Menopausal hormone therapy and risk of gastrointestinal cancer: nested case-control study within a prospective cohort, and meta-analysis.
Use of menopausal hormone therapy (HT) has been associated with reduced risk of colorectal cancer; evidence for its effect on other gastrointestinal cancers is limited. We conducted a nested case-control study within a UK cohort, and meta-analyses combining our results with those from published studies. Our study included women aged 50+ in the UK General Practice Research Database (GPRD): 1,054 with oesophageal, 750 with gastric and 4,708 with colorectal cancer, and 5 age- and practice-matched controls per case. Relative risks (RRs) and 95% confidence intervals (CIs) for cancer in relation to prospectively-recorded HT prescriptions were estimated by conditional logistic regression. Women prescribed HT had a reduced risk of oesophageal cancer (adjusted RR for 1+ vs. no HT prescriptions, 0.68, 95% CI 0.53-0.88; p = 0.004), gastric cancer (0.75, 0.54-1.05; p = 0.1) and colorectal cancer (0.81, 0.73-0.90; p < 0.001). There were no significant differences in cancer risk by HT type, estimated duration of HT use or between past and current users. In meta-analyses, risks for ever vs. never use of HT were significantly reduced for all three cancers (summary RR for oesophageal cancer, 0.68, 0.55-0.84, p < 0.001; for gastric cancer, 0.78, 0.65-0.94, p = 0.008; for colorectal cancer, 0.84, 0.81-0.88, p < 0.001). In high-income countries, estimated incidence over 5 years of these three cancers combined in women aged 50-64 was 2.9/1,000 in HT users and 3.6/1,000 in never users. The absolute reduction in risk of these cancers in HT users is small compared to the HT-associated increased risk of breast cancer.


Feasibility of surgical randomised controlled trials with a placebo arm: a systematic review.
To find evidence, either corroborating or refuting, for many persisting beliefs regarding the feasibility of carrying out surgical randomised controlled trials with a placebo arm, with emphasis on the challenges related to recruitment, funding, anaesthesia or blinding. Systematic review. The analysis involved studies published between 1959 and 2014 that were identified during an earlier systematic review of benefits and harms of placebo-controlled surgical trials published in 2014. 63 trials were included in the review. The main problem reported in many trials was a very slow recruitment rate, mainly due to the difficulty in finding eligible patients. Existing placebo trials were funded equally often from commercial and non-commercial sources. General anaesthesia or sedation was used in 41% of studies. Among the reviewed trials, 81% were double-blinded, and 19% were single-blinded. Across the reviewed trials, 96% (range 50-100%) of randomised patients completed the study. The withdrawal rate during the study was similar in the surgical and in the placebo groups. This review demonstrated that placebo-controlled surgical trials are feasible, at least for procedures with a lower level of invasiveness, but also that recruitment is difficult. Many of the presumed challenges to undertaking such trials, for example, funding, anaesthesia or blinding of patients and assessors, were not reported as obstacles to completion in any of the reviewed trials.


Predictors of stroke in patients with impaired glucose tolerance: results from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial.
Risk factors for stroke are well-established in general populations but sparsely studied in individuals with impaired glucose tolerance. We identified predictors of stroke among participants with impaired glucose tolerance in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Cox proportional-hazard regression models were constructed using baseline variables, including the 2 medications studied, valsartan and nateglinide. Among 9306 participants, 237 experienced a stroke over 6.4 years. Predictors of stroke included classical risk factors such as existing cerebrovascular and coronary heart disease, higher pulse pressure, higher low-density lipoprotein cholesterol, older age, and atrial fibrillation. Other factors, including previous venous thromboembolism, higher waist circumference, lower estimated glomerular filtration rate, lower heart rate, and lower body mass index, provided additional important predictive information, yielding a C-index of 0.72. Glycemic measures were not predictive of stroke. Variables associated with stroke were similar in participants with no prior history of cerebrovascular disease at baseline. The most powerful predictors of stroke in patients with impaired glucose tolerance included a combination of established risk factors and novel variables, such as previous venous thromboembolism and elevated waist circumference, allowing moderately effective identification of high-risk individuals.


Reward associations magnify memory-based biases on perception.
Long-term spatial contextual memories are a rich source of predictions about the likely locations of relevant objects in the environment and should enable tuning of neural processing of unfolding events to optimize perception and action. Of particular importance is whether and how the reward outcome of past events can impact perception. We combined behavioral measures with recordings of brain activity with high temporal resolution to test whether the previous reward outcome associated with a memory could modulate the impact of memory-based biases on perception, and if so, the level(s) at which visual neural processing is biased by reward-associated memory-guided attention. Data showed that past rewards potentiate the effects of spatial memories upon the discrimination of target objects embedded within complex scenes starting from early perceptual stages. We show that a single reward outcome of learning impacts on how we perceive events in our complex environments.


Chronic reduction of plasma free fatty acid improves mitochondrial function and whole-body insulin sensitivity in obese and type 2 diabetic individuals.
Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) (1)H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P < 0.001). Mitochondrial ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible.


Canadian hereditary angioedema guideline.
Hereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.


Role of prostanoids in gastrointestinal cancer.
Chronic inflammation is a risk factor for gastrointestinal cancer and other diseases. Most studies have focused on cytokines and chemokines as mediators connecting chronic inflammation to cancer, whereas the involvement of lipid mediators, including prostanoids, has not been extensively investigated. Prostanoids are among the earliest signaling molecules released in response to inflammation. Multiple lines of evidence suggest that prostanoids are involved in gastrointestinal cancer. In this Review, we discuss how prostanoids impact gastrointestinal cancer development. In particular, we highlight recent advances in our understanding of how prostaglandin E2 induces the immunosuppressive microenvironment in gastrointestinal cancers.


Influence of attentional demands on the processing of emotional facial expressions in the amygdala.
Recent studies have cast doubts on the appealing idea that the processing of threat-related stimuli in the amygdala is unconstrained by the availability of attentional resources. However, these studies exclusively used face stimuli presented at fixation and it is unclear whether their conclusion can apply to peripheral face stimuli. Thus, we designed an experiment in which we manipulated the perceptual attentional load of the task used to divert attention from peripheral face stimuli: participants were presented simultaneously with four peripheral pictures (two faces, either both neutral or both fearful, and two houses) that were slightly tilted, and had to match two of these pictures (defined by their position on the screen) either for orientation of the tilt or for identity. The identity task was confirmed to involve greater attentional load than the orientation task by differences in accuracy, reaction times, subsequent face recognition performance, and patterns of activation in several cortical regions. In the orientation task, ignored fearful faces led to stronger activation in the right amygdala than ignored neutral faces. However, this differential response was abolished when participants performed the difficult identity-matching task. Thus, emotional processing of peripheral faces in the amygdala also appears to depend on the available perceptual attentional resources.


Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity.
This article reviews the clinical manifestations of mitochondrial toxicity associated with the use of nucleoside analog reverse transcriptase inhibitors (NRTIs) and outlines strategies to manage these sequelae. NRTIs are the key components of the antiretroviral combinations used in the management of patients infected with HIV. The available NRTIs differ in their convenience of administration, frequency of dosing, resistance profiles, and side-effect profiles. NRTIs act as competitive inhibitors of the RNA/DNA polymerase reverse transcriptase of HIV and cause chain termination in the growing viral DNA chain. Many of the important and treatment-limiting side effects of NRTIs may be related to the effect of these agents on human DNA polymerases, in particular, mitochondrial DNA polymerase gamma. Depletion of mitochondrial DNA during chronic NRTI therapy may lead to cellular respiratory dysfunction and generalized and tissue- and drug-specific toxicities, including myopathy, peripheral neuropathy, and lactic acidosis. Recently, it has been proposed that the fat redistribution syndrome, or lipodystrophy, reported during chronic antiretroviral therapy is a manifestation of the differential impact of at least some NRTIs on peripheral and visceral adipocytes. Management of potential mitochondrial toxicity during NRTI therapy remains a challenge. A range of nutritional supplements, both as treatments and prophylaxes, have been proposed, and some have been investigated in vitro; no in vivo studies have yet been conducted. The information in this review was compiled using MEDLINE and AIDSLINE searches of the literature, including conference abstracts. At present, interruption of NRTI therapy or substitution of the probable causative agent with alternative NRTIs that appear to be better tolerated represents the mainstay of management for mitochondrial toxicity and its clinical manifestations.


Proliferation potential of spinal meningiomas.
The goal of the present study was to quantitatively assess the proliferation index and progesterone receptor status of spinal versus intracranial meningiomas and to determine if these biological indicators can describe the clinical behavior of these tumors. This information could provide the spinal surgeon with important additional information concerning surgical management and follow-up recommendations for the individual patient. The study group consisted of 26 patients with spinal and 241 patients with intracranial meningiomas. Patients with atypical or anaplastic tumors as well as with neurofibromatosis type II were excluded from the study. Furthermore both groups were matched according to age, sex and resection grade (total resection according the Simpson classification). Proliferation index (Ki-67 Labelling index [LI]) and progesterone-receptor (PR) status of spinal and intracranial meningiomas were compared. Clinical charts including surgical and histological records and imaging studies were reviewed. Correlations with histological subtype, intratumoral calcifications, tumor vascularity and recurrence-free survival were analyzed. Compared to the spinal group with a mean Ki-67 LI of 2.48% and a positive PR-status of 46%, proliferation rates of intracranial meningiomas were significant higher (Ki-67 LI 3.6%; P-value 0.041). No significant difference in PR status was seen (spinal PR-status 46%, P-value 0.261). Furthermore spinal meningiomas were less vascularized and showed less intratumoral calcifications. Time to recurrence was similar in spinal and intracranial tumors. Spinal and intracranial meningiomas differ in their proliferation activity but not in their PR status. However, despite lower proliferation rates, time to recurrence in spinal and cranial meningiomas is comparable in totally excised tumors. Further studies are needed to determine the role of other biological indicators in spinal meningioma growth and response to therapy.


Brain damage treated with non proven intensive training 2003-2011: a Norwegian cost analysis.
There has been an increased request for intensive training and rehabilitation of patients with brain damage in Norway. These programs are demanding with regard to personnel, travelling, time and economic resources. We aimed to indicate cost and gain to make these programs cost-effective. A retrospective study included all patients referred to the Northern Norway Regional Health Authority (NNRHA) trust during the nine years period 2003-2011. All referrals to the NNRHA trust for the economic coverage of foreign based rehabilitation or habilitation programs (The Advanced Bio-Mechanical Rehabilitation (ABR), Institutes of Achievement of Human Potential program (IAHP) (Doman Method), Family Hope Center (FHC) program and the Kozijavkin Method) were included. 17 patients were detected and 15 fulfilled the inclusion criteria for funding. Median age was 8 years (1-31 years). Cost from the specialist health care point of view was calculated. A cut-off limit of €57,000/quality adjusted life year (QALY) and a 4% discount rate was employed. The undiscounted cost per patient enrolled was calculated €133,210 (discounted €121,348). To make these therapies cost effective, a total of at least 2.13 QALYs (2.34 undiscounted QALYs) must be gained per patient enrolled. Such a gain could not be indicated and we doubt it is achievable. Non-proven intensive training programs for patients with brain damage are costly. As long as their effect has not been documented, health care services should not spend resources on these programs outside clinical trials.


When the face reveals what words do not: facial expressions of emotion, smiling, and the willingness to disclose childhood sexual abuse.
For survivors of childhood sexual abuse (CSA), verbal disclosure is often complex and painful. The authors examined the voluntary disclosure-nondisclosure of CSA in relation to nonverbal expressions of emotion in the face. Consistent with hypotheses derived from recent theorizing about the moral nature of emotion, CSA survivors who did not voluntarily disclose CSA showed greater facial expressions of shame, whereas CSA survivors who voluntarily disclosed CSA expressed greater disgust. Expressions of disgust also signaled sexual abuse accompanied by violence. Consistent with recent theorizing about smiling behavior, CSA nondisclosers made more polite smiles, whereas nonabused participants expressed greater genuine positive emotion. Discussion addressed the implications of these findings for the study of disclosure of traumatic events, facial expression, and the links between morality and emotion.


Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis.
We investigated whether citrullinated tenascin-C (cTNC), an extracellular matrix protein expressed at high levels in the joints of patients with rheumatoid arthritis (RA), is a target for the autoantibodies in RA. Citrullinated sites were mapped by mass spectrometry in the fibrinogen-like globe (FBG) domain of tenascin-C treated with peptidylarginine deiminases (PAD) 2 and 4. Antibodies to cyclic peptides containing citrullinated sites were screened in sera from patients with RA by ELISA. Potential cross-reactivity with well-established anticitrullinated protein antibody (ACPA) epitopes was tested by inhibition assays. The autoantibody response to one immunodominant cTNC peptide was then analysed in 101 pre-RA sera (median 7 years before onset) and two large independent RA cohorts. Nine arginine residues within FBG were citrullinated by PAD2 and PAD4. Two immunodominant peptides cTNC1 (VFLRRKNG-cit-ENFYQNW) and cTNC5 (EHSIQFAEMKL-cit-PSNF-cit-NLEG-cit-cit-KR) were identified. Antibodies to both showed limited cross-reactivity with ACPA epitopes from α-enolase, vimentin and fibrinogen, and no reactivity with citrullinated fibrinogen peptides sharing sequence homology with FBG. cTNC5 antibodies were detected in 18% of pre-RA sera, and in 47% of 1985 Swedish patients with RA and 51% of 287 North American patients with RA. The specificity was 98% compared with 160 healthy controls and 330 patients with osteoarthritis. There are multiple citrullination sites in the FBG domain of tenascin-C. Among these, one epitope is recognised by autoantibodies that are detected years before disease onset, and which may serve as a useful biomarker to identify ACPA-positive patients with high sensitivity and specificity in established disease.


Neocortical excitation/inhibition balance in information processing and social dysfunction.
Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.


Vaccines for preventing influenza in the elderly.
Vaccines have been the main global weapon to minimise the impact of influenza in the elderly for the last four decades and are recommended worldwide for individuals aged 65 years or older. The primary goal of influenza vaccination in the elderly is to reduce the risk of complications among persons who are most vulnerable. To assess the effectiveness of vaccines in preventing influenza, influenza-like illness (ILI), hospital admissions, complications and mortality in the elderly. To identify and appraise comparative studies evaluating the effects of influenza vaccines in the elderly. To document types and frequency of adverse effects associated with influenza vaccines in the elderly. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register (The Cochrane Library 2009, issue 4); MEDLINE (January 1966 to October Week 1 2009); EMBASE (1974 to October 2009) and Web of Science (1974 to October 2009). Randomised controlled trials (RCTs), quasi-RCTs, cohort and case-control studies assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. Any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo or with no intervention was considered. We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching. We further stratified by co-administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines. We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications and deaths. We included 75 studies. Overall we identified 100 data sets. We identified one RCT assessing efficacy and effectiveness. Although this seemed to show an effect against influenza symptoms it was underpowered to detect any effect on complications (1348 participants). The remainder of our evidence base included non-RCTs. Due to the general low quality of non-RCTs and the likely presence of biases, which make interpretation of these data difficult and any firm conclusions potentially misleading, we were unable to reach clear conclusions about the effects of the vaccines in the elderly. The available evidence is of poor quality and provides no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older. To resolve the uncertainty, an adequately powered publicly-funded randomised, placebo-controlled trial run over several seasons should be undertaken.


Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds.
The RAS gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein-protein interactions. We have refined crystallization conditions for KRAS169Q61H-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein-protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein-protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds). Unlike the Abd series of RAS binders, PPIN-1 and PPIN-2 compounds were not competed by the inhibitory anti-RAS intracellular antibody fragment and did not show any RAS-effector inhibition properties. By fusing the common, anchoring part from the two new compounds with the inhibitory substituents of the Abd series, we have created a set of compounds that inhibit RAS-effector interactions with increased potency. These fused compounds add to the growing catalog of RAS protein-protein inhibitors and show that building a chemical series by crossing over two chemical series is a strategy to create RAS-binding small molecules.


SIRT3 reverses aging-associated degeneration.
Despite recent controversy about their function in some organisms, sirtuins are thought to play evolutionarily conserved roles in lifespan extension. Whether sirtuins can reverse aging-associated degeneration is unknown. Tissue-specific stem cells persist throughout the entire lifespan to repair and maintain tissues, but their self-renewal and differentiation potential become dysregulated with aging. We show that SIRT3, a mammalian sirtuin that regulates the global acetylation landscape of mitochondrial proteins and reduces oxidative stress, is highly enriched in hematopoietic stem cells (HSCs) where it regulates a stress response. SIRT3 is dispensable for HSC maintenance and tissue homeostasis at a young age under homeostatic conditions but is essential under stress or at an old age. Importantly, SIRT3 is suppressed with aging, and SIRT3 upregulation in aged HSCs improves their regenerative capacity. Our study illuminates the plasticity of mitochondrial homeostasis controlling stem cell and tissue maintenance during the aging process and shows that aging-associated degeneration can be reversed by a sirtuin.


Identification of valid housekeeping genes for quantitative RT-PCR analysis of cardiosphere-derived cells preconditioned under hypoxia or with prolyl-4-hydroxylase inhibitors.
Infarction irreversibly damages the heart, with formation of an akinetic scar that may lead to heart failure. Endogenous cardiac stem cells (CSCs) are a promising candidate cell source for restoring lost tissue and thereby preventing heart failure. CSCs may be isolated in vitro, via the formation of cardiospheres, to give cardiosphere-derived cells (CDCs). Although qRT-PCR analyses of CDCs have been performed, no justification for the selection of the housekeeping gene has been published. Here, we evaluated the most suitable housekeeping gene for RNA expression analysis in CDCs cultured under normoxia, hypoxia or with prolyl-4-hydroxylase inhibitors (PHDIs), from both neonatal and adult rats, to determine the effects of ageing and different culture conditions on the stability of the housekeeping gene for CDCs. Six candidate housekeeping genes, [glyceraldehyde-3-phosphate dehydrogenase (GAPDH), beta-actin (Actb), hypoxanthine phosphoribosyltransferase 1 (HPRT-1), beta-2-microtubulin (β2M), 60S acidic ribosomal protein large P1 (RPLP-1) and TATA box binding protein (Tbp)] were evaluated in this study. Analysis using geNorm and NormFinder revealed that GAPDH was the most constant housekeeping gene among all genes tested under normoxia for both neonatal and adult CDCs, whereas Actb was the most stable housekeeping gene under hypoxia. For the PHDI-treated CDCs, overall, GADPH, Actb and β2M were more consistently expressed, whereas HPRT-1, RPLP-1 and Tbp showed unstable expression. The ranking for β2M, HPRT-1 and RPLP-1 stability was different for neonatal and adult cells, indicating that expression of these genes was age-dependent. Lastly, independent of age or culture conditions, Tbp was the least stable housekeeping gene. In conclusion, a combination of Actb and GADPH gave the most reliable normalization for comparative analyses of gene transcription in neonatal and adult rat CDCs preconditioned by hypoxia or PHDIs.


A Snapshot-Based Mechanism for Celestial Orientation.
In order to protect their food from competitors, ball-rolling dung beetles detach a piece of dung from a pile, shape it into a ball, and roll it away along a straight path [1]. They appear to rely exclusively on celestial compass cues to maintain their bearing [2-8], but the mechanism that enables them to use these cues for orientation remains unknown. Here, we describe the orientation strategy that allows dung beetles to use celestial cues in a dynamic fashion. We tested the underlying orientation mechanism by presenting beetles with a combination of simulated celestial cues (sun, polarized light, and spectral cues). We show that these animals do not rely on an innate prediction of the natural geographical relationship between celestial cues, as other navigating insects seem to [9, 10]. Instead, they appear to form an internal representation of the prevailing celestial scene, a "celestial snapshot," even if that scene represents a physical impossibility for the real sky. We also find that the beetles are able to maintain their bearing with respect to the presented cues only if the cues are visible when the snapshot is taken. This happens during the "dance," a behavior in which the beetle climbs on top of its ball and rotates about its vertical axis [11]. This strategy for reading celestial signals is a simple but efficient mechanism for straight-line orientation.


Expansion of CORE-SINEs in the genome of the Tasmanian devil.
The genome of the carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii, Order: Dasyuromorphia), was sequenced in the hopes of finding a cure for or gaining a better understanding of the contagious devil facial tumor disease that is threatening the species' survival. To better understand the Tasmanian devil genome, we screened it for transposable elements and investigated the dynamics of short interspersed element (SINE) retroposons. The temporal history of Tasmanian devil SINEs, elucidated using a transposition in transposition analysis, indicates that WSINE1, a CORE-SINE present in around 200,000 copies, is the most recently active element. Moreover, we discovered a new subtype of WSINE1 (WSINE1b) that comprises at least 90% of all Tasmanian devil WSINE1s. The frequencies of WSINE1 subtypes differ in the genomes of two of the other Australian marsupial orders. A co-segregation analysis indicated that at least 66 subfamilies of WSINE1 evolved during the evolution of Dasyuromorphia. Using a substitution rate derived from WSINE1 insertions, the ages of the subfamilies were estimated and correlated with a newly established phylogeny of Dasyuromorphia. Phylogenetic analyses and divergence time estimates of mitochondrial genome data indicate a rapid radiation of the Tasmanian devil and the closest relative the quolls (Dasyurus) around 14 million years ago. The radiation and abundance of CORE-SINEs in marsupial genomes indicates that they may be a major player in the evolution of marsupials. It is evident that the early phases of evolution of the carnivorous marsupial order Dasyuromorphia was characterized by a burst of SINE activity. A correlation between a speciation event and a major burst of retroposon activity is for the first time shown in a marsupial genome.


Modeling N-methyl-D-aspartate-induced bursting in dopamine neurons.
Burst firing of dopaminergic neurons of the substantia nigra pars compacta can be induced in vitro by the glutamate agonist N-methyl-D-aspartate. It has been suggested that the interburst hyperpolarization is due to Na+ extrusion by a ouabain-sensitive pump [Johnson et al. (1992) Science 258, 665-667]. We formulate and explore a theoretical model, with a minimal number of currents, for this novel mechanism of burst generation. This minimal model is further developed into a more elaborate model based on observations of additional currents and hypotheses about their spatial distribution in dopaminergic neurons [Hounsgaard (1992) Neuroscience 50, 513-518; Llinás et al. (1984) Brain Res. 294, 127-132]. Using the minimal model, we confirm that interaction between the regenerative, inward N-methyl-D-aspartate-mediated current and the outward Na(+)-pump current is sufficient to generate the slow oscillation (approximately 0.5 Hz) underlying the burst. The negative-slope region of the N-methyl-D-aspartate channel's current-voltage relation is indispensable for this slow rhythm generation. The time-scale of Na(+)-handling determines the burst's slow frequency. Moreover, we show that, given the constraints of sodium handling, such bursting is best explained mechanistically by using at least two spatial, cable-like compartments: a soma where action potentials are produced and a dendritic compartment where the slow rhythm is generated. Our result is consistent with recent experimental evidence that burst generation originates in distal dendrites [Seutin et al. (1994) Neuroscience 58, 201-206]. Responses of the model to a number of electrophysiological and pharmacological stimuli are consistent with known responses observed under similar conditions. These include the persistence of the slow rhythm when the tetrodotoxin-sensitive Na+ channel is blocked and when the soma is voltage-clamped at -60 mV. Using our more elaborate model, we account for details of the observed frequency adaptation in N-methyl-D-aspartate-induced bursting, the origin of multiple spiking and bursting mechanisms, and the interaction between two different bursting mechanisms. Besides reproducing several well established firing patterns, this model also suggests that new firing modes, not yet recorded, might also occur in dopaminergic neurons. This model provides mechanistic insights and explanations into the origin of a variety of experimentally observed membrane potential firing patterns in dopaminergic neurons, including N-methyl-D-aspartate-induced bursting and its dendritic origin. Such a model, capable of reproducing a number of realistic behaviors of dopaminergic neurons, could be useful in further studies of the basal ganglia-thalamocortical motor circuit. It may also shed light on bursting that involves N-methyl-D-aspartate channel activity in other neuron types.


Nanostructured lipid systems modified with waste material of propolis for wound healing: Design, in vitro and in vivo evaluation.
Propolis, a natural compound that can accelerate the wound healing process, is mainly used as ethanolic extract. The extractive solution may also be obtained from the propolis by-product (BP), transforming this waste material into a pharmaceutical active ingredient. Even if propolis does not show toxicity, when used as an extract over harmed skin or mucosa, the present ethanol content may be harmful to the tissue recovering, besides hindering the drug release. This study describes the development of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) as topical propolis delivery systems and the investigation of their in vitro and in vivo activities. The extracts were evaluated to guarantee their quality, and the lipid dispersions were characterized with respect to morphology (cryo-TEM), size and diffractometry (X-ray) properties. The occlusive capacity of formulations was also evaluated by an in vitro technique, which determines the occlusion factor. The drug entrapment efficiency (EE), as well as the in vitro drug release profile from the nanoparticulate systems was investigated as well. The size analysis performed through 90days was favorable to a topical administration and the polydispersity index, though not ideal in all cases due to the high content of resins and gums from the extracts, were relatively stable for the SLN. The propolis extract contributes to the occlusive potential of the formulations. The human immortalized keratinocytes presented good cell viability when tested with both extracts (propolis and BP) freely or entrapped in the systems. SLN modified with propolis material provided an acceleration of the in vivo wound healing process.


Computational pan-genomics: status, promises and challenges.
Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case of Homo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic data sets. Instead, novel, qualitatively different computational methods and paradigms are needed. We will witness the rapid extension of computational pan-genomics, a new sub-area of research in computational biology. In this article, we generalize existing definitions and understand a pan-genome as any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations as graphs. We outline how this and other challenges from different application domains translate into common computational problems, point out relevant bioinformatics techniques and identify open problems in computer science. With this review, we aim to increase awareness that a joint approach to computational pan-genomics can help address many of the problems currently faced in various domains.


Consent to transfusion: patients' and healthcare professionals' attitudes towards the provision of blood transfusion information.
Patients should be informed about the risks and benefits of blood transfusion and their consent should be documented. However, this is not routinely practised in the UK, and there have been few studies to investigate patients' and healthcare professionals' attitudes towards this process. To investigate patients' and healthcare professionals' attitudes towards the information patients are provided with about transfusion and obtaining consent for transfusion. A cross-sectional qualitative survey design was employed. Attitudes towards transfusion-related information and consenting to transfusion were assessed using a patient survey and healthcare professional survey. One hundred and ten patients who had received a transfusion aged between 18 and 93 (60 males and 50 females) and 123 healthcare professionals (doctors, nurses and midwives) involved in administering transfusions. Sixty-one patients recalled consenting transfusion. The majority said they were just told they needed a transfusion (N = 67) and only 1 patient said a full discussion about the risks and the benefits of the transfusion took place. However, although 82 patients said they were satisfied with the information, 22 patients reported they would have liked to have been given more details. The majority of healthcare professionals (N = 83) felt that patients were often not given sufficient information about transfusion. Greater efforts should be made to provide information to patients about the risks and benefits of blood transfusions. Future research should explore the most effective ways of delivering this information to patients in an appropriate and timely manner.


Cell cycle checkpoints: preventing an identity crisis.
Cell cycle checkpoints are regulatory pathways that control the order and timing of cell cycle transitions and ensure that critical events such as DNA replication and chromosome segregation are completed with high fidelity. In addition, checkpoints respond to damage by arresting the cell cycle to provide time for repair and by inducing transcription of genes that facilitate repair. Checkpoint loss results in genomic instability and has been implicated in the evolution of normal cells into cancer cells. Recent advances have revealed signal transduction pathways that transmit checkpoint signals in response to DNA damage, replication blocks, and spindle damage. Checkpoint pathways have components shared among all eukaryotes, underscoring the conservation of cell cycle regulatory machinery.


High prevalence of comorbidity and need for up-referral among inpatients at a district-level hospital with specialist tuberculosis services in South Africa: the need for specialist support.
OBJECTIVES. To define the patient population at Cape Town's district-level hospital offering specialist tuberculosis (TB) services, concerning the noted increase in complex, sick HIV-TB co-infected patients requiring increased levels of care. METHODS. A cross-sectional study of all hospitalised adult patients in Brooklyn Chest Hospital (a district-level hospital offering specialist TB services) from 27 - 30 October 2008. Outcome measures were: Type of TB and drug sensitivity, HIV co-infection, comorbidity, Karnofsky performance score, and frequency and reason for referral to other health care facilities. RESULTS. More than two-thirds of patients in the acute wards were HIV-co-infected, of whom 98% had significant comorbidities and 60% had a Karnofsky performance score ≤30. Twenty-eight per cent of patients did not have a confirmed diagnosis of TB. In contrast, long-stay patients with multi-drug-resistant (MDR), pre-extensively (pre-XDR) and extensively drug-resistant (XDR) TB had a lower prevalence of HIV co-infection, but manifested high rates of comorbidity. Overall, one-fifth of patients required up-referral to higher levels of care. CONCLUSIONS. District-level hospitals such as Brooklyn Chest Hospital that offer specialist TB services share the increasing burden of complex, sick, largely HIV-co-infected TB patients with their secondary and tertiary level counterparts. To support these hospitals effectively, outreach, skills transfer through training, and improved radiology resources are required to optimise patient care.


Firing probability and mean firing rates of human muscle vasoconstrictor neurones are elevated during chronic asphyxia.
Elevated muscle sympathetic nerve activity (MSNA) features in many cardiovascular diseases, but how this sympathoexcitation is brought about differs across pathologies. Unitary recordings from post-ganglionic muscle vasoconstrictor neurones in human subjects have shown that the augmented MSNA in the obstructive sleep apnoea syndrome (OSAS) is associated with an increase in firing probability and mean firing rate, and an increase in multiple within-burst firing. Here we characterize the firing properties of muscle vasoconstrictor neurones in patients with chronic obstructive pulmonary disease (COPD), who are chronically asphyxic. We tested the hypothesis that this elevated chemical drive would shift the firing pattern from that seen in healthy subjects to that seen in OSAS. The mean firing probability (52%) and mean firing rate (0.92 Hz) of 17 muscle vasoconstrictor neurones recorded in COPD were comparable to those previously recorded in OSAS (51% and 0.96 Hz), but significantly higher than those recorded in a group of healthy subjects with high levels of resting MSNA (35% and 0.33 Hz). In COPD single neurones fired once in 63% of cardiac intervals, comparable to OSAS (59%), but significantly lower than in the healthy group (78%). Conversely, single neurones fired twice in 25% of cardiac intervals, similar to OSAS (27%), but significantly higher than in the healthy group (18%). We conclude that the chronic asphyxia associated with COPD results in an increase in the firing probability and mean firing frequency of muscle vasoconstrictor neurones and causes a shift towards multiple firing, reflecting an increase in central muscle vasoconstrictor drive.


Localized cartilage assessment with three-dimensional dGEMRIC in asymptomatic hips with normal morphology and cam deformity.
Cam deformities cause femoroacetabular impingement and damage the acetabular labral-chondral complex. The aims of this study were to investigate the potential of delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) to detect cartilage disease in asymptomatic hips with cam deformities compared with morphologically normal hips, establish whether dGEMRIC could identify advanced disease in hips with positive clinical findings, and establish whether cartilage damage correlated with the severity of the cam deformity. Subjects were recruited from a prospective study of individuals with a family history of osteoarthritis and their spouses who served as control subjects. Their symptoms and impingement test results were recorded. Asymptomatic hips with normal radiographic joint-space width were placed in a subgroup according to the presence of a cam deformity and the impingement test result. dGEMRIC was performed on a 3-T system, studying two regions of interest: the anterosuperior aspect of the acetabular cartilage (T1(acet)) and the total femoral and acetabular cartilage (T1(total)). The ratio T1(acet)/T1(total) gave the relative glycosaminoglycan content in the anterosuperior aspect of the acetabular cartilage. The cohort was placed in subgroups by joint morphology, impingement test status, and genetic predisposition; the mean T1 scores were compared, and the alpha angle and T1 were correlated. Of thirty-two subjects (mean age, fifty-two years), nineteen had cam deformities. Hips with a cam deformity had reduced acetabular glycosaminoglycan content compared with normal hips (mean T1(acet)/T1(total), 0.949 and 1.093, respectively; p = 0.0008). Hips with a positive impingement test result had global depletion of glycosaminoglycan compared with hips with a negative result (mean T1(total), 625 ms versus 710 ms; p = 0.0152). T1(acet) inversely correlated with the magnitude of the alpha angle (r = -0.483, p = 0.0038), suggesting that the severity of cartilage damage correlates with the magnitude of the cam deformity. All of these differences occurred irrespective of genetic predisposition. The dGEMRIC technique can detect cartilage damage in asymptomatic hips with cam deformities and no radiographic evidence of joint space narrowing. This damage correlates with cam deformity severity. Further study of the application of dGEMRIC as an imaging biomarker of early osteoarthritis is justified to validate its prognostic accuracy, identify subjects for clinical trials, and evaluate the effectiveness of surgical procedures.


Amino acid transporter genes are essential for FLO11-dependent and FLO11-independent biofilm formation and invasive growth in Saccharomyces cerevisiae.
Amino acids can induce yeast cell adhesion but how amino acids are sensed and signal the modulation of the FLO adhesion genes is not clear. We discovered that the budding yeast Saccharomyces cerevisiae CEN.PK evolved invasive growth ability under prolonged nitrogen limitation. Such invasive mutants were used to identify amino acid transporters as regulators of FLO11 and invasive growth. One invasive mutant had elevated levels of FLO11 mRNA and a Q320STOP mutation in the SFL1 gene that encodes a protein kinase A pathway regulated repressor of FLO11. Glutamine-transporter genes DIP5 and GNP1 were essential for FLO11 expression, invasive growth and biofilm formation in this mutant. Invasive growth relied on known regulators of FLO11 and the Ssy1-Ptr3-Ssy5 complex that controls DIP5 and GNP1, suggesting that Dip5 and Gnp1 operates downstream of the Ssy1-Ptr3-Ssy5 complex for regulation of FLO11 expression in a protein kinase A dependent manner. The role of Dip5 and Gnp1 appears to be conserved in the S. cerevisiae strain ∑1278b since the dip5 gnp1 ∑1278b mutant showed no invasive phenotype. Secondly, the amino acid transporter gene GAP1 was found to influence invasive growth through FLO11 as well as other FLO genes. Cells carrying a dominant loss-of-function PTR3(647::CWNKNPLSSIN) allele had increased transcription of the adhesion genes FLO1, 5, 9, 10, 11 and the amino acid transporter gene GAP1. Deletion of GAP1 caused loss of FLO11 expression and invasive growth. However, deletions of FLO11 and genes encoding components of the mitogen-activated protein kinase pathway or the protein kinase A pathway were not sufficient to abolish invasive growth, suggesting involvement of other FLO genes and alternative pathways. Increased intracellular amino acid pools in the PTR3(647::CWNKNPLSSIN)-containing strain opens the possibility that Gap1 regulates the FLO genes through alteration of the amino acid pool sizes.


Vitamin D status and health correlates among German adults.
To analyze vitamin D status based on serum 25-hydroxyvitamin D (25OHD) measurements, its determinants and health correlates in a representative sample of German adults. A total of 1763 men and 2267 women, 18- to 79-year old, who participated in the representative German National Health Interview and Examination Survey 1998 and the integrated German Nutrition Survey. The median vitamin D intake from both diet and supplements did not meet the recommended level of 5 microg/day, in either men (2.8 microg/day) or women (2.3 microg/day). Altogether 80.9% of men and 88.5% of women had vitamin D intakes below this level. Moderate (12.5-25 nmol/l serum 25OHD levels) and mild (25-50 nmol/l) vitamin D deficiency was prevalent in the adult population in Germany, even in younger age groups. Overall, 57% of men and 58% of women had vitamin D levels below 50 nmol/l. Among 65- to 79-year-old women, the proportion amounted to 75%, even during the sunnier half of the year. In sex-specific multiple linear regression models, independent determinants of serum 25OHD levels consistently included season, vitamin D intake from both diet and supplements, physical activity and living in a partnership. In addition, age and current menopausal hormone use contributed to the model among women, as opposed to time of day of blood sampling and body mass index (marginally) among men. Significantly lower serum 25OHD levels were observed in women with hypertension, cardiovascular diseases and noninsulin-treated diabetes mellitus as well as in men with insulin-treated diabetes mellitus compared with nonaffected participants. Vitamin D deficiency is a public health issue in Germany. We identified a number of determinants with potential for primary prevention of vitamin D deficiency. Risk and benefits of preventive actions need to be examined in further studies.


Post-GWAS gene-environment interplay in breast cancer: results from the Breast and Prostate Cancer Cohort Consortium and a meta-analysis on 79,000 women.
We studied the interplay between 39 breast cancer (BC) risk SNPs and established BC risk (body mass index, height, age at menarche, parity, age at menopause, smoking, alcohol and family history of BC) and prognostic factors (TNM stage, tumor grade, tumor size, age at diagnosis, estrogen receptor status and progesterone receptor status) as joint determinants of BC risk. We used a nested case-control design within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), with 16 285 BC cases and 19 376 controls. We performed stratified analyses for both the risk and prognostic factors, testing for heterogeneity for the risk factors, and case-case comparisons for differential associations of polymorphisms by subgroups of the prognostic factors. We analyzed multiplicative interactions between the SNPs and the risk factors. Finally, we also performed a meta-analysis of the interaction ORs from BPC3 and the Breast Cancer Association Consortium. After correction for multiple testing, no significant interaction between the SNPs and the established risk factors in the BPC3 study was found. The meta-analysis showed a suggestive interaction between smoking status and SLC4A7-rs4973768 (Pinteraction = 8.84 × 10(-4)) which, although not significant after considering multiple comparison, has a plausible biological explanation. In conclusion, in this study of up to almost 79 000 women we can conclusively exclude any novel major interactions between genome-wide association studies hits and the epidemiologic risk factors taken into consideration, but we propose a suggestive interaction between smoking status and SLC4A7-rs4973768 that if further replicated could help our understanding in the etiology of BC.


Cardiac Dysfunction and Metabolic Inflexibility in a Mouse Model of Diabetes Without Dyslipidemia.
Diabetes is a well-established risk factor for heart disease, leading to impaired cardiac function and a metabolic switch toward fatty acid usage. In this study, we investigated if hyperglycemia/hypoinsulinemia in the absence of dyslipidemia is sufficient to drive these changes and if they can be reversed by restoring euglycemia. Using the βV59M mouse model, in which diabetes can be rapidly induced and reversed, we show that stroke volume and cardiac output were reduced within 2 weeks of diabetes induction. Flux through pyruvate dehydrogenase was decreased, as measured in vivo by hyperpolarized [1-13C]pyruvate MRS. Metabolomics showed accumulation of pyruvate, lactate, alanine, tricarboxyclic acid cycle metabolites, and branched-chain amino acids. Myristic and palmitoleic acid were decreased. Proteomics revealed proteins involved in fatty acid metabolism were increased, whereas those involved in glucose metabolism decreased. Western blotting showed enhanced pyruvate dehydrogenase kinase 4 (PDK4) and uncoupling protein 3 (UCP3) expression. Elevated PDK4 and UCP3 and reduced pyruvate usage were present 24 h after diabetes induction. The observed effects were independent of dyslipidemia, as mice showed no evidence of elevated serum triglycerides or lipid accumulation in peripheral organs (including the heart). The effects of diabetes were reversible, as glibenclamide therapy restored euglycemia, cardiac metabolism and function, and PDK4/UCP3 levels.


Breastfeeding and reduced risk of sudden infant death syndrome: a meta-analysis.
Benefits of breastfeeding include lower risk of postneonatal mortality. However, it is unclear whether breastfeeding specifically lowers sudden infant death syndrome (SIDS) risk, because study results have been conflicting. To perform a meta-analysis to measure the association between breastfeeding and SIDS. We identified 288 studies with data on breastfeeding and SIDS through a Medline search (1966-2009), review articles, and meta-analyses. Twenty-four original case-control studies were identified that provided data on the relationship between breastfeeding and SIDS risk. Two teams of 2 reviewers evaluated study quality according to preset criteria; 6 studies were excluded, which resulted in 18 studies for analysis. Univariable and multivariable odds ratios were extracted. A summary odds ratio (SOR) was calculated for the odds ratios by using the fixed-effect and random-effect inverse-variance methods of meta-analysis. The Breslow-Day test for heterogeneity was performed. For infants who received any amount of breast milk for any duration, the univariable SOR was 0.40 (95% confidence interval [CI]: 0.35-0.44), and the multivariable SOR was 0.55 (95% CI: 0.44-0.69). For any breastfeeding at 2 months of age or older, the univariable SOR was 0.38 (95% CI: 0.27-0.54). The univariable SOR for exclusive breastfeeding of any duration was 0.27 (95% CI: 0.24-0.31). Breastfeeding is protective against SIDS, and this effect is stronger when breastfeeding is exclusive. The recommendation to breastfeed infants should be included with other SIDS risk-reduction messages to both reduce the risk of SIDS and promote breastfeeding for its many other infant and maternal health benefits.


Clinical guidelines in the European Union: mapping the regulatory basis, development, quality control, implementation and evaluation across member states.
Clinical guidelines are advocated to improve the quality of care, especially for chronic diseases. However, the regulatory basis of clinical guidelines, their development, quality control, implementation and use as well as evaluation within countries across the European Union is not systematically known. Using information collected from key informants in each country by means of a structured questionnaire, this mapping exercise illustrates the varied status of guideline production in European Union countries. Most European Union countries have an established national, regional or local clinical guideline programme, and a substantial proportion have developed guidelines on the prevention and management of chronic diseases. Several countries have mechanisms in place to ensure the quality of scientific evidence used for the development of guidelines is high and that the process is consistent and transparent. Others are only now taking an interest in guideline development and are taking the first steps towards establishing ways of implementing them. The majority of countries have no legal basis for the development of guidelines and those that have well established systems mostly implement them on a voluntary basis. The process of guideline development varies in its degrees of decentralisation across countries with many different types of organisations taking on this responsibility. There is general acceptance of the value of the instrument developed by the AGREE collaboration for evaluating the methodological robustness of guidelines. However, the extent to which guidelines are implemented in Europe is unknown, as there is no systematic data collection and, in most countries, no structure to enable it. There are few examples of formal evaluations of the development, quality, implementation and use of guidelines. Our findings call for renewed efforts to respond to the severe lack of standardized guideline terminology and accessibility as well as rigorous studies to evaluate the relationship between different ways to develop guidelines and their methodological quality, between their quality and the actual implementation and usage, and finally between implementation and health outcomes.


Predictors of attendance for prostate-specific antigen screening tests and prostate biopsy.
Little is known about factors influencing men's decisions to undergo screening and diagnostic tests for prostate cancer (PCa). Identify predictors of attendance for prostate-specific antigen (PSA) testing and prostate biopsy. Literature searches and interviews with men undergoing PSA testing and prostate biopsy formed the basis of a self-report questionnaire designed to identify predictors of health behaviour, which was completed by men eligible for PSA invitation and prostate biopsy. Multitrait scaling analyses established the final questionnaire content. This revised instrument was distributed to a new cohort of men before PSA testing and biopsy invitations were received. Ethical committee approval was obtained from Trent Multicentre Research Ethics Committee (MREC/01/4/025-21/06/2001). Predictors of health behaviour and attendance rates for PSA test or prostate biopsy were measured. Associations between questionnaire scores and health behaviour (PSA and prostate biopsy attendance) were examined using logistic regression. The provisional 49-item health behaviour questionnaire was completed by 468 of 810 men (57.8%). Multitrait scaling refined the questionnaire to 26 items in six scales (A: health benefits, B: threats to health, C: barriers to testing, D: health intentions, E: external influences, F: current general health). A total of 1455 of 2657 men (54.8%) completed the revised instrument before invitations for PSA test or biopsy were received; 395 (43.4%) and 434 (91.6%) attended. Strong associations between men's health intentions (scale D) and PSA and biopsy attendance (odds ratio: 1.56 or 3.67, respectively; p<0.001) were observed with modest associations between the other five scales and attendance for PSA testing. Average questionnaire response rates represent the major limitation of this study. Knowledge and beliefs about PCa and testing predict men's intentions and attendance for PSA testing and prostate biopsy. Understanding men's health behaviour is important for the management of patients seeking PSA testing in general practice.


Which Patients with Giant Cell Arteritis Will Develop Cardiovascular or Cerebrovascular Disease? A Clinical Practice Research Datalink Study.
To evaluate the risk of cerebrovascular disease and cardiovascular disease (CVD) in patients with giant cell arteritis (GCA), and to identify predictors. The UK Clinical Practice Research Datalink 1991-2010 was used for a parallel cohort study of 5827 patients with GCA and 37,090 age-, sex-, and location-matched controls. A multivariable competing risk model (non-cerebrovascular/CV-related death as the competing risk) determined the relative risk [subhazard ratio (SHR)] between patients with GCA compared with background controls for cerebrovascular disease, CVD, or either. Each cohort (GCA and controls) was then analyzed individually using the same multivariable model, with age and sex now present, to identify predictors of CVD or cerebrovascular disease. Patients with GCA, compared with controls, had an increased risk SHR (95% CI) of cerebrovascular disease (1.45, 1.31-1.60), CVD (1.49, 1.37-1.62), or either (1.47, 1.37-1.57). In the GCA cohort, predictors of "cerebrovascular disease or CVD" included increasing age, > 80 years versus < 65 years (1.98, 1.62-2.42), male sex (1.20, 1.05-1.38), and socioeconomic status, most deprived quintile versus least deprived (1.34, 1.01-1.78). These predictors were also present within the non-GCA cohort. Patients with GCA are more likely to develop cerebrovascular disease or CVD than age-, sex-, and location-matched controls. In common with the non-GCA cohort, patients who are older, male, and from the most deprived compared with least deprived areas have a higher risk of cerebrovascular disease or CVD. Further work is needed to understand how this risk may be mediated by specific behavioral, social, and economic factors.


Supple bodies, healthy minds: yoga, psychedelics and American mental health.
Much discussion about mental health has revolved around treatment models. As interdisciplinary scholarship has shown, mental health knowledge, far from being a neutral product detached from the society that generated it, was shaped by politics, economics and culture. By drawing on case studies of yoga, religion and fitness, this article will examine the ways in which mental health practices-sometimes scientific, sometimes spiritual-have been conceived, debated and applied by researchers and the public. More specifically, it will interrogate the relationship between yoga, psychedelics, South Asian and Eastern religion (as understood and practiced in the USA) and mental health.


Longitudinal mood monitoring in bipolar disorder: Course of illness as revealed through a short messaging service.
Online self-monitoring of mood can be used to investigate differences in course patterns across patient groups. This study explored the feasibility of remote symptom capture with True Colours, a self-rated online mood monitoring tool completed on a weekly basis. Participants with bipolar disorder (N = 297) completed weekly depression and mania questionnaires over an average of 27.5 months (range 1 -81 months). Subgroups defined by sex, age, and bipolar I vs. II status were compared on time in various mood states, number of episodes, and week-to-week mood variability. Compliance with weekly questionnaires was generally high (median, 92% of weeks). Mood symptoms occurred for an average of 55.4% of weeks across the follow-up period. Females spent more time with hypomanic/manic and depressive symptoms and had more depressive episodes compared to males. Younger participants were found to experience more hypomanic/manic episodes and showed greater variability in mood symptoms than older participants. No significant differences in mood symptoms or variability were observed between bipolar I and II patients. This was a naturalistic study with a heterogeneous cohort, and did not include a control group. True Colours does not identify mood fluctuations that may occur in the days between weekly assessments. Monitoring moods through an online tool is both feasible and informative regarding course of illness in patients with bipolar disorder. Interventions aiming to reduce mood variability and manic/hypomanic episodes in the early phases of bipolar disorder may enhance the long-term symptomatic course of the illness.


Nationwide bowel cancer screening programme in England: cohort study of lifestyle factors affecting participation and outcomes in women.
In 2006, the National Health Service Bowel Cancer Screening Programme in England (NHSBCSP) began offering routine population-based biennial faecal occult blood testing (FOBt) at ages 60-69. There is, however, limited information on how characteristics of individuals affect participation and outcomes of screening, and we studied this association by linking NHSBCSP data to a large prospective cohort of women. Electronic linkage of the NHSBCSP and Million Women Study records identified 899 166 women in the study cohort with at least one invitation for screening. NHSBCSP provided information on screening acceptance, FOBt results, screen-detected colorectal cancer and other outcomes. The Million Women Study provided prospectively collected information on personal and lifestyle factors. Multiple regression was used to estimate relative risks (RRs) of factors associated with acceptance and outcomes of screening. Overall, 70% of women (628 976/899 166) accepted their first invitation for bowel cancer screening, of whom 9133 (1.5%) were FOBt-positive, 743 (0.1%) had screen-detected colorectal cancer and 3056 (0.5%) had screen-detected colorectal adenoma. Acceptance was lower in women from the most than the least deprived tertile, in South Asians and in Blacks than in Whites, in current than in never smokers and in obese than in normal weight women: adjusted RRs (95% confidence interval) for acceptance vs not, 0.90 (0.90-0.90); 0.77 (0.75-79); 0.94 (0.92-0.96); 0.78 (0.77-0.78); and 0.88 (0.88-0.89), respectively: P<0.001 for each. These factors were also associated with an increased risk of being FOBt-positive and of having screen-detected adenoma, but were not strongly associated with the risk of screen-detected colorectal cancer. Relative risks for screen-detected adenoma were 1.22 (1.12-1.34), 2.46 (1.75-3.45), 1.61 (1.05-2.48), 1.53 (1.38-1.68) and 1.77 (1.60-1.95), respectively (P<0.001 for all, except for Blacks vs Whites P=0.03). Use of hormone therapy for menopause was associated with reduced risk of screen-detected adenoma, RR ever vs never use, 0.87 (0.81-0.93), P<0.001 and colorectal cancer, 0.78 (0.68-0.91), P=0.001. Among women in England, socioeconomic and lifestyle factors strongly affect participation in routine bowel cancer screening, risk of being FOBt-positive and risk of having screen-detected colorectal adenoma. However, screen-detected colorectal cancer risk is not strongly related to these factors.


Neurological manifestations following partial excision in spinal meningioma: case report.
Presented here is a 16-year-old girl who was referred on 30th January 1996 with diagnosis of cord compression with spastic paraplegia with sensory level at T7/T8. CT scan myelogam confirmed soft tissue density mass displacing cord to the left with no dye being seen beyond T3. Thoracic spine decompressive laminectomy was performed on 1st January 1996 at Nairobi West Hospital extending from T3 to T6 level, which revealed a fibrous haemorrhagic tumour. Histology showed meningioma (mixed fibrous type and meningoepitheliomatous type) with many psammoma bodies. She had a stormy post-operative period, with infection and wound dehiscence. This was treated with appropriate antibiotics and wound care. She was eventually rehabilitated and was able to walk with the aid of a walking frame because of persistent spasticity of right leg. She was seen once as an outpatient by author on 6th July 1996, she was able to use the walking frame, but the right leg was still held in flexion deformity at the knee. She was thus referred to an orthopaedic surgeon for possible tenotomy. She was able to resume her studies at the University ambulating using a wheel chair and walking frame. She presented with worsening of symptoms in 2001 (five years after her first surgery). MRI scan thoracic spine revealed a left anterolateral intradural lesion extending from T3 to T5 vertebral body level compressing and displacing the spinal cord. She had a repeat surgery on 6th March 2001 at Kenyatta National Hospital; spastic paraparesis and urinary incontinenece persisted. She also developed bed sores and recurrent urinary tract infections. She was followed up by the author and other medical personnel in Mwea Mission Hospital where she eventually succumbed in 2005, nine years after her first surgery. This case is presented as a case of incompletely excised spinal meningioma to highlight some of the problems of managing spinal meningiomas when operating microscope and embolisation of tumours are not readily available. Also the family experienced financial constraint in bringing the patient for regular follow-up, and getting access to appropriate antibiotics, catheters and urine bags.


Influence of acupuncture on leptin, ghrelin, insulin and cholecystokinin in obese women: a randomised, sham-controlled preliminary trial.
Obesity is an energy balance problem caused by overeating. Obesity treatment includes diet, exercise, behaviour treatment, pharmacotherapy and surgery; in addition, acupuncture is also an option. To investigate the effect of acupuncture on weight loss and whether a brief acupuncture treatment of 5 weeks can change circulating levels of leptin, ghrelin, insulin and cholecystokinin (CCK) in obese women. 40 women with a body mass index (BMI)>30 kg/m(2) were equally randomised to either an acupuncture group or a sham (non-penetrating) acupuncture group and received treatment at LI4, HT7, ST36, ST44 and SP6 bilaterally. Both groups had two sessions of 20 min/week for a total of 10 sessions. Serum insulin, leptin, plasma ghrelin and CCK levels were measured by ELISA. Acupuncture treatment decreased insulin and leptin levels and induced weight loss, together with a decrease in BMI compared with sham acupuncture. Furthermore, between-group analyses demonstrated increases in plasma ghrelin and CCK levels in subjects who received acupuncture treatment. These findings suggest that acupuncture may help to regulate weight owing to its beneficial effects on hormones such as insulin, leptin, ghrelin and CCK in obese subjects even after a few weeks of treatment.


Variation of cervical cancer incidence in Latin America and the Caribbean.
To provide a comprehensive analysis of the descriptive epidemiology of invasive cervical cancer in Latin America and the Caribbean by analyzing quality data from the area's cancer registries, including data that were excluded from the International Agency for Research on Cancer (IARC) publication, Cancer Incidence in Five Continents, Vol. IX (CI5-IX). This was a descriptive epidemiologic study that involved 20 cancer registries, 9 of which were included by IARC in CI5-IX, and 11 of which were not. Data on invasive cervical cancers diagnosed from 1998-2002 were obtained from IARC. A cervical cancer-specific quality assessment was performed on all registries whether or not they were included in CI5-IX. Data from 14 registries met quality criteria and were analyzed. Incidence rates were calculated and compared across registries. A substantial variation in incidence rates existed among the registries; age-standardized rates ranged from 14.6-44.0 per 100 000 women per year. Mean cervical cancer incidence rates were 10.4% higher for registries included in CI5-IX than for those excluded; however, this difference was not significant (P = 0.541). This study compared cervical cancer rates from a more diverse group of Latin American and Caribbean countries than that of the CI5-IX. The heterogeneity found among registries highlights the importance of examining data from as many registries as possible when characterizing risk across a geographic area. Data from developing countries can be used to better understand cancer distribution and enable Region-specific recommendations on cancer control and prevention once data quality has been established.


Comprehensive morphometry of subcortical grey matter structures in early-stage Parkinson's disease.
Previous imaging studies that investigated morphometric group differences of subcortical regions outside the substantia nigra between non-demented Parkinson's patients and controls either did not find any significant differences, or reported contradictory results. Here, we performed a comprehensive morphometric analysis of 20 cognitively normal, early-stage PD patients and 19 matched control subjects. In addition to relatively standard analyses of whole-brain grey matter volume and overall regional volumes, we examined subtle localized surface shape differences in striatal and limbic grey matter structures and tested their utility as a diagnostic marker. Voxel-based morphometry and volumetric comparisons did not reveal significant group differences. Shape analysis, on the other hand, demonstrated significant between-group shape differences for the right pallidum. Careful diffusion tractography analysis showed that the affected parts of the pallidum are connected subcortically with the subthalamic nucleus, the pedunculopontine nucleus, and the thalamus and cortically with the frontal lobe. Additionally, microstructural measurements along these pathways, but not along other pallidal connections, were significantly different between the two groups. Vertex-wise linear discriminant analysis, however, revealed limited accuracy of pallidal shape for the discrimination between patients and controls. We conclude that localized disease-related changes in the right pallidum in early Parkinson's disease, undetectable using standard voxel-based morphometry or volumetry, are evident using sensitive shape analysis. However, the subtle nature of these changes makes it unlikely that shape analysis alone will be useful for early diagnosis.


Chemical characterization and cytotoxic activity evaluation of Lebanese propolis.
Chemical composition, anti-proliferative and proapoptotic activity as well as the effect of various fractions of Lebanese propolis on the cell cycle distribution were evaluated on Jurkat leukemic T-cells, glioblastoma U251 cells, and breast adenocarcinoma MDA-MB-231 cells using cytotoxic assays, flow cytometry as well as western blot analysis. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that ferulic acid, chrysin, pinocembrin, galangin are major constituents of the ethanolic crude extract of the Lebanese propolis, while the hexane fraction mostly contains chrysin, pinocembrin, galangin but at similar levels. Furthermore chemical analysis was performed using gas chromatography-mass spectrometry (GC-MS) to identify major compounds in the hexane fraction. Reduction of cell viability was observed in Jurkat cells exposed to the ethanolic crude extract and the hexane fraction, while viability of U251 and MDA-MB-231 cells was only affected upon exposure to the hexane fraction; the other fractions (aqueous phase, methylene chloride, and ethyl acetate) were without effect. Maximum toxic effect was obtained when Jurkat cells were cultivated with 90μg/ml of both the crude extract and hexane faction. Toxicity started early after 24h of incubation and remained till 72h. Interestingly, the decrease in cell viability was accompanied by a significant increase in p53 protein expression levels and PARP cleavage. Cell cycle distribution showed an increase in the SubG0 fraction in Jurkat, U251 and MDA-MB-231 cells after 24h incubation with the hexane fraction. This increase in SubG0 was further investigated in Jurkat cells by annexinV/PI and showed an increase in the percentage of cells in early and late apoptosis as well as necrosis. In conclusion, Lebanese propolis exhibited significant cytotoxicity and anti-proliferative activity promising enough that warrant further investigations on the molecular targets and mechanisms of action of Lebanese propolis.


Mandibular intraosseous pseudocarcinomatous hyperplasia: a case report.
Mandibular pseudocarcinomatous hyperplasia is a rare and generally benign pathology. We report on one of these rare cases. The case history of a 73-year-old white man stated that he had a carcinoma of the oropharynx, which was primarily treated with radiotherapy and chemotherapy 4 years prior. As a result of radiotherapy he developed an osteoradionecrosis of his mandible and a consecutive pathological fracture of his left mandibular angle. Subsequent osteosynthesis was performed with a reconstruction plate. When we first saw him, his reconstruction plate was partially exposed with intraoral and extraoral fistulation. The resected bone of his defect-bordering jaw showed the typical pathohistological findings of an intraosseous mandibular pseudocarcinomatous hyperplasia. After a first reconstruction attempt with an iliac crest graft failed, definitive reconstruction of his mandible with a microvascular anastomosed fibula graft was achieved. Intraosseous pseudocarcinomatous hyperplasia of the mandible is a rare differential diagnosis in maxillofacial surgery. Besides other benign epithelial neoplasms, such as calcifying epithelial odontogenic tumor, squamous odontogenic tumor, or different forms of ameloblastoma, the far more frequent invasive squamous cell carcinoma needs to be excluded. A misinterpretation of pseudocarcinomatous hyperplasia as squamous cell carcinoma must be avoided because it can lead to a massive overtreatment.


Tissue localization during resective epilepsy surgery.
Imaging-guided surgery (IGS) systems are widely used in neurosurgical practice. During epilepsy surgery, the authors routinely use IGS landmarks to localize intracranial electrodes and/or specific brain regions. The authors have developed a technique to coregister these landmarks with pre- and postoperative scans and the Montreal Neurological Institute (MNI) standard space brain MRI to allow 1) localization and identification of tissue anatomy; and 2) identification of Brodmann areas (BAs) of the tissue resected during epilepsy surgery. Tracking tissue in this fashion allows for better correlation of patient outcome to clinical factors, functional neuroimaging findings, and pathological characteristics and molecular studies of resected tissue. Tissue samples were collected in 21 patients. Coordinates from intraoperative tissue localization were downloaded from the IGS system and transformed into patient space, as defined by preoperative high-resolution T1-weighted MRI volume. Tissue landmarks in patient space were then transformed into MNI standard space for identification of the BAs of the tissue samples. Anatomical locations of resected tissue were identified from the intraoperative resection landmarks. The BAs were identified for 17 of the 21 patients. The remaining patients had abnormal brain anatomy that could not be meaningfully coregistered with the MNI standard brain without causing extensive distortion. This coregistration and landmark tracking technique allows localization of tissue that is resected from patients with epilepsy and identification of the BAs for each resected region. The ability to perform tissue localization allows investigators to relate preoperative, intraoperative, and postoperative functional and anatomical brain imaging to better understand patient outcomes, improve patient safety, and aid in research.


Factors Associated with Sequelae of Campylobacter and Non-typhoidal Salmonella Infections: A Systematic Review.
Despite the significant global burden of gastroenteritis and resulting sequelae, there is limited evidence on risk factors for sequelae development. We updated and extended previous systematic reviews by assessing the role of antibiotics, proton pump inhibitors (PPI) and symptom severity in the development of sequelae following campylobacteriosis and salmonellosis. We searched four databases, including PubMed, from 1 January 2011 to 29 April 2016. Observational studies reporting sequelae of reactive arthritis (ReA), Reiter's syndrome (RS), irritable bowel syndrome (IBS) and Guillain-Barré syndrome (GBS) following gastroenteritis were included. The primary outcome was incidence of sequelae of interest amongst cases of campylobacteriosis and salmonellosis. A narrative synthesis was conducted where heterogeneity was high. Of the 55 articles included, incidence of ReA (n=37), RS (n=5), IBS (n=12) and GBS (n=9) were reported following campylobacteriosis and salmonellosis. A pooled summary for each sequela was not estimated due to high level of heterogeneity across studies (I2>90%). PPI usage and symptoms were sparsely reported. Three out of seven studies found a statistically significant association between antibiotics usage and development of ReA. Additional primary studies investigating risk modifying factors in sequelae of GI infections are required to enable targeted interventions.


Population-based case-control study of white matter changes on brain imaging in transient ischemic attack and ischemic stroke.
White matter changes (WMC) are a common finding on brain imaging and are associated with an increased risk of ischemic stroke. They are most frequent in small vessel stroke; however, in the absence of comparisons with normal controls, it is uncertain whether WMC are also more frequent than expected in other stroke subtypes. Therefore, we compared WMC in pathogenic subtypes of ischemic stroke versus controls in a population-based study. We evaluated the presence and severity of WMC on computed tomography and on magnetic resonance brain imaging using modified Blennow/Fazekas scale and age-related white matter changes scale, respectively, in a population-based study of patients with incident transient ischemic attack or ischemic stroke (Oxford Vascular Study) and in a study of local controls (Oxford Project to Investigate Memory and Ageing) without history of transient ischemic attack or ischemic stroke, with stratification by stroke pathogenesis (Trial of Org10172 in Acute Stroke Treatment classification). Among 1601 consecutive eligible patients with first-ever ischemic events, 1453 patients had computed tomography brain imaging, 562 had magnetic resonance imaging, and 414 patients had both. Compared with 313 controls (all with computed tomography and 131 with magnetic resonance imaging) and after adjustment for age, sex, diabetes mellitus, and hypertension, moderate/severe WMC (age-related white matter changes scale) were more frequent in patients with small vessel events (odds ratio, 3.51 [95% confidence interval, 2.13-5.76]; P<0.0001) but not in large artery (odds ratio, 1.03 [95% confidence interval, 0.64-1.67]), cardioembolic (odds ratio, 0.87 [95% confidence interval, 0.56-1.34]), or undetermined (odds ratio, 0.90 [95% confidence interval, 0.62-1.30]) subtypes. Results were consistent for ischemic stroke and transient ischemic attack, for other scales, and for magnetic resonance imaging and computed tomography separately. In contrast to small vessel ischemic events, WMC were not independently associated with other pathogenic subtypes, suggesting that WMC are unlikely to be an independent risk factor for nonsmall vessel events.


Identification of a small-molecule ligand of the epigenetic reader protein Spindlin1 via a versatile screening platform.
Epigenetic modifications of histone tails play an essential role in the regulation of eukaryotic transcription. Writer and eraser enzymes establish and maintain the epigenetic code by creating or removing posttranslational marks. Specific binding proteins, called readers, recognize the modifications and mediate epigenetic signalling. Here, we present a versatile assay platform for the investigation of the interaction between methyl lysine readers and their ligands. This can be utilized for the screening of small-molecule inhibitors of such protein-protein interactions and the detailed characterization of the inhibition. Our platform is constructed in a modular way consisting of orthogonal in vitro binding assays for ligand screening and verification of initial hits and biophysical, label-free techniques for further kinetic characterization of confirmed ligands. A stability assay for the investigation of target engagement in a cellular context complements the platform. We applied the complete evaluation chain to the Tudor domain containing protein Spindlin1 and established the in vitro test systems for the double Tudor domain of the histone demethylase JMJD2C. We finally conducted an exploratory screen for inhibitors of the interaction between Spindlin1 and H3K4me3 and identified A366 as the first nanomolar small-molecule ligand of a Tudor domain containing methyl lysine reader.


Perceived Benefits, Harms, and Views About How to Share Data Responsibly: A Qualitative Study of Experiences With and Attitudes Toward Data Sharing Among Research Staff and Community Representatives in Thailand.
The Thailand Major Overseas Programme coordinates large multi-center studies in tropical medicine and generates vast amounts of data. As the data sharing movement gains momentum, we wanted to understand attitudes and experiences of relevant stakeholders about what constitutes good data sharing practice. We conducted 15 interviews and three focus groups discussions involving 25 participants and found that they generally saw data sharing as something positive. Data sharing was viewed as a means to contribute to scientific progress and lead to better quality analysis, better use of resources, greater accountability, and more outputs. However, there were also important reservations including potential harms to research participants, their communities, and the researchers themselves. Given these concerns, several areas for discussion were identified: data standardization, appropriate consent models, and governance.


Burden, causes, and outcomes of people with epilepsy admitted to a rural hospital in Kenya.
People with epilepsy (PWE) develop complications and comorbidities often requiring admission to hospital, which adds to the burden on the health system, particularly in low-income countries. We determined the incidence, disability-adjusted life years (DALYs), risk factors, and causes of admissions in PWE. We also examined the predictors of prolonged hospital stay and death using data from linked clinical and demographic surveillance system. We studied children and adults admitted to a Kenyan rural hospital, between January 2003 and December 2011, with a diagnosis of epilepsy. Poisson regression was used to compute incidence and rate ratios, logistic regression to determine associated factors, and the DALY package of the R-statistical software to calculate years lived with disability (YLD) and years of life lost (YLL). The overall incidence of admissions was 45.6/100,000 person-years of observation (PYO) (95% confidence interval [95% CI] 43.0-48.7) and decreased with age (p < 0.001). The overall DALYs were 3.1/1,000 (95% CI, 1.8-4.7) PYO and comprised 55% of YLD. Factors associated with hospitalization were use of antiepileptic drugs (AEDs) (odds ratio [OR] 5.36, 95% CI 2.64-10.90), previous admission (OR 11.65, 95% CI 2.65-51.17), acute encephalopathy (OR 2.12, 95% CI 1.07-4.22), and adverse perinatal events (OR 2.87, 95% CI 1.06-7.74). Important causes of admission were epilepsy-related complications: convulsive status epilepticus (CSE) (38%), and postictal coma (12%). Age was independently associated with prolonged hospital stay (OR 1.02, 95% CI 1.00-1.04) and mortality (OR, 1.07, 95% CI 1.04-1.10). Epilepsy is associated with significant number of admissions to hospital, considerable duration of admission, and mortality. Improved supply of AEDs in the community, early initiation of treatment, and adherence would reduce hospitalization of PWE and thus the burden of epilepsy on the health system.


Peer review of the pesticide risk assessment for bees for the active substance thiamethoxam considering the uses as seed treatments and granules.
The EFSA was asked by the European Commission to perform an updated risk assessment of neonicotinoids, including thiamethoxam, as regards the risk to bees, as a follow-up of previous mandates received from the European Commission on neonicotinoids. The context of the evaluation was that required by the European Commission in accordance with Article 21 of Regulation (EC) No 1107/2009 to review the approval of active substances in light of new scientific and technical knowledge and monitoring data. In this context and in accordance with Article 31 of Regulation (EC) No 178/2002, EFSA has been previously asked by European Commission to organise an open call for data in order to collect new scientific information as regards the risk to bees from the neonicotinoid pesticide active substances clothianidin, thiamethoxam and imidacloprid applied as seed treatments and granules in the EU. The conclusions were reached on the basis of the evaluation of the supported uses as an insecticide of thiamethoxam applied as seed treatments and granules, on the new relevant data collected in the framework of the open call organised by EFSA and on the updated literature search performed by EFSA. The reliable endpoints, appropriate for use in regulatory risk assessment derived from the submitted studies and literature data as well as any other relevant data available at national level and made available to EFSA, are presented. Concerns are identified.


Are interventions to reduce sitting at workplace effective?
It is common for family physicians in developing nations like India to encounter patients whose profession demands sedentary lifestyle. Such patients present with back problems, obesity, cardiovascular diseases and diabetes and ask doctors for advice on how to decrease sitting. Workplaces need to address this issue by inculcating strategies to decrease sitting and improve health of their employees. Occupational physicians too need to suggest evidence-based strategies to employers. This article provides an evidence based summary about what interventions are actually effective for decreasing sitting at workplace.


A novel mouse model of a patient mucolipidosis II mutation recapitulates disease pathology.
Mucolipidosis II (MLII) is a lysosomal storage disorder caused by loss of N-acetylglucosamine-1-phosphotransferase, which tags lysosomal enzymes with a mannose 6-phosphate marker for transport to the lysosome. In MLII, the loss of this marker leads to deficiency of multiple enzymes and non-enzymatic proteins in the lysosome, leading to the storage of multiple substrates. Here we present a novel mouse model of MLII homozygous for a patient mutation in the GNPTAB gene. Whereas the current gene knock-out mouse model of MLII lacks some of the characteristic features of the human disease, our novel mouse model more fully recapitulates the human pathology, showing growth retardation, skeletal and facial abnormalities, increased circulating lysosomal enzymatic activities, intracellular lysosomal storage, and reduced life span. Importantly, MLII behavioral deficits are characterized for the first time, including impaired motor function and psychomotor retardation. Histological analysis of the brain revealed progressive neurodegeneration in the cerebellum with severe Purkinje cell loss as the underlying cause of the ataxic gait. In addition, based on the loss of Npc2 (Niemann-Pick type C 2) protein expression in the brain, the mice were treated with 2-hydroxypropyl-β-cyclodextrin, a drug previously reported to rescue Purkinje cell death in a mouse model of Niemann-Pick type C disease. No improvement in brain pathology was observed. This indicates that cerebellar degeneration is not primarily triggered by loss of Npc2 function. This study emphasizes the value of modeling MLII patient mutations to generate clinically relevant mouse mutants to elucidate the pathogenic molecular pathways of MLII and address their amenability to therapy.


Increased sensitivity in proton transfer reaction mass spectrometry by incorporation of a radio frequency ion funnel.
A drift tube capable of simultaneously functioning as an ion funnel is demonstrated in proton transfer reaction mass spectrometry (PTR-MS) for the first time. The ion funnel enables a much higher proportion of ions to exit the drift tube and enter the mass spectrometer than would otherwise be the case. An increase in the detection sensitivity for volatile organic compounds of between 1 and 2 orders of magnitude is delivered, as demonstrated using several compounds. Other aspects of analytical performance explored in this study include the effective E/N (ratio of electric field to number density of the gas) and dynamic range over which the drift tube is operated. The dual-purpose drift tube/ion funnel can be coupled to various types of mass spectrometers to increase the detection sensitivity and may therefore offer considerable benefits in PTR-MS work.


Regulation of parkin and PINK1 by neddylation.
Neddylation is a posttranslational modification that plays important roles in regulating protein structure and function by covalently conjugating NEDD8, an ubiquitin-like small molecule, to the substrate. Here, we report that Parkinson's disease (PD)-related parkin and PINK1 are NEDD8 conjugated. Neddylation of parkin and PINK1 results in increased E3 ligase activity of parkin and selective stabilization of the 55 kDa PINK1 fragment. Expression of dAPP-BP1, a NEDD8 activation enzyme subunit, in Drosophila suppresses abnormalities induced by dPINK1 RNAi. PD neurotoxin MPP(+) inhibits neddylation of both parkin and PINK1. NEDD8 immunoreactivity is associated with Lewy bodies in midbrain dopaminergic neurons of PD patients. Together, these results suggest that parkin and PINK1 are regulated by neddylation and that impaired NEDD8 modification of these proteins likely contributes to PD pathogenesis.


Ovarian cancer and body size: individual participant meta-analysis including 25,157 women with ovarian cancer from 47 epidemiological studies.
Only about half the studies that have collected information on the relevance of women's height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships. Individual data on 25,157 women with ovarian cancer and 81,311 women without ovarian cancer from 47 epidemiological studies were collected, checked, and analysed centrally. Adjusted relative risks of ovarian cancer were calculated, by height and by body mass index. Ovarian cancer risk increased significantly with height and with body mass index, except in studies using hospital controls. For other study designs, the relative risk of ovarian cancer per 5 cm increase in height was 1.07 (95% confidence interval [CI], 1.05-1.09; p<0.001); this relationship did not vary significantly by women's age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. For body mass index, there was significant heterogeneity (p<0.001) in the findings between ever-users and never-users of menopausal hormone therapy, but not by the 11 other factors listed above. The relative risk for ovarian cancer per 5 kg/m(2) increase in body mass index was 1.10 (95% CI, 1.07-1.13; p<0.001) in never-users and 0.95 (95% CI, 0.92-0.99; p=0.02) in ever-users of hormone therapy. Ovarian cancer is associated with height and, among never-users of hormone therapy, with body mass index. In high-income countries, both height and body mass index have been increasing in birth cohorts now developing the disease. If all other relevant factors had remained constant, then these increases in height and weight would be associated with a 3% increase in ovarian cancer incidence per decade. Please see later in the article for the Editors' Summary.


Neural and behavioral substrates of mood and mood regulation.
A review of behavioral and neurobiological data on mood and mood regulation as they pertain to an understanding of mood disorders is presented. Four approaches are considered: 1) behavioral and cognitive; 2) neurobiological; 3) computational; and 4) developmental. Within each of these four sections, we summarize the current status of the field and present our vision for the future, including particular challenges and opportunities. We conclude with a series of specific recommendations for National Institute of Mental Health priorities. Recommendations are presented for the behavioral domain, the neural domain, the domain of behavioral-neural interaction, for training, and for dissemination. It is in the domain of behavioral-neural interaction, in particular, that new research is required that brings together traditions that have developed relatively independently. Training interdisciplinary clinical scientists who meaningfully draw upon both behavioral and neuroscientific literatures and methods is critically required for the realization of these goals.