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Articles by Fraser Young in JoVE

 JoVE Bioengineering

Electric Field-controlled Directed Migration of Neural Progenitor Cells in 2D and 3D Environments

1School of Dentistry, Cardiff Institute of Tissue Engineering & Repair, Cardiff University, 2Shandong Qianfoshan Hospital, Shandong University School of Medicine, 3Dermatology and Ophthalmology Research, Institute for Regenerative Cures, University of California at Davis


JoVE 3453

This protocol demonstrates methods used to establish 2D and 3D environments in custom-designed electrotactic chambers, which can track cells in vivo/ex vivo using time-lapse recording at the single cell level, in order to investigate galvanotaxis/electrotaxis and other cellular responses to direct current (DC) electric fields (EFs).

Other articles by Fraser Young on PubMed

Validity of a Reactive Agility Test for Australian Football

To study the validity of a video-based reactive agility test in Australian footballers.

Canadian Initiatives to Prevent Hypertension by Reducing Dietary Sodium

Hypertension is the leading risk for premature death in the world. High dietary sodium is an important contributor to increased blood pressure and is strongly associated with other important diseases (e.g., gastric cancer, calcium containing kidney stones, osteoporosis, asthma and obesity). The average dietary sodium intake in Canada is approximately 3400 mg/day. It is estimated that 30% of hypertension, more than 10% of cardiovascular events and 1.4 billion dollars/year in health care expenses are caused by this high level of intake in Canada. Since 2006, Canada has had a focused and evolving effort to reduce dietary sodium based on actions from Non Governmental Organizations (NGO), and Federal and Provincial/Territorial Government actions. NGOs initiated Canadian sodium reduction programs by developing a policy statement outlining the health issue and calling for governmental, NGO and industry action, developing and disseminating an extensive health care professional education program including resources for patient education, developing a public awareness campaign through extensive media releases and publications in the lay press. The Federal Government responded by striking a Intersectoral Sodium Work Group to develop recommendations on how to implement Canada's dietary reference intake values for dietary sodium and by developing timelines and targets for foods to be reduced in sodium, assessing key research gaps with funding for targeted dietary sodium based research, developing plans for public education and for conducting evaluation of the program to reduce dietary sodium. While food regulation is a Federal Government responsibility Provincial and Territorial governments indicated reducing dietary sodium needed to be a priority. Federal and Provincial Ministers of Health have endorsed a target to reduce the average consumption of sodium to 2300 mg/day by 2016 and the Deputy Ministers of Health have tasked a joint committee to review the recommendations of the Sodium Work Group and report back to them.

Mobile Health for Drug Dose Optimisation

Mobile health monitoring in the management of long term conditions has potential benefits for patient care, especially when coupled with active adjustment of medication dosage. We report studies of patient-led self-titration of oral glucose lowering medication (OGLM) and insulin in type 2 diabetes, and dose adjustments (including dose increases) in oral chemotherapy for metastatic colorectal or breast cancer. Monitoring compliance was high in each case, and the feasibility of patients self-titrating OGLM or insulin following an agreed treatment plan was demonstrated. Chemotherapy dose increases supported by detailed toxicity profiles collected by phone have also been demonstrated.

Effects of Interelectrode Distance on the Robustness of Myoelectric Pattern Recognition Systems

Myoelectric pattern recognition control can potentially provide upper limb amputees with intuitive control of multiple prosthetic functions. However, the lack of robustness of myoelectric pattern recognition algorithms is a barrier for clinical implementation. One issue that can contribute to poor system performance is electrode shift, which is a change in the location of the electrodes with respect to the underlying muscles that occurs during donning and doffing and daily use. We investigated the effects of interelectrode distance and feature choice on system performance in the presence of electrode shift. Increasing the interelectrode distance from 2 cm to 4 cm significantly (p<0.01) improved classification accuracy in the presence of electrode shifts of up to 2 cm. In a controllability test, increasing the interelectrode distance from 2 cm to 4 cm improved the user's ability to control a virtual prosthesis in the presence of electrode shift. Use of an autoregressive feature set significantly (p<0.01) reduced sensitivity to electrode shift when compared to use of a traditional time-domain feature set.

Evaluating Acceptance of an Electronic Data Management System at a Tertiary Care Institution

This research reports on satisfaction with the introduction of an electronic document management system in a tertiary hospital environment. A buffet of training and familiarization options were offered: one-on-one training, open house, drop-in, e-learning, classroom training, and self-study. It was found that professions differ in their pattern of satisfaction with training and they also differ in their satisfaction with both the usefulness and the ease of use of the system. Satisfaction among administrators was highest and that among nurses lowest. There was an association between attendance at the open house event and satisfaction with the system.

Meeting the Four-hour Deadline in an A&E Department

Accident and emergency (A&E) departments experience a secondary peak in patient length of stay (LoS) at around four hours, caused by the coping strategies used to meet the operational standards imposed by government. The aim of this paper is to build a discrete-event simulation model that captures the coping strategies and more accurately reflects the processes that occur within an A&E department.

Why Are Some Evidence-based Care Recommendations in Chronic Obstructive Pulmonary Disease Better Implemented Than Others? Perspectives of Medical Practitioners

Clinical guidelines for management of patients with chronic obstructive pulmonary disease (COPD) include recommendations based on high levels of evidence, but gaps exist in their implementation. The aim of this study was to examine the perspectives of medical practitioners regarding implementation of six high-evidence recommendations for the management of people with COPD.

Paediatric Nurses' Knowledge and Attitudes Related to Breastfeeding and the Hospitalised Infant

Breastfeeding and breastmilk are essential to hospitalised infants and young children and paediatric nurses are required to have breastfeeding knowledge. However, few studies have investigated paediatric nurses' knowledge and attitudes towards breastfeeding. A descriptive, cross-sectional survey design was used to investigate breastfeeding knowledge, knowledge related to breastfeeding the hospitalised infant, policy and guideline awareness, and attitudes to breastfeeding. Participants demonstrated excellent breastfeeding attitudes and general knowledge but deficits in breastfeeding knowledge related to specific outcomes were identified.

Kiwisch Von Rotterau--a Pioneer of European Obstetrics, Gynecology and Gynecopathology

A Public Health Approach to the Impact of Climate Change on Health in Southern Africa - Identifying Priority Modifiable Risks

Anthropogenic climate change and anticipated adverse impacts on human health as outlined by the Intergovernmental Panel on Climate Change (IPCC) are taken as given. A conceptual model for thinking about the spectrum of climate-related health risks ranging from distal and infrastructural to proximal and behavioural and their relation to the burden of disease pattern typical of sub-Saharan Africa is provided. The model provides a tool for identifying modifiable risk factors with a view to future research, specifically into the performance of interventions to reduce the impact of climate change.

Responding to Climate Change in Southern Africa - the Role of Research

Projections show that the effects of climate change in Africa will not be uniform over the region. The region is extremely vulnerable to the impact of climate change because of poverty, a high pre-existing disease burden, fragmented health services and existing water and food insecurity. Despite the consensus that locally relevant information is necessary to inform policy and practice related to climate change, very few studies assessing the association between climate change and health in southern Africa have been conducted. More complete information is therefore urgently needed for the southern African region to estimate the health risks from projected future changes in climate.

Signaling by SHH Rescues Facial Defects Following Blockade in the Brain

The Frontonasal Ectodermal Zone (FEZ) is a signaling center in the face that expresses Sonic hedgehog (Shh) and regulates patterned growth of the upper jaw. Blocking SHH in the forebrain blocks Shh expression in the FEZ and creates malformations resembling holoprosencephaly (HPE), while inhibition of BMP signaling in the mesenchyme blocks FEZ formation and causes similar dysmorphology. Thus, the brain could regulate FEZ formation by SHH or BMP signaling, and if so, activating one of these pathways in the face might alleviate the effects of repression of SHH in the brain. We blocked SHH signaling in the brain while adding SHH or BMP between the neural and facial ectoderm of the frontonasal process. When applied early, SHH restored Shh expression in the FEZ and significantly improved shape outcomes, which contrasts with our previous experiments that showed later SHH treatments have no effect. BMP soaked beads introduced early and late caused apoptosis that exacerbated malformations. Finally, removal of Smoothened from neural crest cells did not inhibit Shh expression in the FEZ. Collectively, this work suggests that a direct, time-sensitive SHH signal from the brain is required for the later induction of Shh in the FEZ. We propose a testable model of FEZ activation and discuss signaling mediators that may regulate these interactions. Developmental Dynamics, 2011. © 2011 Wiley Periodicals, Inc.

A Systematic Review of Global Publication Trends Regarding Long-term Outcomes of ADHD

There is increased global recognition of attention deficit hyperactivity disorder (ADHD) as a serious medical condition with long-term consequences. Although originally conceived of as a childhood disorder, ADHD is being increasingly recognized in adults. Individual geographic regions may have specific interests and objectives for the study of ADHD. A systematic review of long-term outcomes (LTOs) in ADHD was conducted to evaluate research on ADHD LTOs on a global scale. Studies that were at least 2 years in duration were examined. A total of 351 studies were identified in the final analysis. We identified nine outcomes of interest and classified studies by specific geographical regions, age groups studied and study design by region and over time. Published studies of LTOs in ADHD have increased in all geographical regions over the past three decades, with a peak number of 42 publications in 2008. This rise in publications on ADHD LTOs may reflect a rise in global interest and recognition of consequences and impairment associated with ADHD. Although many world regions have published on ADHD LTOs, the majority of studies have emerged from the US and Canada, followed by Europe. While investigators in the US and Canada were predominantly interested in drug addiction as a LTO, European researchers were more interested in antisocial behavior, and Eastern Asian investigators focused on both of these LTOs as well as self-esteem. Geographical differences in the focus of ADHD LTO studies may reflect regional variations in cultural values. Proportionally fewer prospective longitudinal studies and proportionally more retrospective and cross-sectional studies have been published in more recent decades. Finally, more studies focusing on ADHD in adolescents and adults have been conducted in recent years, and particularly adolescents in Eastern Asia. These changes in basic study design may reflect an increase in the recognition that ADHD is a lifetime chronic disorder. This systematic review analysis of publication trends in ADHD LTOs reflects geographically based interests that change over time.

Assessing the Benefits and Risks of Translocations in Changing Environments: a Genetic Perspective

Translocations are being increasingly proposed as a way of conserving biodiversity, particularly in the management of threatened and keystone species, with the aims of maintaining biodiversity and ecosystem function under the combined pressures of habitat fragmentation and climate change. Evolutionary genetic considerations should be an important part of translocation strategies, but there is often confusion about concepts and goals. Here, we provide a classification of translocations based on specific genetic goals for both threatened species and ecological restoration, separating targets based on 'genetic rescue' of current population fitness from those focused on maintaining adaptive potential. We then provide a framework for assessing the genetic benefits and risks associated with translocations and provide guidelines for managers focused on conserving biodiversity and evolutionary processes. Case studies are developed to illustrate the framework.

Bumps Along the ACO Road

The success of ACOs will depend on whether they can avoid difficulties inherent in six areas: Measuring costs. Computing expected costs. Managing prevention and wellness. Managing resources per case type. Managing the direct cost of resource units and fixed costs. Addressing conflicting incentives.

Back Pain in Adolescent Athletes

Back pain in the young athlete is a common complaint and often perceived as a challenging problem. A well-directed approach will usually provide the practitioner with a higher comfort zone. The etiology of back pain in the pediatric and adolescent population is different from that of the adult population due to the presence of open physes and increased linear growth velocity. In addition, the frequency and intensity of sports participation in children continues to increase, leading to more overuse injuries. This review article will discuss the anatomy and physiology of the spine and pelvis, as well as focus on the chronic and overuse causes of back pain in the young athlete.

Leveraging EDI Files to Improve Your Revenue Cycle

Exponential Complexity of the Quantum Adiabatic Algorithm for Certain Satisfiability Problems

We determine the complexity of several constraint satisfaction problems using the quantum adiabatic algorithm in its simplest implementation. We do so by studying the size dependence of the gap to the first excited state of "typical" instances. We find that, at large sizes N, the complexity increases exponentially for all models that we study. We also compare our results against the complexity of the analogous classical algorithm WalkSAT and show that the harder the problem is for the classical algorithm, the harder it is also for the quantum adiabatic algorithm.

Transient Neonatal Diabetes with Two Novel Mutations in the KCNJ11 Gene and Response to Sulfonylurea Treatment in a Preterm Infant

Neonatal diabetes mellitus (NDM) is a rare condition that can be either transient or permanent. K(ATP) channel (Kir6.2 or SUR1) mutation, chromosome 6 abnormalities, insulin, or glucokinase gene mutations can lead to isolated NDM. Cases caused by Kir6.2 mutation usually result in permanent NDM (PNDM) rather than transient NDM (TNDM). The majority of patients with the Kir6.2 or SUR1 mutation can be successfully managed with a sulfonylurea agent, without the need for insulin. We report a preterm male with NDM having two novel missense mutations, E322A and D352H, in the KCNJ11 gene. At 2 months of age, successful transition from insulin to glibenclamide (glyburide) therapy of the patient was managed. At 5 months of age, his diabetes went in to remission.

The Prevalence of STIV C92-Like Proteins in Acidic Thermal Environments

A new type of viral-induced lysis system has recently been discovered for two unrelated archaeal viruses, STIV and SIRV2. Prior to the lysis of the infected host cell, unique pyramid-like lysis structures are formed on the cell surface by the protrusion of the underlying cell membrane through the overlying external S-layer. It is through these pyramid structures that assembled virions are released during lysis. The STIV viral protein c92 is responsible for the formation of these lysis structures. We searched for c92-like proteins in viral sequences present in multiple viral and cellular metagenomic libraries from Yellowstone National Park acidic hot spring environments. Phylogenetic analysis of these proteins demonstrates that, although c92-like proteins are detected in these environments, some are quite divergent and may represent new viral families. We hypothesize that this new viral lysis system is common within diverse archaeal viral populations found within acidic hot springs.

Infectious Diseases [2011:1]

Clinical Safety Evaluation of F(ab')(2) Antivenom (Crotalus Durissus - Bothrops Asper) Administration in Dogs

Antivenoms consisting of selective antigen binding antibody fragments, or F(ab')(2), are becoming more popular in human and veterinary medicine, owing to their preferred kinetics, tissue distribution, and removal of the Fc binding portion of IgG. Consequences of antivenom administration can include acute and delayed reactions, dependent, in part, on the antivenom's donor source, purity, and composition. This study evaluated an equine-derived polyvalent F(ab')(2) pit viper antivenom in healthy dogs of various size, age, and breed under controlled conditions. Dogs were allocated into 6 treatment groups (n = 10 per group) based on weight (3 weight groups) and dose (2 dose groups) and administered F(ab')(2) antivenom over 1 hour by IV infusion. Dogs were observed for adverse events at 3, 6, 12, and 24 hours after administration and blood was collected for CBC and serum biochemistry before and at 24 hours postadministration.

Current Knowledge and Future Research on Infant Feeding in the Context of HIV: Basic, Clinical, Behavioral, and Programmatic Perspectives

In 2008, between 129,000 and 194,000 of the 430,000 pediatric HIV infections worldwide were attributable to breastfeeding. Yet in many settings, the health, economic, and social consequences of not breastfeeding would have dire consequences for many more children. In the first part of this review we provide an overview of current knowledge about infant feeding in the context of HIV. Namely, we describe the benefits and risks of breastmilk, the evolution of recommended infant feeding modalities in high-income and low-income countries in the last two decades, and contextualize the recently revised guidelines for infant feeding in the context of HIV current knowledge. In the second section, we suggest areas for future research on the postnatal prevention of mother-to-child transmission of HIV (PMTCT) in developing and industrialized countries. We suggest two shifts in perspective. The first is to evaluate PMTCT interventions more holistically, to include the psychosocial and economic consequences as well as the biomedical ones. The second shift in perspective should be one that contextualizes postnatal PMTCT efforts in the cascade of maternal health services. We conclude by discussing basic, clinical, behavioral, and programmatic research questions pertaining to a number of PMTCT efforts, including extended postnatal ARV prophylaxis, exclusive breastfeeding promotion, counseling, breast milk pasteurization, breast milk banking, novel techniques for making breast milk safer, and optimal breastfeeding practices. We believe the research efforts outlined here will maximize the number of healthy, thriving, HIV-free children around the world.

Crushing Artifacts Resulting in Small Blue Cell Clusters That Simulate Small Cell Carcinoma

Remission in Early Rheumatoid Arthritis: Predicting Treatment Response

OBJECTIVE: Optimizing therapeutic strategies to induce remission requires an understanding of the initial features predicting remission. Currently no suitable model exists. We aim to develop a remission score using predictors of remission in early rheumatoid arthritis (RA). METHODS: We used a dataset from a UK randomized controlled trial that evaluated intensive treatment with conventional combination therapy, to develop a predictive model for 24-month remission. We studied 378 patients in the trial who received 24 months' treatment. Our model was validated using data from a UK observational cohort (Early RA Network, ERAN). A group of 194 patients was followed for 24 months. Remission was defined as 28-joint Disease Activity Score < 2.6. Logistic regression models were used to estimate the associations between remission and potential baseline predictors. RESULTS: Multivariate logistic regression analyses showed age, sex, and tender joint count (TJC) were independently associated with 24-month remission. The multivariate remission score developed using the trial data correctly classified 80% of patients. These findings were replicated using ERAN. The remission score has high specificity (98%) but low sensitivity (13%). Combining data from the trial and ERAN, we also developed a simplified remission score that showed that younger men with a TJC of 5 or lower were most likely to achieve 24-month remission. Remission was least likely in older women with high TJC. Rheumatoid factor, rheumatoid nodules, and radiographic damage did not predict remission. CONCLUSION: Remission can be predicted using a score based on age, sex, and TJC. The score is relevant in clinical trial and routine practice settings.

Outcomes of Inborn and Transported Extremely Premature Very Low Birth Weight Infants in Hawai'i

Objective:  Delivery of premature infants outside tertiary care centers is not always preventable. The aim of this study is to compare rates of survival and common morbidities in extremely premature babies transported to a level III facility versus those born at the level III center. Study Design:  Retrospective chart review was performed on all neonates born at ≤28 weeks gestation with birth weight ≤ 1500 grams who were admitted to the Newborn Intensive Care Unit at Kapi'olani Medical Center for Women and Children (KMCWC) between Jan 1, 2000 to Dec 31, 2005. Infants were divided into two groups, those born at KMCWC (Inborn) and those born at level I institutions and subsequently transported (Transport) to KMCWC. Results:  A total of 394 neonates met study criteria, 349 were inborn while 45 were transported. Survival rates were identical for both groups. However, the Transport Group survivors displayed a significantly longer mean length of stay (LOS) and higher rate of severe retinopathy of prematurity (ROP) than those in the Inborn Group (p ≤ 0.01). Conclusion:  Identical rates of survival in both groups suggests that community medical professionals are providing satisfactory care to stabilize critical neonates without reducing their chances of survival. However, increased LOS and higher rate of ROP in the transport group suggest that differences in medical management during the first few hours of life may adversely affect outcomes. © 2012 The Authors. Pediatrics International © 2012 Japan Pediatric Society.

Alcohol-associated Risks for Young Adults with Type 1 Diabetes: a Narrative Review

Aim:  To undertake a narrative review of the impact and pattern of alcohol consumption in young adults with Type 1 diabetes. Methods:  Data sources: MEDLINE, EMBASE, PsycINFO, The Cochrane Library, Web of Science, meeting abstracts of the European Association for the Study of Diabetes, the American Diabetes Association and Diabetes UK, Current Controlled Trials, ClinicalTrials.gov, UK Clinical Research Network, scrutiny of bibliographies of retrieved papers and contact with experts in the field. Inclusion criteria: relevant studies of any design of alcohol consumption and young adults with Type 1 diabetes (age 14-25 years) were included. The key outcomes were the quantity, pattern and impact of alcohol consumption, the effect on diabetes control and the effect of interventions to minimize the risks of alcohol for this population. Results:  Six articles and two conference abstracts met the inclusion criteria. There were six cross-sectional studies, one qualitative study and one within-subjects design study. Quality of studies was variable. Alcohol use amongst young adults with Type 1 diabetes was reported to be common and potentially harmful. There was a paucity of evidence on interventions to minimize the risks of alcohol in this target group. Conclusions:  Research is required to understand the social context of alcohol consumption in this population with a view to developing appropriate interventions to minimize the risks associated with its use. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Standardization of Pluripotent Stem Cell Cultures for Toxicity Testing

Introduction: Pluripotent stem cell (PSC) lines offer a unique opportunity to derive various human cell types that can be exploited for human safety assessments in vitro and as such contribute to modern mechanistically oriented toxicity testing. Areas covered: This article reviews the two major types of PSC cultures that are currently most promising for toxicological applications: human embryonic stem cell lines and human induced PSC lines. Through the review, the article explains how these cell types will improve the current safety evaluations of chemicals and will allow a more efficient selection of drug candidates. Additionally, the article discusses the important issues of maintaining PSCs as well as their differentiation efficiency. Expert opinion: The demonstration of the reliability and relevance of in vitro toxicity tests for a given purpose is mandatory for their use in regulatory toxicity testing. Given the peculiar nature of PSCs, a high level of standardization of undifferentiated cell cultures as well as of the differentiation process is required in order to ensure the establishment of robust test systems. It is, therefore, of pivotal importance to define and internationally agree on crucial parameters to judge the quality of the cellular models before enrolling them for toxicity testing.

The Role of the EBV-encoded Latent Membrane Proteins LMP1 and LMP2 in the Pathogenesis of Nasopharyngeal Carcinoma (NPC)

Although frequently expressed in EBV-positive malignancies, the contribution of the oncogenic latent membrane proteins, LMP1 and LMP2, to the pathogenesis of nasopharyngeal carcinoma (NPC) is not fully defined. As a key effector in EBV-driven B cell transformation and an established "transforming" gene, LMP1 displays oncogenic properties in rodent fibroblasts and induces profound morphological and phenotypic effects in epithelial cells. LMP1 functions as a viral mimic of the TNFR family member, CD40, engaging a number of signalling pathways that induce morphological and phenotypic alterations in epithelial cells. Although LMP2A plays an essential role in maintaining viral latency in EBV infected B cells, its role in epithelial cells is less clear. Unlike LMP1, LMP2A does not display "classical" transforming functions in rodent fibroblasts but its ability to engage a number of potentially oncogenic cell signalling pathways suggests that LMP2A can also participate in EBV-induced epithelial cell growth transformation. Here we review the effects of LMP1 and LMP2 on various aspects of epithelial cell behaviour highlighting key aspects that may contribute to the pathogenesis of NPC.

Interictal Pain in Primary Headache Syndromes

Primary headache disorders are generally characterized by the pain, time course, and associated symptoms of their attacks, but often are accompanied by milder interictal pain. Patients with chronic migraine, chronic tension-type headache, hemicrania continua, and new daily-persistent headache have constant pain more often than not. Patients with trigeminal autonomic cephalalgias such as cluster headache commonly have interictal pain as well, usually much milder and unilateral to the side of attacks. Even those with rare headache types, including hypnic headache and trigeminal neuralgia, commonly have interictal pain. This review describes the incidence of interictal pain in primary headache disorders and suggests the significance and biological meanings of this pain.

Increasing Smokers' Risk Perception Improves CT Screening Participation

Assessing Disease Severity in Pompe Disease: The Roles of a Urinary Glucose Tetrasaccharide Biomarker and Imaging Techniques

Defining disease severity in patients with Pompe disease is important for prognosis and monitoring the response to therapies. Current approaches include qualitative and quantitative assessments of the disease burden, and clinical measures of the impact of the disease on affected systems. The aims of this manuscript were to review a noninvasive urinary glucose tetrasaccharide biomarker of glycogen storage, and to discuss advances in imaging techniques for determining the disease burden in Pompe disease. The glucose tetrasaccharide, Glcα1-6Glcα1-4Glcα1-4Glc (Glc(4) ), is a glycogen-derived limit dextrin that correlates with the extent of glycogen accumulation in skeletal muscle. As such, it is more useful than traditional biomarkers of tissue damage, such as CK and AST, for monitoring the response to enzyme replacement therapy in patients with Pompe disease. Glc(4) is also useful as an adjunctive diagnostic test for Pompe disease when performed in conjunction with acid alpha-glucosidase activity measurements. Review of clinical records of 208 patients evaluated for Pompe disease by this approach showed Glc(4) had 94% sensitivity and 84% specificity for Pompe disease. We propose Glc(4) is useful as an overall measure of disease burden, but does not provide information on the location and distribution of excess glycogen accumulation. In this manuscript we also review magnetic resonance spectroscopy and imaging techniques as alternative, noninvasive tools for quantifying glycogen and detailing changes, such as fibrofatty muscle degeneration, in specific muscle groups in Pompe disease. These techniques show promise as a means of monitoring disease progression and the response to treatment in Pompe disease. © 2012 Wiley Periodicals, Inc.

Saccular Cysts: A Current Review of Characteristics and Management

OBJECTIVES/HYPOTHESIS: To review a large cohort of adult saccular cyst patients and update current management of saccular cysts. STUDY DESIGN: Retrospective review of treatment of adult patients with saccular cysts. METHODS: Medical records were reviewed of all adult patients with saccular cysts identified between July 1, 2005 and August 31, 2009 at a tertiary care voice center. RESULTS: Sixteen patients were identified. All complained of dysphonia. Saccular cysts were predominantly left-sided (62.5%). The majority were anterior (85.7%); 14.3% were combined anterior/lateral. There were no isolated lateral saccular cysts. Surgical intervention was performed in 13 patients (81%); 100% were endoscopic. No patient required an external approach. Two patients recurred (15%), both within 2 months, and were managed conservatively. CONCLUSIONS: Saccular cyst is uncommonly encountered but can cause debilitating or even life-threatening symptoms. Over time, management of these lesions has changed dramatically. With current, improved endoscopic techniques, most saccular cysts can be managed endoscopically with great success rates, often without the need for an external approach.

Inferring Expertise in Knowledge and Prediction Ranking Tasks

We apply a cognitive modeling approach to the problem of measuring expertise on rank ordering problems. In these problems, people must order a set of items in terms of a given criterion (e.g., ordering American holidays through the calendar year). Using a cognitive model of behavior on this problem that allows for individual differences in knowledge, we are able to infer people's expertise directly from the rankings they provide. We show that our model-based measure of expertise outperforms self-report measures, taken both before and after completing the ordering of items, in terms of correlation with the actual accuracy of the answers. These results apply to six general knowledge tasks, like ordering American holidays, and two prediction tasks, involving sporting and television competitions. Based on these results, we discuss the potential and limitations of using cognitive models in assessing expertise.

Agreement Between Self-report and Prescription Data in Medical Records for Pregnant Women

BACKGROUND Clinical teratology studies often rely on patient reports of medication use in pregnancy with or without other sources of information. Electronic medical records (EMRs), administrative databases, pharmacy dispensing records, drug registries, and patients' self-reports are all widely used sources of information to assess potential teratogenic effect of medications. The objective of this study was to assess comparability of self-reported and prescription medication data in EMRs for the most common therapeutic classes. METHODS The study population included 404 pregnant women prospectively recruited from five prenatal care clinics affiliated with the University of New Mexico. Self-reported information on prescription medications taken since the last menstrual period (LMP) was obtained by semistructured interviews in either English or Spanish. For validation purposes, EMRs were reviewed to abstract information on medications prescribed between the LMP and the date of the interview. Agreement was estimated by calculating a kappa (κ) coefficient, sensitivity, and specificity. RESULTS In this sample of socially-disadvantaged (i.e., 67.9% high school education or less, 48.5% no health insurance), predominantly Latina (80.4%) pregnant women, antibiotics and antidiabetic agents were the most prevalent therapeutic classes. The agreement between the two sources substantially varied by therapeutic class, with the highest level of agreement seen among antidiabetic and thyroid medications (κ ≥0.8) and the lowest among opioid analgesics (κ = 0.35). CONCLUSIONS Results indicate a high concordance between self-report and prescription data for therapeutic classes used chronically, while poor agreement was observed for medications used intermittently, on an 'as needed" basis, or in short courses. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.

Complement Factor H Genetic Variant and Age-related Macular Degeneration: Effect Size, Modifiers and Relationship to Disease Subtype

BACKGROUND: Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking. METHODS: To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry. RESULTS: In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies. CONCLUSION: The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.

Dynamic Ligand Modulation of EPO Receptor Pools, and Dysregulation by Polycythemia-Associated EPOR Alleles

Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for erythropoiesis; can modulate non-erythroid target tissues; and have been reported to affect the progression of certain cancers. Basic studies of EPOR expression and trafficking, however, have been hindered by low-level EPOR occurrence, and the limited specificity of anti-EPOR antibodies. Consequently, these aspects of EPOR biology are not well defined, nor are actions of polycythemia- associated mutated EPOR alleles. Using novel rabbit monoclonal antibodies to intracellular, PY- activated and extracellular EPOR domains, the following properties of the endogenous hEPOR in erythroid progenitors first are unambiguously defined. 1) High- Mr EPOR forms become obviously expressed only when EPO is limited. 2) EPOR-68K plus -70K species sequentially accumulate, and EPOR-70K comprises an apparent cell surface EPOR population. 3) Brefeldin A, N-glycanase and associated analyses point to EPOR-68K as a core-glycosylated intracellular EPOR pool (of modest size). 4) In contrast to recent reports, EPOR inward trafficking is shown (in UT7epo cells, and primary proerythroblasts) to be sharply ligand-dependent. Beyond this, when C-terminal truncated hEPOR-T mutant alleles as harbored by polycythemia patients are co-expressed with the wild-type EPOR in EPO-dependent erythroid progenitors, several specific events become altered. First, EPOR-T alleles are persistently activated upon EPO- challenge, yet are also subject to apparent turn-over (to low-Mr EPOR products). Furthermore, during exponential cell growth EPOR-T species become both over-represented, and hyper-activated. Interestingly, EPOR-T expression also results in an EPO dose-dependent loss of endogenous wild-type EPOR's (and, therefore, a squelching of EPOR C-terminal- mediated negative feedback effects). New knowledge concerning regulated EPOR expression and trafficking therefore is provided, together with new insight into mechanisms via which mutated EPOR-T polycythemia alleles dysregulate the erythron. Notably, specific new tools also are characterized for studies of EPOR expression, activation, action and metabolism.

CD14 Deficiency Impacts Glucose Homeostasis in Mice Through Altered Adrenal Tone

The toll-like receptors comprise one of the most conserved components of the innate immune system, signaling the presence of molecules of microbial origin. It has been proposed that signaling through TLR4, which requires CD14 to recognize bacterial lipopolysaccharide (LPS), may generate low-grade inflammation and thereby affect insulin sensitivity and glucose metabolism. To examine the long-term influence of partial innate immune signaling disruption on glucose homeostasis, we analyzed knockout mice deficient in CD14 backcrossed into the diabetes-prone C57BL6 background at 6 or 12 months of age. CD14-ko mice, fed either normal or high-fat diets, displayed significant glucose intolerance compared to wild type controls. They also displayed elevated norepinephrine urinary excretion and increased adrenal medullary volume, as well as an enhanced norepinephrine secretory response to insulin-induced hypoglycemia. These results point out a previously unappreciated crosstalk between innate immune- and sympathoadrenal- systems, which exerts a major long-term effect on glucose homeostasis.

Outcome of Smoking Cessation Counselling of HIV-positive Persons by HIV Care Physicians

OBJECTIVES: Smoking is the most prevalent modifiable risk factor for cardiovascular diseases among HIV-positive persons. We assessed the effect on smoking cessation of training HIV care physicians in counselling. METHODS: The Swiss HIV Cohort Study (SHCS) is a multicentre prospective observational database. Our single-centre intervention at the Zurich centre included a half day of standardized training for physicians in counselling and in the pharmacotherapy of smokers, and a physicians' checklist for semi-annual documentation of their counselling. Smoking status was then compared between participants at the Zurich centre and other institutions. We used marginal logistic regression models with exchangeable correlation structure and robust standard errors to estimate the odds of smoking cessation and relapse. RESULTS: Between April 2000 and December 2010, 11 056 SHCS participants had 121 238 semi-annual visits and 64 118 person-years of follow-up. The prevalence of smoking decreased from 60 to 43%. During the intervention at the Zurich centre from November 2007 to December 2009, 1689 participants in this centre had 6068 cohort visits. These participants were more likely to stop smoking [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.07-1.42; P = 0.004] and had fewer relapses (OR 0.75; 95% CI 0.61-0.92; P = 0.007) than participants at other SHCS institutions. The effect of the intervention was stronger than the calendar time effect (OR 1.19 vs. 1.04 per year, respectively). Middle-aged participants, injecting drug users, and participants with psychiatric problems or with higher alcohol consumption were less likely to stop smoking, whereas persons with a prior cardiovascular event were more likely to stop smoking. CONCLUSIONS: An institution-wide training programme for HIV care physicians in smoking cessation counselling led to increased smoking cessation and fewer relapses.

A Systematic Review of Case-mix Adjustment Models for Stroke

Objective: To identify any externally validated prognostic model for predicting outcome in unselected populations following acute stroke comprising variables feasible for collection in routine care.Data sources: Searches were run in MEDLINE, EMBASE, CINAHL, PsycInfo, AMED and ISI Web of Science with no limits on publication date or language.Review methods: Any study describing the development or external validation of a discernible prognostic model to predict any valid outcome following acute stroke was included. Papers were retained if they met pre-specified inclusion criteria identified from previous reviews and pertinent discussion papers. Data extraction focused on methodological quality of model development, generalizability and feasibility of variable collection. Model performance was examined through consideration of external validation studies.Results: Seventeen externally validated models were identified from 43 papers fulfilling inclusion criteria. Quality of studies describing model development was variable and model performance in external validation studies was generally poor. Models were generally constructed through secondary use of randomized trial or stroke database data. Prognostic variables broadly encompassed markers of stroke severity, pre-stroke function and comorbidities. One model that fulfilled the review criteria and had extensive external validation in a range of post-stroke populations was identified (the Six Simple Variables model).Conclusion: The Six Simple Variables model performed well in six external validation studies, although prediction of outcome in patients with milder strokes was less reliable. Other models identified in this review have been developed using robust methodology but comprise more complex clinical variables which may limit their utility in routine stroke care.

Patterns of Loosening of Polyethylene Keeled Glenoid Components After Shoulder Arthroplasty for Primary Osteoarthritis: Results of a Multicenter Study with More Than Five Years of Follow-up

The aim of this study was to radiographically analyze the long-term glenoid migration patterns following total shoulder arthroplasty to better understand the factors responsible for loosening.

Novel and Recurrent Non-truncating Mutations of the MITF Basic Domain: Genotypic and Phenotypic Variations in Waardenburg and Tietz Syndromes

The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.European Journal of Human Genetics advance online publication, 18 January 2012; doi:10.1038/ejhg.2011.234.

Evolution Advocate Turns to Climate

Identification of a Small Molecule Yeast TORC1 Inhibitor with a Multiplex Screen Based on Flow Cytometry

TOR (target of rapamycin) is a serine/threonine kinase, evolutionarily conserved from yeast to human, which functions as a fundamental controller of cell growth. The moderate clinical benefit of rapamycin in mTOR-based therapy of many cancers favors the development of new TOR inhibitors. Here we report a high-throughput flow cytometry multiplexed screen using five GFP-tagged yeast clones that represent the readouts of four branches of the TORC1 signaling pathway in budding yeast. Each GFP-tagged clone was differentially color-coded, and the GFP signal of each clone was measured simultaneously by flow cytometry, which allows rapid prioritization of compounds that likely act through direct modulation of TORC1 or proximal signaling components. A total of 255 compounds were confirmed in dose-response analysis to alter GFP expression in one or more clones. To validate the concept of the high-throughput screen, we have characterized CID 3528206, a small molecule most likely to act on TORC1 as it alters GFP expression in all five GFP clones in a manner analogous to that of rapamycin. We have shown that CID 3528206 inhibited yeast cell growth and that CID 3528206 inhibited TORC1 activity both in vitro and in vivo with EC(50)'s of 150 nM and 3.9 μM, respectively. The results of microarray analysis and yeast GFP collection screen further support the notion that CID 3528206 and rapamycin modulate similar cellular pathways. Together, these results indicate that the HTS has identified a potentially useful small molecule for further development of TOR inhibitors.

Total Dietary Fat and Fatty Acid Content Modifies Plasma Phospholipid Fatty Acids, Desaturase Activity Indices, and Urinary Prostaglandin E in Women

Compared with diets high in fat, low-fat diets are associated with reduced risk of cardiovascular disease. We hypothesized that a low-fat (LF) (20% fat) and an LF high-omega-3 (n-3) fatty acid diet (LFn3) (23% fat with 3% as α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid [DHA]) would enhance n-3 composition of plasma phospholipid fatty acid and reduce urinary prostaglandin E(2) (PGE(2)) relative to a high-fat diet (HF) (40% fat) and that these changes would be associated with alterations in δ5 desaturase (D5D) and δ6 desaturase (D6D) activity. Phospholipid fatty acids and urinary PGE(2) were measured, and D5D and D6D activity indices calculated in a crossover trial in 17 postmenopausal women fed each of 3 test diets (HF, LF, and LFn3) for 8-week feeding periods. Desaturase activity indices were calculated as D5D, 20:4n-6/20:3n-6, and D6D, 20:3n-6/18:2n-6. Plasma phospholipid fatty acid, α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid (DPA), DHA, and total n-3 fatty acids increased, whereas linoleic acid and arachidonic acid decreased with consumption of LFn3. The LF resulted in enhanced arachidonic acid and DHA. High fat reduced D6D, whereas both HF and LF increased D5D. Urinary PGE(2) was reduced in response to both the LF and LFn3 diets. Low-fat diets, with or without long-chain n-3 fatty acids, promote positive health effects due in part to favorable alteration of plasma phospholipid fatty acid profiles and modification in desaturase activity indices, suggesting that the type and amount of fat consumed are modifiable risk factors for the prevention of cardiovascular disease.

Should Women Get Left Ventricular Assist Device Support?: Findings from INTERMACS

BACKGROUND: -Small studies have reported women to have worse outcomes and more adverse events after implantation of mechanical circulatory support device compared to men. To further evaluate sex differences in outcome we utilized the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). METHODS AND RESULTS: -There were 401 women (pulsatile devices=78) and 1535 men (pulsatile devices=402) from 89 institutions who were prospectively entered into the INTERMACS database for primary implantation of a left ventricular assist device (LVAD) between June 23, 2006 until March 31, 2010. Extensive pre-implant data and outcome data was collected on all patients. With a mean follow-up of 7 months, 67 females (17%) died and 250 males (16%) died. There was no statistically significant sex difference in mortality for either pulsatile (p=0.82) or continuous-flow devices (p=0.95) in adjusted and unadjusted models. There were also no statistically significant sex differences with time to first infection, bleeding or device malfunction. However, female gender was associated with an increase hazard of first neurologic event (adjusted hazard ratio 1.44 [1.05-1.96], p=0.020). CONCLUSIONS: -There were no significant sex differences in mortality, time to first infection, bleeding or device malfunction with either pulsatile or continuous-flow LVADs. However, women had an increased risk of first neurologic event. For urgent/emergent mechanical support, the benefit of LVAD support likely outweighs the risk but it remains less clear for women undergoing elective LVAD implantation.

Galectin Secretion and Binding to Adult Fasciola Hepatica During Chronic Liver Fluke Infection of Sheep

Galectins are increasingly recognised as important mediators of immune homeostasis and disease regulation, but comparatively little is known about their role in parasite infection. This study investigates the interaction between two ovine galectins, galectin-11 and galectin-14, and the parasitic liver fluke, F. hepatica. Galectin-14 was found in eosinophils infiltrating the tissue surrounding infected bile ducts and secreted in the connective tissue, while galectin-11 was specifically induced in epithelial cells of bile ducts from infected sheep. Strong nuclear staining was observed for galectin-11. Both galectins were found to be secreted into the bile fluid of parasite infected sheep, and were also detected in the excretory/secretory products of adult flukes, following their removal from the ovine host. Recombinant galectin-14, but not recombinant galectin-11, was found to bind specifically to the surface tegument of adult flukes in a carbohydrate dependent manner. This study shows for the first time that both galectin-14 and galectin-11 are produced in liver tissue after chronic liver fluke infection and that they can directly interact with the parasite in the bile ducts. Galectin-11 may also be involved in epithelial cell turnover and cancerogenesis.

Activity, Expression and Genetic Variation of Canine β-Defensin 103: A Multifunctional Antimicrobial Peptide in the Skin of Domestic Dogs

The skin functions as more than a physical barrier to infection. Epithelial cells of the skin can synthesize antimicrobial peptides, including defensins, which exhibit direct antimicrobial activity. Here we characterize the expression pattern, genetic variation and activity of the major β-defensin expressed in canine skin, canine β-defensin 103 (CBD103). The gene encoding CBD103 exhibits two forms of polymorphism: a common 3-basepair deletion allele and a gene copy-number variation. Golden retrievers and Labrador retrievers were the only breeds that encoded the variant allele of CBD103, termed CBD103ΔG23. Both these breeds also exhibited a CBD103 gene copy-number polymorphism that ranged from 2 to 4 gene-copies per diploid genome. Recombinant CBD103 and CBD103ΔG23, as well as the human ortholog human β-defensin 3 (hBD3) and hBD3ΔG23, showed potent and comparable antimicrobial killing against both methicillin-susceptible and methicillin-resistant Staphylococcus pseudintermedius. Skin biopsy specimens from dogs with atopic dermatitis revealed CBD103 expression levels similar to those in healthy controls and comparable at lesional and nonlesional sites. This expression pattern in dogs differs from the previously reported reduced expression of the human ortholog in atopic dermatitis. Overall, the similarities of CBD103 and its human ortholog reported here support the notion that the domestic dog may serve as a valuable model for studying β-defensin biology in the skin.

Solid Pattern Yolk Sac Tumor: A Morphologic and Immunohistochemical Study of 52 Cases

Yolk sac tumors may exhibit numerous patterns. One that has received little attention overall, yet is not uncommon, is a solid pattern, which is especially prone to misinterpretation, usually as seminoma, in biopsy specimens from metastatic or mediastinal sites. This distinction is of critical importance as the 2 tumors are treated differently. To determine features useful in the diagnosis of solid yolk sac tumor we reviewed 52 germ cell tumors (28 testicular primaries, 21 metastases from the testis, and 3 mediastinal primaries) that had a yolk sac tumor component with foci of solid growth, defined as a sheet-like arrangement of tumor cells occupying >2 mm and with no or only rare microcysts. Solid yolk sac tumor was almost always associated with other patterns, most commonly microcystic/reticular (75%), glandular (35%), and myxoid (25%). The solid foci consisted of sheets of cells with usually abundant cytoplasm that was mostly (85%) pale to clear and frequently had intercellular basement membrane deposits (75%), rare microcysts (67%), significant nuclear pleomorphism (65%), and hyaline globules (65%). In 2 cases (4%), the cells were small with scant cytoplasm (blastema-like variant). A myxoid background (39%), lymphocytic infiltrate (17%), and an appliqué pattern (8%) were sometimes observed. On immunostaining, AE1/AE3 cytokeratin and glypican 3 provided the most intense and diffuse reactivity for solid yolk sac tumor, whereas α-fetoprotein was negative in 38%. CD117 stained 59%, whereas only rare cells in 1 case (3%) were weakly reactive for podoplanin; OCT3/4 was uniformly negative. We conclude that solid yolk sac tumor can generally be recognized by careful morphologic evaluation, especially its association with other yolk sac tumor patterns, the presence of intercellular band-like deposits of basement membrane, occasional microcysts, nuclear pleomorphism, intracellular hyaline globules, and usual absence of lymphocytes. In difficult cases a concise immunohistochemical panel consisting of AE1/AE3, glypican 3, and OCT3/4 distinguishes solid yolk sac tumor from other neoplasms. α-fetoprotein stains are commonly negative or weak and focal in solid yolk sac tumor and cannot be solely relied on for diagnosis. Common CD117 positivity in solid pattern yolk sac tumors makes it an unreliable discriminator between yolk sac tumor and seminoma.

Hidradenoma Papilliferum with Mixed Histopathologic Features of Syringocystadenoma Papilliferum and Anogenital Mammary-like Glands: Report of a Case and Review of the Literature

Hidradenoma papilliferum of the anogenital region was previously believed to originate from apocrine glands but has recently been accepted as originating from anogenital mammary-like glands. We describe a case of hidradenoma papilliferum with mixed features of syringocystadenoma papilliferum and mammary-like glands from the left labia majora of a 25-year-old woman. Histopathologically, the lesion showed an epithelial lining with apocrine secretion, and like syringocystadenoma papilliferum, the lesion extended from the epithelium as invaginations into the dermis. Adjacent to this lesion were ductal and glandular structures resembling normal mammary tissue. This review of the literature highlights the heterogeneity and complexity of lesions arising from anogenital mammary-like glands, and this case serves as further documentation of the association between anogenital mammary-like glands and hidradenoma papilliferum.

Microscale Functional Cytomics for Studying Hematologic Cancers

An important problem in translational cancer research is our limited ability to functionally characterize behaviors of primary patient cancer cells and associated stromal cell types, and relate mechanistic understanding to therapy selection. Functional analyses of primary samples face at least three major challenges: limited availability of primary samples for testing, paucity of functional information extracted from samples, and lack of functional methods accessible to many researchers. We developed a microscale cell culture platform that overcomes these limitations, especially for hematologic cancers. A key feature of the platform is the ability to compartmentalize small populations of adherent and non-adherent cells in controlled microenvironments that can better reflect physiological conditions and enable cell-cell interaction studies. Custom image analysis was developed to measure cell viability and protein subcellular localizations in single cells to provide insights into heterogeneity of cellular responses. We validated our platform by assessing viability and nuclear translocations of NF-κB and STAT3 in multiple myeloma cells exposed to different conditions including cocultured bone marrow stromal cells. We further assessed its utility by analyzing NF-κB activation in a primary chronic lymphocytic leukemia patient sample. Our platform can be applied to myriad biological questions, enabling high-content functional cytomics of primary hematologic malignancies.

STAT1-deficient Mice Spontaneously Develop Estrogen Receptor Alpha-positive Luminal Mammary Carcinomas

ABSTRACT: INTRODUCTION: Although breast cancers expressing estrogen receptor-alpha (ERalpha) and progesterone receptors (PR) are the most common form of mammary malignancy in humans, it has been difficult to develop a suitable mouse model showing similar steroid hormone responsiveness. STAT transcription factors play critical roles in mammary gland tumorigenesis, but the precise role of STAT1 remains unclear. Herein, we show that a subset of human breast cancers display reduced STAT1 expression and that mice lacking STAT1 surprisingly develop ERalpha+/PR+ mammary tumors. METHODS: We used a combination of approaches, including histological examination, gene targeted mice, gene expression analysis, tumor transplantaion, and immunophenotyping, to pursue this study. RESULTS: 45% (37/83) of human ERalpha+ and 22% (17/78) of ERalpha- breast cancers display undetectable or low levels of STAT1 expression in neoplastic cells. In contrast, STAT1 expression is elevated in epithelial cells of normal breast tissues adjacent to the malignant lesions, suggesting that STAT1 is selectively downregulated in the tumor cells during tumor progression. Interestingly, the expression levels of STAT1 in the tumor-infiltrating stromal cells remain elevated, indicating that single-cell resolution analysis of STAT1 level in primary breast cancer biopsies is necessary for accurate assessment. Female mice lacking functional STAT1 spontaneously develop mammary adenocarcinomas that comprise >90% ERalpha+/PR+ tumor cells, and depend on estrogen for tumor engraftment and progression. Phenotypic markers analyses demonstrate that STAT1-/- mammary tumors arise from luminal epithelial cells, but not myoepithelial cells. In addition, the molecular signature of the STAT1-/- mammary tumors overlaps closely to that of human luminal breast cancers. Finally, introduction of wildtype STAT1, but not a STAT1 mutant lacking the critical Tyr701 residue, into STAT1-/- mammary tumor cells results in apoptosis, demonstrating that the tumor suppressor function of STAT1 is cell-autonomous and requires its transcriptional activity. CONCLUSIONS: Our findings demonstrate that STAT1 suppresses mammary tumor formation and its expression is frequently lost during breast cancer progression. Spontaneous mammary tumors that develop in STAT1-/- mice closely recapitulate the progression, ovarian hormone responsiveness, and molecular characteristics of human luminal breast cancer, the most common subtype of human breast neoplasms, and thus represent a valuable platform for testing novel treatments and detection modalities.

Endovascular Treatment of Subclavian Artery Stenosis Associated with Vertebral Artery Pseudoaneurysm

Awareness and Knowledge of Human Papillomavirus in the Swedish Adult Population

To assess awareness and knowledge of human papillomavirus (HPV) in the adult Swedish population.

Intra-Articular Corticosteroid Injections to the Temporomandibular Joints Are Safe and Appear to Be Effective Therapy in Children With Juvenile Idiopathic Arthritis

PURPOSE: The purpose of this study was to evaluate the safety and efficacy of intra-articular corticosteroid injections (IACIs) of the temporomandibular joint (TMJ) in children with juvenile idiopathic arthritis (JIA) when administered by an oral and maxillofacial surgeon without imaging guidance. MATERIALS AND METHODS: This was a retrospective study of children with JIA, seen at a single center, who were selected based on having received IACIs of the TMJ. All subjects received the intervention, which consisted of referral to a single oral and maxillofacial surgeon for TMJ IACI with 5 to 10 mg triamcinolone hexacetonide, under general anesthesia. Primary outcomes assessed in all subjects were the safety of the procedure and efficacy as determined by the change in maximal incisal opening (MIO). In addition, a subset of 31 subjects underwent repeat magnetic resonance imaging of the TMJ, permitting analysis of the change in the acute and chronic findings of arthritis in those patients. RESULTS: Sixty-three patients (68% female) received 137 IACIs. The mean age for diagnosis of JIA was 8.5 years, and the mean age at presentation for TMJ injections was 10 years. The injections were well tolerated: only 1 patient developed the steroid complication of hypopigmentation, and none developed degeneration or ankylosis. In terms of efficacy, the mean MIO increased from 40.8 ± 0.93 to 43.5 ± 0.90 mm (P = .001); in addition, changing the unit of analysis to individual joints, in patients who underwent repeat magnetic resonance imaging examination, 51% of TMJs showed magnetic resonance imaging evidence of improvement of arthritic changes, of whom 18% had complete resolution of TMJ arthritis. CONCLUSIONS: The results indicate that IACI of the TMJ can be safely performed by experienced oral and maxillofacial surgeons without a requirement for computed tomographic guidance. In addition, these results show that IACI may be effective in the management of TMJ arthritis, although further studies are required.

Urological Leaks After Pelvic Exenterations Comparing Formation of Colonic and Ileal Conduits

BACKGROUND: The aim of this study was to assess possible risk factors for urinary leakage of a newly formed urinary conduit after a partial or total pelvic exenteration. METHODS: An analysis was conducted from prospectively collected data of patients who underwent a pelvic exenteration with conduit formation for advanced and recurrent pelvic cancer. RESULTS: Of 232 patients undergoing a pelvic exenteration, 74 (32%) had a conduit formed. Of these, 47 (64%) had an ileal conduit compared with 27 (36%) a colonic conduit. Twelve (16%) patients developed a leak, of which nine occurred within the first month. Factors associated with a conduit leak included involvement of R2 surgical margins (43%), the magnitude of the exenteration and a current cardiovascular medical history (27%). Leaks were not found to be associated with either radiotherapy or chemotherapy. The 30-day leak rate for ileal conduits was 17% (8/47) and 4% (1/27) for colonic conduits with enterocutaneous fistula only occurring in the ileal conduit group (2/47). Fistula, drained collections and sepsis occurred in 40% of ileal and 19% of colonic conduits (p < 0.01). Patients with a conduit leak had a longer length of stay (59 versus 23 days, p < 0.001). CONCLUSIONS: Urine leaks after conduit formation in association with exenterations are relatively common with a prolonged length of hospital stay. Positive surgical margins and exenterations involving all four quadrants of the pelvis were associated with higher leak rates. There was no evidence of a difference between ileal and colonic conduits and number of leaks. However colonic conduits had less total complications including sepsis, leak and pelvic collections with comparatively no complications of a small bowel fistula.

The Use of Inverse Gas Chromatography for the Study of Lactose and Pharmaceutical Materials Used in Dry Powder Inhalers

Inverse gas chromatography (IGC) is a sensitive technique for the measurement of powder surface properties, especially surface energetics. Given the importance of these characteristics to the performance of dry powder inhaler formulations (DPIs), it is unsurprising that IGC has been applied to the study of these systems. Monitoring batch-to-batch variation and the effects of processing steps are established uses of IGC in this field and the relevant studies are discussed. A less established use of IGC is for the prediction of DPI performance. Although some groups have found a negative relationship between the dispersive surface energy of one formulation component and fine particle delivery, such studies often have a number of limitations. More complex approaches have failed to produce consistent results. Further, more carefully designed, studies are required in this area. In the final section of this article, some areas for on-going research are discussed, including the need to critically assess the best method for the calculation of the specific free energy of adsorption with pharmaceutical materials.

The Effect of Including a Series of Isometric Conditioning Contractions to the Rowing Warm-up on 1000 M Rowing Ergometer Time Trial Performance

Rowing requires strength, power, and strength-endurance for optimal performance. A rowing based warm-up could be enhanced by exploiting the postactivation potentiation (PAP) phenomenon, acutely enhancing power output at the beginning of a race where it's needed most. Minimal research has investigated the effects of PAP on events of longer duration (i.e., 1000 m rowing). The purpose of this research was to investigate the effects of PAP on 1000 m rowing ergometer performance through the use of two different warm-up procedures: 1) a rowing warm-up combined with a series of isometric conditioning contractions, known as the potentiated warm-up (PW), and 2) a rowing warm-up only (NW). The isometric conditioning contractions in the PW were performed by "pulling" an immovable handle on the rowing ergometer, consisting of 5 sets of 5s (2s at submaximal intensity, and 3s at maximal intensity), with a 15s recovery between sets. The 1000 m rowing ergometer time trial was performed after each warm-up condition, whereby mean power output, mean stroke rate, and split time were assessed every 100 m. Ten Australian national level rowers served as the subjects, and performed both conditions in a counterbalanced order on separate days. The PW reduced 1000 m time by 0.8% (p > 0.05). The PW improved mean power output by 6.6% (p < 0.01) and mean stroke rate by 5.2% (p < 0.01) over the first 500 m; resulting in a reduction of 500 m time by 1.9% (p < 0.01), compared to the NW. It appears that the inclusion of isometric conditioning contractions to the rowing warm-up enhance short-term rowing ergometer performance (especially at the start of a race) to a greater extent than a rowing warm-up alone.

Sequential Genetic Change at the TP53 and Chemokine Receptor CXCR4 Locus During Transformation of Human Ovarian Surface Epithelium

Early genetic events in the development of high-grade serous ovarian cancer (HGSOC) may define the molecular basis of the profound structural and numerical instability of chromosomes in this disease. To discover candidate genetic changes we sequentially passaged cells from a karyotypically normal hTERT immortalised human ovarian surface epithelial line (IOSE25) resulting in the spontaneous formation of colonies in soft agar. Cell lines transformed ovarian surface epithelium 1 and 4 (TOSE 1 and 4) established from these colonies had an abnormal karyotype and altered morphology, but were not tumourigenic in immunodeficient mice. TOSE cells showed loss of heterozygosity (LOH) at TP53, increased nuclear p53 immunoreactivity and altered expression profile of p53 target genes. The parental IOSE25 cells contained a missense, heterozygous R175H mutation in TP53, whereas TOSE cells had LOH at the TP53 locus with a new R273H mutation at the previous wild-type TP53 allele. Cytogenetic and array CGH analysis of TOSE cells also revealed a focal genomic amplification of CXCR4, a chemokine receptor commonly expressed by HGSOC cells. TOSE cells had increased functional CXCR4 protein and its abrogation reduced epidermal growth factor receptor (EGFR) expression, as well as colony size and number. The CXCR4 ligand, CXCL12, was epigenetically silenced in TOSE cells and its forced expression increased TOSE colony size. TOSE cells had other cytogenetic changes typical of those seen in HGSOC ovarian cancer cell lines and biopsies. In addition, enrichment of CXCR4 pathway in expression profiles from HGSOC correlated with enrichment of a mutated TP53 gene expression signature and of EGFR pathway genes. Our data suggest that mutations in TP53 and amplification of the CXCR4 gene locus may be early events in the development of HGSOC, and associated with chromosomal instability.Oncogene advance online publication, 23 January 2012; doi:10.1038/onc.2011.653.

Inhibition of Androgen-responsive LNCaP Prostate Cancer Cell Tumor Xenograft Growth by Dietary Phenethyl Isothiocyanate Correlates with Decreased Angiogenesis and Inhibition of Cell Attachment

Phenethyl isothiocyanate (PEITC) is a candidate anticancer compound found in certain cruciferous vegetables. In our tumor cell xenograft model, dietary administration of PEITC (100-150 mg/kg body weight/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth. We found that dietary treatment with PEITC significantly inhibited tumor platelet/endothelial cell adhesion molecule (PECAM-1/CD31) expression, a marker of angiogenesis. By contrast, we did not find the inhibitory effects of PEITC on tumor growth to be associated with alteration of specific markers for apoptosis, cell proliferation or androgen receptor-mediated pathways. Consistent with in vivo results, PEITC exerted little effects on cell proliferation, cell cycle and androgen-dependent pathways. Interestingly, PEITC significantly attenuated LNCaP cell plating efficiency that correlated with inhibition of integrin family proteins integrin β1, α2 and α6 mRNA expression. Thus, PEITC may be a dietary factor that inhibits androgen-responsive prostate tumor growth indirectly by selectively targeting factors involved in the tumor microenvironment.

Serial MRI and CSF Analysis in a Dog Treated with Intrathecal Amphotericin B for Protothecosis

A 3 yr old female spayed English setter mixed-breed dog presented with diarrhea, weight loss, side stepping to the right, and a right head tilt. Rectal and cerebrospinal fluid cytology and culture confirmed a diagnosis of Prototheca zopfii. MRI of the brain showed inflammation of the brain and meninges, ventriculomegaly, and syringomyelia. Treatment with prednisone, itraconazole, and amphotericin B lipid complex administered intrathecally yielded transient improvement. Progressive brainstem signs were noted, and a repeat MRI and cerebrospinal fluid analysis documented persistent disease. This is the first description of the MRI findings and treatment with intrathecal amphoteracin B lipid complex for protothecosis of the central nervous system. Protothecosis should be considered in dogs with chronic diarrhea and compatible MRI findings.

Management of Patients Diagnosed with Lobular Carcinoma in Situ at Needle Core Biopsy at a Community-based Outpatient Facility

The objective of our study was to show the importance of surgical excision after the diagnosis of lobular carcinoma in situ (LCIS) based on needle core biopsy.

The Karyopherin Sal3 is Required for Nuclear Import Of the Core RNA Interference Pathway Protein Rdp1

RNA-dependent RNA polymerase activity is required for RNA interference (RNAi) in many lower eukaryotes including the fission yeast Schizosacchromyces pombe. Together with Ago1 and Dcr1, the RNA-dependent RNA polymerase Rdp1 is critical for RNA-dependent transcriptional- and post-transcriptional gene silencing. Although the bulk of Rdp1 is localized to the nucleus, Ago1 and Dcr1 are primarily cytoplasmic. This may reflect the fact that Rdp1 is required early in the RNAi pathway to generate double strand RNA from transcripts that originate from centromeric loci. The relatively large size of Rdp1 (139.4 kD) precludes passive diffusion of the enzyme into the nucleus suggesting that karyopherin-dependent transport is involved in nuclear targeting of this enzyme. In this study, we report that the karyopherin/importin β3 homolog Sal3 is required for nuclear import of Rdp1 in S. pombe. Loss of nuclear Rdp1 was associated with substantially reduced transcriptional gene silencing, and surprisingly, post-transcriptional gene silencing which occurs in the cytoplasm of other eukaryotes, was also significantly affected. Together, these results identify Sal3 as a modulator of RNAi-dependent transcriptional gene silencing as well as a potential link between nuclear import and post-transcriptional gene silencing.

Expansion and Re-examination of Digit Span Effort Indices on the WAIS-IV

The Digit Span subtest was significantly revised for the WAIS-IV as an ordinal sequencing trial was added to increase working memory demands. The present investigation sought to validate an expanded version of Reliable Digit Span (RDS-R) as well as age-corrected scaled score (ACSS) from the recently revised Digit Span. Archival data were collected from 259 veterans completing the WAIS-IV Digit Span subtest and Word Memory Test (WMT). Veterans failing the WMT performed significantly worse (p < .001) on the ACSS, RDS-R, and traditional RDS. Operational characteristics of the ACSS, RDS-R, and RDS were essentially equivalent; however, sensitivity was quite modest when selecting cutoffs with strong specificity. While current results suggest that Digit Span effort indices can contribute to the detection of suboptimal effort, additional symptom validity indicators should be employed to compensate for limited sensitivity.

Host Conservatism, Host Shifts and Diversification Across Three Trophic Levels in Two Neotropical Forests

Host-parasite systems have been models for understanding the connection between shifts in resource use and diversification. Despite theoretical expectations, ambiguity remains regarding the frequency and importance of host switches as drivers of speciation in herbivorous insects and their parasitoids. We examine phylogenetic patterns with multiple genetic markers across three trophic levels using a diverse lineage of geometrid moths (Eois), specialist braconid parasitoids (Parapanteles) and plants in the genus Piper. Host-parasite associations are mapped onto phylogenies, and levels of cospeciation are assessed. We find nonrandom patterns of host use within both the moth and wasp phylogenies. The moth-plant associations in particular are characterized by small radiations of moths associated with unique host plants in the same geographic area (i.e. closely related moths using the same host plant species). We suggest a model of diversification that emphasizes an interplay of factors including host shifts, vicariance and adaptation to intraspecific variation within hosts.

Investigation of a Supplementary Tool to Assist in the Prioritization of Emphasis Areas in North American Strategic Highway Safety Plans

An important potential benefit of a jurisdiction developing an upper-level traffic safety policy statement, such as a strategic highway safety plan (SHSP) or a traffic safety action plan, is the creation of a manageable number of focus areas, known as emphasis areas. The responsible agencies in the jurisdiction can then direct their finite resources in a systematic and strategic way designed to maximize the effort to reduce the number and severity of roadway collisions. In the United States, the federal government through AASHTO has suggested 22 potential emphasis areas. In Canada, CCMTA's 10 potential emphasis areas have been listed for consideration. This study reviewed the SHSP and traffic safety action plan of 53 jurisdictions in North America, and conducted descriptive data analyses to clarify the issues that currently affect the selection and prioritization process of jurisdiction-specific emphasis areas. We found that the current process relies heavily on high-level collision data analysis and communication among the SHSP stakeholders, but may not be the most efficient and effective way of selecting and prioritizing the emphasis areas and allocating safety improvement resources. This study then formulated a formal collision diagnosis test, known as the beta-binomial test, to clarify and illuminate the selection and the prioritization of jurisdiction-specific emphasis areas. We developed numerical examples to demonstrate how engineers can apply the proposed diagnosis test to improve the selection and prioritization of individual jurisdictions' emphasis areas.

Effects of Citrate Acid Concentrate (Citrasate®) on Heparin N Requirements and Hemodialysis Adequacy: A Multicenter, Prospective Noninferiority Trial

Background: Citrasate®, citric acid dialysate (CD), contains 2.4 mEq of citric acid (citrate), instead of acetic acid (acetate) as in standard bicarbonate dialysate. Previous studies suggest CD may improve dialysis adequacy and decrease heparin requirements, presumably due to nonsystemic anticoagulant effects in the dialyzer. Methods: We prospectively evaluated 277 hemodialysis patients in eight outpatient facilities to determine if CD with reduced heparin N (HN) would maintain dialyzer clearance. Subjects progressed through four study periods [baseline (B): bicarbonate dialysate + 100% HN; period 1 (P1): CD + 100% HN; period 2 (P2): CD + 80% HN; period 3 (P3): CD + 66.7% HN]. The predefined primary endpoint was noninferiority (margin -8%) of the percent change in mean dialyzer conductivity clearance between baseline and P2. Results: Subjects were 57.4% male, 41.7% white, 54.3% black, and 44.4% diabetic; mean age was 59 ± 14.4 years; mean time on dialysis was 1,498 ± 1,165 days; 65.7% had arteriovenous fistula, 19.9% arteriovenous graft, 14.4% catheters, and 27.8% used antiplatelet agents. Mean dialyzer clearance increased 0.9% (P1), 1.0% (P2), and 0.9% (P3) with CD despite heparin reduction. SpKt/V remained stable (B: 1.54 ± 0.29; P1: 1.54 ± 0.28; P2: 1.55 ± 0.27; P3: 1.54 ± 0.26). There was no significant difference in dialyzer/dialysis line thrombosis, post-HD time to hemostasis, percent of subjects with adverse events (AEs), or study-related AEs. Conclusions: CD was safe, effective, and met all study endpoints. Dialyzer clearance increased approximately 1% with CD despite 20-33% heparin reduction. Over 92% of P3 subjects demonstrated noninferiority of dialyzer clearance with CD and 33% HN reduction. There was no significant difference in dialyzer clotting, bleeding, or adverse events.

Evidence for Using Bisphosphonate to Treat Legg-Calvé-Perthes Disease

BACKGROUND: The rationale for using bisphosphonate (BP) therapy for Legg-Calvé-Perthes disease (LCPD) is the potential to prevent substantial femoral head deformity during the fragmentation phase by inhibiting osteoclastic bone resorption. However, it is unclear whether BP therapy decreases femoral head deformity. QUESTIONS/PURPOSES: In this systematic review, we answered the following questions: (1) Does bisphosphonate (BP) therapy decrease femoral head deformity and improve pain and function in LCPD or other juvenile osteonecrotic conditions? And (2) does BP therapy decrease femoral head deformity in experimental studies of juvenile femoral head osteonecrosis? METHODS: We searched the literature from 1966 to 2011 for clinical and experimental studies on BP therapy for juvenile femoral head osteonecrosis. Studies specifically addressing clinical and/or radiographic/histologic outcomes pertaining to pain and function and femoral head morphology were analyzed. RESULTS: Three Level IV clinical studies met our inclusion criteria. Only one study initiated BP therapy during the precollapsed stage of osteonecrosis and reported prevention of femoral head deformity in nine of 17 patients. All studies noted subjective improvements of pain and gait in patients treated with intravenous BPs. Of the eight experimental studies reviewed, seven reported reduced femoral head deformity and six found better preservation of trabecular framework in animals treated with BPs. CONCLUSIONS: Clinical evidence lacks consistent patient groups and drug protocols to draw definitive conclusions that BP therapy can decrease femoral head deformity in juvenile osteonecrotic conditions. Experimental studies suggest BP therapy protects the infarcted femoral head from deformity, but it lacks bone anabolic effect. Further basic and clinical research are required to determine the potential role of BPs as a medical treatment for LCPD.

Arctic Tipping Points: Governance in Turbulent Times

Interacting forces of climate change and globalization are transforming the Arctic. Triggered by a non-linear shift in sea ice, this transformation has unleashed mounting interest in opportunities to exploit the region's natural resources as well as growing concern about environmental, economic, and political issues associated with such efforts. This article addresses the implications of this transformation for governance, identifies limitations of existing arrangements, and explores changes needed to meet new demands. It advocates the development of an Arctic regime complex featuring flexibility across issues and adaptability over time along with an enhanced role for the Arctic Council both in conducting policy-relevant assessments and in promoting synergy in interactions among the elements of the emerging Arctic regime complex. The emphasis throughout is on maximizing the fit between the socioecological features of the Arctic and the character of the governance arrangements needed to steer the Arctic toward a sustainable future.

Erratum To: Can Gaze Avoidance Explain Why Individuals with Asperger's Syndrome Can't Recognise Emotions From Facial Expressions?

Disparities in NIH Funding for Epilepsy Research

Non-destructive Quantification of Cereal Roots in Soil Using High-resolution X-ray Tomography

One key constraint to further understanding plant root development is the inability to observe root growth in situ due to the opaque nature of soil. Of the present non-destructive techniques, computed tomography (CT) is best able to capture the complexities of the edaphic environment. This study compared the accuracy and impact of X-ray CT measurement of in situ root systems with standard technology (soil core washing and WinRhizo analysis) in the context of treatments that differed in the vertical placement of phosphorus fertilizers within the soil profile. Although root lengths quantified using WinRhizo were 8% higher than that observed in the same plants using CT, measurements of root length by the two methodologies were highly correlated. Comparison of scanned and unscanned plants revealed no effect of repeated scanning on plant growth and CT was not able to detect any changes in roots between phosphorus treatments that was observed using WinRhizo. Overall, the CT technique was found to be fast, safe, and able to detect roots at high spatial resolutions. The potential drawbacks of CT relate to the software to digitally segment roots from soil and air, which will improve significantly as automated segmentation algorithms are developed. The combination of very fast scans and automated segmentation will allow CT methodology to realize its potential as a high-throughput technique for the quantification of roots in soils.

Gene Regulation Systems for Gene Therapy Applications in the Central Nervous System

Substantial progress has been made in the development of novel gene therapy strategies for central nervous system (CNS) disorders in recent years. However, unregulated transgene expression is a significant issue limiting human applications due to the potential side effects from excessive levels of transgenic protein that indiscriminately affect both diseased and nondiseased cells. Gene regulation systems are a tool by which tight tissue-specific and temporal regulation of transgene expression may be achieved. This review covers the features of ideal regulatory systems and summarises the mechanics of current exogenous and endogenous gene regulation systems and their utility in the CNS.

Divergent Outcomes of Gold(i)-catalyzed Indole Additions to 3,3-disubstituted Cyclopropenes

Depending on the conditions employed, gold(I)-catalyzed addition of indoles to 3,3-disubstituted cyclopropenes can be controlled to yield either 3-(E)-vinylindoles (3) or bis-indolylalkanes (4). If the cyclopropene substituents are sterically bulky, unprecedented gold-catalyzed oxidation under air occurs to yield bis-indolylalkene (5) and epoxide (6) at room temperature.

Divergent Body Mass Index Trajectories Between Aboriginal and Non-aboriginal Canadians 1994-2009-an Exploration of Age, Period, and Cohort Effects

Aboriginal Canadians have a high burden of obesity and obesity-related chronic conditions. Body mass index (BMI) trajectories from 1994 to 2009 were estimated for Aboriginal and non-Aboriginal Canadians using self-reported height and weight data from the National Population Health Survey to explore age, period, and cohort effects of BMI change.

Neuronal-derived Nitric Oxide Modulates the Activity of Mouse Detrusor Smooth Muscle

AIMS: We investigated the roles of neuronal-derived nitric oxide (NO) in the modulation of spontaneous activity of mouse detrusor smooth muscle. METHODS: Detrusor smooth muscle strips were isolated from nNOS gene knock-out (nNOS(-/-) ) mice and their wild type siblings (nNOS(+/+) ). The properties of smooth muscle cells were assessed using intracellular electrophysiology and Ca(2+) imaging by laser-scanning confocal microscopy. The effects of an nNOS inhibitor, 7-nitro indazole (7-NI) on electrically evoked contractility were assessed using nNOS(+/+) mouse detrusor strips. RESULTS: In spontaneously active cells, the frequency of spontaneous action potentials (sAPs) and whole cell Ca(2+) flashes in nNOS(-/-) preparations was lower than that in the nNOS(+/+) preparations. The frequency of sAPs was enhanced by a nitric oxide donor, diethylamine NONOate sodium salt (NONOate; 100 µM), both when used alone and when the cGMP pathway was blocked by 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, 10 µM). 7-NI (100 µM) significantly suppressed the electrically evoked contraction of mouse detrusor strips. CONCLUSIONS: We suggest that neuronal-derived NO facilitates the generation of spontaneous activity via a cGMP-independent pathway, and consequently enhances the evoked contraction of detrusor. Dysregulation of nNOS containing nerves may underlie bladder pathologies. Neurourol. Urodynam. © 2012 Wiley Periodicals, Inc.

Dysfunction of the TP53 Tumor Suppressor Gene in Lymphoid Malignancies

Mutations of the TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers including lymphomas. Tumor suppression by p53 occurs via both transcription-dependent activities in the nucleus by which p53 regulates transcription of genes involved in cell cycle, DNA repair, apoptosis, signaling, transcription, and metabolism; and transcription-independent activities that induces apoptosis and autophagy in the cytoplasm. In lymphoid malignancies, the frequency of TP53 deletions and mutations is lower than in other types of cancer. Nonetheless, the status of TP53 is an independent prognostic factor in most lymphoma types. Dysfunction of TP53 with wild-type coding sequence can result from deregulated gene expression, stability and activity of p53. To overcome TP53 pathway inactivation, therapeutic delivery of wild-type p53, activation of mutant p53, inhibition of MDM2-mediated degradation of p53, and activation of p53-dependent and -independent apoptotic pathways have been explored experimentally and in clinical trials. We review the mechanisms of TP53 dysfunction, recent advances implicated in lymphomagenesis, and therapeutic approaches to overcoming p53 inactivation.

Preoperative Proteinuria Is Associated with Long-Term Progression to Chronic Dialysis and Mortality After Coronary Artery Bypass Grafting Surgery

AIMS: Preoperative proteinuria is associated with post-operative acute kidney injury (AKI), but whether it is also associated with increased long- term mortality and end -stage renal disease (ESRD) is unknown. METHODS AND RESULTS: We studied 925 consecutive patients undergoing CABG. Demographic and clinical data were collected prospectively, and patients were followed for a median of 4.71 years after surgery. Proteinuria, according to dipstick tests, was defined as mild (trace to 1+) or heavy (2+ to 4+) according to the results of the dipstick test. A total of 276 (29.8%) patients had mild proteinuria before surgery and 119 (12.9%) patients had heavy proteinuria. During the follow-up, the Cox proportional hazards model demonstrated that heavy proteinuria (hazard ratio [HR], 27.17) was an independent predictor of long-term ESRD. There was a progressive increased risk for mild proteinuria ([HR], 1.88) and heavy proteinuria ([HR], 2.28) to predict all-cause mortality compared to no proteinuria. Mild ([HR], 2.57) and heavy proteinuria ([HR], 2.70) exhibited a stepwise increased ratio compared to patients without proteinuria for long-term composite catastrophic outcomes (mortality and ESRD), which were independent of the baseline GFR and postoperative acute kidney injury (AKI). CONCLUSION: Our study demonstrated that proteinuria is a powerful independent risk factor of long-term all-cause mortality and ESRD after CABG in addition to preoperative GFR and postoperative AKI. Our study demonstrated that proteinuria should be integrated into clinical risk prediction models for long-term outcomes after CABG. These results provide a high priority for future renal protective strategies and methods for post-operative CABG patients.

Discovery and Validation of Molecular Biomarkers for Colorectal Adenomas and Cancer with Application to Blood Testing

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Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer

Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response.

Ultraviolet A1 Phototherapy: a British Photodermatology Group Workshop Report

Whole-body ultraviolet (UV)A1 (340-400 nm) phototherapy was first introduced 30 years ago, but is currently available in the UK in only three dermatology departments. A workshop to discuss UVA1 was held by the British Photodermatology Group in May 2009, the aim of which was to provide an overview of UVA1 phototherapy and its role in practice, and to identify areas in which further studies are required. The conclusions were that UVA1 phototherapy is an effective treatment in several inflammatory skin diseases, including localized scleroderma and atopic eczema (AE); however, deficiencies and limitations exist in the published evidence base. For most diseases, such as AE, other treatments also exist, which are generally more effective than UVA1. However, for some diseases, particularly morphoea, the evidence of efficacy is stronger for UVA1 than for other treatments. Acute adverse effects of UVA1 are minimal. The risk of long-term adverse effects, particularly skin cancer, is unknown. Medium to high doses of UVA1 are needed for efficacy in most situations, but the equipment to deliver such doses is large, expensive and difficult to install. UVA1 is currently underprovided, and the recommendation of the workshop is that more tertiary centres should have access to UVA1 phototherapy in the UK.

Detection of Suboptimal Effort with Symbol Span: Development of a New Embedded Index

Developing embedded indicators of suboptimal effort on objective neurocognitive testing is essential for detecting increasingly sophisticated forms of symptom feigning. The current study explored whether Symbol Span, a novel Wechsler Memory Scale-fourth edition measure of supraspan visual attention, could be used to discriminate adequate effort from suboptimal effort. Archival data were collected from 136 veterans classified into Poor Effort (n = 42) and Good Effort (n = 94) groups based on symptom validity test (SVT) performance. The Poor Effort group had significantly lower raw scores (p < .001) and age-corrected scaled scores (p < .001) than the Good Effort group on the Symbol Span test. A raw score cutoff of <14 produced 83% specificity and 50% sensitivity for detection of Poor Effort. Similarly, sensitivity was 52% and specificity was 84% when employing a cutoff of <7 for Age-Corrected Scale Score. Collectively, present results suggest that Symbol Span can effectively differentiate veterans with multiple failures on established free-standing and embedded SVTs.

Assessing Self-Efficacy to Reduce One's Drinking: Further Evaluation of the Alcohol Reduction Strategies-Current Confidence Questionnaire

AIMS: To evaluate the psychometric properties of a previously published questionnaire designed to assess young drinkers' self-efficacy to employ 31 cognitive-behavioral alcohol reduction strategies. METHODS: Undergraduates (n = 353) recruited from a large Midwestern university completed the previously published Alcohol Reduction Strategies-Current Confidence questionnaire (and other measures) for a self-selected heavy drinking setting. RESULTS: Item loadings from a principal components analysis, a high internal consistency reliability coefficient, and a moderate mean inter-item correlation suggested that all 31 items comprised a single scale. Correlations of questionnaire scores with selected aspects of drinking history and personality provided support for criterion and discriminant validity, respectively. Women reported higher current confidence to use these strategies than did men, but current confidence did not vary as a function of recent binge status. CONCLUSION: Given this further demonstration of its psychometric qualities, this questionnaire holds promise as a clinical tool to identify clients who lack confidence in their ability to employ cognitive-behavioral coping strategies to reduce their drinking.

Caenorhabditis Elegans Battling Starvation Stress: Low Levels of Ethanol Prolong Lifespan in L1 Larvae

The nematode Caenorhabditis elegans arrests development at the first larval stage if food is not present upon hatching. Larvae in this stage provide an excellent model for studying stress responses during development. We found that supplementing starved larvae with ethanol markedly extends their lifespan within this L1 diapause. The effects of ethanol-induced lifespan extension can be observed when the ethanol is added to the medium at any time between 0 and 10 days after hatching. The lowest ethanol concentration that extended lifespan was 1 mM (0.005%); higher concentrations to 68 mM (0.4%) did not result in increased survival. In spite of their extended survival, larvae did not progress to the L2 stage. Supplementing starved cultures with n-propanol and n-butanol also extended lifespan, but methanol and isopropanol had no measurable effect. Mass spectrometry analysis of nematode fatty acids and amino acids revealed that L1 larvae can incorporate atoms from ethanol into both types of molecules. Based on these data, we suggest that ethanol supplementation may extend the lifespan of L1 larvae by either serving as a carbon and energy source and/or by inducing a stress response.

Epigenetic Mechanisms in Cartilage and Osteoarthritis: DNA Methylation, Histone Modifications and MicroRNAs

Osteoarthritis (OA) is a complex multifactorial disease with a strong genetic component. Several studies have suggested or identified epigenetic events that may play a role in OA progression and the gene expression changes observed in diseased cartilage. The aim of this review is to inform about current research in epigenetics and epigenetics in OA. Epigenetic mechanisms include DNA methylation, histone modifications, and microRNAs. Collectively, these enable the cell to respond quickly to environmental changes and can be inherited during cell division. However, aberrant epigenetic modifications are associated with a number of pathological conditions, including OA. Advancements in epigenetic research suggests that global analysis of such modifications in OA are now possible, however, with the exception of microRNAs, it will be a significant challenge to demonstrate how such events impact on the disease.

Comparing Fecal Immunochemical Testing: Improved Standardization Is Needed

Candidates Play to the Right on Science

Cost-effectiveness of Multi-component Interventions to Prevent Delirium in Older People Admitted to Medical Wards

Introduction: there is evidence to suggest that delirium incidence can be reduced in older people admitted to medical services using multi-component interventions that target delirium risk factors. The cost-effectiveness of this approach is uncertain. We therefore developed a novel cost-effectiveness model for delirium prevention.Method: we compared multi-component delirium prevention intervention with usual care using a model based on a decision tree analysis. The model was used to estimate the incremental net monetary benefit (INMB). The robustness of the cost-effectiveness result was explored using deterministic and probabilistic sensitivity analyses.Result: the multi-component prevention intervention was cost-effective when compared with usual care. It was associated with an INMB of £2,200 using a cost-effectiveness threshold of £20,000 per quality-adjusted life year (QALY). It remained cost-effective in the majority of the deterministic sensitivity analyses and was cost-effective in 96.8% of the simulations carried out in the probabilistic sensitivity analysis.Discussion: our analysis has shown convincingly that multi-component prevention interventions for delirium should be considered as a cost-effective health-care strategy for medically ill people admitted to hospital. It is an attractive intervention for health-care planners as they strive to reconfigure their services to better meet the needs of an ageing population.

Bimolecular Electron Transfers That Deviate from the Sandros-Boltzmann Dependence on Free Energy: Steric Effect

As we reported recently, endergonic to mildly exergonic electron transfer between neutral aromatics (benzenes and biphenyls) and their radical cations in acetonitrile follows a Sandros-Boltzmann (SB) dependency on the reaction free energy (ΔG); i.e., the rate constant is proportional to 1/[1 + exp(ΔG/RT)]. We now report deviations from this dependency when one reactant is sterically crowded: 1,4-di-tert-butylbenzene (C1), 1,3,5-tri-tert-butylbenzene (C2), or hexaethylbenzene (C3). Obvious deviation from SB behavior is observed with C1. Stronger deviation is observed with the more crowded C2 and C3, where steric hindrance increases the interplanar separation at contact by ∼1 Å, significantly decreasing the π orbital overlap. Consequently, electron transfer (k(et)) within the contact pair becomes slower than diffusional separation (k(-d)), causing deviation from the SB dependency, especially near ΔG = 0. Fitting the data to a standard electron-transfer theory gives small matrix elements (∼5-7 meV) and reasonable reorganization energies. A small systematic difference between reactions of C3 with benzenes vs biphenyls is rationalized in terms of small differences in the electron-transfer parameters that are consistent with previous data. The influence of solvent viscosity on the competition between k(et) and k(-d) was investigated by comparing reactions in acetonitrile and propylene carbonate.

Cognitive Vulnerabilities, Negative Life Events, and Depressive Symptoms in Young Adolescents

Negative patterns of thinking, termed cognitive vulnerabilities, have been identified as risk factors for the development of depressive symptoms when adolescents experience negative life events. This study evaluated the associations among three cognitive vulnerabilities (i.e., dysfunctional attitudes, negative inferential style, and ruminative response style) and negative life events with depressive symptoms in a sample of young adolescents. All three cognitive vulnerabilities were found to be significantly associated with depressive symptoms. Furthermore, ruminative response style was found to have a significant unique contribution to the number of depressive symptoms. Findings suggest that cognitive vulnerabilities, particularly rumination, may be instrumental in explaining the development of depressive symptoms in young adolescents.

Vascular Graft Infections

Prosthetic vascular grafting is a commonly performed procedure that is central to the management of arterial disease and renal failure. Though rare, vascular graft infections (VGI) are potentially devastating, and carry a high rate of mortality and amputation. Despite extensive research and clinical experience, VGI remain a daunting therapeutic challenge for surgeons and infectious disease specialists. This article reviews the pathogenesis of VGI, in particular the role of biofilms, as well as the current state of clinical management including diagnostic modalities, surgical options for treatment, antimicrobial therapy, and preventive measures.

A Framework for Discussion on How to Improve Prevention, Management, and Control of Hypertension in Canada

Increased blood pressure is a leading risk for premature death and disability. The causes of increased blood pressure are intuitive and well known. However, the fundamental basis and means for improving blood pressure control are highly integrated into our complex societal structure both inside and outside our health system and hence require a comprehensive discussion of the pathway forward. A group of Canadian experts was appointed by Hypertension Canada with funding from Public Health Agency of Canada and the Heart and Stroke Foundation of Canada, Canadian Institute for Health Research (HSFC-CIHR) Chair in Hypertension Prevention and Control to draft a discussion Framework for prevention and control of hypertension. The report includes an environmental scan of past and current activities, proposals for key indicators, and targets to be achieved by 2020, and what changes are likely to be required in Canada to achieve the proposed targets. The key targets are to reduce the prevalence of hypertension to 13% of adults and improve control to 78% of those with hypertension. Broad changes in government policy, research, and health services delivery are required for these changes to occur. The Hypertension Framework process is designed to have 3 phases. The first includes the experts' report which is summarized in this report. The second phase is to gather input and priorities for action from individuals and organizations for revision of the Framework. It is hoped the Framework will stimulate discussion and input for its full intended lifespan 2011-2020. The third phase is to work with individuals and organizations on the priorities set in phase 2.

Plant and Animal Endemism in the Eastern Andean Slope: Challenges to Conservation

ABSTRACT: BACKGROUND: The Andes-Amazon basin of Peru and Bolivia is one of the most data-poor, biologically rich, and rapidly changing areas of the world. Conservation scientists agree that this area hosts extremely high endemism, perhaps the highest in the world, yet we know little about the geographic distributions of these species and ecosystems within country boundaries. To address this need, we have developed conservation data on endemic biodiversity (~800 species of birds, mammals, and amphibians) and terrestrial ecological systems (~90; groups of vegetation communities resulting the action of ecological processes, substrates, and/or environmental gradients) with which we conducted a fine scale conservation prioritization across the Amazon watershed of Peru and Bolivia. We modelled the geographic distributions of 435 endemic plants and all 347 endemic vertebrate species, from existing museum and herbaria specimens at a regional conservation practitioner's scale (1:250,000-1:1,000,000), based on the best available tools and geographic data. We mapped ecological systems, endemic species concentrations, and irreplaceable areas with respect to national level protected areas. RESULTS: We found that sizes of endemic species distributions ranged widely (< 20 km2 to > 200,000 km2) across the study area. Bird and mammal endemic species richness was greatest within a narrow 2500-3000 m elevation band along the length of the Andes Mountains. Endemic amphibian richness was highest at 1000-1500 m elevation and concentrated in the southern half of the study area. Geographical distribution of plant endemism was highly taxon-dependent. Irreplaceable areas, defined as locations with the highest number of species with narrow ranges, overlapped slightly with areas of high endemism, yet generally exhibited unique patterns across the study area by species group. We found that many endemic species and ecological systems are lacking national-level protection; a third of endemic species have distributions completely outside of national protected areas. Protected areas cover only 20% of areas of high endemism and 20% of irreplaceable areas. Almost 40% of the 91 ecological systems are in serious need of protection (=< 2% of their ranges protected). CONCLUSIONS: We identify for the first time, areas of high endemic species concentrations and high irreplaceability that have only been roughly indicated in the past at the continental scale. We conclude that new complementary protected areas are needed to safeguard these endemics and ecosystems. An expansion in protected areas will be challenged by geographically isolated micro-endemics, varied endemic patterns among taxa, increasing deforestation, resource extraction, and changes in climate. Relying on pre-existing collections, publically accessible datasets and tools, this working framework is exportable to other regions plagued by incomplete conservation data.

Vitamin A Supplementation Improves Retinal Function in Infants at Risk of Retinopathy of Prematurity

OBJECTIVE: Preterm infants show reduced retinal sensitivity at term corrected age compared with newborn term infants. We tested the hypothesis that retinal sensitivity in preterm infants is improved by early, high-dose vitamin A. STUDY DESIGN: We report a double-blind, randomized controlled trial of infants <32 weeks' gestation and/or <1501 g birth weight. Supplemented infants received additional intramuscular vitamin A 10 000 IU 3 times weekly from day 2 for a minimum of 2 weeks or until establishment of oral feeding. Hepatic stores were assessed by relative dose response (RDR). The primary outcome measure was cone-corrected dark-adapted retinal rod sensitivity measured by electroretinogram at 36 weeks' postmenstrual age (PMA). RESULTS: Eighty-nine infants (42 supplemented and 47 controls) were recruited. Plasma retinol was higher in supplemented infants at 7 and 28 days (median, 1.0 vs 0.5 μmol/L and 0.7 vs 0.6 μmol/L; P < .001 and .03, respectively). Neither plasma retinol nor RDR differed between groups at 36 weeks' PMA. Retinal sensitivity was greater in supplemented infants (-0.81 vs -0.61 log cd • s • m(-2); P < .03) and was not related to RDR. CONCLUSIONS: Early high-dose intramuscular vitamin A supplementation for infants at risk of retinopathy of prematurity improves retinal function at 36 weeks' PMA.

Effect of Combined Locally Delivered Growth Factors and Systemic Sildenafil Citrate on Microrecanalization in Biodegradable Conduit for Vas Deferens Reconstruction

OBJECTIVE: To investigate the effect of the combination of locally delivered growth factors and oral sildenafil citrate on cross-conduit microrecanalization. METHODS: A total of 42 rats were divided into 7 groups. Of the 42 rats, 6 underwent bilateral vasectomy and bilateral end-to-end vasovasostomy and 12 underwent bilateral vasectomy. Of the latter 12, 6 received sildenafil citrate orally (10 mg/kg/d) for 24 weeks and 6 received placebo. A total of 24 rats underwent bilateral vasectomy and bilateral reconstruction with implantation of a 5-mm biodegradable conduit that bridged the 2 vasal ends. Of the 24 rats with conduits, 12 also had 250 pg of transforming growth factor-β and 12.5 pg of platelet-derived growth factor-β sustained release nanoparticles placed in immediate proximity to the conduit. The remaining 12 rats with conduits (6 without growth factors and 6 with growth factors) also received sildenafil citrate orally (10 mg/kg/d) for 24 weeks; the others received placebo. The reconstructed segments were harvested for histologic examination at 24 weeks. RESULTS: Five of 6 primary vasovasostomy and no vasectomy-only rats sired litters. Significantly more microcanals per conduit were observed in rats receiving sildenafil citrate: without growth factors, 3.9 vs. 0 canals/conduit (P < 0.001); with growth factors, 5.5 vs. 0.25 canals/conduit (P < 0.001). The rats receiving sildenafil citrate with growth factors showed a trend toward more microcanals per conduit than the rats receiving sildenafil citrate without growth factors (5.5 vs 3.9; P = .10). Rats receiving growth factors but no sildenafil citrate did not produce more canals than the rats receiving neither growth factor nor sildenafil citrate (0.25 vs 0; P = NS). CONCLUSION: Orally administered sildenafil citrate enhances formation of microcanalization after postvasectomy reconstruction using a biodegradable conduit in a rat model. Locally delivered growth factors appear to increase the number of microcanals.

An Improved Method for Glycosaminoglycan Analysis by LC-MS/MS of Urine Samples Collected on Filter Paper

BACKGROUND: Mucopolysaccharidoses are complex lysosomal storage disorders caused by any of eleven different enzyme deficiencies resulting in the accumulation of substrates, mainly glycosaminoglycans (GAGs), in various tissues and biological fluids. METHOD: We developed and validated a urine filter paper methodology for the analysis of GAGs using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for mucopolysaccharidoses type I, type II and type VI patients. We focused on 2 objectives: first, its applicability to high-risk screening, and secondly, to facilitate the collection and shipping of samples to reference centers as part of diagnostic investigation, as well as from treated patients needing to be monitored for assessment of the efficacy of treatment. GAGs in urine dried onto filter paper were extracted and subjected to methanolysis to obtain the repeating disaccharides of the molecules. We devised a multiple reaction monitoring method in positive electrospray ionization mode. RESULTS: The use of deuterated internal standards for dermatan sulfate (DS) and heparan sulfate (HS) reduced a troubling matrix effect. The resulting CVs were <14%. Linearity assessment showed Pearson correlation coefficients of 0.999 and 0.997, for DS and HS, respectively. The stability on filter paper was good for DS and HS for up to 6weeks at various temperatures. CONCLUSION: We devised a robust and efficient LC-MS/MS methodology for GAGS quantification in urine dried on filter paper and subjected to environmental conditions likely to be encountered during collection, storage and shipping of specimens from referring physicians to medical centers.

Effects of (-) Mammea A/BB Isolated from Calophyllum Brasiliense Leaves and Derivatives on Mitochondrial Membrane of Leishmania Amazonensis

We have previously demonstrated antileishmanial activity on Leishmania amazonensis of the natural (1-2), synthetic (7) and derivatives of coumarin (-) mammea A/BB (3-6) isolated from the dichloromethane extract of Calophyllum brasiliense leaves. The aim of the present study was to evaluate morphological and ultrastructural alterations in Leishmania amazonensis induced by these compounds. In promastigote forms, all seven compounds produced significant morphological and ultrastructural alterations, as revealed by scanning and transmission electron microscopy. The compound 5,7-dihydroxy-8-(2-methylbutanoyl)-6-(3-methylbutyl)-4-phenyl-chroman-2-one (3), the most active antileishmanial with LD(50) of 0.9μM), induced cell shrinkage and a rounded appearance of the cells. Parasites incubated in the presence of compound (3) showed ultrastructural changes, such as the appearance of mitochondrial swelling with a reduction in the density of the mitochondrial matrix and the presence of vesicles inside the mitochondrion, indicating damage and significant change in this organelle; abnormal chromatin condensation, alterations in the nuclear envelope, intense atypical cytoplasmic vacuolization, and the appearance of autophagic vacuoles were also observed. In addition, the compound (3) may be acting to depolarize the mitochondrial membrane potential of the cells, leading to death of the parasite.

Nanofiber Scaffold Gradients for Interfacial Tissue Engineering

We have designed a 2-spinnerette device that can directly electrospin nanofiber scaffolds containing a gradient in composition that can be used to engineer interfacial tissues such as ligament and tendon. Two types of nanofibers are simultaneously electrospun in an overlapping pattern to create a nonwoven mat of nanofibers containing a composition gradient. The approach is an advance over previous methods due to its versatility - gradients can be formed from any materials that can be electrospun. A dye was used to characterize the 2-spinnerette approach and applicability to tissue engineering was demonstrated by fabricating nanofibers with gradients in amorphous calcium phosphate nanoparticles (nACP). Adhesion and proliferation of osteogenic cells (MC3T3-E1 murine pre-osteoblasts) on gradients was enhanced on the regions of the gradients that contained higher nACP content yielding a graded osteoblast response. Since increases in soluble calcium and phosphate ions stimulate osteoblast function, we measured their release and observed significant release from nanofibers containing nACP. The nanofiber-nACP gradients fabricated herein can be applied to generate tissues with osteoblast gradients such as ligaments or tendons. In conclusion, these results introduce a versatile approach for fabricating nanofiber gradients that can have application for engineering graded tissues.

Low Prevalence of Bovine Tuberculosis in Somali Pastoral Livestock, Southeast Ethiopia

A cross-sectional study of bovine tuberculosis (BTB) detected by the comparative intradermal tuberculin test (CIDT) was conducted in livestock of the Somali region in southeast Ethiopia-in four pastoral associations from January to August 2009. In 94 herds, each of 15 cattle, camels, and goats was tested per herd leading to a total of 1,418 CIDT tested animals, with 421 cattle, 479 camels, and 518 goats. A herd was considered positive if it had at least one reactor. Prevalence per animal species was calculated using a xtgee model for each species. The individual animal prevalence was 2.0% [95% confidence interval (CI), 0.5-8.4], 0.4% (95% CI, 0.1-3%), and 0.2% (95% CI, 0.03-1.3) in cattle, camels, and goats, respectively. Prevalence of avian mycobacterium purified protein derivative (PPD) reactors in cattle, camels, and goats was 0.7% (95% CI, 0.2-2.0%), 10.0% (95% CI, 7.0-14.0%), and 1.9 (95% CI, 0.9-4.0%), respectively, whereby camels had an odds ratio of 16.5 (95% CI, 5.0-55.0) when compared to cattle. There was no significant difference between livestock species in BTB positivity. In the present study, the prevalence of bovine tuberculosis was low in Somali pastoral livestock in general and in camels and goats in particular. The high proportion of camel reactors to avian PPD needs further investigation of its impact on camel production.

Paracoccus Rhizosphaerae Sp. Nov., a Novel Species Isolated from the Rhizosphere of a Plant Crossostephium Chinense (L.) Makino (Seremban)

A Gram-negative organism producing coccoid cells (CC-CCM15-8T) isolated from a rhizosphere soil sample of the plant Crossostephium chinense (L.) Makino (Seremban) from Budai Township, Chiayi County, Taiwan was taxonomically studied. 16S rRNA gene sequence analysis indicated a clear allocation of the isolate CC-M15-8T to the Paracoccus cluster, showing the highest similarities to the type strains of Paracoccus beibuensis (98.8%), Paracoccus homiensis (97.6%), Paracoccus aestuarii (97.7%) and Paracoccus zeaxanthinifaciens (97.7%). The fatty acids profile comprising the major fatty acid C18:1 ω7c beside the characteristic hydroxylated fatty acid C10:0 3-OH supported the grouping of strain CC-M15-8T to the genus Paracoccus. The polyamine pattern consisted of the major components putrescine and spermidine. Ubiqinone Q10 was the major quinone type (95%) Ubiquinone Q-9 could also be detected (5%). The complex polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholin, unidentified phospholipids, lipids and two glycolipids. DNA-DNA hybridizations between CC-M15-8T and Paracoccus beibuensis LMG 25871T, Paracoccus aestuarii DSM 19484T, P. zeaxanthinifacienss LMG 21993T and P. homiensis KACC 11518T resulted in values of 24.9% (34.8%, reciprocal analysis), 15.7% (17.5%, reciprocal analysis), 17.7% (23.4%, reciprocal analysis), and 16.0%, respectively. These data as well as the physiological and biochemical tests allowing a phenotypic differentiation of strain CC-M15-8T from the most closely related Paracoccus species it is concluded, that CC-M15-8T represents novel species of the genus Paracoccus, for which we propose the name Paracoccus rhizosphaerae sp. nov. The type strain is CC-CCM15-8T (= LMG 26205T = CCM 7904T).

Ecological Succession of Bacterial Communities During Conventionalization of Germ-Free Mice

Little is known about the dynamics of early ecological succession during experimental conventionalization of the GI tract; thus, we measured changes in bacterial communities over time, at two different mucosal sites (cecum and jejunum), using germ-free C57BL/6 mice as the recipients of cecal contents (input community) from a C57BL/6 donor mouse. Bacterial communities were monitored using pyrosequencing of 16S rRNA gene amplicon libraries from the cecum and jejunum and analyzed by a variety of ecological metrics. Bacterial communities, at day 1 post-conventionalization, in the cecum and jejunum had lower diversity and were distinct from the input community (dominated by either Escherichia or Bacteroides). However, by days 7 and 21, the recipient communities had become significantly diverse and the cecal communities resembled those of the donor and donor littermates confirming that the transfer of cecal contents will result in reassembly of the community in the cecum 7 - 21 days later. However, bacterial communities in the recipient jejunum displayed significant structural heterogeneity compared to each other, the donor inoculum or the donor littermates, suggesting that the bacterial community of the jejunum is more dynamic during the first 21 days of conventionalization. This study demonstrates that (A) mature input communities do not simply reassemble at mucosal sites during conventionalization - they first transform into a "pioneering" community and over time take on the appearance, in membership and structure, to the original input community and (B) the specific mucosal environment plays a role in shaping the community.

Sex Ratios in the Arctic-do Man-made Chemicals Matter?

The objective was to analyze the variation of secondary sex ratios across the Arctic and to estimate the time trend. The rationale for this was claims in news media that, in the Arctic, sex ratios have become reduced due to exposure to anthropogenic contaminants in the environment.

The Evaluation of E-Cadherin and Vimentin As Biomarkers of Clinical Outcomes Among Patients with Non-small Cell Lung Cancer Treated with Erlotinib As Second- or Third-line Therapy

E-Cadherin and vimentin protein expression was assessed in late stage non-small cell lung cancer tumors from the placebo controlled clinical trial, NCIC-CTG BR.21, to determine if these markers had the potential to predict outcome of erlotinib therapy. E-Cadherin and vimentin protein expression levels were assessed in tumors from 95 patients, who were representative of the overall population, using semi-quantitative immunohistochemistry. The percentage of tumor cells with grades 0, 1, 2, or 3 membrane staining of E-cadherin and cytoplasmic staining of vimentin was measured. Three scoring methods and multiple cut-offs were explored to determine if these markers were able to divide patients into groups with different overall survival (OS). A cut-off point for E-cadherin of ≥40% tumor cells with staining of +2 and +3 and a cut-off for vimentin of ≥10% of tumors cell with any staining provided the optimal stratification. The OS hazard ratio (HR) for E-cadherin(+) versus E-cadherin(-) in the erlotinib-treated patients was 0.68 (0.35-1.33) compared with 1.48 (0.69-3.15) in the placebo patients and the OS (HR) for erlotinib versus placebo was 0.47 (0.26-0.88) in E-cadherin(+) patients compared with 1.12 (0.52-2.44) in the E-cadherin(-) patients. The OS (HR) for vimentin(+) versus vimentin(-) in the erlotinib-treated patients was 0.65 (0.31-1.38) compared to 2.32 (1.09-4.94) in the placebo-treated patients and the OS (HR) for erlotinib versus placebo was 0.26 (0.11-0.63) in vimentin(+) compared to 0.99 (0.55-1.76) in the vimentin(-) patients. Similar trends were observed for progression-free survival and response rate. E-Cadherin and vimentin are biomarkers worthy of additional study as predictive markers of outcome of erlotinib therapy.

Nucleic Acid-Based Therapy Approaches for Huntington's Disease

Huntington's disease (HD) is caused by a dominant mutation that results in an unstable expansion of a CAG repeat in the huntingtin gene leading to a toxic gain of function in huntingtin protein which causes massive neurodegeneration mainly in the striatum and clinical symptoms associated with the disease. Since the mutation has multiple effects in the cell and the precise mechanism of the disease remains to be elucidated, gene therapy approaches have been developed that intervene in different aspects of the condition. These approaches include increasing expression of growth factors, decreasing levels of mutant huntingtin, and restoring cell metabolism and transcriptional balance. The aim of this paper is to outline the nucleic acid-based therapeutic strategies that have been tested to date.

Librarian Integration in a Four-year Medical School Curriculum: a Timeline

The Taubman Health Sciences Library (THL) is integrated in all four years of the University of Michigan Medical School (UMMS) curriculum. Information resources are introduced at strategic points throughout the curriculum so that students receive training at times when they are most likely to need the resource. Most of the core instruction sessions are taught in teams that consist of librarians and UMMS faculty, which provides unique learning opportunities for students. This article describes each THL instruction activity in the four-year undergraduate UMMS curriculum and provides commentary on the overall effectiveness of this integrated approach to instruction.

The Impact of the Georgia Health Sciences University Nursing Faculty Practice on Tobacco Cessation Rates

Nursing faculty practice groups can play a vital role in tobacco cessation in academic medical centers. Outcomes from the Georgia Health Sciences University Nursing Faculty Practice Group Tobacco Cessation Program revealed 64% abstinence outcomes at the end of treatment (N = 160) over a 2-year period from the campus-wide tobacco-free policy initiation. A nurse-led, evidence-based, interdisciplinary approach can be an effective strategy to make a difference in the lives of tobacco-dependent individuals, while at the same time integrating practice with education and research.

Early Peak Temperature and Mortality in Critically Ill Patients with or Without Infection

PURPOSE: To determine whether fever is associated with an increased or decreased risk of death in patients admitted to an intensive care unit (ICU) with infection. METHODS: We evaluated the independent association between peak temperature in the first 24 h after ICU admission and in-hospital mortality according to whether there was an admission diagnosis of infection using a database of admissions to 129 ICUs in Australia and New Zealand (ANZ) (n = 269,078). Subsequently, we sought to confirm or refute the ANZ database findings using a validation cohort of admissions to 201 ICUs in the UK (n = 366,973). RESULTS: A total of 29,083/269,078 (10.8%) ANZ patients and 103,191/366,973 (28.1%) of UK patients were categorised as having an infection. In the ANZ cohort, adjusted in-hospital mortality risk progressively decreased with increasing peak temperature in patients with infection. Relative to the risk at 36.5-36.9°C, the lowest risk was at 39-39.4°C (adjusted OR 0.56; 95% CI 0.48-0.66). In patients without infection, the adjusted mortality risk progressively increased above 39.0°C (adjusted OR 2.07 at 40.0°C or above; 95% CI 1.68-2.55). In the UK cohort, findings were similar with adjusted odds ratios at corresponding temperatures of 0.77 (95% CI 0.71-0.85) and 1.94 (95% CI 1.60-2.34) for infection and non-infection groups, respectively. CONCLUSIONS: Elevated peak temperature in the first 24 h in ICU is associated with decreased in-hospital mortality in critically ill patients with an infection; randomised trials are needed to determine whether controlling fever increases mortality in such patients.

Limitations of Perturbative Techniques in the Analysis of Rhythms and Oscillations

Perturbation theory is an important tool in the analysis of oscillators and their response to external stimuli. It is predicated on the assumption that the perturbations in question are "sufficiently weak", an assumption that is not always valid when perturbative methods are applied. In this paper, we identify a number of concrete dynamical scenarios in which a standard perturbative technique, based on the infinitesimal phase response curve (PRC), is shown to give different predictions than the full model. Shear-induced chaos, i.e., chaotic behavior that results from the amplification of small perturbations by underlying shear, is missed entirely by the PRC. We show also that the presence of "sticky" phase-space structures tend to cause perturbative techniques to overestimate the frequencies and regularity of the oscillations. The phenomena we describe can all be observed in a simple 2D neuron model, which we choose for illustration as the PRC is widely used in mathematical neuroscience.

Factor Structure of the Disgust Scale-Revised in an Adolescent Sample

Although recent research with the Disgust Scale-Revised (DS-R) has contributed to current knowledge regarding the structure of disgust, this line of research has exclusively employed adult samples. The current study extended existing research by examining the factor structure of the DS-R in an adolescent sample (N = 637). Exploratory factor analysis revealed three factors: Contagion, Mortality, and Contact Disgust. Subsequent to removing three items due to inadequate factor loadings, confirmatory factor analysis provided support for the 3-factor model across gender, grade level, and racial subgroups. Tests of item-intercept invariance also revealed no differences in item means across grade level. However, three and four items were associated with differences across race and gender, respectively. Latent factor means were also found to be invariant across racial groups and grade level, but not across gender. Implications of the DS-R factor structure in this adolescent sample and its domains are discussed.

The Relationship Between ADHD Symptoms, Mood Instability, and Self-Reported Offending

Objective: To investigate the relative importance of ADHD symptoms, mood instability, and antisocial personality disorder traits in predicting self-reported offending. Method: A total of 295 Icelandic students completed two scales of offending behavior and measures of ADHD symptoms, mood instability, and antisocial personality traits. Results: Self-reported offending from the two independent scales correlated significantly with ADHD symptoms, mood instability, and antisocial personality traits with medium to large effect size. Multiple regressions showed that ADHD symptoms contributed to the two outcome measures beyond that of age and gender with a medium effect size. The ADHD effects were only partly mediated by mood instability and antisocial personality traits for general offending but were almost completely mediated by the more reactive measure of antisocial behavior. Conclusion: ADHD appears to be a potential risk factor for general offending in its own right irrespective of the presence of comorbidity, whereas mood instability is more important with regard to reactive behavior. (J. of Att. Dis. 2011; XX(X) 1-XX).

Acute Dialysis Risk in Living Kidney Donors

BACKGROUND: Reduced kidney function confers a higher risk of acute kidney injury at the time of an inciting event, such as sepsis. Whether the same is true in those with reduced renal mass from living kidney donation is unknown.METHODS: We conducted a population-based matched cohort study of all living kidney donors in the province of Ontario, Canada who underwent donor nephrectomy from 1992 to 2009. We manually reviewed the medical records of these living kidney donors and linked this information to provincial health care databases. Non-donors were selected from the healthiest segment of the general population.RESULTS: There were 2027 donors and 20 270 matched non-donors. The median age was 43 years (interquartile range 34-50) and individuals were followed for a median of 6.6 years (maximum 17.7 years). The primary outcome was acute dialysis during any hospital stay. Reasons for hospitalization included infectious diseases, cardiovascular diseases and hematological malignancies. Only one donor received acute dialysis in follow-up (6.5 events per 100 000 person-years), a rate which was statistically no different than 14 non-donors (9.4 events per 100 000 person-years).CONCLUSIONS: These results are reassuring for the practice of living kidney donation. Longer follow-up of this and other donor cohorts will provide more precise estimates about this risk.

Cognitive Dysfunction in Psychiatric Disorders: Characteristics, Causes and the Quest for Improved Therapy

Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.

A Phase 2 Cancer Chemoprevention Biomarker Trial of Isoflavone G-2535 (Genistein) in Presurgical Bladder Cancer Patients

The soy compound genistein has been observed preclinically to inhibit bladder cancer growth with one potential mechanism being inhibition of epidermal growth factor receptor phosphorylation (p-EGFR). A phase 2 randomized, placebo-controlled trial investigated whether daily, oral genistein (300 or 600 mg/day as the purified soy extract G-2535) for 14-21 days before surgery alters molecular pathways in bladder epithelial tissue in 59 subjects diagnosed with urothelial bladder cancer (median age 71). G-2535 treatment was well tolerated; observed toxicities were primarily mild to moderate gastrointestinal or metabolic and usually not attributed to study drug. Genistein was detected in plasma and urine of subjects receiving G-2535 at concentrations greater than placebo subjects' but were not dose-dependent. Reduction in bladder cancer tissue p-EGFR staining between the placebo arm and the combined genistein arms was significant at the protocol-specified significance level of 0.10 (p=0.07). This difference was most prominent when comparing the 300 mg group vs placebo (p=0.015), but there was no significant reduction in p-EGFR staining between the 600 mg group and placebo. No difference in normal bladder epithelium p-EGFR staining was observed between treatment groups. No significant differences in tumor tissue staining between treatment groups was observed for COX-2, Ki-67, activated caspase 3, Akt, p-Akt, MAPK, or p-MAPK. No significant differences in urinary Survivin or BLCA-4 levels between treatment groups were observed. Genistein displayed a possible bimodal effect (more effective at the lower dose) on bladder cancer tissue EGFR phosphorylation that should be evaluated further, possibly in combination with other agents.

Transitions in the Early-life of Late Preterm Infants: Vulnerabilities and Implications for Postpartum Care

The focus of this article is on the transition of late preterm infants from hospital to home. The current state of literature related to mortality, morbidities, emergency department visits, and rehospitalization underscores the vulnerability of late preterm infants following discharge from hospital. Universal provision of postpartum care to late preterm infants is viewed as an environmental support intended to facilitate transition of these vulnerable infants from hospital to home. Gaps in provision of postpartum care of late preterm infants are situated within the discussion of guidelines and models of postpartum care (home vs clinic) of late preterm infants.

SNR Increase in Carotid Atheroma MRI: a Comparison of 1.5 T and 3 T

Objectives: This study reports quantitative comparisons of SNR at 1.5 T and 3 T from images of carotid atheroma obtained using a multicontrast, cardiac-gated, blood-suppressed fast spin echo protocol.Methods: 18 subjects, with carotid atherosclerosis (>30% stenosis) confirmed on ultrasound, were imaged on both 1.5 and 3 T systems using phased array coils with matched hardware specifications. T(1)-weighted (T(1)W), T(2)-weighted (T(2)W) and proton density-weighted (PDW) images were acquired with identical scan times. Multiple slices were prescribed to encompass both the carotid bifurcation and the plaque. Image quality was quantified using the signal to noise ratio (SNR) and contrast to noise ratio (CNR). A phantom experiment was also performed to validate the SNR method and confirm the size of the improvement in SNR. Comparisons of the SNR values from the vessel wall with muscle and plaque/lumen CNR measurements were performed at a patient level. To account for the multiple comparisons a Bonferroni correction was applied.Results: One subject was excluded from the protocol due to image quality and protocol failure. The mean improvement in SNR in plaque was 1.9, 2.1 and 2.1 in T(1)W, T(2)W and PDW images respectively. All plaque SNR improvements were statistically significant at the p<0.05 level. The phantom experiment reported an improvement in SNR of 2.4 for PDW images.Conclusions: Significant gains in SNR can be obtained for carotid atheroma imaging at 3 T compared with 1.5 T. There was also a trend towards increased CNR. However, this was not significant after the application of the Bonferroni correction.

CCL11 Elicits Secretion of RNases from Mouse Eosinophils and Their Cell-free Granules

Rapid secretion of eosinophil-associated RNases (EARs), such as the human eosinophilic cationic protein (ECP), from intracellular granules is central to the role of eosinophils in allergic diseases and host immunity. Our knowledge regarding allergic inflammation has advanced based on mouse experimental models. However, unlike human eosinophils, capacities of mouse eosinophils to secrete granule proteins have been controversial. To study mechanisms of mouse eosinophil secretion and EAR release, we combined an RNase assay of mouse EARs with ultrastructural studies. In vitro, mouse eosinophils stimulated with the chemokine eotaxin-1 (CCL11) secreted enzymatically active EARs (EC(50) 5 nM) by piecemeal degranulation. In vivo, in a mouse model of allergic airway inflammation, increased airway eosinophil infiltration (24-fold) correlated with secretion of active RNases (3-fold). Moreover, we found that eosinophilic inflammation in mice can involve eosinophil cytolysis and release of cell-free granules. Cell-free mouse eosinophil granules expressed functional CCR3 receptors and secreted their granule proteins, including EAR and eosinophil peroxidase in response to CCL11. Collectively, these data demonstrate chemokine-dependent secretion of EARs from both intact mouse eosinophils and their cell-free granules, findings pertinent to understanding the pathogenesis of eosinophil-associated diseases, in which EARs are key factors.-Shamri, R., Melo, R. C. N., Young, K. M., B.-B, M., Xenakis, J. J., Spencer, L. A., Weller, P. F. CCL11 elicits secretion of RNases from mouse eosinophils and their cell-free granules.

The Prevalence and Predictors of Airway Hyper-Responsiveness in Sarcoidosis

SUMMARY AT A GLANCE: We found a higher prevalence of airway hyper-responsiveness (AHR) in patients with sarcoidosis using direct (histamine) challenge than indirect (hypertonic saline) challenge, and AHR was inversely associated with baseline % predicted FEV(1) . This suggests that AHR in sarcoidosis reflects the consequences of airway remodelling following inflammation. ABSTRACT: Background and objective:  Obstructive airflow limitation is the most common physiological impairment in sarcoidosis. This study determined the prevalence of airway hyper-responsiveness (AHR) in sarcoidosis, the correlation between responses to direct (using histamine) and indirect (using hypertonic saline) bronchial challenge, and the clinical, physiological and radiological predictors of AHR. Methods:  Subjects with sarcoidosis and a baseline forced expiratory volume in one second (FEV(1) ) >35% predicted underwent hypertonic and histamine challenge, lung function testing and HRCT of the chest. AHR was defined as a 15% fall in FEV(1) to hypertonic saline, and a 20% fall in FEV(1) to histamine. Results:  The 52 subjects had well preserved lung function (FEV(1 ) = 2.8L ± 0.7, 87% predicted). AHR was detected in 5/47 (11%) to hypertonic saline and 19/43 (44%) to histamine challenge. On univariate analysis, response to histamine challenge was predicted by conglomerate fibrosis (p = 0.02) and reticular pattern (p = 0.03) on HRCT. The baseline % predicted FEV(1) was significantly inversely associated with AHR on univariate (p = 0.004), and multivariate analysis (p = 0.01) when adjusted by HRCT patterns. Conclusions:  The higher prevalence of AHR using histamine challenge than hypertonic saline challenge, and the association with baseline % predicted FEV(1) , suggests that the AHR in sarcoidosis may reflect the consequences of airway remodelling following inflammation. © 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.

Genetic Susceptibility to Invasive Meningococcal Disease: MBL2 Structural Polymorphisms Revisited in a Large Case-control Study and a Systematic Review

Invasive infection caused by Neisseria meningitidis is a worldwide public health problem. Previous reports have indicated that carriage of common 'defective' structural polymorphisms of the host mannose-binding lectin gene (MBL2) greatly increases an individual's risk of developing the disease. We report the largest case-control study so far to investigate the effect of these polymorphisms in meningococcal disease (296 PCR-positive cases and 5196 population controls, all of European ancestry) and demonstrate that no change in risk is associated with the polymorphisms overall or in any age-defined subgroup. This finding contrasts with two smaller studies that reported an increase in risk. A systematic review of all studies of MBL2 polymorphisms in people of European ancestry published since 1999, including 24 693 individuals, revealed a population frequency of the combined 'defective'MBL2 allele of 0.230 (95% confidence limits: 0.226-0.234). The past reported associations of increased risk of meningococcal disease were because of low 'defective' allele frequencies in their study control populations (0.13 and 0.04) that indicate systematic problems with the studies. The data from our study and all other available evidence indicate that MBL2 structural polymorphisms do not predispose children or adults to invasive meningococcal disease.

Where Do Hands Go? An Audit of Sequential Hand-touch Events on a Hospital Ward

BACKGROUND: Reservoirs of pathogens could establish themselves at forgotten sites on a ward, posing a continued risk for transmission to patients via unwashed hands. AIM: To track potential spread of organisms between surfaces and patients, and to gain a greater understanding into transmission pathways of pathogens during patient care. METHODS: Hand-touch activities were audited covertly for 40 × 30 min sessions during summer and winter, and included hand hygiene on entry; contact with near-patient sites; patient contact; contact with clinical equipment; hand hygiene on exit; and contact with sites outside the room. FINDINGS: There were 104 entries overall: 77 clinical staff (59 nurses; 18 doctors), 21 domestic staff, one pharmacist and five relatives. Hand-hygiene compliance among clinical staff before and after entry was 25% (38/154), with higher compliance during 20 summer periods [47%; 95% confidence interval (CI): 35.6-58.8] than during 20 winter periods (7%; 95% CI: 3.2-14.4; P < 0.0001). More than half of the staff (58%; 45/77) touched the patient. Staff were more likely to clean their hands prior to contact with a patient [odds ratio (OR): 3.44; 95% CI: 0.94-16.0); P = 0.059] and sites beside the patient (OR: 6.76; 95% CI: 1.40-65.77; P = 0.0067). Nearly half (48%; 37/77) handled patient notes and 25% touched the bed. Most frequently handled equipment inside the room were intravenous drip (30%) and blood pressure stand (13%), and computer (26%), notes trolley (23%) and telephone (21%) outside the room. CONCLUSION: Hand-hygiene compliance remains poor during covert observation; understanding the most frequent interactions between hands and surfaces could target sites for cleaning.

Enhancer Decommissioning by LSD1 During Embryonic Stem Cell Differentiation

Transcription factors and chromatin modifiers are important in the programming and reprogramming of cellular states during development. Transcription factors bind to enhancer elements and recruit coactivators and chromatin-modifying enzymes to facilitate transcription initiation. During differentiation a subset of these enhancers must be silenced, but the mechanisms underlying enhancer silencing are poorly understood. Here we show that the histone demethylase lysine-specific demethylase 1 (LSD1; ref. 5), which demethylates histone H3 on Lys 4 or Lys 9 (H3K4/K9), is essential in decommissioning enhancers during the differentiation of mouse embryonic stem cells (ESCs). LSD1 occupies enhancers of active genes that are critical for control of the state of ESCs. However, LSD1 is not essential for the maintenance of ESC identity. Instead, ESCs lacking LSD1 activity fail to differentiate fully, and ESC-specific enhancers fail to undergo the histone demethylation events associated with differentiation. At active enhancers, LSD1 is a component of the NuRD (nucleosome remodelling and histone deacetylase) complex, which contains additional subunits that are necessary for ESC differentiation. We propose that the LSD1-NuRD complex decommissions enhancers of the pluripotency program during differentiation, which is essential for the complete shutdown of the ESC gene expression program and the transition to new cell states.

Precision Measurement: A Comb in the Extreme Ultraviolet

Critical Difference Applied to Exercise-induced Oxidative Stress: the Dilemma of Distinguishing Biological from Statistical Change

Even though intense exercise has traditionally been associated with a statistically significant accumulation of blood-borne biomarkers of free radical-mediated lipid peroxidation, it remains to be determined if the oxidative stress response is biologically significant. To examine biological significance, we calculated the critical difference of selected biomarkers of oxidants-antioxidants in the peripheral circulation of ten male subjects aged 24 ± 3 years. Venous blood was drawn in the resting supine position every hour over an 8-h period (Study 1). As proof-of-concept, supine venous blood was also obtained at rest and following maximal cycling exercise in a separate group of 13 males, mean age 22 ± 3 years (Study 2). The critical difference of electron paramagnetic resonance spin-trapped alkoxyl free radicals, lipid hydroperoxides, malondialdehyde, ascorbic acid, retinol, lycopene, α-tocopherol, β-carotene and α-carotene was calculated as 121%, 28%, 50%, 9%, 29%, 106%, 13%, 28% and 107%, respectively (Study 1). Maximal exercise was associated with a statistically significant (P < 0.05 vs. rest) reduction in α-tocopherol and retinol, and a corresponding rise in alkoxyl free radicals and lipid hydroperoxides (Study 2). However, these changes were all within the critical difference percentage value. In conclusion, these findings highlight the importance of distinguishing biological from statistical significance when assessing the physiological and clinical impact of exercise-induced oxidative stress.

A Molecular Guide to the Taxonomy of Arbuscular Mycorrhizal Fungi

Anticoagulant Activity of Select Dietary Supplements

This review considers the potential of certain dietary supplements, including garlic, Ginkgo biloba, ginger, ginseng, fish oil, and vitamin E, to interfere with hemostasis. Dietary supplements are common components of the diet in the United States, with about half the US adult population taking some type of dietary supplement regularly. It has been suggested that some supplements could adversely affect coagulation when taken alone or in combination with antiplatelet medications. Supplements could alter hemostasis by a variety of mechanisms, such as reducing platelet aggregation or inhibiting arachidonic acid, a cellular signaling messenger and inflammatory intermediate. To conduct this review, multiple databases were searched using a variety of search terms to ensure relevant papers were located. Moderate to severe adverse events, such as spinal epidural hematoma, spontaneous intracerebral hemorrhage, retrobulbar hemorrhage, subarachnoid hemorrhage, spontaneous hyphema, and postoperative bleeding, have occasionally been anecdotally associated with consumption of dietary supplements. However, the number of controlled studies in the literature is too limited to demonstrate consistent anticoagulant effects of dietary supplements alone or in combination with drug therapy.

In-Vitro Studies of Toxic Shock Toxin-1 Secreting Staphylococcus Aureus and Implications for Burn Care in Children

BACKGROUND: The main etiologic agent of toxic shock syndrome (TSS) is the toxic shock syndrome toxin-1 (TSST-1) protein secreted by Staphylococcus aureus. Diagnosis of TSS is difficult and is significantly under-diagnosed in young children with burns due to the non-specific presentation coupled with a rapid deterioration in patient condition. METHODS: The lytic and cytolytic activity of a number of clinical and laboratory TSST-1 positive strains of methicillin-susceptible S. aureus ( MSSA 101, 253, 279 and RN4282 respectively) and Pseudomonas aeruginosa PAO1 strain were tested in-vitro using an assay designed to assess the relative exotoxin activity of bacteria using phospholipid vesicles and a T-cell toxicity assay. In addition, the activity of lytic exotoxins such as delta-toxin and the secretion of non-lytic TSST-1 toxin from S. aureus was measured using the vesicle assay and Western blotting over the 20 hour growth of TSST-1 positive S. aureus culture. RESULTS: Both the vesicle and T-cell assays suggest a lytic exotoxin-mediated mechanism of vesicle rupture and T - cell death, with high levels of vesicle lysis and T-cell toxicity. Importantly the clinical TSST-1 positive MSSA strains exhibited lytic exotoxin production as well as TSST-1 expression as confirmed by Western blot. CONCLUSION: We suggest that there is no correlation between the expression of TSST-1 and lack of exotoxin production. We also suggest that apurulence in a S. aureus infected burn wound in a child should not be used to rule out TSS.

Digital Chest Radiography Image Quality Assessment with Dose Reduction

A retrospective study of digital chest radiography was performed to compare the image quality and dose parameters from two X-ray rooms in different areas of the same hospital using identical X-ray units but different local protocol for obtaining chest PA and lateral radiographs. Image quality of radiographs was assessed from the printed films using well established European guidelines and modified criteria. Patient entrance surface air kerma was calculated using technical data recorded for each radiograph and measured output of the X-ray unit. Effective dose and dose to radiosensitive organs was estimated using dose calculation software PCXMC. There was no statistical significant difference in the evaluated image quality using either technique, median entrance surface air kerma to the patient reduced significantly with added filtration technique and use of normal density setting. Phantom measurements indicated that an additional filtration of 0.1 mm Cu + 1 mm Al in the X-ray beam alone reduced the entrance surface air kerma by 35%.

Comparing Retrospective Reports to Real-Time/Real-Place Mobile Assessments in Individuals With Schizophrenia and a Nonclinical Comparison Group

Retrospective reports are often used as the primary source of information for important diagnostic decisions, treatment, and clinical research. Whether such reports accurately represent individuals' past experiences in the context of a serious mental illness such as schizophrenia is unclear. In the current study, 24 individuals with schizophrenia and 26 nonclinical participants used a mobile device to complete multiple real-time/real-place assessments daily, over 7 consecutive days. At the end of the week, participants were also asked to provide a retrospective report summarizing the same period. Comparison of the data captured by the 2 methods showed that participants from both groups retrospectively overestimated the intensity of negative and positive daily experiences. In the clinical group, overestimations for affect were greater than for psychotic symptoms, which were relatively comparable to their retrospective reports. In both samples, retrospective reports were more closely associated with the week's average than the most intense or most recent ratings captured with a mobile device. Multilevel modeling revealed that much of the variability in weekly assessments was not explained by between-person differences and could not be captured by a single retrospective estimate. Based on the findings of this study, clinicians and researchers should be aware that while retrospective summary reports of the severity of certain symptoms compare relatively well with average momentary ratings, they are limited in their ability to capture variability in one's affective or psychotic experiences over time.

The Etiology of Observed Negative Emotionality from 14 to 24 months

We examined the magnitude of genetic and environmental influences on observed negative emotionality at age 14, 20, and 24 months. Participants were 403 same-sex twin pairs recruited from the Longitudinal Twin Study whose emotional responses to four different situations were coded by independent raters. Negative emotionality showed significant consistency across settings, and there was evidence of a latent underlying negative emotionality construct. Heritability decreased, and the magnitude of shared environmental influences increased, for the latent negative emotionality construct from age 14 to 24 months. There were significant correlations between negative emotionality assessed at age 14, 20, and 24 months, and results suggested common genetic and shared environmental influences affecting negative emotionality across age, and that age-specific influences are limited to non-shared environmental influences, which include measurement error.

Squat Exercise Biomechanics During Short-radius Centrifugation

Centrifuge-induced artificial gravity (AG) with exercise is a promising comprehensive countermeasure against the physiological de-conditioning that results from exposure to weightlessness. However, body movements onboard a rotating centrifuge are affected by both the gravity gradient and Coriolis accelerations. The effect of centrifugation on squat exercise biomechanics was investigated, and differences between AG and upright squat biomechanics were quantified.

Pyridine Alkaloids from Senna Multijuga As Acetylcholinesterase Inhibitors

As part of an ongoing research project on Senna and Cassia species, five new pyridine alkaloids, namely, 12'-hydroxy-7'-multijuguinol (1), 12'-hydroxy-8'-multijuguinol (2), methyl multijuguinate (3), 7'-multijuguinol (4), and 8'-multijuguinol (5), were isolated from the leaves of Senna multijuga (syn. Cassiamultijuga). Their structures were elucidated on the basis of spectroscopic data analysis. Mass spectrometry was used for confirmation of the positions of the hydroxy groups in the side-chains of 1, 2, 4, and 5. All compounds exhibited weak in vitro acetylcholinesterase inhibitory activity as compared with the standard compound physostigmine.

Clogging Influence on Metals Migration and Removal in Sub-surface Flow Constructed Wetlands

Chromium (Cr) and Nickel (Ni) removal from secondary effluent has been evaluated in a four year research program to determine the effectiveness of Sub-Surface Flow (SSF) Constructed Wetlands (cw(s)). Tests were performed in small scale (10l/h) and full scale (150m(3)/d) SSF cw(s). Metals removal was also assessed as a function of increased clogging that occurred in the cw(s) over the course of the study. Cr and Ni content were evaluated in sediments at various locations along the flow path and in plant tissues by sampling Phragmites australis roots, stems and leaves. Clogging was evaluated by measuring hydraulic conductivity at the same sampling locations at the beginning and at the end of the experiment. Residence Time Distribution (RTD) curves were also assessed at the beginning and after 48months; the skewness of the RTDs increased over this period. Proportionality between increasing clogging and sediment accumulation of metals was observed, especially for Ni. Adsorption to the original matrix and the accumulated sediment is a removal mechanism consistent with available data.

The Influence of Cattle Breed on Susceptibility to Bovine Tuberculosis in Ethiopia

Bovine tuberculosis in domestic livestock such as cattle is an economically important disease with zoonotic potential, particularly in countries with emerging economies. We discuss the findings of recent epidemiological and immunological studies conducted in Ethiopia on host susceptibility differences between native zebu and the exotic Holstein-Friesian cattle that are increasingly part of the Ethiopian National herd, due to the drive to increase milk yields. These findings support the hypothesis that native Zebu cattle are more resistant to bovine tuberculosis. We also summarise the results of experimental infections that support the epidemiological data, and of laboratory experiments that suggest a role for the innate immune response, and in particular interleukin-6, in the outcome of bovine tuberculosis infection.

KRAS Mutations in Ovarian Low-grade Endometrioid Adenocarcinoma: Association with Concurrent Endometriosis

The association between ovarian endometrioid adenocarcinoma and endometriosis is well established. However, not all endometrioid adenocarcinomas are directly related to endometriosis, and it has been suggested that there may be clinicopathologic differences between endometriosis-positive and endometriosis-negative tumors. Molecular alterations in endometrioid adenocarcinoma include KRAS and BRAF mutations, but the incidence of these abnormalities in previous reports has been highly variable (0%-36% and 0%-24%, respectively). This may be explained by relatively small sample sizes in earlier studies but could also reflect difficulties in accurately classifying high-grade ovarian malignancies. In the current study, we investigated KRAS and BRAF mutations in 78 low-grade (FIGO grade 1 and 2) endometrioid adenocarcinomas and compared the results with the presence of endometriosis in the tumor-associated ovary and/or in other pelvic sites. KRAS mutations were identified in 12 (29%) of 42 endometriosis-associated endometrioid adenocarcinomas with satisfactory analysis but in only 1 (3%) of 29 tumors in which endometriosis was not identified. BRAF mutation was identified only in a single endometriosis-associated case. These findings support the hypothesis that endometriosis-associated and independent endometrioid adenocarcinoma may develop via different molecular pathways and that KRAS mutations have an important role only in the former tumors. In contrast, BRAF mutations do not appear to have a significant role in either endometrioid adenocarcinoma subgroup. This may be relevant to future targeted therapies in patients with high-stage or recurrent disease and indicate that histopathologists should carefully examine endometrioid adenocarcinoma specimens, including nonneoplastic tissues, for the presence of endometriosis.

Blood Flow Restriction: Rationale for Improving Bone

Low intensity exercise with blood flow restriction has been shown to increase muscle hypertrophy and strength similar to high intensity resistance exercise. Interestingly, low intensity resistance exercise to failure has shown the same muscle protein synthesis response as higher intensity exercise, questioning the need for blood flow restriction during low intensity exercise. The purpose of this manuscript is to discuss the mechanisms and potential benefits of blood flow restricted exercise on bone adaptation and provide rationale as to why low load resistance exercise to failure would be unlikely to produce these benefits. The studies completed thus far support the hypothesis that training with blood flow restriction may provide not only a novel modality to induce adaptation in muscle but also bone, which was previously thought to only occur with higher intensity/impact exercise. We hypothesize that the main mechanism behind the proposed favorable bone responses observed thus far is through increased intramedullary pressure and interstitial fluid flow within the bone caused by venous occlusion. Therefore, although similar muscular benefits may be observed from low intensity exercise performed to failure (e.g. strength, hypertrophy, and endurance), the response of bone might be different, highlighting the potential importance of the blood flow restriction stimulus.

The Fourth INTERMACS Annual Report: 4,000 Implants and Counting

The Fourth Annual Report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) summarizes and analyzes the first 5 years of patient and data collection. With more than 4,000 patients entered into the database, the evolution of pump technology, strategy at implant, and pre-implant patient profiles are chronicled. A risk factor analysis of the entire adult primary implant population is provided, and the recent composition of patient profiles is examined. Current actuarial survival with continuous-flow pumps exceeds 80% at 1 year and 70% at 2 years.

Snf1/AMPK Regulates Gcn5 Occupancy, H3 Acetylation and Chromatin Remodelling at S. Cerevisiae ADY2 Promoter

The ability of cells to respond to changes in their environment is mediated by transcription factors that remodel chromatin and reprogram expression of specific subsets of genes. In Saccharomyces cerevisiae, changes in carbon source lead to gene induction by Adr1 and Cat8 that are known to require the upstream function of the Snf1 protein kinase, the central regulator of carbon metabolism, to exert their activating effect. How Snf1 facilitates transcription activation by Adr1 and Cat8 is not known. Here we show that under derepressing conditions, deletion of SNF1 abolishes the increase of histone H3 acetylation at the promoter of the glucose-repressed ADY2 gene, and as a consequence profoundly affects the chromatin structural alterations accompanying transcriptional activation. Adr1 and Cat8 are not required to regulate the acetylation switch and show only a partial influence on chromatin remodelling at this promoter, though their double deletion completely abolishes mRNA accumulation. Finally, we show that under derepressing conditions the recruitment of the histone acetyltransferase Gcn5 is abolished by SNF1 deletion, possibly explaining the lack of increased histone H3 acetylation and nucleosome remodelling. The results highlight a mechanism by which signalling to chromatin provides an essential permissive signal that is required for activation by glucose-responsive transcription factors.

Discovery of [(2R,5R)-5-{[(5-Fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): A Dual Orexin Receptor Antagonist with Potent Sleep-Promoting Properties

Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexin 1 and orexin 2 receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional in vivo activity in preclinical sleep models, and has advanced into phase II clinical trials for the treatment of insomnia.

Silent Intralesional Microhemorrhage As a Risk Factor for Brain Arteriovenous Malformation Rupture

BACKGROUND AND PURPOSE: We investigated whether brain arteriovenous malformation silent intralesional microhemorrhage, that is, asymptomatic bleeding in the nidal compartment, might serve as a marker for increased risk of symptomatic intracranial hemorrhage (ICH). We evaluated 2 markers to assess the occurrence of silent intralesional microhemorrhage: neuroradiological assessment of evidence of old hemorrhage-imaging evidence of bleeding before the outcome events-and hemosiderin positivity in hematoxylin and eosin-stained paraffin block sections. METHODS: We identified cases from our brain arteriovenous malformation database with recorded neuroradiological data or available surgical paraffin blocks. Using 2 end points, index ICH or new ICH after diagnosis (censored at treatment, loss to follow-up, or death), we performed logistic or Cox regression to assess evidence of old hemorrhage and hemosiderin positivity adjusting for age, sex, deep-only venous drainage, maximal brain arteriovenous malformation size, deep location, and associated arterial aneurysms. RESULTS: Evidence of old hemorrhage was present in 6.5% (n=975) of patients and highly predictive of index ICH (P<0.001; OR, 3.97; 95% CI, 2.1-7.5) adjusting for other risk factors. In a multivariable model (n=643), evidence of old hemorrhage was an independent predictor of new ICH (hazard ratio, 3.53; 95% CI, 1.35-9.23; P=0.010). Hemosiderin positivity was found in 36.2% (29.6% in unruptured; 47.8% in ruptured; P=0.04) and associated with index ICH in univariate (OR, 2.18; 95% CI, 1.03-4.61; P=0.042; n=127) and multivariable models (OR, 3.64; 95% CI, 1.11-12.00; P=0.034; n=79). CONCLUSIONS: The prevalence of silent intralesional microhemorrhage is high and there is evidence for an association with both index and subsequent ICH. Further development of means to detect silent intralesional microhemorrhage during brain arteriovenous malformation evaluation may present an opportunity to improve risk stratification, especially for unruptured brain arteriovenous malformations.

Regulation of Prelamin A but Not Lamin C by MiR-9, a Brain-specific MicroRNA

Lamins A and C, alternatively spliced products of the LMNA gene, are key components of the nuclear lamina. The two isoforms are found in similar amounts in most tissues, but we observed an unexpected pattern of expression in the brain. Western blot and immunohistochemistry studies showed that lamin C is abundant in the mouse brain, whereas lamin A and its precursor prelamin A are restricted to endothelial cells and meningeal cells and are absent in neurons and glia. Prelamin A transcript levels were low in the brain, but this finding could not be explained by alternative splicing. In lamin A-only knockin mice, where alternative splicing is absent and all the output of the gene is channeled into prelamin A transcripts, large amounts of lamin A were found in peripheral tissues, but there was very little lamin A in the brain. Also, in knockin mice expressing exclusively progerin (a toxic form of prelamin A found in Hutchinson-Gilford progeria syndrome), the levels of progerin in the brain were extremely low. Further studies showed that prelamin A expression, but not lamin C expression, is down-regulated by a brain-specific microRNA, miR-9. Expression of miR-9 in cultured cells reduced lamin A expression, and this effect was abolished when the miR-9-binding site in the prelamin A 3' UTR was mutated. The down-regulation of prelamin A expression in the brain could explain why mouse models of Hutchinson-Gilford progeria syndrome are free of central nervous system pathology.

Assembly of Reconfigurable One-dimensional Colloidal Superlattices Due to a Synergy of Fundamental Nanoscale Forces

We report that triangular gold nanoprisms in the presence of attractive depletion forces and repulsive electrostatic forces assemble into equilibrium one-dimensional lamellar crystals in solution with interparticle spacings greater than four times the thickness of the nanoprisms. Experimental and theoretical studies reveal that the anomalously large d spacings of the lamellar superlattices are due to a balance between depletion and electrostatic interactions, both of which arise from the surfactant cetyltrimethylammonium bromide. The effects of surfactant concentration, temperature, ionic strength of the solution, and prism edge length on the lattice parameters have been investigated and provide a variety of tools for in situ modulation of these colloidal superstructures. Additionally, we demonstrate a purification procedure based on our observations that can be used to efficiently separate triangular nanoprisms from spherical nanoparticles formed concomitantly during their synthesis.

Human Ovarian Cancer Stem/progenitor Cells Are Stimulated by Doxorubicin but Inhibited by Mullerian Inhibiting Substance

Women with late-stage ovarian cancer usually develop chemotherapeutic-resistant recurrence. It has been theorized that a rare cancer stem cell, which is responsible for the growth and maintenance of the tumor, is also resistant to conventional chemotherapeutics. We have isolated from multiple ovarian cancer cell lines an ovarian cancer stem cell-enriched population marked by CD44, CD24, and Epcam (3+) and by negative selection for Ecadherin (Ecad-) that comprises less than 1% of cancer cells and has increased colony formation and shorter tumor-free intervals in vivo after limiting dilution. Surprisingly, these cells are not only resistant to chemotherapeutics such as doxorubicin, but also are stimulated by it, as evidenced by the significantly increased number of colonies in treated 3+Ecad- cells. Similarly, proliferation of the 3+Ecad- cells in monolayer increased with treatment, by either doxorubicin or cisplatin, compared with the unseparated or cancer stem cell-depleted 3-Ecad+ cells. However, these cells are sensitive to Mullerian inhibiting substance (MIS), which decreased colony formation. MIS inhibits ovarian cancer cells by inducing G1 arrest of the 3+Ecad- subpopulation through the induction of cyclin-dependent kinase inhibitors. 3+Ecad- cells selectively expressed LIN28, which colocalized by immunofluorescence with the 3+ cancer stem cell markers in the human ovarian carcinoma cell line, OVCAR-5, and is also highly expressed in transgenic murine models of ovarian cancer and in other human ovarian cancer cell lines. These results suggest that chemotherapeutics may be stimulative to cancer stem cells and that selective inhibition of these cells by treating with MIS or targeting LIN28 should be considered in the development of therapeutics.

A Controlled Trial of a Cognitive Skills Program for Personality-Disordered Offenders

Objective: There is a need to find effective treatments for individuals with antisocial and borderline personality disorder who are known to be difficult to engage and treat. Many of these individuals share considerable overlap with symptoms of ADHD, hence this study aimed to evaluate the Reasoning and Rehabilitation ADHD program (R&R2 ADHD) among patients with severe personality disorder. Method: A total of 31 males detained in a "dangerous and severe personality disorder" unit completed questionnaires at baseline and post treatment to assess social problem solving, violent attitudes, anger, ADHD symptoms, emotional control, and social functioning. A total of 16 patients participated in the group condition, and their scores were compared with 15 waiting-list controls who received treatment as usual. Results: In all, 76% of group participants completed the program. In contrast to controls, they showed significant improvements in scores with mainly medium effect sizes. Conclusion: R&R2 ADHD was effective in a small sample of severely personality-disordered offenders. (J. of Att. Dis. 2011; XX(X) 1-XX).

Restoration of Adipose Function in Obese, Glucose-tolerant Men Following Pioglitazone Treatment is Associated with CCAAT Enhancer-binding Protein β Upregulation

Obese adipose tissue (AT) exhibits increased macrophage number. Pro-inflammatory CD16+ peripheral monocyte numbers are also reported to increase with obesity. The current study was undertaken to simultaneously investigate obesity-associated changes in CD16+ monocytes and adipose tissue macrophages (ATM). In addition, a pilot randomised placebo controlled trial using the peroxisome proliferator-activated receptor (PPAR) agonists, pioglitazone and fenofibrate was performed to determine their effects on CD14+/CD16+ monocytes, ATM and cardiometabolic and adipose dysfunction indices. Obese glucose-tolerant men (n=32) were randomised to placebo, pioglitazone (30 mg/day) and fenofibrate (160 mg/day) for 12 weeks. A blood sample was taken to assess levels of serum inflammatory markers and circulating CD14+/CD16+ monocyte levels via flow cytometry. A subcutaneous (sc) AT biopsy was performed to determine adipocyte cell surface and AT macrophage (ATM) number, the latter was determined via assessment of CD68 expression by immunohistochemisty (IHC) and real time PCR. SC AT mRNA expression of CCAAT enhancer-binding protein β (CEBPβ), sterol regulatory element-binding protein 1c (SREBP1c), PPARγ2, insulin receptor substrate 1 (IRS-1), glucose transporter type 4 (GLUT 4) and tumour necrosis factor α (TNF-α) were also assessed. Comparisons were made between obese and lean controls (n=16) at baseline, and pre- and post-PPAR agonist treatment. Obese individuals had significantly increased adipocyte cell surface, % CD14+/CD16+ monocyte numbers and ATM number (all p=0.0001). Additionally, serum TNF-α levels were significantly elevated (p=0.017) and adiponectin levels reduced (total: p=0.0001; high: p=0.022) with obesity. ATM number and % of CD14+/CD16+ monocytes correlated significantly (P=0.05). Pioglitazone improved adiponectin levels significantly (p=0.0001), and resulted in the further significant enlargement of adipocytes (p=0.05), without effect on % CD14+/CD16+ or ATM number. Pioglitazone treatment also significantly increased sc AT expression of CEBPβ mRNA. The finding that improvements in obesity-associated insulin resistance following pioglitazone were associated with increased adipocyte cell surface and systemic adiponectin levels, supports the centrality of AT to the cardiometabolic derangement underlying the development of T2D and CVD.

The Rapid Onset of Multiple Squamous Cell Carcinomas in Two Patients Commenced on Ustekinumab As Treatment of Psoriasis

We report the cases of two patients who developed eruptive cutaneous squamous cell carcinomas (SCC) soon after commencement of ustekinumab, as treatment of moderate to severe plaque type psoriasis. Ustekinumab is a human monoclonal antibody with a novel mechanism, selectively targeting the shared p40 subunit of interleukin-12 (IL-12) and IL-23. Its efficacy has been well documented in three large phase-III trials (PHOENIX I, PHEONIX 2, ACCEPT). Safety data on this new biological agent continue to grow. To date, no link between ustekinumab and cutaneous carcinogenesis has been demonstrated and, to our knowledge, these cases are the first of their kind. Importantly, both these patients had independent risk factors for developing non-melanoma skin cancers; however, the specific time correlation with the administration of ustekinumab is of note. Our report suggests that ustekinumab may allow the development of cutaneous carcinomata in predisposed individuals.

Effects of Cyclodextrins on the Flavor of Goat Milk and Its Yogurt

  Goat milk fat includes several branched chain fatty acids (BCFAs), like 4-methyloctanoic acid, which when free, are responsible for goaty flavor. This flavor limits the market opportunities for goat milk. Prior research showed that cyclodextrins (CDs) can reduce goaty flavor, presumably by binding free fatty acids. This research extends that observation. In odor ranking trials in citrate buffer at pH 4.8, β-CD concentrations between 0% and 0.35% were increasingly effective in reducing odor intensity due to 4-methyloctanoic acid, but only when present in high molar excess. α-CD was also effective, but γ-CD was not. In lipase-treated goat milk only β-CD was effective but at much lower molar excess, a difference potentially explained by several factors. One was that BCFAs bind to CDs in marked preference to their straight chain isomers. Displacement experiments with phenolphthalein disproved that hypothesis. The ability of β-CD to reduce goaty flavor intensity extended to yogurt. An analytical panel showed that flavor of goat yogurt was reduced by addition of β-CD, but only if added before heating and fermentation. A hedonic trial showed that consumers preferred unsweetened and sweet/vanilla-flavored goat yogurt more when β-CD was included, P= 0.004 and 0.016, respectively. Males liked all yogurts more than females (P < 0.01), but there was a treatment × gender interaction (P= 0.016) for sweet/vanilla yogurt: sweet/vanilla masked the goaty flavor for males but not females. This results parallels previously demonstrated gender effects for sheepmeat flavor caused by BCFAs. Practical Application:  β-Cyclodextrin masks goaty flavor in yogurt, and with its GRAS status means it could be used in commercial goat yogurts and similar products so the real or perceived nutritional advantages of goat milk are not lost to goaty flavor.

Action is Required to Safeguard the Future of Academic Medicine in the UK

The Diet of Wild Black-fronted Titi Monkeys Callicebus Nigrifrons During a Bamboo Masting Year

Black-fronted titi monkeys, Callicebus nigrifrons, are endemic primates of the Atlantic forest of Brazil, and little is known about their diet and how it is affected by seasonal changes. The aim of this study is to analyze the diet of C. nigrifrons during a bamboo masting year. This study was conducted in the reserve RPPN Santuário do Caraça, MG, and the collection of data was carried out from January 2007 to January 2008 through monthly campaigns. The feeding behaviour of four habituated groups in the same forest fragment was observed. The data were collected through focal animal observations of 10 min each with instantaneous recording of behaviour every 30 s, totalling 220.5 h of observations during 71 field days. The diet of groups consisted of 43.4% fruit, 37.0% seeds, 8.2% leaves, 6.2% flowers, 2.5% animal matter and 2.7% non-identified/other items. At least 51 species of plants were consumed. More than half of the diet comprised only five species: Merostachys fischeriana (bamboo, 32.3%), Solanum cinnamomum (nightshade, 8.7%), Vitex spp. (Lamiaceae, 4.5%), Casearia decandra (wild honeytree, 3.8%) and Amaioua guianensis (woody dioecious species, 3.7%). According to the values obtained from Levins' index analysis (0.05-0.28) our subjects had a narrow diet width. The individuals in this study were able to incorporate significant amounts of bamboo seeds in their diet, and this was inversely related to fruit consumption. In conclusion, C. nigrifrons was able to amply exploit a bamboo masting event, which generated a narrow diet width.

Clinical Implications of the Transversus Abdominis Plane Block in Adults

The transversus abdominis plane (TAP) block is a relatively new regional anesthesia technique that provides analgesia to the parietal peritoneum as well as the skin and muscles of the anterior abdominal wall. It has a high margin of safety and is technically simple to perform, especially under ultrasound guidance. A growing body of evidence supports the use of TAP blocks for a variety of abdominal procedures, yet, widespread adoption of this therapeutic adjunct has been slow. In part, this may be related to the limited sources for anesthesiologists to develop an appreciation for its sound anatomical basis and the versatility of its clinical application. As such, we provide a brief historical perspective on the TAP block, describe relevant anatomy, review current techniques, discuss pharmacologic considerations, and summarize the existing literature regarding its clinical utility with an emphasis on recently published studies that have not been included in other systematic reviews or meta-analyses.

The Effect of Lutein- and Zeaxanthin-rich Foods V. Supplements on Macular Pigment Level and Serological Markers of Endothelial Activation, Inflammation and Oxidation: Pilot Studies in Healthy Volunteers

The aim of the present study was to compare the effect of lutein- and zeaxanthin-rich foods and supplements on macular pigment level (MPL) and serological markers of endothelial activation, inflammation and oxidation in healthy volunteers. We conducted two 8-week intervention studies. Study 1 (n 52) subjects were randomised to receive either carrot juice (a carotene-rich food) or spinach powder (a lutein- and zeaxanthin-rich food) for 8 weeks. Study 2 subjects (n 75) received supplements containing lutein and zeaxanthin, β-carotene, or placebo for 8 weeks in a randomised, double-blind, placebo-controlled trial. MPL, serum concentrations of lipid-soluble antioxidants, inter-cellular adhesion molecule 1, vascular cell adhesion molecule 1, C-reactive protein and F2-isoprostane levels were assessed at baseline and post-intervention in both studies. In these intervention studies, no effects on MPL or markers of endothelial activation, inflammation or oxidation were observed. However, the change in serum lutein and zeaxanthin was associated or tended to be associated with the change in MPL in those receiving lutein- and zeaxanthin-rich foods (lutein r 0·40, P = 0·05; zeaxanthin r 0·30, P = 0·14) or the lutein and zeaxanthin supplement (lutein r 0·43, P = 0·03; zeaxanthin r 0·22, P = 0·28). In both studies, the change in MPL was associated with baseline MPL (food study r - 0·54, P < 0·001; supplement study r - 0·40, P < 0·001). We conclude that this 8-week supplementation with lutein and zeaxanthin, whether as foods or as supplements, had no significant effect on MPL or serological markers of endothelial activation, inflammation and oxidation in healthy volunteers, but may improve MPL in the highest serum responders and in those with initially low MPL.

Penile Doppler Sonographic and Clinical Characteristics in Peyronie's Disease And/or Erectile Dysfunction: an Analysis of 1500 Men with Male Sexual Dysfunction

Study Type - Therapy (cohort) Level of Evidence 4 What's known on the subject? and What does the study add? Penile colour Doppler ultrasonography (CDU) can be an invaluable investigative tool to characterize penile abnormalities to complement clinical history and physical examination in the evaluation of men with Peyronie's disease (PD) and/or erectile dysfunction (ED). Although CDU findings between men with PD and those with ED were not markedly different, subtle differences were observed. The classic penile CDU findings in men with PD comprise tunical thickening, intracavernosal fibrosis, septal fibrosis and intracavernosal calcification, while, in men with ED, low peak systolic velocity and high end-diastolic velocity are found on penile haemodynamics. Previously published studies have focused predominantly on either ED or PD exclusively, or examine the risk of progression to ED in the PD population. To our knowledge, this is the largest and most comprehensive analysis of penile CDU and clinical findings in men with PD and/or ED. The large sample size and multivariable analysis allow meaningful interpretation of the results. This study has found some substantial differences in the penile CDU findings of men with PD and/or ED that have not previously been reported. Although the risk factors of ED may be greater than those for PD, there is crossover in age, cardiovascular risk factors, trauma and penile CDU findings in men with PD and/or ED. OBJECTIVE: •  To explore the differences in penile colour Doppler ultrasonography (CDU) findings between men with Peyronie's disease (PD) and those with erectile dysfunction (ED). MATERIALS AND METHODS: •  Patients presenting with PD and/or ED who underwent penile CDU were recruited to the study. •  Patient demographics, comorbidities, International Index of Erectile Function-5 scores, previous therapies and physical findings were documented. •  Penile curvature, presence of tunical thickening, septal fibrosis, intracavernosal fibrosis and calcification, and cavernosal vascular status were recorded. RESULTS: •  A total of 1500 men underwent penile CDU during the 10-year period. Of these men, 891 men presented with PD and 609 men had ED only. •  Men with ED had higher rates of diabetes and coronary artery disease (P < 0.05). •  Isolated tunical thickening was more common in older men and in the PD cohort. The presence of intracavernosal fibrosis correlated strongly with difficulty maintaining erection (P < 0.05). Impaired cavernosal arterial flow was observed in men with decrease penile rigidity and penile pain, while higher end-diastolic velocities were found in men with difficulty maintaining erection and tunical thickening on penile CDU. CONCLUSIONS: •  Men with PD and ED had many similarities and differences on penile CDU. •  Penile CDU continues to be an invaluable clinical tool in the management of men with male sexual dysfunction.

Impact of Deleting 5 DSM-IV Personality Disorders on Prevalence, Comorbidity, and the Association Between Personality Disorder Pathology and Psychosocial Morbidity

OBJECTIVE: A high rate of comorbidity among the personality disorders has been consistently identified as a problem. To address the problem of excessive comorbidity, the DSM-5 Personality and Personality Disorders Work Group recommended reducing the number of specific personality disorder diagnoses from 10 to 5 by eliminating paranoid, schizoid, histrionic, narcissistic, and dependent personality disorders. No study has examined the impact of this change. The present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project examined the impact of eliminating these 5 personality disorders on the prevalence of personality disorders in a large sample of psychiatric outpatients presenting for treatment, comorbidity among the personality disorders, and association with psychosocial morbidity. METHOD: From September 1997 to June 2008, 2,150 psychiatric patients presenting to the Rhode Island Hospital outpatient practice were evaluated with semistructured diagnostic interviews for DSM-IV Axis I and Axis II disorders and measures of psychosocial morbidity. RESULTS: More than one-quarter of the patients were diagnosed with one of the 10 DSM-IV personality disorders (28.6%, n = 614). When 5 personality disorders were excluded from consideration, then 25.8% (n = 555) were diagnosed with at least 1 of the 5 personality disorders proposed for retention in DSM-5, and the comorbidity rate dropped from 29.8% to 21.3%. Compared to patients without a personality disorder, the patients with either a retained or an excluded personality disorder had greater psychosocial morbidity. There was little difference in psychosocial morbidity between patients with a retained and an excluded personality disorder. CONCLUSIONS: The Personality and Personality Disorders Work Group's desired goal of reducing comorbidity would be achieved by deleting 5 personality disorders, although comorbidity would not be eliminated. The reduction of comorbidity could come with a cost of false-negative diagnoses. The results therefore do not provide unambiguous support for the DSM-5 proposed elimination of 5 personality disorders.

High Levels of Nuclear MYC Protein Predict the Presence of MYC Rearrangement in Diffuse Large B-cell Lymphoma

Determining the presence of MYC gene rearrangements is becoming an increasingly important part of the diagnostic workup in aggressive lymphoma. Cytogenetic MYC alterations aid in differentiating diffuse large B-cell lymphoma (DLBCL) from Burkitt lymphoma. In addition, MYC aberrations are associated with poor prognosis in DLBCL. Fluorescence in situ hybridization and karyotyping are standard tests for detecting MYC aberrations, but these techniques are laborious and expensive. Here, we studied MYC status of 219 DLBCLs and Burkitt lymphomas using fluorescence in situ hybridization, immunohistochemistry, and quantitative real-time polymerase chain reaction (QRT-PCR). Overall, 15% of the cases had an MYC break. QRT-PCR analysis of MYC expression showed that 72% of DLBCLs with an MYC break had aberrantly high or low levels of MYC transcript. Excluding the cases with aberrantly low MYC expression, we found a significant positive correlation between levels of MYC transcripts and MYC tumor cells; however, QRT-PCR is not readily applicable as a screening tool. Immunohistochemically, all tumors showed a nuclear staining pattern that was simple to evaluate. The percentage of MYC lymphoma cells correlated closely with MYC rearrangement status. In all, 93% of cases with an MYC break had ≥80% MYC cells, in contrast to 3% of nonrearranged cases (P<0.0001). Receiver operating characteristic curve analysis showed ≥70% MYC tumor cells to be the optimal cutoff (sensitivity=100%, specificity=93%). Area under the receiver operating characteristic curve was 0.992, indicating that immunostaining for Myc protein is an excellent screening test to predict whether an MYC rearrangement is present.

Overweight and Obesity in Military Personnel: Socio-demographic Predictors

In the United States (U.S.), nationally representative civilian studies have shown that Body Mass Index (BMI) is associated with select socio-demographic characteristics. Active-duty military personnel are not included in these surveys and the persistence of these associations in military personnel is unknown. Data from the worldwide, representative 2002 and 2005 Department of Defense (DoD) Surveys of Health Related Behaviors among active duty military personnel were used to assess the prevalence of overweight and obesity and, the association of BMI with socio-demographic characteristics. The final response bases included 12,756 (2002) and 16,146 (2005) personnel. Results indicated that the combined prevalence of overweight and obesity in military personnel increased to an all-time high in 2005 (60.5%) with higher prevalence of obesity in 2005 compared to 2002 (12.9% vs. 8.7, respectively, P ≤ 0.01),. Holding other variables constant, regression analysis indicated that women were significantly less likely than men to be overweight or obese in both survey years (P ≤ 0.0001), which is contrary to civilian data. Similar to civilian data, the prevalence of obesity was significantly associated with increased age, black or Hispanic/Latino race/ethnicity, and being married (P ≤ 0.01). U.S. military personnel are not immune to the U.S. obesity epidemic. Demographic characteristics associated with being overweight should be considered when developing military-sponsored weight management programs.

MiR-141 Modulates Androgen Receptor Transcriptional Activity in Human Prostate Cancer Cells Through Targeting the Small Heterodimer Partner Protein

BACKGROUND: Aberrant expressions of microRNAs, including upregulation of miR-141, are closely associated with the tumorigenesis of prostate cancer (PCa). The orphan receptor small heterodimer partner (Shp) is a co-repressor to androgen receptor (AR) and represses AR-regulated transcriptional activity. METHODS: Here, we investigated the correlation of Shp expression with the cellular level of miR-141 and its effects on AR transcriptional activity in non-malignant and malignant human prostate epithelial cell lines. RESULTS: We found that Shp was downregulated in multiple PCa cell lines. The mature form of miR-141 was upregulated in PCa cells. miR-141 could target 3'-untranslated region of Shp mRNA resulting in translational suppression and RNA degradation. Moreover, enforced expression of Shp or inhibition of miR-141 function by anti-miR-141 attenuated AR-regulated transcriptional activity in AR-responsive LNCaP cells. Phenethyl isothiocyanate, a natural constituent of many edible cruciferous vegetables, increased Shp expression, downregulated miR-141, and inhibited AR transcriptional activity in LNCaP cells. CONCLUSIONS: Shp is a target for miR-141 and it is downregulated in cultured human PCa cells with the involvement of upregulation of miR-141, which promotes AR transcriptional activity. Moreover, Shp and miR-141 could be targets for chemoprevention for PCa. Prostate © 2012 Wiley Periodicals, Inc.

OX40 Ligand Fusion Protein Delivered Simultaneously With the BCG Vaccine Provides Superior Protection Against Murine Mycobacterium Tuberculosis Infection

Mycobacterium tuberculosis infection claims approximately 2 million lives per year, and improved efficacy of the BCG vaccine remains a World Health Organization priority. Successful vaccination against M. tuberculosis requires the induction and maintenance of T cells. Targeting molecules that promote T-cell survival may therefore provide an alternative strategy to classic adjuvants. We show that the interaction between T-cell-expressed OX40 and OX40L on antigen-presenting cells is critical for effective immunity to BCG. However, because OX40L is lost rapidly from antigen-presenting cells following BCG vaccination, maintenance of OX40-expressing vaccine-activated T cells may not be optimal. Delivering an OX40L:Ig fusion protein simultaneously with BCG provided superior immunity to intravenous and aerosol M. tuberculosis challenge even 6 months after vaccination, an effect that depends on natural killer 1.1(+) cells. Attenuated vaccines may therefore lack sufficient innate stimulation to maintain vaccine-specific T cells, which can be replaced by reagents binding inducible T-cell costimulators.

Genomic Epidemiology of the Escherichia Coli O104:H4 Outbreaks in Europe, 2011

The degree to which molecular epidemiology reveals information about the sources and transmission patterns of an outbreak depends on the resolution of the technology used and the samples studied. Isolates of Escherichia coli O104:H4 from the outbreak centered in Germany in May-July 2011, and the much smaller outbreak in southwest France in June 2011, were indistinguishable by standard tests. We report a molecular epidemiological analysis using multiplatform whole-genome sequencing and analysis of multiple isolates from the German and French outbreaks. Isolates from the German outbreak showed remarkably little diversity, with only two single nucleotide polymorphisms (SNPs) found in isolates from four individuals. Surprisingly, we found much greater diversity (19 SNPs) in isolates from seven individuals infected in the French outbreak. The German isolates form a clade within the more diverse French outbreak strains. Moreover, five isolates derived from a single infected individual from the French outbreak had extremely limited diversity. The striking difference in diversity between the German and French outbreak samples is consistent with several hypotheses, including a bottleneck that purged diversity in the German isolates, variation in mutation rates in the two E. coli outbreak populations, or uneven distribution of diversity in the seed populations that led to each outbreak.

The Importance of Velocity Acceleration to Flow-mediated Dilation

The validity of the flow-mediated dilation test has been questioned due to the lack of normalization to the primary stimulus, shear stress. Shear stress can be calculated using Poiseuille's law. However, little attention has been given to the most appropriate blood velocity parameter(s) for calculating shear stress. The pulsatile nature of blood flow exposes the endothelial cells to two distinct shear stimuli during the cardiac cycle: a large rate of change in shear at the onset of flow (velocity acceleration), followed by a steady component. The parameter typically entered into the Poiseuille's law equation to determine shear stress is time-averaged blood velocity, with no regard for flow pulsatility. This paper will discuss (1) the limitations of using Posieuille's law to estimate shear stress and (2) the importance of the velocity profile-with emphasis on velocity acceleration-to endothelial function and vascular tone.

Biological Conversion Assay Using Clostridium Phytofermentans to Estimate Plant Feedstock Quality

ABSTRACT: BACKGROUND: There is currently considerable interest in developing renewable sources of energy. One strategy is the biological conversion of plant biomass to liquid transportation fuel. Several technical hurdles impinge upon the economic feasibility of this strategy, including the development of energy crops amenable to facile deconstruction. Reliable assays to characterize feedstock quality are needed to measure the effects of pre-treatment and processing and of the plant and microbial genetic diversity that influence bioconversion efficiency. RESULTS: We used the anaerobic bacterium Clostridium phytofermentans to develop a robust assay for biomass digestibility and conversion to biofuels. The assay utilizes the ability of the microbe to convert biomass directly into ethanol with little or no pre-treatment. Plant samples were added to an anaerobic minimal medium and inoculated with C. phytofermentans, incubated for 3 days, after which the culture supernatant was analyzed for ethanol concentration. The assay detected significant differences in the supernatant ethanol from wildtype sorghum compared with brown midrib sorghum mutants previously shown to be highly digestible. Compositional analysis of the biomass before and after inoculation suggested that differences in xylan metabolism were partly responsible for the differences in ethanol yields. Additionally, we characterized the natural genetic variation for conversion efficiency in Brachypodium distachyon and shrub willow (Salix spp.). CONCLUSION: Our results agree with those from previous studies of lignin mutants using enzymatic saccharification-based approaches. However, the use of C. phytofermentans takes into consideration specific organismal interactions, which will be crucial for simultaneous saccharification fermentation or consolidated bioprocessing. The ability to detect such phenotypic variation facilitates the genetic analysis of mechanisms underlying plant feedstock quality.

Heart Failure With Preserved Left Ventricular Function: Diagnostic and Therapeutic Challenges in Patients With Diastolic Heart Failure

Heart failure associated with preserved left ventricular ejection fraction (HFpEF) is a condition of increasing importance, not only due to its rising prevalence but also due to the lack of clinical evidence for pharmacologic therapies that are beneficial. Thus, a recent case encountered at the Vanderbilt University Medical Center illustrates the clinical challenges one may encounter in patients with HFpEF. A careful review of the diagnostic challenges of HFpEF or diastolic heart failure, current recommendations for management and a glimpse of upcoming research are presented.

Significance of the Microbiome in Obstructive Lung Disease

The composition of the lung microbiome contributes to both health and disease, including obstructive lung disease. Because it has been estimated that over 70% of the bacterial species on body surfaces cannot be cultured by currently available techniques, traditional culture techniques are no longer the gold standard for microbial investigation. Advanced techniques that identify bacterial sequences, including the 16S ribosomal RNA gene, have provided new insights into the depth and breadth of microbiota present both in the diseased and normal lung. In asthma, the composition of the microbiome of the lung and gut during early childhood development may play a key role in the development of asthma, while specific airway microbiota are associated with chronic asthma in adults. Early bacterial stimulation appears to reduce asthma susceptibility by helping the immune system develop lifelong tolerance to innocuous antigens. By contrast, perturbations in the microbiome from antibiotic use may increase the risk for asthma development. In chronic obstructive pulmonary disease, bacterial colonisation has been associated with a chronic bronchitic phenotype, increased risk of exacerbations, and accelerated loss of lung function. In cystic fibrosis, studies utilising culture-independent methods have identified associations between decreased bacterial community diversity and reduced lung function; colonisation with Pseudomonas aeruginosa has been associated with the presence of certain CFTR mutations. Genomic analysis of the lung microbiome is a young field, but has the potential to define the relationship between lung microbiome composition and disease course. Whether we can manipulate bacterial communities to improve clinical outcomes remains to be seen.

Engineers Are from PDMS-land, Biologists Are from Polystyrenia

As the integration of microfluidics into cell biology research proceeds at an ever-increasing pace, a critical question for those working at the interface of both disciplines is which device material to use for a given application. While PDMS and soft lithography methods offer the engineer rapid prototyping capabilities, PDMS as a material has characteristics that have known adverse effects on cell-based experiments. In contrast, while polystyrene (PS), the most commonly used thermoplastic for laboratory cultureware, has provided decades of grounded and validated research conclusions in cell behavior and function, PS as a material has posed significant challenges in microfabrication. These competing issues have forced microfluidics engineers and biologists to make compromises in how they approach specific research questions, and furthermore, have attenuated the impact of microfluidics on biological research. In this review, we provide a comparison of the attributes of PDMS and PS, and discuss reasons for their popularity in their respective fields. We provide a critical evaluation of the strengths and limitations of PDMS and PS in relation to the advancement and future impact on microfluidic cell-based studies and applications. We believe that engineers have a responsibility to overcome any challenges associated with microfabrication, whether with PS or other materials, and that engineers should provide options and solutions that assist biologists in their experimental design. Our goal is not to advocate for any specific material, but provide guidelines for researchers who desire to choose the most suitable material for their application, and suggest important research directions for engineers working at the interface between microfabrication technology and biological application.

Germline AIP Mutations in Apparently Sporadic Pituitary Adenomas: Prevalence in a Prospective Single-Center Cohort of 443 Patients

Context:Germline mutations of the AIP (aryl-hydrocarbon receptor interacting protein) gene are associated with a predisposition to pituitary adenomas. Such mutations are found in about half of patients with familial acromegaly, but penetrance is incomplete.Objective:We studied the prevalence of germline AIP mutations in a large cohort of patients with apparently sporadic pituitary adenomas.Patients and Setting:A total of 443 patients with pituitary adenomas of all histotypes, who had no familial history of pituitary adenomas or multiple endocrine neoplasia and who were examined at Bicêtre University Hospital, a tertiary referral center, between 2007 and 2010, were enrolled in this prospective study.Methods:The entire coding sequence of the AIP gene was screened for germline mutations. A subgroup of patients were screened for large deletions or duplications of the AIP and MEN1 genes by multiplex ligation-dependent probe amplification.Results:AIP mutations were detected in 16 (3.6%) of the 443 patients, comprising six of 148 patients with acromegaly (4.1%), six of 132 patients with prolactinomas (4.5%), one of 113 patients with nonfunctioning adenomas (0.9%), three of 44 patients with corticotropic adenomas (6.8%), and none of the six patients with thyrotropic adenomas. This is the first report of an AIP mutation leading to a truncated protein in a patient with Cushing's disease. Patients with AIP mutation were younger at diagnosis (24.1 vs. 42.8 yr) and had predominantly macroadenoma (12 of 16). No mutations were found in patients diagnosed after age 40 yr, whereas the prevalence before this age was 7.2% (16 of 222). Studies of seven of the AIP-mutated patients' families showed that one asymptomatic parent carried the same mutation in each case.Conclusion:This large prospective cohort study confirms the very low prevalence of germline AIP mutations in patients with apparently sporadic pituitary adenomas. We propose to limit AIP testing to patients diagnosed before age 40 yr with apparently sporadic large pituitary adenomas, especially GH- or PRL-secreting adenomas.

Role of Quantification of Hepatic Steatosis and Future Remnant Volume in Predicting Hepatic Dysfunction and Complications After Liver Resection for Colorectal Metastases: a Pilot Study

Objectives:  Accurate prediction of safe remnant liver volume to minimize complications following liver resection remains challenging. The aim of this study was to assess whether quantification of steatosis improved the predictive value of preoperative volumetric analysis. Methods:  Thirty patients undergoing planned right or extended right hemi-hepatectomy for colorectal metastases were recruited prospectively. Magnetic resonance imaging was used to assess the level of hepatic steatosis and future remnant liver volume. These data were correlated with data on postoperative hepatic insufficiency, complications and hospital stay. Correlations of remnant percentage, remnant mass to patient mass and remnant mass to body surface area with and without steatosis measurements were assessed. Results:  In 10 of the 30 patients the planned liver resection was altered. Moderate-severe postoperative hepatic dysfunction was seen in 17 patients. Complications arose in 14 patients. The median level of steatosis was 3.8% (range: 1.2-17.6%), but was higher in patients (n= 10) who received preoperative chemotherapy (P= 0.124), in whom the median level was 4.8% (range: 1.5-17.6%). The strongest correlation was that of remnant liver mass to patient mass (r= 0.77, P < 0.001). However, the addition of steatosis quantification did not improve this correlation (r= 0.76, P < 0.001). Conclusions:  This is the first study to combine volumetric with steatosis quantifications. No significant benefit was seen in this small pilot. However, these techniques may be useful in operative planning, particularly in patients receiving preoperative chemotherapy.

The EDLL Motif: A Potent Plant Transcriptional Activation Domain from AP2/ERF Transcription Factors

In plants, the ERF/EREBP family of transcriptional regulators plays a key role in adaptation to various biotic and abiotic stresses. These proteins contain a conserved AP2 DNA-binding domain and several uncharacterized motifs. Here, we describe a short motif, termed "EDLL" which is present in AtERF98/TDR1 and other clade members from the same AP2 sub-family. We show that the EDLL motif, which has a unique arrangement of acidic amino acids and hydrophobic leucines, functions as a strong activation domain. The motif is transferable to other proteins and is active at both proximal and distal positions of target promoters. As such, the EDLL motif is shown to partly overcome the repression conferred by the EAR-containing AtHB2 transcription factor. We further examined the activation potential of EDLL through analysis of the regulation of flowering time by NF-Y (Nuclear Factor-Y) proteins. Genetic evidence indicates that NF-Y protein complexes potentiate the action of CONSTANS in the regulation of flowering in Arabidopsis; we show that the transcriptional activation function of CONSTANS can be substituted by direct fusion of the EDLL activation motif to NF-YB subunits. The EDLL motif represents a potent plant activation domain that can be used as a tool for conferring transcriptional activation potential to heterologous DNA binding proteins. © 2012 MENDEL BIOTECHONOLOGY,INC. The Plant Journal © 2012 Blackwell Publishing Ltd.

Immunohistochemical Testing of Conventional Adenomas for Loss of Expression of Mismatch Repair Proteins in Lynch Syndrome Mutation Carriers: a Case Series from the Australasian Site of the Colon Cancer Family Registry

Debate continues as to the usefulness of assessing adenomas for loss of mismatch repair protein expression to identify individuals with suspected Lynch syndrome. We tested 109 polyps from 69 proven mutation carriers (35 females and 34 males) belonging to 49 Lynch syndrome families. All polyps were tested by immunohistochemistry for four mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. Detailed pathology review was performed by specialist gastrointestinal pathologists. The majority of polyps (86%) were conventional adenomas (n=94), with 65 tubular and 28 tubulovillous adenomas and a single villous adenoma. The remaining 15 lesions (14%) were serrated polyps. Overall, loss of mismatch repair expression was noted for 78/109 (72%) of polyps. Loss of mismatch repair expression was seen in 74 of 94 (79%) conventional adenomas, and 4 of 15 (27%) serrated polyps from mismatch repair gene mutation carriers. In all instances, loss of expression was consistent with the underlying germline mutation. Mismatch repair protein expression was lost in 27 of 29 adenomas with a villous component compared with 47 of 65 adenomas without this feature (93 vs 73%; P=0.028). A strong trend was observed for high-grade dysplasia. Mismatch repair deficiency was observed in 12 of 12 conventional adenomas with high-grade dysplasia compared with 60 of 79 with low-grade dysplasia (100 vs 76%; P=0.065). We were unable to demonstrate a significant association between conventional adenoma size or site and mismatch repair deficiency. All (4/4 or 100%) of the serrated polyps demonstrating mismatch repair deficiency were traditional serrated adenomas from a single family. Diagnostic testing of adenomas in suspected Lynch syndrome families is a useful alternative in cases where cancers are unavailable. The overwhelming majority of conventional adenomas from mutation carriers show loss of mismatch repair protein expression concordant with the underlying germline mutation.Modern Pathology advance online publication, 10 February 2012; doi:10.1038/modpathol.2011.209.

Creatinine- Vs. Cystatin C-based Equations Compared with 99mTcDTPA Scintigraphy to Assess Glomerular Filtration Rate in Chronic Kidney Disease

Background: In chronic kidney disease (CKD), accurate estimation of the glomerular filtration rate (GFR) is mandatory. Gold standard methods for its estimation are expensive and time-consuming. We compared creatinine- versus cystatin C-based equations to measure GFR, employing 99mTc-DTPA scintigraphy as the gold standard. Methods: This was a prospective cross-sectional observational study including 300 subjects. CKD was defined according to K/DOQI guidelines, and patients were separated into groups: stage 1 (G1), n=26; stage 2 (G2), n=52; stage 3 (G3), n=90; stage 4 (G4), n=37; stage 5 (G5), n=60; and control group, n=35. Creatinine-based estimates were from 24-hour creatinine clearance using the Walser formula, Cockcroft-Gault, MDRD-4 and CKD-EPI; cystatin C equations used were Larsson, Larsson modified equation, Grubb and Hoek. Results: Age and body mass index were different among groups; proteinuria, hypertension, diabetes and primary glomerulopathies significantly increased as CKD worsened. In the global assessment, CKD-EPI and Hoek gave the highest correlations with 99mTc-DTPA: ?=0.826, p<0.001 and ?=0.704, p<0.001, respectively. Most significant linear regressions obtained: CKD-EPI vs. 99mTc-DTPA, Hoek vs. 99mTc-DTPA and CKD-EPI vs. Hoek. However, important differences emerged when each group was analyzed separately. Best significant correlations obtained with 99mTc-DTPA: control group, creatinine clearance ?=0.421, p=0.012; G1, Crockoft-Gault ?=0.588, p=0.003; G2, CKD-EPI ?=0.462, p<0.05; G3, CKD-EPI ?=0.508, p<0.001; G4, Hoek ?=0.618, p<0.001; G5, CKD-EPI ?=0.604, p<0.001. Conclusions: At GFR <60 ml/min, CKD-EPI and Hoek equations appeared to best correlate with 99mTcDTPA. In controls and at early stages of CKD, creatinine-based equations correlated better with 99mTc-DTPA, with CKD-EPI being the one with the best degree of agreement.

Human Telomere Disease Due to Disruption of the CCAAT Box of the TERC Promoter

Mutations in the coding region of telomerase complex genes can result in accelerated telomere attrition and human disease. Manifestations of telomere disease include the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia, acute myeloid leukemia, liver cirrhosis, and pulmonary fibrosis. Here we describe a mutation in the CCAAT box (GCAAT) of the TERC gene promoter in a family in which multiple members had typical features of telomeropathy. The genetic alteration in this critical regulatory sequence resulted in reduced reporter gene activity and absent binding of transcription factor NF-Y, likely responsible for reduced TERC levels, decreased telomerase activity, and short telomeres. This is the first description of a pathogenic mutation in the highly conserved CCAAT box, and the first instance of a mutation in the promoter region of TERC producing a telomeropathy. We propose that current mutation screening strategies include gene promoter regions for the diagnosis of telomere diseases. This clinical trial was registered at www.ClinicalTrials.gov, identifier: NCT00071045.

Redundant Catecholamine Signaling Consolidates Fear Memory Via Phospholipase C

Memories for emotionally arousing experiences are typically vivid and persistent. The recurrent, intrusive memories of traumatic events in post-traumatic stress disorder (PTSD) are an extreme example. Stress-responsive neurotransmitters released during emotional arousal are proposed to enhance the consolidation of fear memory. These transmitters may include norepinephrine and epinephrine (NE/E) because stimulating β-adrenergic receptors shortly after training can enhance memory consolidation. However, mice lacking NE/E acquire and consolidate fear memory normally. Here, we show by using pharmacologic and genetic manipulations in mice and rats that NE/E are not essential for classical fear memory consolidation because signaling by the β(2)-adrenergic receptor is redundant with signaling by dopamine at the D(5)-dopaminergic receptor. The intracellular signaling that is stimulated by these receptors to promote consolidation uses distinct G proteins to redundantly activate phospholipase C. The results support recent evidence indicating that blocking β-adrenergic receptors alone shortly after trauma may not be sufficient to prevent PTSD.

LUCAS: a Theoretically Informed Instrument to Assess Clinical Communication in Objective Structured Clinical Examinations

Medical Education 2012: 46: 267-276 Objectives  We reviewed papers describing the development of instruments for assessing clinical communication in undergraduate medical students. The instruments had important limitations: most lacked a theoretical basis, and their psychometric properties were often poor or inadequately investigated and reported. We therefore describe the development of a new instrument, the Liverpool Undergraduate Communication Assessment Scale (LUCAS), which is intended to overcome some of these limitations. We designed LUCAS to reflect the theory that communication is contextually dependent, inherently creative and cannot be fully described within a conceptual framework of discrete skills. Methods  We investigated the preliminary psychometric properties of LUCAS in two studies. To assess construct and external validity, we examined correlations between examiners' LUCAS ratings and simulated patients' ratings of their relationships with students in Year 1 formative (n = 384) and summative (n = 347) objective structured clinical examination (OSCE) samples. Item-total correlations and item difficulty analyses were also performed. The dimensionality of LUCAS was examined by confirmatory factor analysis. We also assessed inter-rater reliability; four raters used LUCAS to rate 40 video-recorded encounters between Year 1 students and simulated patients. Results  Simulated patient ratings correlated with examiner ratings across two OSCE datasets. All items correlated with the total score. Item difficulty showed LUCAS was able to discriminate between student performances. LUCAS had a two-dimensional factor structure: we labelled Factor 1 creative communication and Factor 2 procedural communication. The intraclass correlation coefficient was 0.73 (95% confidence interval 0.54-0.85), indicating acceptable reliability. Conclusions  We designed LUCAS to move the primary focus of examiners away from an assessment of students' enactment of behavioural skills to a judgement of how well students' communication met patients' needs. LUCAS demonstrated adequate reliability and validity. The instrument can be administered easily and efficiently and is therefore suitable for use in medical school examinations.

Large-Scale Gene-Centric Meta-Analysis Across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.

Outcome of the First Electron Microscopy Validation Task Force Meeting

This Meeting Review describes the proceedings and conclusions from the inaugural meeting of the Electron Microscopy Validation Task Force organized by the Unified Data Resource for 3DEM (http://www.emdatabank.org) and held at Rutgers University in New Brunswick, NJ on September 28 and 29, 2010. At the workshop, a group of scientists involved in collecting electron microscopy data, using the data to determine three-dimensional electron microscopy (3DEM) density maps, and building molecular models into the maps explored how to assess maps, models, and other data that are deposited into the Electron Microscopy Data Bank and Protein Data Bank public data archives. The specific recommendations resulting from the workshop aim to increase the impact of 3DEM in biology and medicine.

Initial Experience with Dabigatran Etexilate at Auckland City Hospital

Gait Selection and the Ontogeny of Quadrupedal Walking in Squirrel Monkeys (Saimiri Boliviensis)

Locomotor researchers have long known that adult primates employ a unique footfall sequence during walking. Most mammals use lateral sequence (LS) gaits, in which hind foot touchdowns are followed by ipsilateral forefoot touchdowns. In contrast, most quadrupedal primates use diagonal sequence (DS) gaits, in which hind foot touchdowns are followed by contralateral forefoot touchdowns. However, gait selection in immature primates is more variable, with infants and juveniles frequently using LS gaits either exclusively or in addition to DS gaits. I explored the developmental bases for this phenomenon by examining the ontogeny of gait selection in juvenile squirrel monkeys walking on flat and simulated arboreal substrates (i.e., a raised pole). Although DS gaits predominated throughout development, the juvenile squirrel monkeys nonetheless utilized LS gaits in one-third of the ground strides and in one-sixth of pole strides. Multiple logistic regression analyses showed that gait selection within the juvenile squirrel monkey sample was not significantly associated with either age or body mass per se, arguing against the oft-cited argument that general neuromuscular maturation is responsible for ontogenetic changes in preferred footfall sequence. Rather, lower level biomechanical variables, specifically the position of the whole-body center of mass and the potential for interference between ipsilateral fore and hindlimbs, best explained variation in footfall patterns. Overall, results demonstrate the promise of developmental studies of growth and locomotor development to serve as "natural laboratories" in which to explore how variability in morphology is, or is not, associated with variability in locomotor behavior. Am J Phys Anthropol 2012. © 2012 Wiley Periodicals, Inc.

Macrophage Imaging Within Human Cerebral Aneurysms Wall Using Ferumoxytol-Enhanced MRI: A Pilot Study

OBJECTIVE: Macrophages play a critical role in cerebral aneurysm formation and rupture. The purpose of this study is to demonstrate the feasibility and optimal parameters of imaging macrophages within human cerebral aneurysm wall using ferumoxytol-enhanced MRI. METHODS AND RESULTS: Nineteen unruptured aneurysms in 11 patients were imaged using T2∗-GE-MRI sequence. Two protocols were used. Protocol A was an infusion of 2.5 mg/kg of ferumoxytol and imaging at day 0 and 1. Protocol B was an infusion of 5 mg/kg of ferumoxytol and imaging at day 0 and 3. All images were reviewed independently by 2 neuroradiologists to assess for ferumoxytol-associated loss of MRI signal intensity within aneurysm wall. Aneurysm tissue was harvested for histological analysis. Fifty percent (5/10) of aneurysms in protocol A showed ferumoxytol-associated signal changes in aneurysm walls compared to 78% (7/9) of aneurysms in protocol B. Aneurysm tissue harvested from patients infused with ferumoxytol stained positive for both CD68+, demonstrating macrophage infiltration, and Prussian blue, demonstrating uptake of iron particles. Tissue harvested from controls stained positive for CD68 but not Prussian blue. CONCLUSIONS: Imaging with T2∗-GE-MRI at 72 hours postinfusion of 5 mg/kg of ferumoxytol establishes a valid and useful approximation of optimal dose and timing parameters for macrophages imaging within aneurysm wall. Further studies are needed to correlate these imaging findings with risk of intracranial aneurysm rupture.

Novel Chitosan-polycaprolactone Blends As Potential Scaffold and Carrier for Corneal Endothelial Transplantation

The aim of this prospective study was to evaluate whether blending two kinds of biomaterials, chitosan and polycaprolactone (PCL), can be used as scaffold and carrier for growth and differentiation of corneal endothelial cells (CECs).

The Revised Child Anxiety and Depression Scale-Short Version: Scale Reduction Via Exploratory Bifactor Modeling of the Broad Anxiety Factor

Using a school-based (N = 1,060) and clinic-referred (N = 303) youth sample, the authors developed a 25-item shortened version of the Revised Child Anxiety and Depression Scale (RCADS) using Schmid-Leiman exploratory bifactor analysis to reduce client burden and administration time and thus improve the transportability characteristics of this youth anxiety and depression measure. Results revealed that all anxiety items primarily reflected a single "broad anxiety" dimension, which informed the development of a reduced 15-item Anxiety Total scale. Although specific DSM-oriented anxiety subscales were not included in this version, the items comprising the Anxiety Total scale were evenly pulled from the 5 anxiety-related content domains from the original RCADS. The resultant 15-item Anxiety Total scale evidenced significant correspondence with anxiety diagnostic groups based on structured clinical interviews. The scores from the 10-item Depression Total scale (retained from the original version) were also associated with acceptable reliability in the clinic-referred and school-based samples (α = .80 and .79, respectively); this is in contrast to the alternate 5-item shortened RCADS Depression Total scale previously developed by Muris, Meesters, and Schouten (2002), which evidenced depression scores of unacceptable reliability (α = .63). The shortened RCADS developed in the present study thus balances efficiency, breadth, and scale score reliability in a way that is potentially useful for repeated measurement in clinical settings as well as wide-scale screenings that assess anxiety and depressive problems. These future applications are discussed, as are recommendations for continued use of exploratory bifactor modeling in scale development. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Computational and Visualization Approaches in Respiratory Delivery

Superhydrophobic, Nanotextured Polyvinyl Chloride Films for Delaying Pseudomonas Aeruginosa Attachment to Intubation Tubes and Medical Plastics

Bacterial attachment onto the surface of polymers in medical devices such as polyvinyl chloride (PVC) is influenced by the physicochemical properties of the polymer, including its surface hydrophobicity and roughness. In this study, to prevent biofilm formation onto PVC devices, the PVC surface was modified using a combination of solvent (tetrahydrofuran) and non-solvents (i.e. ethanol and methanol). The surface of unmodified PVC was smooth and relatively hydrophobic (water contact angle (CA)=80°). Ethanol-treated PVCs revealed the presence of micron-sized particulates and porous structures as the concentration of ethanol was increased. Surface hydrophobicity (measured in terms of CA) increased from 73° to 150° as the ethanol concentration increased from 15% to 35% (v/v). In general, methanol-treated PVCs were more hydrophilic compared to those treated with ethanol. The colonization of Pseudomonas aeruginosa PAO1 onto unmodified PVC surface was rapid, and individual bacterial cells could be seen after 6h incubation. On the surface of treated PVC, the secretion of extracellular matrix layers was evident at 18h and P. aeruginosa PAO1 start to form microcolonies at 24h of incubation. The initial attachment of P. aeruginosa PAO1 was delayed to 18 and 24h, respectively in the PVCs treated with 25% (v/v) and 35% (v/v) ethanol. It can be concluded that the treatment used in this study to prepare superhydrophobic PVC surface prevented the colonization of bacteria up to 24h after culture.

Assaying Macrophage Activity in a Murine Model of Inflammatory Bowel Disease Using Fluorine-19 MRI

Macrophages have an important role in the pathogenesis of most chronic inflammatory diseases. A means of non-invasively quantifying macrophage migration would contribute significantly towards our understanding of chronic inflammatory processes and aid the evaluation of novel therapeutic strategies. We describe the use of a perfluorocarbon tracer reagent and in vivo (19)F magnetic resonance imaging (MRI) to quantify macrophage burden longitudinally. We apply these methods to evaluate the severity and three-dimensional distribution of macrophages in a murine model of inflammatory bowel disease (IBD). MRI results were validated by histological analysis, immunofluorescence and quantitative real-time polymerase chain reaction. Selective depletion of macrophages in vivo was also performed, further validating that macrophage accumulation of perfluorocarbon tracers was the basis of (19)F MRI signals observed in the bowel. We tested the effects of two common clinical drugs, dexamethasone and cyclosporine A, on IBD progression. Whereas cyclosporine A provided mild therapeutic effect, unexpectedly dexamethasone enhanced colon inflammation, especially in the descending colon. Overall, (19)F MRI can be used to evaluate early-stage inflammation in IBD and is suitable for evaluating putative therapeutics. Due to its high macrophage specificity and quantitative ability, we envisage (19)F MRI having an important role in evaluating a wide range of chronic inflammatory conditions mediated by macrophages.Laboratory Investigation advance online publication, 13 February 2012; doi:10.1038/labinvest.2012.7.

Monte Carlo Simulation of the Spearman-Kaerber TCID50

ABSTRACT: BACKGROUND: In the biological sciences the TCID50 (median tissue culture infective dose) assay is often used to determine the strength of a virus. METHODS: When the so-called Spearman-Kaerber calculation is used, the ratio between the pfu (the number of plaque forming units, the effective number of virus particles) and the TCID50, theoretically approaches a simple function of Eulers constant. Further, the standard deviation of the logarithm of the TCID50 approaches a simple function of the dilution factor and the number of wells used for determining the ratios in the assay. However, these theoretical calculations assume that the dilutions of the assay are independent, and in practice this is not completely correct. The assay was simulated using Monte Carlo techniques. RESULTS: Our simulation studies show that the theoretical results actually hold true for practical implementations of the assay. Furthermore, the simulation studies show that the distribution of the (the log of) TCID50, although discrete in nature, has a close relationship to the normal distribution. CONCLUSION: The pfu is proportional to the TCID50 titre with a factor of about 0.56 when using the Spearman-Kaerber calculation method. The normal distribution can be used for statistical inferences and ANOVA on the (the log of) TCID50 values is meaningful with group sizes of 5 and above.

Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study

PURPOSETo determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population. PATIENTS AND METHODSWe prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.ResultsOver a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97). CONCLUSIONWe confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.

Pyrvinium, a Potent Small Molecule Wnt Inhibitor, Increases Engraftment and Inhibits Lineage Commitment of Mesenchymal Stem Cells (MSCs)

We and others have found that Wnt signaling inhibition is important in mesenchymal stem cell (MSC) self-renewal. Pyrvinium was identified as a potent Wnt inhibitor in a chemical screen for small molecules. In the present study, we hypothesized that pyrvinium will enhance MSC self-renewal to improve the clinical efficacy of MSC therapy. Pyrvinium increased MSC proliferation in vitro while inhibiting their osteogenic and chondrogenic lineage commitment by reducing cytoplasmic β-catenin. Although MSCs are a promising target for cell therapy, strategies to enhance their survival and maintain their stemness in the wounded area are essential. Using an in vivo model of granulation tissue formation, we demonstrated that pyrvinium enhanced long-term MSC engraftment. Pyrvinium-treated MSC-generated granulation tissue also demonstrated less ectopic differentiation into bone or cartilage. This study highlights the potential of using a therapeutic Wnt inhibitor to enhance MSC-driven regenerative therapy.

Uterine Gene Expression in the Live-bearing Lizard, Chalcides Ocellatus, Reveals Convergence of Squamate and Mammalian Pregnancy Mechanisms

Although the morphological and physiological changes involved in pregnancy in live-bearing reptiles are well studied, the genetic mechanisms that underlie these changes are not known. We used the viviparous African Ocellated Skink, Chalcides ocellatus, as a model to identify a near complete gene expression profile associated with pregnancy using RNA-Seq analyses of uterine transcriptomes. Pregnancy in C. ocellatus is associated with upregulation of uterine genes involved with metabolism, cell proliferation and death, and cellular transport. Moreover, there are clear parallels between the genetic processes associated with pregnancy in mammals and Chalcides in expression of genes related to tissue remodeling, angiogenesis, immune system regulation, and nutrient provisioning to the embryo. In particular, the pregnant uterine transcriptome is dominated by expression of proteolytic enzymes that we speculate are involved both with remodeling the chorioallantoic placenta and histotrophy in the omphaloplacenta. Elements of the maternal innate immune system are downregulated in the pregnant uterus, indicating a potential mechanism to avoid rejection of the embryo. We found a downregulation of major histocompatability complex loci and estrogen and progesterone receptors in the pregnant uterus. This pattern is similar to mammals, but cannot be explained by the mammalian model. The latter finding provides evidence that pregnancy is controlled by different endocrinological mechanisms in mammals and reptiles. Finally, 88% of the identified genes are expressed in both the pregnant and non-pregnant uterus, and thus morphological and physiological changes associated with C. ocellatus pregnancy is likely a result of regulation of genes continually expressed in the uterus rather than the initiation of expression of unique genes.

Gray Matter Textural Heterogeneity As a Potential In-vivo Biomarker of Fine Structural Abnormalities in Asperger Syndrome

Brain imaging studies contribute to the neurobiological understanding of Autism Spectrum Conditions (ASC). Herein, we tested the prediction that distributed neurodevelopmental abnormalities in brain development impact on the homogeneity of brain tissue measured using texture analysis (TA; a morphological method for surface pattern characterization). TA was applied to structural magnetic resonance brain scans of 54 adult participants (24 with Asperger syndrome (AS) and 30 controls). Measures of mean gray-level intensity, entropy and uniformity were extracted from gray matter images at fine, medium and coarse textures. Comparisons between AS and controls identified higher entropy and lower uniformity across textures in the AS group. Data reduction of texture parameters revealed three orthogonal principal components. These were used as regressors-of-interest in a voxel-based morphometry analysis that explored the relationship between surface texture variations and regional gray matter volume. Across the AS but not control group, measures of entropy and uniformity were related to the volume of the caudate nuclei, whereas mean gray-level was related to the size of the cerebellar vermis. Similar to neuropathological studies, our study provides evidence for distributed abnormalities in the structural integrity of gray matter in adults with ASC, in particular within corticostriatal and corticocerebellar networks. Additionally, this in-vivo technique may be more sensitive to fine microstructural organization than other more traditional magnetic resonance approaches and serves as a future testable biomarker in AS and other neurodevelopmental disorders.The Pharmacogenomics Journal advance online publication, 14 February 2012; doi:10.1038/tpj.2012.3.

High-resolution Genome-wide Copy-number Analysis Suggests a Monoclonal Origin of Multifocal Prostate Cancer

Many human cancers present as multifocal lesions. Understanding the clonal origin of multifocal cancers is of both etiological and clinical importance. The molecular basis of multifocal prostate cancer has previously been explored using a limited number of isolated markers and, although independent origin is widely believed, the clonal origin of multifocal prostate cancer is still debatable. We attempted to address clonal origin using a genome-wide copy-number analysis of individual cancer and high-grade prostatic intraepithelial neoplasia (HGPIN) lesions. Using Affymetrix array 6.0 copy-number analysis, we compared the genomic changes detected in 48 individual cancer and HGPIN lesions, isolated from 18 clinically localized prostate cancer cases. Identical genomic copy-number changes, shared by all same-case cancer foci, were detected in all 13 informative cases displaying multiple tumor foci. In addition, individual HGPIN lesions in the two multifocal-HGPIN cases available shared identical genomic changes. Commonly known genomic alterations, including losses at 6q15, 8p21.3-8p21.2, 10q23.2-10q23.31, 16q22.3, 16q23.2-16q23.3 and 21q22.2-21q22.3 regions and gain of 8q24.3 were the most frequently detected changes in this study and each was detected in all same-case foci in at least one case. Microarray data were confirmed by fluorescence in situ hybridization in selected foci. Our high-resolution genome-wide copy-number data suggest that many multifocal cases derive from a single prostate cancer precursor clone and that this precursor may give rise to separate HGPIN foci and may further progress to multifocal invasive prostate cancer. These findings, which demonstrate the monoclonal origin of multifocal prostate cancer, should significantly enhance our understanding of prostate carcinogenesis. © 2012 Wiley Periodicals, Inc.

An Unusual Cause of Tricuspid Regurgitation

Proteinuria: an Ignored Marker of Inflammation and Cardiovascular Disease in Chronic Hemodialysis

Cardiovascular disease is the leading cause of morbidity and mortality in hemodialysis (HD) patients, the main etiologies being diabetes and hypertension. Cardiac and inflammatory biomarkers are usually employed to assess risk or damage, or during follow-up. Proteinuria is considered a strong predictor of morbidity, a cause of inflammation, oxidative stress, hemodynamic alteration, and progression of chronic kidney disease. However, proteinuria is rarely considered in the clinical assessment of HD patients.

Synthesis and Evaluation of Indole-Based Chalcones As Inducers of Methuosis, a Novel Type of Non-Apoptotic Cell Death

Methuosis is a novel caspase-independent form of cell death in which massive accumulation of vacuoles derived from macropinosomes ultimately causes cells to detach from the substratum and rupture. We recently described a chalcone-like compound, 3-(2-methyl-1H indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (i.e. MIPP), which can induce methuosis in glioblastoma and other types of cancer cells. Herein we describe the synthesis and structure-activity relationships of a directed library of related compounds, providing insights into the contributions of the two aryl ring systems and highlighting a potent derivative, 3-(5-methoxy, 2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (i.e. MOMIPP) that can induce methuosis at low μM concentrations. We have also generated biologically active azide derivatives that may be useful for future studies aimed at identifying the protein targets of MOMIPP by photoaffinity labeling techniques. The potential significance of these studies is underscored by the finding that MOMIPP effectively reduces the growth and viability of temozolomide-resistant glioblastoma and doxorubicin-resistant breast cancer cells. Thus, it may serve as a prototype for drugs that could be used to trigger death by methuosis in cancers that are resistant to conventional forms of cell death (e.g. apoptosis).

Micronized Drug Powders in Binary Mixtures and the Effect of Physical Properties on Aerosolization from Combination Drug Dry Powder Inhalers

Objectives: To evaluate physicochemical properties of two micronized drugs, salbutamol sulfate (SS) and beclomethasone dipropionate (BDP) prepared as dry powder inhalation physical blends. Methods: Five different blends of SS:BDP ratios of 0:100, 25:75, 50:50, 75:25, and 100:0 (w/w) were prepared. Aerosolization performance was evaluated using a multistage impinger and a Rotahaler® device. Results: The median SS particle diameter was larger than BDP (4.33 ± 0.37 µm compared to 2.99 ± 0.15 µm, respectively). The SS appeared to have a ribbon-like morphology, while BDP particles had plate-like shape with higher cohesion than SS. This was reflected in the aerosolization performance of the two drugs alone, where SS had a significantly higher fine particle fraction (FPF) than BDP (12.3%, 3.1% and 2.9%, 0.2%, respectively). The study of cohesion versus adhesion for a series of SS and BDP probes on SS and BDP substrates suggested both to be moderately adhesive, verified using scanning Raman microscopy, where a physical association between the two was observed. A plot of loaded versus emitted dose indicated that powder bed fluidization was significantly different when the drugs were tested individually. Furthermore, the FPF of the two drugs from the binary blends, at all three ratios, were similar. Conclusions: Such observations indicate that when these two drugs are formulated as a binary system, the resulting powder structure is altered and the aerosolization performance of each drug is not reflective of the individual drug performance. Such factors could have important implications and should be considered when developing combination dry powder inhalation systems.

Synthesis of ApoSense Compound [(18)F]2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(fluoromethyl)butanoic Acid ([(18)F]NST732) by Nucleophilic Ring Opening of an Aziridine Precursor

INTRODUCTION: The small molecule 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(fluoromethyl)butanoic acid (NST732) is a member of the ApoSense family of compounds, capable of selective targeting, binding and accumulation within cells undergoing apoptotic cell death. It has application in molecular imaging and blood clotting particularly for monitoring antiapoptotic drug treatments. We are investigating a fluorine-18-radiolabeled analog of this compound for positron emission tomography studies. METHODS: We prepared the tosylate precursor methyl 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(tosyloxymethyl)butanoate (4) to synthesize fluorine-18-labeled NST732. Fluorination reaction of the tosylate precursor in 1:1 acetonitrile:dimethylsulfoxide with tetrabutyl ammonium fluoride proceeds through an aziridine intermediate (4A) to afford two regioisomers: 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-fluorobutanoate (5) and methyl 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(fluoromethyl)butanoate (6). Acid hydrolysis of the fluoromethylbutanoate (6) isomer produced NST732. As the fluorination reaction of the tosylate precursor proceeds through an aziridine intermediate (4A) and the fluorination conceivably could be done directly on the aziridine, we have separately prepared an aziridine precursor (4A). Fluorine-18 labeling of the aziridine precursor (4A) was performed with [(18)F]tetrabutyl ammonium fluoride to afford the same two regioisomers (5 and 6). The [(18)F]2-((5-dimethylamino)naphthalene-1-sulfonamido)methyl)-2-fluorobutanoic acid (NST732) was then obtained by the hydrolysis of corresponding [(18)F]-labeled ester (6) with 6 N hydrochloric acid. RESULTS: Two regioisomers obtained from the fluorination reaction of aziridine were easily separated by high-performance liquid chromatography. The total radiochemical yield was 15%±3% (uncorrected, n=18) from the aziridine precursor in a 70-min synthesis time with a radiochemical purity >99%. CONCLUSION: Fluorine-18-labeled ApoSense compound [(18)F]NST732 is prepared in moderate yield by direct fluorination of an aziridine precursor.

When Hard Times Take a Toll: The Distressing Consequences of Economic Hardship and Life Events Within the Family-Work Interface

Using two waves of data from a national survey of working Americans (N = 1,122), we examine the associations among economic hardship, negative life events, and psychological distress in the context of the family-work interface. Our findings demonstrate that family-to-work conflict mediates the effects of economic hardship and negative events to significant others on distress (net of baseline distress and hardship). Moreover, economic hardship and negative events to significant others moderate the association between family-to-work conflict and distress. While negative events to others exacerbate the positive effect of family-to-work conflict on distress, we find the opposite for economic hardship: The positive association between hardship and distress is weaker at higher levels of family-to-work conflict. These patterns hold across an array of family, work, and sociodemographic conditions. We discuss how these findings refine and extend ideas of the stress process model, including complex predictions related to processes of stress-buffering, resource substitution, and role multiplication.

Obama Shoots for Science Increase

Eutrophication Causes Speciation Reversal in Whitefish Adaptive Radiations

Species diversity can be lost through two different but potentially interacting extinction processes: demographic decline and speciation reversal through introgressive hybridization. To investigate the relative contribution of these processes, we analysed historical and contemporary data of replicate whitefish radiations from 17 pre-alpine European lakes and reconstructed changes in genetic species differentiation through time using historical samples. Here we provide evidence that species diversity evolved in response to ecological opportunity, and that eutrophication, by diminishing this opportunity, has driven extinctions through speciation reversal and demographic decline. Across the radiations, the magnitude of eutrophication explains the pattern of species loss and levels of genetic and functional distinctiveness among remaining species. We argue that extinction by speciation reversal may be more widespread than currently appreciated. Preventing such extinctions will require that conservation efforts not only target existing species but identify and protect the ecological and evolutionary processes that generate and maintain species.

Prior HIV Testing Among STD Patients in Guangdong Province, China: Opportunities for Expanding Detection of Sexually Transmitted HIV Infection

BACKGROUND:: Expanding HIV testing is important among individuals at increased risk for sexual HIV transmission in China, but little is known about prior HIV testing experiences among sexually transmitted disease (STD) patients. METHODS:: This cross-sectional study of 1792 outpatients from 6 public STD clinics in Guangdong Province recorded detailed information about ever having been tested for HIV infection in addition to sociodemographic variables, health seeking, clinical STD history, and HIV stigma using a validated survey instrument. RESULTS:: A total of 456 (25.4%) of the STD patients in this sample had ever been tested for HIV infection. STD patients who were male, had higher income, more education, were at City A and City C, received STD services at public facilities, had used intravenous drugs, and had a history of an STD were more likely to ever receive an HIV test in multivariate analysis. Low perceived HIV risk was the most common reason for not receiving an HIV test. Only 7.7% of the sample reported fear of discrimination or loss of face as influencing their lack of HIV testing. CONCLUSION:: Incomplete prior HIV screening among STD patients in China suggests the need for broadening HIV testing opportunities at STD clinics and similar clinical settings attended by those with increased sexual risk.

Obstructive Sleep Apnea and Incidence of Postoperative Delirium After Elective Knee Replacement in the Nondemented Elderly

BACKGROUND:: Postoperative delirium, a common complication in the elderly, can occur following any type of surgery and is associated with increased morbidity and mortality; it may also be associated with subsequent cognitive problems. Effective therapy for postoperative delirium remains elusive because the causative factors of delirium are likely multiple and varied. METHODS:: Patients 65 yr or older undergoing elective knee arthroplasty were prospectively evaluated for postoperative Diagnostic and Statistical Manual of Mental Disorders-IV delirium. Exclusion criteria included dementia, mini-mental state exam score less than 24, delirium, clinically significant central nervous system/neurologic disorder, current alcoholism, or any serious psychiatric disorder. Delirium was assessed on postoperative days 2 and 3 using standardized scales. Patients' preexisting medical conditions were obtained from medical charts. The occurrence of obstructive sleep apnea was confirmed by contacting patients to check their polysomnography records. Data were analyzed using Pearson chi-square or Wilcoxon rank sum tests and multiple logistic regressions adjusted for effects of covariates. RESULTS:: Of 106 enrolled patients, 27 (25%) developed postoperative delirium. Of the 15 patients with obstructive sleep apnea, eight (53%) experienced postoperative delirium, compared with 19 (20%) of the patients without obstructive sleep apnea (P = 0.0123, odds ratio: 4.3). Obstructive sleep apnea was the only statistically significant predictor of postoperative delirium in multivariate analyses. CONCLUSIONS:: This is the first prospective study employing validated measures of delirium to identify an association between preexisting obstructive sleep apnea and postoperative delirium.

Antagonism of CXCR7 Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension

Background:Chemokines may directly participate in the pathogenesis of neonatal chronic hypoxia-induced pulmonary hypertension (PH). While stromal derived factor-1 has been shown to be involved in PH, the role of its most recently discovered receptor, chemokine receptor 7 (CXCR7) remains unclear. We sought to determine whether antagonism of the CXCR7 receptor would decrease pulmonary vascular remodeling in newborn mice exposed to chronic hypoxia by decreasing pulmonary vascular cell proliferation.Methods:Neonatal mice were exposed to hypoxia (fractional inspired oxygen concentration=0.12) or room air (RA) for 2 weeks. After 1 week of exposure, mice received daily injections of placebo or a CXCR7 antagonist (CCX771) from P7 -14. Right ventricular systolic pressure (RVSP), the ratio of the weight of the right ventricle to left ventricle and septum (RV/LV+S), pulmonary vascular cell proliferation and remodeling were determined at P14.Results:As compared to RA, hypoxia placebo mice had a significant increase in the lung protein expression of CXCR7. Whilst hypoxic placebo-treated mice had a significant increase in RVSP, RV/LV+S, pulmonary vascular cell proliferation and remodeling, the administration of CCX771 markedly decreased these changes.Conclusion:These results indicate that antagonism of CXCR7 may be a potent strategy to decrease PH and vascular remodeling.

Identifying Patient-Reported Outcomes in Rheumatoid Arthritis: The Impact of Foot Symptoms on Self-Perceived Quality of Life

BACKGROUND: The importance of patient-reported outcome measures in healthcare is increasingly recognized but these need to be patient generated. Given that foot symptoms are very common in rheumatoid arthritis (RA), we chose a patient-centred model with which to investigate the patients' perspective on how their foot symptoms affected them as individuals and impacted on their self-perceived quality of life, rather than using the traditional approaches of clinical examination (e.g. prevalence of deformities) or radiological assessments. METHODS: A 33-item self-administered postal questionnaire was sent to all people with RA attending outpatient clinics in three hospitals over the course of one month (n = 390). The questionnaire used both quantitative and qualitative approaches to enquire about the nature and extent of foot complaints and how respondents believed this affected their quality of life. RESULTS: In total, 190 usable replies were received (49%). Nearly all respondents (n = 177; 93.2%) reported that their quality of life was adversely affected by their foot complaint(s), with over half describing their quality of life as being badly or very badly affected. When asked to rate how severely foot complaints affected their quality of life using a 10 cm visual analogue scale, the mean score was 5.36 (range 0-10 ± SD 3), indicating that foot complaints have a moderate-to-severe effect on quality of life. Those aspects of daily living most significantly affected were: the ability to walk and the ability to wear a variety of shoes. CONCLUSION: This study demonstrated that people with RA focus on different aspects of the impact of their disease to doctors. Rather than foot deformity or ulceration, disease activity score or health assessment questionnaire score, patients were easily able to pinpoint the key negativities of living with RA in their feet and indicated choice of footwear and ability to walk as crucial. This study and similar ones are key to identifying appropriate patient-reported outcome measures. Copyright © 2012 John Wiley & Sons, Ltd.

Chronic Obstructive Pulmonary Disease Detection During Lung Cancer Screening

Gene Expression Profiling of Porcine Skeletal Muscle in the Early Recovery Phase Following Acute Physical Activity

ABSTRACTAcute physical activity elicits changes in gene expression in skeletal muscles to promote metabolic changes and to repair exercise-induced muscle injuries. In the present time-course study, pigs were submitted to an acute bout of treadmill running until near exhaustion to determine the impact of unaccustomed exercise on global transcriptional profiles in porcine skeletal muscles. Thus, using a combined microarray and candidate gene approach, we identified a suite of genes that are differentially expressed in muscles during post-exercise recovery. Thus, several members of the heat shock protein family and proteins associated with proteolytic events such as the muscle-specific E3 ubiquitin ligase atrogin-1 were significantly up-regulated, suggesting that protein breakdown, prevention of protein aggregation and stabilization of unfolded proteins are important processes for restoring cellular homeostasis. We also detected an up-regulation of genes, which are associated with muscle cell proliferation and differentiation including MUSTN1, ASB5 and CSRP3, possibly reflecting activation, differentiation and fusion of satellite cells to facilitate repair of muscle damage. In addition, exercise increased expression of the orphan nuclear hormone receptor NR4A3, which regulates metabolic functions associated with lipid, carbohydrate and energy homeostasis. Finally, we observed an unanticipated induction of the long non-coding RNA transcript NEAT1, which has been implicated in RNA processing and nuclear retention of adenosine-to-inosine edited mRNAs in the ribonucleoprotein bodies called paraspeckles. These findings expand the complexity of pathways affected by acute contractile activity of skeletal muscle, contributing to a better understanding of the molecular processes that occur in muscle tissue in the recovery phase.

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