JoVE   
You do not have subscription access to articles in this section. Learn more about access.

  JoVE Biology

  
You do not have subscription access to articles in this section. Learn more about access.

  JoVE Neuroscience

  
You do not have subscription access to articles in this section. Learn more about access.

  JoVE Immunology and Infection

  
You do not have subscription access to articles in this section. Learn more about access.

  JoVE Clinical and Translational Medicine

  
You do not have subscription access to articles in this section. Learn more about access.

  JoVE Bioengineering

  
You do not have subscription access to articles in this section. Learn more about access.

  JoVE Applied Physics

  
You do not have subscription access to articles in this section. Learn more about access.

  JoVE Chemistry

  
You do not have subscription access to articles in this section. Learn more about access.

  JoVE Behavior

  
You do not have subscription access to articles in this section. Learn more about access.

  JoVE Environment

|   

JoVE Science Education

General Laboratory Techniques

You do not have subscription access to videos in this collection. Learn more about access.

Basic Methods in Cellular and Molecular Biology

You do not have subscription access to videos in this collection. Learn more about access.

Model Organisms I

You do not have subscription access to videos in this collection. Learn more about access.

Model Organisms II

You do not have subscription access to videos in this collection. Learn more about access.

Essentials of
Neuroscience

You do not have subscription access to videos in this collection. Learn more about access.

Essentials of Developmental Biology

You have subscription access to videos in this collection through your user account.

In JoVE (1)

Other Publications (199)

Articles by Paaqua A. Grant in JoVE

 JoVE Biology

Blastomere Explants to Test for Cell Fate Commitment During Embryonic Development

1Department of Biological Sciences, The George Washington University, 2Department of Anatomy and Regenerative Biology, The George Washington University


JoVE 4458

The fate of an individual embryonic cell can be influenced by inherited molecules and/or by signals from neighboring cells. Utilizing fate maps of the cleavage stage Xenopus embryo, single blastomeres can be identified for culture in isolation to assess the contributions of inherited molecules versus cell-cell interactions.

Other articles by Paaqua A. Grant on PubMed

Molecular Imaging True-colour Spectroscopic Optical Coherence Tomography

Molecular imaging holds a pivotal role in medicine due to its ability to provide invaluable insight into disease mechanisms at molecular and cellular levels. To this end, various techniques have been developed for molecular imaging, each with its own advantages and disadvantages(1-4). For example, fluorescence imaging achieves micrometre-scale resolution, but has low penetration depths and is mostly limited to exogenous agents. Here, we demonstrate molecular imaging of endogenous and exogenous chromophores using a novel form of spectroscopic optical coherence tomography. Our approach consists of using a wide spectral bandwidth laser source centred in the visible spectrum, thereby allowing facile assessment of haemoglobin oxygen levels, providing contrast from readily available absorbers, and enabling true-colour representation of samples. This approach provides high spectral fidelity while imaging at the micrometre scale in three dimensions. Molecular imaging true-colour spectroscopic optical coherence tomography (METRiCS OCT) has significant implications for many biomedical applications including ophthalmology, early cancer detection, and understanding fundamental disease mechanisms such as hypoxia and angiogenesis.

The Prostate Cancer Screening Controversy: Addressing Bioethical Concerns at a Community Health Promotion Event for Men

Summary: There are bioethical concerns related to prostate cancer screening. A new prostate cancer screening approach at a community health promotion event used vouchers to promote informed decision-making in order to reduce these concerns.

Suicide Attempts in 107 Adolescents and Adults with Kleptomania

Suicide attempts in kleptomania have received little investigation. This study examined rates, correlates, and predictors of suicide attempts in kleptomania. A total of 107 adolescent and adult subjects (n = 32 [29.9%] males) with DSM-IV kleptomania were assessed with standard measures of symptom severity, psychiatric comorbidity, and functional impairment. Subjects had high rates of suicide attempts (24.3%). The suicide attempt in 92.3% of those who attempted suicide was attributed specifically to kleptomania. Suicide attempts were associated with current and life-time bipolar disorder (p = .047) and lifetime personality disorder (p = .049). Individuals with kleptomania have high rates of suicide attempts. Bipolar disorder is associated with suicide attempts in individuals with kleptomania and underscores the importance of carefully assessing and monitoring suicidality in patients with kleptomania.

Incidental Phosphorus and Nitrogen Loss from Grassland Plots Receiving Chemically Amended Dairy Cattle Slurry

Chemical amendment of dairy cattle slurry has been shown to effectively reduce incidental phosphorus (P) losses in runoff; however, the effects of amendments on incidental nitrogen (N) losses are not as well documented. This study examined P and N losses in runoff during three simulated rainfall events 2, 10 and 28 days after a single application of unamended/chemically amended dairy cattle slurry. Twenty-five hydraulically isolated plots, each measuring 0.9 m by 0.4 m and instrumented with runoff collection channels, were randomly assigned the following treatments: (i) grass-only, (ii) slurry-only (the study-control), (iii) slurry amended with industrial grade liquid alum comprising 8% Al₂O₃, (iv) slurry amended with industrial grade liquid poly-aluminum chloride (PAC) comprising 10% Al₂O₃, and (v) slurry amended with lime. During the first rainfall event, lime was ineffective but alum and PAC effectively reduced dissolved reactive P (DRP) (by 95 and 98%, respectively) and total P (TP) flow-weighted-mean-concentrations (by 82 and 93%, respectively) in runoff compared to the study-control. However, flow-weighted-mean-concentrations of ammonium-N (NH₄--N) in runoff were increased with alum- (81%) and lime-treated (11%) slurry compared to the study-control whereas PAC reduced the NH₄--N by 82%. Amendments were not observed to have a significant effect on NO₃--N losses during this study. Slurry amendments reduced P losses for the duration of the study, whereas the effect of amendments on N losses was not significant following the first event. Antecedent volumetric water content of the soil or slope of the plots did not appear to affect runoff volume. However, runoff volumes (and consequently loads of P and N) were observed to increase for the chemically amended plots compared to the control and soil-only plots. This work highlights the importance of considering both P and N losses when implementing a specific nutrient mitigation measure.

Cardiovascular Reactivity to and Recovery from Stressful Tasks Following a Mindfulness Analog in College Students with a Family History of Hypertension

Abstract Objectives: Ninety-seven (97) undergraduates with a family history of hypertension participated in a study that evaluated the effects of a brief mindfulness-induction on cardiovascular reactivity and recovery to two stressors. Materials and methods: Participants were randomized to either a mindfulness-induction or control condition and were then exposed to the cold pressor task (CPT) followed by the mirror-tracing task (MT). Blood pressure and heart rate were measured at baseline and postinduction, as well as during and immediately following each stressor. Results: There were no group differences in reactivity to either stressor. Participants in the mindfulness-analog condition experienced significantly greater latency to systolic blood pressure recovery following the CPT and a tendency toward greater latency to diastolic blood pressure recovery, although these findings were not replicated with the MT task. Conclusions: These results are contrary to what was hypothesized and to the anecdotal evidence available regarding effects of comprehensive mindfulness interventions on reactivity. The findings are discussed with respect to purported mechanisms of mindfulness and learning theory.

Palliative Care and End of Life: the Caregiver

Informal caregivers are a key component of end-of-life/palliative care and are increasingly recognized as recipients of care. Numerous factors affect the care they give and they have significant care needs themselves. The purpose of this survey was to identify key research questions, priorities, and next steps for research on caregivers and palliative care. A literature search of publications between 2006 and 2011 was conducted, yielding 109 studies that were evaluated on type, quality, topic, and other factors. An interdisciplinary group of healthcare professionals examined results and recommended research priorities. Existing research is primarily descriptive in nature, with few interventions to guide practice. Future research priorities include factors influencing caregivers and roles, information and support needs, caregiver health, end-of-life issues, healthcare disparities, and delivery and costs of care. Conclusions include that expanding the science will contribute to improving caregiver performance and health.

Equality of Employment Opportunities for Nurses at the Point of Qualification: An Exploratory Study

BACKGROUND: Securing employment after qualification is of utmost importance to newly qualified nurses to consolidate knowledge and skills. The factors that influence success in gaining this first post are not known. OBJECTIVES: The study aimed to describe the first post gained after qualification in terms of setting, nature of employment contract and geographical distribution and explore the relationship between a range of factors (including ethnicity) and employment at the point of qualification. DESIGN: An exploratory study using structured questionnaires and secondary analysis of data routinely collected by the universities about students and their progress during their course. SETTINGS: The study was conducted in eight universities within a large, multicultural city in the UK as part of the 'Readiness for Work' research programme. PARTICIPANTS: Eight hundred and four newly qualified nurses who had successfully completed a diploma or degree from one of the universities; a response rate of 77% representing 49% of all graduating students in the study population. METHODS: Data were collected by self-completed semi-structured questionnaires administered to students at the time of qualification and at three months post-qualification. Routinely collected data from the universities were also collected. RESULTS: Fifty two percent of participants had been offered a job at the point of qualification (85% of those who had applied and been interviewed). Of these, 99% had been offered a nursing post, 88% in the city studied, 67% in the healthcare setting where they had completed a course placement. 44% felt "confident" and 32% "very confident" about their employment prospects. Predictors of employment success included ethnicity, specialty of nursing and university attended. Predictors of confidence and preparedness for job seeking included ethnicity, nursing specialty, gender and grade of degree. Newly qualified nurses from non-White/British ethnic groups were less likely to get a job and feel confident about and prepared for job seeking. CONCLUSIONS: This study has demonstrated that ethnicity does lead to employment disadvantage for newly qualified nurses. This is an important contribution towards recognizing and describing the evidence so that appropriate responses and interventions can be developed. It is important that universities and healthcare institutions work closely together to support students at this important time in their nursing career.

Obesity in Mice with Adipocyte-specific Deletion of Clock Component Arntl

Adipocytes store excess energy in the form of triglycerides and signal the levels of stored energy to the brain. Here we show that adipocyte-specific deletion of Arntl (also known as Bmal1), a gene encoding a core molecular clock component, results in obesity in mice with a shift in the diurnal rhythm of food intake, a result that is not seen when the gene is disrupted in hepatocytes or pancreatic islets. Changes in the expression of hypothalamic neuropeptides that regulate appetite are consistent with feedback from the adipocyte to the central nervous system to time feeding behavior. Ablation of the adipocyte clock is associated with a reduced number of polyunsaturated fatty acids in adipocyte triglycerides. This difference between mutant and wild-type mice is reflected in the circulating concentrations of polyunsaturated fatty acids and nonesterified polyunsaturated fatty acids in hypothalamic neurons that regulate food intake. Thus, this study reveals a role for the adipocyte clock in the temporal organization of energy regulation, highlights timing as a modulator of the adipocyte-hypothalamic axis and shows the impact of timing of food intake on body weight.

SynSysNet: Integration of Experimental Data on Synaptic Protein-protein Interactions with Drug-target Relations

We created SynSysNet, available online at http://bioinformatics.charite.de/synsysnet, to provide a platform that creates a comprehensive 4D network of synaptic interactions. Neuronal synapses are fundamental structures linking nerve cells in the brain and they are responsible for neuronal communication and information processing. These processes are dynamically regulated by a network of proteins. New developments in interaction proteomics and yeast two-hybrid methods allow unbiased detection of interactors. The consolidation of data from different resources and methods is important to understand the relation to human behaviour and disease and to identify new therapeutic approaches. To this end, we established SynSysNet from a set of ∼1000 synapse specific proteins, their structures and small-molecule interactions. For two-thirds of these, 3D structures are provided (from Protein Data Bank and homology modelling). Drug-target interactions for 750 approved drugs and 50 000 compounds, as well as 5000 experimentally validated protein-protein interactions, are included. The resulting interaction network and user-selected parts can be viewed interactively and exported in XGMML. Approximately 200 involved pathways can be explored regarding drug-target interactions. Homology-modelled structures are downloadable in Protein Data Bank format, and drugs are available as MOL-files. Protein-protein interactions and drug-target interactions can be viewed as networks; corresponding PubMed IDs or sources are given.

Darunavir is Predominantly Unbound to Protein in Cerebrospinal Fluid and Concentrations Exceed the Wild-type HIV-1 Median 90% Inhibitory Concentration

OBJECTIVES: Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC(90)). METHODS: Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography-tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir. RESULTS: Twenty-nine matched CSF-plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC(90) for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma. CONCLUSIONS: Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.

The Kynurenine Pathway in Brain Tumor Pathogenesis

Brain tumors are among the most common and most chemoresistant tumors. Despite treatment with aggressive treatment strategies, the prognosis for patients harboring malignant gliomas remains dismal. The kynurenine pathway (KP) is the principal route of L-tryptophan catabolism leading to the formation of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+)), and important neuroactive metabolites, including the neurotoxin, quinolinic acid (QUIN), the neuroprotective agent, picolinic acid (PIC), the T(H)17/Treg balance modulator, 3-hydroxyanthranilic acid (3-HAA), and the immunosuppressive agent, L-kynurenine (KYN). This review provides a new perspective on KP dysregulation in defeating antitumor immune responses, specifically bringing light to the lower segment of the KP, particularly QUIN-induced neurotoxicity and downregulation of the enzyme α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) as a potential mechanism of tumor progression. Given its immunosuppressive effects, 3-HAA produced from the KP may also play a role in suppressing antitumor immunity in human tumors. The enzyme indoleamine 2, 3-dioxygenase (IDO-1) initiates and regulates the first step of the KP in most cells. Mounting evidence directly implicates that the induction and overexpression of IDO-1 in various tumors is a crucial mechanism facilitating tumor immune evasion and persistence. Tryptophan 2, 3-dioxygenase (TDO-2), which initiates the same first step of the KP as IDO-1, has likewise recently been shown to be a mechanism of tumoral immune resistance. Further, it was also recently shown that TDO-2-dependent production of KYN by brain tumors might be a novel mechanism for suppressing antitumor immunity and supporting tumor growth through the activation of the Aryl hydrocarbon receptor (AhR). This newly identified TDO-2-KYN-AhR signaling pathway opens up exciting future research opportunities and may represent a novel therapeutic target in cancer therapy. Our discussion points to a number of KP components, namely TDO-2, IDO-1, and ACMSD, as important therapeutic targets for the treatment of brain cancer. Targeting the KP in brain tumors may represent a viable strategy likely to prevent QUIN-induced neurotoxicity and KYN and 3-HAA-mediated immune suppression.

Role of PKC and CaV1.2 in Detrusor Overactivity in a Model of Obesity Associated with Insulin Resistance in Mice

Obesity/metabolic syndrome are common risk factors for overactive bladder. This study aimed to investigate the functional and molecular changes of detrusor smooth muscle (DSM) in high-fat insulin resistant obese mice, focusing on the role of protein kinase C (PKC) and Ca(v)1.2 in causing bladder dysfunction. Male C57BL/6 mice were fed with high-fat diet for 10 weeks. In vitro functional responses and cystometry, as well as PKC and Ca(v)1.2 expression in bladder were evaluated. Obese mice exhibited higher body weight, epididymal fat mass, fasting glucose and insulin resistance. Carbachol (0.001-100 µM), α,β-methylene ATP (1-10 µM), KCl (1-300 mM), extracellular Ca(2+) (0.01-100 mM) and phorbol-12,13-dibutyrate (PDBu; 0.001-3 µM) all produced greater DSM contractions in obese mice, which were fully reversed by the Ca(v)1.2 blocker amlodipine. Cystometry evidenced augmented frequency, non-void contractions and post-void pressure in obese mice that were also prevented by amlodipine. Metformin treatment improved the insulin sensitivity, and normalized the in vitro bladder hypercontractility and cystometric dysfunction in obese mice. The PKC inhibitor GF109203X (1 µM) also reduced the carbachol induced contractions. PKC protein expression was markedly higher in bladder tissues from obese mice, which was normalized by metformin treatment. The Ca(v)1.2 channel protein expression was not modified in any experimental group. Our findings show that Ca(v)1.2 blockade and improvement of insulin sensitization restores the enhanced PKC protein expression in bladder tissues and normalizes the overactive detrusor. It is likely that insulin resistance importantly contributes for the pathophysiology of this urological disorder in obese mice.

DSM-5 Field Survey: Skin Picking Disorder

Pathologic skin picking (skin picking disorder [SPD]) is a prevalent and disabling condition, which has received increasing study. It is timely to consider including SPD in DSM-5. The aim of this field survey was to investigate possible diagnostic criteria for SPD.

Complementary Combinations: What Treatments Will Become Key to the Battle Against Acute Myelogenous Leukemia?

Chronic Administration of Dietary Grape Seed Extract Increases Colonic Expression of Gut Tight Junction Protein Occludin and Reduces Fecal Calprotectin: a Secondary Analysis of Healthy Wistar Furth Rats

Animal studies have demonstrated the potential of grape seed extract (GSE) to prevent metabolic syndrome, obesity, and type 2 diabetes. Recently, metabolic endotoxemia induced by bacterial endotoxins produced in the colon has emerged as a possible factor in the etiology of metabolic syndrome. Improving colonic barrier function may control endotoxemia by reducing endotoxin uptake. However, the impact of GSE on colonic barrier integrity and endotoxin uptake has not been evaluated. We performed a secondary analysis of samples collected from a chronic GSE feeding study with pharmacokinetic end points to examine potential modulation of biomarkers of colonic integrity and endotoxin uptake. We hypothesized that a secondary analysis would indicate that chronic GSE administration increases colonic expression of intestinal tight junction proteins and reduces circulating endotoxin levels, even in the absence of an obesity-promoting stimulus. Wistar Furth rats were administered drinking water containing 0.1% GSE for 21 days. Grape seed extract significantly increased the expression of gut junction protein occludin in the proximal colon and reduced fecal levels of the neutrophil protein calprotectin, compared with control. Grape seed extract did not significantly reduce serum or fecal endotoxin levels compared with control, although the variability in serum levels was widely increased by GSE. These data suggest that the improvement of gut barrier integrity and potential modulation of endotoxemia warrant investigation as a possible mechanism by which GSE prevents metabolic syndrome and associated diseases. Further investigation of this mechanism in high-fat feeding metabolic syndrome and obesity models is therefore justified.

Ageing Towards 21 As a Risk Factor for Young Adult Suicide in the UK and Ireland

Aims. Youth and young adult suicide has increasingly appeared on international vital statistics as a rising trend of concern in age-specific mortality over the past 50 years. The reporting of suicide deaths in 5-year age bands, which has been the international convention to date, may mask a greater understanding of year-on-year factors that may accelerate or ameliorate the emergence of suicidal thoughts, acts and fatal consequences. The study objective was to identify any year-on-year period of increased risk for youth and young adult suicide in the UK and Ireland. Methods. Collation and examination of international epidemiological datasets on suicide (aged 18-35) for the UK and Ireland 2000-2006 (N = 11 964). Outcome measures included the age distribution of suicide mortality in international datasets from the UK and Ireland, 2000-2006. Results. An accelerated pattern of risk up to the age of 20 for the UK and Ireland which levels off moderately thereafter was uncovered, thus identifying a heretofore unreported age-related epidemiological transition for suicide. Conclusions. The current reporting of suicide in 5-year age bands may conceal age-related periods of risk for suicide. This may have implications for suicide prevention programmes for young adults under age 21.

β-hydroxy-β-methylbutyrate Did Not Enhance High Intensity Resistance Training-induced Improvements in Myofiber Dimensions and Myogenic Capacity in Aged Female Rats

Older women exhibit blunted skeletal muscle hypertrophy following resistance training (RT) compared to other age and gender cohorts that is partially due to an impaired regenerative capacity. In the present study, we examined whether β-hydroxy-β-methylbutyrate (HMB) provision to aged female rodents would enhance regenerative mechanisms and facilitate RT-induced myofiber growth. Nineteen-month old female Sprague-Dawley rats were randomly divided into three groups: HMB (0.48 g/kg/d; n = 6), non-HMB (n = 6), and control (n = 4). HMB and non-HMB groups underwent RT every third day for 10 weeks using a ladder climbing apparatus. Whole body strength, grip strength, and body composition was evaluated before and after RT. The gastrocnemius and soleus muscles were analyzed using magnetic resonance diffusion tensor imaging, RT-PCR, and immunohistochemistry to determine myofiber dimensions, transcript expression, and satellite cells/myonuclei, respectively. ANOVAs were used with significance set at p < 0.05. There were significant time effects (pre vs. post) for whole body strength (+262%), grip strength (+17%), lean mass (+20%), and fat mass (-19%). Both RT groups exhibited significant increases in the mean myofiber cross-sectional area (CSA) in the gastrocnemius and soleus (+8-22%) compared to control. Moreover, both groups demonstrated significant increases in the numbers of satellite cells (+100-108%) and myonuclei (+32%) in the soleus but not the gastrocnemius. A significant IGF-I mRNA elevation was only observed in soleus of the HMB group (+33%) whereas MGF and myogenin increased significantly in both groups (+32-40%). Our findings suggest that HMB did not further enhance intense RT-mediated myogenic mechanisms and myofiber CSA in aged female rats.

The Role of DNA Methylation and Histone Modifications in Transcriptional Regulation in Humans

Although the field of genetics has grown by leaps and bounds within the last decade due to the completion and availability of the human genome sequence, transcriptional regulation still cannot be explained solely by an individual's DNA sequence. Complex coordination and communication between a plethora of well-conserved chromatin modifying factors are essential for all organisms. Regulation of gene expression depends on histone post translational modifications (HPTMs), DNA methylation, histone variants, remodeling enzymes, and effector proteins that influence the structure and function of chromatin, which affects a broad spectrum of cellular processes such as DNA repair, DNA replication, growth, and proliferation. If mutated or deleted, many of these factors can result in human disease at the level of transcriptional regulation. The common goal of recent studies is to understand disease states at the stage of altered gene expression. Utilizing information gained from new high-throughput techniques and analyses will aid biomedical research in the development of treatments that work at one of the most basic levels of gene expression, chromatin. This chapter will discuss the effects of and mechanism by which histone modifications and DNA methylation affect transcriptional regulation.

Rapid Coupling Between Ice Volume and Polar Temperature over the Past 150,000 years

Current global warming necessitates a detailed understanding of the relationships between climate and global ice volume. Highly resolved and continuous sea-level records are essential for quantifying ice-volume changes. However, an unbiased study of the timing of past ice-volume changes, relative to polar climate change, has so far been impossible because available sea-level records either were dated by using orbital tuning or ice-core timescales, or were discontinuous in time. Here we present an independent dating of a continuous, high-resolution sea-level record in millennial-scale detail throughout the past 150,000 years. We find that the timing of ice-volume fluctuations agrees well with that of variations in Antarctic climate and especially Greenland climate. Amplitudes of ice-volume fluctuations more closely match Antarctic (rather than Greenland) climate changes. Polar climate and ice-volume changes, and their rates of change, are found to covary within centennial response times. Finally, rates of sea-level rise reached at least 1.2 m per century during all major episodes of ice-volume reduction.

Parental Social Support, Coping Strategies, Resilience Factors, Stress, Anxiety and Depression Levels in Parents of Children with MPS III (Sanfilippo Syndrome) or Children with Intellectual Disabilities (ID)

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of four enzymes involved in the catabolism of the glycosaminoglycan heparan sulphate. It is a degenerative disorder, with a progressive decline in children's intellectual and physical functioning. There is currently no cure for the disorder. To date there is a paucity of research on how this disorder impacts parents psychological functioning. Specifically, research in the area has failed to employ adequate control groups to assess if the impact of this disorder on parents psychological functioning differs from parenting a child with intellectual disability (ID). The current study examined child behaviour and parental psychological functioning in 23 parents of children with MPS III and 23 parents of children with ID. Parents completed postal questionnaires about their child's behaviour and abilities and their own psychological functioning. Parents of children with MPS III reported fewer behavioural difficulties as their child aged, more severe level of intellectual disability, and similar levels of perceived social support, coping techniques, stress, anxiety and depression levels as parents of children with ID. Both groups of parents scored above the clinical cut off for anxiety and depression. Parents of children with MPS III rated themselves as significantly less future-orientated and goal directed than parents of children with ID. Services should develop support packages for parents of children with MPS III that incorporate an understanding of the unique stressors and current-difficulty approach of this population. Future research should examine gender differences between parental psychological functioning, using mixed qualitative and quantitative approaches, and utilise matched developmental level and typically developing control groups.

Sampling of Herbicides in Streams During Flood Events

In stream water xenobiotics usually occur as pulses in connection with floods caused by surface run-off and tile drainage following precipitation events. In streams located in small agricultural catchments we monitored herbicide concentrations during flood events by applying an intensive sampling programme of ½ h intervals for 7 h. In contrast to grab sampling under non-flood conditions, clearly elevated concentrations were recorded during the floods, and pulses varying in occurrence, duration and concentration were recorded. Pulses of recently applied herbicides were the most prominent, but also agricultural herbicides used in previous seasons caused pulses in the streams. Asynchronism of chemographs may be related to the characteristics of the compounds as well as their transport pathways and transformation in compartments between the source and the point of sampling in the stream. Thus, the occurrence of chemographs is difficult to predict, which ought to be taken into account when designing a sampling strategy. Even though the chemographs of herbicides and their transformation products (glyphosate and aminomethylphosphonic acid (AMPA) as well as terbuthylazine and desethylterbuthylazine) seem to be synchronous, their occurrence may still be difficult to predict. It is evident that grab sampling under non-flood conditions yields insufficient information on the dynamics of occurrence of herbicides in stream water, both with respect to environmental effects and the calculation of the load to a recipient. In conclusion, the design of a sampling strategy regarding herbicides in stream waters should adequately consider the aim of the investigation.

Dynamic Trends in Cardiac Surgery: Why the Logistic EuroSCORE is No Longer Suitable for Contemporary Cardiac Surgery and Implications for Future Risk Models

OBJECTIVES: Progressive loss of calibration of the original EuroSCORE models has necessitated the introduction of the EuroSCORE II model. Poor model calibration has important implications for clinical decision-making and risk adjustment of governance analyses. The objective of this study was to explore the reasons for the calibration drift of the logistic EuroSCORE. METHODS: Data from the Society for Cardiothoracic Surgery in Great Britain and Ireland database were analysed for procedures performed at all National Health Service and some private hospitals in England and Wales between April 2001 and March 2011. The primary outcome was in-hospital mortality. EuroSCORE risk factors, overall model calibration and discrimination were assessed over time. RESULTS: A total of 317 292 procedures were included. Over the study period, mean age at surgery increased from 64.6 to 67.2 years. The proportion of procedures that were isolated coronary artery bypass grafts decreased from 67.5 to 51.2%. In-hospital mortality fell from 4.1 to 2.8%, but the mean logistic EuroSCORE increased from 5.6 to 7.6%. The logistic EuroSCORE remained a good discriminant throughout the study period (area under the receiver-operating characteristic curve between 0.79 and 0.85), but calibration (observed-to-expected mortality ratio) fell from 0.76 to 0.37. Inadequate adjustment for decreasing baseline risk affected calibration considerably. DISCUSSIONS: Patient risk factors and case-mix in adult cardiac surgery change dynamically over time. Models like the EuroSCORE that are developed using a 'snapshot' of data in time do not account for this and can subsequently lose calibration. It is therefore important to regularly revalidate clinical prediction models.

Toxicities, Complications, and Clinical Encounters During Intraperitoneal Chemotherapy in 17 Women with Ovarian Cancer

PURPOSE OF THE RESEARCH: Intraperitoneal (IP) chemotherapy is a viable and superior treatment to standard intravenous (IV) chemotherapy in women with small volume residual ovarian cancer following optimal debulking. Despite this clinical advantage, widespread adoption of the treatment regimen has been hampered by concerns related to toxicities and complications. The purpose of this descriptive study was to describe nursing implications related to toxicities, complications and clinical encounters in 17 women with ovarian cancer who received IP chemotherapy. METHODS AND SAMPLE: Women with ovarian cancer who received IP chemotherapy at one NCI-designated comprehensive cancer center were accrued. Data related to IP chemotherapy summary, clinical encounters and admissions were obtained through comprehensive chart audits. KEY RESULTS: Common treatment-related toxicities included nausea and vomiting, fatigue, hypomagnesia, pain, neuropathy, anemia, and constipation. Reasons for dose-modifications were multi-factorial, and were primarily related to catheter complications and chemotherapy toxicities. The number of clinical encounters was high, and they were primarily related to admissions for inpatient IP chemotherapy and follow-up clinic visits. CONCLUSIONS: Treatment-related toxicities and complications were common in women with ovarian cancer who received IP chemotherapy. Use of IP chemotherapy results in multiple clinical encounters, such as outpatient clinic visits and inpatient admissions. Nursing is a critical part of the interdisciplinary approach in caring for women treated with IP chemotherapy. Interdisciplinary teams with high levels of knowledge and skills related to IP chemotherapy administration are needed to manage treatment-related toxicities and complications, and support multiple clinical encounters during treatment.

Proximal Correlates of Metabolic Phenotypes During 'at-risk' and 'case' Stages of the Metabolic Disease Continuum

Objective:To examine the social and behavioural correlates of metabolic phenotypes during 'at-risk' and 'case' stages of the metabolic disease continuum.Design:Cross-sectional study of a random population sample.Participants:A total of 718 community-dwelling adults (57% female), aged 18-92 years from a regional South Australian city.Measurements:Total body fat and lean mass and abdominal fat mass were assessed by dual energy x-ray absorptiometry. Fasting venous blood was collected in the morning for assessment of glycated haemoglobin, plasma glucose, serum triglycerides, cholesterol lipoproteins and insulin. Seated blood pressure (BP) was measured. Physical activity and smoking, alcohol and diet (96-item food frequency), sleep duration and frequency of sleep disordered breathing (SDB) symptoms, and family history of cardiometabolic disease, education, lifetime occupation and household income were assessed by questionnaire. Current medications were determined by clinical inventory.Results:36.5% were pharmacologically managed for a metabolic risk factor or had known diabetes ('cases'), otherwise were classified as the 'at-risk' population. In both 'at-risk' and 'cases', four major metabolic phenotypes were identified using principal components analysis that explained over 77% of the metabolic variance between people: fat mass/insulinemia (FMI); BP; lipidaemia/lean mass (LLM) and glycaemia (GLY). The BP phenotype was uncorrelated with other phenotypes in 'cases', whereas all phenotypes were inter-correlated in the 'at-risk'. Over and above other socioeconomic and behavioural factors, medications were the dominant correlates of all phenotypes in 'cases' and SDB symptom frequency was most strongly associated with FMI, LLM and GLY phenotypes in the 'at-risk'.Conclusion:Previous research has shown FMI, LLM and GLY phenotypes to be most strongly predictive of diabetes development. Reducing SDB symptom frequency and optimising the duration of sleep may be important concomitant interventions to standard diabetes risk reduction interventions. Prospective studies are required to examine this hypothesis.

A Severe Pneumonia Due to Methicillin Resistant Staphylococcus Aureus Clone USA 300: Implications of Vertical Transmission

Staphylococcus aureus is an important pathogen in both community and healthcare associated pneumonia. We describe a case of severe pneumonia caused by the methicillin resistant Staphylococcus aureus (MRSA) clone USA 300 in a 44-year old post-partum woman and the subsequent vertical transmission of this virulent organism to her neonate.

Do Social Support, Stigma, and Social Problem-solving Skills Predict Depressive Symptoms in People Living with HIV? A Mediation Analysis

Social support, stigma, and social problem solving may be mediators of the relationship between sign and symptom severity and depressive symptoms in people living with HIV (PLWH). However, no published studies have examined these individual variables as mediators in PLWH. This cross-sectional, correlational study of 150 PLWH examined whether social support, stigma, and social problem solving were mediators of the relationship between HIV-related sign and symptom severity and depressive symptoms. Participants completed self-report questionnaires during their visits at two HIV outpatient clinics in the Southeastern United States. Using multiple regression analyses as a part of mediation testing, social support, stigma, and social problem solving were found to be partial mediators of the relationship between sign and symptom severity and depressive symptoms, considered individually and as a set.

Intra- and Inter-rater Reliability of the Detection of Tears of the Supraspinatus Central Tendon on MRI by Shoulder Surgeons

BACKGROUND: The purpose of this study was to determine the intra- and inter-rater reliability of detecting full- and partial-thickness tears of the supraspinatus intramuscular central tendon on magnetic resonance imaging (MRI) by orthopaedic shoulder surgeons. Full-thickness tears of this tendon have previously been associated with the failure of nonsurgical management of rotator cuff tears. METHODS: Shoulder MRIs from 40 patients entered into a prospective rotator cuff disease database were independently reviewed by two musculoskeletal (MSK) radiologists in order to determine if there was a partial- or full-thickness tear of the supraspinatus central tendon. The MRIs were randomly sorted and distributed to 16 fellowship-trained shoulder surgeons. The surgeons then similarly diagnosed each patient. After a 1-month interval, surgeons repeated the evaluation with the same set of randomly reordered MRIs. Surgeon intra- and inter-rater reliability was determined with the kappa statistic. Agreement and inter-rater reliability were also determined between the shoulder surgeons and MSK radiologists. RESULTS: For full-thickness tears, the intra-rater reliability was excellent (0.86 ± 0.1, 95% confidence interval (CI): 0.81, 0.91) and the agreement was 93.4% ± 4.6, 95% CI: 91.1, 95.8. Inter-rater reliability for both rounds was also excellent (0.77 and 0.74). The agreement between the shoulder surgeons and MSK radiologists was 92.9% ± 3.9, 95% CI: 90.9, 94.9, and the kappa was 0.85 ± 0.08, 95% CI: 0.81, 0.89. Including partial-thickness tears resulted in agreement of 65-92% and kappa values of 0.59-0.72. CONCLUSION: The reliability for the MRI detection of full thickness tears of the supraspinatus central tendon among shoulder surgeons and between shoulder surgeons and MSK radiologists was excellent.

Linking the Development of Ventilator-Induced Injury to Mechanical Function in the Lung

Management of ALI/ARDS involves supportive ventilation at low tidal volumes (V (t)) to minimize the rate at which ventilator induced lung injury (VILI) develops while the lungs heal. However, we currently have few details to guide the minimization of VILI in the ALI/ARDS patient. The goal of the present study was to determine how VILI progresses with time as a function of the manner in which the lung is ventilated in mice. We found that the progression of VILI caused by over-ventilating the lung at a positive end-expiratory pressure of zero is accompanied by progressive increases in lung stiffness as well as the rate at which the lung derecruits over time. We were able to accurately recapitulate these findings in a computational model that attributes changes in the dynamics of recruitment and derecruitment to two populations of lung units. One population closes over a time scale of minutes following a recruitment maneuver and the second closes in a matter of seconds or less, with the relative sizes of the two populations changing as VILI develops. This computational model serves as a basis from which to link the progression of VILI to changes in lung mechanical function.

Transient Serum Exposure Regimes to Support Dual Differentiation of Human Mesenchymal Stem Cells

Human mesenchymal stem cells (MSCs), which can generate both osteoblasts and chondrocytes, represent an ideal resource for orthopaedic repair using tissue-engineering approaches. One major difficulty for the development of osteochondral constructs using undifferentiated MSCs is that serum is typically used in culture protocols to promote differentiation of the osteogenic component, whereas existing chondrogenic differentiation protocols rely on the use of serum-free conditions. In order to define conditions which could be compatible with both chondrogenic and osteogenic differentiation in a single bioreactor, we have analysed the efficiency of new biphasic differentiation regimes based on transient serum exposure followed by serum-free treatment. MSC differentiation was assessed either in serum-free medium or with a range of transient exposure to serum, and compared to continuous serum-containing treatment. Although osteogenic differentation was not supported in the complete absence of serum, marker expression and extensive mineralization analyses established that 5 days of transient exposure triggered a level of differentiation comparable to that observed when serum was present throughout. This initial phase of serum exposure was further shown to support the successful chondrogenic differentiation of MSCs, comparable to controls maintained in serum-free conditions throughout. This study indicates that a culture based on temporal serum exposure followed by serum-free treatment is compatible with both osteogenic and chondrogenic differentiation of MSCs. These results will allow the development of novel strategies for osteochondral tissue engineering approaches using MSCs for regenerative medicine. Copyright © 2012 John Wiley & Sons, Ltd.

Another Perspective on 'the Effect of Different Alcohol Drinking Patterns in Early to Mid Pregnancy on the Child's Intelligence, Attention, and Executive Function'

High Dynamic Range Microscope Infrared Imaging of Silicon Nanophotonic Devices

A noninvasive diagnostic technique based on wavelength-resolved and magnified infrared images of weakly scattered light from a silicon photonic device may be useful to infer component characteristics, such as waveguide-resonator coupling, loss, quality factor, etc., at multiple locations, without the constraint of input/output couplers. Here, we demonstrate the benefit of high dynamic range microscope imaging for a silicon coupled microresonator device.

Effects of the Campylobacter Jejuni CJIE1 Prophage Homologs on Adherence and Invasion in Culture, Patient Symptoms, and Source of Infection

Prophages of enteric bacteria are frequently of key importance for the biology, virulence, or host adaptation of their host. Some C. jejuni isolates carry homologs of the CJIE1 (CMLP 1) prophage that carry cargo genes potentially involved in virulence. Possible role(s) of CJIE1 homologs in the biology and virulence of C. jejuni were therefore investigated by using in vitro cell culture assays and by assessing the association of C. jejuni isolates with and without these prophages with patients' symptoms, with source, and with clonal lineages within the C. jejuni population.

Commentary on Durkee Et al. (2012): Adolescents in a Webbed World

Properties of Membrane-Incorporated WALP Peptides That Are Anchored on Only One End

Peptides of the "WALP" family, acetyl-GWW(LA)(n)LWWA-[ethanol]amide, have proven to be opportune models for investigating lipid-peptide interactions. Because the average orientations and motional behavior of the N- and C-terminal Trp (W) residues differ, it is of interest to investigate how the positions of the tryptophans influence the properties of the membrane-incorporated peptides. To address this question, we synthesized acetyl-GGWW(LA)(n)-ethanolamide and acetyl-(AL)(n)WWG-ethanolamide, in which n = 4 or 8, which we designate as "N-anchored" and "C-anchored" peptides, respectively. Selected (2)H or (15)N labels were incorporated for solid-state nuclear magnetic resonance (NMR) spectroscopy. These peptides can be considered "half"-anchored WALP peptides, having only one pair of interfacial Trp residues near either the amino or the carboxyl terminus. The hydrophobic lengths of the (n = 8) peptides are similar to that of WALP23. These longer half-anchored WALP peptides incorporate into lipid bilayers as α-helices, as reflected in their circular dichroism spectra. Solid-state NMR experiments indicate that the longer peptide helices assume defined transmembrane orientations with small non-zero average tilt angles and moderate to high dynamic averaging in bilayer membranes of 1,2-dioleoylphosphatidylcholine, 1,2-dimyristoylphosphatidylcholine, and 1,2-dilauroylphosphatidylcholine. The intrinsically small apparent tilt angles suggest that interactions of aromatic residues with lipid headgroups may play an important role in determining the magnitude of the peptide tilt in the bilayer membrane. The shorter (n = 4) peptides, in stark contrast to the longer peptides, display NMR spectra that are characteristic of greatly reduced motional averaging, probably because of peptide aggregation in the bilayer environment, and CD spectra that are characteristic of β-structure.

Re: Key Questions in Vitamin D Research

Thought Disorder in the Meta-structure of Psychopathology

BACKGROUND: Dimensional models of co-morbidity have the potential to improve the conceptualization of mental disorders in research and clinical work, yet little is known about how relatively uncommon disorders may fit with more common disorders. The present study estimated the meta-structure of psychopathology in the US general population focusing on the placement of five under-studied disorders sharing features of thought disorder: paranoid, schizoid, avoidant and schizotypal personality disorders, and manic episodes as well as bipolar disorder. Method Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions, a face-to-face interview of 34 653 non-institutionalized adults in the US general population. The meta-structure of 16 DSM-IV Axis I and Axis II psychiatric disorders, as assessed by the Alcohol Use Disorder and Associated Disabilities Interview Schedule DSM-IV version (AUDADIS-IV), was examined using exploratory and confirmatory factor analysis. RESULTS: We document an empirically derived thought disorder factor that is a subdomain of the internalizing dimension, characterized by schizoid, paranoid, schizotypal and avoidant personality disorders as well as manic episodes. Manic episodes exhibit notable associations with both the distress subdomain of the internalizing dimension as well as the thought disorder subdomain. The structure was replicated for bipolar disorder (I or II) in place of manic episodes. CONCLUSIONS: As our understanding of psychopathological meta-structure expands, incorporation of disorders characterized by detachment and psychoticism grows increasingly important. Disorders characterized by detachment and psychoticism may be well conceptualized, organized and measured as a subdimension of the internalizing spectrum of disorders. Manic episodes and bipolar disorder exhibit substantial co-morbidity across both distress and thought disorder domains of the internalizing dimension. Clinically, these results underscore the potential utility of conceptualizing patient treatment needs using an approach targeting psychopathological systems underlying meta-structural classification rubrics.

Lower Blood Pressure Associated with Higher Mortality in Retrospective Study of Patients with Newly Diagnosed Type 2 Diabetes

Unequal Allocation and Allocation Concealment

EuPathDB: The Eukaryotic Pathogen Database

EuPathDB (http://eupathdb.org) resources include 11 databases supporting eukaryotic pathogen genomic and functional genomic data, isolate data and phylogenomics. EuPathDB resources are built using the same infrastructure and provide a sophisticated search strategy system enabling complex interrogations of underlying data. Recent advances in EuPathDB resources include the design and implementation of a new data loading workflow, a new database supporting Piroplasmida (i.e. Babesia and Theileria), the addition of large amounts of new data and data types and the incorporation of new analysis tools. New data include genome sequences and annotation, strand-specific RNA-seq data, splice junction predictions (based on RNA-seq), phosphoproteomic data, high-throughput phenotyping data, single nucleotide polymorphism data based on high-throughput sequencing (HTS) and expression quantitative trait loci data. New analysis tools enable users to search for DNA motifs and define genes based on their genomic colocation, view results from searches graphically (i.e. genes mapped to chromosomes or isolates displayed on a map) and analyze data from columns in result tables (word cloud and histogram summaries of column content). The manuscript herein describes updates to EuPathDB since the previous report published in NAR in 2010.

The Power of Information: Health Information and UK Agendas

The Department of Health published a new health information strategy in May 2012. The document provides a framework for health information in England over the next 10 years. Health information developments in England, however, do not mirror developments in other parts of the United Kingdom. This article is a personal reflection on the new health information strategy in England, including comparison with developments in the other UK nations.

The Significance of Increased Influenza Notifications During Spring and Summer of 2010-11 in Australia

Please cite this paper as: Kelly et al. (2012) The significance of increased influenza notifications during spring and summer of 2010-11 in Australia. Influenza and Other Respiratory Viruses. DOI: 10.1111/irv.12057. Background & objective  During the temperate out-of-season months in Australia in late 2010 and early 2011, an unprecedented high number of influenza notifications were recorded. We aimed to assess the significance of these notifications. Methods  For Australia, we used laboratory-confirmed cases notified to the WHO FluNet surveillance tool; the percentage of these that were positive; notifications by state and influenza type and subtype; and surveillance data from Google FluTrends. For the state of Victoria, we used laboratory-confirmed notified cases and influenza-like illness (ILI) proportions. We compared virus characterisation using haemagglutination-inhibition assays and phylogenetic analysis of the haemagglutinin gene for seasonal and out-of-season notifications. Results  The increase in notifications was most marked in tropical and subtropical Australia, but the number of out-of-season notifications in temperate Victoria was more than five times higher than the average of the previous three seasons. However, ILI proportions in spring-summer were not different to previous years. All out-of-season viruses tested were antigenically and genetically similar to those tested during either the 2010 or 2011 influenza seasons. An increase in the number of laboratories testing for influenza has led to an increase in the number of tests performed and cases notified. Conclusion  An increase in influenza infections in spring-summer of 2010-11 in tropical and temperate Australia was not associated with any differences in virus characterisation compared with viruses that circulated in the preceding and following winters. This increase probably reflected a natural variation in out-of-season virus circulation, which was amplified by increased laboratory testing.

Cardiovascular Disease Burden in Acute Public Hospitals in Ireland: Estimates for 2021 and 2031

BACKGROUND: Ireland is undergoing a demographic shift to a higher proportion of older people in the population. It is expected that this demographic shift will significantly increase the burden of care on an already overstretched acute hospitals system. AIM: This study was conducted to estimate the future burden of care on acute public hospitals pertaining to 'diseases of the circulatory system' and 'procedures on cardiovascular system' in Ireland using Hospital In-Patient Enquiry (HIPE) data for 2006 and population projections for 2021 and 2031. METHODS: Age-specific rates derived from HIPE data for 2006 and census figures for the same year were applied to population projections for 2021 and 2031 to get case number estimates in those years. RESULTS: The number of discharges with a primary diagnosis of diseases of the circulatory system is estimated to increase by 51 % by 2021 and 97 % by 2031 relative to 2006 figures. For people aged 65+ years, case numbers are estimated to increase by 65 % by 2021 and 133 % by 2031 relative to 2006 case numbers. The number of procedures performed is estimated to increase by 47 % by 2021 and 82 % by 2031 relative to 2006 figures. For people aged 65+ years, case numbers are estimated to increase by 63 % by 2021 and 120 % by 2031 relative to 2006 case numbers. CONCLUSION: The results reflect the aging of the Irish population. The expected increases in case numbers will pose significant burden on acute public hospitals and the cost of providing care.

Risky Decision-making in HIV-associated Neurocognitive Disorders (HAND)

Individuals infected with HIV show moderate deficits in decision-making, but the ecological relevance of such deficits on everyday functioning has not previously been described. This study sought to examine the magnitude, cognitive correlates, and everyday functioning impact of risky decision-making impairment in HIV-associated neurocognitive disorders (HAND). Participants included 68 HIV+ individuals with HAND, 78 HIV+ individuals without HAND, and 51 HIV- comparison participants, who were administered the Iowa Gambling Task (IGT) alongside a comprehensive neuropsychological test battery and self-report measures assessing aspects of everyday functioning. HIV+ individuals with HAND performed more poorly on the IGT relative to the other two groups, most notably during the last three trial blocks. Within the HIV+ group, IGT performance during the last three trial blocks was most strongly associated with cognitive flexibility, but was not significantly related to declines in instrumental activities of daily living (IADLs), unemployment, or medication non-adherence. While overall IGT performance across the last three trial blocks may be helpful diagnostically in identifying decision-making impairment in HAND, examination of alternate, more specific metrics (e.g., individual deck selections across trial blocks) may be more useful in delineating the role of poor decision-making in HIV-related disability, and should be examined in future research.

N-butyl-2-cyanoacrylate (NBCA) Tissue Adhesive As a Haemostatic Agent in a Venous Malformation of the Mandible

Cyanoacrylate tissue glue has many uses. We describe a case involving a 27-year-old man with a low-flow venous malformation that affected the right side of his face including the mandible. After extraction of the lower right eight, torrential haemorrhage was successfully arrested using N-butyl-2-cyanoacrylate (NBCA) glue. We think that it may be of use not only in the management of patients with vascular malformations, but also in the treatment of recalcitrant haemorrhage after dentoalveolar surgery.

Additional Requirements for Complex Interventions

Visualizing Natural Image Statistics

Natural image statistics is an important area of research in cognitive sciences and computer vision. Visualization of statistical results can help identify clusters and anomalies as well as analyze deviation, distribution and correlation. Furthermore, they can provide visual abstractions and symbolism for categorized data. In this paper, we begin our study of visualization of image statistics by considering visual representations of power spectra, which are commonly used to visualize different categories of images. We show that they convey a limited amount of statistical information about image categories and their support for analytical tasks is ineffective. We then introduce several new visual representations, which convey different or more information about image statistics. We apply ANOVA to the image statistics to help select statistically more meaningful measurements in our design process. A task-based user evaluation was carried out to compare the new visual representations with the conventional power spectra plots. Based on the results of evaluation, we made further improvement of visualization by introducing composite visual representations of image statistics.

Developmental Origins of Genotype-phenotype Correlations in Chronic Diseases of Old Age

In recent years, genome wide association studies have revolutionized the understanding of the genetic architecture of complex disease, particularly in the context of disorders that present in old age, such as type 2 diabetes and cardiovascular disease. This new era is made all the more compelling by the fact that, through extensive validation efforts, there is now very strong consensus among human geneticists on what the key loci are that contribute to the pathogenesis of these traits. However, as these variants have been almost exclusively uncovered in an adult setting, there is the question of when these genetic variants start exerting their effects; indeed many may start setting up an individual's predisposition to a disease of old age very early on in life. To this end, we review what breakthroughs have been made in elucidating which of these genetic factors are operating in childhood and conversely what discoveries have actually been made in the pediatric setting that have then been found subsequently to increase one's risk of a late-onset disease. After all, it well known that complex traits like obesity, type 2 diabetes and inflammatory bowel disease are strongly determined by genetic factors, but the isolation of genes in these complex phenotypes in adults has been impeded by interaction with strong environmental factors. Distillation of the genetic component in these complex traits, which will at least partially have origins in childhood, should be easier to determine in a pediatric setting, where the relatively short period of a child's lifetime limits the impact of environmental exposure.

Functional Exercise After Total Hip Replacement (FEATHER) a Randomised Control Trial

ABSTRACT:

Long-term Type 1 Diabetes Influences Haematopoietic Stem Cells by Reducing Vascular Repair Potential and Increasing Inflammatory Monocyte Generation in a Murine Model

AIMS/HYPOTHESIS: We sought to determine the impact of long-standing type 1 diabetes on haematopoietic stem/progenitor cell (HSC) number and function and to examine the impact of modulating glycoprotein (GP)130 receptor in these cells. METHODS: Wild-type, gp130 (-/-) and GFP chimeric mice were treated with streptozotocin to induce type 1 diabetes. Bone marrow (BM)-derived cells were used for colony-formation assay, quantification of side population (SP) cells, examination of gene expression, nitric oxide measurement and migration studies. Endothelial progenitor cells (EPCs), a population of vascular precursors derived from HSCs, were compared in diabetic and control mice. Cytokines were measured in BM supernatant fractions by ELISA and protein array. Flow cytometry was performed on enzymatically dissociated retina from gfp (+) chimeric mice and used to assess BM cell recruitment to the retina, kidney and blood. RESULTS: BM cells from the 12-month-diabetic mice showed reduced colony-forming ability, depletion of SP-HSCs with a proportional increase in SP-HSCs residing in hypoxic regions of BM, decreased EPC numbers, and reduced eNos (also known as Nos3) but increased iNos (also known as Nos2) and oxidative stress-related genes. BM supernatant fraction showed increased cytokines, GP130 ligands and monocyte/macrophage stimulating factor. Retina, kidney and peripheral blood showed increased numbers of CD11b(+)/CD45(hi)/ CCR2(+)/Ly6C(hi) inflammatory monocytes. Diabetic gp130 (-/-) mice were protected from development of diabetes-induced changes in their HSCs. CONCLUSIONS/INTERPRETATION: The BM microenvironment of type 1 diabetic mice can lead to changes in haematopoiesis, with generation of more monocytes and fewer EPCs contributing to development of microvascular complications. Inhibition of GP130 activation may serve as a therapeutic strategy to improve the key aspects of this dysfunction.

Transferability and Fine Mapping of Type 2 Diabetes Loci in African Americans: The Candidate Gene Association Resource Plus Study

Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10(-8)). Locus-wide analysis demonstrated significant associations (P(emp) < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.

Risks and Predictors of Current Suicidality in HIV-infected Heroin Users in Treatment in Yunnan, China: A Controlled Study

OBJECTIVE:: Suicide is an important public health problem in China. Elsewhere injection drug use and HIV infection have independently been associated with suicidality, but research has often overlooked these high-risk groups in China. We determined the frequency and predictors of suicidal ideas in Chinese, HIV-infected (HIV+) and uninfected (HIV-) heroin injection drug users in treatment (IDUs) and a control sample. We hypothesized that rates of suicidal ideas would be significantly higher among IDUs compared to controls, and highest among HIV+ IDUs. METHOD:: We assessed suicidal ideas within the past two weeks in HIV+ (N = 204) and HIV- (N = 202) heroin IDUs in methadone treatment in Yunnan, a province at the intersection of the heroin and HIV epidemics, and in demographically matched, uninfected non-drug using controls (N = 201). RESULTS:: Rates of suicidality were higher in IDUs than controls but there was no additive effect of HIV infection (HIV+ IDU 43.1%; HIV- IDU 37.1%; controls 8.5%). Among HIV+ IDUs suicidality was associated most strongly with a combination of prior history of major depression, low perceived social support, and experience of HIV-relevant stress, but not with AIDS diagnosis. Among HIV- IDUs suicidality was associated with prior history of major depressive or alcohol use disorder. Less than 25% of IDUs with suicidality had histories of mood or alcohol use diagnoses. CONCLUSION:: Because suicidal ideation is frequent in IDUs in China, regardless of HIV status, and is not fully accounted for by past psychiatric history, additional research may be warranted.

Collagen-nanofiber Hydrogel Composites Promote Contact Guidance of Human Lymphatic Microvascular Endothelial Cells and Directed Capillary Tube Formation

Collagen and fibronectin matrices are known to stimulate migration of microvascular endothelial cells and the process of tubulogenesis, but the physical, chemical, and topographical cues for directed vessel formation have yet to be determined. In this study, growth, migration, elongation, and tube formation of human lymphatic microvascular endothelial cells (LECs) were investigated on electrospun poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(L-lactic-co-D-lactic acid) (PLDL) nanofiber-coated substrates, and correlated with fiber density and diameter. Directed migration of LECs was observed in the presence of aligned nanofibers, whereas random fiber alignment slowed down migration and growth of LECs. Cell guidance was significantly enhanced in the presence of more hydrophobic PLDL polymer nanofibers compared to PLGA (10:90). Subsequent experiments with tube-forming assays reveal the ability of resorbable hydrophobic nanofibers >300 nm in diameter to promote cell guidance in collagen gels without direct cell-fiber contact, in contrast to the previously reported contact-guidance phenomena. Our results show that endothelial cell guidance is possible within nanofiber/collagen-gel constructs that mimic the native extracellular matrix in terms of size and orientation of fibrillar components. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2012.

Is the ASVAB ST Composite Score a Reliable Predictor of First-attempt Graduation for the U.S. Army Operating Room Specialist Course?

The U.S. Army Operating Room Specialist (68D) Course provides first class medical technician training to U.S. Army enlisted soldiers of the Army Medical Command. With a failure rate of approximately 12% over a 2-year period, this study was commissioned to determine whether the Armed Services Vocational Aptitude Battery (ASVAB) skilled technical (ST) Score served as a reliable predictor for successful first-attempt completion of the 68D course. A sample size of 373 was analyzed via a multivariate binary logistic regression model with 6 distinct independent variables. This study found that the ASVAB ST score, gender, and rank were predictors to first-attempt successful completion of the 68D training program. Specifically, students with an ST score 10 points higher than their peers were 5 times more likely to graduate. In addition, females were 2.5 times more likely to succeed than males and Army Privates (E2) were 3.2 times more likely than Privates (El). Specialists, Corporals (E4), Sergeants (E5), and Staff Sergeants (E6) combined, were 34 times more likely to succeed than Els. Although further study may be warranted, increasing the minimum ST score requirement in the admission guidelines and/or specific preventive assistance for lower-ranked students may decrease the first-attempt failure rate.

Types of Urethral Catheter for Reducing Symptomatic Urinary Tract Infections in Hospitalised Adults Requiring Short-term Catheterisation: Multicentre Randomised Controlled Trial and Economic Evaluation of Antimicrobial- and Antiseptic-impregnated Urethral Catheters (the CATHETER Trial)

Catheter-associated urinary tract infection (CAUTI) is a major preventable cause of harm for patients in hospital and incurs significant costs for health-care providers such as the UK NHS. Many preventative strategies and measures have been introduced to minimise CAUTI risk, including the use of antimicrobial catheters. However, there is considerable uncertainty regarding their usefulness in terms of reducing symptomatic CAUTI, and whether or not they are cost-effective.

Hepatic Fibrosis Persists and Progresses Despite Biochemical Improvement in Children Treated With Intravenous Fish Oil Emulsion

OBJECTIVES:: Intestinal failure associated liver disease (IFALD) is a multifactorial process which can culminate in cirrhosis and need for transplantation. Fish oil-based lipid emulsions (FOE) reportedly reverse hyperbilirubinemia but there is little data on their effect on the histopathology of IFALD. METHODS:: We blindly examined sequential liver biopsy data on six children receiving FOE, with scoring of cholestasis, inflammation, fibrosis and ductal proliferation based on standardized systems. This information was correlated with biochemical and clinical data to determine any possible relationship between biologic and histologic improvement. RESULTS:: The median gestational age was 35 weeks, median birthweight 2064 g and commonest reason for intestinal loss was gastroschisis (5/6 children). Median intestinal length was 26 cm beyond the ligament of Treitz and most children had roughly 2/3 of their colonic length. It was observed that while hyperbilirubinemia reversed and hepatic synthetic function was preserved across timepoints, fibrosis was persistent in 2 cases, progressive in 3 cases, and regressed in only one. It remained severe (grade 2 or higher) in 5 of 6 children at last biopsy. Histologic findings of cholestasis improved in all patients and inflammation improved in 5 of 6 children. There were mixed effects on ductal proliferation and steatosis. CONCLUSIONS:: In children treated with FOE, reversal of hyperbilirubinemia is not reflected by a similar histologic regression of fibrosis at the timepoints studied. Children with IFALD should have active ongoing treatment and be considered for early referral to an Intestinal Failure Program even with a normalized bilirubin.

Preresection Obesity Increases the Risk of Hepatobiliary Complications in Short Bowel Syndrome

Patients developing the short bowel syndrome (SBS) are at risk for hepatobiliary disease, as are morbidly obese individuals. We hypothesized that morbidly obese SBS individuals would be at increased risk for developing hepatobiliary complications. We reviewed 79 patients with SBS, 53 patients with initial body mass index (BMI) < 35 were controls. Twenty-six patients with initial BMI > 35 were the obese group. Obese patients were more likely to be weaned off parenteral nutrition (PN) (58% vs. 21%). Pre-resection BMI was significantly lower in controls (26 vs. 41). BMI at 1, 2, and 5 years was decreased in controls but persistently increased in obese patients. Obese patients were more likely to undergo cholecystectomy prior to SBS (42% vs. 32%) and after SBS (80% vs. 39%, p < 0.05). Fatty liver was more frequent in the obese group prior to SBS (23% vs. 0%, p < 0.05) but was similar to controls after SBS (23% vs. 15%). Fibrosis (8% vs. 13%) and cirrhosis/portal hypertension (19% vs. 21%) were similar in obese and control groups. Overall, end stage liver disease (ESLD) was similar in obese and control groups (19% vs. 11%) but was significantly higher in obese patients receiving PN (45% vs. 14%, p < 0.05). Obese patients developing SBS are at increased risk of developing hepatobiliary complications. ESLD was similar in the two groups overall but occurs more frequently in obese patients maintained on chronic PN.

New Loci Associated with Birth Weight Identify Genetic Links Between Intrauterine Growth and Adult Height and Metabolism

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Junín Virus Pathogenesis and Virus Replication

Junín virus, the etiological agent of Argentine hemorrhagic fever, causes significant morbidity and mortality. The virus is spread through the aerosolization of host rodent excreta and endemic to the humid pampas of Argentina. Recently, significant progress has been achieved with the development of new technologies (e.g. reverse genetics) that have expanded knowledge about the pathogenesis and viral replication of Junín virus. We will review the pathogenesis of Junín virus in various animal models and the role of innate and adaptive immunity during infection. We will highlight current research regarding the role of molecular biology of Junín virus in elucidating virus attenuation. We will also summarize current knowledge on Junín virus pathogenesis focusing on the recent development of vaccines and potential therapeutics.

Relationships Among Neurocognitive Status, Medication Adherence Measured by Pharmacy Refill Records, and Virologic Suppression in HIV-infected Persons

BACKGROUND:: Optimal antiretroviral therapy (ART) effectiveness depends upon medication adherence, which is a complex behavior with many contributing factors including neurocognitive function. Pharmacy refill records offer a promising and practical tool to assess adherence. METHODS:: A substudy of the CHARTER (CNS HIV Anti-Retroviral Therapy Effects Research) study was conducted at the Johns Hopkins University (JHU) and the University of Washington (UW). Pharmacy refill records were the primary method to measure ART adherence, indexed to a "sentinel" drug with the highest central nervous system penetration effectiveness score.Standardized neuromedical, neuropsychological, psychiatric and substance use assessments were performed at enrollment and at 6 months. Regression models were used to determine factors associated with adherence and the relationships between adherence and change in plasma and cerebrospinal fluid HIV RNA concentrations between visits. RESULTS:: Among 80 (33 JHU, 47 UW) participants, the mean adherence score was 86.4% with no difference by site. In the final multivariable model, better neurocognitive function was associated with better adherence, especially among participants who were at JHU, male, and HIV-infected for a longer time-period. Worse performance on working memory tests was associated with worse adherence. Better adherence predicted greater decreases in cerebrospinal fluid HIV RNA between visits. CONCLUSION:: Poorer global neurocognitive functioning and deficits in working memory were associated with lower adherence defined by a pharmacy refill record measure, suggesting that assessments of cognitive function, and working memory in particular, may identify patients at risk for poor ART adherence who would benefit from adherence support.

Trophic Cascades Induced by Lobster Fishing Are Not Ubiquitous in Southern California Kelp Forests

Fishing can trigger trophic cascades that alter community structure and dynamics and thus modify ecosystem attributes. We combined ecological data of sea urchin and macroalgal abundance with fishery data of spiny lobster (Panulirus interruptus) landings to evaluate whether: (1) patterns in the abundance and biomass among lobster (predator), sea urchins (grazer), and macroalgae (primary producer) in giant kelp forest communities indicated the presence of top-down control on urchins and macroalgae, and (2) lobster fishing triggers a trophic cascade leading to increased sea urchin densities and decreased macroalgal biomass. Eight years of data from eight rocky subtidal reefs known to support giant kelp forests near Santa Barbara, CA, USA, were analyzed in three-tiered least-squares regression models to evaluate the relationships between: (1) lobster abundance and sea urchin density, and (2) sea urchin density and macroalgal biomass. The models included reef physical structure and water depth. Results revealed a trend towards decreasing urchin density with increasing lobster abundance but little evidence that urchins control the biomass of macroalgae. Urchin density was highly correlated with habitat structure, although not water depth. To evaluate whether fishing triggered a trophic cascade we pooled data across all treatments to examine the extent to which sea urchin density and macroalgal biomass were related to the intensity of lobster fishing (as indicated by the density of traps pulled). We found that, with one exception, sea urchins remained more abundant at heavily fished sites, supporting the idea that fishing for lobsters releases top-down control on urchin grazers. Macroalgal biomass, however, was positively correlated with lobster fishing intensity, which contradicts the trophic cascade model. Collectively, our results suggest that factors other than urchin grazing play a major role in controlling macroalgal biomass in southern California kelp forests, and that lobster fishing does not always catalyze a top-down trophic cascade.

"Proof-of-concept" Evaluation of an Automated Sputum Smear Microscopy System for Tuberculosis Diagnosis

"TBDx" is an innovative smear microscopy system that automatically loads slides onto a microscope, focuses and digitally captures images and then classifies smears as positive or negative using computerised algorithms.

Evaluating the Predictive Abilities of Community Occupancy Models Using AUC While Accounting for Imperfect Detection

The ability to accurately predict patterns of species' occurrences is fundamental to the successful management of animal communities. To determine optimal management strategies, it is essential to understand species-habitat relationships and how species habitat use is related to natural or human-induced environmental changes. Using five years of monitoring data in the Chesapeake and Ohio Canal National Historical Park, Maryland, USA, we developed four multispecies hierarchical models for estimating amphibian wetland use that account for imperfect detection during sampling. The models were designed to determine which factors (wetland habitat characteristics, annual trend effects, spring/summer precipitation, and previous wetland occupancy) were most important for predicting future habitat use. We used the models to make predictions about species occurrences in sampled and unsampled wetlands and evaluated model projections using additional data. Using a Bayesian approach, we calculated a posterior distribution of receiver operating characteristic area under the curve (ROC AUC) values, which allowed us to explicitly quantify the uncertainty in the quality of our predictions and to account for false negatives in the evaluation data set. We found that wetland hydroperiod (the length of time that a wetland holds water), as well as the occurrence state in the prior year, were generally the most important factors in determining occupancy. The model with habitat-only covariates predicted species occurrences well; however, knowledge of wetland use in the previous year significantly improved predictive ability at the community level and for two of 12 species/species complexes. Our results demonstrate the utility of multispecies models for understanding which factors affect species habitat use of an entire community (of species) and provide an improved methodology using AUC that is helpful for quantifying the uncertainty in model predictions while explicitly accounting for detection biases.

Returning to Work After Stroke: Perspectives of Employer Stakeholders, a Qualitative Study

Purpose More than 40 % of working age adults with stroke fail to return to work. The work context is a key factor in return to work, but little is known about the experiences of employers in supporting employees with stroke. The aim of this study was to explore return to work after stroke from the employer perspective, to identify key features associated with success and to seek participants' views regarding the role of healthcare in return to work. Methods Data was gathered through 18 semi-structured interviews with employer stakeholders and included small business owners, line managers, human resources and occupational health staff. Data was analysed thematically. Results The main themes identified were: the impact of stroke on the employer, characteristics of the employee, communication, knowledge and information, experience of other stakeholders, integrating healthcare in return to work. Conclusion Employers face complex emotional and practical issues when helping an employee return to work after stroke, for which many lack knowledge and experience. The range and quality of support networks that they access is variable and advice and support from clinicians is welcomed. Further research is necessary to investigate how such support could be funded and integrated within existing service provision.

Clinical and Histological Features of Idiosyncratic Acute Liver Injury Caused by Temozolomide

A High-resolution Radiation Hybrid Map of the River Buffalo Major Histocompatibility Complex and Comparison with BoLA

The major histocompatibility complex (MHC) in mammals codes for antigen-presenting proteins. For this reason, the MHC is of great importance for immune function and animal health. Previous studies revealed this gene-dense and polymorphic region in river buffalo to be on the short arm of chromosome 2, which is homologous to cattle chromosome 23. Using cattle-derived STS markers and a river buffalo radiation hybrid (RH) panel (BBURH(5000) ), we generated a high-resolution RH map of the river buffalo MHC region. The buffalo MHC RH map (cR(5000) ) was aligned with the cattle MHC RH map (cR(12000) ) to compare gene order. The buffalo MHC had similar organization to the cattle MHC, with class II genes distributed in two segments, class IIa and class IIb. Class IIa was closely associated with the class I and class III regions, and class IIb was a separate cluster. A total of 53 markers were distributed into two linkage groups based on a two-point LOD score threshold of ≥8. The first linkage group included 32 markers from class IIa, class I and class III. The second linkage group included 21 markers from class IIb. Bacterial artificial chromosome clones for seven loci were mapped by fluorescence in situ hybridization on metaphase chromosomes using single- and double-color hybridizations. The order of cytogenetically mapped markers in the region corroborated the physical order of markers obtained from the RH map and served as anchor points to align and orient the linkage groups.

Cancer Identified Incidentally in the Prostate Following Radical Cystoprostatectomy: an Australian Study

BACKGROUND: The aim of this study was to determine the incidence and tumour characteristics of incidental prostatic cancer in Australian men with primary bladder cancer undergoing radical cystoprostatectomy (RCP). METHOD: Cystoprostatectomy specimens were reviewed for a 10-year period from a leading pathology centre in the state of New South Wales, Australia. Stamey classification was used to define significant prostate cancer. RESULTS: One hundred twenty-nine patients underwent RCP, 50 (39%) had prostatic adenocarcinoma, of which 35 (70%) were clinically significant. Apical involvement was seen in 10 (20%) of which 8 (16%) were clinically significant. High-grade intraepithelial neoplasia was seen in 27 (21%) and urothelial carcinoma or extension of bladder tumour was seen in 15 (12%) and 10 (8%) respectively. Bladder carcinoma in situ (CIS) was strongly associated with presence of urethral disease (P = 0.008). CONCLUSION: High rates of prostatic involvement with adenocarcinoma and as well as urothelial malignancy was detected in patients with primary bladder cancer undergoing cystoprostatectomy. Large proportions of prostate adenocarcinoma were clinically significant. Presence of bladder CIS was significantly associated with presence of prostatic urethral disease.

PROSPECTIVE CORRELATES OF DRINKING CESSATION: VARIATION ACROSS THE LIFE COURSE

AIMS: To assess age variation in correlates of drinking cessation. DESIGN: Prospective study of a U.S. general population sample. SETTING: Face-to-face household interviews. PARTICIPANTS: Past-year ≥monthly drinkers interviewed at baseline and 3-year follow-up (n=14,885). MEASUREMENTS: Baseline values and selected changes over follow-up in alcohol consumption, alcohol use disorder (AUD), sociodemographic and health characteristics, other substance use and psychiatric comorbidity were used to predict drinking cessation in three age groups FINDINGS: Correlates of drinking cessation varied over the life course, with pregnancy/presence of an infant, nicotine or drug use disorder, incident AUD, cluster A personality disorder, liver disease and incident retirement being important at younger ages and high-school graduation, family income ≥$70,000, volume of ethanol intake, Asian race/ethnicity, mood disorder and incident cardiovascular disease being significant at older ages. Age-invariant correlates included smoking cessation over follow-up, OR=2.82 (95% CI=1.62-4.92) to 3.45 (2.20-5.39); college education, OR=0.42 (0.27-0.65) to 0.54 (0.36-0.83); Black and Hispanic race/ethnicity, OR = 1.74 (1.18-2.29) to 1.88 (1.21-2.93) and 1.58 (1.11-1.25) to 1.73 (0.83-3.63), respectively, and months since last drink, OR=1.24 (1.13-1.36) to1.29 (1.19-1.39). CONCLUSIONS: Factors associated with ceasing alcohol use in US adults appear to differ over the life course, reflecting age variation in both their prevalence and impact and supporting the importance of role transitions and health problems (the "sick quitter" effect). The most consistent correlates of drinking cessation included factors reflecting ability/inability to give up potentially addictive substances and factors associated with perceived acceptability of drinking and subgroup-specific drinking contexts that might facilitate/impede continued drinking.

Suppressed or Unsuppressed HIV in Adults on Antiretroviral Therapy in Zambia: Who is at Risk?

Purpose of the study: To determine factors associated with suppressed or unsuppressed HIV in adults receiving combination antiretroviral therapy (cART) in Zambia. Methods: This was a cross-sectional study conducted between August 2008 and October 2009 in 16 Zambian communities nested within the ZAMSTAR trial [1]. Adult TB cases identified at a TB clinic of each community and their adult household members were invited to participate in the study. A structured interview was used to obtain information on the participants' social, demographic and clinical characteristics. Socio-economic position (SEP) was measured using household wealth indices used in demographic health surveys. Principal component analysis was used to determine the cut-off for high (wealthy) and low (poor) SEP. Depression symptoms were measured using the Center for Epidemiological Studies Depression scale (CES-D). A cut-off of≥22 on the CES-D was used to define current depression [2]. Participants were included in this analysis if they were found to be receiving cART for>90 days at the time of the interview. The outcome was HIV suppression (viral load≤300 copies/ml). In both univariable and multivariable analyses, log Poisson regression models with robust standard errors adjusted for the 16 communities were used to calculate the risk ratios (RR), 95% confidence intervals (CI) and p-values of factors associated with HIV suppression. In multivariable analysis, each variable was independently assessed for its association with HIV suppression while minimally adjusting for a priori confounders (age, gender and education level). Summary of results: There were 520 patients receiving cART for>90 days. The median age was 35 years (inter-quartile range: 31-41) and 328/520 (63.1%) were married (Table).Of the 520 patients, 442 (85.0%) had HIV suppression while 78 (15.0%) did not. At univariable analysis, having high SEP was negatively associated with HIV suppression while receiving ZDV+3TC+EFV was positively associated with HIV suppression. At multivariable analysis, patients with high SEP were less likely to have HIV suppression than those with low SEP. Conclusions: Patients with high SEP were found to be at risk of having unsuppressed HIV. There is need for targeted interventions that can improve HIV outcomes in this group of patients receiving cART in Zambia.

Autoimmune Hepatitis: A Comprehensive Review

Autoimmune hepatitis (AIH) is an immune-mediated liver disorder characterised by female preponderance, elevated transaminase and immunoglobulin G levels, seropositivity for autoantibodies and interface hepatitis. Presentation is highly variable, therefore AIH should be considered during the diagnostic workup of any increase in liver enzyme levels. Overlap/variant forms of the disease, presenting with concomitant features of primary biliary cirrhosis or primary sclerosing cholangitis are increasingly recognised. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil or, failing that, calcineurin inhibitors. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure (encephalopathy grade II-IV) at diagnosis, will require liver transplantation. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4(pos) T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. Animal models faithfully representing the human condition are needed to unravel the contribution of innate and adaptive, effector and regulatory immune responses. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells, which ultimately aim to restore tolerance to liver-derived antigens.

Systemic Perturbation of the ERK Signaling Pathway by the Proteasome Inhibitor, MG132

Inhibition of the ubiquitin-proteasome protein degradation pathway has been identified as a viable strategy for anti-tumor therapy based on its broad effects on cell proliferation. By the same token, the variety of elicited effects confounds the interpretation of cell-based experiments using proteasome inhibitors such as MG132. It has been proposed that MG132 treatment reduces growth factor-stimulated phosphorylation of extracellular signal-regulated kinases (ERKs), at least in part through upregulation of dual specificity phosphatases (DUSPs). Here, we show that the effects of MG132 treatment on ERK signaling are more widespread, leading to a reduction in activation of the upstream kinase MEK. This suggests that MG132 systemically perturbs the intracellular phosphoproteome, impacting ERK signaling by reducing phosphorylation status at multiple levels of the kinase cascade.

Prevalence and Risk Factors for HIV CSF Viral Escape: Results from the CHARTER and HNRP Cohorts

Background: During HAART, HIV RNA can be detectable (>50 cop/mL) in CSF when it is undetectable in plasma, a condition termed CSF viral escape (CVE). The aim of the current analysis was to determine the prevalence and risk factors for CVE in two large US cohorts. Methods: 1,264 volunteers enrolled in CHARTER or HNRP at their most recent visit between 2003 and 2011 were included in this cross-sectional analysis if their HIV RNA level in plasma was undetectable while on stable HAART (>6 months) and if they had CSF collected. Potential risk factors were identified using univariable and multivariable analysis. Odds ratios for detected risk factors were calculated. Results: Mean age was 46 years, 82% were men, 70% had AIDS, 22% were HCV+, 49% were Caucasians, median CD4 nadir was 129, and 38% were cognitively impaired. CVE was present in 55 (4.35%) with a median HIV RNA in CSF of 155 (IQR 80-283). The table summarizes the main analysis results. CVE was associated with longer durations of HIV disease, higher platelet count, higher total serum protein, and higher CSF white blood cells (WBCs). CVE was also associated with treatment-associated factors, including use of boosted PIs and unboosted atazanavir. Conclusions: In this large, cross-sectional analysis, CVE was uncommon in subjects on effective HAART. A combination of disease and treatment factors were associated with CVE. The associations with higher levels of CSF WBCs, blood platelets, and serum total protein may reflect greater immune activation. Treatment with PI-based HAART was particularly associated with CVE, especially if unboosted atazanavir was part of the regimen. CVE was not associated with neurocognitive impairment. Prospective analyses are needed for better characterization of CVE.

Activation of the ACE2/Angiotensin-(1-7)/Mas Receptor Axis Enhances the Reparative Function of Dysfunctional Diabetic Endothelial Progenitors

We tested the hypothesis that activation of the protective arm of the renin angiotensin system (RAS), the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis, corrects the vasoreparative dysfunction typically seen in the CD34(+) cells isolated from diabetic individuals. Peripheral blood CD34(+) cells from patients with diabetes were compared with those of nondiabetic controls. Ang-(1-7) restored impaired migration and nitric oxide bioavailability/cGMP in response to stromal cell-derived factor and resulted in a decrease in NADPH oxidase activity. The survival and proliferation of CD34(+) cells from diabetic individuals were enhanced by Ang-(1-7) in a Mas/phosphatidylinositol 3-kinase (PI3K)/Akt-dependent manner. ACE2 expression was lower and ACE2 activators xanthenone and diminazine aceturate were less effective in inducing the migration in cells from patients with diabetes compared with controls. Ang-(1-7) overexpression by lentiviral gene modification restored both the in vitro vasoreparative functions of diabetic cells and the in vivo homing efficiency to areas of ischemia. A cohort of patients who remained free of microvascular complications despite having a history of longstanding inadequate glycemic control had higher expression of ACE2/Mas mRNA than patients with diabetes with microvascular complications matched for age, sex, and glycemic control. Thus, ACE2/Ang-(1-7)\Mas pathway activation corrects existing diabetes-induced CD34(+) cell dysfunction and also confers protection from development of this dysfunction.

Influence of Nitrogen and Sulfur Intake on Bovine Uterine PH Throughout the Luteal Phase

Previous research has reported that diets high in protein and sulfur decreased uterine pH in cattle. The objective of this study was to determine the effect of high N and/or high S intake on uterine pH. Holstein (n = 15) and Angus-cross (n = 5) heifers (337.5 ± 8.4 kg of BW) were randomly assigned to 1 of 4 diets: control (CON; 13.4% CP and 0.17% S); high nitrogen (HN; CON plus urea supplement); high sulfur (HS; CON plus calcium sulfate); or both high nitrogen and sulfur (HNS). Diets were individually fed at 2.6% of BW on a dry matter basis using Calan gates and estrus was synchronized to occur on d 13 (d 0 = start of dietary treatment). Blood samples were collected on d -2 and daily (d 1 to 28) at 1400 h to determine concentrations of plasma urea nitrogen (PUN), sulfate (d 1, 4, 8, 12, 16, 20, 24 and 28), and progesterone. Uterine pH was measured on d 16, 20, 24, and 28 (d 3, 7, 11, and 15 of the estrous cycle). There was a treatment, time, and treatment by time interaction (P < 0.01) on concentrations of PUN. There was an effect of treatment (P < 0.01) on concentrations of sulfate, with concentrations being increased in HS compared with CON, HN and HNS (P < 0.01), and HNS increased compared to CON (P < 0.01) and HN (P < 0.01). Uterine pH was increased in HN and HNS compared to CON (P < 0.02), while HS was not different from any treatment (P > 0.11). There was no effect of time (P = 0.26) or treatment by time interaction (P = 0.71) on uterine pH. In summary, uterine pH was increased in HN and HNS compared to CON, while HS was intermediate, and was associated with increased concentrations of PUN.

The INIA19 Template and NeuroMaps Atlas for Primate Brain Image Parcellation and Spatial Normalization

The INIA19 is a new, high-quality template for imaging-based studies of non-human primate brains, created from high-resolution, T(1)-weighted magnetic resonance (MR) images of 19 rhesus macaque (Macaca mulatta) animals. Combined with the comprehensive cortical and sub-cortical label map of the NeuroMaps atlas, the INIA19 is equally suitable for studies requiring both spatial normalization and atlas label propagation. Population-averaged template images are provided for both the brain and the whole head, to allow alignment of the atlas with both skull-stripped and unstripped data, and thus to facilitate its use for skull stripping of new images. This article describes the construction of the template using freely available software tools, as well as the template itself, which is being made available to the scientific community (http://nitrc.org/projects/inia19/).

Rilpivirine/tenofovir/emtricitabine Fixed-dose Combination is an Efficacious and Well-tolerated "switch" Regimen for Patients on Therapy

The rilpivirine/tenofovir/emtricitabine fixed-dose combination (RTE FDC) (Complera, Eviplera) is a potent convenient, well-tolerated antiretroviral regimen. While it is officially indicated only for treatment-naïve patients, it is attractive for use as a regimen to switch to for patients experiencing toxicities or side effects, or who simply want a regimen with fewer pills. This is a retrospective review of patients who switched to RTE FDC from other antiretroviral regimens in a large HIV specialty private practice. 111 patients were identified who switched to RFE FDC from other regimens who had at least six months follow-up (median 8 months). 44 were previously taking the efavirenz/tenofovir/emtricitabine fixed-dose combination (ETE FDC) (Atripla), 24 nevirapine with NRTIs, 16 protease-based regimens, 10 on raltegravir with NRTIs, and 17 on various other regimens. Patients had been on therapy for a median of 6.25 years. 86 patients had an HIV PCR<20 at the time of switch, 21 had low grade positive PCRs (<400) and 4 patients switched after an interruption in therapy with viral loads of 5880-88,000. Median CD4 cell count at the time of switch was 663 (range 142-2244). 14 patients had previously failed treatment and had resistance mutations; 4 with M184V, 5 with K103N, but none with rilpivirine nor tenofovir-specific resistance mutations. One patient discontinued RFE FDC after a single PCR of 520; all others have remained undetectable at most recent visit (91<20, 19<400). Median CD4 cell count on the most recent visit is 656. Creatinine (first visit after switch) increased by a mean of 0.04 mg/dl (0.05 in those switching from a non-tenofovir containing regimen, 0.04 in those switching from a tenofovir containing regimen). There was no significant change in LFTs. Mean cholesterol decreased by 18 mg/dl (23 in those switching from ETE FDC, 12 from protease inhibitors, 27 from nevirapine and 2 from raltegravir). Six patients co-infected with hepatitis B remain with an undetectable hepatitis B PCR. Patients were asked to complete a questionnaire, rating their new and old regimens on a scale of one (bad) to ten (good) (Table). For appropriate patients wishing to switch their treatment regimen for toxicity, side-effects or even just pill burden, RTE FDC is an efficacious, well tolerated, convenient alternative.

Raltegravir 800 Mg Once-daily is Efficacious in Already Virologically Suppressed Patients

Raltegravir is a potent, extremely well tolerated antiretroviral, and is a component of a preferred regimen in many treatment guidelines. Despite its indication as a twice-daily (400 mg BID) drug, there has always been interest in once-daily (800 mg QD) use of raltegravir (RTG). The "QD Merck", however, showed a higher rate of virologic failure in subjects taking RTG QD with Truvada as opposed to twice daily (BID). This trial, however, was in treatment-naïve patients, and the majority of virologic failures were in those with high viral loads. In patients already virologically suppressed on antiretroviral therapy a regimen including QD raltegravir is more convenient, and may still be effective for virologic suppression. This is a retrospective review of patients in a large HIV-specialty private practice. 105 patients were identified who have been on QD RTG for at least 6 months (median 23, range 6-55 months). 70 patients were also on Truvada, 10 on Epzicom, 7 on atazanavir, and 18 on more than two additional drugs. All patients had undetectable (<200) viral loads when starting QD RTG, and had been on other treatment for a median of 117 months (range 13-276). Median CD4 count on starting QD RTG was 606 (range 154-1358). 50 patients had been previously on BID RTG for a median of 12 months; 55 started directly on a QD RTG regimen. 32 patients had a history of previous treatment failure/resistance, although mostly to drugs not included in the current regimen. All patients remain undetectable (PCR<200 copies/ml) with no treatment failures seen. In clinically stable patients already suppressed on antiretroviral therapy, including BID RTG regimens, a switch to QD RTG appears to be effective at maintaining long-term virologic control. QD dosing is certainly more convenient, and may improve adherence.

Reelin is a Target of Polyglutamine Expanded Ataxin-7 in Human Spinocerebellar Ataxia Type 7 (SCA7) Astrocytes

Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder that results from polyglutamine expansion of the ataxin-7 (ATXN7) protein. Remarkably, although mutant ATXN7 is expressed throughout the body, pathology is restricted primarily to the cerebellum and retina. One major goal has been to identify factors that contribute to the tissue specificity of SCA7. Here we describe the development and use of a human astrocyte cell culture model to identify reelin, a factor intimately involved in the development and maintenance of Purkinje cells and the cerebellum as a whole, as an ATXN7 target gene. We found that polyglutamine expansion decreased ATXN7 occupancy, which correlated with increased levels of histone H2B monoubiquitination, at the reelin promoter. Treatment with trichostatin A, but not other histone deacetylase inhibitors, partially restored reelin transcription and promoted the accumulation of mutant ATXN7 into nuclear inclusions. Our findings suggest that reelin could be a previously unknown factor involved in the tissue specificity of SCA7 and that trichostatin A may ameliorate deleterious effects of the mutant ATXN7 protein by promoting its sequestration away from promoters into nuclear inclusions.

Attenuated Salmonella Typhimurium Lacking the Pathogenicity Island-2 Type 3 Secretion System Grow to High Bacterial Numbers Inside Phagocytes in Mice

Intracellular replication within specialized vacuoles and cell-to-cell spread in the tissue are essential for the virulence of Salmonella enterica. By observing infection dynamics at the single-cell level in vivo, we have discovered that the Salmonella pathogenicity island 2 (SPI-2) type 3 secretory system (T3SS) is dispensable for growth to high intracellular densities. This challenges the concept that intracellular replication absolutely requires proteins delivered by SPI-2 T3SS, which has been derived largely by inference from in vitro cell experiments and from unrefined measurement of net growth in mouse organs. Furthermore, we infer from our data that the SPI-2 T3SS mediates exit from infected cells, with consequent formation of new infection foci resulting in bacterial spread in the tissues. This suggests a new role for SPI-2 in vivo as a mediator of bacterial spread in the body. In addition, we demonstrate that very similar net growth rates of attenuated salmonellae in organs can be derived from very different underlying intracellular growth dynamics.

Vitamin D3 As a Novel Treatment for Irritable Bowel Syndrome: Single Case Leads to Critical Analysis of Patient-centred Data

Irritable bowel syndrome (IBS) is a chronic and debilitating functional disorder of the gastrointestinal tract with serious and detrimental impacts on quality of life. Its aetiology is largely unknown and the identification of effective management strategies remains far from complete. This paper first reports, a case of a 41-year-old woman IBS sufferer who reported significant symptom improvements with high-dose vitamin D3 supplementation. The sufferer identified a substantial body of patient data surrounding this potential therapy on social media sites, and this paper, therefore, also reports the findings from a systematic analysis of patient-centred, internet-based data surrounding this phenomenon. Data from 37 IBS sufferers commenting on the effect of vitamin D supplementation on their condition were located; approximately 70% of these reported that high-dose supplementation improved their IBS symptoms. A randomised controlled trial into the effect of vitamin D supplementation on IBS symptomatology to test this association scientifically is merited.

Neurovirological Correlation with HIV-associated Neurocognitive Disorders and Encephalitis in a HAART-era Cohort

OBJECTIVE:: Replicating HIV-1 in the brain is present in HIV encephalitis (HIVE) and microglial nodule encephalitis (MGNE) and is putatively linked with HIV-associated neurocognitive disorders (HAND). A clinico-neurovirological correlation was conducted to elucidate the relationship between brain viral load and clinical phenotype. SUBJECTS: and assays: HIV gag/pol RNA and DNA copies were quantified with RT-PCR or PCR in 148 HAART-era brain specimens. Comparison to HAND, HIVE and MGNE and correlation with neuropsychological (NP) test scores were done using one-way ANOVA with Tukey-Kramer and Spearman's tests respectively. RESULTS:: Brain HIV RNA was higher in subjects with HAND plus HIVE vs without HAND (delta = 2.48 log10 units, n = 27 vs 36, p < 0.001). In HAND without HIVE or MGNE, brain HIV RNA was not significantly different vs without HAND (p = 0.314). Worse NP scores correlated significantly with higher HIV RNA and interferon responses in brain specimens (p<0.001), but not with HIV RNA levels in premortem blood plasma (n = 114) or cerebrospinal fluid (n = 104). In subjects with MGNE, brain HIV RNA was slightly higher versus without MGNE (p<0.01), and much lower versus with HIVE (p<0.001). CONCLUSION:: Brain HIV RNA and to a lesser extent HIV DNA are correlated with worse NP performance in the 6 months before death. Linkage occurs primarily in patients with HIVE and MGNE; while on HAART these patients could obtain added NP improvement by further reducing brain HIV. Patients not in those groups are less certain to obtain added NP benefit.

Dual Inhibition of Bcl-2 and Bcl-xL Strikingly Enhances PI3K Inhibition-induced Apoptosis in Human Myeloid Leukemia Cells Through a GSK3- and Bim-dependent Mechanism

Effects of concomitant inhibition of the PI3K/AKT/mTOR pathway and Bcl-2/Bcl-xL (BCL2L1) were examined in human myeloid leukemia cells. Tetracycline-inducible Bcl-2 and Bcl-xL dual knockdown sharply increased PI3K/AKT/mTOR inhibitor lethality. Conversely, inducible knockdown or dominant-negative AKT increased whereas constitutively active AKT reduced lethality of the Bcl-2/Bcl-xL inhibitor ABT-737. Furthermore, PI3K/mTOR inhibitors (e.g., BEZ235, PI-103) synergistically increased ABT-737-mediated cell death in multiple leukemia cell lines and reduced colony-formation in leukemic but not normal CD34+ cells. Notably, increased lethality was observed in 4/6 primary AML specimens. Responding, but not non-responding, samples exhibited basal AKT phosphorylation. PI3K/mTOR inhibitors markedly down-regulated Mcl-1 but increased Bim binding to Bcl-2/Bcl-xL; the latter effect was abrogated by ABT-737. Combined treatment also markedly diminished Bax/Bak binding to Mcl-1, Bcl-2 or Bcl-xL. Bax, Bak, or Bim (BCL2L11) knockdown, or Mcl-1 over-expression significantly diminished regimen-induced apoptosis. Interestingly, pharmacologic inhibition or shRNA knockdown of GSK3α/β significantly attenuated Mcl-1 down-regulation and decreased apoptosis. In a systemic AML xenograft model, dual tet-inducible knockdown of Bcl-2/Bcl-xL sharply increased BEZ235 anti-leukemic effects. In a subcutaneous xenograft model, BEZ235 and ABT-737 co-administration significantly diminished tumor growth, down-regulated Mcl-1, activated caspases, and prolonged survival. Together, these findings suggest that anti-leukemic synergism between PI3K/AKT/mTOR inhibitors and BH3 mimetics involves multiple mechanisms, including Mcl-1 down-regulation, release of Bim from Bcl-2/Bcl-xL as well as Bak and Bax from Mcl-1/Bcl-2/Bcl-xL, and GSK3α/β, culminating in Bax/Bak activation and apoptosis. They also argue that combining PI3K/AKT/mTOR inhibitors with BH3-mimetics warrants attention in AML, particularly in the setting of basal AKT activation and/or addiction.

Development and Evaluation of Thin-film Flexible Microelectrode Arrays for Retinal Stimulation and Recording

We have described the development of a flexible microelectrode array with potential applications in the large scale recording of neural signals and in focal electrical stimulation for use as a prosthetic implant in degenerative retinal diseases. The array under test consisted of 61 platinum electrodes of 5 µm diameter with 60 µm spacing connected by 8 µm wide gold tracks encased in a flexible polyimide substrate of 15 µm thickness from which recordings were taken from 16 electrodes. The device was tested on an exposed frog eyecup preparation which is characterized by small retinal ganglion cells of similar dimensions to those present in the human retina. The responses of these cells evoked by photic stimulation consisted of trains of action potentials of high signal-to noise ratio at each of the recording sites. Delivery of cathodal constant voltage pulses and constant current pulses to specific electrodes in the array led to the generation of action potentials in adjacent electrodes, implying that retinal ganglion cells in the proximity had been stimulated. Since prolonged stimulation with supra-threshold voltages impaired neither electrode structure nor retinal function, these results provide a sound basis for scaling up the number of array electrodes to deliver focal electrical pulses to the retina, as would be required by a viable epiretinal prosthesis.

Substance Use is a Risk Factor for Neurocognitive Deficits and Neuropsychiatric Distress in Acute and Early HIV Infection

The acute and early stages of HIV infection (AEH) are characterized by substantial viral replication, immune activation, and alterations in brain metabolism. However, little is known about the prevalence and predictors of neurocognitive deficits and neuropsychiatric disturbances during this period. The present study examined the impact of demographic, HIV disease, and substance use factors on HIV-associated neurocognitive impairment and self-reported neuropsychiatric distress among 46 antiretroviral-naive adults with median duration of infection of 75 days relative to a sample of 21 HIV seronegative (HIV-) adults with comparable demographics and risk factors. Participants were administered a brief neurocognitive battery that was adjusted for demographics and assessed executive functions, memory, psychomotor speed, and verbal fluency, as well as the Profile of Mood States, a self-report measure of neuropsychiatric distress. Odds ratios revealed that AEH participants were nearly four times more likely than their seronegative counterparts to experience neurocognitive impairment, particularly in the areas of learning and information processing speed. Similarly, AEH was associated with a nearly fivefold increase in the odds of neuropsychiatric distress, most notably in anxiety and depression. Within the AEH sample, HIV-associated neurocognitive impairment was associated with problematic methamphetamine use and higher plasma HIV RNA levels, whereas neuropsychiatric distress was solely associated with high-risk alcohol use. Extending prior neuroimaging findings, the results from this study indicate that HIV-associated neurocognitive impairment and neuropsychiatric distress are highly prevalent during AEH and are associated with high-risk substance use.

Age at Onset in Trichotillomania:clinical Variables and Neurocognitive Performance

Objective: Trichotillomania (TTM), or compulsive hair pulling, is a common psychiatric disorder characterized by psychosocial impairment and reduced quality of life. The aim of this retrospective study was to characterize the impact of age at TTM onset on clinical variables and neuropsychological function using a variety of clinical and neurocognitive measures.Method: The study sample included 98 adult treatment-seeking individuals with a DSM-IV diagnosis of TTM. Correlates were explored by grouping participants into childhood-onset (onset at ≤ 11 years old, n = 42) or later-onset (≥ 12 years old, n = 56) TTM and via linear regression. All subjects underwent a semistructured clinical interview with a psychiatrist and completed a variety of paper-pencil tests regarding TTM severity and quality of life. A subset (n = 44) of subjects underwent neurocognitive testing assessing motor inhibition and set-shifting compared to a sample (n = 27) of age- and gender-matched healthy controls. Data were collected from September 2006 through July 2011.Results: Postpubertal age at onset was significantly associated with greater TTM symptom severity. Clinically, the later-onset group pulled their hair for a significantly greater amount of time daily (P = .008), had higher clinician-rated TTM severity on the Clinical Global Impressions-Severity of Illness scale (P = .042), and had higher patient-rated severity on the Massachusetts General Hospital Hairpulling Scale (P = .022) compared to healthy controls. On the neurocognitive tasks, later-onset TTM was characterized by stop-signal impairments (P = .020) and relatively spared set-shifting, consistent with previous studies in the literature. In contrast, the childhood-onset manifestation was associated with set-shifting deficits in stages of the task completed and total errors adjusted (both P < .001) but relatively spared stop-signal performance compared to healthy controls.Conclusion: Results indicate that childhood-onset of TTM is common, as confirmed by the fact that 42.9% of our sample met childhood-onset criteria, and may differ neurobiologically from the prototypical later-onset form. Future neurobiological and treatment studies should measure age at onset and explore further these putative differences.Trial Registration ClinicalTrials.gov identifiers: NCT00354770 and NCT00775229.

Facilitators and Barriers to Medication Adherence in an HIV Prevention Study Among Men Who Have Sex with Men in the IPrEx Study in Chiang Mai, Thailand

Abstract In 2008, the Pre-exposure Prophylaxis Initiative (iPrEx) study expanded to include men who have sex with men (MSM) in Chiang Mai, Thailand. In full, 114 participants from Chiang Mai joined this international double-blinded trial of daily FTC-TDF (Truvada®) or placebo as a pre-exposure prophylaxis (PrEP) HIV prevention strategy. To better understand the characteristics of iPrEx participants specifically from this underserved population in Thailand, and gain insights into their experiences of trying to take a daily tablet as part of this blinded PrEP trial, we conducted a qualitative study. In 2010, 32 MSM iPrEx participants provided in-depth interviews and an additional 14 joined focus group discussions. Results of the qualitative analyzes suggested that participants held generally positive attitudes toward the iPrEx study and study medication and related this to high rates of adherence to the daily regimen. Participants also reflected on the provision of quality health care as part of participation in the trial, as well as support from clinical research staff, family and friends as helpful in supporting high rates of study medication adherence. Discourse concerning challenges to adherence included medication taking behavior, which was contextualized by lifestyle, living arrangement, social life, social stigma in terms of being mistakenly identified as HIV positive or unintentional disclosure of sexual identity to family and friends, and relationship conflicts with partners. The results provide broader perspectives of participant experiences of the study medication and daily adherence in the larger contexts of the MSM community, close relationships, and the study climate, and can be leveraged in constructing PrEP adherence support approaches within these communities.

Magnetic Resonance Contrast and Biological Effects of Intracellular Superparamagnetic Iron Oxides on Human Mesenchymal Stem Cells with Long-term Culture and Hypoxic Exposure

BACKGROUND AIMS: Human mesenchymal stem cells (hMSCs) have gained interest for treatment of stroke injury. Using in vitro culture, the purpose of this study was to investigate the long-term detectability of hMSCs by magnetic resonance imaging (MRI) after transfection with a superparamagnetic iron oxide (SPIO) and evaluate the effects of SPIO on cellular activity, particularly under an ischemic environment. METHODS: hMSCs were exposed to low doses of SPIOs. After a short incubation period, cells were cultured for additional 1, 7 and 14 d to evaluate proliferation, colony formation and multilinear potential. Labeled cells were imaged and evaluated in agarose to quantify R(2) and R(2)∗ contrast at each time point. Cells were placed in a low-oxygen, low-serum environment and tested for cytotoxicity. In addition, labeled cells were transplanted into an ischemic stroke model and evaluated with ex vivo MRI and histology. RESULTS: Cellular events such as proliferation and differentiation were not affected at any of the exposures tested when cultured for 14 d. The low iron exposure and short incubation time are sufficient for detectability with MRI. However, the higher iron dosage results in higher calcification and cytotoxicity under in vitro ischemic conditions. Transplantation of the hMSCs labeled with an initial exposure of 22.4 μg of Fe showed excellent retention of contrast in stroke-induced rats. CONCLUSIONS: Although SPIO labeling is stable for long-term MRI detection and has limited effects on the multilineage potential of hMSCs, high-dose SPIO labeling may affect hMSC survival under serum and oxygen withdrawal.

Pseudo-Outbreak of VRE Colonization in a Neonatal Intensive Care Unit Using Spectraâ„¢ VRE Surveillance Media

From November 2011 through March 2012, we surveyed 409 babies in our neonatal intensive care unit for rectal colonization with vancomycin-resistant enterococci. Using Spectraâ„¢ VRE media (Remel Diagnostics, Lenexa, KS), we identified one neonate colonized with vancomycin-resistant E. faecium. In addition, 55 (13%) of the surveillance cultures yielded false-positive results with vancomycin-susceptible E. faecalis. During the same time period, 580 rectal swabs were collected from adult patients resulting in 20 (3%) false-positive cultures. The difference in false-positive rates between cultures from babies and adults was statistically significant (p<0.001), prompting an investigation of factors that might influence the elevated false-positive rate in the neonates including patient demographics, nutrition and topical ointments applied at the time of testing. Older neonates, median age of 6 wk, were more likely to have false-positive cultures than younger neonates with median age of 3 wk. (p< 0.001). The younger neonates receiving Similac Expert Care products were less likely to have false-positive surveillance cultures than those receiving other formulas (p<0.001). Application of topical products was not associated with false-positive cultures. The false-positive E. faecalis strains were typed by Diversilab rep-PCR (bioMerieux, Marcy-l'Etoile, France) and found to represent 8 different groups of isolates. The utility of the Spectraâ„¢ VRE media appeared to be significantly impacted by the age of the patients screened.

The Volume and PH of Residual Pharyngeal Fluid Aspirated from the Taper Guardâ„¢ Evac Endotracheal Tube Following Elective Surgery: A Prospective Pilot Study

BACKGROUND: Oro-pharyngeal suctioning prior to extubation aims to minimize post-extubation tracheal soiling from remaining fluid. We investigated the amount and nature of any fluid remaining after such suctioning and contributing factors. METHODS: ASA I - III patients undergoing elective surgery under general anesthesia with endotracheal intubation participated in this prospective observational pilot study. Following oro-pharyngeal suctioning immediately prior to extubation, a dedicated port of the endotracheal tube (Taper Guardâ„¢ Evac Endotracheal Tube) was aspirated. The amount and pH of residual fluid was recorded. Data collection included age, sex, body mass index, co-morbidities, ASA status, procedure type and duration. The Chi-Square, Wilcoxon Rank-Sum, t-tests, and univariate regression analysis were used as appropriate. RESULTS: Ninety-eight patients completed the study. The mean aspirated volume in 38 (38.8%) patients was 0.9 + 1.3 ml and sixty patients (61.2%) had no aspirate. A body mass index of > 30 kg/m2 was associated with the presence of fluid (p < 0.03), and a higher volume (p=0.03). The fluid pH was 7 + 0.81 (mean + SD). A duration of surgery > 120 minutes predicted a lower pH. CONCLUSION: The prevalence and amount of residual fluid after oro-pharyngeal suctioning was low and likely clinically insignificant. A higher body mass index was associated with a higher incidence and volume of residual fluid. Longer procedure duration determined a slightly lower pH, with a mildly acidic pH range. The possibility of a lower fluid pH after prolonged surgery contributing to postoperative sore throat via mucosal irritation warrants investigation.

Early Onset, EBV-negative PTLD in Pediatric Liver-small Bowel Transplant Recipients: a Spectrum of Plasma Cell Neoplasms with Favorable Prognosis

Epstein-Barr virus (EBV)-negative post-transplantation lymphoproliferative disorders (PTLD) are rare compared to EBV-positive PTLD, occur later after transplantation, and have a poor response to treatment. Few studies have reported EBV-negative PTLD in pediatric solid organ transplant (SOT) recipients. We describe five cases of EBV-negative PTLD in recipients of combined liver and small bowel (L/SB) allografts ranging in age from 16 months to 7 years. EBV-negative PTLD developed 9 to 22 months after transplantation (median, 15 months). Morphologically, the lesions ranged from atypical plasma cell hyperplasia (a term not currently included in World Health Organization classification) to plasmacytoma-like. In all cases, in situ hybridization for EBV was negative, and molecular studies demonstrated clonal IgH gene rearrangements. Protein electrophoresis showed multiple clonal paraproteins in 4 of 5 cases. In 2 cases with a donor-recipient gender mismatch, FISH cytogenetics demonstrated that the plasma cells are of mixed donor/recipient origin. One patient died prior to therapy. Four patients were treated with high-dose dexamethasone, and one patient subsequently required thalidomide. All four remain in remission 75-128 months (median, 86 months) after diagnosis. In contrast to reports of EBV-negative PTLD cases in adults, these plasma cell lesions occur early after transplantation, and resolve completely after minimal treatment.

Sexual Behaviour and Sexual Health of Australian Prisoners

Left- and Right-circularly Polarized Light in Cascade Conical Diffraction

A cascade conical diffraction system consisting of three optically biaxial KGd(WO4)2 crystals is considered. The effect of left- and right-handed circularly polarized incident light on the ring patterns produced away from the focal image plane of the system, the plane in which the incident beam waist would be focused if the crystals were isotropic, is investigated. Images and intensity distributions for scaled distances (ζ values) of 2.75, 3.00, and 3.25 from the focal image plane are presented. A discrepancy between the patterns produced depending on the handedness of the incident beam is observed in agreement with the recent theoretical predictions.

Using Electronic Referral with Digital Imaging Between Primary and Secondary Ophthalmic Services: a Long Term Prospective Analysis of Regional Service Redesign

PurposeDemands on publicly funded ophthalmic services worldwide continue to increase with new treatments, waiting time targets, working time limits, and restricted budgets. These highlight the necessity to develop innovative ways of utilising existing capacity more effectively.MethodA new regional, fully electronic ophthalmic-referral service with digital imaging was trialled using existing information-technology (IT) infrastructure. Following successful pilot study, the service was rolled out regionally. Service delivery data was prospectively collated for all the attendances in the year prior to (2006) and the year following (2008) introduction.ResultsComparing 2006 against 2008, median waiting times reduced (14 vs 4 weeks), and fewer new patients were observed (8714 vs 7462 P<0.0001), with 1359 referrals receiving electronic diagnosis (e-diagnosis). New patient did not arrive (635 vs 503 P<0.0001) and emergencies also reduced (2671 v 1984 P<0.0001).DiscussionNovel use of existing IT infrastructure improves communication between primary and secondary care. This promotes more effective use of limited outpatient capacity by retaining patients with non-progressive, asymptomatic pathology in the community, whilst fast-tracking patients with sight-threatening disease. Resultant significant, sustained improvements in regional service delivery point to a simple model that could easily be adopted by other providers of universal healthcare globally.Eye advance online publication, 21 December 2012; doi:10.1038/eye.2012.278.

Vitamin D Receptor (VDR) Polymorphisms and Risk of Ovarian Cancer in Caucasian and African American Women

OBJECTIVE: Polymorphisms in the vitamin D receptor (VDR) gene have been shown in some studies to be associated with the risk of epithelial ovarian cancer (EOC) in Caucasian women. There are no published reports among African Americans. METHODS: Case-control data from the North Carolina Ovarian Cancer Study were analyzed using logistic regression to determine the association between seven VDR polymorphisms and EOC in both Caucasians (513 cases, 532 controls) and African Americans (74 cases, 79 controls). In a larger sample of African-Americans (125 cases, 155 controls), we assessed associations between six SNPs in proximity of rs795232. RESULTS: African American women who carried at least one minor allele of rs7975232 were at higher risk for invasive EOC controlling for age and admixture with an odds ratio (OR) for association under the log-additive model of 2.08 (95% confidence interval (CI)=1.19, 3.63, p=0.010). No association was observed between any of the VDR variants and EOC among Caucasians. A larger sample of African Americans revealed a nearly two-fold increased risk of invasive EOC associated with rs7305032, a SNP in proximity to rs7975232 (R(2)=0.369) with a log-additive OR of 1.87 (95% CI=1.20, 2.93, p=0.006). CONCLUSIONS: This is the first report showing VDR variants associated with ovarian cancer risk in African American women. A larger study of African American women is needed to confirm these findings. These results imply that vitamin D exposure is a possible modifiable risk factor of ovarian cancer among African Americans.

Antibody Responses to Human Immunodeficiency Virus Envelope from Infections with Multiple Subtypes Utilize the 1F7-idiotypic Repertoire

A common idiotype of anti-HIV antibodies (Abs), designated as 1F7, was recently observed on anti-HIV broadly neutralizing Abs (BnAbs). The presence of the 1F7-idiotype on BnAbs suggests that continuous selection of 1F7-idiotypic Abs may allow these clones to achieve the somatic hypermutation necessary for broad neutralization. As the selection of type-specific BnAbs occurs in the setting of infections with a wide array of HIV subtypes, we investigated Abs from subjects infected with diverse subtypes for the selection of 1F7-idiotypic Abs. We observed the 1F7-idiotype on anti-viral Abs in infections with various HIV subtypes. Furthermore, gp140-specific 1F7-idiotypic Abs recognized the gp140 antigens from several HIV subtypes. These results demonstrate that the 1F7-idiotype is a common characteristic of Abs from infections with diverse HIV subtypes, and suggests that early cross-reactivity of 1F7-idiotypic clones may act in conjunction with somatic hypermutation to produce BnAbs.

Inflammation in the Pathogenesis of Microvascular Complications in Diabetes

Diabetes and hyperglycemia create a proinflammatory microenvironment that progresses to microvascular complications such as nephropathy, retinopathy, and neuropathy. Diet-induced insulin resistance is a potential initiator of this change in type 2 diabetes which can increase adipokines and generate a chronic low-grade inflammatory state. Advanced glycation end-products and its receptor, glycation end-products AGE receptor axis, reactive oxygen species, and hypoxia can also interact to worsen complications. Numerous efforts have gained way to understanding the mechanisms of these modulators and attenuation of the inflammatory response, however, effective treatments have still not emerged. The complexity of inflammatory signaling may suggest a need for multi-targeted therapy. This review presents recent findings aimed at new treatment strategies.

Confined Compression of Collagen Hydrogels

Reconstituted collagen hydrogels are often used for in vitro studies of cell-matrix interaction and as scaffolds for tissue engineering. Understanding the mechanical and transport behaviours of collagen hydrogels is therefore extremely important, albeit difficult due to their very high water content (typically >99.5%). In the present study the mechanical behaviour of collagen hydrogels in confined compression was investigated using biphasic theory (J Biomechemical Engineering 102 (1980) 73), to ascertain whether the technique is sufficiently sensitive to determine differences in the characteristics of hydrogels of between 0.2% and 0.4% collagen. Peak stress, equilibrium stress, aggregate modulus and hydraulic permeability of the hydrogels exhibited sensitivity to collagen content, demonstrating that the technique is clearly able to discriminate between hydrogels with small differences in collagen content and may also be sensitive to factors that affect matrix remodelling. The results also offer additional insight into the deformation-dependent permeability of collagen hydrogels. This study suggests that confined compression, together with biphasic theory, is a suitable technique for assessing the mechanical properties of collagen hydrogels.

Influence of Uncertainties in the Material Properties of Brain Tissue on the Probabilistic Volume of Tissue Activated

The aim of this study was to examine the influence of uncertainty of the material properties of brain tissue on the probabilistic voltage response and the probabilistic volume of tissue activated in a volume conductor model of deep brain stimulation. To quantify the uncertainties of the desired quantities without changing the deterministic model, a nonintrusive projection method was used by approximating these quantities by a polynomial expansion on a multi-dimensional basis known as Polynomial Chaos. The coefficients of this expansion were computed with a multi-dimensional quadrature on sparse Smolyak grids. The deterministic model combines a finite element model based on a digital brain atlas and a multi-compartmental model of mammalian nerve fibres. The material properties of brain tissue were modelled as uniform random parameters using data from several experimental studies. Different magnitudes of uncertainty in the material properties were computed to allow predictions on the resulting uncertainties in the desired quantities. The results showed a major contribution of the uncertainties in the electrical conductivity values of brain tissue on the voltage response as well as on the predicted volume of tissue activated, while the influence of the uncertainties in the relative permittivity was negligible.

Parallel Loss-of-Function at the RPM1 Bacterial Resistance Locus in Arabidopsis Thaliana

Dimorphism at the Resistance to Pseudomonas syringae pv. maculicola 1 (RPM1) locus is well documented in natural populations of Arabidopsis thaliana and has been portrayed as a long-term balanced polymorphism. The haplotype from resistant plants contains the RPM1 gene, which enables these plants to recognize at least two structurally unrelated bacterial effector proteins (AvrB and AvrRpm1) from bacterial crop pathogens. A complete deletion of the RPM1 coding sequence has been interpreted as a single event resulting in susceptibility in these individuals. Consequently, the ability to revert to resistance or for alternative R-gene specificities to evolve at this locus has also been lost in these individuals. Our survey of variation at the RPM1 locus in a large species-wide sample of A. thaliana has revealed four new loss-of-function alleles that contain most of the intervening sequence of the RPM1 open reading frame. Multiple loss-of-function alleles may have originated due to the reported intrinsic cost to plants expressing the RPM1 protein. The frequency and geographic distribution of rpm1 alleles observed in our survey indicate the parallel origin and maintenance of these loss-of-function mutations and reveal a more complex history of natural selection at this locus than previously thought.

Conservative Interventions for Incontinence in People with Dementia or Cognitive Impairment, Living at Home: a Systematic Review

ABSTRACT: BACKGROUND: Dementia is a distressing and disabling illness with worldwide estimates of increased numbers of people with the condition. Two thirds of people with dementia live at home and policies in many countries seek to support more people for longer in this setting. Incontinence both contributes to carer burden and is also a significant factor in the decision to move into care homes. A review was conducted for evidence of effectiveness for conservative interventions, which are non-pharmacological and non-surgical interventions, for the prevention or management of incontinence in community dwelling people with dementia. METHOD: Fourteen electronic databases were searched, including MEDLINE, EMBASE and CINAHL (from inception to 2012). Assessments of risk of bias were made. Meta-analysis was inappropriate due to the heterogeneity of the interventions and outcome measurements. A narrative analysis was undertaken. RESULTS: From 427 identified abstracts, 56 studies were examined but only three met the inclusion criteria, all more than a decade old. All three focused on urinary incontinence. Two studies were exploratory or pilot studies. All had a control arm. The interventions were of advice for the carer to implement. Two included toileting education of prompted voiding or an individualised toileting schedule. There was insufficient evidence to support or rule out effectiveness of any of these interventions. Some interventions were unacceptable for some carers. None specifically reported the perspective of the person with dementia. CONCLUSIONS: There was insufficient evidence from any studies to recommend any strategies. There remains an urgent need for both research and also clinical guidance for health professionals tailored to community settings where the majority of people with dementia live.

Implementing Biosecurity Measures on Dairy Farms in Ireland

Dairy farms in Ireland are expanding in preparation for a new era of unrestricted milk production with the elimination of the European Union (EU) production quotas in 2015. Countries experiencing a changing agricultural demographic, including farm expansion, can benefit from documenting the implementation of on-farm biosecurity. The objectives of this study were to document and describe influences on biosecurity practices and related opinions on dairy farms. A representative response rate of 64% was achieved to a nationwide telesurvey of farmers. A 20% discrepancy was found between self-declared and truly 'closed' herds indicating a lack of understanding of the closed herd concept. Although >72% of farmers surveyed considered biosecurity to be important, 53% stated that a lack of information might prevent them from improving their biosecurity. Logistic regression highlighted regional, age, and farm-size related differences in biosecurity practices and opinions towards its implementation. Farmers in the most dairy cattle dense region were three times more likely to quarantine purchased stock than were their equivalents in regions where dairy production was less intense (P=0.012). Younger farmers in general were over twice as likely as middle-aged farmers to implement biosecurity guidelines (P=0.026). The owners of large enterprises were almost five times more likely to join a voluntary animal health scheme (P=0.003), and were over three times more likely to pay a premium price for health accredited animals (P=0.02) than were those farming small holdings. The baseline data recorded in this survey will form the basis for more detailed sociological and demographic research which will facilitate the targeting of future training of the farming community in biosecurity.

An Empirical Evaluation of the Structure of DSM-IV Personality Disorders in a Nationally Representative Sample: Results of Confirmatory Factor Analysis in the National Epidemiologic Survey on Alcohol and Related Conditions Waves 1 and 2

Individual personality disorders (PD) are grouped into three clusters in the DSM-IV (A, B, and C). There is very little empirical evidence available concerning the validity of this model in the general population. The current study included all 10 of the DSM-IV PD assessed in Wave 1 and Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Confirmatory factor analysis was used to evaluate three plausible models of the structure of Axis II personality disorders (the current hierarchical DSM-IV three-factor model in which individual PD are believed to load on their assigned clusters, which in turn load onto a single Axis II factor; a general single-factor model; and three independent factors). Each of these models was tested in both the total and also separately for gender. The higher order DSM-IV model demonstrated good fit to the data on a number of goodness-of-fit indices. The results for this model were very similar across genders. A model of PD based on the current DSM-IV hierarchical conceptualization of a higher order classification scheme received strong empirical support through confirmatory factor analysis using a number of goodness-of-fit indices in a nationally representative sample. Other models involving broad, higher order personality domains such as neuroticism in relation to personality disorders have yet to be tested in epidemiologic surveys and represent an important avenue for future research.

Population-based Breast Cancer Screening in a Primary Care Network

Objectives: To assess the ability of a health information technology system to facilitate population- based breast cancer screening. Study Design: Cohort study with 2-year follow-up after a 1-year cluster randomized trial. Methods: Study population was women 42 to 69 years old receiving care within a 12-practice primary care network. The management informatics system (1) identified women overdue for mammograms, (2) connected them to primary care providers using a web-based tool, (3) created automatically generated outreach letters for patients specified by providers, (4) monitored for subsequent mammography scheduling and completion, and (5) provided practice delegates with a list of women remaining unscreened for reminder phone calls. Eligible women overdue for a mammogram during a 1-year study period included those overdue at study start (prevalent cohort) and those who became overdue during follow-up (incident cohort). The main outcome measure was mammography completion rates over 3 years. Results: Among 32,688 eligible women, 9795 (30%) were overdue for screening (4487 intervention, 5308 control). Intervention patients were somewhat younger, more likely to be non-Hispanic white, and more likely to have health insurance compared with control patients. Adjusted completion rates in the prevalent cohort (n = 6697) were significantly higher among intervention patients after 3 years (51.7% vs 45.8%; P = .002). For patients in the incident cohort (n = 3098), adjusted completion rates after 2 years were 53.8% versus 48.7%, respectively (P = .052). Conclusions: Population-based informatics systems can enable sustained increases in mammography screening rates beyond rates seen with office-based visit reminders.

T-regs in Autoimmune Hepatitis-systemic Lupus Erythematosus/mixed Connective Tissue Disease Overlap Syndrome Are Functionally Defective and Display a Th1 Cytokine Profile

Autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinaemia, autoantibodies and interface hepatitis, is occasionally associated with systemic autoimmune manifestations [systemic lupus erythematosus (SLE); mixed connective tissue disease (MCTD)]. In both AIH and SLE/MCTD numerical and/or functional impairment of regulatory T-cells (T-regs) is believed to favour autoimmunity. To investigate whether immune-tolerance breakdown profiles differ in patients with AIH and SLE/MCTD, isolated AIH or systemic autoimmunity, we studied phenotypic and functional features of T-regs in 10 patients with AIH-SLE/MCTD, 22 with AIH, 12 with SLE and 20 healthy subjects. Compared to health, CD4(pos)CD25(pos) cells were decreased in number and expressed high levels of the CD127 activation marker in all three disease groups; in AIH-SLE/MCTD and in SLE they displayed low levels of FOXP3. In AIH-SLE/MCTD, they also contained a high proportion of IFNγ positive cells, indicating a Th1 profile. Similarly, in AIH-SLE/MCTD, CD4(pos)CD25(pos)CD25(high) T-regs were reduced in number and contained an increased proportion of activated CD127(pos) and IFNγ(pos) cells. Such skewing towards a Th1 profile was also present at effector level, as a high frequency of IFNγ-producing cells was observed within AIH-SLE/MCTD CD4(pos)CD25(neg) responder cells. Impairment in suppressor function both of CD4(pos)CD25(pos) cells and CD4(pos)CD25(pos)CD127(neg) T-regs was observed in all three autoimmune conditions, but while addition of CD4(pos)CD25(pos)CD127(neg) T-regs decreased CD4(pos)CD25(neg) responder cell proliferation in healthy subjects and partially in AIH patients, it had no effect in AIH-SLE/MCTD and SLE patients. In conclusion, in AIH-SLE/MCTD T-regs display a distinctive phenotypic and functional signature, characterized by marked activation, elevated IFNγ production and by a profound impairment of suppressive function, suggesting that multiple autoimmune manifestations may derive from a complex defect of immune-regulation.

How Big is the 'next Big Thing'? Estimating the Burden of Non-communicable Diseases in Low- and Middle-income Countries

Estimating the Incidence of Colorectal Cancer in Sub-Saharan Africa: A Systematic Analysis

Nearly two-thirds of annual mortality worldwide is attributable to non-communicable diseases (NCDs), with 70% estimated to occur in low- and middle-income countries (LMIC). Colorectal cancer (CRC) accounts for over 600 000 deaths annually, but data concerning cancer rates in LMIC is very poor. This study analyses the data available to produce an estimate of the incidence of colorectal cancer in Sub-Saharan Africa (SSA).

An Estimate of the Prevalence of Epilepsy in Sub-Saharan Africa: A Systematic Analysis

Epilepsy is a leading serious neurological condition worldwide and has particularly significant physical, economic and social consequences in Sub-Saharan Africa. This paper aims to contribute to the understanding of epilepsy prevalence in this region and how this varies by age and sex so as to inform understanding of the disease characteristics as well as the development of infrastructure, services and policies.

What Maintains the Central North Pacific Genetic Discontinuity in Pacific Herring?

Pacific herring show an abrupt genetic discontinuity in the central North Pacific that represents secondary contact between refuge populations previously isolated during Pleistocene glaciations. Paradoxically, high levels of gene flow produce genetic homogeneity among ocean-type populations within each group. Here, we surveyed variability in mtDNA control-region sequences (463 bp) and nine microsatellite loci in Pacific herring from sites across the North Pacific to further explore the nature of the genetic discontinuity around the Alaska Peninsula. Consistent with previous studies, little divergence (Φ(ST)  = 0.011) was detected between ocean-type populations of Pacific herring in the North West Pacific, except for a population in the Yellow Sea (Φ(ST)  = 0.065). A moderate reduction in genetic diversity for both mtDNA and microsatellites in the Yellow Sea likely reflects founder effects during the last colonization of this sea. Reciprocal monophyly between divergent mtDNA lineages (Φ(ST)  = 0.391) across the Alaska Peninsula defines the discontinuity across the North Pacific. However, microsatellites did not show a strong break, as eastern Bering Sea (EBS) herring were more closely related to NE Pacific than to NW Pacific herring. This discordance between mtDNA and microsatellites may be due to microsatellite allelic convergence or to sex-biased dispersal across the secondary contact zone. The sharp discontinuity between Pacific herring populations may be maintained by high-density blocking, competitive exclusion or hybrid inferiority.

White Matter Abnormalities in Skin Picking Disorder: A Diffusion Tensor Imaging Study

Skin picking disorder (SPD) is characterized by the repetitive and compulsive picking of skin, resulting in tissue damage. Neurocognitive findings in SPD implicate difficulty with response inhibition (suppression of pre-potent motor responses). This function is dependent on the integrity of the right frontal gyrus and the anterior cingulate cortices, and white-matter tracts connecting such neural nodes. It was hypothesized that SPD would be associated with reduced fractional anisotropy in regions implicated in top-down response suppression, particularly white-matter tracts in proximity of the bilateral anterior cingulate and right frontal (especially orbitofrontal and inferior frontal) cortices. 13-subjects meeting proposed SPD criteria for DSM-5 free from other current psychiatric comorbidities, and 12 healthy comparison subjects underwent MRI with a 3-T system. Between-group comparisons of imaging data underwent voxelwise analysis with permutation modeling and cluster correction. Fractional anisotropy (measured using diffusion tensor imaging) was the primary outcome measure. Subjects with SPD exhibited significantly reduced fractional anisotropy in tracts distributed bilaterally, which included the anterior cingulate cortices. Fractional anisotropy did not correlate significantly with SPD disease severity, or depressive or anxiety scores. These findings implicate disorganization of white-matter tracts involved in motor generation and suppression in the pathophysiology of SPD, findings remarkably similar to those previously reported in trichotillomania. This study adds considerable support to the notion that-in addition to the phenomenological and comorbid overlap between SPD and trichotillomania-these disorders likely share overlapping neurobiology.Neuropsychopharmacology advance online publication, 16 January 2013; doi:10.1038/npp.2012.241.

'Perineal Keystone Design Perforator Island Flap' for Perineal and Vulval Reconstruction

Implementation of a Web-based Tool for Patient Medication Self-management: the Medication Self-titration Evaluation Programme (Med-STEP) for Blood Pressure Control

Informatics tools may help support hypertension management.

Awareness of and Attitudes Towards Heat Waves Within the Context of Climate Change Among a Cohort of Residents in Adelaide, Australia

Heat waves are a public health concern in Australia and unprecedented heat waves have been recorded in Adelaide over recent years. The aim of this study was to examine the perception and attitudes towards heat waves in the context of climate change among a group of residents in Adelaide, an Australian city with a temperate climate. A cross-sectional study was conducted in the summer of 2012 among a sample of 267 residents. The results of the survey found that television (89.9%), radio (71.2%), newspapers (45.3%) were the main sources from which respondents received information about heat waves. The majority of the respondents (73.0%) followed news about heat waves very or somewhat closely. About 26.6% of the respondents were extremely or very concerned about the effects of heat waves on them personally. The main issues that were of personal concern for respondents during a heat wave were their personal comfort (60.7%), their garden (48.7%), and sleeping well (47.6%). Overall, respondents were more concerned about the impacts of heat waves to the society than on themselves. There was a significant association between gender (χ² = 21.2, df = 3, p = 0.000), gross annual household income (p = 0.03) and concern for the societal effects of heat waves. Less than half (43.2%) of the respondents believed that heat waves will extremely or very likely increase in Adelaide according to climate projections. Nearly half (49.3%) believed that the effects of heat waves were already being felt in Adelaide. These findings may inform the reframing and communication strategies for heat waves in Adelaide in the context of climate change.

Incorporating Deep and Shallow Components of Genetic Structure into the Management of Alaskan Red King Crab

Observed patterns of genetic variability among marine populations are shaped not only by contemporary levels of gene flow, but also by divergences during historical isolations. We examined variability at 15 SNP loci and in mtDNA sequences (COI, 665 bp) in red king crab from 17 localities in the North Pacific. These markers define three geographically distinct evolutionary lineages (SNPs, F(CT) = 0.054; mtDNA Φ(CT) = 0.222): (i) Okhotsk Sea-Norton Sound-Aleutian Islands, (ii) southeastern Bering Sea-western Gulf of Alaska, and (iii) Southeast Alaska. Populations in the Bering Sea and in Southeast Alaska are genetically heterogeneous, but populations in the center of the range are homogeneous. Mitochondrial DNA diversity drops from h = 0.91 in the northwestern Pacific to h = 0.24 in the Southeast Alaska. Bayesian skyline plots (BSPs) indicate postglacial population expansions, presumably from ice-age refugia. BSPs of sequences simulated under a demographic model defined by late Pleistocene temperatures failed to detect demographic variability before the last glacial maximum. These results sound a note of caution for the interpretation of BSPs. Population fragmentation in the Bering Sea and in Southeast Alaskan waters requires population management on a small geographic scale, and deep evolutionary partitions between the three geographic groups mandate regional conservation measures.

Correction: Prostate Specific Membrane Antigen (PSMA) Regulates Angiogenesis Independently of VEGF During Ocular Neovascularization

[This corrects the article on p. e41285 in vol. 7.].

Family History is a Predictor for Appendicitis in Adults in the Emergency Department

A family history of appendicitis has been reported to increase the likelihood of the diagnosis in children and in a retrospective study of adults. We compare positive family history with the diagnosis of acute appendicitis in a prospective sample of adults.

Progressive Supranuclear Palsy: High-Field-Strength MR Microscopy in the Human Substantia Nigra and Globus Pallidus

Purpose: To characterize changes in the magnetic resonance (MR) relaxation properties of progressive supranuclear palsy (PSP) and tissue from neurologically normal brains by using high-resolution (21.1-T, 900-MHz) MR microscopy of postmortem human midbrain and basal ganglia. Materials and Methods: This HIPAA-compliant study was approved by the institutional review board at the Mayo Clinic and informed consent was obtained. Postmortem tissue from age-matched PSP (n = 6) and control (n = 3) brains was imaged by using three-dimensional fast low-angle shot MR imaging with isotropic resolution of 50 μm. Relaxation times and parametric relaxation maps were generated from spin-echo and gradient-recalled-echo sequences. MR findings were correlated with histologic features by evaluating the presence of iron by using Prussian blue and ferritin and microglia burden as determined by a custom-designed color deconvolution algorithm. T2 and T2*, signal intensities, percent pixels (that could not be fitted in a pixel-by-pixel regression analysis due to severe hypointensity), and histologic data (total iron, ferritin, and microglia burden) were statistically analyzed by using independent sample t tests (P < .05). Results: PSP specimens showed higher iron burden in the cerebral peduncles and substantia nigra than did controls. However, only the putamen was significantly different, and it correlated with a decrease of T2* compared with controls (-48%; P = .043). Similarly, substantia nigra showed a significant decrease of T2* signal in PSP compared with controls (-57%; P = .028). Compared with controls, cerebral peduncles showed increased T2 (38%; P = .026) and T2* (34%; P = .014), as well as higher T2 signal intensity (57%; P = .049). Ferritin immunoreactivity was the opposite from iron burden and was significantly lower compared with controls in the putamen (-74%; P = .025), red nucleus (-61%; P = .018), and entire basal ganglia section (-63%; P = .016). Conclusion: High-field-strength MR microscopy yielded pronounced differences in substantia nigra and globus pallidus of PSP compared with control brains. Histologic data also suggested that the predominant iron in PSP is hemosiderin, not ferritin. Iron in the brain is a contrast enhancer and potential biomarker for PSP. © RSNA, 2012.

Living Vs. Deceased Donor Liver Transplantation for Hepatocellular Carcinoma: a Systematic Review and Meta-analysis

Experimental studies suggest that the regenerating liver provides a "fertile field" for the growth of hepatocellular carcinoma (HCC). However, clinical studies report conflicting results comparing living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) for HCC. Thus, disease-free survival (DFS) and overall survival (OS) were compared after LDLT and DDLT for HCC in a systematic review and meta-analysis. Twelve studies satisfied eligibility criteria for DFS, including 633 LDLT and 1232 DDLT. Twelve studies satisfied eligibility criteria for OS, including 637 LDLT and 1050 DDLT. Altogether, there were 16 unique studies; 1, 2, and 13 of these were rated as high, medium, and low quality, respectively. Studies were heterogeneous, non-randomized, and mostly retrospective. The combined hazard ratio was 1.59 (95% confidence interval [CI]: 1.02-2.49; I(2)  = 50.07%) for DFS after LDLT vs. DDLT for HCC, and 0.97 (95% CI: 0.73-1.27; I(2 ) = 5.68%) for OS. This analysis provides evidence of lower DFS after LDLT compared with DDLT for HCC. Improved study design and reporting is required in future research to ascribe the observed difference in DFS to study bias or biological risk specifically associated with LDLT.

Initial Orthostatic Hypotension and Cerebral Blood Flow Regulation: Effect of α1-adrenoreceptor Activity

We examined the hypothesis that α(1)-adrenergic blockade would lead to an inability to correct initial orthostatic hypotension (IOH) and cerebral hypoperfusion, leading to symptoms of presyncope. Twelve normotensive humans (aged 25 ± 1 yr; means ± SE) attempted to complete a 3-min upright stand, 90 min after the administration of either α(1)-blockade (prazosin, 1 mg/20 kg body wt) or placebo. Continuous beat-to-beat measurements of middle cerebral artery velocity (MCAv; Doppler), blood pressure (finometer), heart rate, and end-tidal Pco(2) were obtained. Compared with placebo, the α(1)-blockade reduced resting mean arterial blood pressure (MAP) (-15%; P < 0.01); MCAv remained unaltered (P ≥ 0.28). Upon standing, although the absolute level of MAP was lower following α(1)-blockade (39 ± 10 mmHg vs. 51 ± 14 mmHg), the relative difference in IOH was negligible in both trials (mean difference in MAP: 2 ± 2 mmHg; P = 0.50). Compared with the placebo trial, the declines in MCAv and Pet(CO(2)) during IOH were greater in the α(1)-blockade trial by 12 ± 4 cm/s and 4.4 ± 1.3 mmHg, respectively (P ≤ 0.01). Standing tolerance was markedly reduced in the α(1)-blockade trial (75 ± 17 s vs. 180 ± 0 s; P < 0.001). In summary, while IOH was little affected by α(1)-blockade, the associated decline in MCAv was greater in the blockade condition. Unlike in the placebo trial, the extent of IOH and cerebral hypoperfusion failed to recover toward baseline in the α(1)-blockade trial leading to presyncope. Although the development of IOH is not influenced by the α(1)-adrenergic receptor pathway, this pathway is critical in the recovery from IOH to prevent cerebral hypoperfusion and ultimately syncope.

Copy Number Variation on Chromosome 10q26.3 for Obesity Identified by a Genome-wide Study

Background: Obesity is a highly heritable disease defined by high body mass index (BMI). However, a large proportion of the heritability of obesity remains unexplained. Copy number variations (CNVs) might contribute to the missing heritability of obesity. Methods: We conducted genome-wide CNV analyses on obesity phenotypes, including BMI and body fat mass in a discovery sample of 2215 unrelated white subjects. After quality control, 314 CNVs were used for association tests. For significant CNVs identified, follow-up replication analyses were performed in three independent samples, including an unrelated sample of 1000 white subjects (OM sample), a family-based sample of 8385 white subjects (FHS sample), and an African-American sample of 1479 obesity cases and 1575 lean controls (AA sample). Results: Genome-wide CNV analyses detected that a CNV located at 10q26.3, which, even after multiple testing corrections, showed a strong association with both BMI (P = 2.30 × 10(-4), β = 2.164) and body fat mass (P = 6.76 × 10(-5), β = 4.126). This CNV was successfully replicated in the three replication samples (OM sample: P = 0.0465 for BMI, 0.0435 for fat mass; FHS sample: P = 0.0038 for BMI; AA sample: P = 0.0023 for obesity). Quantitative PCR validated this CNV, which covers a gene, CYP2E1. The protein encoded by CYP2E1 involves the synthesis of cholesterol, steroids and other lipids, which may have a potential impact on obesity. Conclusion: Our findings suggest the significant contribution of CNV10q26.3 to the pathogenesis of obesity.

Optimization of Wildlife Management in a Large Game Reserve Through Waterpoints Manipulation: A Bio-economic Analysis

Surface water is one of the constraining resources for herbivore populations in semi-arid regions. Artificial waterpoints are constructed by wildlife managers to supplement natural water supplies, to support herbivore populations. The aim of this paper is to analyse how a landowner may realize his ecological and economic goals by manipulating waterpoints for the management of an elephant population, a water-dependent species in the presence of water-independent species. We develop a theoretical bio-economic framework to analyse the optimization of wildlife management objectives (in this case revenue generation from both consumptive and non-consumptive use and biodiversity conservation), using waterpoint construction as a control variable. The model provides a bio-economic framework for analysing optimization problems where a control has direct effects on one herbivore species but indirect effects on the other. A landowner may be interested only in maximization of profits either from elephant offtake and/or tourism revenue, ignoring the negative effects that could be brought about by elephants to biodiversity. If the landowner does not take the indirect effects of waterpoints into consideration, then the game reserve management, as the authority entrusted with the sustainable management of the game reserve, might use economic instruments such as subsidies or taxes to the landowners to enforce sound waterpoint management.

RE: Validity and Use of the UV Index; the Benefit of Solar UVB in Reducing Risk of Cancer is Strong

Per2 Mutation Recapitulates the Vascular Phenotype of Diabetes in the Retina and Bone Marrow

In this study, we assessed whether Per2 clock gene-mutant mice exhibit a vascular phenotype similar to diabetes. Per2 (B6.129-Per2(tm1Drw)/J) or wild-type control mice 4 and 12 months of age were used. To evaluate diabetes-like phenotype in Per2 mutant mice, retina was quantified for mRNA expression, and degree of diabetic retinopathy was evaluated. Bone marrow neuropathy was studied by staining femurs for tyrosine hydroxylase (TH) and neurofilament 200 (NF-200). The rate of proliferation and quantification of bone marrow progenitor cells (BMPCs) was performed, and a threefold decrease in proliferation and 50% reduction in nitric oxide levels were observed in Per2 mutant mice. TH-positive nerve processes and NF-200 staining were reduced in Per2 mutant mice. Both retinal protein and mRNA expression of endothelial nitric oxide synthase were decreased by twofold. Other endothelial function genes (VEGFR2, VEGFR1) were downregulated (1.5-2-fold) in Per2 mutant retinas, whereas there was an upregulation of profibrotic pathway mediated by transforming growth factor-β1. Our studies suggest that Per2 mutant mice recapitulate key aspects of diabetes without the metabolic abnormalities, including retinal vascular damage, neuronal loss in the bone marrow, and diminished BMPC function.

Reproducibility of Echocardiographic Techniques for Sequential Assessment of Left Ventricular Ejection Fraction and Volumes: Application to Patients Undergoing Cancer Chemotherapy

The aim of this study was to identify the best echocardiographic method for sequential quantification of left ventricular (LV) ejection fraction (EF) and volumes in patients undergoing cancer chemotherapy.

Evolution of GluN2A/B Cytoplasmic Domains Diversified Vertebrate Synaptic Plasticity and Behavior

Two genome duplications early in the vertebrate lineage expanded gene families, including GluN2 subunits of the NMDA receptor. Diversification between the four mammalian GluN2 proteins occurred primarily at their intracellular C-terminal domains (CTDs). To identify shared ancestral functions and diversified subunit-specific functions, we exchanged the exons encoding the GluN2A (also known as Grin2a) and GluN2B (also known as Grin2b) CTDs in two knock-in mice and analyzed the mice's biochemistry, synaptic physiology, and multiple learned and innate behaviors. The eight behaviors were genetically separated into four groups, including one group comprising three types of learning linked to conserved GluN2A/B regions. In contrast, the remaining five behaviors exhibited subunit-specific regulation. GluN2A/B CTD diversification conferred differential binding to cytoplasmic MAGUK proteins and differential forms of long-term potentiation. These data indicate that vertebrate behavior and synaptic signaling acquired increased complexity from the duplication and diversification of ancestral GluN2 genes.

Synaptic Scaffold Evolution Generated Components of Vertebrate Cognitive Complexity

The origins and evolution of higher cognitive functions, including complex forms of learning, attention and executive functions, are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 million years ago) was genome duplication and subsequent diversification of postsynaptic genes. Here we report, to our knowledge, the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in each of the four Dlg paralogs showed that simple associative learning required Dlg4, whereas Dlg2 and Dlg3 diversified to have opposing functions in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed that Dlg2's role in complex learning, cognitive flexibility and attention has been highly conserved over 100 million years. Dlg-family mutations underlie psychiatric disorders, suggesting that genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness.

Cell Selective Cardiovascular Biology of Microsomal Prostaglandin E Synthase-1

Global deletion of microsomal prostaglandin E synthase 1 (mPGES-1) in mice attenuates the response to vascular injury without a predisposition to thrombogenesis or hypertension. However, enzyme deletion results in cell-specific differential use by prostaglandin synthases of the accumulated prostaglandin H(2) substrate. Here, we generated mice deficient in mPGES-1 in vascular smooth muscle cells, endothelial cells, and myeloid cells further to elucidate the cardiovascular function of this enzyme.

PLK1 Inhibitors Synergistically Potentiate HDAC Inhibitor Lethality in Imatinib Mesylate-Sensitive or -Resistant BCR/ABL+ Leukemia Cells In Vitro and In Vivo

To determine whether Polo-like kinase 1 (PLK1) inhibitors (e.g., BI2536) and histone deacetylase (HDAC) inhibitors (e.g., vorinostat) interact synergistically in the BCR/ABL(+) leukemia cells sensitive or resistant to imatinib mesylate (IM) in vitro and in vivo.

Transferrin Saturation and Hospital Length of Stay and Mortality in Medicare Beneficiaries

To evaluate in a large, nationally representative cohort the association between high serum transferrin saturation (TS) and hospital length of stay and mortality in older adults.

Drug Resistance and Pseudoresistance: an Unintended Consequence of Enteric Coating Aspirin

Low dose aspirin reduces the secondary incidence of myocardial infarction and stroke. Drug resistance to aspirin might result in treatment failure. Despite this concern, no clear definition of aspirin resistance has emerged, and estimates of its incidence have varied remarkably. We aimed to determine the commonality of a mechanistically consistent, stable, and specific phenotype of true pharmacological resistance to aspirin-such as might be explained by genetic causes.

Integrating Tuberculosis and HIV Services in Low- and Middle-income Countries: a Systematic Review

Given the imperative to scale up integrated tuberculosis (TB) and HIV services in settings where both are of major public health importance, we aimed to synthesise knowledge concerning implementation of TB/HIV service integration.

The Chelsea Critical Care Physical Assessment Tool (CPAx): Validation of an Innovative New Tool to Measure Physical Morbidity in the General Adult Critical Care Population; an Observational Proof-of-concept Pilot Study

To develop a scoring system to measure physical morbidity in critical care - the Chelsea Critical Care Physical Assessment Tool (CPAx).

Surviving Colorectal Cancer: Long-term, Persistent Ostomy-Specific Concerns and Adaptations

PURPOSE:: The purpose of this article was to describe persistent ostomy-specific concerns and adaptations in long-term (>5 years) colorectal cancer survivors with ostomies. SUBJECTS AND SETTINGS:: Thirty-three colorectal cancer survivors who participated in 8 gender- and health-related quality of life stratified focus groups and 130 colorectal cancer survivors who provided written comments to 2 open-ended questions on ostomy location and pouch problems participated in the study. Data were collected on health maintenance organization members in Oregon, southwestern Washington, and northern California. METHODS:: Qualitative data were analyzed for the 8 focus groups and written comments from 2 open-ended survey questions. Discussions from the focu s groups were recorded, transcribed, and analyzed using content analysis. Written content from the open-ended questions was derived from a mailed questionnaire on health-related quality of life in survivors with ostomies and analyzed using content analysis. RESULTS:: Discussions related to persistent ostomy-related issues more than 5 years after formation were common. Persistent ostomy-related issues were focused on clothing restrictions and adaptations, dietary concerns, issues related to ostomy equipment and self-care, and the constant need to find solutions to adjust and readjust to living with an ostomy. CONCLUSIONS:: Ostomy-specific concerns persist 5 years and more for long-term colorectal cancer survivors after initial ostomy formation. Adaptations tend to be individualized and based on trial and error. Findings underscore the need to develop long-term support mechanisms that survivors can access to promote better coping and adjustment to living with an ostomy.

Spectrum of Non-tuberculous Mycobacteria Identified Using Standard Biochemical Testing Vs. 16S Sequencing [Short Communication]

Non-tuberculous mycobacterial isolates from gold miners were speciated using standard biochemical testing (SBT) and 16S rDNA sequencing. Of 237 isolates tested, SBT identified 126, compared with all 237 identified using sequencing. Of 111 isolates unspeciated by SBT but identified by sequencing, 38 (34.2%) were identified as Mycobacterium gordonae and 8 (7.2%) were new species. Of 126 isolates speciated by both methods, 37 were discordant, with 14/17 M. gordonae isolates incorrectly identified as M. scrofulaceum using SBT. The majority of these were the potentially pathogenic strain D, M. gordonae. Sequencing is preferable where available to guide treatment.

Screening for Major Depressive Disorder in Adults with Cerebral Glioma: an Initial Validation of 3 Self-report Instruments

No depression screening tool is validated for use in cases of cerebral glioma. To address this, we studied the operating characteristics of the Hospital Anxiety and Depression Scale (Depression subscale) (HAD-D), the Patient Health Questionnaire-9 (PHQ-9), and the Distress Thermometer (DT) in glioma patients.We conducted a twin-center prospective observational cohort study of major depressive disorder (MDD), according to the Diagnostic and Statistical Manual, 4th edition, in adults with a new diagnosis of cerebral glioma receiving active management or "watchful waiting." At each of 3 interviews over a 6-month period, patients completed the screening questionnaires and received a structured clinical interview to diagnose MDD. Internal consistency, area under the receiver operating characteristics curve (AUC), sensitivity, specificity, positive predictive value, and positive likelihood ratio were calculated. A maximum of 154 patients completed the DT, 133 completed the HAD-D, and 129 completed the PHQ-9. The HAD-D and PHQ-9 showed good internal consistency (α ≥ 0.77 at all timepoints). Median AUCs were 0.931 ± 0.074 for the HAD-D and 0.915 ± 0.055 for the PHQ-9. The optimal threshold was 7+ for the HAD-D, but 8+ had similar operating characteristics. There was no consistently optimal PHQ-9 threshold, but 10+ was optimal in the largest sample. The DT was inferior to the multi-item instruments. Clinicians can screen for depression in well-functioning glioma patients using the HAD-D at the existing recommended lower threshold of 8+, or the PHQ-9 at a threshold of 10+. Due to a modest positive predictive value of either instrument, patients scoring above these thresholds need a clinical assessment to diagnose or exclude depression.

Therapy-induced Clearance of HCV Core Antigen from Plasma Predicts an End of Treatment Viral Response

During viral assembly, viral proteins are released into plasma and can be used to infer viral load. The Architect hepatitis C virus (HCV) core antigen (Ag) assay is a potential alternative to HCV RNA quantification for measuring response to therapy and predicting an end of treatment viral response (EOTR). The HCVp22Ag assay was used to infer viral load in 68 window RNA-containing samples and in 284 samples from baseline to week 14 of ribavirin/interferon treatment in 23 patients with EOTR including three who relapsed, 20 not achieving EOTR and 11 controls. HCV Ag and RNA correlated well (r = 0.86) with linear dose responses on dilution. In patients on therapy and control patients, plasma HCV antigen was detected in 51 of 54 with an interpolated LOD cut off between 10(3) and 10(4) RNA IU/mL. Plasma HCV antigenaemia and plasma RNA levels were significantly different in EOTR from non-EOTR patients at 3 days after treatment start and all times thereafter. Positive and negative EOTR predictive values for HCV RNA >2 log drop and HCV Ag loss at 12 weeks were 70% and 74%, 85% and 93% respectively. HCV Ag reactivity has a linear dose response independent of genotype and correlates well with HCV RNA. The failure to clear HCV Ag is as accurate as the failure to clear HCV RNA at twelve weeks into therapy in predicting the likelihood of failure to achieve EOTR. HCV Ag potentially offers a convenient alternative to RNA measurement for defining a futility flag in HCV therapy.

The Bipolar-depressive Continuum in the National Epidemiologic Survey on Alcohol and Related Conditions

MDA-9/Syntenin and IGFBP-2 Promote Angiogenesis in Human Melanoma

Melanoma differentiation-associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacologic approaches were used to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma, and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, chorioallantoic membrane (CAM) assays and xenograft tumor animal models. Gain-of-function and loss-of-function experiments confirm that MDA-9/syntenin induces angiogenesis by augmenting expression of several proangiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/syntenin in which MDA-9/syntenin interacts with the extracellular matrix (ECM), activating Src and FAK resulting in activation by phosphorylation of Akt, which induces hypoxia inducible factor 1-α (HIF-1α). The HIF-1α activates transcription of insulin growth factor-binding protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete VEGF-A augmenting tumor angiogenesis. Our studies delineate an unanticipated cell nonautonomous function of MDA-9/syntenin in the context of angiogenesis, which may directly contribute to its metastasis-promoting properties. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (nonautonomous). Cancer Res; 73(2); 844-54. ©2012 AACR.

Quantification of the Effects of Antibodies on the Extra- and Intracellular Dynamics of Salmonella Enterica

Antibodies are known to be essential in controlling Salmonella infection, but their exact role remains elusive. We recently developed an in vitro model to investigate the relative efficiency of four different human immunoglobulin G (IgG) subclasses in modulating the interaction of the bacteria with human phagocytes. Our results indicated that different IgG subclasses affect the efficacy of Salmonella uptake by human phagocytes. In this study, we aim to quantify the effects of IgG on intracellular dynamics of infection by combining distributions of bacterial numbers per phagocyte observed by fluorescence microscopy with a mathematical model that simulates the in vitro dynamics. We then use maximum likelihood to estimate the model parameters and compare them across IgG subclasses. The analysis reveals heterogeneity in the division rates of the bacteria, strongly suggesting that a subpopulation of intracellular Salmonella, while visible under the microscope, is not dividing. Clear differences in the observed distributions among the four IgG subclasses are best explained by variations in phagocytosis and intracellular dynamics. We propose and compare potential factors affecting the replication and death of bacteria within phagocytes, and we discuss these results in the light of recent findings on dormancy of Salmonella.

An Intervention to Improve Adherence and Management of Symptoms for Patients Prescribed Oral Chemotherapy Agents: an Exploratory Study

Use of oral chemotherapy agents to treat cancer has increased. Patients are responsible for adhering to complex regimens while managing symptoms from adverse effects of the chemotherapy.

The Elevated Copper Binding Strength of Amyloid-β Aggregates Allows the Sequestration of Copper from Albumin: A Pathway to Accumulation of Copper in Senile Plaques

Copper coexists with amyloid-β (Aβ) peptides at a high concentration in the senile plaques of Alzheimer's disease (AD) patients and has been linked to oxidative damage associated with AD pathology. However, the origin of copper and the driving force behind its accumulation are unknown. We designed a sensitive fluorescent probe, Aβ(1-16)(Y10W), by substituting the tyrosine residue at position 10 in the hydrophilic domain of Aβ(1-42) with tryptophan. Upon mixing Cu(II), Aβ(1-16)(Y10W), and aliquots of Aβ(1-42) taken from samples incubated for different lengths of time, we found that the Cu(II) binding strength of aggregated Aβ(1-42) has been elevated by more than 2 orders of magnitude with respect to that of monomeric Aβ(1-42). Electron paramagnetic spectroscopic measurements revealed that the Aβ(1-42) aggregates, unlike their monomeric form, can seize copper from human serum albumin, an abundant copper-containing protein in brain and cerebrospinal fluid. The significantly elevated binding strength of the Aβ(1-42) aggregates can be rationalized by a Cu(II) coordination sphere constituted by three histidines from two adjacent Aβ(1-42) molecules. Our work demonstrates that the copper binding affinity of Aβ(1-42) is dependent on its aggregation state and provides new insight into how and why senile plaques accumulate copper in vivo.

Detection of Postmortem Human Cerebellar Cortex and White Matter Pathways Using High Angular Resolution Diffusion Tractography: A Feasibility Study

Imaging three-dimensional cerebellar connectivity using diffusion tractography is challenging because of the ubiquitous features of crossing axonal pathways within a folium as well as intersecting pathways from neighboring folia. We applied high-angular resolution diffusion imaging (HARDI) tractography to intact postmortem adult brainstem and cerebellum to examine the 3-dimensional white matter and local gray matter pathways. The middle cerebellar peduncles conveyed fibers from the rostral pons to the lateral and caudal aspects of the cerebellar hemisphere, and from the caudal pons to medial and rostral parts of the cerebellar hemisphere. In the cerebellar cortex, tractography detected tangential coherence superficially in the cerebellar cortex and revealed fibers coursing parallel to the long axis of the folia. These fibers were consistent with the location and direction of parallel fibers in the molecular layer. Crossing with these parallel fibers were tangential fibers running perpendicular to the long axis of the folia, consistent with axons of the cortical interneurons - stellate cells and basket cells. These tangential fibers within the cerebellar cortex were distinct from the fibers linking the cerebellar cortex with the deep cerebellar nuclei and the brainstem. Our results show the potential for HARDI tractography to resolve axonal pathways from different neuronal elements within the cerebellar cortex, and improve our understanding of adult cerebellar neural circuitry and connectivity in both white and gray matter.

Histologic Analysis of Chronic Rejection in Small Bowel Transplantation: Mucosal and Vascular Alterations

Chronic rejection is a significant barrier to small bowel allograft survival. Although chronic rejection primarily involves vessels of the submucosa, serosa, and mesentery, some mucosal alterations have been suggested to be correlative.

The Role of Hypovitaminosis D in Pregnancy-related Venous Thromboembolism

Pseudostatic and Dynamic Nanomechanics of the Tunica Adventitia in Elastic Arteries Using Atomic Force Microscopy

Tunica adventitia, the outer layer of blood vessels, is an important structural feature, predominantly consisting of collagen fibrils. This study uses pseudostatic atomic force microscopy (AFM) nanoindentation at physiological conditions to show that the distribution of indentation modulus and viscous creep for the tunica adventitia of porcine aorta and pulmonary artery are distinct. Dynamic nanoindentation demonstrates that the viscous dissipation of the tunica adventitia of the aorta is greater than the pulmonary artery. We suggest that this mechanical property of the aortic adventitia is functionally advantageous due to the higher blood pressure within this vessel during the cardiac cycle. The effects on pulsatile deformation and dissipative energy losses are discussed.

The Role of Animal Products and Vitamin D in Risk of Breast Cancer

Disability-adjusted Life Years (DALYs) for 291 Diseases and Injuries in 21 Regions, 1990-2010: a Systematic Analysis for the Global Burden of Disease Study 2010

Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time.

A Comparative Risk Assessment of Burden of Disease and Injury Attributable to 67 Risk Factors and Risk Factor Clusters in 21 Regions, 1990-2010: a Systematic Analysis for the Global Burden of Disease Study 2010

Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time.

Infections with Spore-forming Bacteria in Persons Who Inject Drugs, 2000-2009

Since 2000 in the United Kingdom, infections caused by spore-forming bacteria have been associated with increasing illness and death among persons who inject drugs (PWID). To assess temporal and geographic trends in these illnesses (botulism, tetanus, Clostridium novyi infection, and anthrax), we compared rates across England and Scotland for 2000-2009. Overall, 295 infections were reported: 1.45 per 1,000 PWID in England and 4.01 per 1,000 PWID in Scotland. The higher rate in Scotland was mainly attributable to C. novyi infection and anthrax; rates of botulism and tetanus were comparable in both countries. The temporal and geographic clustering of cases of C. novyi and anthrax into outbreaks suggests possible contamination of specific heroin batches; in contrast, the more sporadic nature of tetanus and botulism cases suggests that these spores might more commonly exist in the drug supply or local environment although at varying levels. PWID should be advised about treatment programs, injecting hygiene, risks, and vaccinations.

GWAS of Blood Cell Traits Identifies Novel Associated Loci and Epistatic Interactions in Caucasian and African-American Children

Hematological traits are important clinical indicators, the genetic determinants of which have not been fully investigated. Common measures of hematological traits include red blood cell (RBC) count, hemoglobin concentration (HGB), hematocrit (HCT), mean corpuscular hemoglobin (MCH), MCH concentration (MCHC), mean corpuscular volume (MCV), platelet count (PLT) and white blood cell (WBC) count. We carried out a genome-wide association study of the eight common hematological traits among 7943 African-American children and 6234 Caucasian children. In African Americans, we report five novel associations of HBE1 variants with HCT and MCHC, the alpha-globin gene cluster variants with RBC and MCHC, and a variant at the ARHGEF3 locus with PLT, as well as replication of four previously reported loci at genome-wide significance. In Caucasians, we report a novel association of variants at the COPZ1 locus with PLT as well as replication of four previously reported loci at genome-wide significance. Extended analysis of an association observed between MCH and the alpha-globin gene cluster variants demonstrated independent effects and epistatic interaction at the locus, impacting the risk of iron deficiency anemia in African Americans with specific genotype states. In summary, we extend the understanding of genetic variants underlying hematological traits based on analyses in African-American children.

Achilles Tendon Lengthening: Friend or Foe in the Diabetic Foot?

: Literature in the past decade has shown that Achilles tendon-lengthening surgery in addition to total contact casting decreases the rate of plantar ulcer recurrence in the forefoot and midfoot; however, the risk of heel ulceration or recurrent equinus deformity with new forefoot or midfoot wounds is not insignificant. The purpose of this study was to compare the rate of recurrent ulceration between the patient groups who have undergone soft-tissue repair of diabetic forefoot or midfoot wounds either with or without concomitant Achilles tendon-lengthening surgery.

Palliative Care Opportunities for Women with Advanced Ovarian Cancer Associated with Intraperitoneal Chemotherapy

Abstract Intraperitoneal chemotherapy poses both potential benefits as a cancer treatment and negative consequences on patient and family quality of life. The profound multi-dimensional quality of life impact of intraperitoneal (IP) chemotherapy upon women with advanced ovarian cancer makes the early integration of palliative care particularly important for this population. Numerous opportunities occur throughout the treatment process to improve the delivery of biopsychosocial-spiritual support to women receiving IP chemotherapy.

A Multicentre Observational Study of the Outcomes of Screening Detected Sub-aneurysmal Aortic Dilatation

Currently most abdominal aortic aneurysm screening programmes discharge patients with aortic diameter of less than 30 mm. However, sub-aneurysmal aortic dilatation (25 mm-29 mm) does not represent a normal aortic diameter. This observational study aimed to determine the outcomes of patients with screening detected sub aneurysmal aortic dilatation.

Those with Erectile Dysfunction Should Also Be Tested for Serum 25-hydroxyvitamin D Concentration

Exploiting Pathogens' Tricks of the Trade for Engineering of Plant Disease Resistance: Challenges and Opportunities

With expansion of our understanding of pathogen effector strategies and the multiplicity of their host targets, it is becoming evident that novel approaches to engineering broad-spectrum resistance need to be deployed. The increasing availability of high temporal gene expression data of a range of plant-microbe interactions enables the judicious choices of promoters to fine-tune timing and magnitude of expression under specified stress conditions. We can therefore contemplate engineering a range of transgenic lines designed to interfere with pathogen virulence strategies that target plant hormone signalling or deploy specific disease resistance genes. An advantage of such an approach is that hormonal signalling is generic so if this strategy is effective, it can be easily implemented in a range of crop species. Additionally, multiple re-wired lines can be crossed to develop more effective responses to pathogens.

Intracranial Dual-Mode IVUS and Hyperthermia Using Circular Arrays: Preliminary Experiments

In this study, we investigated the feasibility of using 3.5-Fr (3 Fr = 1 mm) circular phased-array intravascular ultrasound (IVUS) catheters for minimally invasive, image-guided hyperthermia treatment of tumors in the brain. Feasibility was demonstrated in two ways: (1) by inserting a 3.5-Fr IVUS catheter through skull burr holes, for 20 MHz brain imaging in the pig model, and (2) by testing a modified circular array for therapy potential with 18.5-MHz and 9-MHz continuous wave (CW) excitation. The imaging transducer's performance was superior to our previous 9-MHz mechanical IVUS prototype. The therapy catheter transducer was driven by CW electrical power at 18.5 MHz, achieving temperature changes reaching +8°C at a depth of 2 mm in a human glioblastoma grown on the flank of a mouse with minimal transducer resistive heating of +2°C. Further hyperthermia trials showed that 9-MHz CW excitation produced temperature changes of +4.5°C at a depth of 12 mm-a sufficient temperature rise for our long-term goal of targeted, controlled drug release via thermosensitive liposomes for therapeutic treatment of 1-cm-diameter glioblastomas.

A Comparison of Psychosocial Outcomes In Elderly Alzheimer Caregivers And Noncaregivers

To conduct an analysis of the stress, coping, and mood consequences of Alzheimer caregiving.

CT Dose Reduction Applications: Available Tools on the Latest Generation of CT Scanners

Increasing concerns about radiation dose have led CT manufacturers to further develop radiation dose reduction tools in the latest generation of CT scanners. These tools include automated tube current modulation, automated tube potential selection, and iterative reconstruction. This review details the principles underlying each of these 3 dose reduction utilities and their different permutations on each of the major vendors' equipment. If available on the user's equipment, all 3 of these tools should be used in conjunction to enable maximum radiation dose savings.

Ultrasound-guided Transversus Abdominal Plane Block with Multimodal Analgesia for Pain Management After Total Abdominal Hysterectomy

BACKGROUND: Transversus abdominis plane (TAP) block has been shown to provide pain relief after abdominal procedures. However, TAP block combined with multimodal analgesia technique have not been assessed in a randomized controlled trial. This randomized, controlled, observer-blinded study was designed to evaluate the analgesic efficacy of bilateral ultrasound-guided TAP blocks with or without acetaminophen and non-steroidal anti-inflammatory drug (NSAID) combination. METHODS: Patients undergoing total abdominal hysterectomy were randomized to one of three groups. Group 1 (n = 25) received a TAP block and ketorolac 30 mg, IV at the end of surgery and then ketorolac plus paracetamol 650 mg, orally, every 6 h for 24 h. Group 2 (n = 24) received only TAP block at the end of surgery. Group 3 (n = 25) received ketorolac 30 mg, IV at the end of surgery and then ketorolac plus paracetamol 650 mg, orally, every 6 h for 24 h. All patients received IV-PCA morphine for 24-h, postoperatively. All patients received a standardized general anaesthetic technique and dexamethasone 4 mg and ondansetron 4 mg, IV for antiemetic prophylaxis. RESULTS: There were no statistically significant differences in pain at rest between the groups. However, the pain on coughing (dynamic pain) in Group 1 was significantly less variable, compared with the other two groups (P = 0.012). Opioid consumption and occurrences of nausea, vomiting, and rescue antiemetic were similar in three the groups. CONCLUSIONS: The combination of TAP block and acetaminophen and NSAID provided less variability in dynamic pain compared with either treatment alone.

Biological Perspectives: Ketamine As an Alternative Treatment for Treatment-resistant Depression

Developing Psychotherapists' Competence Through Clinical Supervision: Protocol for a Qualitative Study of Supervisory Dyads

ABSTRACT: BACKGROUND: Mental health professionals face unique demands and stressors in their work, resulting in high rates of burnout and distress. Clinical supervision is a widely adopted and valued mechanism of professional support, development, and accountability, despite the very limited evidence of specific impacts on therapist or client outcomes. The current study aims to address this by exploring how psychotherapists develop competence through clinical supervision and what impact this has on the supervisees' practice and their clients' outcomes. This paper provides a rationale for the study and describes the protocol for an in-depth qualitative study of supervisory dyads, highlighting how it addresses gaps in the literature. METHODS: The study of 16-20 supervisor-supervisee dyads uses a qualitative mixed method design, with two phases. In phase one, supervisors who are nominated as expert by their peers are interviewed about their supervision practice. In phase two, supervisors record a supervision session with a consenting supervisee; interpersonal process recall interviews are conducted separately with supervisor and supervisee to reflect in depth on the teaching and learning processes occurring. All interviews will be transcribed, coded and analysed to identify the processes that build competence, using a modified form of Consensual Qualitative Research (CQR) strategies. Using a theory-building case study method, data from both phases of the study will be integrated to develop a model describing the processes that build competence and support wellbeing in practising psychotherapists, reflecting the accumulated wisdom of the expert supervisors. DISCUSSION: The study addresses past study limitations by examining expert supervisors and their supervisory interactions, by reflecting on actual supervision sessions, and by using dyadic analysis of the supervisory pairs. The study findings will inform the development of future supervision training and practice and identify fruitful avenues for future research.

Memantine Reduces Stealing Behavior and Impulsivity in Kleptomania: a Pilot Study

Kleptomania is characterized by repetitive stealing behavior and has been associated with deleterious unwanted outcomes including forensic contact and increased rates of suicidal behavior. Very few trials have been conducted to investigate pharmacological treatment options for this neglected condition. Memantine is an NMDA-receptor antagonist that has shown promising results in the treatment of other behavioral addictions and substance addictions. Twelve individuals with kleptomania received memantine (10 mg/day, titrated to 30 mg/day maximum depending on clinical response and tolerability) over the course of 8 weeks, in an open-label trial. The effects of treatment were quantified using well-validated measures and select neurocognitive tests (last observation carried forward analyses). Kleptomania disease severity scores decreased across all measures considered, and 11 (91.7%) of the participants met the responder criteria (35% improvement on the primary effectiveness measure plus CGI improved/very much improved; significant improvements were also observed in terms of mood, anxiety, and disability scores along with a significant improvement in stop-signal response inhibition. Memantine was generally well tolerated. This study shows the effectiveness of memantine in reducing urges to shoplift and shoplifting behavior along with improving impulsivity, mood, anxiety, and psychosocial functioning.

Shared and Distinct Genetic Influences Among Different Measures of Pulmonary Function

We examined shared and distinct genetic influences among standard measures of pulmonary functions: ratio of forced expiratory volume at 1 s to forced vital capacity (FEV1/FVC) and percent predicted values for forced expiratory volume at 1 s (FEV1%p), forced expiratory flow (FEFmax%p), and maximal voluntary ventilation (MVV%p) in 978-1,048 middle-aged (mean age = 55 years) male-male twins from the Vietnam Era Twin Study of Aging. A common latent factor (h(2) = 0.30) accounted for the correlations among these measures. This factor accounted for 54-81 % of the heritability of FEV1%p, FEFmax%p and MVV%p, but only explained 16 % of the heritability of FEV1/FVC. The remaining heritability of FEV1/FVC was explained by genetic influences independent of the common factor. Our findings suggest that while a common latent phenotype accounts for the relationships among different pulmonary function measures, the majority of genetic influences underlying FEV1/FVC-an index of pulmonary obstruction-are distinct from those underlying other pulmonary function measures.

Mortality and Potential Years of Life Lost Attributable to Alcohol Consumption by Race and Sex in the United States in 2005

Alcohol has been linked to health disparities between races in the US; however, race-specific alcohol-attributable mortality has never been estimated. The objective of this article is to estimate premature mortality attributable to alcohol in the US in 2005, differentiated by race, age and sex for people 15 to 64 years of age.

Convincing Yourself to Care About Others: an Intervention for Enhancing Benevolence Values

OBJECTIVE: To study value change, this research presents an intervention with multiple exercises, designed to instigate change through both effortful and automatic routes. Aiming to increase the importance attributed to benevolence values, which reflect the motivation to help and care for others, the intervention combines three mechanisms for value change (self-persuasion, consistency-maintenance and priming). METHOD: In three experiments, 142 undergraduates (67% male, ages 19-26) participated in an intervention emphasizing the importance of either helping others (benevolence condition) or recognizing flexibility in personality (control condition). We measured the importance of benevolence values before and after the task. RESULTS: In Experiment 1, the intervention increased U.S. participants' benevolence values. In Experiment 2, we replicated these effects in a different culture (Israel) and also showed that by enhancing benevolence values, the intervention increased participants' willingness to volunteer to help others. Experiment 3 showed that the increases in the importance of benevolence values lasted at least four weeks. CONCLUSION: Our results provide evidence that value change does not require fictitious feedback or information about social norms, but can occur through a 30-min intervention that evokes both effortful and automatic processes.

Faecal Microbiota in Lean and Obese Dogs

Previous work has shown obesity to be associated with changes in intestinal microbiota. While obesity is common in dogs, limited information is available about the role of the intestinal microbiota. The aim of this study was to investigate whether alterations in the intestinal microbiota may be associated with canine obesity. Using 16S rRNA gene pyrosequencing and quantitative real-time PCR, we evaluated the composition of the faecal microbiota in 22 lean and 21 obese pet dogs, as well as in five research dogs fed ad libitum and four research dogs serving as lean controls. Firmicutes, Fusobacteria and Actinobacteria were the predominant bacterial phyla. The phylum Actinobacteria and the genus Roseburia were significantly more abundant in the obese pet dogs. The order Clostridiales significantly increased under ad libitum feeding in the research dogs. Canine intestinal microbiota is highly diverse and shows considerable interindividual variation. In the pet dogs, influence on the intestinal microbiota besides body condition, like age, breed, diet or lifestyle, might have masked the effect of obesity. The study population of research dogs was small, and further work is required before the role of the intestinal microbiota in canine obesity is clarified.

Vitamin D Status of Exclusively Breastfed Infants Aged 2-3 Months

BACKGROUND: New Zealand in 2008 adopted WHO policy which recommends that all infants are exclusively breast fed until 6 months of age. The benefits of this policy for the infant are undisputed; however, this policy has the potential to adversely impact on infant vitamin D status. A number of countries now recommend that all breastfed infants receive daily vitamin D supplementation of 400 IU to prevent rickets. New Zealand has no policy on the vitamin D supplementation of 'low-risk' breastfed infants. There are no data on the vitamin D status of exclusively breastfed infants in the first few months of life in New Zealand. AIM: To describe serum 25-hydroxy-vitamin D (25(OH)D) concentrations in exclusively breastfed infants aged 2-3 months. DESIGN/METHODS: Healthy term exclusively breastfed infants who were receiving no vitamin D supplements were enrolled over a 15-month period. A capillary blood sample was obtained from each infant. Serum 25(OH)D was measured using isotope-dilution liquid chromatography-tandem mass spectrometry. RESULTS: 94 infants were enrolled (mean age 10 weeks). Median 25(OH)D concentration was 53 nmol/l (IQR 14-100 nmol/l). 23 (24%) infants had serum 25(OH)D concentration <27.5 nmol/l. Infants enrolled during winter had a median (IQR) 25(OH)D serum concentration of 21 nmol/l (14,31). Infants enrolled during summer had a median (IQR) 25(OH)D concentration of 75 nmol/l (55 100) (winter vs summer, p<0.0001). CONCLUSIONS: Vitamin D deficiency is prevalent in exclusively breastfed infants in New Zealand. Vitamin D supplementation should be considered as part of New Zealand's child health policy.

Usability of Virtual-reality Simulation Training in Obstetric Ultrasonography: a Prospective Cohort Study

OBJECTIVES: Prospective cohort study to assess the usability of virtual-reality (VR) simulation for obstetric ultrasound trainees. METHODS: Twenty-six participants were recruited; 18 obstetric ultrasound trainees (with little formal ultrasonography training) and eight certified experts. They all performed five sequential VR-simulated crown-rump length (CRL) scans in a single session and three repetitions of bi-parietal diameter (BPD), occipito-frontal diameter (OFD), and femur length (FL). Outcome measures included mean percentage deviation from target for all measurements. Time taken to perform each type of scan was recorded. RESULTS: The mean percentage difference for the first scan was significantly greater for the trainee group than for the expert group for BPD (p=0.035), OFD (p=0.010), FL (p=0.008) and for time taken for first the CRL (p<0.001) and fetal biometry scan (p=0.015), demonstrating trainees were initially significantly less accurate and less efficient. Over subsequent scans, the trainees became more accurate for all measurements with a significant improvement shown for OFD and FL (p<0.05). The time for trainees to complete CRL and fetal biometry scans decreased significantly (all p<0.05) with repetition, to near-expert efficiency. CONCLUSIONS: All sonographers were able to use the simulator and produce clinically meaningful biometry results. With repetition beginners quickly approached near-expert levels of accuracy and speed. These data demonstrate that obstetricians with minimal experience can improve their ultrasonographic skills with short phase VR-simulation training. The speed of improvement suggests that VR simulation might be useful for a warm-up exercise before clinical training sessions to limit the impact of training on clinical service.

The Activation Peptide Cleft Exposed by Thrombin Cleavage of FXIII-A2 Contains a Recognition Site for the Fibrinogen α Chain

Formation of a stable fibrin clot is dependent upon interactions between FXIII and fibrin. We have previously identified a key residue on the αC of fibrin(ogen) (Glu396) involved in binding activated FXIII-A(2) (FXIII-A(2)*), however the functional role of this interaction and binding site(s) on FXIII-A(2)* remains unknown. In the present study we i) characterised the functional implications of this interaction, ii) identified by LC-MS/MS the interacting residues on FXIII-A(2)* following chemical cross-linking of fibrin(ogen) αC389-402 peptides to FXIII-A(2)* and iii) carried out molecular modelling of the FXIII-A(2)*/peptide complex to identify contact site(s) involved. Results demonstrated that inhibition of the FXIII-A(2)*/αC interaction using αC389-402 peptide (Pep1) significantly decreased incorporation of biotinamido-pentylamine and α2-antiplasmin to fibrin, and fibrin cross-linking, in contrast to Pep1-E396A and scrambled peptide controls. Pep1 did not inhibit TG-2 activity, and incorporation of biotinyl-TVQQEL to fibrin was only weakly inhibited. Molecular modelling predicted that Pep1 binds the activation peptide cleft (AP-Cleft) within the β-sandwich domain of FXIII-A(2)* localising αC cross-linking Q366 to the FXIII-A(2)* active site. Our findings demonstrate that binding of fibrin αC389-402 to the exposed AP-cleft is fundamental to clot stabilisation, and furthermore presents this region of FXIII-A(2)* as a potential site involved in glutamine-donor substrate recognition.

Piet Mondrian's Trees and the Evolution in Understanding Multiple Sclerosis, Charcot Prize Lecture 2011

Four questions were posed about multiple sclerosis (MS) at the 2011 Charcot Lecture, Oct. 22, 2011. 1. The Male/Female Disparity: Why are women developing MS so much more frequently than men? 2. Neuronal and Glial Protection: Are there guardian molecules that protect the nervous system in MS? 3. Predictive Medicine: With all the approved drugs, how can we rationally decide which one to use? 4. The Precise Scalpel vs. the Big Hammer for Therapy: Is antigen-specific therapy for demyelinating disease possible? To emphasize how our views on the pathogenesis and treatment of MS are evolving, and given the location of the talk in Amsterdam, Piet Mondrian's progressive interpretations of trees serve as a heuristic.

Co-Morbidities in Persons Infected with HIV: Increased Burden with Older Age and Negative Effects on Health-Related Quality of Life

Abstract This study sought to determine the synergistic effects of age and HIV infection on medical co-morbidity burden, along with its clinical correlates and impact on health-related quality of life (HRQoL) across the lifespan in HIV. Participants included 262 individuals across four groups stratified by age (≤40 and ≥50 years) and HIV serostatus. Medical co-morbidity burden was assessed using a modified version of the Charlson Co-morbidity Index (CCI). Multiple regression accounting for potentially confounding demographic, psychiatric, and medical factors revealed an interaction between age and HIV infection on the CCI, with the highest medical co-morbidity burden in the older HIV+cohort. Nearly half of the older HIV+group had at least one major medical co-morbidity, with the most prevalent being diabetes (17.8%), syndromic neurocognitive impairment (15.4%), and malignancy (12.2%). Affective distress and detectable plasma viral load were significantly associated with the CCI in the younger and older HIV-infected groups, respectively. Greater co-morbidity burden was uniquely associated with lower physical HRQoL across the lifespan. These findings highlight the prevalence and clinical impact of co-morbidities in older HIV-infected adults and underscore the importance of early detection and treatment efforts that might enhance HIV disease outcomes.

Using Wastewater and High-rate Algal Ponds for Nutrient Removal and the Production of Bioenergy and Biofuels

This paper projects a positive outcome for large-scale algal biofuel and energy production when wastewater treatment is the primary goal. Such a view arises partly from a recent change in emphasis in wastewater treatment technology, from simply oxidising the organic matter in the waste (i.e. removing the biological oxygen demand) to removing the nutrients - specifically nitrogen and phosphorus - which are the root cause of eutrophication of inland waterways and coastal zones. A growing need for nutrient removal greatly improves the prospects for using new algal ponds in wastewater treatment, since microalgae are particularly efficient in capturing and removing such nutrients. Using a spreadsheet model, four scenarios combining algae biomass production with the making of biodiesel, biogas and other products were assessed for two of Australia's largest wastewater treatment plants. The results showed that super critical water reactors and anaerobic digesters could be attractive pathway options, the latter providing significant savings in greenhouse gas emissions. Combining anaerobic digestion with oil extraction and the internal economies derived from cheap land and recycling of water and nutrients on-site could allow algal oil to be produced for less than US$1 per litre.

Biomarkers to Help Guide Management of Patients With Pulmonary Nodules

RATIONALE: Indeterminate pulmonary nodules are a common radiographic finding and require further evaluation because of the concern for lung cancer. OBJECTIVE: We developed an algorithm to assign patients to a low or high-risk category for lung cancer, based on a combination of serum biomarker levels and nodule size. METHODS: For the serum biomarker assay, we determined levels of carcinoembryonic antigen, alpha-1-antitrypsin and squamous cell carcinoma antigen. Serum data and nodule size from a training set of 509 patients with (n=298) and without (n=211) lung cancer were subjected to classification and regression tree and logistic regression analyses. Multiple models were developed and tested in an independent, blinded validation set for their ability to categorize patients with (n=203) or without (n=196) lung cancer as being low or high-risk for lung cancer. MEASUREMENTS AND MAIN RESULTS: In all models, a large percentage of individuals in the validation study with small nodules (< 1 cm) were assigned to the low-risk group, and a large percentage of individuals with large nodules (≥ 3 cm) were assigned to the high-risk group. In the validation study, the classification and regression tree algorithm had overall sensitivity, specificity, and positive and negative predictive values for determining lung cancer of 88%, 82%, 84%, 87%, respectively. The logistic regression model had overall sensitivity, specificity, and positive and negative predictive values of 80%, 89%, 89%, and 81%, respectively. CONCLUSION: Integration of biomarkers with lung nodule size has the potential to help guide the management of patients with indeterminate pulmonary nodules.

WNT10B/β-catenin Signalling Induces HMGA2 and Proliferation in Metastatic Triple-negative Breast Cancer

Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β-catenin signalling leading to up-regulation of HMGA2. Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients.

Reliable Identification of Deep Sulcal Pits: the Effects of Scan Session, Scanner, and Surface Extraction Tool

Sulcal pit analysis has been providing novel insights into brain function and development. The purpose of this study was to evaluate the reliability of sulcal pit extraction with respect to the effects of scan session, scanner, and surface extraction tool. Five subjects were scanned 4 times at 3 MRI centers and other 5 subjects were scanned 3 times at 2 MRI centers, including 1 test-retest session. Sulcal pits were extracted on the white matter surfaces reconstructed with both Montreal Neurological Institute and Freesurfer pipelines. We estimated similarity of the presence of sulcal pits having a maximum value of 1 and their spatial difference within the same subject. The tests showed high similarity of the sulcal pit presence and low spatial difference. The similarity was more than 0.90 and the spatial difference was less than 1.7 mm in most cases according to different scan sessions or scanners, and more than 0.85 and about 2.0 mm across surface extraction tools. The reliability of sulcal pit extraction was more affected by the image processing-related factors than the scan session or scanner factors. Moreover, the similarity of sulcal pit distribution appeared to be largely influenced by the presence or absence of the sulcal pits on the shallow and small folds. We suggest that our sulcal pit extraction from MRI is highly reliable and could be useful for clinical applications as an imaging biomarker.

Process Evaluations for Cluster-randomised Trials of Complex Interventions: a Proposed Framework for Design and Reporting

ABSTRACT: BACKGROUND: Process evaluations are recommended to open the 'black box' of complex interventions evaluated in trials, but there is limited guidance to help researchers design process evaluations. Much current literature on process evaluations of complex interventions focuses on qualitative methods, with less attention paid to quantitative methods. This discrepancy led us to develop our own framework for designing process evaluations of cluster-randomised controlled trials. METHODS: We reviewed recent theoretical and methodological literature and selected published process evaluations; these publications identified a need for structure to help design process evaluations. We drew upon this literature to develop a framework through iterative exchanges, and tested this against published evaluations. RESULTS: The developed framework presents a range of candidate approaches to understanding trial delivery, intervention implementation and the responses of targeted participants. We believe this framework will be useful to others designing process evaluations of complex intervention trials. We also propose key information that process evaluations could report to facilitate their identification and enhance their usefulness. CONCLUSION: There is no single best way to design and carry out a process evaluation. Researchers will be faced with choices about what questions to focus on and which methods to use. The most appropriate design depends on the purpose of the process evaluation; the framework aims to help researchers make explicit their choices of research questions and methods.Trial registration: Clinicaltrials.gov NCT01425502.

Coping and Health-related Quality of Life in Individuals with Heart Failure: An Integrative Review

OBJECTIVES: The purpose of this review is to examine and synthesize recent literature regarding the influence of coping on constructs contributing to health-related quality of life (HRQOL) in individuals with heart failure (HF). BACKGROUND: Poor HRQOL is associated with HF-related outcomes, including increased mortality and poor self-care. Coping may influence HRQOL. METHODS: An review of empirical literature was conducted utilizing CINAHL, PsycARTICLES, and PubMed computerized databases for a period of January 2000 to December 2011. RESULTS: Only studies investigating coping and physical and psychological HRQOL were found that met the inclusion criteria (N = 16), with 13 studies examining coping and psychological HRQOL, two studies examining coping and physical HRQOL, and one study investigating coping and physical and psychological HRQOL. CONCLUSIONS: Emotion-focused strategies are negatively associated with physical and psychological HRQOL, whereas, problem-focused strategies are positively associated with physical and psychological HRQOL in individuals with HF. Lack of experimental studies limits the inference of causality.

Validity of Proposed DSM-5 Diagnostic Criteria for Nicotine Use Disorder: Results from 734 Israeli Lifetime Smokers

BACKGROUND: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) proposes aligning nicotine use disorder (NUD) criteria with those for other substances, by including the current DSM fourth edition (DSM-IV) nicotine dependence (ND) criteria, three abuse criteria (neglect roles, hazardous use, interpersonal problems) and craving. Although NUD criteria indicate one latent trait, evidence is lacking on: (1) validity of each criterion; (2) validity of the criteria as a set; (3) comparative validity between DSM-5 NUD and DSM-IV ND criterion sets; and (4) NUD prevalence. Method Nicotine criteria (DSM-IV ND, abuse and craving) and external validators (e.g. smoking soon after awakening, number of cigarettes per day) were assessed with a structured interview in 734 lifetime smokers from an Israeli household sample. Regression analysis evaluated the association between validators and each criterion. Receiver operating characteristic analysis assessed the association of the validators with the DSM-5 NUD set (number of criteria endorsed) and tested whether DSM-5 or DSM-IV provided the most discriminating criterion set. Changes in prevalence were examined. RESULTS: Each DSM-5 NUD criterion was significantly associated with the validators, with strength of associations similar across the criteria. As a set, DSM-5 criteria were significantly associated with the validators, were significantly more discriminating than DSM-IV ND criteria, and led to increased prevalence of binary NUD (two or more criteria) over ND. CONCLUSIONS: All findings address previous concerns about the DSM-IV nicotine diagnosis and its criteria and support the proposed changes for DSM-5 NUD, which should result in improved diagnosis of nicotine disorders.

Problematic Internet Use and Associated Risks in a College Sample

OBJECTIVE: The Internet is commonly used among young adults; however, Internet use may become a problematic behavior. Past research has examined Internet behavior in young adults and its relationship to other behaviors and health issues, yet further research is needed to gain a more comprehensive understanding of this relationship. METHOD: A sample (n=2108) of college students (56.9% female) was examined using a self-report Internet survey concerning demographic characteristics, Internet use, health behaviors, psychosocial functioning, and psychiatric comorbidities. The IAT was used to determine levels of problematic Internet use (limited use (none or almost no use), mild use (typical user), moderate use (occasional problems) and severe use (frequent, serious problems)) and the MINI for testing for psychiatric problems. RESULTS: We found that 237 students (12.9%) met criteria for limited Internet use, 1502 (81.8%) for mild Internet use and 98 (5.3%) for moderate to severe Internet use. Variables significantly associated with greater frequency of Internet use included lower Grade Point Average (p=.006), less frequent exercise (p=.018), higher PHQ-9 scores (p<.0001) (indicative of greater depression symptoms) and higher Perceived Stress Scores (p<.0001). CONCLUSIONS: These data indicate that moderate to severe Internet use is associated with a range of psychosocial problems in young adults. More research is needed to better understand the relationship between Internet use and physical and mental health, as well as academic variables.

Effect of Barrett's Esophagus Surveillance on Esophageal Preservation, Tumor Stage, and Survival with Esophageal Adenocarcinoma

OBJECTIVES: Surveillance endoscopy has been recommended for patients with Barrett's esophagus; however, recent studies have questioned the importance owing to the new, lower, estimates of the rate of progression of Barrett's esophagus to cancer. The aim of the present study was to compare the tumor stage, survival, and frequency of esophageal preservation in patients who presented with progression of Barrett's esophagus within a surveillance program versus those who presented with prevalent disease. METHODS: A retrospective chart review was performed of all patients treated for high-grade dysplasia or esophageal adenocarcinoma from 2005 to 2010. The surveillance group included patients who had had at least 1 endoscopy and biopsy confirming intestinal metaplasia (with or without low-grade dysplasia) 6 months or more before the endoscopy showing progression. RESULTS: A total of 224 patients were included in the present study, 36 in the surveillance group and 188 in the prevalence group. The surveillance patients had significantly earlier stage tumors (P < .0001) and were more likely to undergo endoscopic therapy and to keep their esophagus (44% vs 11%, P < .0001) than were patients with prevalent disease. Furthermore, the patients in the surveillance group were less likely to have lymph node metastases and had better overall and disease-free survival. No patient with high-grade dysplasia or an intramucosal tumor died of cancer. CONCLUSIONS: Patients within a surveillance program for Barrett's esophagus had better survival and were less likely to have an esophagectomy than those who presented with prevalent disease. Treatment of intramucosal cancer was curative, and improved survival with surveillance was not secondary to lead time bias. Surveillance endoscopy remains important in patients with Barrett's esophagus.

Complete Mitochondrial Genomes from Four Subspecies of Common Chaffinch (Fringilla Coelebs): New Inferences About Mitochondrial Rate Heterogeneity, Neutral Theory, and Phylogenetic Relationships Within the Order Passeriformes

We describe whole mitochondrial genome sequences from four subspecies of the common chaffinch (Fringilla coelebs), and compare them to 31 publicly available mitochondrial genome sequences from other Passeriformes. Rates and patterns of mitochondrial gene evolution are analyzed at different taxonomic levels within this avian order, and evidence is adduced for and against the nearly neutral theory of molecular evolution and the role of positive selection in shaping genetic variation of this small but critical genome. We find evidence of mitochondrial rate heterogeneity in birds as in other vertebrates, likely due to differences in mutational pressure across the genome. Unlike in gadine fish and some of the human mitochondrial work we do not observe strong support for the nearly neutral theory of molecular evolution; instead evidence from molecular clocks, distribution of dN/dS ratios at different levels of the taxonomic hierarchy and in different lineages, McDonald-Kreitman tests within Fringillidae, and site-specific tests of selection within Passeriformes, all point to a role for positive selection, especially for the complex I NADH dehydrogenase genes. The protein-coding mitogenome phylogeny of the order Passeriformes is broadly consistent with previously-reported molecular findings, but provides support for a sister relationship between the superfamilies Muscicapoidea and Passeroidea on a short basal internode of the Passerida where relationships have been difficult to resolve. An unexpected placement of the Paridae (represented by Hume's groundpecker) within the Muscicapoidea was observed. Consistent with other molecular studies the mtDNA phylogeny reveals paraphyly within the Muscicapoidea and a sister relationship of Fringilla with Carduelis rather than Emberiza.

Sickle Cell Disease in Pregnancy: Maternal Complications in a Medicaid-Enrolled Population

Higher frequencies of pregnancy complications have been reported among women with sickle cell disease (SCD) compared with those without SCD; however, past studies are limited by small sample size, narrow geographic area, and use of hospital discharge data. We compared the prevalence of maternal complications among intrapartum and postpartum women with SCD to those without SCD in a large, geographically diverse sample. Data from the 2004-2010 Truven Health MarketScan(®) Multi-State Medicaid databases were used to assess the prevalence of maternal complications among intrapartum and postpartum women 15-44 years of age with and without SCD whose race was reported as black. The comparison group of women without SCD was further divided into those with chronic conditions associated with multi-organ failure and those without chronic conditions. Multivariable log-binomial regression models were used to calculate adjusted prevalence ratios for outcomes for women with SCD compared with women in the two comparison groups. Of the 335,348 black women with a delivery during 2004-2010, 1,526 had a diagnosis of SCD (0.5 %). Compared with women without SCD who had chronic conditions, women with SCD had higher prevalence of deep vein thrombosis, pulmonary embolism, obstetric shock, pneumonia, sepsis, postpartum infection, and transfusions. SCD was also positively associated with acute renal failure, cerebrovascular disorder, respiratory distress syndrome, eclampsia, postpartum hemorrhage, preterm birth, and ventilation when compared with women without SCD and chronic conditions. Overall, women with SCD have increased prevalence of pregnancy complications, even when compared with a group of women with similar risk for multi-organ failure.

Childhood Sexual Abuse and Early Substance Use in Adolescent Girls: The Role of Familial Influences

AIM: To assess the extent to which the association between childhood sexual abuse (CSA) and early use of alcohol, cigarettes, and cannabis in adolescent girls is mediated by risk factors that tend to cluster in families where CSA occurs. DESIGN: An abridged version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was administered by telephone. Participants: 3,761 female twins aged 18-29 (14.6% African American, 85.4% European American). MEASUREMENTS: CSA experiences and history of substance use were queried in the SSAGA-based interviews. FINDINGS: After controlling for familial influences on early substance use by including co-twin early use status in models, separate Cox proportional hazards regression analyses predicting onset of alcohol, cigarette, and cannabis use revealed a significant association with CSA. The effect was observed through age 19 for cigarettes and through age 21 for cannabis, but was limited to age 14 or younger for alcohol, with the most pronounced risk before age 10 (HR=4.59; CI: 1.96-10.74). CSA-associated risk for initiation of cigarette and cannabis use was also highest in the youngest age range, but the decline with age was much more gradual and the hazard ratios significantly lower (1.70; CI:1.13-2.56 for cigarettes and 2.34, CI:1.58-3.46 for cannabis). CONCLUSIONS: Childhood sexual abuse history is a distinct risk factor for use of cigarettes and cannabis, and a very strong predictor of early age at first drink.

The Function of ORAOV1/LTO1, a Gene That is Overexpressed Frequently in Cancer: Essential Roles in the Function and Biogenesis of the Ribosome

ORAOV1 (oral cancer overexpressed) is overexpressed in many solid tumours, making a key contribution to the development of cancer, but the cellular role of ORAOV1 is unknown. The yeast orthologue of this protein is encoded by the hitherto uncharacterized essential gene, YNL260c. Expression of ORAOV1 restores viability to yeast cells lacking YNL260c. Under nonpermissive conditions, our conditional mutants of YNL260c are defective in the maturation of the 60S ribosomal subunit, whereas maturation of the 40S subunit is unaffected. Also, initiation of translation is abrogated when YNL260c function is lost. YNL260c is indispensible for life in oxygen, but is nonessential under anaerobic conditions. Consequently, the toxic affects of aerobic metabolism on biogenesis and function of the ribosome are alleviated by YNL260c, hence, we rename YNL260c as LTO1; required for biogenesis of the large ribosomal subunit and initiation of translation in oxygen. Lto1 is found in a complex with Rli1/ABCE1, an ATP-binding cassette (ABC)-ATPase bearing N-terminal [4Fe-4S] clusters. Like Lto1, the Rli1/ABCE1 [4Fe-4S] clusters are not required for viability under anaerobic conditions, but are essential in the presence of oxygen. Loss of Lto1 function renders cells susceptible to hydroperoxide pro-oxidants, though this type of sensitivity is specific to certain types of oxidative stress as the lto1 mutants are not sensitive to an agent that oxidizes thiols. These findings reflect a functional interaction between Lto1 and the Rli1/ABCE1 [4Fe-4S] clusters, as part of a complex, which relieves the toxic effects of reactive oxygen species (ROS) on biogenesis and function of the ribosome. This complex also includes Yae1, which bridges the interaction between Lto1 and Rli1/ABCE1. Interactions between members of this complex were demonstrated both in vivo and in vitro. An increased generation of ROS is a feature shared by many cancers. The ORAOV1 complex could prevent ROS-induced ribosomal damage, explaining why overexpression of ORAOV1 is so common in solid tumours.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.604.

Sickle Erythrocytes Target Cytotoxics to Hypoxic Tumor Microvessels and Potentiate a Tumoricidal Response

Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs) but not normal RBCs (NLRBCs) to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP) induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2)O(2) and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.

Penile Implants Among Prisoners-A Cause for Concern?

We report the prevalence of penile implants among prisoners and determine the independent predictors for having penile implants. Questions on penile implants were included in the Sexual Health and Attitudes of Australian Prisoners (SHAAP) survey following concerns raised by prison health staff that increasing numbers of prisoners reported having penile implants while in prison.

BioSM: A Metabolomics Tool for Identifying Endogenous Mammalian Biochemical Structures in Chemical Structure Space

The structural identification of unknown biochemical compounds in complex biofluids continues to be a major challenge in metabolomics research. Using LC/MS there are currently two major options for solving this problem: searching small biochemical databases, which often do not contain the unknown of interest, or searching large chemical databases which include large numbers of non-biochemical compounds. Searching larger chemical databases (larger chemical space) increases the odds of identifying an unknown biochemical compound, but only if non-biochemical structures can be eliminated from consideration. In this paper we present BioSM; a cheminformatics tool that uses known endogenous mammalian biochemical compounds (as scaffolds) and graph matching methods to identify endogenous mammalian biochemical structures in chemical structure space. The results of a comprehensive set of empirical experiments suggest that BioSM identifies endogenous mammalian biochemical structures with high accuracy. In a leave-one-out cross validation experiment, BioSM correctly predicted 95% of 1,388 Kyoto Encyclopedia of Genes and Genomes (KEGG) compounds as endogenous mammalian biochemicals using 1,565 scaffolds. Analysis of two additional biological datasets containing 2,330 human metabolites (HMDB) and 2,416 plant secondary metabolites (KEGG) resulted in biochemical annotations of 89% and 72% of the compounds respectively. When a dataset of 3,895 drugs (DrugBank and USAN) was tested, 48% of these structures were predicted to be biochemical. However, when a set of synthetic chemical compounds (Chembridge and Chemsynthesis databases) were examined, only 29% of the 458,207 structures were predicted to be biochemical. Moreover, BioSM predicted that 34% of 883,199 randomly selected compounds from PubChem were biochemical. We then expanded the scaffold list to 3,927 biochemical compounds and reevaluated the above datasets to determine whether scaffold number influenced model performance. Although there were significant improvements in model sensitivity and specificity using the larger scaffold list, the dataset comparison results were very similar. These results suggest that additional biochemical scaffolds will not further improve our representation of biochemical structure space and that the model is reasonably robust. BioSM provides a qualitative (yes/no) and quantitative (ranking) method for endogenous mammalian biochemical annotation of chemical space, and thus will be useful in the identification of unknown biochemical structures in metabolomics. BioSM is freely available at http://metabolomics.pharm.uconn.edu.

Etravirine in CSF is Highly Protein Bound

OBJECTIVES: Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α(1)-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC(50)) for wild-type HIV (0.9 ng/mL). METHODS: Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8-2000 (plasma) and 0.78-200 (CSF) ng/mL. RESULTS: Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC(50) in any of the specimens. CONCLUSIONS: Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.

National Risk Prediction Model for Elective Abdominal Aortic Aneurysm Repair

BACKGROUND: Mortality results for elective abdominal aortic aneurysm (AAA) repair are published by the Vascular Society of Great Britain and Ireland. These mortality results are not currently risk-adjusted. The objective of this study was to develop a national risk prediction model for elective AAA repair. METHODS: Data for consecutive patients undergoing elective AAA repair from the National Vascular Database between April 2008 and March 2011 were analysed. Multiple logistic regression and backwards model selection were used for model development. The study outcome measure was in-hospital mortality. Model calibration and discrimination were assessed for all AAA repairs, and separately for open repair and endovascular aneurysm repair (EVAR) subgroups. RESULTS: There were 312 in-hospital deaths among 11 423 AAA repairs (2·7 (95 per cent confidence interval (c.i.) 2·4 to 3·0) per cent): 230 after 4940 open AAA repairs (4·7 (4·1 to 5·3) per cent) and 82 after 6483 EVARs (1·3 (1·0 to 1·6) per cent). Variables associated with in-hospital death included in the final model were: open repair, increasing age, female sex, serum creatinine level over 120 µmol/l, cardiac disease, abnormal electrocardiogram, previous aortic surgery or stent, abnormal white cell count, abnormal serum sodium level, AAA diameter and American Society of Anesthesiologists fitness grade. The area under the receiver operating characteristic (ROC) curve was 0·781 (95 per cent c.i. 0·756 to 0·806) with a bias-corrected value of 0·774. Model calibration was good (P = 0·963) based on the Hosmer-Lemeshow goodness-of-fit test, (bias-corrected) calibration curves, risk group assessment and recalibration regression. CONCLUSION: This multivariable model for elective AAA repair can be used to risk-adjust outcome analyses and provide patient-specific estimates of in-hospital mortality risk for open AAA repair or EVAR. Copyright © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Investigation of the Fate of Trifluralin in Shrimp

Juvenile Pacific white shrimp (Litopenaeus vannamei) were exposed to trifluralin at 0.1 and 0.01 mg•L-1 for 72 hours under controlled conditions. Samples of shrimp and tank water were collected at intervals up to 48 days after exposure. Analysis of the shrimp tissues by Gas Chromatography-Mass Spectrometry (GC-MS), and ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-qToF-MS) in combination with profiling and metabolite ID software (Agilent MET-ID and Mass Profiler Professional) detected the presence of parent trifluralin together with two main transformation products (TPs), 2-ethyl-7-nitro-5-(trifluoromethyl)benzimidazole (TP1) and 2-amino-6-nitro-4-(trifluoromethyl)phenyl)propylamine (TP2). The highest concentration of trifluralin, determined by GC-MS was 120 µg•kg-1 at zero day withdrawal. Residues of trifluralin (CCα= 0.25 µg•kg-1, CCβ=0.42 µg•kg-1) were detectable for up to 7 days after exposure. Similarly, the highest concentrations of TP1 and TP 2, determined by Liquid Chromatography- Mass Spectrometry/Mass Spectrometry (LC-MS/MS) were 14 and 18 µg•kg-1 respectively. Residues of TP1 (CCα= 0.05 µg•kg-1, CCβ=0.09 µg•kg-1) and TP2 (CCα= 0.1 µg•kg-1, CCβ = 0.17 µg•kg-1) were detectable for up to 4 and 24 withdrawal days respectively.

Does Caregiver Well-being Predict Stroke Survivor Depressive Symptoms? A Mediation Analysis

Background and Purpose: Studies suggest that family caregiver well-being (ie, depressive symptoms and life satisfaction) may affect stroke survivor depressive symptoms. We used mediation analysis to assess whether caregiver well-being might be a factor explaining stroke survivor depressive symptoms, after controlling for demographic factors and stroke survivor impairments and problems. Methods: Caregiver/stroke participant dyads (N = 146) completed measures of stroke survivor impairments and problems and depressive symptoms and caregiver depressive symptoms and life satisfaction. Mediation analysis was used to examine whether caregiver well-being mediated the relationship between stroke survivor impairments and problems and stroke survivor depressive symptoms. Results: As expected, more stroke survivor problems and impairments were associated with higher levels of stroke survivor depressive symptoms (P < .0001). After controlling for demographic factors, we found that this relationship was partially mediated by caregiver life satisfaction (29.29%) and caregiver depressive symptoms (32.95%). Although these measures combined to account for 40.50% of the relationship between survivor problems and impairments and depressive symptoms, the direct effect remained significant. Conclusions: Findings indicate that stroke survivor impairments and problems may affect family caregivers and stroke survivors and a high level of caregiver distress may result in poorer outcomes for stroke survivors. Results highlight the likely importance of intervening with both stroke survivors and family caregivers to optimize recovery after stroke.

Effect of Pressure Support Vs Unassisted Breathing Through a Tracheostomy Collar on Weaning Duration in Patients Requiring Prolonged Mechanical Ventilation: A Randomized Trial

IMPORTANCE Patients requiring prolonged mechanical ventilation (>21 days) are commonly weaned at long-term acute care hospitals (LTACHs). The most effective method of weaning such patients has not been investigated. OBJECTIVE To compare weaning duration with pressure support vs unassisted breathing through a tracheostomy collar in patients transferred to an LTACH for weaning from prolonged ventilation. DESIGN, SETTING, AND PARTICIPANTS Between 2000 and 2010, a randomized study was conducted in tracheotomized patients transferred to a single LTACH for weaning from prolonged ventilation. Of 500 patients who underwent a 5-day screening procedure, 316 did not tolerate the procedure and were randomly assigned to receive weaning with pressure support (n = 155) or a tracheostomy collar (n = 161). Survival at 6- and 12-month time points was also determined. MAIN OUTCOME MEASURE Primary outcome was weaning duration. Secondary outcome was survival at 6 and 12 months after enrollment. RESULTS Of 316 patients, 4 were withdrawn and not included in analysis. Of 152 patients in the pressure-support group, 68 (44.7%) were weaned; 22 (14.5%) died. Of 160 patients in the tracheostomy collar group, 85 (53.1%) were weaned; 16 (10.0%) died. Median weaning time was shorter with tracheostomy collar use (15 days; interquartile range [IQR], 8-25) than with pressure support (19 days; IQR, 12-31), P = .004. The hazard ratio (HR) for successful weaning rate was higher with tracheostomy collar use than with pressure support (HR, 1.43; 95% CI, 1.03-1.98; P = .033) after adjusting for baseline clinical covariates. Use of the tracheostomy collar achieved faster weaning than did pressure support among patients who did not tolerate the screening procedure between 12 and 120 hours (HR, 3.33; 95% CI, 1.44-7.70; P = .005), whereas weaning time was equivalent with the 2 methods in patients who did not tolerate the screening procedure within 0 to 12 hours. Mortality was equivalent in the pressure-support and tracheostomy collar groups at 6 months (55.92% vs 51.25%; 4.67% difference, 95% CI, -6.4% to 15.7%) and at 12 months (66.45% vs 60.00%; 6.45% difference, 95% CI, -4.2% to 17.1%). CONCLUSION AND RELEVANCE Among patients requiring prolonged mechanical ventilation and treated at a single long-term care facility, unassisted breathing through a tracheostomy, compared with pressure support, resulted in shorter median weaning time, although weaning mode had no effect on survival at 6 and 12 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01541462.

Age-dependent Molecular Alterations in the Autophagy Pathway in HIVE Patients and in a Gp120 Tg Mouse Model: Reversal with Beclin-1 Gene Transfer

Aged (>50 years old) human immunodeficiency virus (HIV) patients are the fastest-growing segment of the HIV-infected population in the USA and despite antiretroviral therapy, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group. Autophagy is an intracellular clearance pathway for aggregated proteins and aged organelles; dysregulation of autophagy is implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, and HAND. Here, we hypothesized that dysregulated autophagy may contribute to aging-related neuropathology in HIV-infected individuals. To explore this possibility, we surveyed autophagy marker levels in postmortem brain samples from a cohort of well-characterized <50 years old (young) and >50 years old (aged) HIV+ and HIV encephalitis (HIVE) patients. Detailed clinical and neuropathological data showed the young and aged HIVE patients had higher viral load, increased neuroinflammation and elevated neurodegeneration; however, aged HIVE postmortem brain tissues showed the most severe neurodegenerative pathology. Interestingly, young HIVE patients displayed an increase in beclin-1, cathepsin-D and light chain (LC)3, but these autophagy markers were reduced in aged HIVE cases compared to age-matched HIV+ donors. Similar alterations in autophagy markers were observed in aged gp120 transgenic (tg) mice; beclin-1 and LC3 were decreased in aged gp120 tg mice while mTor levels were increased. Lentivirus-mediated beclin-1 gene transfer, that is known to activate autophagy pathways, increased beclin-1, LC3, and microtubule-associated protein 2 expression while reducing glial fibrillary acidic protein and Iba1 expression in aged gp120 tg mice. These data indicate differential alterations in the autophagy pathway in young versus aged HIVE patients and that autophagy reactivation may ameliorate the neurodegenerative phenotype in these patients.

Seroprevalence of Dengue in American Samoa, 2010

Lack of Non-Specific Protection Against All-Cause, Non-Rotavirus Gastroenteritis by Vaccination with Orally Administered Rotavirus Vaccine

OBJECTIVES:: Acute gastroenteritis (AGE) is recognized as a global, common threat to child survival, especially in developing countries. Rotavirus, in particular, has been implicated as a leading cause of severe AGE; however, there are numerous other pathogens that also cause AGE. Several studies have demonstrated that oral vaccination against rotavirus has generated the unanticipated benefit of protecting against AGE caused by non-rotavirus pathogens. METHODS:: Safety and efficacy of the pentavalent bovine-human reassortant rotavirus vaccine (PRV, RotaTeq™, Merck & Co., Inc., Whitehouse Station, NJ) were studied in multiple populations including children of the Navajo and White Mountain Apache (N/WMA) tribes in the southwest United States. Stool specimens were collected from children with AGE and tested for rotavirus using an enzyme immunoassay. Analyses were conducted to detect the presence or absence of a vaccine-effect on incidence, severity and duration of AGE in which rotavirus was not detected. RESULTS:: The majority of AGE (N = 558: 472 non-rotavirus vs. 86 rotavirus) occurred between August 2002 and March 2004 among children ranging from ages 4-23 months. The incidence of non-rotavirus AGE was similar by vaccine groups with an incidence rate ratio of 1.07 (IRR = vaccinated/unvaccinated, 95% CI: 0.89-1.29). The hazards of 1, 2, 3 or any AGE in which rotavirus was not detected differed little by vaccination status (p > 0.05). Duration of symptoms and severity of non-rotavirus AGE were similar by vaccine group. CONCLUSIONS:: There was no vaccine effect on frequency or severity of non-rotavirus AGE.

Fluorescence Amplified Fragment Length Polymorphism Compared to Pulsed Field Gel Electrophoresis for Listeria Monocytogenes Sub-typing

ABSTRACT: BACKGROUND: Listeriosis is a severe infection which mainly affects pregnant women, neonates and immuno-compromised adults. ANSES's Laboratory for Food safety has been the European Union Reference Laboratory (EURL) for L. monocytogenes in the food chain since 2006. Pulsed Field Gel Electrophoresis (PFGE) is routinely used in the EURL for the surveillance of L. monocytogenes isolated from foods, animals and the environment. One of the main EURL activities is to evaluate alternative molecular subtyping methods to PFGE, and integrate their use within the National Reference Laboratories (NRL) network. Since 2008, the United Kingdom (UK)-NRL for L. monocytogenes at the Health Protection Agency (HPA), London, has used fluorescent Amplified Fragment Length Polymorphism (fAFLP) for the routine surveillance of L. monocytogenes isolated from human clinical cases, food and food processing environments in the UK. This study compares fAFLP with PFGE for subtyping L. monocytogenes. RESULTS: A panel of 109 L. monocytogenes isolates from either human cases of listeriosis, foods, food processing environments and animals were used for the comparative evaluation. Among these, 2 strains were tested from duplicate culture by both methods. The panel also included field isolates, isolates associated with outbreaks or sporadic cases and reference strains. The two strains tested in duplicate displayed the same fAFLP and PFGE types. Strains known to be epidemiologically associated with one another were found to have unique PFGE and fAFLP types. FAFLP and PFGE divided the strains into 76 and 82 distinct profiles, or types, respectively. The discriminatory index calculated was 0.993 and 0.996 for fAFLP and PFGE, respectively. CONCLUSIONS: The discriminatory ability of fAFLP was similar to that of PFGE for the subtyping of L. monocytogenes isolates. As a less labour intensive technique fAFLP may be a better method to use than PFGE in investigating outbreaks of human listeriosis and tracking the source of contamination in food processing facilities in real time.

Reply

Multidisciplinary Staged Surgical Management of Bifrontal Meningoencephalocele with Long-term Follow-up

The authors report on an infant with a bifrontal encephalocele that was associated with multisuture craniosynostosis, spasticity, and a progressively severe epilepsy. They describe the initial presentation, genetic screening results, staged multidisciplinary operative plans, clinical course, complications, and long-term surgical and developmental follow-up. To their knowledge, the comprehensive surgical management of this type of complicated congenital cranial anomaly has not been previously described. Surgical management was staged and multidisciplinary and required careful attention to all 3 components of the condition: 1) hydrocephalus, 2) frontal meningoencephalocele, and 3) epilepsy.

Global NeuroAIDS Roundtable

In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the "Global NeuroAIDS Roundtable" in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research. At the "Global NeuroAIDS Roundtable", presentations of preliminary research indicated that HIV-associated neurocognitive impairment is prevalent in all countries examined regardless of which HIV clade is present in the region. The only clear-cut difference between HIV-1 clades was in relation to subtypes A and D in Uganda. However, a key point that emerged from the discussions was that there is an urgent need to standardize neurocognitive assessment methodologies across the globe before definitive conclusions can be drawn regarding the relationship between HIV clade diversity and neuropathogenesis. Future research directions were also discussed at the roundtable with particular emphasis on the potential of viral and host factor molecular interactions to impact the pathophysiology of HIV-associated neurocognitive disorders (HAND) from a global perspective.

Dopaminergic Foundations of Schizotypy As Measured by the German Version of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE)-a Suitable Endophenotype of Schizophrenia

The concept of schizotypy or "psychosis proneness" captures individual differences in perceptual, cognitive, and affective experiences that may relate to a range of psychotic disorders. The concept is an important way to assess the contribution of pre-existing psychological and genetically based biological features to the development of illnesses such as schizophrenia (so called endophenotypes). The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) is a widely used multi-dimensional measure of the construct and consists of four scales which mirror several groups of psychotic symptoms: Unusual Experiences (UnEx; positive symptoms), Cognitive Disorganization (CogDis; cognitive symptoms), Introvertive Anhedonia (IntAn; negative symptoms), and Impulsive Nonconformity (ImpNon; impulsive and antisocial symptoms). For the purpose of evaluating the suitability of schizotypy as an endophenotype of schizophrenia the current version of the O-LIFE was translated into German: its psychometric properties (including re-test reliability and construct validity) were examined in a large sample (n > 1200) and compared to those of the English original. The German version was both highly reliable and consistent with the original. The study aimed to show that schizotypy as measured by the O-LIFE can indeed be regarded as an endophenotype of schizophrenia in terms of genetic associations regarding relevant dopamine-related candidate polymorphisms of schizotypy [i.e., Val(158)Met-polymorphism of the COMT gene, uVNTR of the MAOA gene, Taq1A-polymorphism of the DRD2 gene, VNTR of the SLC6A3 (DAT) gene]. We also wanted to compare the genetic associations of the O-LIFE to those published using other operationalizations of schizotypy. Our results show a large number of significant associations and borderline-significant trends between the O-LIFE sub-scales and a range of genes, thereby supporting using the O-LIFE in the search for endophenotypic markers.

Clinical and Neurocognitive Markers of Suicidality in Young Adults

BACKGROUND: Suicide represents a leading cause of death in young people, yet relatively little is known regarding the neurobiological sequelae of preceding suicidal thoughts and behaviours. Although some studies have reported cognitive deficits associated with suicidality, very few studies have been undertaken in young people, especially from non-clinical contexts. AIMS: To quantify cognitive deficits associated with suicidality using a representative sample of young people, recruited from the general community using media advertisements. METHOD: 304 adults (18-29 years) undertook the Mini-International Neuropsychiatric Inventory (MINI) suicidality module, along with Cambridge Gamble and Stop-Signal tasks. Suicidality was defined as non-zero MINI scores (broad definition) and a past history of suicide attempt(s) (narrow definition). Clinical features and cognitive performance were compared between those with and those without suicidality, using analysis of variance/chi-square; findings were further explored using linear regression. RESULTS: Suicidality was relatively common (broad definition: 14.8%; narrow definition: 5.3%) in young people and was associated with impaired decision-making on the Cambridge Gamble task (p < 0.05, Bonferroni corrected at the analysis level of each suicidality definition). Linear regression demonstrated that decision-making performance was associated with a significant incremental benefit with respect to predicting suicidality, over and above the utility of demographic and clinical variables considered (p < 0.05 uncorrected). CONCLUSIONS: Impaired decision-making exists in young people with suicidality, and may thereby predispose towards a range of suicidal thoughts and behaviours. Further work is needed to clarify the chain of progression from such thoughts/behaviours, which are relatively common, through to actual suicide, which is not.

Waiting
simple hit counter