarly, substitutions of several amino acid residues in the Sz. pombe Lys7p PPTase domain (G79A, R80K and P81A in Core 1; F93W, D94E, F95W and N96D in Core 1a; G124A, V125I and D126E in Core 2; K172R, E173D and K177R in Core 3) also resulted in no activation of Lys1p and no AAR activity. The Sz. pombe Lys1p amino acid sequence showed a high degree of similarity to other fungal Lys2p proteins; however, the Lys7p amino acid sequence showed much less similarity to other bacterial, fungal and animal PPTases representing several phylogenetic groups.
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15546124
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The validity of the family relationships index as a screening tool for psychological risk in families of cancer patients.
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The Family Relationships Inventory (FRI) has been proposed as a measure of psychological risk however its validity has only been tested in one cross-sectional study against another measure of family functioning where patients had less than six months to live. The current study presented longitudinal data on the validity of the FRI in identifying family dysfunction, and clinical levels of depression and anxiety in 48 families where the patient had been recently diagnosed. Over the three phases, the FRI identified all families at risk of family dysfunction, 88% or more families with one or more members with clinical depression and 78% or more with a member with clinical levels of anxiety. The FRI was also far more sensitive in identifying families with a member with clinical levels of depression and anxiety than the General Functioning (FAD-GF) scale of the Family Assessment Device. Although other measures of screening adequacy (such as specificity), suggested that the FRI identified too many false positives, the higher sensitivity of the FRI makes it preferable to the FAD-GF as a screening measure for families at risk of a poor psychological outcome in the oncology setting. However, because of the FRI's poor specificity, further follow-up of those families that are identified as being at some risk of a poor psychological outcome should be undertaken before referral to a mental health professional is warranted.
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15546123
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Considerations in clinical trials of combination antifungal therapy.
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The cure rate for serious fungal diseases with currently available agents used as monotherapy is not optimal. The introduction of new classes of antifungal drugs in the last few years naturally leads to the hypothesis that antifungal drugs used in combination may be more effective than the same drugs used alone. The design and interpretation of combination therapy studies raise challenges beyond those encountered when drugs are studied as monotherapy in the treatment of a disease. The definition of combination therapy, the study design, the selection of appropriate patient populations, and the selection of end points, as well as practical considerations, are all important in the design and interpretation of clinical trials of combination therapies. Although combination therapies hold the promise of improved efficacy, it is important to prove this hypothesis, because they also may be associated with increased toxicity and increased drug costs. A careful consideration of study design factors before the initiation of a trial will help obtain the most useful information for patients in this important area.
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15546122
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Combination therapy for invasive mycoses: evaluation of past clinical trial designs.
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Despite the availability of new antifungals, single-agent therapy frequently falls short of high cure rates. Combination therapy offers potentially higher cure rates, especially for resistant organisms. In vitro studies and experimental animal models have provided conflicting data. Retrospective, randomized, controlled clinical studies were reviewed. Results indicate a clear advantage for polyene and flucytosine combination therapy in cryptococcal meningitis and a possible advantage for combination amphotericin B and fluconazole for candidemia. Unfortunately, the few studies published have been flawed by design problems that have compromised the determination of outcome. Study review allows investigators the opportunity to design future studies to ensure optimal evaluation of efficacy. Combination antifungal therapy is advantageous in cryptococcal diseases and may have a role in the treatment of invasive candidiasis. The greatest potential exists for combination therapy against aspergillosis and resistant fungi in patients with refractory mycotic disease who experience failure of monotherapy.
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15546121
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Design of efficacy trials of cytokines in combination with antifungal drugs.
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Resolution of invasive fungal infections is often dependent on recovery from an immunocompromised state, which indicates that host defense mechanisms are extremely important in the clearance of fungal pathogens. Immunotherapy aimed at enhancement of host defense mechanisms may improve clinical outcome of invasive mycoses. The design of trials of immunotherapy against fungal pathogens requires profound knowledge of the host defense mechanisms that are involved in invasive fungal infections. Prospective phase II studies with recombinant granulocyte colony-stimulating factor and interferon-gamma have been done. Recombinant interferon-gamma is a candidate for phase III trials of adjunctive immunotherapy for cryptococcal meningitis, invasive aspergillosis, and candidemia, but the proper design of future trials will be crucial to establish whether immunotherapy is of clinical value in the treatment of invasive fungal infections.
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15546120
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Issues in clinical trials of prophylaxis of fungal infections.
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The validity of the results of a clinical trial is highly dependent upon the design of the trial. The definition of disease, the selection criteria for enrollment in the trial, the selection of the study and control drugs, and the end points all affect whether the information obtained from the trial ultimately is useful in making decisions in clinical practice. These factors all apply to the design of clinical trials of the prophylaxis of infectious diseases. In addition, prophylaxis trials have several important differences from the design of trials of the treatment of those same diseases. The risk-benefit analysis for trials of prophylaxis is different, in that asymptomatic patients are exposed to the drug and more patients will be exposed than will develop the disease under study. Standardization of the design of such clinical trials will allow more efficient development of new drugs and will allow clinicians to compare more accurately the safety and efficacy of prophylactic agents.
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15546119
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Design of aerosolized amphotericin b formulations for prophylaxis trials among lung transplant recipients.
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Emphasis has been placed on the need for antifungal prophylaxis when transplanted organs are directly exposed to the environment. In lung transplantation, one strategy for prevention has been aerosolization of polyenes into the lung. Despite widespread use of amphotericin B aerosols, there are still few studies on how to validate their effectiveness or optimize pharmacokinetics. We compared results of several of our own studies of lung transplant recipients receiving formulations of amphotericin B with results of other studies. Recent aerosol studies suggest that aerosols of a lipid formulation of amphotericin B are safe and better tolerated than is amphotericin B deoxycholate. Their use in prophylaxis is associated with very few pulmonary fungal infections. This safe drug delivery at a local body site to directly protect the transplanted organ without systemic antifungal drug exposure is attractive from a cost and toxicity standpoint. However, careful multicenter, comparative studies are still needed to ensure that this strategy is consistently successful.
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15546118
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Antifungal prophylaxis in solid-organ transplant recipients: considerations for clinical trial design.
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There are several key issues regarding clinical trial design for antifungal prophylaxis in organ transplant recipients. The existing and emerging data on the epidemiology and risk factors for invasive mycoses in organ transplant recipients formed the basis for discerning the subgroups that may be targeted for prophylaxis, the unique end points to be considered, and the attributes of currently available drugs that may be suitable candidates for antifungal prophylaxis. Epidemiological characteristics of invasive mycoses in organ transplant recipients have evolved sufficiently to warrant thoughtful reconsideration of the subsets of patients and the fungal pathogens to be targeted for antifungal prophylactic trials in the current era. Safety and tolerability of antifungal agents and outcome stratified by severity of illness are important end points given the potential for drug interactions with immunosuppressive agents and the fact that a beneficial effect of prophylaxis on outcome has been difficult to document in organ transplant recipients. Clinical trial design for antifungal prophylaxis must carefully consider the unique issues pertaining to the selection of patients most likely to benefit, as well as the tolerability and drug interactions of antifungal agents in organ transplant recipients.
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15546117
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Clinical trials of antifungal prophylaxis among patients in surgical intensive care units: concepts and considerations.
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Fungal infections are important clinical infections in patients in surgical intensive care units. In some institutions, antifungal prophylaxis has become commonplace, and increasing resistance has been reported. However, trials of antifungal prophylaxis are hampered by difficulties in trial design, and the findings may not be generalizable. Issues in clinical trial design are reviewed from existing and theoretical perspectives. Identification of a primary hypothesis with a sound epidemiological basis is essential. The study must include institutions where fungal infections have a high and well-studied incidence. A high-risk patient population should be identified and enrolled. The agent selected should have an appropriate spectrum, be easily delivered to the population selected, and be cost effective with few adverse events. At present, fluconazole appears to be the best agent for targeted prophylaxis. The primary end point of the study should be based on an easily measured outcome, for example, days free from fungal infection rather than death due to fungal infection. Trials of antifungal prophylaxis for patients in surgical intensive care units have had problems in design, and several issues in the conceptual basis of future clinical trials must be addressed.
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15546116
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Clinical trials of antifungal prophylaxis among patients undergoing surgery.
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Invasive mycoses have emerged as a major cause of morbidity and mortality. Epidemiological studies have shown that surgery services have the highest rate of Candida infections in the hospital. In addition to classical risk factors, heavy Candida colonization, recurrent gastrointestinal perforations, and acute pancreatitis are frequently associated with invasive candidiasis. Because prompt initiation of antifungal therapy is critical for cure but difficult to accomplish, prevention of fungal infections may play an important role in this clinical setting; however, few prophylactic or preemptive studies have been done to date. The choice, route of administration, and dose of the antifungal and comparator regimens and the use of clinically relevant and robust study end points are critical for the trial design. Various criteria have been used to identify patients at risk of candidiasis: surgical condition, presence of multiple risk factors, colonization indexes, or expected length of stay in the intensive care unit. Some are not selective enough, and others are time consuming and expensive. Rigorous selection of high-risk patients is crucial to optimize the risk-benefit ratio of preventive antifungal strategies. The aim is to maximize chances of reducing morbidity and mortality while minimizing treatment costs, exposure of low-risk patients to adverse events, and emergence of resistant fungal strains.
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15546115
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How to improve the design of trials of antifungal prophylaxis among neutropenic adults with acute leukemia.
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The risk for invasive fungal infections in patients with acute leukemia is generally low (4%-8%), and the routine use of fungal prophylaxis is not warranted except in specific high-risk groups that should be identified among this population. In a prophylactic study with a new agent, fluconazole or itraconazole oral solution represent good choices for the comparator because they are proven better than placebo or oral nonabsorbable antifungal agents in reducing the risk of invasive fungal infections in patients with acute leukemia. Because prophylaxis is most valuable when the risk of infection is high, patients with well-understood risk factors (severe mucosal disruption caused by chemotherapy, impaired cell-mediated immunity caused by steroids or fludarabine, use of a central venous catheter, and colonization by Candida species) should be selected. The end points for antifungal prophylactic trials should focus on proven and probable invasive fungal infections. Superficial and mucosal fungal infections do not represent a primary end point for these studies. Poor compliance should be considered as an interruption of treatment due to side effects and should be included in the criteria for failure. Fungus-related mortality should be evaluated as a failure of prophylaxis, whereas overall mortality may be influenced by many other cofactors. Differences in gastrointestinal toxicity of antifungal agents may limit the use of double-blind designs in some situations.
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15546114
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Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole versus voriconazole after allogeneic hematopoietic cell transplantation.
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Aspergillus infections pose the toughest infectious challenges to the clinician caring for hematopoietic cell transplant recipients. About 15% of patients become infected, with a case fatality rate of approximately 65%. To date, no effective prophylactic strategies have been developed. Voriconazole, a recently licensed extended-spectrum azole, with demonstrated efficacy against aspergillus, is currently being tested as a potential prophylactic agent against aspergillus and other invasive fungal infections. Logistic issues--such as patient selection, choice of comparator, blinding of study drugs, duration of study drug administration, and how to handle empirical amphotericin B for possible invasive fungal infections--and analytic concerns, including choice and definition of the primary end point and the potential confounding effect of informative censoring (as a result of noninfectious events), were considered in the design of the clinical trial. The trial is now under way, with a projected 3-year enrollment period. Each design decision shaped the trial in a way that permitted certain questions to be answered while not allowing others to be addressed. Once completed, the trial's results must be interpreted in light of these design details.
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15546113
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Issues in the design of the fluconazole prophylaxis trials in patients undergoing hematopoietic stem cell transplantation.
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Today, invasive candidal infections are much less of a problem in patients undergoing hematopoietic stem cell transplantation (HSCT) than they were in the 1980s, principally because of widespread application of effective antifungal prophylaxis strategies. Two randomized, placebo-controlled studies performed in the early 1990s were instrumental in demonstrating the protective effects of fluconazole. Although both studies showed that candidiasis is prevented by fluconazole prophylaxis, controversies regarding optimal administration guidelines and the impact on survival after HSCT have persisted over the last decade. Details of how these trials were done, including the patients enrolled and end points evaluated, explain many of the different findings and controversies. An understanding of design issues can help explain current controversies and can assist in development of future prophylaxis studies.
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15546112
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The design of clinical trials that evaluate antifungal prophylaxis and combination therapy: introduction and overview.
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On 8 February 2003, the second in a series of meetings in honor of John E. Bennett, M.D., was convened in New York City. A report from the previous meeting was published in 2003. The goal of this second meeting was to discuss the design of clinical trials in prophylaxis and combination therapy. This supplement presents 12 articles by leading clinicians who are currently active in trials in this area and presents a current view of the unmet needs and challenges.
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15546111
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Clinical efficacy of newer agents in short-duration therapy for community-acquired pneumonia.
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Streptococcus pneumoniae, the most important respiratory tract pathogen implicated in community-acquired pneumonia (CAP), is becoming increasingly resistant in vitro to the beta -lactams and macrolides, and fluoroquinolone resistance has been detected. A growing body of evidence suggests that prolonged antimicrobial use may contribute directly and indirectly to increased antimicrobial resistance among common respiratory pathogens. Long-term exposure to antimicrobial agents, especially less-potent agents, directly increases selection pressure for resistance. Indirectly, poor patient compliance, multiple daily dosing, and the increased risk of adverse events further complicate the resistance issue and diminish the efficacy of long-term antimicrobial use. Controlled clinical trials addressing the appropriate duration of therapy for CAP are lacking. However, available data suggest that with appropriate antibiotic selection, based on appropriate spectrum, potency, and pharmacokinetic/pharmacodynamic profile, lower respiratory tract infections in outpatients can be successfully treated in <7 days rather than the 7-14 days currently recommended.
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15546110
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Acute community-acquired bacterial sinusitis: continuing challenges and current management.
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Acute sinusitis is one of the most common infections seen in general clinical practice. The most common cause of acute sinusitis is viral; however, many patients receive a prescription for an antibiotic. Such injudicious prescribing habits have a major impact on health care costs, contribute to the increasing prevalence of drug-resistant strains of common respiratory pathogens, and reflect many of the challenges in differentiating viral and bacterial disease. Sinus puncture and culture of the aspirate, the diagnostic reference standard in the research setting, are not appropriate for routine clinical practice. However, certain clinical signs and symptoms that do not improve or that worsen after 7-10 days are currently accepted criteria for diagnosis of bacterial sinusitis. Accurate diagnosis can select patients who would benefit most from antimicrobial use. Antimicrobial agents should be selected on the basis of local resistance patterns, and their spectrum of activity should cover the common bacterial pathogens, including resistant strains.
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15546109
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Increased antibiotic resistance in respiratory tract pathogens: PROTEKT US--an update.
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Three major North American surveillance programs have tracked antimicrobial resistance patterns among isolates of Streptococcus pneumoniae and other common respiratory tract pathogens. The Canadian Bacterial Surveillance Network shows the progressive increase in resistance among pneumococcal S. pneumoniae to penicillin, trimethoprim-sulfamethoxazole, macrolides, and fluoroquinolones. The data from the Tracking Resistance in the United States Today study also show a steady rise in pneumococcal resistance among common antibiotics as well as an increase in multidrug-resistant S. pneumoniae. The US component of the Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin study has detected increasing resistance to many antimicrobial agents among common respiratory isolates, with marked geographic variations in resistance patterns. The patterns of resistance detected by these major surveillance programs are a warning signal regarding the continued emergence of resistance among community-acquired respiratory tract pathogens.
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15546094
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Infrequent reinfection after successful treatment for hepatitis C virus infection in injection drug users.
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We followed-up 18 injection drug users for a mean of 33.8 months (range, 4-55 months) after successful treatment for hepatitis C virus (HCV) infection. Fifteen (83%) of the patients remained HCV RNA-negative, 1 patient was not tested, and 2 patients had test results positive for HCV RNA. The estimated rate of reinfection as a result of injection drug use was 0-4.1 cases per 100 person-years (cumulative incidence, 0%-12.6% at 48 months after completion of treatment). Of 50 patients originally treated, 15 (30%) were HCV RNA-negative 3 years later.
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15546093
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Association between tea ingestion and invasive Bacillus cereus infection among children with cancer.
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Bacillus cereus is an emerging pathogen that causes invasive disease in immunocompromised hosts. A case-control study, prompted by a clinical case, demonstrated an association between dietary tea ingestion and B. cereus bacteremia. Policies designed to interrupt transmission of this pathogen to susceptible patients should be considered.
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15546092
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Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing.
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Inhalation of nitric oxide (NO) improved arterial oxygenation and enabled the reduction of inspired oxygen therapy and airway pressure support in patients with severe acute respiratory syndrome (SARS). In addition, chest radiography showed decreased spread or density of lung infiltrates, and the physiological effects remained after termination of inhaled NO therapy. These findings suggest not only a pulmonary vasodilator effect of inhaled NO, but also an effect on SARS.
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15546091
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Native valve endocarditis due to coagulase-negative staphylococci: report of 99 episodes from the International Collaboration on Endocarditis Merged Database.
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Using a large cohort of patients from the International Collaboration on Endocarditis Merged Database, we compared coagulase-negative staphylococcal (CoNS) native-valve endocarditis (NVE) to NVE caused by more common pathogens. Rates of heart failure and mortality were similar between patients with CoNS NVE and patients with Staphylococcus aureus NVE, but rates for both groups were significantly higher than rates for patients with NVE due to viridans streptococci. These results emphasize the importance of CoNS as a cause of NVE and the potential for serious complications with this infection.
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15546090
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Oral miltefosine for leishmaniasis in immunocompromised patients: compassionate use in 39 patients with HIV infection.
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Oral miltefosine was administered to 39 human immunodeficiency virus (HIV)-infected patients with leishmaniasis for whom standard leishmaniasis treatment had failed. Initial response was achieved in 25 patients (64%), including 16 patients (43%) with initial parasitological cure. Repeated responses after relapse and tolerability of long courses of treatment indicate the potential for development of optimized dosage schemes.
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15546089
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Gynecomastia among HIV-infected patients is associated with hypogonadism: a case-control study.
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The prevalence, risk factors, and potential hormonal abnormalities associated with gynecomastia in a cohort of HIV-infected men are poorly understood. Breast enlargement was assessed in consecutively evaluated HIV-infected men, and gynecomastia was subsequently confirmed with sonography. For each patient with breast enlargement, a randomly selected control subject without breast enlargement was studied. Clinical data were obtained, including age, body mass index, clinically evident lipodystrophy, prior symptomatic hyperlactatemia, current antiretroviral therapy and duration of exposure to each antiretroviral drug, history of injection drug use, and serological status regarding hepatitis B and hepatitis C. Laboratory parameters, including plasma HIV-1 RNA load, CD4 cell count, free testosterone index, and levels of fasting triglycerides, cholesterol, prolactin, total testosterone, sex hormone-binding globulin, 17-beta-estradiol, follicle-stimulating hormone, luteinizing hormone, and thyroid-stimulating hormone, were measured. There were 44 of 2275 patients with breast enlargement, of whom 40 (1.8%) had gynecomastia. The mean free testosterone index (+/-SD) was significantly lower among the 40 patients with gynecomastia (42.6%+/-24.0%) than among the 44 control subjects (58.0%+/-25.3%) (P=.006). Although the proportion of patients who were receiving treatment with zidovudine, stavudine, and/or efavirenz at the time of the present study was significantly different between case patients and control subjects, the duration of exposure to each individual antiretroviral drug was not. Lipoatrophy (adjusted odds ratio [OR], 5.6; 95% confidence interval [CI], 1.7-18.6; P=.005), hepatitis C (adjusted OR, 6.1; 95% CI, 1.8-20.6; P=.003), and hypogonadism (adjusted OR, 7.6; 95% CI, 1.8-32.2; P=.003) were independent factors associated with gynecomastia. The data suggest that gynecomastia among HIV-infected patients is related to hypogonadism, rather than to an adverse effect of antiretroviral drugs.
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15546088
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Hepatitis C virus coinfection increases mortality in HIV-infected patients in the highly active antiretroviral therapy era: data from the HIV Atlanta VA Cohort Study.
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We compared survival among patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) with that among patients infected solely with HIV. Descriptive, bivariate, and survival analyses were conducted using data for all HIV-positive patients who were seen during the period of January 1997 through May 2001 in the HIV Atlanta VA Cohort Study (HAVACS) and who had been tested for HCV antibody since 1992 (n=970). The prevalence of HCV coinfection was 31.6%, and coinfected patients were significantly more likely to be older, black, and injection drug users. In multivariate analysis, the duration of survival from the time of diagnosis of acquired immunodeficiency syndrome (AIDS) was significantly shortened for HIV-HCV-coinfected patients (hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.09-3.10), as was time from HIV diagnosis to death (HR, 2.47; 95% CI, 1.26-4.82). Recovery of CD4+ cell count from the time of initiation of HAART did not differ significantly by coinfection status. HCV coinfection is common in this HIV-infected population and negatively affects survival from the time of both HIV and AIDS diagnoses, although this is apparently not associated with a difference in CD4+ cell recovery while receiving HAART. These findings differ from those of a previous study that was conducted in this cohort in the pre-HAART era, which found no association between HIV-HCV coinfection and HIV disease progression.
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15546087
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Long-term follow-up of HIV-infected individuals who have significant increases in CD4+ cell counts during antiretroviral therapy.
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Descriptions of the durability and consequences of immune reconstitution in patients who start highly active antiretroviral therapy (HAART) while severely immunosuppressed are limited. Patients with previous CD4+ cell counts <50 cells/mm3, all of whom had HAART-induced increases in CD4+ cell counts of >100 cells/mm3 on 2 separate occasions (measured sequentially at least 4 weeks apart), were enrolled in a prospective trial and observed every 16-32 weeks. Evaluations included assessments for new opportunistic complications, virologic (human immunodeficiency virus [HIV] RNA load) and immunologic (CD4+ cell count) responses, or death. The median follow-up duration for 612 subjects was 184 weeks (range, 8-216 weeks). The rate of increase in CD4+ cell counts was approximately 5.9 cells/mm3 every 8 weeks, with the degree of increase associated with the baseline HIV RNA load (<500 vs. > or =500 copies/mL). Subsequent measurements of virologic suppression based on HIV RNA levels were also associated with predicted CD4+ cell responses. Thirty-three AIDS-defining illnesses were reported (1.75 events per 100 person-years of follow-up); >40% (14 cases) occurred with higher than expected CD4+ cell counts. CD4+ cell count increases are related to virological control, with continuing increases seen in individuals who are immunosuppressed. Opportunistic illnesses and/or complications are infrequent but can occur at any time, even in patients who maintained an elevated CD4+ cell count.
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15546086
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Rickettsioses and the international traveler.
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The rickettsioses--zoonotic bacterial infections transmitted to humans by arthropods--were for many years considered to be oddities in travel medicine. During the previous 2 decades, however, reports of >450 travel-associated cases have been published worldwide, the vast majority being murine typhus caused by Rickettsia typhi, Mediterranean spotted fever caused by Rickettsia conorii, African tick bite fever caused by Rickettsia africae, and scrub typhus caused by Orientia tsutsugamushi. Most patients present with a benign febrile illness accompanied by headache, myalgia, and cutaneous eruptions, but severe complications and fatalities are occasionally seen. Current microbiological tests include culture, polymerase chain reaction, and serological analysis, of which only the latter method is widely available. Tetracyclines are the drugs of first choice and should be prescribed whenever a case of rickettsiosis is suspected. Preventive measures rely on minimizing the risk of arthropod bites when traveling in areas of endemicity.
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15546085
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Raccoon roundworm encephalitis.
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The raccoon roundworm, Baylisascaris procyonis, is increasingly recognized as a cause of zoonotic visceral, ocular, and neural larva migrans and, in particular, of devastating encephalitis in young children. Exposure occurs mainly at raccoon latrines, where large numbers of infective eggs may be accidentally ingested. Risk factors for infection include contact with raccoon latrines, pica/geophagia, age of <4 years, and male sex. The severity of central nervous system (CNS) disease depends on the number of eggs ingested, the extent and location of larval migration, and the severity of ensuing inflammation and necrosis. Diagnosis of Baylisascaris encephalitis is based on clinical CNS disease, peripheral and cerebrospinal fluid eosinophilia, deep white matter lesions visible by magnetic resonance imaging, and positive results of serologic tests. Treatment efficacy in clinical cases is poor, but albendazole prevents disease if given promptly after infection. Considering the seriousness of this disease and limitations of diagnosis and treatment, prevention of infection with eggs is of utmost importance.
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15546084
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Development and experience with an algorithm to evaluate suspected smallpox cases in the United States, 2002-2004.
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Concerns that smallpox, an eradicated disease, might reappear because of a bioterror attack and limited experience with smallpox diagnosis in the United States prompted us to design a clinical algorithm. We used clinical features of classic smallpox to classify persons presenting with suspected smallpox rashes into 3 categories: those with high, those with moderate, and those with low risk of having smallpox. The classification guides subsequent diagnostic strategies, limiting smallpox laboratory testing to high-risk persons to minimize the number of false-positive test results. From January 2002 through June 2004, the Centers for Disease Control and Prevention (CDC) received 43 consultations regarding suspected smallpox cases. No patient was at high risk for having smallpox. One patient was tested for the presence of variola virus. Varicella was the diagnosis for 23 cases (53%). The algorithm worked well to guide clinical and public health responses to suspected smallpox cases. The poster is available from CDC, and an interactive version and laboratory protocol are available at http://www.bt.cdc.gov/agent/smallpox/diagnosis/riskalgorithm/index.asp. We recommend use of the algorithm in the United States and elsewhere.
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15546083
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Utility of Aspergillus antigen detection in specimens other than serum specimens.
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The detection of circulating galactomannan in serum is an important tool for the early diagnosis of invasive aspergillosis. A commercial enzyme-linked immunosorbent assay (Platelia Aspergillus; BioRad) was shown to be both highly sensitive and specific for detection of galactomannan in serum samples. Despite the fact that this assay is validated for serum samples, specimens of other body fluids are increasingly used for detection of galactomannan, including urine, bronchoalveolar lavage fluid, and cerebrospinal fluid. Review of the literature shows that galactomannan can be detected in each of these samples from patients with invasive aspergillosis with higher sensitivity than is the case with culture, as well as early in the course of infection. However, the evidence thus far is based on case reports--predominantly retrospective studies--that often include heterogeneous patient populations and limited numbers of cases of proven infection. Clearly, well-designed prospective studies with systematic sampling and use of consensus case definitions are needed to compare the performance of antigen detection in samples other than serum specimens with that in serum specimens.
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15546082
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Emergence of new strains of methicillin-resistant Staphylococcus aureus in a neonatal intensive care unit.
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Genetically distinct strains of methicillin-resistant Staphylococcus aureus (MRSA) of community rather than hospital origin have emerged in many areas of the United States. We determined if MRSA strains causing bacteremia in infants treated from birth in a neonatal intensive care unit (NICU) demonstrated the genetic traits of community-associated MRSA. A retrospective cohort study was conducted among NICU infants with bacteremia due to MRSA during 2003 in a large tertiary care center NICU in Houston. MRSA isolates were characterized by antimicrobial susceptibility testing and staphylococcal cassette chromosome mec (SCCmec) typing by polymerase chain reaction. All MRSA cases were reviewed for clinical severity of infection and outcome. During 2003, a total of 8 (47%) of 17 infants with bacteremia due to S. aureus had MRSA infection. Isolates from 6 (75%) of these 8 infants carried the SCCmec genes (class B mec and ccr2) that are characteristic of community MRSA; 4 isolates were type IVa. All 6 isolates were resistant to beta-lactam antibiotics and erythromycin; 1 was also resistant to clindamycin. One isolate was nontypeable, and another carried the SCCmec type II gene (typical of hospital-associated strains) and was susceptible only to vancomycin. Seven (88%) of 8 infants presented in septic shock. Despite initial treatment with vancomycin, 3 (38%) died, and 3 survivors had complications requiring prolonged antimicrobial therapy; these 6 infants had MRSA isolates with genetic characteristics of isolates of community origin. Community-associated MRSA strains have emerged as a significant cause of sepsis in neonates hospitalized in NICU since birth and have caused disseminated infection with substantial morbidity and mortality.
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15546081
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Use of stool collection kits delivered to patients can improve confirmation of etiology in foodborne disease outbreaks.
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In 68% of foodborne disease outbreaks, no etiologic pathogen is identified. In two-thirds of outbreaks with no identified etiology, no stool specimens are submitted for testing. From April 2001 to March 2003, we pilot-tested use of prepackaged, self-contained stool specimen collection kits in 3 states, delivered to and from patients by courier or mail, to improve rates of specimen collection in the outbreak setting. Specimens were tested for bacterial and viral pathogens at health department laboratories, and results were correlated with epidemiological investigation data. Specimens were returned by > or =1 person in 52 (96%) of 54 outbreaks in which kits were deployed; in total, 263 (76%) of 347 persons who received kits returned specimens. Resolution of symptoms was the most commonly cited reason for nonsubmission of kits. An etiology was confirmed in 37 (71%) of 52 outbreaks with specimens returned; 28 (76%) were attributable to norovirus, and 9 (24%) were attributed to bacterial pathogens. Stool kits were well received and cost an average of approximately 43 dollars per specimen returned. In two-thirds of foodborne disease outbreaks in which delivered stool collection kits were successfully deployed, an etiologic organism was identified. Delivery of kits to and from patients to improve rates of stool collection in outbreaks in which specimens might otherwise not be submitted could substantially reduce the number of outbreaks with an unknown etiology.
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15546080
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A high-morbidity outbreak of methicillin-resistant Staphylococcus aureus among players on a college football team, facilitated by cosmetic body shaving and turf burns.
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Athletics-associated methicillin-resistant Staphylococcus aureus (MRSA) infections have become a high-profile national problem with substantial morbidity. To investigate an MRSA outbreak involving a college football team, we conducted a retrospective cohort study of all 100 players. A case was defined as MRSA cellulitis or skin abscess diagnosed during the period of 6 August (the start of football camp) through 1 October 2003. We identified 10 case patients (2 of whom were hospitalized). The 6 available wound isolates had indistinguishable pulsed-field gel electrophoresis patterns (MRSA strain USA300) and carried the Panton-Valentine leukocidin toxin gene, as determined by polymerase chain reaction. On univariate analysis, infection was associated (P<.05) with player position (relative risk [RR], 17.5 and 11.7 for cornerbacks and wide receivers, respectively), abrasions from artificial grass (i.e., "turf burns"; RR, 7.2), and body shaving (RR, 6.1). Cornerbacks and wide receivers were a subpopulation with frequent direct person-to-person contact with each other during scrimmage play and drills. Three of 4 players with infection at a covered site (hip or thigh) had shaved the affected area, and these infections were also associated with sharing the whirlpool > or =2 times per week (RR, 12.2; 95% confidence interval, 1.4-109.2). Whirlpool water was disinfected with dilute povidone-iodine only and remained unchanged between uses. MRSA was likely spread predominantly during practice play, with skin breaks facilitating infection. Measures to minimize skin breaks among athletes should be considered, including prevention of turf burns and education regarding the risks of cosmetic body shaving. MRSA-contaminated pool water may have contributed to infections at covered sites, but small numbers limit the strength of this conclusion. Nevertheless, appropriate whirlpool disinfection methods should be promoted among athletic trainers.
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15546079
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Use of maximal sterile barriers during central venous catheter insertion: clinical and economic outcomes.
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We performed a cost-effectiveness analysis to determine the effect of maximal sterile barriers (MSBs) on reducing central venous catheter (CVC)--related infections. Use of MSBs when placing CVCs may reduce the risk of infections but is more cumbersome, time-consuming, and expensive than other techniques. We developed a decision analytic model in which a patient could have a CVC placed with either an MSB or a less stringent technique. We calculated total direct medical costs and the incidences of catheter-related bloodstream infections, catheter colonization, and death. Use of MSBs lowered costs (from 621 dollars to 369 dollars per catheter insertion) and decreased the incidences of catheter-related bloodstream infections (from 5.3% to 2.8%), catheter colonization with local infection (from 5.5% to 2.9%) and death (from 0.8% to 0.4%). MSBs improved patient safety throughout all sensitivity analyses. Use of MSBs during CVC insertion likely lowers medical costs and decreases the incidences of catheter colonization, catheter-related bloodstream infections, and death. Cost savings were found over a wide range of clinical and economic assumptions, suggesting that MSBs should be routinely used when CVCs are inserted.
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15546077
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Longitudinal risk of herpes simplex virus (HSV) type 1, HSV type 2, and cytomegalovirus infections among young adolescent girls.
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Cross-sectional seroprevalence studies indicate that infections with herpes simplex virus (HSV) types 1 (HSV-1) and 2 (HSV-2) and cytomegalovirus (CMV) are common. However, data on the rates of acquisition of these infections are limited. A 3-year longitudinal study of HSV-1, HSV-2, and CMV seroprevalence was conducted in a cohort of 174 adolescent girls (age at enrollment, 12-15 years). At study entry, 41% of the girls reported a history of sexual activity, and by the end of the study, 73% reported a history of sexual activity. At enrollment, 71% of all participants were seropositive for CMV, 44% were seropositive for HSV-1, and 7% were seropositive for HSV-2. By the end of the study, 81% of the girls were seropositive for CMV, 49% were seropositive for HSV-1, and 14% were seropositive for HSV-2. Among girls with a history of sexual activity, 15.5% were HSV-2 seropositive at the beginning of the study, and 18.9% were HSV-2 seropositive at the end of the study. The attack rates, based on the number of cases per 100 person-years, were 13.8 for CMV infection and 3.2 for HSV-1 infection (among all girls) and 4.4 for HSV-2 infection (among girls with a history of sexual activity). Participants with preexisting HSV-1 antibodies were associated with a significantly lower attack rate for HSV-2 infection. A generalized estimating equation model indicated that participants with a longer history of sexual activity and those who had more sexually transmitted diseases during the 6-month periods before the study visits were more likely to be HSV-2 seropositive. This longitudinal study of adolescent girls found high baseline CMV and HSV-1 seroprevalence rates and substantial attack rates for all 3 pathogens.
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15546075
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The influence of human N-acetyltransferase genotype on the early bactericidal activity of isoniazid.
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The elimination of isoniazid is subject to the influence of the N-acetyltransferase 2 (NAT2) genotype, and individuals may be homozygotic slow, heterozygotic fast, or homozygotic fast acetylators of isoniazid. The early bactericidal activity (EBA) of an antituberculosis agent can be determined by quantitative culture of Mycobacterium tuberculosis in sputum samples obtained from patients with pulmonary tuberculosis during the first days of treatment. In these studies, the EBA of isoniazid during the first 2 days of treatment was determined for 97 patients with sputum smear-positive pulmonary tuberculosis following isoniazid doses of < or =37.5 mg, 75 mg, 150 mg, 300 mg, and 600 mg. The NAT2 genotype was determined in 70 patients, and the association between EBA and genotype was examined in this subgroup. Similarly, the relationship between EBA and isoniazid serum concentration was evaluated in 87 patients. The mean EBA of isoniazid increased with dose, but it levelled off between doses of 150 mg (mean EBA, 0.572) and 300 mg (mean EBA, 0.553). Significant differences were found in the mean EBA of isoniazid between the homozygous slow acetylator group and the heterozygous fast acetylator group and between the homozygous slow acetylator group and the homozygous fast acetylator group, but not between the heterozygous fast acetylator group and the homozygous fast acetylator group. The EBA appeared to reach a maximum at a 2-h isoniazid concentration of 2-3 microg/mL. These data confirm a significant effect of NAT2 genotype on the EBA of isoniazid over a range of doses.
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15546074
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An open, randomized, controlled trial of penicillin, doxycycline, and cefotaxime for patients with severe leptospirosis.
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Leptospirosis is an important cause of fever in the rural tropics. Since 1996, there has been a marked increase in the incidence of leptospirosis in northeastern Thailand. Although leptospirosis generally is susceptible to antibiotics, there is no consensus regarding the optimal treatment for severe leptospirosis. An open-label, randomized comparison of parenteral cefotaxime, penicillin G sodium (hereafter known as "penicillin G"), and doxycycline for the treatment of suspected severe leptospirosis was conducted. The study involved 540 patients admitted to 4 hospitals in northeastern Thailand. A total of 264 patients (48.9%) had leptospirosis confirmed by serologic testing or culture. The overall mortality rate was 5%. There were no significant differences between the antibiotics with regard to associated mortality, defervescence, or time to resolution of abnormal findings of laboratory tests either among all study participants or among the subgroup of patients with confirmed leptospirosis. A total of 132 patients had rickettsial infection diagnosed, and, for these patients, treatment with doxycycline was superior to treatment with penicillin G. Doxycycline or cefotaxime is a satisfactory alternative to penicillin G for the treatment of severe leptospirosis.
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15546073
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Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation.
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We hypothesized that chemoprophylaxis with the echinocandin micafungin would be an effective agent for antifungal prophylaxis during neutropenia in patients undergoing hematopoietic stem cell transplantation (HSCT). We therefore conducted a randomized, double-blind, multi-institutional, comparative phase III trial, involving 882 adult and pediatric patients, of 50 mg of micafungin (1 mg/kg for patients weighing <50 kg) and 400 mg of fluconazole (8 mg/kg for patients weighing <50 kg) administered once per day. Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treatment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT (80.0% in the micafungin arm vs. 73.5% in the fluconazole arm [difference, 6.5%]; 95% confidence interval, 0.9%-12%; P=.03). This randomized trial demonstrates the efficacy of an echinocandin for antifungal prophylaxis in neutropenic patients.
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15546072
|
Successful desensitization to enfuvirtide after a hypersensitivity reaction in an HIV-1-infected man.
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We report a case of successful, rapid desensitization to enfuvirtide after a hypersensitivity reaction in a man with highly drug-resistant human immunodeficiency virus type 1 infection. The patient was desensitized in a monitored intensive care unit and tolerated the rapid desensitization protocol without any serious adverse effects. This case illustrates the ability to safely desensitize patients with limited treatment options who require enfuvirtide therapy.
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15546071
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Two cases of fatal shock after transfusion of platelets contaminated by Staphylococcus aureus: role of superantigenic toxins.
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We detected Staphylococcus aureus superantigenic toxins in the platelet infusion bags that had been used for 2 patients who subsequently developed transfusion-associated Staphylococcus aureus infection. Both patients, who were immunodeficient, developed manifestations of toxic shock syndrome and septic shock, and they died soon after the onset of infection.
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15546070
|
Syphilitic hepatitis in HIV-infected patients: a report of 7 cases and review of the literature.
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A recent resurgence of primary and secondary syphilis has been observed in certain population groups, particularly among persons infected with human immunodeficiency virus (HIV). Liver involvement is an infrequently recognized complication of early syphilis, with no previous reports among HIV-infected patients. We describe 7 cases of syphilitic hepatitis in HIV-positive individuals and review the literature. At our institutions, all patients presented with a rash consistent with secondary syphilis. Each case was characterized by a conspicuous increase in serum alkaline phosphatase level (mean level +/- standard deviation, 905 +/- 523.6 IU/L) and milder elevations in serum transaminase levels. The mean CD4+ absolute T cell count was 317 cells/mm3, and the median rapid plasma reagin (RPR) titer was 1 : 128. There was a significant correlation between higher CD4+ cell counts and the RPR titers (R=0.93; P=.002). Symptomatic resolution and biochemical improvement, particularly a significant decrease in serum alkaline phosphatase levels (P=.02), occurred following antibiotic therapy. Hepatic dysfunction is not uncommon in HIV-infected persons and is attributable to multiple causes. In the appropriate clinical setting, syphilitic hepatitis is an easily diagnosed and reversible etiology of liver dysfunction. The recognition of this entity will prevent unnecessary evaluation of abnormal liver enzyme levels in HIV-positive patients.
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15546069
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Mechanisms of action in the prevention of recurrent mood disorders.
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Since long-term treatment is a need in many patients with mood disorders, knowledge on mechanisms of action in the prevention of recurrence is of major relevance. Follow-up studies, which are best suited to prove the linkage of causal factors and mechanisms with the clinical course of the disorders, are rare. Another approach to search for preventive mechanisms is to address actions of pharmacological agents, which are effective in prophylactic treatment of mood disorders. Studies over the past several years have indicated that intracellular signaling cascades mediate long-term pharmacological effects via modulation of transcription factors and gene expression of neurotrophic and neuroprotective factors which may interfere with recurrence of affective illness. The impact of treatment on stress responsive systems varies with different therapeutic strategies and the relevance of a treatment-related modification of stress reliability for the course of the disease is not clear. Functional and structural actions of mood stabilizers and of antidepressants on mood-relevant anatomical circuits and modulation of chronobiological alterations also appear to be involved in preventive mechanisms in mood disorders. Moreover, cognitive mediators of prophylactic effects have been described. Combined clinical and biological studies should assess the relevance of those modes of action for the long-term course of mood disorders.
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15546068
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Basic pathophysiological mechanisms in depression: what are they and how might they affect the course of the illness?
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Basic pathophysiological mechanisms in affective disorders are discussed. Studies carried out suggest that changes in neurogenesis do not underlie the behavioral changes which lead to helplessness. Since the behavioral changes leading to depressive or anxious behaviors are not correlated with changes in neurogenesis it appears unlikely that a decrease in the rate of neurogenesis is the basis for depression. A modified gene expression resulting in both functional and structural brain changes remains the most consistent hypothesis to explain how affective disorders may occur. An alternative candidate, synaptogenesis, appears as a likely candidate and requires further experimental testing.
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15546067
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Affective disorders: basic principles regarding clinical course, long-term therapeutic and prophylactic strategies.
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Affective disorders, mainly depressive and bipolar afflictions are life-long recurrent diseases and require constant treatment and prophylaxis. Both acute and maintenance therapeutic strategies have to be applied to the special subgroups of the depressive and bipolar spectrum. Despite the development of new pharmacological agents and psychotherapeutical settings, the long-term prognosis, especially functional outcome, did not change considerably in comparison to past decades.
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15546066
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Mechanisms of relapse prevention in schizophrenia.
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A relapse can be expected in 70 % of patients after the first schizophrenic episode; in parallel 70 % of patients show an incomplete remission of the disorder after the first episode. This includes a cognitive decline and persistence of schizophrenic negative symptoms, often associated with social disabilities, social decline and a worsened quality of life. The risk for a relapse after a schizophrenic episode remains increased throughout the patient's lifetime. Moreover, the risk for chronic disorder increases with every relapse of the patient. Therefore relapse prevention is a primary focus in the treatment of schizophrenia. Studies point out that atypical antipsychotics have advantages in relapse prevention of schizophrenia compared to the "classical" antipsychotics, although comparative studies are still lacking. The main risk factor for a relapse is the withdrawal of antipsychotic medication. Nonbiological factors such as high-expressed emotions, adverse life events and stress contribute to an increased risk of schizophrenic relapse. Studies of relapse after withdrawal of antipsychotic medication revealed that noradrenergic, serotonergic, and dopaminergic neurotransmission are involved, low serotonergic and high dopaminergic neurotransmission are associated with a relapse, and possibly high noradrenergic neurotransmission plays a role in short-term relapses. Inflammation and the activation of certain cytokines, which have rarely been studied to date, seem to have an even higher impact on schizophrenic relapse. Methodological aspects of these studies are discussed. Biological mechanisms of relapse may not become fully elucidated before the mechanisms of the schizophrenic pathophysiology are clarified.
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15546065
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Etiopathogenetic mechanisms in long-term course of schizophrenia.
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Schizophrenia is a severe mental disorder with a relapsing long-term course in 80 % of the sufferers. The underlying neurobiological principles of the long-term course are widely unknown. Therefore an attempt is made to evaluate data from structural imaging and neuropsychology to shed some light on these mechanisms. Interestingly there was a significant correlation between length of illness and volume reduction in the prefrontal grey matter in schizophrenia. There was a lack of such a correlation for the whole brain volume, white matter volume or the grey matter volume outside the prefrontal lobe. Furthermore none of the neuropsychological measures correlated with length of illness. Both findings are supported by data from prospective studies up to five years demonstrating a significant loss of frontal grey matter volume, but no change of cognitive dysfunction in the course of time. The attempt is made to connect prefrontal grey matter loss with post-mortem findings of reduced neuropil but preserved cytoarchitecture leading to recently described candidate genes and their function.
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15546064
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Course and long-term treatment of schizophrenic psychoses.
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As there is a lack of clear biological correlates for most psychiatric disorders, follow-up studies regarding course, outcome and prognosis of psychiatric disorders play an important role in psychiatric research, especially in terms of validation of psychiatric diagnoses and other psychiatric concepts, such as the concept of negative symptoms. Long-term studies also have their place in the description and evaluation of first treatment procedures. The first part of this paper will describe some general aspects of the long-term course and outcome of schizophrenic psychoses. The problem of relapses and relapse prevention will then be discussed. Especially data from recent studies will be considered in this overview.
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15546063
|
Concepts on neurological disease evolution.
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Degenerative neurological diseases evolve progressively with an insidious onset, while relapsing neurological diseases may remit completely or result in progressive deficits. Since the affected systems can be assessed by clinical evaluation and ascribed to disease-specific pathology--today already in vivo using neuroimaging, the mechanisms underlying neurological disease manifestation can also be studied. For the most frequent neurological diseases with a relapsing clinical course, such as multiple sclerosis, brain infarction and epilepsy, it is shown that disease-specific aetiopathogenesis, lesion-specific pathophysiology and unspecific bystanders determine disease manifestation. Nevertheless, prediction of progression or relapse of a neurological disease is poor due to ill-defined relations of molecular genetic markers and disease evolution. Recent research on aetiopathogenesis and pathophysiology providing new perspectives for selective therapeutic interventions and relapse prevention is discussed.
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15546062
|
Effect of chronic antidepressant treatment on beta-receptor coupled signal transduction cascade. Which effect matters most?
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Beta-receptor down-regulation has been described as a common biochemical effect of chronic treatment with many but not all antidepressant drugs. Beta-receptor activation leads to elevated intracellular levels of cAMP followed by the activation of several protein kinases which in turn activate various transcription factors. One of those, CREP has received increasing interest as an relevant component within the antidepressant drug modulated signal cascade as it represents a down-stream signal not only of the beta-receptor but also of serotonin receptor activation. Chronic treatment with many antidpressant drugs has been shown to alter CREP levels in several brain regions. While beta-receptor down-regulation by chronic antidepressant treatment has been a consistent finding, alterations of CREP levels have been observed in both direction. Similarly divergent findings have been reported for BDNF a major gene targeted of CREB, where most but not all findings suggest up-regulation at least at the message level following chronic antidepressant treatment. Because of these rather divergent data, we investigated the possible effects of chronic treatment (9 or 19 days) with three different antidepressant drugs (reboxetine, citalopram, imipramine) on the individual parameters of the beta-receptor coupled signal transduction cascade. All animals were also tested for possible antidepressant effects using the forced swimming test. While beta-receptor density was down-regulated by reboxetine and imipramine but not citalopram, CREB protein was only mildly elevated after 9 days, and not changed or slightly reduced after 19 days. BDNF protein levels were not or only slightly enhanced, but only for the 9 days treatment. Citalopram was most active. Under the conditions chosen, all three drugs were active in the forced swimming test. Taken together, the findings reported make it difficult to identify one single component of the beta-receptor coupled signal transduction cascade as common final target of chronic antidepressant treatment.
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15546061
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The etiopathogenesis of schizophrenias.
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There is no generally accepted model explaining the aetiopathogenesis of schizophrenias. In recent years, hypotheses with a focus on single aspects of neurotransmission, single major genetic loci or single brain areas were predominating. Now, these different approaches converge to systemic models including neurotransmission, genetic changes and neurodevelopmental malformation of brain structures. Such systemic models will explain more aspects of schizophrenias than the recent confined hypotheses.
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15546060
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Mathematical-statistical concepts for modelling and prediction of longterm follow-up.
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Newer statistical methods for modeling and prediction of long-term follow-up in schizophrenia are presented. These include the extended Cox model, the Generalized Estimating Equations (GEE) method and the Artificial Neural Networks (ANN) approach.
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15546059
|
Course typologies, treatment principles, and research concepts.
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In order to explore the mechanisms of illness course and outcome and to improve treatment in schizophrenia and affective disorders, a theoretical framework as provided by the biopsychosocial concept, e. g. the vulnerability-stress-coping model, has been applied. To develop a coherent and valid research strategy, however, respective model components have to be translated into neuroscience concepts and operationalized accordingly. Course characteristics (typologies, markers), course influences (determinants, triggers, modifiers) and course predictors are discussed from a theoretical perspective. Building on this discussion, an integrative concept of illness course and course mechanisms is proposed. Finally, further research recommendations are given. Future research should elaborate on the neurobiological characteristics of course and outcome in methodologically adequate prospective interventional long-term studies.
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15546057
|
[Social psychiatry without sociology. Analysis of a scientific journal].
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Psychiatry and Sociology have followed separate avenues in Germany since the mid 1970 s. The aim of this work is to investigate their present relationship by means of an analysis of a scientific journal. All original works dealing with social psychiatric subjects and appearing in Psychiatrische Praxis in the years 2002 and 2003 were analysed. Sociologists appear to be a minority among the authors. Questions that are explicitly related to sociological theories were an exception, and sociological authors have hardly been quoted. Social psychiatric research in Germany is still conducted without Sociology. If social psychiatry is to gain in importance as a scientific discipline, closer cooperation with its mother discipline is imperative. As an example, the application of the rational choice theory in psychiatric research is discussed.
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15546056
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[Acute psychiatric day hospital treatment: is the effectiveness of this treatment approach still questionable?].
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Currently, there is still a severe lack of methodologically sound empirical studies on acute psychiatric day hospital treatment in German-speaking countries that analyse the effectiveness of this increasingly important mode of service provision. Within a randomised controlled study design implemented at the Department of Psychiatry and Psychotherapy, Dresden University of Technology, 99 general psychiatric patients received conventional inpatient treatment and 92 patients received acute day hospital treatment. At up to four time-points during the index-treatment episode patients were assessed at different levels of outcome: Psychopathology was rated by researchers using the Brief Psychiatric Rating Scale (24-Item-Version), and patients evaluated their satisfaction with treatment (Patientenbogen zur Behandlungszufriedenheit); at admission and discharge patients also assessed their subjective quality of life (Manchester Assessment of Quality of Life). Mean scale scores of these instruments are used for the intention-to-treat-analysis. Discharge status on these scales as well as mean ratings on these scales within the index-treatment episode serve as measures of effectiveness. For statistically identifying differences between the two settings five linear (co-)variance-analytical models were calculated for each target variable. Four models were adjusted to baseline-rating or to the individual period spent in treatment. Initially, both groups did not differ in their relevant socio-demographic and illness-related features. Day hospital treatment (87,7 days) lasted significantly longer than inpatient treatment (67,8 days). Only results from an unadjusted statistical model as well as from a model adjusted to the individual period of index-hospitalisation demonstrated superior effectiveness of day hospital treatment on the discharge status of psychopathological symptomatology. However, in all statistical models there were no systematic differences of treatment-effectiveness related to satisfaction with treatment and subjective quality of life. For the first time in German-speaking countries, this study provides evidence for the effectiveness of acute day hospital treatment as compared to conventional inpatient treatment. If detailed eligibility criteria for patients are used as defined here, approximately 30 % of the general psychiatric patients in need of acute hospital-based treatment may be cared for in this special mode of day hospital service provision.
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15546055
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[Quality of care in internal medicine in German psychiatric hospitals].
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Study on selected aspects of structural quality of care in internal medicine in German psychiatric hospitals. Investigation by questionnaire completed by medical directors of German psychiatric hospitals (response quote 48.8 %). Descriptive data from 81 hospitals with 25 920 inpatient beds are presented relating to various indicators of structural quality of care in internal medicine (e. g. availability of internal medicine consultations, diagnostic equipment, as ECG, clinical chemistry laboratory, ultrasound). We found evidence of a satisfactory infrastructure relating to internal medicine in a majority of hospitals. However, there exist also indications of significant deficits pertaining to certain aspects of medical care in the institutions investigated. With regard to the importance of medical comorbidity in clinical psychiatry the availability of adequate resources in internal medicine is a relevant indicator of quality of care in psychiatric hospitals.
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15546054
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[Problematic consumption of addictive drugs in psychiatric rehabilitation].
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Is an inferior outcome of psychiatric rehabilitation to be expected with patients who consume alcohol or addictive drugs in a problematic manner during rehabilitation treatment? Files and final reports from patients admitted to psychiatric rehabilitation during three successive years were analyzed. Data of patients with or without problematic use of psychotropic substances were compared. Patients with a problematic pattern of alcohol or drug consumption have a stronger propensity to quit psychiatric rehabilitation when a) using hard drugs or when b) bearing a diagnosis beyond the schizophrenia spectrum. The outcome of rehabilitation efforts of the subsample with a problematic use of drugs shows an unfavorable tendency concerning housing, but a better result in the vocational area. The problem has to be considered in a differenciated manner, which means that, in general, clients with a problematic use of alcohol or drugs should not automatically be excluded from psychiatric rehabilitation.
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15546053
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[Motor skills and psychiatric disturbances in children].
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Within the multiprofessional diagnostic in the psychiatric treatment for children an age-group of in-patients was examined using the coordination test for children (KTK) with regard to physical ability. The ascertained results and classifications of the motor skills were related to ICD 10 diagnosis on level 1 (clinical psychiatric syndrom) and level 2 (circumscribed disturbance of the development) as well as to issues of the anamnese- and report-documentation in order to ascertain correlations between child psychiatry disorder and motor development. More than 40 % of the children examined showed motor deficiency. Moreover, it was evident that girls attained significantly lower KTK-results than boys. The statistical results did not show any distinct effects to "diagnosis" and "age". The high quota of obviously impaired and disturbed children reflects the general decline of motor skills and does not seem to be attributed to the demand for psychiatric treatment for children and youth.
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15546052
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[The impact of social welfare policies on the deinstitutionalisation of the mentally ill in Germany].
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In Germany the competent institution for supported housing for mentally ill and handicapped persons is traditionally the regional welfare authority, while welfare authorities on state (Lander) level hold the competencies for accommodation in hostels and homes: Assessment of the impact of policies that try to overcome this separation of competencies. 1. Analysis of the practise of distributing the competencies for accommodation for mental ill and handicapped persons in the 16 German Lander. 2. Assessment of the supply with accommodation for mental ill and handicapped persons in the Lander. 3. Investigation of a possible relationship between distribution of competencies for accommodation and number of accommodation in supported housing and hostels/homes. Data about available accommodation in supported housing and hostels are inconsistently limited and available. As far as this data can be interpreted, Lander that have the administrative and particularly financial competency for accommodation uniquely organised, generally offer more supported housing. At the same time they provide relatively less accommodation in hostels and homes. Despite having the competencies for accommodation uniquely organised, some Lander continue to provide accommodation for mentally ill persons predominantly in hostels and homes. A comprehensive and between the Lander comparable system of documentation of accommodation for mentally ill and handicapped persons is highly needed. Unique organisation of competencies for accommodation of mental ill and handicapped persons is a necessary - however not commensurate precondition for the increase of the supply in supported housing. Beyond that, other factors seem to be influential, such as political will, attitudes towards the mentally ill, interests of hostel providers, pre-existing hostel infrastructure. In respect of these factors more research is needed.
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15546050
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Suppression subtractive hybridization cDNA libraries to identify differentially expressed genes from contrasting fish habitats.
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Suppression subtractive hybridization complementary DNA libraries identified differentially expressed genes in liver tissue of winter flounder collected from the highly impacted Raritan-Hudson estuary versus those from less industrialized estuaries farther south in New Jersey. Distinct transcript profiles emerged in the fish from these different habitats. A total of 251 clones from the forward (upregulated with anthropogenic impact) and reverse (downregulated with anthropogenic impact) subtracted libraries were sequenced. In the upregulated library immune response transcripts, including complement C-3, C-7, factor H, factor Bf/C2, differentially regulated trout protein 1, and the antimicrobial hepcidin, indicated the pollution-impacted fish were under a high viral or bacterial load. Transcripts for cytochrome P450 1A, P450 3A, and glutathione S-transferase, important components of phase I and II metabolism of xenobiotics, were found in the upregulated-with-pollution library. Vitellogenins I and II and egg envelope protein (zp) appeared to be downregulated. A homologue of the tumor suppressor p33(ING1) (down) and hepatocyte growth factor-like protein (up) may indicate liver damage or hepatocellular carcinoma or hepatoma. These expression patterns, confirmed by quantitative polymerase chain reaction, indicate that transcript analysis is a useful method for assessing the health of local habitats and the organisms therein.
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15546049
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Isolation of new Symbiodinium strains from tridacnid giant clam (Tridacna crocea) and sea slug (Pteraeolidia ianthina) using culture medium containing giant clam tissue homogenate.
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Recent molecular biological studies have revealed that some photosymbiotic invertebrates dwelling in coral reefs host several genetically different dinoflagellates, Symbiodinium species, as symbionts. However, little is known about the difference in physiologic characteristics among these symbionts living in a single host, because some Symbiodinium strains are difficult to culture in vitro. To isolate some of these Symbiodinium strains, we have developed an agar culture medium plate containing antibiotics and a giant clam tissue homogenate. Using-this medium we isolated two new Symbiodinium strains from two molluscan hosts, Tridacna crocea and Pteraeolidia ianthina, each of which hosted two different Symbiodinium strains belonging to Symbiodinium C and D, respectively. The tissue homogenate was essential for the growth of Symbiodinium D. Although it was not essential for the growth of Symbiodinium C, it did stimulate the initial growth. For the isolation of some Symbiodinium strains, isolation medium containing host homogenate is effective.
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15546048
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Isolation and characterization of a fucoidan-degrading marine bacterial strain and its fucoidanase.
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A marine bacterial strain that degraded fucoidan from Kjellmaniella crassifolia (class Phaeophyceae, order Laminariales, family Laminariaceae) was isolated in our laboratory. The strain was gram-negative, ubiquinone 8 was the predominant respiratory quinone, and the GC-content of its genomic DNA was 36%. The cells of the strain were rod-shaped (2.0 microm long x 1.0 microm wide), and each cell was motile by means of one polar flagellum. Phylogenetic analysis of its 16S ribosomal DNA sequence indicated that it was a member of the family Alteromonadaceae. It produced a type of extracellular fucoidanase, an endosulfated fucan-digesting enzyme. The enzyme was purified with 3500-fold purity at 12.0% yield. Optimum conditions for the enzyme reaction were approximately pH 6.5 to 8.0 and temperature 30 degrees to 35 degrees C. The enzyme was activated by calcium ions, and maximum activity was observed in the presence of greater than 30 mM calcium ion.
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15546047
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Preliminary study on linkage mapping based on microsatellite DNA and AFLP markers using homozygous clonal fish in ayu (Plecoglossus altivelis).
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A mapping referential family (F(1)) of ayu was produced by crossing a normal diploid male with a homozygous clonal female. A genetic linkage map was constructed using 191 amplified fragment length polymorphism (AFLP) and 4 microsatellite DNA markers. A total of 178 loci were mapped in 36 linkage groups comprising 1659.6 cM, which includes approximately 77.3% to 81.8% of the total genome. As the markers were randomly distributed over the genome, they showed high efficiency for the construction of a wide linkage map.
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15546046
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Measurement of EROD activity: caution on spectral properties of standards used.
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The activity of the enzyme 7-ethoxy-resorufin- O-deethylase (EROD) has been extensively used in biomonitoring studies for more than a decade. Although the analytical procedure is simple, it is often poorly characterized. In this study spectral properties of particular standard compounds used to measure EROD activity (ethoxyresorufin and resorufin, standards from Molecular Probes) were tested in order to optimize excitation and emission wavelengths to be used in the fluorimetric assay of EROD activity. The optimal excitation wavelength for the detection of resorufin was 560 nm. At this wavelength the excitation represents only 37% of its maximum level for ethoxyresorufin, while it represents 86% for resorufin. This allows discrimination between the fluorescence emitted by both standards, favoring the formed resorufin. Our results demonstrate that any analytical work using spectrofluorometry to measure EROD activity should be preceded by precise determination of the spectral characteristics of each set of standards used.
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15546045
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Fine spatial structure of Atlantic hake (Merluccius merluccius) stocks revealed by variation at microsatellite loci.
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Genetic variation at 5 microsatellite loci was analyzed for European hake Merluccius merluccius sampled from 9 different regions in the Atlantic Ocean and the Mediterranean Sea. Significant genetic differentiation was found between samples, suggesting a fine subdivision of Atlantic and Mediterranean hake stocks. These results are discussed in the context of the decline of demersal fish species, probably due to overfishing.
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15546044
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Degradation of 2,4-dichlorophenoxyacetic acid (2,4-d) by a hypersaline microbial mat and related functional changes in the mat community.
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Microbial mats possibly possess degradation capacities for haloorganic pollutants because of their wide range of different functional groups of microorganisms combined with extreme diurnal changes in pH, oxygen, and sulfide gradients. In this study, 20 mg/l of the chlorinated herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) was applied to a pristine hypersaline cyanobacterial mat from Guerrero Negro, Mexico, under a light regime of 12 h dark/12 h light (600 mumol photons/m(2)s). The loss of 2,4-D was followed by chemical GC analysis; functional changes within the mat were determined with microelectrodes for oxygen, photosynthesis, pH, and sulfide. The depletion of 2,4-D due to photooxidation or sorption processes was checked in control experiments. Within 13 days, the light/dark incubated mats degraded 97% of the herbicide, while in permanent darkness only 35% were degraded. Adsorption of 2,4-D to the mat material, agar, or glass walls was negligible (4.6%), whereas 21% of the herbicide was degraded photochemically. The 2,4-D removal rate in the light/dark incubations was comparable to values reported for soils. The phototrophic community of the mat was permanently inhibited by the 2,4-D addition by 17% on average. The sulfate reduction in the entire mat and the respiration in the photic zone were inhibited more strongly but returned to original levels. Since at the end of the experiment the photosynthetic and respiratory activity of the mats were almost as high as in the beginning and 2,4-D almost completely disappeared, we conclude that the examined mats represent a robust and effective system for the degradation of the herbicide where probably the aerobic heterotrophic population is a major player in the degradation process.
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15546043
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Degradation of 4-chlorophenol at low temperature and during extreme temperature fluctuations by Arthrobacter chlorophenolicus A6.
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Low average temperatures and temperature fluctuations in temperate soils challenge the efficacy of microbial strains used for clean up of pollutants. In this study, we investigated the cold tolerance of Arthrobacter chlorophenolicus A6, a microorganism previously shown to degrade high concentrations of 4-chlorophenol at 28 degrees C. Luciferase activity from a luc-tagged derivative of the strain (A6L) was used to monitor the metabolic status of the population during 4-chlorophenol degradation. The A6L strain could degrade 200-300 mug mL(-1) 4-chlorophenol in pure cultures incubated at 5 degrees C, although rates of degradation, growth and the metabolic status of the cells were lower at 5 degrees C compared to 28 degrees C. When subjected to temperature fluctuations between 5 and 28 degrees C, A6L continued to degrade 4-chlorophenol and remained active. In soil microcosm experiments, the degradation rates were significantly faster the first week at 28 degrees C, compared to 5 degrees C. However, this difference was no longer seen after 7 days, and equally low 4-chlorophenol concentrations were reached after 17 days at both temperatures. During 4-chlorophenol degradation in soil, CFU and luciferase activity values remained constant at both 5 and 28 degrees C. However, once most of the 4-chlorophenol was degraded, both values decreased by 1-1.5 logarithmic values at 28 degrees C, whereas they remained constant at 5 degrees C, indicating a high survival of the cells at low temperatures. Because of the ability of A. chlorophenolicus A6 to degrade high concentrations of 4-chlorophenol at 5 degrees C, together with its tolerance to temperature fluctuations and stress conditions found in soil, this strain is a promising candidate for bioaugmentation of chlorophenol-contaminated soil in temperate climates.
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15546042
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Microbial community structure and oxidative enzyme activity in nitrogen-amended north temperate forest soils.
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Large regions of temperate forest are subject to elevated atmospheric nitrogen (N) deposition which can affect soil organic matter dynamics by altering mass loss rates, soil respiration, and dissolved organic matter production. At present there is no general model that links these responses to changes in the organization and operation of microbial decomposer communities. Toward that end, we studied the response of litter and soil microbial communities to high levels of N amendment (30 and 80 kg ha(-1) yr(-1)) in three types of northern temperate forest: sugar maple/basswood (SMBW), sugar maple/red oak (SMRO), and white oak/black oak (WOBO). We measured the activity of extracellular enzymes (EEA) involved directly in the oxidation of lignin and humus (phenol oxidase, peroxidase), and indirectly, through the production of hydrogen peroxide (glucose oxidase, glyoxal oxidase). Community composition was analyzed by extracting and quantifying phospholipid fatty acids (PLFA) from soils. Litter EEA responses at SMBW sites diverged from those at oak-bearing sites (SMRO, BOWO), but the changes were not statistically significant. For soil, EEA responses were consistent across forests types: phenol oxidase and peroxidase activities declined as a function of N dose (33-73% and 5-41%, respectively, depending on forest type); glucose oxidase and glyoxal oxidase activities increased (200-400% and 150-300%, respectively, depending on forest type). Principal component analysis (PCA) ordinated forest types and treatment responses along two axes; factor 1 (44% of variance) was associated with phenol oxidase and peroxidase activities, factor 2 (31%) with glucose oxidase. Microbial biomass did not respond to N treatment, but nine of the 23 PLFA that formed >1 mol% of total biomass showed statistically significant treatment responses. PCA ordinated forest types and treatment responses along three axes (36%, 26%, 12% of variance). EEA factors 1 and 2 correlated negatively with PLFA factor 1 ( r = -0.20 and -0.35, respectively, n = 108) and positively with PLFA factor 3 ( r = +0.36 and +0.20, respectively, n = 108). In general, EEA responses were more strongly tied to changes in bacterial PLFA than to changes in fungal PLFA. Collectively, our data suggests that N inhibition of oxidative activity involves more than the repression of ligninase expression by white-rot basidiomycetes.
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15546041
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Genetic diversity of bacterial communities of serpentine soil and of rhizosphere of the nickel-hyperaccumulator plant Alyssum bertolonii.
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Serpentine soils are characterized by high levels of heavy metals (Ni, Co, Cr), and low levels of important plant nutrients (P, Ca, N). Because of these inhospitable edaphic conditions, serpentine soils are typically home to a very specialized flora including endemic species as the nickel hyperaccumulator Alyssum bertolonii. Although much is known about the serpentine flora, few researches have investigated the bacterial communities of serpentine areas. In the present study bacterial communities were sampled at various distances from A. bertolonii roots in three different serpentine areas and their genetic diversity was assessed by terminal restriction fragment length polymorphism (T-RFLP) analysis. The obtained results indicated the occurrence of a high genetic diversity and heterogeneity of the bacterial communities present in the different serpentine areas. Moreover, TRFs (terminal restriction fragments) common to all the investigated A. bertolonii rhizosphere samples were found. A new cloning strategy was applied to 27 TRFs that were sequenced and taxonomically interpreted as mainly belonging to Gram-positive and alpha-Proteobacteria representatives. In particular, cloned TRFs which discriminated between rhizosphere and soil samples were mainly interpreted as belonging to Proteobacteria representatives.
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15546040
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Biological soil crusts of sand dunes in Cape Cod National Seashore, Massachusetts, USA.
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Biological soil crusts cover hundreds of hectares of sand dunes at the northern tip of Cape Cod National Seashore (Massachusetts, USA). Although the presence of crusts in this habitat has long been recognized, neither the organisms nor their ecological roles have been described. In this study, we report on the microbial community composition of crusts from this region and describe several of their physical and chemical attributes that bear on their environmental role. Microscopic and molecular analyses revealed that eukaryotic green algae belonging to the genera Klebsormidium or Geminella formed the bulk of the material sampled. Phylogenetic reconstruction of partial 16S rDNA sequences obtained from denaturing gradient gel electrophoresis (DGGE) fingerprints also revealed the presence of bacterial populations related to the subclass of the Proteobacteria, the newly described phylum Geothrix/ Holophaga/ Acidobacterium, the Cytophaga/ Flavobacterium/ Bacteroides group, and spirochetes. The presence of these crusts had significant effects on the hydric properties and nutrient status of the natural substrate. Although biological soil crusts are known to occur in dune environments around the world, this study enhances our knowledge of their geographic distribution and suggests a potential ecological role for crust communities in this landscape.
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15546039
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Bacterial density and community structure associated with aggregate size fractions of soil-feeding termite mounds.
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The building and foraging activities of termites are known to modify soil characteristics such as the heterogeneity. In tropical savannas the impact of the activity of soil-feeding termites ( Cubitermes niokoloensis) has been shown to affect the properties of the soil at the aggregate level by creating new soil microenvironments (aggregate size fractions) [13]. These changes were investigated in greater depth by looking at the microbial density (AODC) and the genetic structure (automated rRNA intergenic spacer analysis: ARISA) of the communities in the different aggregate size fractions (i.e., coarse sand, fine sand, coarse silt, fine silt, and dispersible clays) separated from compartments (internal and external wall) of three Cubitermes niokoloensis mounds. The bacterial density of the mounds was significantly higher (1.5 to 3 times) than that of the surrounding soil. Within the aggregate size fractions, the termite building activity resulted in a significant increase in bacterial density within the coarser fractions (>20 mum). Multivariate analysis of the ARISA profiles revealed that the bacterial genetic structures of unfractionated soil and soil aggregate size fractions of the three mounds was noticeably different from the savanna soil used as a reference. Moreover, the microbial community associated with the different microenvironments in the three termite mounds revealed three distinct clusters formed by the aggregate size fractions of each mound. Except for the 2-20 mum fraction, these results suggest that the mound microbial genetic structure is more dependent upon microbial pool affiliation (the termite mound) than on the soil location (aggregate size fraction). The causes of the specificity of the microbial community structure of termite mound aggregate size fractions are discussed.
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15546038
|
Microbial communities associated with electrodes harvesting electricity from a variety of aquatic sediments.
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The microbial communities associated with electrodes from underwater fuel cells harvesting electricity from five different aquatic sediments were investigated. Three fuel cells were constructed with marine, salt-marsh, or freshwater sediments incubated in the laboratory. Fuel cells were also deployed in the field in salt marsh sediments in New Jersey and estuarine sediments in Oregon, USA. All of the sediments produced comparable amounts of power. Analysis of 16S rRNA gene sequences after 3-7 months of incubation demonstrated that all of the energy-harvesting anodes were highly enriched in microorganisms in the delta-Proteobacteria when compared with control electrodes not connected to a cathode. Geobacteraceae accounted for the majority of delta-Proteobacterial sequences or all of the energy-harvesting anodes, except the one deployed at the Oregon estuarine site. Quantitative PCR analysis of 16S rRNA genes and culturing studies indicated that Geobacteraceae were 100-fold more abundant on the marine-deployed anodes versus controls. Sequences most similar to microorganisms in the family Desulfobulbaceae predominated on the anode deployed in the estuarine sediments, and a significant proportion of the sequences recovered from the freshwater anodes were closely related to the Fe(III)-reducing isolate, Geothrix fermentans. There was also a specific enrichment of microorganisms on energy harvesting cathodes, but the enriched populations varied with the sediment/water source. Thus, future studies designed to help optimize the harvesting of electricity from aquatic sediments or waste organic matter should focus on the electrode interactions of these microorganisms which are most competitive in colonizing anodes and cathodes.
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15546037
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The biogeography and phylogeny of unicellular cyanobacterial symbionts in sponges from Australia and the Mediterranean.
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The distribution, host associations, and phylogenetic relationships of the unicellular cyanobacterial symbionts of selected marine sponges were investigated with direct 16s rDNA sequencing. The results indicate that the symbionts of the marine sponges Aplysina aerophoba, Ircinia variabilis, and Petrosia ficiformis from the Mediterranean, four Chondrilla species from Australia and the Mediterranean, and Haliclona sp. from Australia support a diversity of symbionts comprising at least four closely related species of Synechococcus. These include the symbionts presently described as Aphanocapsa feldmannii from P. ficiformis and Chondrilla nucula. A fifth symbiont from Cymbastela marshae in Australia is an undescribed symbiont of sponges, related to Oscillatoria rosea. One symbiont, Candidatus Synechococcus spongiarum, was found in diverse sponge genera in the Mediterranean Sea and the Indian, Pacific, and Southern oceans, whereas others were apparently more restricted in host association and distribution. These results are discussed in terms of the biodiversity and biogeographic distributions of cyanobacterial symbionts.
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15546035
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Anemia in patients on combined androgen block therapy for prostate cancer.
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To study the effect of combined androgen block therapy on hemoglobin and hematocrit values in patients with prostate cancer. One hundred and thirty-six patients with adenocarcinoma of prostate were treated with combined androgen block (orchiectomy and flutamide 250 mg, tid). Complete blood counts were determined before and after 1, 2, 3, 6, 9 and 12 months of therapy. The hemoglobin and hematocrit levels declined significantly in all patients and at all the time points after treatment (P<0.05). Prostate cancer patients treated with combined androgen block would develop obvious anemia. Recombinant human erythropoietin can be used to treat patients with severe anemia.
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15546034
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Acute scrotum due to arterial bleeding mimicking non-seminomatous germ cell tumor.
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Men with testicular tumors usually present with painless increase in testis size incidentally noticed by the patient. We report a case of a young patient presenting as an emergency with acute onset of massive right-sided testicular pain without previous injury. After physical examination testicular torsion could not be excluded. Ultrasound examination of the testis was suspicious for testicular tumor. Surgical exploration of the right testis by inguinal approach was performed revealing subcapsular arterial bleeding due to a small nonseminomatous germ cell tumor non-palpable on clinical examination.
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15546032
|
Clinical and pathological correlation of the microdeletion of Y chromosome for the 30 patients with azoospermia and severe oligoasthenospermia.
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To review the accumulated 30 patients with different area of Y chromosome microdeletions, focusing on their correlation with the clinical and pathological findings. A total of 334 consecutive infertile men with azoospermia (218 patients) and severe oligoasthenospermia (116 patients) were screened. Complete physical and endocrinological examinations, general chromosome study and multiplex polymerase chain reaction assay to evaluate the Y chromosome microdeletion were performed. Ten patients received testicular biopsy. Then the clinical and pathological findings were analyzed with reference to the areas of Y chromosome microdeletion. There is a decline of the percentage of sperm appearing in semen in the group that the gene deletion region from AZFc to AZFb. The clinical evidence of the impairment (decreased testicular size and elevated serum FSH) is also relevantly aggravated in this group. However, the pathology of testicular biopsy specimen was poorly correlated with the different deletion areas of the Y chromosome, which may be due to the limited number of specimens. The clinical correlation of spermatogenic impairment to the different AZF deletion regions may provide the information for the infertile couples in pre-treatment counseling.
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15546031
|
Ultrastructural changes of penile tunica albuginea in diabetic rats.
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To clarify the ultrastructural changes of penile tunica albuginea (TA) in streptozotocin (STZ)-induced diabetic rats. Intraperitoneal injection of STZ was used to induce diabetes mellitus (DM) in 12 Sprague Dawley rats. Ten rats (age and weight-matched) were used as control. Blood samples from the tail snips of the rats were used for the determination of serum glucose levels with SureStep Plus Blood Meter. At week 4 and 10 after the injection, half of the rats in each group were sacrificed and penile samples were obtained from the middle third of the penile shaft for the examination of TA under scanning electron microscopy. In the diabetic group, the serum glucose levels were higher (P<0.01 at both time points) and the TA were thinner (P<0.05) than those of the controls. In the control group, the fibers of TA were rich and arranged regularly and undulated, while in the diabetic group, the fibers were diminished, lost the undulations and were arranged irregularly. In rats, DM appeared to impair the penile TA ultrastructures and this impairment could contribute to diabetic erectile dysfunction in part by impairing the veno-occlusive function.
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15546030
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Cycloheximide prevents production of arresting, a fraction of 30-50 kDa obtained from seminiferous tubule conditioned medium.
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To evaluate the effect of a protein synthesis inhibitor cycloheximide on arresting activity in spermatogenesis and sperm count in male rats. The study used seminiferous tubule (ST) segments from adult rats cultured in vitro with or without cycloheximide to condition culture media, which have been concentrated, size fractioned (30-50 kDa) and administered 7 days to adult rats by intraperitoneal injections. The effects on testicular and epididymal weights, spermatogenesis and epididymal sperm count were determined. The fraction (30-50 kDa), named arresting, obtained from the culture without cycloheximide decreased testicular and epididymal weights (P<0.01) and reduced the epididymal sperm count significantly. Study of the spermatogenic cycle by transillumination showed spermatogenic arrest at stage VII in rats treated with arresting compared to that observed in controls. The length of stage VII in the group receiving the seminiferous tubules culture media with cycloheximide (30-50 KDa CHX-STCM fraction) was similar to control. The difference in the effect may be the result of the presence or absence of arresting, a protein secreted by the tubules.
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15546029
|
Relationship between metabolic syndrome and erectile dysfunction.
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To determine the relationship between metabolic syndrome (MS) and erectile dysfunction (ED) and to see which risk factors correlated the best with ED. Seventy-nine cardiology clinic outpatients with coronary artery disease (CAD) and lipid metabolism disorder were recruited. They were categorized as having MS, hypertension (blood pressure greater than 130/85 mmHg) and dyslipidemia. ED was classified based on International Index of Erectile Function scores. Patients were grouped into quartiles based on body mass index (BMI). Chi-square, Pearson's correlation and regression tests were used for statistical analysis. The mean age of the patients was 56.6 years. ED was diagnosed in 59 (74.7 %) of the 79 patients. In the 38 patients with MS, all had ED. ED was not significantly correlated with cholesterol levels (P>0.05), but was found often in patients who had both hypercholesterolemia and HT (P<0.01). Nineteen (76 %) of the 25 patients who had dyslipidemia had ED. However, ED was not significantly correlated with dyslipidemia (P >0.05). Twenty-two of the 23 patients who had BMI greater than 30 had ED, which was significantly more prevalent than that in those who had normal BMI (P<0.01). ED was seen in 38 of 53 smoker patients. Although ED was more prevalent in cigarette smokers, it was not significantly different from non-smokers (P>0.5). ED is present in a high percentage of patients with MS. Among multiple risk factors for ED, MS correlates the most highly. The next most important risk group is the patients with hypertension +hypercholestrolemia and obesity (BMI 30).
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15546028
|
Plasma transforming growth factor-beta1 levels in patients with erectile dysfunction.
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To evaluate the plasma TGF-beta1 level in erectile dysfunction (ED) patients of various causes. Sixty-two patients with ED and 26 potent men were subjected to the study. Based on multidisciplinary work-ups, including medical history, physical examinations, blood tests with lipid profile and hormones, penile duplex Doppler ultrasonogram and neurophysiological tests, causes for ED were classified as psychogenic (n=15), neurogenic (n=16) and vasculogenic (n=31). The plasma TGF-beta1 level was measured by the ELISA method. The plasma TGF-beta1 level was significantly increased in the ED group (6.7+/-4.9 ng/mL), compared to the control (4.0 +/-2.1 ng/mL) (P<0.01). In the ED groups, there was a significant increase in the vasculogenic group (9.0 +/-5.5 ng/mL), compared to the psychogenic (3.8 +/-1.8 ng/mL) and neurogenic groups (4.8+/-3.2 ng/mL) (P<0.01). Of the vascular risk factors, both the smoking (7.5 +/-4.7 ng/mL) and dyslipidemia groups (7.4+/-4.4 ng/mL) showed significantly increased plasma TGF-beta1 levels, compared to the non-smokers (5.5+/-2.8 ng/mL), and those without dyslipidemia (4.8+/-2.8 ng/mL) (P<0.05). Vascular risk factors are associated with an elevated plasma TGF-beta1 level, which may contribute to cavernous fibrosis and ED.
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15546027
|
Prevalence and risk factors of erectile dysfunction in three cities of China: a community-based study.
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To determine the age-adjusted prevalence of erectile dysfunction (ED) in 3 big cities of China and to explore its potential sociodemographic, medical and lifestyle correlates. A cross-sectional, population-based survey was conducted in three cities of China. Structured questionnaires were administered to 2 226 men, aged 20 - 86 years, by trained interviewers. The age-adjusted prevalence of ED was 28.34 % (mild 15.99 %, moderate 7.14 %, severe 5.21 %). In the men above 40, the prevalence was 40.2 %. Age was positively correlated with ED (P<0.01). Education was negatively correlated with ED (P<0.01). Spouse companionship, living condition were positively correlated with ED (P<0.01). Histories of cardiovascular disease, diabetes, and hyperlipidemia were positively correlated with ED (P<0.01). Cigarette smoking was not correlated with ED (P>0.05), while the cigarette consumption and duration were positively correlated with ED (P<0.01). Alcohol drinking is negatively correlated with ED (P<0.01). The duration of drinking was positively correlated with ED (P<0.01). Weekly alcohol consumption was not correlated with ED (P>0.05). The prevalence of ED increased with age. Cardiovascular disease, diabetes and hyperlipidemia were positively correlated with the increased prevalence. Sociodemographic and lifestyle factors, such as education, spouse companionship, living condition, cigarette and alcohol consumption or duration also have association with the prevalence of ED.
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15546026
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Joint action of phoxim and fenvalerate on reproduction in male rats.
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To evaluate the joint action of phoxim and fenvalerate on the reproductive function in male Sprague-Dawley rats. The 2 x 2 factorial analysis experiment was used in the study. The pesticides were orally given at daily doses of phoxim (Pho) 8.2 mg/kg, fenvalerate (Fen) 3.3 mg/kg and Pho 8.2+Fen 3.3 mg/kg (Pho:Fen = 5:2), 5 days a week for 60 days. Sperm motility was measured with computer-assisted sperm motility analysis (CASA) and daily sperm production estimated. Immunoenzymatic method and electron microscopy were used to evaluate the serum testosterone and the testicular morphology, respectively. There were significant decreases in sperm motility parameters in the treated animals, including straight line velocity (VSL), beat cross frequency (BCF), linearity (LIN) and straightness (STR). After treated with Fen, significant decreases in VSL, LIN and STR were demonstrated. Significant decreases of daily sperm production were seen in animals treated with Pho and Pho+Fen in comparison with the controls. Serum testosterone levels were not significantly changed in the treated groups. Factorial ANOVA showed that no significant interactions were noted between Pho and Fen in sperm motility, sperm production and serum testosterone. Both the single and mixed pesticides caused various degrees of testicular lesions, involving vacuolation of endoplasmic reticulum and necrosis of Sertoli cells. The pesticides may cause sperm motility changes and testicular lesions in male rats. The action of Pho and Fen may be additive.
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15546025
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Radio-protective effect of vitamin E on spermatogenesis in mice exposed to gamma-irradiation: a flow cytometric study.
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To investigate the effect of vitamin E on the radioprotection of spermatogenesis and chromatin condensation of spermatozoa during passage through the epididymis in mice exposed to irradiation. Adult outbred male ICR mice were orally administered natural vitamin E (VE, D-alpha-tocopheryl acetate) at 400 IU/kg for 7 days before exposure to 1 Gy of gamma-irradiation. The animals were sacrificed at day 1, 7, 14, 21, 28, 35 and 70 post-irradiation (IR) and the percentage of testicular germ cells and epididymal sperm chromatin condensation was analyzed using flow cytometry. Serum D-alpha-tocopheryl acetate levels were 47.4+/-3.2 microg/dL in the treated group, yet it could not be detected in the control group. The testicular weight of irradiated mice pretreated with VE+IR was significantly (P<0.05) higher than that of those without VE treatment (IR) at day 14 and 21 post-irradiation. The percentage of primary spermatocytes (4C) in the VE+IR group was comparable to the controls but significantly (P<0.05) higher than those in the IR group from day 7 to 35 post-irradiation. The percentage of round spermatids (1C) in the VE+IR group was also significantly (P<0.05) higher than those in the IR group at day 28 post-irradiation. The primary spermatocytes : spermatogonia ratio in the IR group was significantly (P<0.05) declined at day 7 to 35 post-irradiation when compared to the VE+IR and control groups. The round spermatid : spermatogonia ratio in the VE+IR group was significantly (P<0.05) higher than that of the IR group at day 14 and 28 post-irradiation. The chromatin condensation of epididymal spermatozoa measured by propidium iodide uptake was not affected by 1 Gy of gamma-irradiation. The administration of VE prior to irradiation protects spermatogenic cells from radiation.
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15546024
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Effect of prenatal exposure to diethylstilbestrol on gubernacular development in fetal male mice.
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To study the effect of prenatal exposure to diethylstilbestrol (DES) and the role of actin and proliferating cell nuclear antigen (PCNA) on testicular gubernaculum development in fetal male Kunming mice. Pregnant mice were randomly assigned to 6 groups and injected with DES subcutaneously from gestational day 9 (E9) to day 17 (E17) at doses of 0, 25, 50, 100, 200 microg.kg-1.d-1 in 0.2 mL dimethyl sulfoxide (DMSO). On E17 they were sacrificed and fetuses quickly removed for fixation. Male fetuses were sliced on serial coronal plane. Histological changes were observed under the light microscope (LM) and ultrastructural changes with the scanning and transmission electron microscopes (SEM and TEM). The expression intensity of actin and PCNA in the gubernacula was quantitated by immunohistochemistry. The mortality of the fetuses was higher in the DES-treated groups than that in the DMSO and saline controls (P<0.05). Under LM the gubernacula were seen to be poorly developed with smaller bulbs. On SEM the bulbs lose the clear demarcation between the mesenchymal inner core and the muscular outer layer and looked like a small cone instead of the normal cylindrical appearance. On TEM there were some smaller disordered myofibrils and sparse cytoplasmic organelles in the gubernacular muscular cells of the treated groups. The expression intensity of actin and PCNA in the gubernacula was significantly weaker in the treated groups than that in the DMSO and saline controls (P<0.05). DES induces underdevelopment of the gubernacula in a dose-dependent manner in fetal male mice and down regulates the actin and PCNA expression.
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15546022
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Relationship between acrosin activity of human spermatozoa and oxidative stress.
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To study the association between seminal oxidative stress and human sperm acrosin activity. It is a prospective study consisting of 30 infertile men and 12 fertile normozoospermic volunteers. A full history, clinical examination and scrotal ultrasound were done to exclude other related factors such as smoking and varicocele. Presence of white blood cells (WBCs) in semen samples was evaluated by peroxidase staining. Lipid peroxidation in spermatozoa was induced after incubating with ferrous sulphate (4 mmol/L) and sodium ascorbate (20 mmol/L). Induced peroxidation of spermatozoa was assessed by determining the production of thiobarbituric acid reactive substances (TBARS). Acrosin activity was measured using the gelatinolysis technique. The halo diameters around the sperm heads and the percentages of spermatozoa showing halo formation were evaluated. An acrosin activity index was calculated by multiplying the halo diameter by the halo formation rate. A significant difference was observed in acrosin activity parameters and TBARS levels between samples with WBCs (1 multiply 10(6)/mL of ejaculate) and those without. This difference was also noted between the normozoospermic and the oligoasthenoteratozoospermic semen samples. The TBARS production by spermatozoa had a significant negative correlation with the acrosin activity index (r = -0.89, P 0.001). The presence of oxidative stress in an individual with leukocytospermia and/or abnormal semen parameters is associated with impaired sperm function as measured by its acrosin activity.
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15546023
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Abrogation of heat-shock protein (HSP)70 expression induced cell growth inhibition and apoptosis in human androgen-independent prostate cancer cell line PC-3m.
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To investigate the effect of abrogating heat shock protein (HSP) 70 expression by antisense HSP70 oligonucleotides treatment on human androgen-independent prostate cancer cell line PC-3m growth. PC-3m cells were treated with 0-16 mmol/L antisense HSP70 oligomers for 0-100 hr. Cell growth inhibition was analyzed using a trypan blue dye exclusion test. Apoptotic cells were detected and confirmed by flow cytometric analysis and DNA fragmentation analysis. The protein expression of HSP70 and bcl-2 affected by antisense HSP70 oligomers were determined using Western blot. Antisense HSP70 oligomer induced apoptosis and then inhibited proliferation of PC-3m cells in a dose- and time-dependent manner. Ladder-like patterns of DNA fragments were observed in PC-3m cells treated with 10 mmol/L antisense HSP70 oligomer for 48 hr or 8 mmol/L for 72 hr on agarose gel electrophoresis. Antisense HSP70 oligomer pretreatment enhanced the subsequent induction of apoptosis by heat shock in PC-3m cells. In addition, undetectable HSP70 expression was observed at a concentration of 10 mmol/L antisense HSP70 oligomer treatment for 48 hr or 8 mmol/L for 72 hr in Western blot, which was paralleled by decreased expression levels of anti-apoptotic protein bcl-2. HSP70 antisense oligomer treatment abrogates the expression of HSP70, which may disrupt HSP70-bcl-2-interactions and further down-regulate bcl-2 expression, in turn inducing apoptosis and inhibiting cell growth in PC-3m cells.
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15546021
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Male infertility: risk factors in Mongolian men.
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To determine the most common risk factors of male infertility in Mongolian men attending an infertility clinic. A prospective, case-control study was conducted in which 430 men were enrolled. All the men had sought their first infertility evaluation between 1998-2002 in the State Research Center on Maternal Child Health, Ulaanbaatar, Mongolia. They were divided into two groups depending on the results of their semen analysis: 191 with abnormal semen and 239 with normal semen profile. Univariate and multivariate analyses were performed to determine any association between risk factors and semen abnormality. Logistic regression analysis demonstrated that the testicular volume, a history of sexually transmitted infections (STI), epididymitis and testicular damage all have statistically significant associations with semen abnormality, when controlled for multiple risk factors. Adjusted odds ratios of 3.4 for mumps orchitis, 2.3 for other orchitis and 3.9 for testicular injury were found. Gonorrhoea, the most commonly reported STIs in this study, gave an adjusted odds ratio of 1.0 for having one or more sperm abnormality. An adjusted odds ratio for subjects with a history of other STIs was 2.7. However, as a predictor of azoospermia, STIs had very high odds ratio, being 5.6 in patients with gonorrhoea and 7.6 in patients with other STIs. A history of pathology involving testicular damage appeared to have the strongest impact on male infertility in Mongolia. STIs have less impact on semen quality except when complicated by orchitis, epididymitis and vasal obstruction.
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15546020
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A preliminary study on the rheological properties of human ejaculate and changes during liquefaction.
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To study the changes in rheological properties, namely the parameters of the hysteresis loops and yield stress versus time for human semen after ejaculation. Ejaculates were obtained from volunteers and immediately put into the test cup of a Brookfield Programmable DV-11 Rheometer, by which the hysteresis loops and yield stress were determined. (1) Yield stress values dropped down from more than 3000 mPa to 60 mPa in about 5 minutes after ejaculation; (2) The shape of the hysteresis loops of shear stress versus shear rate was changed from the counter-clockwise direction, that enclosed a large area, into the clockwise direction, that enclosed a very small area. Human ejaculate originally possesses semi-solid or visco-elastic body behavior and in 5 minutes after liquefaction, it becomes a thixotropic fluid or shearing thinning fluid with very low viscosity.
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15546018
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Combination of genistein with ionizing radiation on androgen-independent prostate cancer cells.
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To study the effect of the combined use of genistein and ionizing radiation (IR) on prostate DU145 cancer cells. DU145, an androgen-independent human prostate cancer cell line, was used in the experiment. Clonogenic assay was used to compare the survival of DU145 cells after treatments with genistein alone and in combination with graded IR. Apoptosis was assayed by DNA ladder and TUNEL stain. Cell cycle alterations were observed by flow cytometry and related protein expressions by immunoblotting. Clonogenic assay demonstrated that genistein, even at low to medium concentrations, enhanced the radiosensitivity of DU145 cells. Twenty-four hours after treatment with IR and/or genistein, apoptosis was mainly seen with genistein at high concentrations and was minimally related to IR. At 72 h, apoptosis also occurred in treatment with lower concentration of genistein, especially when combined with IR. While both IR and genistein led to G2/M cell cycle arrest, combination of them further increased the DU145 cells at G2/M phase. This G2/M arrest was largely maintained at 72 h, accompanied by increasing apoptosis and hyperdiploid cell population. Cell-cycle related protein analysis disclosed biphasic changes in cyclin B1 and less dramatically cdc-2, but stably elevated p21 cip1 levels with increasing genistein concentrations. Genistein enhanced the radiosensitivity of DU145 prostate cancer cells. The mechanisms might be involved in the increased apoptosis, prolonged cell cycle arrest and impaired damage repair.
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15546019
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Quantitative (stereological) study of incomplete spermatogenic suppression induced by testosterone undecanoate injection in rats.
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To evaluate the key lesions in spermatogenesis suppressed partially by testosterone undecanoate (TU) treatment. Adult male SD rats were treated with vehicle or TU (19 mg/kg) injection (i.m.) every 15 days for 130 days. The numbers of all types of cells (nuclei) in the seminiferous tubules and the interstitial tissue were estimated using a contemporary stereological tool, the optical disector. In response to TU treatment, the numbers of non-type B spermatogonia, type B spermatogonia and late elongated spermatids per testis were reduced to 51 %, 66 % and 14 % of the controls, respectively. The conversion ratios from type B spermatogonia to early spermatocytes and pachytene spermatocytes were not significantly affected and the ratios to the later germ cell types fell to 51 % - 65 % of the controls. Less than 1.0 % of immature round spermatids were seen sloughing into the tubule lumen, 4.0 % of elongated spermatids retained in the seminiferous epithelium, and about half of the elongated spermatid nuclei appreciably malformed. Leydig cells were atrophied but their number and the peritubular myoid cell number per testis were unchanged. Double inhibition of spermatogenesis (i.e. inhibition at spermiation and spermatogonial conversion to type B spermatogonia), a scenario seen in the monkey and human following gonadotrophin withdrawal, was not sufficiently effective for a complete spermatogenic suppression in the rat after TU treatment, probably due to ineffective inhibition of the Leydig cell population and therefore the intra-testicular testosterone levels.
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15546016
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Italian Board of Orthodontics. Case Nr. 1: early treatment.
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The patient was a 9 year 3 month old female with a normodivergent skeleto-dental Class II malocclusion in the mixed dentition characterized by maxillary incisors which were both protrusive and spaced. There was by a deep Curve of Spee and a deep bite with palatal impingement. Facially, the profile was convex when compared to the esthetic line. The nasolabial angle was normal and the face was symmetrical (Figs. 1-8, Tab. I). The functional movements and T.M.J analysis were within normal limits. The periodontum and hygeine were good. Because of the patient's age, a 2 phase non extraction treatment approach was planned. In the first phase, the intent was to reduce the overbite and overjet for funtional reasons, reducing the possibility of trauma to the maxillary incisors, and control the Class II skeltodental relationships. In the second phase, Class I relationships would be obtained with a normal overjet and overbite and an improved profile. However, in reality, treatment became a 1 phase treatment because there was no interruption between the first and second phase of treatment.
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