A Novel, Orally Delivered Antibody Therapy and Its Potential to Prevent Clostridioides difficile Infection in Pre-clinical Models

Clostridioides difficile infection (CDI) is a toxin-mediated infection in the gut and a major burden on healthcare facilities worldwide. We rationalized that it would be beneficial to design an antibody therapy that is delivered to, and is active at the site of toxin production, rather than neutralizing the circulating and luminal toxins after significant damage of the layers of the intestines has occurred. Here we describe a highly potent therapeutic, OraCAb, with high antibody titers and a formulation that protects the antibodies from digestion/inactivation in the gastrointestinal tract. The potential of OraCAb to prevent CDI in an in vivo hamster model and an in vitro human colon model was assessed. In the hamster model we optimized the ratio of the antibodies against each of the toxins produced by C. difficile (Toxins A and B). The concentration of immunoglobulins that is effective in a hamster model of CDI was determined. A highly significant difference in animal survival for those given an optimized OraCAb formulation versus an untreated control group was observed. This is the first study testing the effect of oral antibodies for treatment of CDI in an in vitro gut model seeded with a human fecal inoculum. Treatment with OraCAb successfully neutralized toxin production and did not interfere with the colonic microbiota in this model. Also, treatment with a combination of vancomycin and OraCAb prevented simulated CDI recurrence, unlike vancomycin therapy alone. These data demonstrate the efficacy of OraCAb formulation for the treatment of CDI in pre-clinical models

Validity of self reported male balding patterns in epidemiological studies

BACKGROUND: Several studies have investigated the association between male pattern baldness and disease such as prostate cancer and cardiovascular disease. Limitations in the lack of standardized instruments to measure male pattern baldness have resulted in researchers measuring balding patterns in a variety of ways. This paper examines the accuracy and reliability of assessment of balding patterns by both trained observers and men themselves, using the Hamilton-Norwood classification system. METHODS: An observational study was carried out in Western Australia with 105 male volunteers aged between 30 and 70 years. Participants completed a short questionnaire and selected a picture that best represented their balding pattern. Two trained data collectors also independently assessed the participant's balding pattern using the same system and the men's self assessment was compared with the trained observer's assessment. In a substudy, observers assessed the balding pattern in a photo of the man aged 35 years while the man independently rated his balding at that age. RESULTS: Observers were very reliable in their assessment of balding pattern (85% exact agreement, κ = 0.83). Compared to trained observers, men were moderately accurate in their self-assessment of their balding status (48–55% exact agreement, κ = 0.39–0.46). For the substudy the exact agreement between the men and the observers was 67% and the agreement within balding groups was 87%. CONCLUSIONS: We recommend that male balding patterns be assessed by trained personnel using the Hamilton-Norwood classification system. Where the use of trained personnel is not feasible, men's self assessment both currently and retrospectively has been shown to be adequate

The role of receptivity in the courtship behavior of Podocnemis erythrocephala in captivity

The courtship behavior of Podocnemis erythrocephala (Red-headed Amazon River Turtle) in captivity was studied to examine female receptivity and male response to female rejection. We observed 20 females and 39 males in 150 sessions (3–6 h/day for a total of 450 h). In 36% of the trials, there was no interaction between males and females, and 20% of the trials resulted in copulations. All males introduced into tanks approached females, and eventually there was aggression among the males. In 48% of the experiments, females also searched for or approached males. When males initially approached females, they either accepted the male’s advances (14%), rejected the male passively (38%), or rejected the male aggressively (48%). In 86% of the cases where males were rejected, 4% attempted to approach females again, and in 51% they were ultimately successful

The Use of Twitter to Track Levels of Disease Activity and Public Concern in the U.S. during the Influenza A H1N1 Pandemic

Twitter is a free social networking and micro-blogging service that enables its millions of users to send and read each other's “tweets,” or short, 140-character messages. The service has more than 190 million registered users and processes about 55 million tweets per day. Useful information about news and geopolitical events lies embedded in the Twitter stream, which embodies, in the aggregate, Twitter users' perspectives and reactions to current events. By virtue of sheer volume, content embedded in the Twitter stream may be useful for tracking or even forecasting behavior if it can be extracted in an efficient manner. In this study, we examine the use of information embedded in the Twitter stream to (1) track rapidly-evolving public sentiment with respect to H1N1 or swine flu, and (2) track and measure actual disease activity. We also show that Twitter can be used as a measure of public interest or concern about health-related events. Our results show that estimates of influenza-like illness derived from Twitter chatter accurately track reported disease levels

Presence of HIF-1 and related genes in normal mucosa, adenomas and carcinomas of the colorectum

Expression of the transcription factor hypoxia-inducible factor 1 (HIF-1), which plays a key role in cellular adaptation to hypoxia, was investigated in normal colorectal mucosa (ten), adenomas (61), and carcinomas (23). Tissue samples were analyzed for HIF-1α, its upstream regulators, von Hippel–Lindau factor, AKT, and mammalian target of rapamycin (mTOR) and its downstream targets glucose transporter 1 (GLUT1), carbonic anhydrase IX, stromal-cell-derived factor 1 (SDF-1) by immunohistochemistry. In normal colorectal mucosa, HIF-1α was observed in almost all nuclei of surface epithelial cells, probably secondary to a gradient of oxygenation, as indicated by pimonidazole staining. The same staining pattern was present in 87% of adenomas. In carcinomas, HIF-1α was present predominantly around areas of necrosis (78%). Active AKT and mTOR, were present in all adenomas, carcinomas, and in normal colorectal mucosa. GLUT1 and SDF-1 were present in the normal surface epithelium of all adenoma cases, whereas in the carcinoma GLUT1 was located around necrotic regions and SDF-1 was present in all epithelial cells. In conclusion, HIF-1α appears to be physiologically expressed in the upper part of the colorectal mucosa. The present observations support that upregulation of HIF-1α and its downstream targets GLUT1 and SDF-1 in colorectal adenomas and carcinomas may be due to hypoxia, in close interaction with an active phosphatidylinositol 3-kinases–AKT–mTOR pathway

Informed consent for MRI and fMRI research: Analysis of a sample of Canadian consent documents

<p>Abstract</p> <p>Background</p> <p>Research ethics and the measures deployed to ensure ethical oversight of research (e.g., informed consent forms, ethics review) are vested with extremely important ethical and practical goals. Accordingly, these measures need to function effectively in real-world research and to follow high level standards.</p> <p>Methods</p> <p>We examined approved consent forms for Magnetic Resonance Imaging (MRI) and functional Magnetic Resonance Imaging (fMRI) studies approved by Canadian research ethics boards (REBs).</p> <p>Results</p> <p>We found evidence of variability in consent forms in matters of physical and psychological risk reporting. Approaches used to tackle the emerging issue of incidental findings exposed extensive variability between and within research sites.</p> <p>Conclusion</p> <p>The causes of variability in approved consent forms and studies need to be better understood. However, mounting evidence of administrative and practical hurdles within current ethics governance systems combined with potential sub-optimal provision of information to and protection of research subjects support other calls for more scrutiny of research ethics practices and applicable revisions.</p

Occurrence, Risk Factors, Prognosis and Prevention of Swimming-Induced Pulmonary Oedema: a Systematic Review

Background: Swimming-induced pulmonary oedema (SIPE) can affect people with no underlying health problems,but may be life threatening and is poorly understood. The aim of this systematic review was to synthesise the evidence on SIPE incidence, prevalence, risk factors, short- and long-term outcomes, recurrence and effectiveness of interventions to prevent recurrences. Methods: We carried out a literature search using bibliographic databases and reference lists. Risk of bias was assessed by adapting existing quality assessment tools including those developed by the National Heart Lung and Blood Institute. Results: Nine studies met the inclusion criteria. Quantitative synthesis was not possible because of study heterogeneity. Five studies, which differed from each other in case definition, swimming environment, population characteristics and denominators, reported an incidence of 0.01% of UK triathlons raced over 5 years in unspecified swimming environments(one study, not fully reported, of men and women of unspecified age); 0.5% of river races swum over 3 days in Sweden(one study,of men and women up to the age of 70);and 1.8–26.7% of time trials in the sea around Israel (three studies of male teenage military trainees). One study reported that 1.4% of triathletes in the USA had experienced SIPE. One study found that hypertension, female sex, fish oil use, long course distance and another lower initial lung volumes and flows were risk factors for SIPE. A third study reported that higher mean pulmonary artery pressures and pulmonary artery wedge pressures, and lower tidal volumes were associated with SIPE. Three studies suggested that SIPE symptoms usually resolve within 24 h, although a restrictive deficit in lung function persisted for a week in one small study. We found no studies that reported deaths from SIPE. The single small study of longer-term outcomes reported no difference between affected and unaffected swimmers. Two studies suggested that around 30% of people report recurrences of SIPE. Two very small uncontrolled studies of the effect of sildenafil for recurrence prevention were inconclusive. Conclusions: SIPE may be an important public health problem affecting the growing number of recreational open water swimmers. Further research should clarify the frequency of SIPE among recreational open water swimmers, confirm reported risk factors and explore others, explore long-term consequences and test interventions to prevent recurrence

Prostate cancer and body size at different ages: an Italian multicentre case–control study

We investigated the influence of anthropometric measures at diagnosis and at different ages on prostate cancer risk using an Italian multicentre case-control study conducted between 1991 and 2002 of 1294 histologically confirmed cases and 1451 controls admitted to the same network of hospitals for acute non-neoplastic conditions. Height, weight, body mass index (BMI), waist-to-hip ratio, lean body mass 1 year before diagnosis/interview were not significantly associated with risk. However, a positive association with high BMI at age 30 years was found (odds ratio=1.2 for BMI> or =24.7 vs <22.7) and: for less differentiated prostate cancer, with BMI 1 year before diagnosis/interview. This study supports possible relationships between high body mass in young adulthood, and a tendency to high weight throughout adult life, and the risk of prostate cancer

MAGI-1 Modulates AMPA Receptor Synaptic Localization and Behavioral Plasticity in Response to Prior Experience

It is well established that the efficacy of synaptic connections can be rapidly modified by neural activity, yet how the environment and prior experience modulate such synaptic and behavioral plasticity is only beginning to be understood. Here we show in C. elegans that the broadly conserved scaffolding molecule MAGI-1 is required for the plasticity observed in a glutamatergic circuit. This mechanosensory circuit mediates reversals in locomotion in response to touch stimulation, and the AMPA-type receptor (AMPAR) subunits GLR-1 and GLR-2, which are required for reversal behavior, are localized to ventral cord synapses in this circuit. We find that animals modulate GLR-1 and GLR-2 localization in response to prior mechanosensory stimulation; a specific isoform of MAGI-1 (MAGI-1L) is critical for this modulation. We show that MAGI-1L interacts with AMPARs through the intracellular domain of the GLR-2 subunit, which is required for the modulation of AMPAR synaptic localization by mechanical stimulation. In addition, mutations that prevent the ubiquitination of GLR-1 prevent the decrease in AMPAR localization observed in previously stimulated magi-1 mutants. Finally, we find that previously-stimulated animals later habituate to subsequent mechanostimulation more rapidly compared to animals initially reared without mechanical stimulation; MAGI-1L, GLR-1, and GLR-2 are required for this change in habituation kinetics. Our findings demonstrate that prior experience can cause long-term alterations in both behavioral plasticity and AMPAR localization at synapses in an intact animal, and indicate a new, direct role for MAGI/S-SCAM proteins in modulating AMPAR localization and function in the wake of variable sensory experience

Dicer Is Associated with Ribosomal DNA Chromatin in Mammalian Cells

Background: RNA silencing is a common term for pathways utilizing small RNAs as sequence-specific guides to repress gene expression. Components of the RNA silencing machinery are involved in different aspects of chromatin function in numerous organisms. However, association of RNA silencing with chromatin in mammalian cells remains unclear. Methodology/Principal Findings: Immunostaining of mitotic chromosomes with antibodies visualizing either endogenous or ectopically expressed Dicer in mammalian cells revealed association of the protein with ribosomal DNA (rDNA) repeats. Chromatin immunoprecipitations and bisulfite sequencing experiments indicated that Dicer is associated with transcribed regions of both active and silenced genes in rDNA arrays of interphase chromosomes. Metabolic labeling of the mouse embryonic stem (ES) cells lacking Dicer did not reveal apparent defect in rRNA biogenesis though pre-rRNA synthesis in these cells was decreased, likely as a consequence of their slower growth caused by the loss of miRNAs. We analyzed in detail chromatin structure of rDNA but did not find any epigenetic changes at rDNA loci in Dicer 2/2 ES cells. Instead, we found that rDNA methylation is rather low in primary tissues, contrasting with rDNA methylation patterns in transformed cell lines. Conclusion/Significance: We found that Dicer, a key component of RNA silencing pathways, can be detected in association with rDNA chromatin in mammalian cells. The role of this particular localization of Dicer is not readily apparent since th