Alcohol use and misuse, self-harm and subsequent mortality: an epidemiological and longitudinal study from the multicentre study of self-harm in England.
Alcohol use and misuse are strongly associated with self-harm and increased risk of future self-harm and suicide. The UK general population prevalence of alcohol use, misuse and alcohol-attributable harm has been rising. We have investigated the prevalence of and trends in alcohol use and misuse in self-harm patients and their associations with repeat self-harm and subsequent death. We used patient data from the Multicentre Study of Self-Harm in England for 2000-2009 and UK mortality data for patients presenting from 2000 to 2007 who were followed up to the end of 2009. Alcohol involvement in acts of self-harm (58.4%) and alcohol misuse (36.1%) were somewhat higher than found previously in self-harm patients. Alcohol involvement and misuse were most frequent in men, those aged 35-54 years and those from white ethnicities. The frequency of alcohol misuse increased between 2000 and 2009, especially in women. Repetition of self-harm was associated with alcohol involvement in self-harm and particularly with alcohol misuse. Risk of suicide was increased significantly in women misusing alcohol. Alcohol use and misuse in self-harm patients appears to have increased in recent years, particularly in women. The association of alcohol with greater risk of self-harm repetition and mortality highlights the need for clinicians to investigate alcohol use in self-harm patients. Ready availability of alcohol treatment staff in general hospitals could facilitate appropriate aftercare and the prevention of adverse outcomes.


Sleep-dependent memory consolidation and accelerated forgetting.
Accelerated long-term forgetting (ALF) is a form of memory impairment in which learning and initial retention of information appear normal but subsequent forgetting is excessively rapid. ALF is most commonly associated with epilepsy and, in particular, a form of late-onset epilepsy called transient epileptic amnesia (TEA). ALF provides a novel opportunity to investigate post-encoding memory processes, such as consolidation. Sleep is implicated in the consolidation of memory in healthy people and a deficit in sleep-dependent memory consolidation has been proposed as an explanation for ALF. If this proposal were correct, then sleep would not benefit memory retention in people with ALF as much as in healthy people, and ALF might only be apparent when the retention interval contains sleep. To test this theory, we compared performance on a sleep-sensitive memory task over a night of sleep and a day of wakefulness. We found, contrary to the hypothesis, that sleep benefits memory retention in TEA patients with ALF and that this benefit is no smaller in magnitude than that seen in healthy controls. Indeed, the patients performed significantly more poorly than the controls only in the wake condition and not the sleep condition. Patients were matched to controls on learning rate, initial retention, and the effect of time of day on cognitive performance. These results indicate that ALF is not caused by a disruption of sleep-dependent memory consolidation. Instead, ALF may be due to an encoding abnormality that goes undetected on behavioural assessments of learning, or by a deficit in memory consolidation processes that are not sleep-dependent.


Comparative responsiveness and minimal change for the Oxford Elbow Score following surgery.
To assess the responsiveness and minimal change for the Oxford Elbow Score (OES) using anchor- and distribution-based approaches. A prospective observational study of 104 patients undergoing elbow surgery at a specialist orthopaedic hospital was carried out. Patients completed the OES and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaires (both scored on a 0 to 100 scale) pre- and 6 months post-surgery. Transition items (used as anchors) assessed perceived changes following surgery. Indicators of responsiveness were the effect size; the anchor-based minimal clinically important difference (MCID) and best cut-point on the receiver operator characteristic (ROC) curve; and the distribution-based minimal detectable change (MDC). The three elbow-specific OES scales (Function, Pain, Social-Psychological) produced generally larger effect sizes (0.79, 1.14 and 1.18, respectively) than the upper-limb-specific DASH scale (0.76). Clear associations were observed between transition items and all OES and DASH scores (all r > |0.35|). The MCIDs for the OES Function scale and the DASH were similar (approximately 10), but were larger for the OES Pain and Social-Psychological scales (approximately 18), reflecting their lower (i.e. poorer) baseline scores and larger effect sizes. The MCIDs were, however, only consistently larger than the MDCs for the OES Pain domain. The OES Function scale and the DASH performed similarly on ROC analysis, but with the OES Pain and Social-Psychological scales demonstrating superior efficiency. For elbow surgery, the 12-item three-scale OES is highly responsive to 6-month post-operative outcomes, with its performance being generally better than that of the 30-item one-scale DASH. Study estimates of minimal change for the OES may be useful for informing sample size calculations and interpreting outcomes in future clinical trials.


The interaction of affective with psychotic processes: a test of the effects of worrying on working memory, jumping to conclusions, and anomalies of experience in patients with persecutory delusions.
Worry has traditionally been considered in the study of common emotional disorders such as anxiety and depression, but recent studies indicate that worry may be a causal factor in the occurrence and persistence of persecutory delusions. The effect of worry on processes traditionally associated with psychosis has not been tested. The aim of the study was to examine the short-term effects of a bout of worry on three cognitive processes typically considered markers of psychosis: working memory, jumping to conclusions, and anomalous internal experience. Sixty-seven patients with persecutory delusions in the context of a non-affective psychotic disorder were randomised to a worry induction, a worry reduction, or a neutral control condition. They completed tests of the cognitive processes before and after the randomisation condition. The worry induction procedure led to a significant increase in worry. The induction of worry did not affect working memory or jumping to conclusions, but it did increase a range of mild anomalous experiences including feelings of unreality, perceptual alterations, and temporal disintegration. Worry did not affect the occurrence of hallucinations. The study shows that a period of worry causes a range of subtle odd perceptual disturbances that are known to increase the likelihood of delusions. It demonstrates an interaction between affective and psychotic processes in patients with delusions.


Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease.
The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of the ECM contributes to a broad range of neurological disorders. However, despite this importance, our understanding of the ECM composition remains very limited mainly due to difficulties in its isolation. To address this, we developed an approach to extract the cerebrovascular ECM from mouse and human post-mortem normal brain tissues. We then used mass spectrometry with off-line high-pH reversed-phase fractionation to increase the protein detection. This identified more than 1000 proteins in the ECM-enriched fraction, with > 66% of the proteins being common between the species. We report 147 core ECM proteins of the human brain vascular matrisome, including collagens, laminins, fibronectin and nidogens. We next used network analysis to identify the connection between the brain ECM proteins and cerebrovascular diseases. We found that genes related to cerebrovascular diseases, such as COL4A1, COL4A2, VCAN and APOE were significantly enriched in the cerebrovascular ECM network. This provides unique mechanistic insight into cerebrovascular disease and potential drug targets. Overall, we provide a powerful resource to study the functions of brain ECM and highlight a specific role for brain vascular ECM in cerebral vascular disease.


Ischemic heart disease: comprehensive evaluation by cardiovascular magnetic resonance.
Considerable technical advances over the past decade have increased the clinical application of cardiovascular magnetic resonance (CMR) imaging. A comprehensive CMR examination can accurately measure left and right ventricular size and function, identify the presence and extent of reversible versus irreversible myocardial injury, and detect inducible ischemia. Streamlined protocols allow such a CMR examination to be a time-efficient diagnostic tool in patients with coronary artery disease. Moreover, edema imaging with T2-weighted CMR allows the detection of acute coronary syndromes. In this review, we present the relevant CMR methods and discuss practical uses of CMR in acute and chronic ischemic heart disease.


Risk of pneumococcal bacteremia in Kenyan children with glucose-6-phosphate dehydrogenase deficiency.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency state in humans. The clinical phenotype is variable and includes asymptomatic individuals, episodic hemolysis induced by oxidative stress, and chronic hemolysis. G6PD deficiency is common in malaria-endemic regions, an observation hypothesized to be due to balancing selection at the G6PD locus driven by malaria. G6PD deficiency increases risk of severe malarial anemia, a key determinant of invasive bacterial disease in malaria-endemic settings. The pneumococcus is a leading cause of invasive bacterial infection and death in African children. The effect of G6PD deficiency on risk of pneumococcal disease is undefined. We hypothesized that G6PD deficiency increases pneumococcal disease risk and that this effect is dependent upon malaria. We performed a genetic case-control study of pneumococcal bacteremia in Kenyan children stratified across a period of falling malaria transmission between 1998 and 2010. Four hundred twenty-nine Kenyan children with pneumococcal bacteremia and 2677 control children were included in the study. Among control children, G6PD deficiency, secondary to the rs1050828 G>A mutation, was common, with 11.2% (n = 301 of 2677) being hemi- or homozygotes and 33.3% (n = 442 of 1329) of girls being heterozygotes. We found that G6PD deficiency increased the risk of pneumococcal bacteremia, but only during a period of high malaria transmission (P = 0.014; OR 2.33, 95% CI 1.19-4.57). We estimate that the population attributable fraction of G6PD deficiency on risk of pneumococcal bacteremia in areas under high malaria transmission is 0.129. Our data demonstrate that G6PD deficiency increases risk of pneumococcal bacteremia in a manner dependent on malaria. At the population level, the impact of G6PD deficiency on invasive pneumococcal disease risk in malaria-endemic regions is substantial. Our study highlights the infection-associated morbidity and mortality conferred by G6PD deficiency in malaria-endemic settings and adds to our understanding of the potential indirect health benefits of improved malaria control.


3D multi-slab diffusion-weighted readout-segmented EPI with real-time cardiac-reordered K-space acquisition.
The aim of this study was to develop, implement, and demonstrate a three-dimensional (3D) extension of the readout-segmented echo-planar imaging (rs-EPI) sequence for diffusion imaging. Potential k-space acquisition schemes were assessed by simulating their associated spatial point spread functions. Motion-induced phase artifacts were also simulated to test navigator corrections and a real-time reordering of the k-space acquisition relative to the cardiac cycle. The cardiac reordering strategy preferentially chooses readout segments closer to the center of 3D k-space during diastole. Motion-induced phase artifacts were quantified by calculating the voxel-wise temporal variation in a set of repeated diffusion-weighted acquisitions. Based on the results of these simulations, a 2D navigated multi-slab rs-EPI sequence with real-time cardiac reordering was implemented. The multi-slab implementation enables signal-to-noise ratio-optimal repetition times of 1-2 s. Cardiac reordering was validated in simulations and in vivo using the multi-slab rs-EPI sequence. In comparisons with standard k-space acquisitions, cardiac reordering was shown to reduce the variability due to motion-induced phase artifacts by 30-50%. High-resolution diffusion tensor imaging data acquired with the cardiac-reordered multi-slab rs-EPI sequence are presented. A 3D multi-slab rs-EPI sequence with cardiac reordering has been demonstrated in vivo and is shown to provide high-quality 3D diffusion-weighted data sets.


Smoking, secondhand smoke, and cotinine levels in a subset of EPIC cohort.
Several countries are discussing new legislation regarding the ban on smoking in public places, based on the growing evidence of the hazards of secondhand smoke (SHS) exposure. The objective of the present study is to quantitatively assess the relationship between smoking, SHS, and serum cotinine levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From a study on lung cancer in the EPIC cohort, questionnaire information on smoking was collected at enrolment, and cotinine was measured in serum. Three statistical models were applied by using samples available in a cross-section design: (i) cotinine levels by categories combining smoking and SHS (n = 859); (ii) the effect of hours of passive smoking exposure in nonsmokers only (n = 107); (iii) the effect of the number of cigarettes consumed per day in current smokers only (n = 832). All models were adjusted for country, sex, age, and body mass index. Among nonsmokers, passive smokers presented significant differences in cotinine compared with nonexposed, with a marked (but not significant) difference among former-smokers. A one hour per day increment of SHS gave rise to a significant 2.58 nmol/L (0.45 ng/mL) increase in mean serum cotinine (P < 0.001). In current smokers, a one cigarette per day increment gave rise to a significant 22.44 nmol/L (3.95 ng/mL) increase in cotinine mean (P < 0.001). There is clear evidence that not only tobacco smoking but also involuntary exposure increases cotinine levels. This study strengthens the evidence for the benefits of a smoking ban in public places.


Effect of tubular inhomogeneities on filter properties of thick ascending limb of Henle's loop.
We used a simple mathematical model of rat thick ascending limb (TAL) of the loop of Henle to predict the impact of spatially inhomogeneous NaCl permeability, spatially inhomogeneous NaCl active transport, and spatially inhomogeneous tubular radius on luminal NaCl concentration when sustained, sinusoidal perturbations were superimposed on steady-state TAL flow. A mathematical model previously devised by us that used homogeneous TAL transport and fixed TAL radius predicted that such perturbations result in TAL luminal fluid NaCl concentration profiles that are standing waves. That study also predicted that nodes in NaCl concentration occur at the end of the TAL when the tubular fluid transit time equals the period of a periodic perturbation, and that, for non-nodal periods, sinusoidal perturbations generate non-sinusoidal oscillations (and thus a series of harmonics) in NaCl concentration at the TAL end. In the present study we find that the inhomogeneities transform the standing waves and their associated nodes into approximate standing waves and approximate nodes. The impact of inhomogeneous NaCl permeability is small. However, for inhomogeneous active transport or inhomogeneous radius, the oscillations for non-nodal periods tend to be less sinusoidal and more distorted than in the homogeneous case and to thus have stronger harmonics. Both the homogeneous and non-homogeneous cases predict that the TAL, in its transduction of flow oscillations into concentration oscillations, acts as a low-pass filter, but the inhomogeneities result in a less effective filter that has accentuated non-linearities.


LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation.
Eukaryotic cells have a layer of heterochromatin at the nuclear periphery. To investigate mechanisms regulating chromatin distribution, we analyzed heterochromatin organization in different tissues and species, including mice with mutations in the lamin B receptor (Lbr) and lamin A (Lmna) genes that encode nuclear envelope (NE) proteins. We identified LBR- and lamin-A/C-dependent mechanisms tethering heterochromatin to the NE. The two tethers are sequentially used during cellular differentiation and development: first the LBR- and then the lamin-A/C-dependent tether. The absence of both LBR and lamin A/C leads to loss of peripheral heterochromatin and an inverted architecture with heterochromatin localizing to the nuclear interior. Myoblast transcriptome analyses indicated that selective disruption of the LBR- or lamin-A-dependent heterochromatin tethers have opposite effects on muscle gene expression, either increasing or decreasing, respectively. These results show how changes in NE composition contribute to regulating heterochromatin positioning, gene expression, and cellular differentiation during development.


Connection of discontinuous segments in early functional recovery from thoracic ossification of the posterior longitudinal ligament treated with posterior instrumented surgery.
The objective of this study was to investigate the relationship between morphological changes in thoracic ossification of the posterior longitudinal ligament (T-OPLL) and postoperative neurological recovery after thoracic posterior fusion surgery. Changes of OPLL morphology and postoperative recovery in cases with T-OPLL have not been examined. In this prospective study, the authors evaluated data from 44 patients (23 male and 21 female) who underwent posterior decompression and fusion surgery with instrumentation for the treatment of T-OPLL at our hospital. The patients' mean age at surgery was 50.7 years (range 38-68 years). The minimum duration of follow-up was 2 years. The location of thoracic ossification of the ligamentum flavum (T-OLF), T-OLF at the OPLL level, OPLL morphology, fusion range, estimated blood loss, operative time, pre- and postoperative Japanese Orthopaedic Association (JOA) scores, and JOA recovery rate were investigated. Reconstructed sagittal multislice CT images were obtained before and at 3 and 6 months and 1 and 2 years after surgery. The basic fusion area was 3 vertebrae above and below the OPLL lesion. All parameters were compared between patients with and without continuity across the disc space at the OPLL at 3 and 6 months after surgery. The preoperative morphology of OPLL was discontinuous across the disc space between the rostral and caudal ossification regions on sagittal CT images in all but one of the patients. Postoperatively, these segments became continuous in 42 patients (97.7%; occurring by 6.6 months on average) without progression of OPLL thickness. Patients with continuity at 3 months had significantly lower rates of diabetes mellitus (p < 0.05) and motor palsy in the lower extremities (p < 0.01). The group with continuity also had significantly higher mean postoperative JOA scores at 3 (p < 0.01) and 6 (p < 0.05) months and mean JOA recovery rates at 3 and 6 months (both p < 0.01) after surgery. Preoperatively, discontinuity of rostral and caudal ossified lesions was found on CT in all patients but one of this group of 44 patients who needed surgery for T-OPLL. Rigid fixation with instrumentation may have allowed these segments to connect at the OPLL. Such OPLL continuity at an early stage after surgery may accelerate spinal cord recovery.


Physical and social contextual influences on children's leisure-time physical activity: an ecological momentary assessment study.
This study used real-time electronic surveys delivered through mobile phones, known as Ecological Momentary Assessment (EMA), to determine whether level and experience of leisure-time physical activity differ across children's physical and social contexts. Children (N = 121; ages 9 to 13 years; 52% male, 32% Hispanic/Latino) participated in 4 days (Fri.-Mon.) of EMA during nonschool time. Electronic surveys (20 total) assessed primary activity (eg, active play/sports/exercise), physical location (eg, home, outdoors), social context (eg, friends, alone), current mood (positive and negative affect), and enjoyment. Responses were time-matched to the number of steps and minutes of moderate-to-vigorous physical activity (MVPA; measured by accelerometer) in the 30 minutes before each survey. Mean steps and MVPA were greater outdoors than at home or at someone else's house (all P < .05). Steps were greater with multiple categories of company (eg, friends and family together) than with family members only or alone (all P < .05). Enjoyment was greater outdoors than at home or someone else's house (all P < .05). Negative affect was greater when alone and with family only than friends only (all P < .05). Results describing the value of outdoor and social settings could inform context-specific interventions in this age group.


Association between SNP heterozygosity and quantitative traits in the Framingham Heart Study.
Associations between multilocus heterozygosity and fitness traits, also termed heterozygosity and fitness correlations (HFCs), have been reported in numerous organisms. These studies, in general, indicate a positive relationship between heterozygosity and fitness traits. We studied the association between genome-wide heterozygosity at 706 non-synonymous and synonymous SNPs and 19 quantitative traits, including morphological, biochemical and fitness traits in the Framingham Heart Study. Statistically significant association was found between heterozygosity and systolic and diastolic blood pressures as well as left ventricular diameter and wall thickness. These results suggest that heterozygosity may be associated with traits, such as blood pressure that closely track environmental variations. Balancing selection may be operating in the maintenance of heterozygosity and the major components of blood pressure and hypertension. Genome wide SNP heterozygosity may be used to understand the phenomenon of dominance as well as the evolutionary basis of many quantitative traits in humans.


Planar patch clamp approach to characterize ionic currents from intact lysosomes.
Since its launch in the early 1980s, the patch clamp method has been extensively used to study ion channels in the plasma membrane, but its application to the study of intracellular ion channels has been limited. Unlike the plasma membrane, intracellular membranes are usually not stable enough to withstand mechanical manipulation by glass electrodes during seal formation and rupturing of the membrane. To circumvent these problems, we developed a method involving the immobilization of isolated organelles on a solid matrix planar glass chip. This glass chip contains a microstructured hole that supports the formation of gigaseals and subsequent electrophysiological recordings despite the high fragility of intracellular membranes. Here, we report the experimental details of this method using lysosomes, which are the smallest cellular organelles, as a model system. We demonstrate that we can record endogenous ionic currents from wild-type lysosomes, as well as from lysosomes overexpressing ion channels, and expect that this method will provide electrophysiological access to a broad range of intracellular ion channels.


Chronic cough due to occupational factors.
Within the large variety of subtypes of chronic cough, either defined by their clinical or pathogenetic causes, occupational chronic cough may be regarded as one of the most preventable forms of the disease. Next to obstructive airway diseases such as asthma or chronic obstructive pulmonary disease, which are sometimes concomitant with chronic cough, this chronic airway disease gains importance in the field of occupational medicine since classic fiber-related occupational airway diseases will decrease in the future. Apart from acute accidents and incidental exposures which may lead to an acute form of cough, there are numerous sources for the development of chronic cough within the workplace. Over the last years, a large number of studies has focused on occupational causes of respiratory diseases and it has emerged that chronic cough is one of the most prevalent work-related airway diseases. Best-known examples of occupations related to the development of cough are coal miners, hard-rock miners, tunnel workers, or concrete manufacturing workers. As chronic cough is often based on a variety of non-occupational factors such as tobacco smoke, a distinct separation into either occupational or personally -evoked can be difficult. However, revealing the occupational contribution to chronic cough and to the symptom cough in general, which is the commonest cause for the consultation of a physician, can significantly lead to a reduction of the socioeconomic burden of the disease.


Competitive figure skating injuries.
The nature, type and frequency of injuries occurring at a national figure skating competition were examined. Data was compiled from the medical history form of all 208 participants and the on-site evaluations of the 55 skaters who presented for treatment. Twenty-six percent of all the skaters were injured during the competition. Senior skaters accounted for more injuries than their junior counterparts. Pairs skaters appeared to be more susceptible to injury, incurring significantly more injuries than singles or dance skaters. As in other reports, injuries to the lower extremities predominated. Low back injury comprised 14.6% of all injuries. Thirty-five (64%) of the 55 injuries were exacerbations of a pre-existing injury and twenty (36%) were new ones. Most competitive figure skating injuries are of the overuse type, suggesting a need to evaluate predisposing factors and methods of rehabilitation.


Incidence of convulsive epilepsy in a rural area in Kenya.
There are only a few studies of incidence of epilepsy in low and middle income countries (LMICs). These are often small and conducted in specific age groups or areas where the prevalence of risk factors is high; therefore, these studies are not representative of the wider populations. We determined the incidence of convulsive epilepsy (CE) in a large rural population in Kenya. We conducted two cross-sectional surveys 5 years apart within a health and demographic surveillance system. Initially we identified residents without epilepsy who were then reexamined in the follow-up survey to determine incidence. We estimated the overall incidence of CE and incidence by age-group, sex, and by administrative location. Estimates were adjusted for attrition during case identification and for the sensitivity of the screening method. In a cohort of 151,408 people, 194 developed CE over the 5 years. The minimum crude incidence rate was 37.6/100,000 persons per year (95% confidence interval (CI) 32.7-43.3) and adjusted for loss to follow-up, and the sensitivity of the survey methodology was 77.0/100,000 persons per year (95% CI 67.7-87.4). Incidence was highest in children 6-12 years (96.1/100,000 persons per year; 95% CI 78.4-117.9), and was lowest in the 29-49 year age group (37.4/100,000 persons per year; 95% CI 25.7-54.7). We estimated a high incidence of convulsive epilepsy in this population. Incidence was highest early and late in life, suggesting that preventive interventions should target exposures that occur in these age groups. Incidence of focal epilepsy was more than twice that of generalized epilepsy, suggesting that etiologies that are amenable to intervention were most important in this population. It is likely that incidence is underestimated because of the early mortality of incident cases.


Novel methodologies for biomarker discovery in atherosclerosis.
Identification of subjects at increased risk for cardiovascular events plays a central role in the worldwide efforts to improve prevention, prediction, diagnosis, and prognosis of cardiovascular disease and to decrease the related costs. Despite their high predictive value on population level, traditional risk factors fail to fully predict individual risk. This position paper provides a summary of current vascular biomarkers other than the traditional risk factors with a special focus on the emerging -omics technologies. The definition of biomarkers and the identification and use of classical biomarkers are introduced, and we discuss the limitations of current biomarkers such as high sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (NT-proBNP). This is complemented by circulating plasma biomarkers, including high-density lipoprotein (HDL), and the conceptual shift from HDL cholesterol levels to HDL composition/function for cardiovascular risk assessment. Novel sources for plasma-derived markers include microparticles, microvesicles, and exosomes and their use for current omics-based analytics. Measurement of circulating micro-RNAs, short RNA sequences regulating gene expression, has attracted major interest in the search for novel biomarkers. Also, mass spectrometry and nuclear magnetic resonance spectroscopy have become key complementary technologies in the search for new biomarkers, such as proteomic searches or identification and quantification of small metabolites including lipids (metabolomics and lipidomics). In particular, pro-inflammatory lipid metabolites have gained much interest in the cardiovascular field. Our consensus statement concludes on leads and needs in biomarker research for the near future to improve individual cardiovascular risk prediction.


Congenital pulmonary lymphangiectasia.
Congenital pulmonary lymphangiectasia (PL) is a rare developmental disorder involving the lung, and characterized by pulmonary subpleural, interlobar, perivascular and peribronchial lymphatic dilatation. The prevalence is unknown. PL presents at birth with severe respiratory distress, tachypnea and cyanosis, with a very high mortality rate at or within a few hours of birth. Most reported cases are sporadic and the etiology is not completely understood. It has been suggested that PL lymphatic channels of the fetal lung do not undergo the normal regression process at 20 weeks of gestation. Secondary PL may be caused by a cardiac lesion. The diagnostic approach includes complete family and obstetric history, conventional radiologic studies, ultrasound and magnetic resonance studies, lymphoscintigraphy, lung functionality tests, lung biopsy, bronchoscopy, and pleural effusion examination. During the prenatal period, all causes leading to hydrops fetalis should be considered in the diagnosis of PL. Fetal ultrasound evaluation plays a key role in the antenatal diagnosis of PL. At birth, mechanical ventilation and pleural drainage are nearly always necessary to obtain a favorable outcome of respiratory distress. Home supplemental oxygen therapy and symptomatic treatment of recurrent cough and wheeze are often necessary during childhood, sometimes associated with prolonged pleural drainage. Recent advances in intensive neonatal care have changed the previously nearly fatal outcome of PL at birth. Patients affected by PL who survive infancy, present medical problems which are characteristic of chronic lung disease.


Association of Random Plasma Glucose Levels With the Risk for Cardiovascular Disease Among Chinese Adults Without Known Diabetes.
Diabetes is a known risk factor for cardiovascular disease (CVD). Substantial uncertainty remains, however, about the relevance to CVD risk for blood glucose levels below the diabetes threshold. To examine the association of random plasma glucose (RPG) levels with the risk for major CVD in Chinese adults without known diabetes. This prospective cohort study included 467 508 men and women aged 30 to 79 years with no history of diabetes, ischemic heart disease (IHD), stroke, or transient ischemic attack. Participants were recruited from 5 urban and 5 rural diverse locations across China from June 25, 2004, to July 15, 2008, and followed up to January 1, 2014. Baseline and usual (longer-term average) RPG level. Cardiovascular deaths, major coronary events (MCE) (including fatal IHD and nonfatal myocardial infarction), ischemic stroke (IS), major occlusive vascular disease (MOVD) (including MCE or IS), and intracerebral hemorrhage. Preliminary validation of stroke and IHD events demonstrated positive predictive values of approximately 90% and 85%, respectively. Cox regression yielded adjusted hazard ratios (aHRs) for CVD associated with RPG levels. Among the 467 508 participants (41.0% men; 59.0% women; mean [SD] age, 51 [11] years), a significant positive association of baseline RPG levels with CVD risks continued to 4.0 mmol/L (72 mg/dL). After adjusting for regression dilution bias, each 1-mmol/L (18-mg/dL) higher usual RPG level above 5.9 mmol/L (106 mg/dL) was associated with an 11% higher risk for cardiovascular death (6645 deaths; aHR, 1.11; 95% CI, 1.10-1.13). Similarly strong positive associations were seen for MCE (3270 events; aHR, 1.10; 95% CI, 1.08-1.13), IS (19 153 events; aHR, 1.08; 95% CI, 1.07-1.09), and MOVD (22 023 events; aHR, 1.08; 95% CI, 1.07-1.09). For intracerebral hemorrhage, the association was weaker, but also significant (4326 events; aHR, 1.05; 95% CI, 1.02-1.07). These associations persisted after excluding participants who developed diabetes during follow-up. Among adult Chinese without diabetes, lower RPG levels are associated with lower risks for major CVDs, even within a normal range of blood glucose levels.


The implications of non-linear biological oscillations on human electrophysiology for electrohypersensitivity (EHS) and multiple chemical sensitivity (MCS).
The 'informational content' of Earth's electromagnetic signaling is like a set of operating instructions for human life. These environmental cues are dynamic and involve exquisitely low inputs (intensities) of critical frequencies with which all life on Earth evolved. Circadian and other temporal biological rhythms depend on these fluctuating electromagnetic inputs to direct gene expression, cell communication and metabolism, neural development, brainwave activity, neural synchrony, a diversity of immune functions, sleep and wake cycles, behavior and cognition. Oscillation is also a universal phenomenon, and biological systems of the heart, brain and gut are dependent on the cooperative actions of cells that function according to principles of non-linear, coupled biological oscillations for their synchrony. They are dependent on exquisitely timed cues from the environment at vanishingly small levels. Altered 'informational content' of environmental cues can swamp natural electromagnetic cues and result in dysregulation of normal biological rhythms that direct growth, development, metabolism and repair mechanisms. Pulsed electromagnetic fields (PEMF) and radiofrequency radiation (RFR) can have the devastating biological effects of disrupting homeostasis and desynchronizing normal biological rhythms that maintain health. Non-linear, weak field biological oscillations govern body electrophysiology, organize cell and tissue functions and maintain organ systems. Artificial bioelectrical interference can give false information (disruptive signaling) sufficient to affect critical pacemaker cells (of the heart, gut and brain) and desynchronize functions of these important cells that orchestrate function and maintain health. Chronic physiological stress undermines homeostasis whether it is chemically induced or electromagnetically induced (or both exposures are simultaneous contributors). This can eventually break down adaptive biological responses critical to health maintenance; and resilience can be compromised. Electrohypersensitivity can be caused by successive assaults on human bioelectrochemical dynamics from exogenous electromagnetic fields (EMF) and RFR or a single acute exposure. Once sensitized, further exposures are widely reported to cause reactivity to lower and lower intensities of EMF/RFR, at which point thousand-fold lower levels can cause adverse health impacts to the electrosensitive person. Electrohypersensitivity (EHS) can be a precursor to, or linked with, multiple chemical sensitivity (MCS) based on reports of individuals who first develop one condition, then rapidly develop the other. Similarity of chemical biomarkers is seen in both conditions [histamines, markers of oxidative stress, auto-antibodies, heat shock protein (HSP), melatonin markers and leakage of the blood-brain barrier]. Low intensity pulsed microwave activation of voltage-gated calcium channels (VGCCs) is postulated as a mechanism of action for non-thermal health effects.


Cell-specific information processing in segregating populations of Eph receptor ephrin-expressing cells.
Cells have self-organizing properties that control their behavior in complex tissues. Contact between cells expressing either B-type Eph receptors or their transmembrane ephrin ligands initiates bidirectional signals that regulate cell positioning. However, simultaneously investigating how information is processed in two interacting cell types remains a challenge. We implemented a proteomic strategy to systematically determine cell-specific signaling networks underlying EphB2- and ephrin-B1-controlled cell sorting. Quantitative mass spectrometric analysis of mixed populations of EphB2- and ephrin-B1-expressing cells that were labeled with different isotopes revealed cell-specific tyrosine phosphorylation events. Functional associations between these phosphotyrosine signaling networks and cell sorting were established with small interfering RNA screening. Data-driven network modeling revealed that signaling between mixed EphB2- and ephrin-B1-expressing cells is asymmetric and that the distinct cell types use different tyrosine kinases and targets to process signals induced by cell-cell contact. We provide systems- and cell-specific network models of contact-initiated signaling between two distinct cell types.


The global burden of tuberculosis: results from the Global Burden of Disease Study 2015.
An understanding of the trends in tuberculosis incidence, prevalence, and mortality is crucial to tracking of the success of tuberculosis control programmes and identification of remaining challenges. We assessed trends in the fatal and non-fatal burden of tuberculosis over the past 25 years for 195 countries and territories. We analysed 10 691 site-years of vital registration data, 768 site-years of verbal autopsy data, and 361 site-years of mortality surveillance data using the Cause of Death Ensemble model to estimate tuberculosis mortality rates. We analysed all available age-specific and sex-specific data sources, including annual case notifications, prevalence surveys, and estimated cause-specific mortality, to generate internally consistent estimates of incidence, prevalence, and mortality using DisMod-MR 2.1, a Bayesian meta-regression tool. We assessed how observed tuberculosis incidence, prevalence, and mortality differed from expected trends as predicted by the Socio-demographic Index (SDI), a composite indicator based on income per capita, average years of schooling, and total fertility rate. We also estimated tuberculosis mortality and disability-adjusted life-years attributable to the independent effects of risk factors including smoking, alcohol use, and diabetes. Globally, in 2015, the number of tuberculosis incident cases (including new and relapse cases) was 10·2 million (95% uncertainty interval 9·2 million to 11·5 million), the number of prevalent cases was 10·1 million (9·2 million to 11·1 million), and the number of deaths was 1·3 million (1·1 million to 1·6 million). Among individuals who were HIV negative, the number of incident cases was 8·8 million (8·0 million to 9·9 million), the number of prevalent cases was 8·9 million (8·1 million to 9·7 million), and the number of deaths was 1·1 million (0·9 million to 1·4 million). Annualised rates of change from 2005 to 2015 showed a faster decline in mortality (-4·1% [-5·0 to -3·4]) than in incidence (-1·6% [-1·9 to -1·2]) and prevalence (-0·7% [-1·0 to -0·5]) among HIV-negative individuals. The SDI was inversely associated with HIV-negative mortality rates but did not show a clear gradient for incidence and prevalence. Most of Asia, eastern Europe, and sub-Saharan Africa had higher rates of HIV-negative tuberculosis burden than expected given their SDI. Alcohol use accounted for 11·4% (9·3-13·0) of global tuberculosis deaths among HIV-negative individuals in 2015, diabetes accounted for 10·6% (6·8-14·8), and smoking accounted for 7·8% (3·8-12·0). Despite a concerted global effort to reduce the burden of tuberculosis, it still causes a large disease burden globally. Strengthening of health systems for early detection of tuberculosis and improvement of the quality of tuberculosis care, including prompt and accurate diagnosis, early initiation of treatment, and regular follow-up, are priorities. Countries with higher than expected tuberculosis rates for their level of sociodemographic development should investigate the reasons for lagging behind and take remedial action. Efforts to prevent smoking, alcohol use, and diabetes could also substantially reduce the burden of tuberculosis. Bill & Melinda Gates Foundation.


The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function.
Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues and gene sets contributing to mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health.


Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors.
Human cytomegalovirus (HCMV) infection is largely asymptomatic in the immunocompetent host, but remains a major cause of morbidity in immunosuppressed individuals. Using the recently described technique of staining antigen-specific CD8(+) T cells with peptide-HLA tetrameric complexes, we have demonstrated high levels of antigen-specific cells specific for HCMV peptides and show that this may exceed 4% of CD8(+) T cells in immunocompetent donors. Moreover, by staining with tetramers in combination with antibodies to cell surface markers and intracellular cytokines, we demonstrate functional heterogeneity of HCMV-specific populations. A substantial proportion of these are effector cytotoxic T lymphocytes, as demonstrated by their ability to lyse peptide-pulsed targets in "fresh" killing assays. These data suggest that the immune response to HCMV is periodically boosted by a low level of HCMV replication and that sustained immunological surveillance contributes to the maintenance of host-pathogen homeostasis. These observations should improve our understanding of the immunobiology of persistent viral infection.


A mathematical model for interpretable clinical decision support with applications in gynecology.
Over time, methods for the development of clinical decision support (CDS) systems have evolved from interpretable and easy-to-use scoring systems to very complex and non-interpretable mathematical models. In order to accomplish effective decision support, CDS systems should provide information on how the model arrives at a certain decision. To address the issue of incompatibility between performance, interpretability and applicability of CDS systems, this paper proposes an innovative model structure, automatically leading to interpretable and easily applicable models. The resulting models can be used to guide clinicians when deciding upon the appropriate treatment, estimating patient-specific risks and to improve communication with patients. We propose the interval coded scoring (ICS) system, which imposes that the effect of each variable on the estimated risk is constant within consecutive intervals. The number and position of the intervals are automatically obtained by solving an optimization problem, which additionally performs variable selection. The resulting model can be visualised by means of appealing scoring tables and color bars. ICS models can be used within software packages, in smartphone applications, or on paper, which is particularly useful for bedside medicine and home-monitoring. The ICS approach is illustrated on two gynecological problems: diagnosis of malignancy of ovarian tumors using a dataset containing 3,511 patients, and prediction of first trimester viability of pregnancies using a dataset of 1,435 women. Comparison of the performance of the ICS approach with a range of prediction models proposed in the literature illustrates the ability of ICS to combine optimal performance with the interpretability of simple scoring systems. The ICS approach can improve patient-clinician communication and will provide additional insights in the importance and influence of available variables. Future challenges include extensions of the proposed methodology towards automated detection of interaction effects, multi-class decision support systems, prognosis and high-dimensional data.


Defining Disease Phenotypes in Primary Care Electronic Health Records by a Machine Learning Approach: A Case Study in Identifying Rheumatoid Arthritis.
1) To use data-driven method to examine clinical codes (risk factors) of a medical condition in primary care electronic health records (EHRs) that can accurately predict a diagnosis of the condition in secondary care EHRs. 2) To develop and validate a disease phenotyping algorithm for rheumatoid arthritis using primary care EHRs. This study linked routine primary and secondary care EHRs in Wales, UK. A machine learning based scheme was used to identify patients with rheumatoid arthritis from primary care EHRs via the following steps: i) selection of variables by comparing relative frequencies of Read codes in the primary care dataset associated with disease case compared to non-disease control (disease/non-disease based on the secondary care diagnosis); ii) reduction of predictors/associated variables using a Random Forest method, iii) induction of decision rules from decision tree model. The proposed method was then extensively validated on an independent dataset, and compared for performance with two existing deterministic algorithms for RA which had been developed using expert clinical knowledge. Primary care EHRs were available for 2,238,360 patients over the age of 16 and of these 20,667 were also linked in the secondary care rheumatology clinical system. In the linked dataset, 900 predictors (out of a total of 43,100 variables) in the primary care record were discovered more frequently in those with versus those without RA. These variables were reduced to 37 groups of related clinical codes, which were used to develop a decision tree model. The final algorithm identified 8 predictors related to diagnostic codes for RA, medication codes, such as those for disease modifying anti-rheumatic drugs, and absence of alternative diagnoses such as psoriatic arthritis. The proposed data-driven method performed as well as the expert clinical knowledge based methods. Data-driven scheme, such as ensemble machine learning methods, has the potential of identifying the most informative predictors in a cost-effective and rapid way to accurately and reliably classify rheumatoid arthritis or other complex medical conditions in primary care EHRs.


Staphylococcus aureus Isolates from Bovine Mastitis in Eight Countries: Genotypes, Detection of Genes Encoding Different Toxins and Other Virulence Genes.
Staphylococcus aureus is recognized worldwide as one of the major agents of dairy cow intra-mammary infections. This microorganism can express a wide spectrum of pathogenic factors used to attach, colonize, invade and infect the host. The present study evaluated 120 isolates from eight different countries that were genotyped by RS-PCR and investigated for 26 different virulence factors to increase the knowledge on the circulating genetic lineages among the cow population with mastitis. New genotypes were observed for South African strains while for all the other countries new variants of existing genotypes were detected. For each country, a specific genotypic pattern was found. Among the virulence factors, fmtB, cna, clfA and leucocidins genes were the most frequent. The sea and sei genes were present in seven out of eight countries; seh showed high frequency in South American countries (Brazil, Colombia, Argentina), while sel was harboured especially in one Mediterranean country (Tunisia). The etb, seb and see genes were not detected in any of the isolates, while only two isolates were MRSA (Germany and Italy) confirming the low diffusion of methicillin resistance microorganism among bovine mastitis isolates. This work demonstrated the wide variety of S. aureus genotypes found in dairy cattle worldwide. This condition suggests that considering the region of interest might help to formulate strategies for reducing the infection spreading.


In vivo MRI characterization of progressive cardiac dysfunction in the mdx mouse model of muscular dystrophy.
The mdx mouse has proven to be useful in understanding the cardiomyopathy that frequently occurs in muscular dystrophy patients. Here we employed a comprehensive array of clinically relevant in vivo MRI techniques to identify early markers of cardiac dysfunction and follow disease progression in the hearts of mdx mice. Serial measurements of cardiac morphology and function were made in the same group of mdx mice and controls (housed in a non-SPF facility) using MRI at 1, 3, 6, 9 and 12 months after birth. Left ventricular (LV) and right ventricular (RV) systolic and diastolic function, response to dobutamine stress and myocardial fibrosis were assessed. RV dysfunction preceded LV dysfunction, with RV end systolic volumes increased and RV ejection fractions reduced at 3 months of age. LV ejection fractions were reduced at 12 months, compared with controls. An abnormal response to dobutamine stress was identified in the RV of mdx mice as early as 1 month. Late-gadolinium-enhanced MRI identified increased levels of myocardial fibrosis in 6, 9 and 12-month-old mdx mice, the extent of fibrosis correlating with the degree of cardiac remodeling and hypertrophy. MRI could identify cardiac abnormalities in the RV of mdx mice as young as 1 month, and detected myocardial fibrosis at 6 months. We believe these to be the earliest MRI measurements of cardiac function reported for any mice, and the first use of late-gadolinium-enhancement in a mouse model of congenital cardiomyopathy. These techniques offer a sensitive and clinically relevant in vivo method for assessment of cardiomyopathy caused by muscular dystrophy and other diseases.


Carriers of mitochondrial DNA macrohaplogroup L3 basal lineages migrated back to Africa from Asia around 70,000 years ago.
The main unequivocal conclusion after three decades of phylogeographic mtDNA studies is the African origin of all extant modern humans. In addition, a southern coastal route has been argued for to explain the Eurasian colonization of these African pioneers. Based on the age of macrohaplogroup L3, from which all maternal Eurasian and the majority of African lineages originated, the out-of-Africa event has been dated around 60-70 kya. On the opposite side, we have proposed a northern route through Central Asia across the Levant for that expansion and, consistent with the fossil record, we have dated it around 125 kya. To help bridge differences between the molecular and fossil record ages, in this article we assess the possibility that mtDNA macrohaplogroup L3 matured in Eurasia and returned to Africa as basal L3 lineages around 70 kya. The coalescence ages of all Eurasian (M,N) and African (L3 ) lineages, both around 71 kya, are not significantly different. The oldest M and N Eurasian clades are found in southeastern Asia instead near of Africa as expected by the southern route hypothesis. The split of the Y-chromosome composite DE haplogroup is very similar to the age of mtDNA L3. An Eurasian origin and back migration to Africa has been proposed for the African Y-chromosome haplogroup E. Inside Africa, frequency distributions of maternal L3 and paternal E lineages are positively correlated. This correlation is not fully explained by geographic or ethnic affinities. This correlation rather seems to be the result of a joint and global replacement of the old autochthonous male and female African lineages by the new Eurasian incomers. These results are congruent with a model proposing an out-of-Africa migration into Asia, following a northern route, of early anatomically modern humans carrying pre-L3 mtDNA lineages around 125 kya, subsequent diversification of pre-L3 into the basal lineages of L3, a return to Africa of Eurasian fully modern humans around 70 kya carrying the basal L3 lineages and the subsequent diversification of Eurasian-remaining L3 lineages into the M and N lineages in the outside-of-Africa context, and a second Eurasian global expansion by 60 kya, most probably, out of southeast Asia. Climatic conditions and the presence of Neanderthals and other hominins might have played significant roles in these human movements. Moreover, recent studies based on ancient DNA and whole-genome sequencing are also compatible with this hypothesis.


Osteoporosis prevention and nutrition.
Although calcium and vitamin D have been the primary focus of nutritional prevention of osteoporosis, recent research has clarified the importance of several additional nutrients and food constituents. Further, results of calcium and vitamin D supplementation trials have been inconsistent, suggesting that reliance on this intervention may be inadequate. In addition to dairy, fruit and vegetable intake has emerged as an important modifiable protective factor for bone health. Several nutrients, including magnesium, potassium, vitamin C, vitamin K, several B vitamins, and carotenoids, have been shown to be more important than previously realized. Rather than having a negative effect on bone, protein intake appears to benefit bone status, particularly in older adults. Regular intake of cola beverages shows negative effects and moderate alcohol intake shows positive effects on bone, particularly in older women. Current research on diet and bone status supports encouragement of balanced diets with plenty of fruit and vegetables, adequate dairy and other protein foods, and limitation of foods with low nutrient density.


When giving feels good. The intrinsic benefits of sacrifice in romantic relationships for the communally motivated.
Who benefits most from making sacrifices for others? The current study provides one answer to this question by demonstrating the intrinsic benefits of sacrifice for people who are highly motivated to respond to a specific romantic partner's needs noncontingently, a phenomenon termed communal strength. In a 14-day daily-experience study of 69 romantic couples, communal strength was positively associated with positive emotions during the sacrifice itself, with feeling appreciated by the partner for the sacrifice, and with feelings of relationship satisfaction on the day of the sacrifice. Furthermore, feelings of authenticity for the sacrifice mediated these associations. Several alternative hypotheses were ruled out: The effects were not due to individuals higher in communal strength making qualitatively different kinds of sacrifices, being more positive in general, or being involved in happier relationships. Implications for research and theory on communal relationships and positive emotions are discussed.


RNA and imidazoquinolines are sensed by distinct TLR7/8 ectodomain sites resulting in functionally disparate signaling events.
TLRs 7 and 8 are pattern recognition receptors controlling antiviral host defense or autoimmune diseases. Apart from foreign and host RNA, synthetic RNA oligoribonucleotides (ORN) or small molecules of the imidazoquinoline family activate TLR7 and 8 and are being developed as therapeutic agonists. The structure-function relationships for RNA ORN and imidazoquinoline sensing and consequent downstream signaling by human TLR7 and TLR8 are unknown. Proteome- and genome-wide analyses in primary human monocyte-derived dendritic cells here showed that TLR8 sensing of RNA ORN versus imidazoquinoline translates to ligand-specific differential phosphorylation and transcriptional events. In addition, TLR7 and 8 ectodomains were found to discriminate between RNA ORN and imidazoquinolines by overlapping and nonoverlapping recognition sites to which murine loss-of-function mutations and human naturally occurring hyporesponsive polymorphisms map. Our data suggest TLR7 and TLR8 can signal in two different "modes" depending on the class of ligand. Considering RNA ORN and imidazoquinolines have been regarded as functionally interchangeable, our study highlights important functional incongruities whose understanding will be important for developing TLR7 or 8 therapeutics with desirable effector and safety profiles for in vivo application.


Pituitary tumor-transforming gene expression is a prognostic marker for tumor recurrence in squamous cell carcinoma of the head and neck.
The proto-oncogene pituitary tumor-transforming gene (PTTG) has been shown to be abundantly overexpressed in a large variety of neoplasms likely promoting neo-vascularization and tumor invasiveness. In this study, we investigated a potential role for PTTG mRNA expression as a marker to evaluate the future clinical outcome of patients diagnosed with primary cancer of the head and neck. Tumor samples derived from primary tumors of 89 patients suffering from a squamous cell carcinoma were analyzed for PTTG mRNA-expression and compared to corresponding unaffected tissue. Expression levels were correlated to standard clinico-pathological parameters based on a five year observation period. In almost all 89 tumor samples PTTG was found to be overexpressed (median fold increase: 2.1) when compared to the unaffected tissue specimens derived from the same patient. The nodal stage correlated with PTTG transcript levels with significant differences between pN0 (median expression: 1.32) and pN+ (median expression: 2.12; P = 0.016). In patients who developed a tumor recurrence we detected a significantly higher PTTG expression in primary tumors (median expression: 2.63) when compared to patients who did not develop a tumor recurrence (median expression: 1.29; P = 0.009). Since the median expression of PTTG in patients with tumor stage T1/2N0M0 that received surgery alone without tumor recurrence was 0.94 versus 3.82 in patients suffering from a tumor recurrence (P = 0.006), PTTG expression might provide a feasible mean of predicting tumor recurrence. Elevated PTTG transcript levels might be used as a prognostic biomarker for future clinical outcome (i.e. recurrence) in primary squamous cell carcinomas of the head and neck, especially in early stages of tumor development.


Prospective study of one million deaths in India: rationale, design, and validation results.
Over 75% of the annual estimated 9.5 million deaths in India occur in the home, and the large majority of these do not have a certified cause. India and other developing countries urgently need reliable quantification of the causes of death. They also need better epidemiological evidence about the relevance of physical (such as blood pressure and obesity), behavioral (such as smoking, alcohol, HIV-1 risk taking, and immunization history), and biological (such as blood lipids and gene polymorphisms) measurements to the development of disease in individuals or disease rates in populations. We report here on the rationale, design, and implementation of the world's largest prospective study of the causes and correlates of mortality. We will monitor nearly 14 million people in 2.4 million nationally representative Indian households (6.3 million people in 1.1 million households in the 1998-2003 sample frame and 7.6 million people in 1.3 million households in the 2004-2014 sample frame) for vital status and, if dead, the causes of death through a well-validated verbal autopsy (VA) instrument. About 300,000 deaths from 1998-2003 and some 700,000 deaths from 2004-2014 are expected; of these about 850,000 will be coded by two physicians to provide causes of death by gender, age, socioeconomic status, and geographical region. Pilot studies will evaluate the addition of physical and biological measurements, specifically dried blood spots. Preliminary results from over 35,000 deaths suggest that VA can ascertain the leading causes of death, reduce the misclassification of causes, and derive the probable underlying cause of death when it has not been reported. VA yields broad classification of the underlying causes in about 90% of deaths before age 70. In old age, however, the proportion of classifiable deaths is lower. By tracking underlying demographic denominators, the study permits quantification of absolute mortality rates. Household case-control, proportional mortality, and nested case-control methods permit quantification of risk factors. This study will reliably document not only the underlying cause of child and adult deaths but also key risk factors (behavioral, physical, environmental, and eventually, genetic). It offers a globally replicable model for reliably estimating cause-specific mortality using VA and strengthens India's flagship mortality monitoring system. Despite the misclassification that is still expected, the new cause-of-death data will be substantially better than that available previously.


Sleep homeostasis, habits and habituation.
The importance of sleep for behavioural performance during waking is long-established, but the underlying reasons and mechanisms remain elusive. Waking and sleep are associated with changes in the levels of GluA1 AMPAR subunit in synaptic membranes, while studies using genetically-modified mice have identified an important role for GluA1-dependent synaptic plasticity in a non-associative form of memory that underlies short-term habituation to recently experienced stimuli. Here we posit that sleep may play a role in dishabituation, which restores attentional capacity and maximises the readiness of the animal for learning and goal-directed behaviour during subsequent wakefulness. Furthermore we suggest that sleep disturbance may fundamentally change the nature of behaviour, making it more model-free and habitual as a result of reduced attentional capacity.


Minocycline decreases liver injury after hemorrhagic shock and resuscitation in mice.
Patients that survive hemorrhage and resuscitation (H/R) may develop a systemic inflammatory response syndrome (SIRS) that leads to dysfunction of vital organs (multiple organ dysfunction syndrome, MODS). SIRS and MODS may involve mitochondrial dysfunction. Under pentobarbital anesthesia, C57BL6 mice were hemorrhaged to 30 mm Hg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer's solution containing minocycline, tetracycline (both 10 mg/kg body weight) or vehicle. Serum alanine aminotransferase (ALT), necrosis, apoptosis and oxidative stress were assessed 6 h after resuscitation. Mitochondrial polarization was assessed by intravital microscopy. After H/R with vehicle or tetracycline, ALT increased to 4538 U/L and 3999 U/L, respectively, which minocycline decreased to 1763 U/L (P < 0.01). Necrosis and TUNEL also decreased from 24.5% and 17.7 cells/field, respectively, after vehicle to 8.3% and 8.7 cells/field after minocycline. Tetracycline failed to decrease necrosis (23.3%) but decreased apoptosis to 9 cells/field (P < 0.05). Minocycline and tetracycline also decreased caspase-3 activity in liver homogenates. Minocycline but not tetracycline decreased lipid peroxidation after resuscitation by 70% (P < 0.05). Intravital microscopy showed that minocycline preserved mitochondrial polarization after H/R (P < 0.05). In conclusion, minocycline decreases liver injury and oxidative stress after H/R by preventing mitochondrial dysfunction.


Effect of urgent treatment for transient ischaemic attack and minor stroke on disability and hospital costs (EXPRESS study): a prospective population-based sequential comparison.
Evidence is available on the effectiveness and costs of treatments to reduce stroke risk in long-term secondary prevention. However, there are few data on the costs and outcomes of urgent assessment and treatment after the onset of transient ischaemic attack (TIA) or minor stroke. The Early use of eXisting PREventive Strategies for Stroke (EXPRESS) study showed that urgent assessment and treatment reduced the 90-day risk of recurrent stroke by about 80%. We now report the effect of the EXPRESS intervention on admissions to hospital, costs, and disability. EXPRESS was a prospective population-based before (phase 1: April 1, 2002, to Sept 30, 2004) versus after (phase 2: Oct 1, 2004, to March 31, 2007) study of the effect of early assessment and treatment of TIA or minor stroke on the risk of early recurrent stroke. This report assesses the effect of the introduction of the phase 2 clinic on admissions to hospital within 90 days, hospital bed-days, hospital costs, and 6-month new disability (progression from no disability before event [modified Rankin scale score < or =2 points] to disability at 6 months [modified Rankin scale score >2 points]) or death, compared with the phase 1 clinic. To assess the main predictors of these outcomes, multivariate regression analyses were done. The 90-day risk of fatal or disabling stroke was reduced in phase 2 (1 of 281 vs 16 of 310; p=0.0005). Hospital admissions for recurrent stroke were also lower in phase 2 than in phase 1 (5 vs 25; p=0.001), which reduced the overall number of hospital bed-days compared with phase 1 (672 vs 1957 days; p=0.017). Hospital bed-days for admissions to hospital due to vascular causes were also lower in phase 2 (427 vs 1365 days; p=0.016), which generated savings of 624 pounds per patient referred to the phase 2 clinic (p=0.028). Results from the multivariate analyses showed that assessment in phase 2 was an independent predictor of reduced disability, days in hospital, and costs. Urgent assessment and treatment of patients with TIA or minor stroke who were referred to a specialist outpatient clinic reduced subsequent hospital bed-days, acute costs, and 6-month disability.


Visual neglect after right posterior cerebral artery infarction.
To investigate the characteristics and neuroanatomical correlates of visual neglect after right-sided posterior cerebral artery (PCA) infarction. 15 patients with acute PCA strokes were screened for the presence of neglect on a comprehensive battery of cognitive tests. Extra tests of visual perception were also carried out on six patients. To establish which areas were critically associated with neglect, the lesions of patients with and without neglect were compared. Neglect of varying severity was documented in 8 patients. In addition, higher-order visual perception was impaired in 5 of the 6 patients. Neglect was critically associated with damage to an area of white matter in the occipital lobe corresponding to a white matter tract connecting the parahippocampal gyrus with the angular gyrus of the parietal lobe. Lesions of the thalamus or splenium of the corpus callosum did not appear necessary or sufficient to cause neglect, but may mediate its severity in these patients. PCA stroke can result in visual neglect. Interruption of the white matter fibres connecting the parahippocampal gyrus to the angular gyrus may be important in determining whether a patient will manifest neglect.


Reduced inotropic reserve and increased susceptibility to cardiac ischemia/reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice.
The role of the creatine kinase (CK)/phosphocreatine (PCr) energy buffer and transport system in heart remains unclear. Guanidinoacetate-N-methyltransferase-knockout (GAMT-/-) mice represent a new model of profoundly altered cardiac energetics, showing undetectable levels of PCr and creatine and accumulation of the precursor (phospho-)guanidinoacetate (P-GA). To characterize the role of a substantially impaired CK/PCr system in heart, we studied the cardiac phenotype of wild-type (WT) and GAMT-/- mice. GAMT-/- mice did not show cardiac hypertrophy (myocyte cross-sectional areas, hypertrophy markers atrial natriuretic factor and beta-myosin heavy chain). Systolic and diastolic function, measured invasively (left ventricular conductance catheter) and noninvasively (MRI), were similar for WT and GAMT-/- mice. However, during inotropic stimulation with dobutamine, preload-recruitable stroke work failed to reach maximal levels of performance in GAMT-/- hearts (101+/-8 mm Hg in WT versus 59+/-7 mm Hg in GAMT-/-; P<0.05). (31)P-MR spectroscopy experiments showed that during inotropic stimulation, isolated WT hearts utilized PCr, whereas isolated GAMT-/- hearts utilized P-GA. During ischemia/reperfusion, GAMT-/- hearts showed markedly impaired recovery of systolic (24% versus 53% rate pressure product recovery; P<0.05) and diastolic function (eg, left ventricular end-diastolic pressure 23+/-9 in WT and 51+/-5 mm Hg in GAMT-/- during reperfusion; P<0.05) and incomplete resynthesis of P-GA. GAMT-/- mice do not develop hypertrophy and show normal cardiac function at low workload, suggesting that a fully functional CK/PCr system is not essential under resting conditions. However, when acutely stressed by inotropic stimulation or ischemia/reperfusion, GAMT-/- mice exhibit a markedly abnormal phenotype, demonstrating that an intact, high-capacity CK/PCr system is required for situations of increased cardiac work or acute stress.


Suicidal imagery in a previously depressed community sample.
This study sought to replicate previous findings of vivid suicide-related imagery in previously suicidal patients in a community sample of adults with a history of depression. Twenty-seven participants were interviewed regarding suicidal imagery. Seventeen participants reported prior suicidal ideation or behaviour in the clinical assessment, and the vast majority of these also reported experiencing suicide-related imagery when at their most depressed and despairing, in many cases in the form of flash-forwards to imagined future suicidal acts. Interestingly, five of the 10 participants who did not report suicidal ideation or behaviour in the clinical interview also described prominent imagery related to themes of death and suicide, but in several cases, these images were associated with meanings that seemed to act to reduce the likelihood of subsequent suicidal acts. Severity of prior suicidality was associated with lower levels of imagery-related distress and higher levels of imagery-related comfort. These findings support the idea that suicide-related imagery is an important component in the phenomenology of depression and despair and hint at potentially important differences in the meaning associated with such imagery between those individuals who report experiencing suicidal ideation or behaviour when depressed and those who do not. The findings are consistent with Joiner's model of acquired capability for suicide through habituation to pain and fear of suicide and suggest that it may be useful to tackle such imagery directly in the treatment of suicidal patients.


Development and validation of nursing resource weights for the Belgian Nursing Minimum Dataset in general hospitals: a Delphi questionnaire survey approach.
Internationally, nursing is not well represented in hospital financing systems. In Belgium a nursing weight system exists to adjust budget allocation for differences in nurse staffing requirements, but there is a need for revision. Arguments include the availability of a nursing minimum dataset and the adverse consequences of the current historically based nursing weight system. The development and validation of nursing resource weights for the revised Belgium nursing minimum dataset (NMDS). Two independent cross sectional Delphi-surveys. A convenience sample of 222 head nurses from 69 Belgian hospitals participated in the cross sectional survey methods. To assess validity 112 patient case records from 61 nursing wards of 35 Belgian general hospitals representing general, surgical, pediatric, geriatric and intensive care were selected. Nursing resource weights were constructed based on Delphi survey results by NMDSII intervention. The patient case Delphi survey results were used as the primary source for validation. A series of additional validation measures were calculated, based on the different patient classification systems. Finally, three validated nursing resource weighting systems were compared to the constructed NMDSII weighting system: the use of 'Closon', 'Ghent' and WIN weights. A coherent set of nursing resource weights was developed. The comparison of nurse resource weights, based on the survey per NMDS intervention versus the survey on patient cases, yielded high correlations: r=0.74 to r=0.97 (p<0.01) between three case rating questions, as an indication of reliability in terms of internal consistency, and r=0.90 (p<0.01) between summed intervention weights and patient case weights, as an indication of criterion validity in terms of concurrent validity. Other concurrent validity measures based on summed intervention weights versus patient classification dependency weights showed a correlation ranging from r=0.14 to r=0.74. The correlation of summed intervention weights with the Closon, Ghent and WIN weights ranged from r=0.93 to r=0.96 (p<0.01), as a third indication of concurrent validity. A system of valid nursing resource weights has been developed. The system should be further validated within an international context.


Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer.
The agonistic/antagonistic biocharacter of selective estrogen receptor modulators (SERMs) can have therapeutic advantages, particularly in the case of premenopausal breast cancers. Although the contradictory effects of these modulators have been studied in terms of crosstalk between the estrogen receptor α (ER) and coactivator dynamics and growth factor signaling, the molecular basis of these mechanisms is still obscure. We identify a series of regulatory mechanisms controlling cofactor dynamics on ER and SERM function, whose activities require F-box protein 22 (Fbxo22). Skp1, Cullin1, F-box-containing complex (SCFFbxo22) ubiquitylated lysine demethylase 4B (KDM4B) complexed with tamoxifen-bound (TAM-bound) ER, whose degradation released steroid receptor coactivator (SRC) from ER. Depletion of Fbxo22 resulted in ER-dependent transcriptional activation via transactivation function 1 (AF1) function, even in the presence of SERMs. In living cells, TAM released SRC and KDM4B from ER in a Fbxo22-dependent manner. SRC release by TAM required Fbxo22 on almost all ER-SRC-bound enhancers and promoters. TAM failed to prevent the growth of Fbxo22-depleted, ER-positive breast cancers both in vitro and in vivo. Clinically, a low level of Fbxo22 in tumor tissues predicted a poorer outcome in ER-positive/human epidermal growth factor receptor type 2-negative (HER2-negative) breast cancers with high hazard ratios, independently of other markers such as Ki-67 and node status. We propose that the level of Fbxo22 in tumor tissues defines a new subclass of ER-positive breast cancers for which SCFFbxo22-mediated KDM4B degradation in patients can be a therapeutic target for the next generation of SERMs.


The large conformational changes of Hsp90 are only weakly coupled to ATP hydrolysis.
The molecular chaperone heat-shock protein 90 (Hsp90) is one of the most abundant proteins in unstressed eukaryotic cells. Its function is dependent on an exceptionally slow ATPase reaction that involves large conformational changes. To observe these conformational changes and to understand their interplay with the ATPase function, we developed a single-molecule assay that allows examination of yeast Hsp90 dimers in real time under various nucleotide conditions. We detected conformational fluctuations between open and closed states on timescales much faster than the rate of ATP hydrolysis. The compiled distributions of dwell times allow us to assign all rate constants to a minimal kinetic model for the conformational changes of Hsp90 and to delineate the influence of ATP hydrolysis. Unexpectedly, in this model ATP lowers two energy barriers almost symmetrically, such that little directionality is introduced. Instead, stochastic, thermal fluctuations of Hsp90 are the dominating processes.


Neuroprotective potential of phytochemicals.
Cognitive dysfunction is a major health problem in the 21st century, and many neuropsychiatric disorders and neurodegenerative disorders, such as schizophrenia, depression, Alzheimer's Disease dementia, cerebrovascular impairment, seizure disorders, head injury and Parkinsonism, can be severly functionally debilitating in nature. In course of time, a number of neurotransmitters and signaling molecules have been identified which have been considered as therapeutic targets. Conventional as well newer molecules have been tried against these targets. Phytochemicals from medicinal plants play a vital role in maintaining the brain's chemical balance by influencing the function of receptors for the major inhibitory neurotransmitters. In traditional practice of medicine, several plants have been reported to treat cognitive disorders. In this review paper, we attempt to throw some light on the use of medicinal herbs to treat cognitive disorders. In this review, we briefly deal with some medicinal herbs focusing on their neuroprotective active phytochemical substances like fatty acids, phenols, alkaloids, flavonoids, saponins, terpenes etc. The resistance of neurons to various stressors by activating specific signal transduction pathways and transcription factors are also discussed. It was observed in the review that a number of herbal medicines used in Ayurvedic practices as well Chinese medicines contain multiple compounds and phytochemicals that may have a neuroprotective effect which may prove beneficial in different neuropsychiatric and neurodegenerative disorders. Though the presence of receptors or transporters for polyphenols or other phytochemicals of the herbal preparations, in brain tissues remains to be ascertained, compounds with multiple targets appear as a potential and promising class of therapeutics for the treatment of diseases with a multifactorial etiology.


Delivery of crop pollination services is an insufficient argument for wild pollinator conservation.
There is compelling evidence that more diverse ecosystems deliver greater benefits to people, and these ecosystem services have become a key argument for biodiversity conservation. However, it is unclear how much biodiversity is needed to deliver ecosystem services in a cost-effective way. Here we show that, while the contribution of wild bees to crop production is significant, service delivery is restricted to a limited subset of all known bee species. Across crops, years and biogeographical regions, crop-visiting wild bee communities are dominated by a small number of common species, and threatened species are rarely observed on crops. Dominant crop pollinators persist under agricultural expansion and many are easily enhanced by simple conservation measures, suggesting that cost-effective management strategies to promote crop pollination should target a different set of species than management strategies to promote threatened bees. Conserving the biological diversity of bees therefore requires more than just ecosystem-service-based arguments.


Evaluation of type 2 diabetes genetic risk variants in Chinese adults: findings from 93,000 individuals from the China Kadoorie Biobank.
Genome-wide association studies (GWAS) have discovered many risk variants for type 2 diabetes. However, estimates of the contributions of risk variants to type 2 diabetes predisposition are often based on highly selected case-control samples, and reliable estimates of population-level effect sizes are missing, especially in non-European populations. The individual and cumulative effects of 59 established type 2 diabetes risk loci were measured in a population-based China Kadoorie Biobank (CKB) study of 93,000 Chinese adults, including >7,100 diabetes cases. Association signals were directionally consistent between CKB and the original discovery GWAS: of 56 variants passing quality control, 48 showed the same direction of effect (binomial test, p = 2.3 × 10(-8)). We observed a consistent overall trend towards lower risk variant effect sizes in CKB than in case-control samples of GWAS meta-analyses (mean 19-22% decrease in log odds, p ≤ 0.0048), likely to reflect correction of both 'winner's curse' and spectrum bias effects. The association with risk of diabetes of a genetic risk score, based on lead variants at 25 loci considered to act through beta cell function, demonstrated significant interactions with several measures of adiposity (BMI, waist circumference [WC], WHR and percentage body fat [PBF]; all p interaction < 1 × 10(-4)), with a greater effect being observed in leaner adults. Our study provides further evidence of shared genetic architecture for type 2 diabetes between Europeans and East Asians. It also indicates that even very large GWAS meta-analyses may be vulnerable to substantial inflation of effect size estimates, compared with those observed in large-scale population-based cohort studies. Details of how to access China Kadoorie Biobank data and details of the data release schedule are available from www.ckbiobank.org/site/Data+Access .


Parasitoids select plants more heavily infested with their caterpillar hosts: a new approach to aid interpretation of plant headspace volatiles.
Plants produce volatile organic compounds (VOCs) in response to herbivore attack, and these VOCs can be used by parasitoids of the herbivore as host location cues. We investigated the behavioural responses of the parasitoid Cotesia vestalis to VOCs from a plant-herbivore complex consisting of cabbage plants (Brassica oleracea) and the parasitoids host caterpillar, Plutella xylostella. A Y-tube olfactometer was used to compare the parasitoids' responses to VOCs produced as a result of different levels of attack by the caterpillar and equivalent levels of mechanical damage. Headspace VOC production by these plant treatments was examined using gas chromatography-mass spectrometry. Cotesia vestalis were able to exploit quantitative and qualitative differences in volatile emissions, from the plant-herbivore complex, produced as a result of different numbers of herbivores feeding. Cotesia vestalis showed a preference for plants with more herbivores and herbivore damage, but did not distinguish between different levels of mechanical damage. Volatile profiles of plants with different levels of herbivores/herbivore damage could also be separated by canonical discriminant analyses. Analyses revealed a number of compounds whose emission increased significantly with herbivore load, and these VOCs may be particularly good indicators of herbivore number, as the parasitoid processes cues from its external environment.


Equity for excellence in academic institutions: a manifesto for change.
Higher academic institutions in the UK need to drive improvements in equity, diversity, and inclusion (EDI) through sustainable practical interventions. A broad view of inclusivity is based on an intersectional approach that considers race, geographical location, caring responsibilities, disability, neurodiversity, religion, and LGBTQIA+ identities. We describe the establishment of a diverse stakeholder group to develop practical grass-roots recommendations through which improvements can be advanced. We have developed a manifesto for change, comprising six domains through which academic institutions can drive progress through setting short, medium, and long-term priorities. Interventions will yield rewards in recruitment and retention of a diverse talent pool, leading to enhanced impact and output.


Enhanced perceptual priming for neutral stimuli in a traumatic context: A pathway to intrusive memories?
Clinical observations suggest that re-experiencing symptoms are triggered by stimuli that are perceptually similar to those present shortly before the trauma or its worst moments. Two experiments investigated the possible role of perceptual priming in this phenomenon. Volunteers (N = 28, N = 62) watched a series of "traumatic" and neutral picture stories, and completed blurred object identification (priming) and recognition memory tasks. Neutral objects that immediately preceded the "traumatic" stories were more strongly primed, but not better recognised, than objects from neutral stories. Enhanced priming predicted subsequent re-experiencing symptoms. The results support the role of perceptual priming in re-experiencing.


Dynamic construction of a coherent attentional state in a prefrontal cell population.
Prefrontal cortex has been proposed to show highly adaptive information coding, with neurons dynamically allocated to processing task-relevant information. To track this dynamic allocation in monkey prefrontal cortex, we used time-resolved measures of neural population activity in a simple case of competition between target (behaviorally critical) and nontarget objects in opposite visual hemifields. Early in processing, there were parallel responses to competing inputs, with neurons in each hemisphere dominated by the contralateral stimulus. Later, the nontarget lost control of neural activity, with emerging global control by the behaviorally critical target. The speed of transition reflected the competitive weights of different display elements, occurring most rapidly when relative behavioral significance was well established by training history. In line with adaptive coding, the results show widespread reallocation of prefrontal processing resources as an attentional focus is established.


The perfect crime? CCSVI not leaving a trace in MS.
Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system, believed to be triggered by an autoimmune reaction to myelin. Recently, a fundamentally different pathomechanism termed 'chronic cerebrospinal venous insufficiency' (CCSVI) was proposed, provoking significant attention in the media and scientific community. Twenty MS patients (mean age 42.2 ± 13.3 years; median Extended Disability Status Scale 3.0, range 0-6.5) were compared with 20 healthy controls. Extra- and intracranial venous flow direction was assessed by colour-coded duplex sonography, and extracranial venous cross-sectional area (VCSA) of the internal jugular and vertebral veins (IJV/VV) was measured in B-mode to assess the five previously proposed CCSVI criteria. IJV-VCSA ≤ 0.3 cm(2) indicated 'stenosis,' and IJV-VCSA decrease from supine to upright position 'reverted postural control.' The sonographer, data analyser and statistician were blinded to the patient/control status of the participants. No participant showed retrograde flow of cervical or intracranial veins. IJV-VCSA ≤ 0.3 cm(2) was found in 13 MS patients versus 16 controls (p=0.48). A decrease in IJV-VCSA from supine to upright position was observed in all participants, but this denotes a physiological finding. No MS patient and one control had undetectable IJV flow despite deep inspiration (p=0.49). Only one healthy control and no MS patients fulfilled at least two criteria for CCSVI. This triple-blinded extra- and transcranial duplex sonographic assessment of cervical and cerebral veins does not provide supportive evidence for the presence of CCSVI in MS patients. The findings cast serious doubt on the concept of CCSVI in MS.


Submicrometer position control of single trapped neutral atoms.
We optically detect the positions of single neutral cesium atoms stored in a standing wave dipole trap with a subwavelength resolution of 143 nm rms. The distance between two simultaneously trapped atoms is measured with an even higher precision of 36 nm rms. We resolve the discreteness of the interatomic distances due to the 532 nm spatial period of the standing wave potential and infer the exact number of trapping potential wells separating the atoms. Finally, combining an initial position detection with a controlled transport, we place single atoms at a predetermined position along the trap axis to within 300 nm rms.


Regulating Cannabis Social Clubs: A comparative analysis of legal and self-regulatory practices in Spain, Belgium and Uruguay.
Cannabis Social Clubs (CSCs) are a model of non-profit production and distribution of cannabis among a closed circuit of adult cannabis users. CSCs are now operating in several countries around the world, albeit under very different legal regimes and in different socio-political contexts. In this paper we describe and compare the legal framework and the self-regulatory practices of Cannabis Social Clubs in three countries (Spain, Belgium, and Uruguay). The objective of our comparative analysis is to investigate how CSCs operate in each of these countries. To foster discussions about how one might regulate CSCs to promote public health objectives, we conclude this paper with a discussion on the balance between adequate governmental control and self-regulatory competences of CSCs. The data used for this analysis stem from independently conducted local studies by the authors in their countries. Although the particular designs of the studies differ, the data in all three countries was collected through similar data collection methods: analysis of (legal and other documents), field visits to the clubs, interviews with staff members, media content analysis. We identified a number of similarities and differences among the CSCs' practices in the three countries. Formal registration as non-profit association seems to be a common standard among CSCs. We found nevertheless great variation in terms of the size of these organisations. Generally, only adult nationals and/or residents are able to join the CSCs, upon the payment of a membership fee. While production seems to be guided by consumption estimates of the members (Spain and Belgium) or by the legal framework (Uruguay), the thresholds applied by the clubs vary significantly across countries. Quality control practices remain an issue in the three settings studied here. The CSCs have developed different arrangements with regards to the distribution of cannabis to their members. By uncovering the current practices of CSCs in three key settings, this paper contributes to the understanding of the model, which has to some extent been shaped by the self-regulatory efforts of those involved on the ground. We suggest that some of these self-regulatory practices could be accommodated in future regulation in this area, while other aspects of the functioning of the CSCs may require more formal regulation and monitoring. Decisions on this model should also take into account the local context where the clubs have emerged. Finally, the integration of medical supply within this model warrants further attention.


Two sites for modulation of human sympathetic activity by arterial baroreceptors?
1. Peroneal muscle sympathetic nerve activity (MSA), finger blood pressure and cardiac intervals were recorded at rest in 60 healthy subjects, aged 18-71 years. Arterial baroreflex control of MSA was analysed by relating each spontaneous sympathetic burst to the diastolic blood pressure and the cardiac interval of the heart beat during which the burst was generated. The results were expressed as blood pressure/cardiac interval threshold for occurrence of bursts, and as baroreflex sensitivity (i.e. the relationship between diastolic pressure/cardiac interval and burst strength). 2. Significant blood pressure/cardiac interval thresholds were present in all subjects and old subjects had less variability of thresholds than young subjects. In contrast, significant baroreflex sensitivity for diastolic pressure and cardiac interval was present in only 55 and 73 % of the subjects, respectively. There was no age-related difference in sensitivity. 3. In 40 subjects, two 5 min periods from the same recording were analysed. The number of sympathetic bursts and the threshold for occurrence of bursts were reproducible in all subjects. In contrast, significant baroreflex sensitivity in both periods was present in only 30 % (diastolic pressure) and 40 % (cardiac interval) of the subjects. 4. The results show that the baroreflex mechanisms regulating the occurrence and strength of sympathetic bursts are not identical. We suggest that the modulation occurs at two sites, one which determines whether or not a burst will occur, and another at which the strength of the discharge is determined.


Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways.
The relaxation response (RR) is the counterpart of the stress response. Millennia-old practices evoking the RR include meditation, yoga and repetitive prayer. Although RR elicitation is an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia and aging, the underlying molecular mechanisms that explain these clinical benefits remain undetermined. To assess rapid time-dependent (temporal) genomic changes during one session of RR practice among healthy practitioners with years of RR practice and also in novices before and after 8 weeks of RR training, we measured the transcriptome in peripheral blood prior to, immediately after, and 15 minutes after listening to an RR-eliciting or a health education CD. Both short-term and long-term practitioners evoked significant temporal gene expression changes with greater significance in the latter as compared to novices. RR practice enhanced expression of genes associated with energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of genes linked to inflammatory response and stress-related pathways. Interactive network analyses of RR-affected pathways identified mitochondrial ATP synthase and insulin (INS) as top upregulated critical molecules (focus hubs) and NF-κB pathway genes as top downregulated focus hubs. Our results for the first time indicate that RR elicitation, particularly after long-term practice, may evoke its downstream health benefits by improving mitochondrial energy production and utilization and thus promoting mitochondrial resiliency through upregulation of ATPase and insulin function. Mitochondrial resiliency might also be promoted by RR-induced downregulation of NF-κB-associated upstream and downstream targets that mitigates stress.


Task-driven ICA feature generation for accurate and interpretable prediction using fMRI.
Functional Magnetic Resonance Imaging (fMRI) shows significant potential as a tool for predicting clinically important information such as future disease progression or drug effect from brain activity. Multivariate techniques have been developed that combine fMRI signals from across the brain to produce more robust predictive capabilities than can be obtained from single regions. However, the high dimensionality of fMRI data makes overfitting a significant problem. Reliable methods are needed for transforming fMRI data to a set of signals reflecting the underlying spatially extended patterns of neural dynamics. This paper demonstrates a task-specific Independent Component Analysis (ICA) procedure which identifies signals associated with coherent functional brain networks, and shows that these signals can be used for accurate and interpretable prediction. The task-specific ICA parcellations outperformed other feature generation methods in two separate datasets including parcellations based on resting-state data and anatomy. The pattern of response of the task-specific ICA parcellations to particular feature selection strategies indicates that they identify important functional networks associated with the discriminative task. We show ICA parcellations to be robust and informative with respect to non-neural artefacts affecting the fMRI series. Together, these results suggest that task-specific ICA parcellation is a powerful technique for producing predictive and informative signals from fMRI time series. The results presented in this paper also contribute evidence for the general functional validity of the parcellations produced by ICA approaches.