Showing papers by "Tufts University published in 2008"

Genome-wide association studies for complex traits: consensus, uncertainty and challenges

Abstract: The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.

Fission and selective fusion govern mitochondrial segregation and elimination by autophagy

Abstract: Accumulation of depolarized mitochondria within β-cells has been associated with oxidative damage and development of diabetes. To determine the source and fate of depolarized mitochondria, individual mitochondria were photolabeled and tracked through fusion and fission. Mitochondria were found to go through frequent cycles of fusion and fission in a ‘kiss and run' pattern. Fission events often generated uneven daughter units: one daughter exhibited increased membrane potential (Δψm) and a high probability of subsequent fusion, while the other had decreased membrane potential and a reduced probability for a fusion event. Together, this pattern generated a subpopulation of non-fusing mitochondria that were found to have reduced Δψm and decreased levels of the fusion protein OPA1. Inhibition of the fission machinery through DRP1K38A or FIS1 RNAi decreased mitochondrial autophagy and resulted in the accumulation of oxidized mitochondrial proteins, reduced respiration and impaired insulin secretion. Pulse chase and arrest of autophagy at the pre-proteolysis stage reveal that before autophagy mitochondria lose Δψm and OPA1, and that overexpression of OPA1 decreases mitochondrial autophagy. Together, these findings suggest that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagy.

Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes

Abstract: Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms Recent reviews have described the range of assays that have been used for this purpose(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi) Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response

A quantitative analysis of kinase inhibitor selectivity.

Abstract: Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

Identification of RIP1 kinase as a specific cellular target of necrostatins.

Abstract: Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.

Systematic Review of the Empirical Evidence of Study Publication Bias and Outcome Reporting Bias

Abstract: Background The increased use of meta-analysis in systematic reviews of healthcare interventions has highlighted several types of bias that can arise during the completion of a randomised controlled trial. Study publication bias has been recognised as a potential threat to the validity of meta-analysis and can make the readily available evidence unreliable for decision making. Until recently, outcome reporting bias has received less attention.

Cognitive Behavioral Therapy, Sertraline, or a Combination in Childhood Anxiety

Abstract: Background Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in treating these disorders, little is known about their relative or combined efficacy. Methods In this randomized, controlled trial, we assigned 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia to receive 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. We administered categorical and dimensional ratings of anxiety severity and impairment at baseline and at weeks 4, 8, and 12. Results The percentages of children who were rated as very much or much improved on the Clinician Global Impression–Improvement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo (23.7%). Combination therapy was superior to both monotherapies (P<0.001). Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline. Conclusions Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate. (ClinicalTrials.gov number, NCT00052078.)

Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics

Abstract: Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this first of 5 sections of the guidelines of care for psoriasis, we discuss the classification of psoriasis; associated comorbidities including autoimmune diseases, cardiovascular risk, psychiatric/psychologic issues, and cancer risk; along with assessment tools for skin disease and quality-of-life issues. Finally, we will discuss the safety and efficacy of the biologic treatments used to treat patients with psoriasis.

Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy.

Abstract: The phenotypic and functional differences between cells that initiate human breast tumors (cancer stem cells) and those that comprise the tumor bulk are difficult to study using only primary tumor tissue. We embarked on this study hypothesizing that breast cancer cell lines would contain analogous hierarchical differentiation programs to those found in primary breast tumors. Eight human breast cell lines (human mammary epithelial cells, and MCF10A, MCF7, SUM149, SUM159, SUM1315 and MDA.MB.231 cells) were analyzed using flow cytometry for CD44, CD24, and epithelial-specific antigen (ESA) expression. Limiting dilution orthotopic injections were used to evaluate tumor initiation, while serial colony-forming unit, reconstitution and tumorsphere assays were performed to assess self-renewal and differentiation. Pulse-chase bromodeoxyuridine (5-bromo-2-deoxyuridine [BrdU]) labeling was used to examine cell cycle and label-retention of cancer stem cells. Cells were treated with paclitaxol and 5-fluorouracil to test selective resistance to chemotherapy, and gene expression profile after chemotherapy were examined. The percentage of CD44+/CD24- cells within cell lines does not correlate with tumorigenicity, but as few as 100 cells can form tumors when sorted for CD44+/CD24-/low/ESA+. Furthermore, CD44+/CD24-/ESA+ cells can self-renew, reconstitute the parental cell line, retain BrdU label, and preferentially survive chemotherapy. These data validate the use of cancer cell lines as models for the development and testing of novel therapeutics aimed at eradicating cancer stem cells.

Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.

Abstract: In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.

Evaluation of networks of randomized trials.

Abstract: Randomized trials may be designed and interpreted as single experiments or they may be seen in the context of other similar or relevant evidence. The amount and complexity of available randomized evidence vary for different topics. Systematic reviews may be useful in identifying gaps in the existing randomized evidence, pointing to discrepancies between trials, and planning future trials. A new, promising, but also very much debated extension of systematic reviews, mixed treatment comparison (MTC) meta-analysis, has become increasingly popular recently. MTC meta-analysis may have value in interpreting the available randomized evidence from networks of trials and can rank many different treatments, going beyond focusing on simple pairwise-comparisons. Nevertheless, the evaluation of networks also presents special challenges and caveats. In this article, we review the statistical methodology for MTC meta-analysis. We discuss the concept of inconsistency and methods that have been proposed to evaluate it as well as the methodological gaps that remain. We introduce the concepts of network geometry and asymmetry, and propose metrics for the evaluation of the asymmetry. Finally, we discuss the implications of inconsistency, network geometry and asymmetry in informing the planning of future trials.

Epidemiology of Methicillin-Resistant Staphylococcus aureus

Abstract: The frequency of methicillin-resistant Staphylococcus aureus (MRSA) infections continues to grow in hospital-associated settings and, more recently, in community settings in the United States and globally. The increase in the incidence of infections due to S. aureus is partially a consequence of advances in patient care and also of the pathogen's ability to adapt to a changing environment. Infection due to S. aureus imposes a high and increasing burden on health care resources. A growing concern is the emergence of MRSA infections in patients with no apparent risk factors. MRSA infection in community settings involves considerable morbidity and mortality, as does nosocomial MRSA infection. For community-associated MRSA, person-to-person transmission has been reported, and several factors have been shown to predict disease. We examine the trends in both nosocomial and community-associated MRSA infections and explore recent studies of the mechanisms that allow S. aureus to become resistant to currently available drugs.

Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: Overview and guidelines of care for treatment with an emphasis on the biologics

Abstract: Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this second of 5 sections of the guidelines of care for psoriasis, we give an overview of psoriatic arthritis including its cardinal clinical features, pathogenesis, prognosis, classification, assessment tools used to evaluate psoriatic arthritis, and the approach to treatment. Although patients with mild to moderate psoriatic arthritis may be treated with nonsteroidal anti-inflammatory drugs and/or intra-articular steroid injections, the use of disease-modifying antirheumatic drugs, particularly methotrexate, along with the biologic agents, are considered the standard of care in patients with more significant psoriatic arthritis. We will discuss the use of disease-modifying antirheumatic drugs and the biologic therapies in the treatment of patients with moderate to severe psoriatic arthritis.

Advancing Engineering Education in P-12 Classrooms

Abstract: Engineering as a profession faces the challenge of making the use of technology ubiquitous and transparent in society while at the same time raising young learners' interest and understanding of how technology works. Educational efforts in science, technology, engineering, and mathematics (i.e., STEM disciplines) continue to grow in pre-kindergarten through 12th grade (P-12) as part of addressing this challenge. This article explores how engineering education can support acquisition of a wide range of knowledge and skills associated with comprehending and using STEM knowledge to accomplish real world problem solving through design, troubleshooting, and analysis activities. We present several promising instructional models for teaching engineering in P-12 classrooms as examples of how engineering can be integrated into the curriculum. While the introduction of engineering education into P-12 classrooms presents a number of opportunities for STEM learning, it also raises issues regarding teacher knowledge and professional development, and institutional challenges such as curricular standards and high-stakes assessments. These issues are considered briefly with respect to providing direction for future research and development on engineering in P-12.

Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation

Abstract: BACKGROUND Several approaches are available for evaluating heterogeneity in meta-analysis. Sensitivity analyses are often used, but these are often implemented in various non-standardized ways. METHODS We developed and implemented sequential and combinatorial algorithms that evaluate the change in between-study heterogeneity as one or more studies are excluded from the calculations. The algorithms exclude studies aiming to achieve either the maximum or the minimum final I(2) below a desired pre-set threshold. We applied these algorithms in databases of meta-analyses of binary outcome and >/=4 studies from Cochrane Database of Systematic Reviews (Issue 4, 2005, n = 1011) and meta-analyses of genetic associations (n = 50). Two I(2) thresholds were used (50% and 25%). RESULTS Both algorithms have succeeded in achieving the pre-specified final I(2) thresholds. Differences in the number of excluded studies varied from 0% to 6% depending on the database and the heterogeneity threshold, while it was common to exclude different specific studies. Among meta-analyses with initial I(2) > 50%, in the large majority [19 (90.5%) and 208 (85.9%) in genetic and Cochrane meta-analyses, respectively] exclusion of one or two studies sufficed to decrease I(2) 25%, in most cases [16 (57.1%) and 382 (81.3%), respectively) exclusion of one or two studies sufficed to decrease heterogeneity even <25%. The number of excluded studies correlated modestly with initial estimated I(2) (correlation coefficients 0.52-0.68 depending on algorithm used). CONCLUSIONS The proposed algorithms can be routinely applied in meta-analyses as standardized sensitivity analyses for heterogeneity. Caution is needed evaluating post hoc which specific studies are responsible for the heterogeneity.

Shape and Crystal-Plane Effects of Nanoscale Ceria on the Activity of Au-CeO2 Catalysts for the Water–Gas Shift Reaction†

Abstract: The water–gas shift (WGS) reaction (CO+H2OQCO2+H2) plays an important role in fuel processing for polymer electrolyte membrane (PEM) fuel-cell applications. The hydrogen in the reformate gas is upgraded by removal of the carbon monoxide, which is a strong poison of the anode catalysts in current PEM fuel cells. Active shift catalysts that are also stable under the operating conditions of practical fuel-cell systems are under intense study, and nanostructured Au-CeO2, first reported by Fu et al. as a promising lowtemperature shift catalyst, holds a prominent position. This catalyst exploits the strong interaction of ceria with finely dispersed and stabilized gold atoms and clusters on the surface of ceria. Gold nanoparticles and clusters that interact strongly with oxide supports were first described by Haruta et al. to be extremely active CO oxidation catalysts. Numerous studies since then have reaffirmed the activity of well-dispersed gold for CO oxidation and many other reactions. While a full mechanism of this catalytic process still needs to be established, even for the simplest of these reactions (CO oxidation), a careful investigation of the reported strong metal–support interaction through structural studies may provide further mechanistic insights as well as rationalize the design of practical catalysts. For the WGS reaction on Au-CeO2, the importance of nanoscale ceria as a support that stabilizes active gold species has been demonstrated recently. Hydrolysis methods for the synthesis of ceria nanocrystals have proven to be powerful for controlling particle size and crystal shape. For example, Yan et al. have obtained single-crystalline CeO2 nanopolyhedra ({111} and {100}), nanorods ({110} and {100}), and nanocubes ({100}) by hydrolysis of cerium(III) salts, combined with a hydrothermal treatment, and have further found that oxygen storage takes place both at the surface and in the bulk for nanorods and nanocubes but is restricted to the surface for nanopolyhedra, just like its bulk ceria counterpart. Trovarelli et al. have studied the rearrangement of CeO2 crystallites under airaging and the exposure of more reactive {100} surfaces for CO oxidation. Very little is known for Au-CeO2 composite polycrystalline nanomaterials with respect to the shape/crystal plane effect of CeO2 on the gold species< activity/stabilization as highly active catalysts for the WGS reaction. Herein, we present activity correlations with the shape (rod, cube, polyhedron) and crystal plane of nanoscale ceria as a support for gold catalysts for this reaction. The interaction between deposited gold and different crystal orientations is investigated at ambient pressure andmonitored by several analytical techniques, including transmission electron microscopy (TEM), high-resolution TEM (HRTEM), X-ray photoelectron spectroscopy (XPS), and temperature-programmed reduction by hydrogen (H2-TPR). Figure 1 depicts our two-step preparation process, which includes hydrothermal synthesis of ceria nanorods, nano-

Effect of Pharmacotherapy on Rate of Decline of Lung Function in Chronic Obstructive Pulmonary Disease Results from the TORCH Study

Abstract: Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function. No drug has been shown conclusively to reduce this decline. Objectives :I n apost hoc analysis of the Toward a Revolution in COPD Health (TORCH) study, we investigated the effects of combined salmeterol 50 mg plus fluticasone propionate 500 mg, either component alone or placebo, on the rate of post-bronchodilator FEV1 decline in patients with moderate or severe COPD. Methods: A randomized, double-blind, placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries. Of 6,112 patients from the efficacy population, 5,343 were included in this analysis. Measurements and Main Results: Spirometry was measured every 24 weeks for 3 years. There were 26,539 on-treatment observations. The adjusted rate of decline in FEV1 was 55 ml/year for placebo, 42 ml/year for salmeterol, 42 ml/year for fluticasone propionate, and 39 ml/year for salmeterol plus fluticasone propionate. Salmeterol plus fluticasone propionate reduced the rate of FEV1 decline by 16 ml/ year compared with placebo (95% confidence interval [CI], 7–25;P , 0.001). The difference was smaller for fluticasone propionate and salmeterol compared with placebo (13 ml/year; 95% CI, 5–22; P 5 0.003). Rates of decline were similar among the active treatment arms. FEV1 declined faster in current smokers and patients with a lower body mass index, and varied between world regions. Patients who exacerbated more frequently had a faster FEV1 decline. Conclusions: Pharmacotherapy with salmeterol plus fluticasone propionate, or the components, reduces the rate of decline of FEV1 in patients with moderate-to-severe COPD, thus slowing disease progression. Clinical trial (GSK Study Code SCO30003) registered with www. clinicaltrials.gov (NCT00268216).

Effect of Clopidogrel on Early Failure of Arteriovenous Fistulas for Hemodialysis: A Randomized Controlled Trial

Abstract: Context The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. Objective To determine whether clopidogrel reduces early failure of hemodialysis fistulas. Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. Intervention Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. Main Outcome Measures The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. Results Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). Conclusion Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119

Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients

Abstract: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8(+) effector T cells to FoxP3(+) regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.

Reality-based interaction: a framework for post-WIMP interfaces

Abstract: We are in the midst of an explosion of emerging human-computer interaction techniques that redefine our understanding of both computers and interaction. We propose the notion of Reality-Based Interaction (RBI) as a unifying concept that ties together a large subset of these emerging interaction styles. Based on this concept of RBI, we provide a framework that can be used to understand, compare, and relate current paths of recent HCI research as well as to analyze specific interaction designs. We believe that viewing interaction through the lens of RBI provides insights for design and uncovers gaps or opportunities for future research.

Bile Salts and Glycine as Cogerminants for Clostridium difficile Spores

Abstract: Spore formation by Clostridium difficile is a significant obstacle to overcoming hospital-acquired C. difficile-associated disease. Spores are resistant to heat, radiation, chemicals, and antibiotics, making a contaminated environment difficult to clean. To cause disease, however, spores must germinate and grow out as vegetative cells. The germination of C. difficile spores has not been examined in detail. In an effort to understand the germination of C. difficile spores, we characterized the response of C. difficile spores to bile. We found that cholate derivatives and the amino acid glycine act as cogerminants. Deoxycholate, a metabolite of cholate produced by the normal intestinal flora, also induced germination of C. difficile spores but prevented the growth of vegetative C. difficile. A model of resistance to C. difficile colonization mediated by the normal bacterial flora is proposed.

Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy

Abstract: Residual viremia can be detected in most HIV-1-infected patients on antiretroviral therapy despite suppression of plasma RNA to /=1 copy per ml), and all patients had at least one sample with detectable viremia. A nonlinear mixed effects model revealed a biphasic decline in plasma RNA levels occurring over weeks 60 to 384: an initial phase of decay with a half-life of 39 weeks and a subsequent phase with no perceptible decay. The level of pretherapy viremia extrapolated for each phase of decay was significantly correlated with total baseline viremia for each patient (R(2) = 0.27, P = 0.001 and R(2) = 0.19, P < 0.005, respectively), supporting a biological link between the extent of overall baseline viral infection and the infection of long-lived reservoirs. These data suggest that low-level persistent viremia appears to arise from at least two cell compartments, one in which viral production decays over time and a second in which viral production remains stable for at least 7 years.

Consensus Statement on the Diagnosis and Treatment of Children with Idiopathic Short Stature: A Summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop

Abstract: Objective: Our objective was to summarize important advances in the management of children with idiopathic short stature (ISS). Participants: Participants were 32 invited leaders in the field. Evidence: Evidence was obtained by extensive literature review and from clinical experience. Consensus: Participants reviewed discussion summaries, voted, and reached a majority decision on each document section. Conclusions: ISS is defined auxologically by a height below −2 sd score (SDS) without findings of disease as evident by a complete evaluation by a pediatric endocrinologist including stimulated GH levels. Magnetic resonance imaging is not necessary in patients with ISS. ISS may be a risk factor for psychosocial problems, but true psychopathology is rare. In the United States and seven other countries, the regulatory authorities approved GH treatment (at doses up to 53 μg/kg·d) for children shorter than −2.25 SDS, whereas in other countries, lower cutoffs are proposed. Aromatase inhibition increases predicte...