A Drosophila screen identifies a role for histone methylation in ER stress preconditioning.
Stress preconditioning occurs when transient, sublethal stress events impact an organism's ability to counter future stresses. Although preconditioning effects are often noted in the literature, very little is known about the underlying mechanisms. To model preconditioning, we exposed a panel of genetically diverse Drosophila melanogaster to a sublethal heat shock and measured how well the flies survived subsequent exposure to endoplasmic reticulum (ER) stress. The impact of preconditioning varied with genetic background, ranging from dying half as fast to four and a half times faster with preconditioning compared to no preconditioning. Subsequent association and transcriptional analyses revealed that histone methylation, transcriptional regulation, and immune status are all candidate preconditioning modifier pathways. Strikingly, almost all subunits (7/8) in the Set1/COMPASS complex were identified as candidate modifiers of preconditioning. Functional analysis of Set1 knockdown flies demonstrated that loss of Set1 led to the transcriptional dysregulation of canonical ER stress genes during preconditioning. Based on these analyses, we propose a model of preconditioning in which Set1 helps to establish an interim transcriptional 'memory' of previous stress events, resulting in a preconditioned response to subsequent stress.


Genomic reassortment of influenza A virus in North American swine, 1998-2011.
Revealing the frequency and determinants of reassortment among RNA genome segments is fundamental to understanding basic aspects of the biology and evolution of the influenza virus. To estimate the extent of genomic reassortment in influenza viruses circulating in North American swine, we performed a phylogenetic analysis of 139 whole-genome viral sequences sampled during 1998-2011 and representing seven antigenically distinct viral lineages. The highest amounts of reassortment were detected between the H3 and the internal gene segments (PB2, PB1, PA, NP, M and NS), while the lowest reassortment frequencies were observed among the H1γ, H1pdm and neuraminidase segments, particularly N1. Less reassortment was observed among specific haemagglutinin-neuraminidase combinations that were more prevalent in swine, suggesting that some genome constellations may be evolutionarily more stable.


Astragalus saponins Inhibits Lipopolysaccharide-Induced Inflammation in Mouse Macrophages.
Excessive nitric oxide (NO) and pro-inflammatory cytokines are produced during the pathogenesis of inflammatory diseases and cancer. It has been demonstrated that anti-inflammation contributes Astragalus membranaceus saponins (AST)'s beneficial effects in combination of conventional anticancer drugs. However, the immunomodulating property of AST has not been well characterized. In this study, we found that AST suppressed lipopolysaccharide (LPS)-induced generation of NO without causing cytotoxicity in the mouse macrophage RAW264.7. The gene and protein overexpression of inducible NO synthase (iNOS) as well as the production of tumor necrosis factor-[Formula: see text], evoked by LPS, was consistently down-regulated by AST. AST also inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and suppressed nuclear factor (NF)-[Formula: see text]B activation and the associated I[Formula: see text]B[Formula: see text] degradation during LPS insult. Furthermore, AST induced growth inhibition in promyelocytic leukemic HL-60 cells and T-lymphocyte leukemic Jurkat cells, but exerted no cytotoxic effects in normal human peripheral blood mononuclear cells (PBMC). It is known that the chemotherapeutic drug 5-FU can suppress the immune system, which can be identified by a reduced white blood cell count and decreased hematocrit, while the combination of AST and 5-FU can reverse the above hematologic toxicities. To summarize, non-cytotoxic concentrations of AST suppress LPS-induced inflammatory responses via the modulation of p38 MAPK signaling and the inhibition of NO and cytokine release. Importantly, AST can alleviate the hematologic side effects of current chemotherapeutic agents. These findings can facilitate the establishment of AST in the treatment of inflammatory diseases and inflammation-mediated tumor development.


Mechanical Regulation of Protein Translation in the Cardiovascular System.
The cardiovascular system can sense and adapt to changes in mechanical stimuli by remodeling the physical properties of the heart and blood vessels in order to maintain homeostasis. Imbalances in mechanical forces and/or impaired sensing are now not only implicated but are, in some cases, considered to be drivers for the development and progression of cardiovascular disease. There is now growing evidence to highlight the role of mechanical forces in the regulation of protein translation pathways. The canonical mechanism of protein synthesis typically involves transcription and translation. Protein translation occurs globally throughout the cell to maintain general function but localized protein synthesis allows for precise spatiotemporal control of protein translation. This Review will cover studies on the role of biomechanical stress -induced translational control in the heart (often in the context of physiological and pathological hypertrophy). We will also discuss the much less studied effects of mechanical forces in regulating protein translation in the vasculature. Understanding how the mechanical environment influences protein translational mechanisms in the cardiovascular system, will help to inform disease pathogenesis and potential areas of therapeutic intervention.


Mean Platelet Volume as a Biomarker for Thyroid Carcinoma.
AbstractObjective: This study aimed to determine the relationship between MPV and thyroid malignancy by comparing patients who underwent surgery for benign or malignant thyroid diseases. Mean platelet volume (MPV) is a useful early indicator of platelet activation. Platelets differ in terms of functional activity and size. Large platelets are relatively new, more reactive and produce more thrombogenic factors. Therefore, in conditions that involve increased platelet activation, an increase in the proportion of young platelets and MPV is expected. This study involved 146 patients who underwent total thyroidectomy because of benign (99 patients) or malignant (47 patients) diseases of the thyroid. Data on age, sex, MPV, white blood cell (WBC) count, hemoglobin level and platelet count were collected retrospectively. MPV was significantly higher in patients with malignant thyroid diseases than in those with benign thyroid diseases. Age, sex, hemoglobin level, WBC count and platelet count did not significantly differ between the two groups. MPV was significantly higher in patients with thyroid malignancies than in patients with benign thyroid diseases. We propose that MPV might be an important predictive factor for thyroid malignancies. Further prospective studies with a larger number of patients in high-volume endocrine surgery centers are required to confirm our findings.


Quantitative Discrimination of Healthy and Diseased Corneas With Second Harmonic Generation Microscopy.
To analyze the spatial organization of pathological corneas with second harmonic generation (SHG) imaging and to provide a proof of concept to objectively distinguish these from the healthy corneas. A custom-built SHG microscope was used to image the anterior stroma of ex vivo corneas, both control and affected by some representative pathologies. The structure tensor (ST) was employed as a metric to explore and quantify the alterations in the spatial distribution of the collagen lamellae. The collagen arrangement differed between healthy and pathological samples. The former showed a regular distribution and a low structural dispersion (SD < 40°) within the stroma with a well-defined dominant orientation. This regular arrangement drastically turns into a disorganized pattern in pathological corneas (SD > 40°). The combination of SHG imaging and the ST allows obtaining quantitative information to differentiate the stromal collagen organization in healthy and diseased corneas. This approach represents a feasible and powerful technique with potential applications in clinical corneal diagnoses. The ST applied to SHG microscopy images of the corneal stroma provides an experimental objective score to differentiate control from pathological or damaged corneas. Future implementations of this technique in clinical environments might might be a promising tool in Ophthalmology, not only to diagnose and monitor corneal diseases, but also to follow-up surgical outcome.


An electro-osmotic microfluidic system to characterize cancer cell migration under confinement.
We have developed a novel electro-osmotic microfluidic system to apply precisely controlled osmolarity gradients to cancer cells in micro-channels. We observed that albeit adhesion is not required for cells to migrate in such a confined microenvironment, the migrating velocity of cells is strongly influenced by the interactions between the cells and the channel wall, with a stronger adhesion leading to diminished cell motility. Furthermore, through examining more than 20 different types of cancer cells, we found a linear positive correlation between the protein concentration of the aquaporin-4 (AQP4) and the cell migrating speed. Knockdown of AQP4 in invasive re-populated cancer stem cells reduced their migration capability down to the level that is comparable to their parental cancer cells. Interestingly, these observations can all be quantitatively explained by the osmotic engine model where the cell movement is assumed to be driven by cross-membrane ion/water transport, while adhesion acts as a frictional resistance against the cell motility. By providing versatile and controllable features in regulating and characterizing the migration capability of cells, our system may serve as a useful tool in quantifying how cell motility is influenced by different physical and biochemical factors, as well as elucidating the mechanisms behind, in the future.


Walker-assisted gait in rehabilitation: a study of biomechanics and instrumentation.
While walkers are commonly prescribed to improve patient stability and ambulatory ability, quantitative study of the biomechanical and functional requirements for effective walker use is limited. To date no one has addressed the changes in upper extremity kinetics that occur with the use of a standard walker, which was the objective of this study. A strain gauge-based walker instrumentation system was developed for the six degree-of-freedom measurement of resultant subject hand loads. The walker dynamometer was integrated with an upper extremity biomechanical model. Preliminary system data were collected for seven healthy, right-handed young adults following informed consent. Bilateral upper extremity kinematic data were acquired with a six camera Vicon motion analysis system using a Micro-VAX workstation. Internal joint moments at the wrist, elbow, and shoulder were determined in the three clinical planes using the inverse dynamics method. The walker dynamometer system allowed characterization of upper extremity loading demands. Significantly differing upper extremity loading patterns were identified for three walker usage methods. Complete description of upper extremity kinetics and kinematics during walker-assisted gait may provide insight into walker design parameters and rehabilitative strategies.


Detecting community response to water quality violations using bottled water sales.
Drinking-water contaminants pose a risk to public health. When confronted with elevated levels of contaminants, individuals can take actions to reduce exposure. Yet, few studies address averting behavior due to impaired water, particularly in high-income countries. This is a problem of national interest, given that 9 million to 45 million people have been affected by water quality violations in each of the past 34 years. No national analysis has focused on the extent to which communities reduce exposure to contaminated drinking water. Here, we present an assessment that sheds light on how communities across the United States respond to violations of the Safe Drinking Water Act, using consumer purchases of bottled water. This study provides insight into how averting behavior differs across violation types and community demographics. We estimate the change in sales due to water quality violations, using a panel dataset of weekly sales and violation records in 2,151 counties from 2006 to 2015. Critical findings show that violations which pose an immediate health risk are associated with a 14% increase in bottled water sales. Generally, greater averting action is taken against contaminants that might pose a greater perceived health risk and that require more immediate public notification. Rural, low-income communities do not take significant averting action for elevated levels of nitrate, yet experience a higher prevalence of nitrate violations. Findings can inform improvements in public notification and targeting of technical assistance from state regulators and public health agencies in order to reduce community exposure to contaminants.


Suicide Among Inuit: Results From a Large, Epidemiologically Representative Follow-Back Study in Nunavut.
The Inuit population in Canada's North has suffered from high rates of death by suicide. We report on the first large-scale, controlled, epidemiologically representative study of deaths by suicide in an Indigenous population, which investigates risk factors for suicide among all Inuit across Nunavut who died by suicide during a 4-year period. We identified all suicides by Inuit (n = 120) that occurred between January 1, 2003, and December 31, 2006, in Nunavut. For each subject, we selected a community-matched control subject. We used proxy-based procedures and conducted structured interviews with informants to obtain life histories, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I and II diagnoses, and measures of impulsive and (or) aggressive traits. Compared with control subjects, subjects who died by suicide were more likely to have experienced childhood abuse (OR 2.38; 95% CI 1.39 to 4.08), have family histories of major depressive disorder (P = 0.002) and suicide completion (P = 0.02), and have been affected by major depressive disorder (OR 13.00; 95% CI 6.20 to 27.25), alcohol dependence (OR 2.90; 95% CI 1.59 to 5.24), or cannabis dependence (OR 3.96; 95% CI 2.29 to 6.8) in the last 6 months. In addition, subjects who died by suicide were more likely to have been affected with cluster B personality disorders (OR 10.18; 95% CI 3.34 to 30.80) and had higher scores of impulsive and aggressive traits (P < 0.001). At the individual level, clinical risk factors for suicide among Inuit are similar to those observed in studies with the general population, and indicate a need for improved access to mental health services. The high rate of mental health problems among control subjects suggests the need for population-level mental health promotion.


Ectopic expression of rice Xa21 overcomes developmentally controlled resistance to Xanthomonas oryzae pv. oryzae.
Recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) activates the innate immune response. The rice PRR, XA21, confers robust resistance at adult stages to most strains of the bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo). Seedlings are still easily infected by Xoo, causing severe yield losses. Here we report that Xa21 is induced by Xoo infection and that ectopic expression of Xa21 confers resistance at three leaf stage (three-week-old), overcoming the developmental limitation of XA21-mediated resistance. Ectopic expression of Xa21 also up-regulates a larger set of defense-related genes as compared to Xa21 driven by the native promoter. These results indicate that altered regulation of Xa21 expression is useful for developing enhanced resistance to Xoo at multiple developmental stages.


Chromosomal deletions in myelodysplasia.
There are two major classes of genes implicated in human tumorigenesis, the oncogenes and the tumour suppressor genes. In haematological malignancies most emphasis has been placed upon the recurring translocations in which the juxtaposition of two gene sequences has resulted in the activation of an oncogene. Chromosomal loss rather than translocation is the most frequent karyotypic abnormality in the myelodysplastic syndromes, a heterogeneous group of clonal malignant blood disorders characterised by dyshaematopoiesis and/or impaired maturation of haemopoietic cells with frequent evolution to acute leukaemia. Recent attention has focused on the loss of genetic material as a result of chromosomal monosomy or deletion in the myelodysplastic syndromes. The most frequently reported deletions in these myeloid syndromes are of chromosomes 5, 20 and 7. Deletions of chromosomes 11, 12, and 13, although more rarely observed, are also characteristics of the myelodysplastic syndromes. It is probable that the deleted chromosomal bands give the location for as yet unidentified myeloid specific tumour suppressor loci and there is considerable interest in the cloning of these genes. This review discusses the three most frequently observed deletions in MDS; 7q deletion, 5q deletion and 20q deletion taking into account recent evidence on the respective critical regions of gene loss and the role of candidate genes.


Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation.
Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic signaling proteins that participates in normal cellular responses to cytokines and growth factors. Frequently, however, constitutive activation of certain STAT family members, particularly Stat3, has accompanied a wide variety of human malignancies. To identify small molecule inhibitors of Stat3, we investigated the ability of the Stat3 SH2 domain-binding peptide, PY*LKTK (where Y* represents phosphotyrosine), to disrupt Stat3 activity in vitro. The presence of PY*LKTK, but not PYLKTK or PFLKTK, in nuclear extracts results in significant reduction in the levels of DNA binding activities of Stat3, to a lesser extent of Stat1, and with no effect on that of Stat5. Analyses of alanine scanning mutagenesis and deletion derivatives of PY*LKTK reveal that the Leu residue at the Y+1 position and a substituent at the Y-1 position (but not necessarily Pro) are essential for the disruption of active Stat3, thereby mapping the minimum active sequence to the tripeptide, XY*L. Studies involving bead-coupled PY*LKTK peptide demonstrate that this phosphopeptide directly complexes with Stat3 monomers in vitro, suggesting that PY*LKTK disrupts Stat3:Stat3 dimers. As evidence for the functional importance of peptide-directed inhibition of Stat3, PY*LKTK-mts (mts, membrane translocating sequence) selectively inhibits constitutive and ligand-induced Stat3 activation in vivo. Furthermore, PY*LKTK-mts suppresses transformation by the Src oncoprotein, which has been shown previously to require constitutive Stat3 activation. Altogether, we have identified a minimal peptide that inhibits Stat3 signaling and provides the conceptual basis for use of this peptide as a lead for novel peptidomimetic drug design.


Rare musculoskeletal diseases in adults: a research priority setting partnership with the James Lind Alliance.
Osteogenesis imperfecta, fibrous dysplasia/McCune-Albright syndrome and X-linked hypophosphatemia are three rare musculoskeletal diseases characterised by bone deformities, frequent fractures and pain. Little high-quality research exists on appropriate treatment and long-term management of these conditions in adults. This is further worsened by limited research funding in rare diseases and a general mismatch between the existing research priorities and those of the patients. This partnership adopted the James Lind Alliance approach to identify the top 10 research priorities for rare musculoskeletal diseases in adults through joint patient, carer and healthcare professional collaboration. The initial survey for question collection recruited 198 respondents, submitting a total of 988 questions. 77% of the respondents were patients with a rare musculoskeletal disease. Following out-of-scope question exclusion, repeating query grouping and scientific literature check for answers, 39 questions on treatment and long-term management remained. In the second public survey, 220 respondents, of whom 85% were patients with a rare musculoskeletal disease, their carers, relatives or friends, prioritised these uncertainties, which allowed selection of the top 25. In the last stage, patients, carers and healthcare professionals gathered for a priority setting workshop to reach a consensus on the final top 10 research priorities. These focus on the uncertainties surrounding appropriate treatment and holistic long-term disease management, highlighting several aspects indirect to abnormal bone metabolism, such as extra-skeletal symptoms, psychological care of both patients and their families and disease course through ageing. This James Lind Alliance priority setting partnership is the first to investigate rare bone diseases. The priorities identified here were developed jointly by patients, carers and healthcare professionals. We encourage researchers, funding bodies and other stakeholders to use these priorities in guiding future research for those affected by rare musculoskeletal disorders.


Dietary and Lifestyle Risk Factors for Colorectal Cancer in Apparently Healthy Adults in Jordanian Hospitals.
Colorectal cancer (CRC) is a frequently occurring cancer in Jordan. CRC risk is expected to continue rising due to dietary patterns, sedentary lifestyle, and other practices. The aim of this study was to describe the prevalence of dietary and lifestyle risk factors for CRC among patients attending outpatient gastroenterology clinics in Jordan. A descriptive, cross-sectional design was used to collect data from 713 asymptomatic participants. Data was collected using a self-report questionnaire measuring sociodemographic characteristics, dietary habits, physical activity, and lifestyle risk factors of CRC. The mean age of participants was 57.0 ± 8.56 years. The majority of participants were male (71.8 %) and with less than secondary school formal education (60.7 %). The commonest risk factors for CRC among the participants were overweight or obesity (76.1 %), lack of exercise (71.6 %), limited consumption of vegetables (70.8 %), smoking (60.6 %), over consumption of red meat (56.3 %), and diabetes mellitus (24.1 %). Dietary and lifestyle risk factors for CRC are prevalent in Jordan and likely to fuel an upsurge CRC if population-wide educational interventions are not implemented. There is need for greater attention and emphasis on strategies to educate the general population about healthy dietary and lifestyle habits as means of preventing CRC in Jordan.


Importance of glycolysis for the energetics of anoxia-tolerant and anoxia-intolerant teleost hepatocytes.
The importance of glycolysis, as an ATP-producing and substrate-providing pathway, was studied in anoxia-tolerant (goldfish) and anoxia-intolerant (trout) hepatocytes. Inhibition of glycolysis with iodoacetic acid (IAA) left aerobic ATP production largely unaffected in hepatocytes from both species but caused a significant decrease of ATP contents in the goldfish cells. Ouabain-sensitive oxygen consumption (osVo2), an estimate of mitochondrial ATP production coupled to ATP consumption by the Na(+) pump, was significantly reduced in IAA-treated goldfish hepatocytes, whereas it was unaltered in trout hepatocytes. Partial reduction of mitochondrial respiration, achieved by titration with cyanide (CN), strongly stimulated glycolytic flux but did not affect ATP contents of hepatocytes from both species. Under these conditions, osVo2 became undetectable. Rb(+)-uptake rates, providing a direct estimate of Na(+)-pump activity, were in good agreement with estimates derived from osVo2 in IAA-treated cells, showing a decrease in goldfish and no change in trout. However, they indicated persistent Na(+)-pump activity despite the lack of osVo2 in CN-treated cells. Overall, these data indicate that in goldfish hepatocytes Na(+)-pump activity is more dependent on glycolytic ATP production as compared to trout hepatocytes. Protein synthesis of goldfish hepatocytes was inhibited in IAA- and CN-treated cells, possibly reflecting the hierarchical organization of energy metabolism. In trout hepatocytes, protein synthesis could be sustained at control levels, given that energetic substrate provision was not limited.


Current indications, risks, and outcome after pericardiectomy.
A retrospective analysis of the records of 60 patients who underwent pericardiectomy over a 10-year period (1980 to 1990) at The Johns Hopkins Hospital was performed. Indications for operation were effusive disease in 24 patients and constriction in 36 patients. Six patients (10%) with pericardial effusion had pain as the primary symptom necessitating intervention. The operative approach for pericardiectomy was median sternotomy in 52 patients (4 patients required cardiopulmonary bypass) and left anterior thoracotomy in 8 patients. Nine patients (5 with constriction and 4 with effusion) with a prior limited pericardial procedure required formal pericardiectomy. The operative mortality rate for pericardial effusion and constriction was 4.2% and 5.6%, respectively. Follow-up (median follow-up, 56.9 +/- 38.2 months) was obtained on 56 patients (93.3%). Actuarial survival at 1 year, 5 years, and 10 years for all patients was 82.1% +/- 5.1%, 71.7% +/- 6.7%, and 59.8% +/- 12.2%, respectively. A Cox proportional hazards regression analysis was performed using 20 clinical variables. A history of malignancy, previous pericardial procedure, and preoperative New York Heart Association class IV were found to be predictors of poor survival. All patients who underwent operation primarily for effusion with associated pain are alive and have improved functional capacity without steroid use. We conclude that pericardiectomy can be performed with low mortality and can result in good long-term survival and improved functional capacity. Patients who are seen primarily with pain refractory to steroid therapy can be relieved of symptoms with operation.


Nut, corn, and popcorn consumption and the incidence of diverticular disease.
Patients with diverticular disease are frequently advised to avoid eating nuts, corn, popcorn, and seeds to reduce the risk of complications. However, there is little evidence to support this recommendation. To determine whether nut, corn, or popcorn consumption is associated with diverticulitis and diverticular bleeding. The Health Professionals Follow-up Study is a cohort of US men followed up prospectively from 1986 to 2004 via self-administered questionnaires about medical (biennial) and dietary (every 4 years) information. Men reporting newly diagnosed diverticulosis or diverticulitis were mailed supplemental questionnaires. The study included 47,228 men aged 40 to 75 years who at baseline were free of diverticulosis or its complications, cancer, and inflammatory bowel disease and returned a food-frequency questionnaire. Incident diverticulitis and diverticular bleeding. During 18 years of follow-up, there were 801 incident cases of diverticulitis and 383 incident cases of diverticular bleeding. We found inverse associations between nut and popcorn consumption and the risk of diverticulitis. The multivariate hazard ratios for men with the highest intake of each food (at least twice per week) compared with men with the lowest intake (less than once per month) were 0.80 (95% confidence interval, 0.63-1.01; P for trend = .04) for nuts and 0.72 (95% confidence interval, 0.56-0.92; P for trend = .007) for popcorn. No associations were seen between corn consumption and diverticulitis or between nut, corn, or popcorn consumption and diverticular bleeding or uncomplicated diverticulosis. In this large, prospective study of men without known diverticular disease, nut, corn, and popcorn consumption did not increase the risk of diverticulosis or diverticular complications. The recommendation to avoid these foods to prevent diverticular complications should be reconsidered.


A Tightly-Coupled GPS/INS/UWB Cooperative Positioning Sensors System Supported by V2I Communication.
This paper investigates a tightly-coupled Global Position System (GPS)/Ultra-Wideband (UWB)/Inertial Navigation System (INS) cooperative positioning scheme using a Robust Kalman Filter (RKF) supported by V2I communication. The scheme proposes a method that uses range measurements of UWB units transmitted among the terminals as augmentation inputs of the observations. The UWB range inputs are used to reform the GPS observation equations that consist of pseudo-range and Doppler measurements and the updated observation equation is processed in a tightly-coupled GPS/UWB/INS integrated positioning equation using an adaptive Robust Kalman Filter. The result of the trial conducted on the roof of the Nottingham Geospatial Institute (NGI) at the University of Nottingham shows that the integrated solution provides better accuracy and improves the availability of the system in GPS denied environments. RKF can eliminate the effects of gross errors. Additionally, the internal and external reliabilities of the system are enhanced when the UWB observables received from the moving terminals are involved in the positioning algorithm.


Disruption of dentate gyrus blocks effect of visual input on spatial firing of CA1 neurons.
The role of dentate gyrus in hippocampal mnemonic processing is uncertain. One proposed role of dentate gyrus is binding internally generated spatial representation with sensory information on external landmarks. To test this hypothesis, we compared effects of visual input on spatial firing of CA1 neurons in Bax knock-out mice in which dentate gyrus neural circuitry is selectively disrupted. Whereas spatial selectivity of CA1 neuronal firing was significantly higher under normal illumination than complete darkness in wild-type mice, it was similarly low in both illumination conditions in Bax knock-out mice. Also, whereas the spatial location of neuronal firing was more stably maintained in the light than in the dark condition in wild-type mice, it was similarly unstable in both illumination conditions in Bax knock-out mice. These results show that visual input allows selective and stable spatial firing of CA1 neurons in normal animals, but this effect is lost if dentate gyrus neural circuitry is disrupted. Our results provide empirical support for the proposed role of dentate gyrus in aligning internally generated spatial representation to external landmarks in building a unified representation of external space.


Unintentional injuries and parental violence against children during flood: a study in rural Bangladesh.
Violence and injuries are under-reported in developing countries, especially during natural disasters such as floods. Compounding this, affected areas are isolated from the rest of the country. During 2007 Bangladesh experienced two consecutive floods which affected almost one-third of the country. The objective of this study was to examine unintentional injuries to children in rural Bangladesh and parental violence against them during floods, and also to explore the association of socioeconomic characteristics. A cross-sectional rural household survey was conducted in the worst flood-affected areas. A group of 638 randomly selected married women of reproductive age with at least one child at home were interviewed face-to-face using pre-tested structured questionnaires. The chi2 test and logistic regression were used for data analysis. The majority of families (90%) were affected by the flood and were struggling to find food and shelter, resulting in the parents becoming violent towards their children and other family members in the home. Cuts (38%), falls (22%) and near drowning (21%) comprised the majority of unintentional injuries affecting children during the floods. A large number of children were abused by their parents during the floods (70% by mothers and 40% by fathers). The incidence of child injuries and parental violence against children was higher among families living in poor socio-economic conditions, whose parents were of low occupational status and had micro-credit loans during the floods. Floods can have significant effects on childhood injury and parental violence against children. The improvement of socio-economic conditions would assist in preventing child injuries and parental violence.


Secretin receptors mediating rat forestomach relaxation.
Frozen sections of the rat stomach were incubated with 125I-labeled porcine secretin, and then secretin binding sites were localized by autoradiography. Saturable binding was observed only in the muscularis externa (circular and longitudinal smooth muscle layers) of the proximal nonglandular forestomach. Saturable binding was quantitated by densitometry. 125I-porcine secretin bound to a single class of high-affinity binding sites with a dissociation constant of 0.6 nM. Porcine and rat secretins were nearly equipotent in inhibiting saturable 125I-porcine secretin binding, and vasoactive intestinal polypeptide, peptide histidine-isoleucine, and glucagon were much weaker. Carbachol (100 microM) stimulated a sustained increase in tension in forestomach muscle in vitro, and porcine secretin caused relaxation of this stimulated contraction. We conclude that rat forestomach smooth muscle expresses a high-affinity specific secretin binding site that mediates relaxation. This putative secretin receptor may mediate some of the actions of secretin on gastric motility.


An Interprofessional Course on Substance Use Disorders for Health Professions Students.
Substance use disorders (SUDs) affect millions of Americans. Nevertheless, there is insufficient health care resource allocation for these patients. One reason may be the lack of education and training about SUDs in health professions programs. The authors developed a required, interprofessional SUDs course for health professions students completing a one-month psychiatry clerkship within the Duke University Health System starting in November 2015. Students participated in six 1-hour class sessions led by an interdisciplinary faculty. Sessions focused on core areas in SUDs education and used either a lecture with discussion or a small-group team-based learning format. Students completed one motivational interview, attended a 12-step recovery meeting, and wrote a reflection paper. On the first and last day of the clerkship, students measured their attitudes toward individuals with SUDs using the Substance Abuse Attitude Scale (SAAS) and toward interprofessionalism using the Interprofessional Attitudes Scale (IPAS). Seventy-one students participated in the course from November 2015 to May 2016. Fifty-nine (83%) students had paired pre- and postcourse SAAS and IPAS data. On the SAAS, students showed significant improvement in their median total score and nonmoralizing, treatment optimism, and treatment intervention scores. On the IPAS, students showed significant improvement in their median score on the teamwork, roles, and responsibilities domain. The authors will continue to assess the course. Starting in academic year 2016-2017, the course will include four additional elements, and beginning in July 2016, accelerated bachelor of science in nursing students will participate in the course.


NaviCell Web Service for network-based data visualization.
Data visualization is an essential element of biological research, required for obtaining insights and formulating new hypotheses on mechanisms of health and disease. NaviCell Web Service is a tool for network-based visualization of 'omics' data which implements several data visual representation methods and utilities for combining them together. NaviCell Web Service uses Google Maps and semantic zooming to browse large biological network maps, represented in various formats, together with different types of the molecular data mapped on top of them. For achieving this, the tool provides standard heatmaps, barplots and glyphs as well as the novel map staining technique for grasping large-scale trends in numerical values (such as whole transcriptome) projected onto a pathway map. The web service provides a server mode, which allows automating visualization tasks and retrieving data from maps via RESTful (standard HTTP) calls. Bindings to different programming languages are provided (Python and R). We illustrate the purpose of the tool with several case studies using pathway maps created by different research groups, in which data visualization provides new insights into molecular mechanisms involved in systemic diseases such as cancer and neurodegenerative diseases.


Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials.
Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity-predisposing loci with weight loss across 4 years and with weight regain across years 2-4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism×treatment interaction (P = 4.3 × 10(-3)). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 × 10(-4)). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle.


Placental Growth Factor as a Prognostic Tool in Women With Hypertensive Disorders of Pregnancy: A Systematic Review.
The PlGF (placental growth factor) has been largely demonstrated to be associated with the diagnosis of the hypertensive disorders of pregnancy (HDPs); however, it is unclear how useful it is for the prognosis of the condition. Our objective was to provide a summary of important findings of its prognostic ability by systematically reviewing studies that examined the ability of the PlGF, either independently or combined with other factors, to predict maternal and fetal complications resulting from the HDPs. We included studies published before January 30, 2017, reporting on the use of the PlGF as a prognostic test for women with confirmed HDPs or suspected preeclampsia. Of the 220 abstracts identified through MEDLINE, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature), 17 studies were eligible for our review. Prognostic performance was evaluated by sensitivity, specificity, likelihood ratios, and area under the receiver operating characteristic curve. PlGF showed moderate-to-high evidence (likelihood ratios of ≥5 or ≤0.2 or area under the receiver operating characteristic curves ≥0.70) for identifying women at the highest risk of preterm delivery or neonatal outcomes (10/12 studies) but showed no clinically useful performance for the prediction of adverse maternal outcomes. PlGF may aid in the management of women with HDPs to avert fetal complications. Future studies should determine an optimum threshold for the marker to guide delivery and should examine whether its use for predicting adverse maternal outcomes in women with HDPs can be improved.


The Paradox of Self-Fertile Varieties in the Context of Self-Incompatible Genotypes in Olive.
Olive, representing one of the most important fruit crops of the Mediterranean area, is characterized by a general low fruit yield, due to numerous constraints, including alternate bearing, low flower viability, male-sterility, inter-incompatibility, and self-incompatibility (SI). Early efforts to clarify the genetic control of SI in olive gave conflicting results, and only recently, the genetic control of SI has been disclosed, revealing that olive possesses an unconventional homomorphic sporophytic diallelic system of SI, dissimilar from other described plants. This system, characterized by the presence of two SI groups, prevents self-fertilization and regulates inter-compatibility between cultivars, such that cultivars bearing the same incompatibility group are incompatible. Despite the presence of a functional SI, some varieties, in particular conditions, are able to set seeds following self-fertilization, a mechanism known as pseudo-self-compatibility (PSC), as widely reported in previous literature. Here, we summarize the results of previous works on SI in olive, particularly focusing on the occurrence of self-fertility, and offer a new perspective in view of the recent elucidation of the genetic architecture of the SI system in olive. Recent advances in research aimed at unraveling the molecular bases of SI and its breakdown in olive are also presented. The clarification of these mechanisms may have a huge impact on orchard management and will provide fundamental information for the future of olive breeding programs.


Bacillus subtilis BY-kinase PtkA controls enzyme activity and localization of its protein substrates.
Bacillus subtilis BY-kinase PtkA was previously shown to phosphorylate, and thereby regulate the activity of two classes of protein substrates: UDP-glucose dehydrogenases and single-stranded DNA-binding proteins. Our recent phosphoproteome study identified nine new tyrosine-phosphorylated proteins in B. subtilis. We found that the majority of these proteins could be phosphorylated by PtkA in vitro. Among these new substrates, single-stranded DNA exonuclease YorK, and aspartate semialdehyde dehydrogenase Asd were activated by PtkA-dependent phosphorylation. Because enzyme activity was not affected in other cases, we used fluorescent protein tags to study the impact of PtkA on localization of these proteins in vivo. For several substrates colocalization with PtkA was observed, and more importantly, the localization pattern of the proteins enolase, YjoA, YnfE, YvyG, Ugd and SsbA was dramatically altered in DeltaptkA background. Our results confirm that PtkA can control enzyme activity of its substrates in some cases, but also reveal a new mode of action for PtkA, namely ensuring correct cellular localization of its targets.


Role of bisphosphonates in the management of postmenopausal osteoporosis: an update on recent safety anxieties.
Following their introduction in the 1990s, bisphosphonates have become the mainstay of treatment in the management of postmenopausal osteoporosis, and their use continues to rise. Commonly noted adverse effects in clinical practice include gastrointestinal side-effects, acute phase reactions (predominately seen with intravenous preparations) cutaneous reactions and more rarely, ocular side-effects. However, recent reports of potentially serious adverse effects of bisphosphonate therapy, including atypical subtrochanteric and femoral shaft fractures, atrial fibrillation, oesophageal carcinoma and osteonecrosis of the jaw, have prompted concerns regarding the long-term safety of this class of drugs. This review summarizes the benefits and potential adverse effects of bisphosphonates used in the treatment of postmenopausal osteoporosis. Although evidence of a definitive casual relationship between bisphosphonate therapy and serious adverse effects is lacking, concern remains particularly in relation to atypical subtrochanteric and femoral shaft fractures. This has important consequences in terms of determining optimum duration of therapy and how best to target therapy at those most at risk. Recently, attention has focused on individual fracture risk assessment in order to optimize the risk-benefit ratio of treatment for individual patients. A review of the role of hormone replacement therapy in younger women with significant risk of osteoporotic fractures may be timely in these circumstances.


Molecular testing for long-term rejection surveillance in heart transplant recipients: design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) trial.
Acute rejection continues to occur beyond the first year after cardiac transplantation, but the optimal strategy for detecting rejection during this late period is still controversial. Gene expression profiling (GEP), with its high negative predictive value for acute cellular rejection (ACR), appears to be well suited to identify low-risk patients who can be safely managed without routine invasive endomyocardial biopsy (EMB). The Invasive Monitoring Attenuation Through Gene Expression (IMAGE) study is a prospective, multicenter, non-blinded, randomized clinical trial designed to test the hypothesis that a primarily non-invasive rejection surveillance strategy utilizing GEP testing is not inferior to an invasive EMB-based strategy with respect to cardiac allograft dysfunction, rejection with hemodynamic compromise (HDC) and all-cause mortality. A total of 199 heart transplant recipients in their second through fifth post-transplant years have been enrolled in the IMAGE study since January 13, 2005. The study is expected to continue through 2008. The IMAGE study is the first randomized, controlled comparison of two rejection surveillance strategies measuring outcomes in heart transplant recipients who are beyond their first year post-transplant. The move away from routine histologic evaluation for allograft rejection represents an important paradigm shift in cardiac transplantation, and the results of this study have important implications for the future management of heart transplant patients.


Application of highly portable MinION nanopore sequencing technology for the monitoring of nosocomial tuberculosis infection.
Referral hospitals in sub-Saharan Africa concentrate large numbers of tuberculosis (TB) and multidrug-resistant TB (MDR-TB) patients, failed by community TB services. We have previously shown, from enhanced screening and through autopsy studies, a significant burden of missed TB infections at the University Teaching Hospital, Lusaka, Zambia, with many patients dying or being discharged without treatment. With minimal TB isolation facilities and minimal political will to invest in broader screening and isolation, the risk of nosocomial transmission is likely to be extremely high. Studies from other hospitals in low burden settings and in South Africa have shown that next generation sequencing (NGS) is a very powerful tool for rapidly sequencing whole TB genomes and comparing them to confirm or rule out nosocomial transmission. The established platforms for NGS analysis, such as Illumina, are very expensive, immobile, and require regular maintenance, making them a costly inclusion on a research proposal or programmatic intervention grant in Africa. MinION nanopore sequencing has changed the NGS landscape with cheap portable sequencers, rapid simple library preparation (15min), and automated real-time analysis tools. The application of highly portable MinION nanopore sequencing technology for the monitoring of nosocomial TB infection will be discussed. Preliminary data from our pediatric pneumonia study will demonstrate the detection of TB in induced sputum from children admitted to the University Teaching Hospital.


Introduction and overview. Perinatal carcinogenesis: growing a node for epidemiology, risk management, and animal studies.
Perinatal carcinogenesis as a cross-disciplinary concern is the subject of this special issue of Toxicology and Applied Pharmacology, which consists of a total of eight reviews or commentaries in the areas of epidemiology, risk assessment, and animal models. Some of the conclusions from these articles, and the Questions and Answers section that follows most of them, are summarized here. There is adequate reason to suspect that perinatal exposures contribute to human cancer risk, both childhood cancers, and those appearing later in life. The latter type of risk may actually be quantitatively the more important, and involve a wide range of types of effects, but has received only limited attention. With regard to childhood cancers, fetal irradiation and diethylstilbestrol exposure are known etiological agents, and it is likely, but not yet certain, there are additional external causes of a portion of these. Some current focal points of interest here include nitroso compounds, DNA topoisomerase inhibitors, viruses, anti-AIDS drugs, and endocrine disruptors. Regulatory agencies must rely heavily on animal data for estimation of human risk due to perinatal exposures to chemicals, and the quantity and quality of these data presently available for this purpose are greatly limiting. Correctly designed conventional animal studies with suspect chemicals are still needed. Furthermore, genetically engineered mouse models for childhood cancers, especially medulloblastoma, have become available, and could be used for screening of candidate causative agents for this cancer type, and for better understanding of gene-environment interactions.


Multiprofessional education to stimulate collaboration: a circular argument and its consequences.
The current developments in healthcare are unprecedented. The organization of health care is complex. Collaboration is essential to meet all the healthcare needs of patients and to achieve coordinated and unambiguous information. Multiprofessional education (MPE) or multidisciplinary training (MDT) seems a logical step to stimulate teamwork. However, collaboration and MPE are wrestling with the same problems: social identity and acceptance.


Pediatric hydatidosis in the south-east of the Buenos Aires province, Argentina.
Hydatidosis is a zoonosis produced by the metacestode Echinococcus spp. The aims of this research are: to contribute to the knowledge of pediatric hydatidosis in the south-east of Buenos Aires province, to study its evolution from 1993 to 2002 at the Regional Maternity and Pediatric Hospital "Dr. Victorio Tetamanti", to determine the strains involved and to discuss the importance of the disease. The clinical records of diagnosed and/or operated patients were reviewed with regard to the hydatid disease. The strain was determined by using PCRs with Eg1 121a/122a primers. Forty-four cases were analyzed. Fifty nine point one per cent of the patients were boys. The mean age was 8 SD=3.8 years. Sixty one point four per cent had urban residence. Ultrasonography was used in 61% of the cases. The hepatic location was most frequently seen and the liver/lung ratio was 1.25. Ninety point nine per cent of patients received surgical treatment. Albendazole was used in 52% of cases. The average hospitalization time was 11 days. The G1/G2 strain group was determined. This report is the first one of its kind in the studied region. The permanence of hydatidosis in the region depends on the natural transmission of the parasite in the absence of control and prevention measures. The health authorities should implement strategies of prevention and control in the study area.


Satellite observations of smoke from oil fires in kuwait.
Extensive dark smoke clouds associated with burning oil wells in Kuwait have been seen in data from weather satellites since early February 1991. The smoke is dispersed over a wide area. Variable and strong low level winds have held most of the smoke plume below 3 to 5 kilometers within a few hundred kilometers of the source. Thin veils of smoke have been detected in METEOSAT data as far away as 2000 kilometers east of Kuwait, over southwestern Pakistan at heights between 6 and 7 kilometers. The occasional presence of convective clouds over the fires indicates that some scavenging of the smoke is taking place.


Acute presentation of a partially obstructing laryngeal tumour: adjuvant agents to gaseous induction of anaesthesia.
We present the case of a 53-year-old man who attended our emergency department with stridor. He had recently undergone investigation for possible glottic cancer. We discuss the airway management of such a case. We believe this to be the first description of propofol target controlled infusion and clonidine to supplement a sevoflurane gas induction, in order to obtund response to intubation while maintaining spontaneous ventilation. We also consider how airway interventions may impact prognosis and need to be considered.


Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to craving.
Using fMRI, our group previously found that after a sip of alcohol and exposure to alcohol beverage pictures, alcoholics compared to social drinkers had increased differential brain activity in the prefrontal cortex and anterior thalamus. This study extends this earlier work with several improvements including imaging the entire brain (rather than the anterior half previously) and recording craving, while the subjects viewed images within the scanner. In a Philips 1.5 T MRI scanner, 10 nontreatment-seeking alcoholics and 10 age-matched healthy social drinkers were given a sip of alcohol before viewing a 12 min randomized presentation of pictures of alcoholic beverages, nonalcoholic beverages, and two different visual control tasks. During picture presentation, changes in regional brain activity were measured in 15 transverse T2(*)-weighted blood oxygen level dependent slices. Subjects rated their urge to drink after each picture sequence. After a sip of alcohol, while viewing alcohol cues compared to viewing other beverage cues, the alcoholics, but not social drinkers, reported higher craving ratings and had increased activity in the prefrontal cortex and anterior limbic regions. Brain activity in the left nucleus accumbens, anterior cingulate, and left orbitofrontal cortex significantly correlated with subjective craving ratings in alcohol subjects but not in control subjects. This study suggests, as did our earlier study, that alcoholics and not social drinkers, when exposed to alcohol cues, have increased brain activity in areas that reportedly subserve craving for other addictive substances.


The diagnosis and management of infection following instrumented spinal fusion.
A 10-year retrospective audit. (1) The incidence of infection; (2) causative organisms; (3) whether eradication of infection is achievable with spinal implant retention; (4) patient outcome. The reported incidence of infection following posterior spinal instrumentation is between 2.6 and 3.8%. Management of infection is controversial, with some advocating serial wound debridement while others report that infection cannot be eradicated with retention of implants. There are no published data demonstrating that propionibacteria are associated with early postoperative infection. The management of infected cases at our institution includes eventual removal of their implants. Our population was identified by studying the case notes of all patients who had undergone removal of spinal implants and cross-referencing this population with positive microbiology or histology reports. The incidence of infection was 3.7%. Propionibacteria were isolated in 45% of cases. The diagnosis of infection was unexpected in 25% of patients, following removal of implants for prominence of implants or back pain. Sixty per cent of patients with acute postoperative deep wound infection had continuing active infection on subsequent removal of implants, despite long-term antibiotics and wound debridement. Fourty-six per cent of patients had a stable, pain-free spine at the end of their treatment. This is the largest reported series of infections following posterior spinal instrumented fusions of which we are aware. Propionibacteria are a common cause of infection and successful eradication of infection cannot be reliably achieved with antibiotics and wound debridement alone.


Genomic instability and telomerase activity in human bronchial epithelial cells during immortalization by human papillomavirus-16 E6 and E7 genes.
Human papilloma virus types 16 and 18 contribute to the development of cervical carcinomas in which the E6 and E7 genes are frequently retained and expressed in the tumors. Our study explored the ability of the E6 and/or E7 genes to immortalize normal human bronchial epithelial (NHBE) cells and to reactivate telomerase expression in these cells. We have introduced the human papillomavirus type 16 E6 or E7 genes alone or in combination (E6/E7) into NHBE cells using the retroviral construct pLXSN. Cells expressing either the E6 or the E7 oncoproteins alone displayed an increased colony-forming efficiency and a slightly extended in vitro life span before entering a crisis, from which immortalized cell lines were not obtained. Telomerase activity was not detected in cells expressing either E6 or E7 individually. Cells expressing the E6/E7 oncoproteins in combination had a substantially increased life span before entering crisis. A subpopulation of these cells escaped from crisis and achieved 130 population doublings, suggesting immortalization. Telomerase activity was detected in these postcrisis cells, but was not detected prior to crisis. In addition, karyotypic analysis showed evidence of genomic instability in mass cultures as well as clones expressing E6, E7, or E6/E7. Abnormalities included numerous monosomies and trisomies, chromatid gaps and breaks, double minutes, and aberrant chromosomes. These results demonstrate that expression of E6 and/or E7 is sufficient to induce genomic instability and an extended life span to NHBE cells, but the presence of both E6 and E7, along with at least one additional genetic or epigenetic event achieved during crisis, was required for reactivation of telomerase and the immortalization in this human cell type.


Eosinophils in chronically inflamed human upper airway tissues express transforming growth factor beta 1 gene (TGF beta 1).
Transforming growth factor beta (TGF beta) is a multifunctional protein which has been suggested to play a central role in the pathogenesis of chronic inflammation and fibrosis. Nasal polyposis is a condition affecting the upper airways characterized by the presence of chronic inflammation and varying degrees of fibrosis. To examine the potential role of TGF beta in the pathogenesis of this condition, we investigated gene expression and cytokine production in nasal polyp tissues as well as in the normal nasal mucosa. By Northern blot analysis using a porcine TGF beta 1 cDNA probe, we detected TGF beta 1-specific mRNA in nasal polyp tissues, as well as in the tissue from a patient with allergic rhinitis, but not in the normal nasal mucosa. By the combination of tissue section staining with chromotrope 2R with in situ hybridization using the same TGF beta 1 probe, we found that approximately 50% of the eosinophils infiltrating the polyp tissue express the TGF beta 1 gene. In addition, immunohistochemical localization of TGF beta 1 was detected associated with extracellular matrix as well as in cells in the stroma. These results suggest that in nasal polyposis where eosinophils are the most prevalent inflammatory cell, TGF beta 1 synthesized by these cells may contribute to the structural abnormalities such as stromal fibrosis and basement membrane thickening which characterize this disease.


A parasitological evaluation of edible insects and their role in the transmission of parasitic diseases to humans and animals.
From 1 January 2018 came into force Regulation (EU) 2015/2238 of the European Parliament and of the Council of 25 November 2015, introducing the concept of "novel foods", including insects and their parts. One of the most commonly used species of insects are: mealworms (Tenebrio molitor), house crickets (Acheta domesticus), cockroaches (Blattodea) and migratory locusts (Locusta migrans). In this context, the unfathomable issue is the role of edible insects in transmitting parasitic diseases that can cause significant losses in their breeding and may pose a threat to humans and animals. The aim of this study was to identify and evaluate the developmental forms of parasites colonizing edible insects in household farms and pet stores in Central Europe and to determine the potential risk of parasitic infections for humans and animals. The experimental material comprised samples of live insects (imagines) from 300 household farms and pet stores, including 75 mealworm farms, 75 house cricket farms, 75 Madagascar hissing cockroach farms and 75 migrating locust farms. Parasites were detected in 244 (81.33%) out of 300 (100%) examined insect farms. In 206 (68.67%) of the cases, the identified parasites were pathogenic for insects only; in 106 (35.33%) cases, parasites were potentially parasitic for animals; and in 91 (30.33%) cases, parasites were potentially pathogenic for humans. Edible insects are an underestimated reservoir of human and animal parasites. Our research indicates the important role of these insects in the epidemiology of parasites pathogenic to vertebrates. Conducted parasitological examination suggests that edible insects may be the most important parasite vector for domestic insectivorous animals. According to our studies the future research should focus on the need for constant monitoring of studied insect farms for pathogens, thus increasing food and feed safety.


Stabilization of dendritic arbor structure in vivo by CaMKII.
Calcium-calmodulin-dependent protein kinase II (CaMKII) promotes the maturation of retinotectal glutamatergic synapses in Xenopus. Whether CaMKII activity also controls morphological maturation of optic tectal neurons was tested using in vivo time-lapse imaging of single neurons over periods of up to 5 days. Dendritic arbor elaboration slows with maturation, in correlation with the onset of CaMKII expression. Elevating CaMKII activity in young neurons by viral expression of constitutively active CaMKII slowed dendritic growth to a rate comparable to that of mature neurons. CaMKII overexpression stabilized dendritic structure in more mature neurons, whereas CaMKII inhibition increased their dendritic growth. Thus, endogenous CaMKII activity limits dendritic growth and stabilizes dendrites, and it may act as an activity-dependent mediator of neuronal maturation.


Effects of upper respiratory tract illnesses, ibuprofen and caffeine on reaction time and alertness.
Compared with healthy individuals, those with upper respiratory tract illnesses (URTIs) report reduced alertness and have slower reaction times. It is important to evaluate medication that can remove this behavioural malaise. The aim of this study was to compare the effects of a combination of ibuprofen plus caffeine with ibuprofen and caffeine alone, and placebo on malaise associated with URTIs, as measured by psychomotor performance and mood testing. Volunteers were randomly assigned to one of four medication conditions as follows: 200 mg ibuprofen and 100 mg caffeine; 200 mg ibuprofen; 100 mg caffeine; placebo. A single oral dose was given and testing followed for 3 h. Efficacy variables were based on the volunteers' performance, measured by psychomotor performance and mood. The pre-drug results confirmed that those with an URTI had a more negative mood and impaired performance. Results from the simple reaction time task, at both 55- and 110-min post-dosing, showed that a single-dose of caffeinated products (I200/C100 and CAF100) led to significantly faster reaction times than IBU200 and placebo. These effects were generally confirmed with the other performance tasks. Subjective measures showed that the combination of ibuprofen and caffeine was superior to the other conditions. There were no serious adverse events reported, and study medication was well tolerated. The results from the post-drug assessments suggest that a combination of ibuprofen and caffeine was the optimum treatment for malaise associated with URTIs in that it had significant effects on objective performance and subjective measures.


Structural basis of open channel block in a prokaryotic pentameric ligand-gated ion channel.
The flow of ions through cation-selective members of the pentameric ligand-gated ion channel family is inhibited by a structurally diverse class of molecules that bind to the transmembrane pore in the open state of the protein. To obtain insight into the mechanism of channel block, we have investigated the binding of positively charged inhibitors to the open channel of the bacterial homolog GLIC by using X-ray crystallography and electrophysiology. Our studies reveal the location of two regions for interactions, with larger blockers binding in the center of the membrane and divalent transition metal ions binding to the narrow intracellular pore entry. The results provide a structural foundation for understanding the interactions of the channel with inhibitors that is relevant for the entire family.


Microscopic polyangiitis complicated by intracerebral hemorrhage and pulmonary hemorrhage in a pediatric patient.
Female, 10 FINAL DIAGNOSIS: Polyangiitis Symptoms: Intracranial hemorrhage • swelling • oliguria Cyclophosphamide • prednisolone Clinical Procedure: Plasmapheresis Specialty: Paediatric nephrology • nephrology • paediatrics. Rare disease. MPO ANCA-associated vasculitis is very rare in children. Renal disease is almost universally present but lung and central nervous system involvement are not commonly reported. We present a pediatric case of microscopic polyangiitis with the unusual presentation of pauci-immune glomerulonephritis, intracerebral hemorrhage and pulmonary hemorrhage. The neurological and pulmonary symptoms settled after treatment with cyclophosphamide and plasmapheresis. However, there was no renal recovery and the patient was rendered dialysis-dependent. We believe that this is the first reported case of pediatric microscopic polyangiitis with central nervous system involvement. The disease may have a subclinical presentation resulting in chronic damage to different organs. Prompt treatment of acute disease with immunosuppression and plasmapheresis can halt disease progression in these patients.


Relationship of Inb antigen to other antigens on In(Lu)-related p80.
The Ina and Inb antigens have recently been added to the list of diverse erythrocyte blood group antigens whose expression is down-regulated by the In(Lu) gene. Evidence has been provided that these antigens constitute polymorphisms of an erythrocyte glycoprotein previously defined by its reactivity with murine monoclonal antibodies, such as A3D8, and designated In(Lu)-related p80. This study has now confirmed the assignment of the Inb antigen to p80 and has further studied the relationship of the Inb epitope to other p80 epitopes recognized by both monoclonal antibodies as well as polyclonal antiserum produced against purified erythrocyte p80.


Modified Carbapenem Inactivation Method for Phenotypic Detection of Carbapenemase Production among Enterobacteriaceae.
The ability of clinical microbiology laboratories to reliably detect carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) is an important element of the effort to prevent and contain the spread of these pathogens and an integral part of antimicrobial stewardship. All existing methods have limitations. A new, straightforward, inexpensive, and specific phenotypic method for the detection of carbapenemase production, the carbapenem inactivation method (CIM), was recently described. Here we describe a two-stage evaluation of a modified carbapenem inactivation method (mCIM), in which tryptic soy broth was substituted for water during the inactivation step and the length of this incubation was extended. A validation study was performed in a single clinical laboratory to determine the accuracy of the mCIM, followed by a nine-laboratory study to verify the reproducibility of these results and define the zone size cutoff that best discriminated between CP-CRE and members of the family Enterobacteriaceae that do not produce carbapenemases. Bacterial isolates previously characterized through whole-genome sequencing or targeted PCR as to the presence or absence of carbapenemase genes were tested for carbapenemase production using the mCIM; isolates with Ambler class A, B, and D carbapenemases, non-CP-CRE isolates, and carbapenem-susceptible isolates were included. The sensitivity of the mCIM observed in the validation study was 99% (95% confidence interval [95% CI], 93% to 100%), and the specificity was 100% (95% CI, 82% to 100%). In the second stage of the study, the range of sensitivities observed across nine laboratories was 93% to 100%, with a mean of 97%; the range of specificities was 97% to 100%, with a mean of 99%. The mCIM was easy to perform and interpret for Enterobacteriaceae, with results in less than 24 h and excellent reproducibility across laboratories.


Emerging infectious diseases: public health issues for the 21st century.
Infectious diseases are the third leading cause of death in the United States and the leading cause worldwide. As the new millennium approaches, the public health community must replenish capacity depleted during years of inadequate funding while simultaneously incorporating new technologies and planning for the longer term. Among the challenges facing the public health community is the need for coordinated, global, multisectoral approaches to preventing and controlling complex infectious disease problems.


Metal ion and other key water quality constituent attenuation in soil columns.
A set of soil columns was constructed to simulate discharge of disinfected tertiary treated wastewater to a river via nearby land application or indirect discharge. The system was primarily designed to observe the fate of metal ions and nutrients. The following three experiments were conducted: (1) flow through saturated soils only, which simulates indirect discharge where water is directly applied to groundwater; (2) flow through unsaturated soil followed by saturated flow, which simulates vadose then saturated zone transport; and (3) saturated flow only using ethylene diamine tetraacetic acid-metal chelates, which determined effects of metal organic complexes on metal mobility through the soil. Metal ion attenuation was substantial but not complete in experiments 1 and 2 (removal: 68% Cu2+, 43% Ni2+, 98% Pb2+, and 96% Hg2+), which was somewhat contrary to modeling results. Cyanide attenuation was also monitored (92% removal). In experiment 3, lead attenuation was somewhat reduced (92% removal) and delayed (requiring additional residence time); copper attenuation was significantly reduced (38% removal) and delayed; and nickel concentrations were higher in the 28-day sample (> 80 microg/L) than in the column feed water (58 microg/L). Near-complete denitrification and total phosphorus attenuation were observed. For the water quality constituents studied, unsaturated (vadose zone) transport did not appear to add additional benefit.


Women's premonitions prior to the death of their baby in utero and how they deal with the feeling that their baby may be unwell.
To identify whether mothers of stillborn babies had had a premonition that their unborn child might not be well and how they dealt with that premonition. Design. A mixed method approach. One thousand and thirty-four women answered a web questionnaire. Six hundred and fourteen women fulfilled the inclusion criteria of having a stillbirth after the 22nd gestational week and answered questions about premonition. Qualitative content analysis was used for the open questions and descriptive statistics for questions with fixed alternatives. The premonition of an unwell unborn baby. In all, 392 of 614 (64%) of the women had had a premonition that their unborn baby might be unwell; 274 of 614 (70%) contacted their clinic and were invited to come in for a check-up, but by then it was too late because the baby was already dead. A further 88 of 614 (22%) decided to wait until their next routine check-up, believing that the symptoms were part of the normal cycle of pregnancy, and that the fetus would move less towards the end of pregnancy. Thirty women (8%) contacted their clinic, but were told that everything appeared normal without an examination of the baby. Women need to know that a decrease in fetal movements is an important indicator of their unborn baby's health. Healthcare professionals should not delay an examination if a mother-to-be is worried about her unborn baby's wellbeing.


Clinical interventions to reduce stillbirths in sub-Saharan Africa: a mathematical model to estimate the potential reduction of stillbirths associated with specific obstetric conditions.
Stillbirths are among the most common adverse pregnancy outcomes, with 98% occurring in low-income countries. More than one-third occur in sub-Saharan Africa (SSA). However, the medical conditions causing stillbirths and interventions to reduce stillbirths from these conditions are not well documented. We estimated the reductions in stillbirths possible with combinations of interventions. We developed a computerised model to estimate the impact of various interventions on stillbirths caused by the most common conditions. The model considered the location of obstetric care (home, clinic or hospital) and each intervention's efficacy, penetration and utilisation. Maternal transfers were also considered. Pregnancies in SSA in 2012. For each condition, we created a series of scenarios involving different combinations of interventions and modelled their impact on stillbirth rates. Stillbirths associated with various maternal and fetal conditions and the percentage reduction with various interventions. Eight to ten maternal and fetal conditions were responsible for most stillbirths, but none for more than 15%. The most common conditions causing stillbirths in SSA include obstructed labour and uterine rupture, fetal distress and umbilical cord complications, fetal growth restriction, pre-eclampsia/eclampsia, and placental abruption/placenta praevia. Syphilis and malaria contribute smaller numbers. Reducing stillbirths requires appropriate diagnosis and management of each condition, usually including hospital care for monitoring and delivery, often by caesarean section. Maternal syphilis and malaria were the only conditions for which outpatient management alone reduced stillbirth. Most stillbirths in low-income countries occur at term and during labour and therefore are preventable by appropriate obstetric care. Management focused on the maternal and fetal conditions that cause stillbirths is necessary to achieve stillbirth rates approaching those found in high-income countries. Reducing stillbirth incidence requires appropriate management of each causative condition and often caesarean delivery.


Phototherapy: the hospital as risk factor.
In a retrospective study over six years the incidence of phototherapy was examined in two groups of healthy neonates who were born spontaneously and at term in hospital. They were comparable in all respects except that one group was cared for at home and the other group was cared for in hospital. It appeared that the infants in hospital received phototherapy seven times more often than those at home, and surveillance at home was not inferior to that in hospital. There is no reason to assume that neonatal jaundice occurred more often in neonates in hospital than in those at home. Thus the difference in the frequency of treatment with phototherapy between the two groups is ascribed to the influence of the hospital environment, which may encourage intervention.


Familiarity differentially affects right hemisphere contributions to processing metaphors and literals.
The role of the two hemispheres in processing metaphoric language is controversial. While some studies have reported a special role of the right hemisphere (RH) in processing metaphors, others indicate no difference in laterality relative to literal language. Some studies have found a role of the RH for novel/unfamiliar metaphors, but not conventional/familiar metaphors. It is not clear, however, whether the role of the RH is specific to metaphor novelty, or whether it reflects processing, reinterpretation or reanalysis of novel/unfamiliar language in general. Here we used functional magnetic resonance imaging (fMRI) to examine the effects of familiarity in both metaphoric and non-metaphoric sentences. A left lateralized network containing the middle and inferior frontal gyri, posterior temporal regions in the left hemisphere (LH), and inferior frontal regions in the RH, was engaged across both metaphoric and non-metaphoric sentences; engagement of this network decreased as familiarity decreased. No region was engaged selectively for greater metaphoric unfamiliarity. An analysis of laterality, however, showed that the contribution of the RH relative to that of LH does increase in a metaphor-specific manner as familiarity decreases. These results show that RH regions, taken by themselves, including commonly reported regions such as the right inferior frontal gyrus (IFG), are responsive to increased cognitive demands of processing unfamiliar stimuli, rather than being metaphor-selective. The division of labor between the two hemispheres, however, does shift towards the right for metaphoric processing. The shift results not because the RH contributes more to metaphoric processing. Rather, relative to its contribution for processing literals, the LH contributes less.


Health Care Expenditure and Income: A Global Perspective.
This paper investigates the long-run economic relationship between healthcare expenditure and income in the world using data on 167 countries over the period 1995-2012, collected from the World Bank data set. The analysis is carried using panel data methods that allow one to account for unobserved heterogeneity, temporal persistence, and cross-section dependence in the form of either a common factor model or a spatial process. We estimate a global measure of income elasticity using all countries in the sample, and for sub-groups of countries, depending on their geo-political area and income. Our findings suggest that at the global level, health care is a necessity rather than a luxury. However, results vary greatly depending on the sub-sample analysed. Our findings seem to suggest that size of income elasticity depends on the position of different countries in the global income distribution, with poorer countries showing higher elasticity. Copyright © 2016 John Wiley & Sons, Ltd.


Influence of chronic stretching on muscle performance: Systematic review.
The aim of the current study was to investigate the influence of chronic stretching on muscle performance (MP) by a systematic review. The search strategy included MEDLINE, PEDro, Cochrane CENTRAL, LILACS, and manual search from inception to June 2016. Randomized and controlled clinical trials, non-randomized, and single group studies that have analyzed the influence of flexibility training (FT) (using any stretching technique) on MP were included. Differently, studies with special populations (children, elderly, and people with any dysfunction/disease), and articles that have used FT protocols shorter than three weeks or 12 sessions were excluded. The MP assessment could have been performed by functional tests (e.g. jump, sprint, stretch-shortening cycle tasks), isometric contractions, and/or isotonic contractions. Twenty-eight studies were included out of 513. Seven studies evaluated MP by stretch-shortening cycle tasks, Ten studies evaluated MP by isometric contractions, and 13 studies assessed MP by isotonic contractions. We were unable to perform a meta-analysis due to the high heterogeneity among the included studies. In an individual study level analysis, we identified that 14 studies found positive effects of chronic stretching on MP. The improvements were observed only in functional tests and isotonic contractions, isometric contractions were not affected by FT. Therefore, FT might have an influence on dynamic MP. However, more studies are necessary to confirm whether FT can positively affect MP.


Genetic and molecular predictors of high vancomycin MIC in Staphylococcus aureus bacteremia isolates.
An elevated vancomycin MIC is associated with poor outcomes in Staphylococcus aureus bacteremia (SAB) and is reported in patients with methicillin-susceptible S. aureus (MSSA) bacteremia in the absence of vancomycin treatment. Here, using DNA microarray and phenotype analysis, we investigated the genetic predictors and accessory gene regulator (agr) function and their relationship with elevated vancomycin MIC using blood culture isolates from a multicenter binational cohort of patients with SAB. Specific clonal complexes were associated with elevated (clonal complex 8 [CC8] [P < 0.001]) or low (CC22 [P < 0.001], CC88 [P < 0.001], and CC188 [P = 0.002]) vancomycin MIC. agr dysfunction (P = 0.014) or agr genotype II (P = 0.043) were also associated with an elevated vancomycin MIC. Specific resistance and virulence genes were also linked to an elevated vancomycin MIC, including blaZ (P = 0.002), sea (P < 0.001), clfA (P < 0.001), splA (P = 0.001), and the arginine catabolic mobile element (ACME) locus (P = 0.02). These data suggest that inherent organism characteristics may explain the link between elevated vancomycin MICs and poor outcomes in patients with SAB, regardless of the antibiotic treatment received. A consideration of clonal specificity should be included in future research when attempting to ascertain treatment effects or clinical outcomes.


A Novel Human Microbe-Disease Association Prediction Method Based on the Bidirectional Weighted Network.
The survival of human beings is inseparable from microbes. More and more studies have proved that microbes can affect human physiological processes in various aspects and are closely related to some human diseases. In this paper, based on known microbe-disease associations, a bidirectional weighted network was constructed by integrating the schemes of normalized Gaussian interactions and bidirectional recommendations firstly. And then, based on the newly constructed bidirectional network, a computational model called BWNMHMDA was developed to predict potential relationships between microbes and diseases. Finally, in order to evaluate the superiority of the new prediction model BWNMHMDA, the framework of LOOCV and 5-fold cross validation were implemented, and simulation results indicated that BWNMHMDA could achieve reliable AUCs of 0.9127 and 0.8967 ± 0.0027 in these two different frameworks respectively, which is outperformed some state-of-the-art methods. Moreover, case studies of asthma, colorectal carcinoma, and chronic obstructive pulmonary disease were implemented to further estimate the performance of BWNMHMDA. Experimental results showed that there are 10, 9, and 8 out of the top 10 predicted microbes having been confirmed by related literature in these three kinds of case studies separately, which also demonstrated that our new model BWNMHMDA could achieve satisfying prediction performance.


Wnt-1 regulation of connexin43 in cardiac myocytes.
Gap junction channels composed of connexin43 (Cx43) are essential for normal heart formation and function. We studied the potential role of the Wnt family of secreted polypeptides as regulators of Cx43 expression and gap junction channel function in dissociated myocytes and intact hearts. Neonatal rat cardiomyocytes responded to Li(+), which mimics Wnt signaling, by accumulating the effector protein beta-catenin and by inducing Cx43 mRNA and protein markedly. Induction of Cx43 expression was also observed in cardiomyocytes cocultured with Rat-2 fibroblasts or N2A neuroblastoma cells programmed to secrete bioactive Wnt-1. By transfecting a Cx43 promoter-reporter gene construct into cardiomyocytes, we demonstrated that the inductive effect of Wnt signaling was transcriptionally mediated. Enhanced expression of Cx43 increased cardiomyocyte cell coupling, as determined by Lucifer Yellow dye transfer and by calcium wave propagation. Conversely, in a transgenic cardiomyopathic mouse model that exhibits ventricular arrhythmias and gap junctional remodeling, beta-catenin and Cx43 expression were downregulated concordantly. In response to Wnt signaling, the accumulating Cx43 colocalized with beta-catenin in the junctional membrane; moreover, forced expression of Cx43 in cardiomyocytes reduced the transactivation potential of beta-catenin. These findings demonstrate that Wnt signaling is an important modulator of Cx43-dependent intercellular coupling in the heart, and they support the hypothesis that dysregulated signaling contributes to altered impulse propagation and arrhythmia in the myopathic heart.


Radiometric Measurement Comparison on the Integrating Sphere Source Used to Calibrate the Moderate Resolution Imaging Spectroradiometer (MODIS) and the Landsat 7 Enhanced Thematic Mapper Plus (ETM+).
As part of a continuing effort to validate the radiometric scales assigned to integrating sphere sources used in the calibration of Earth Observing System (EOS) instruments, a radiometric measurement comparison was held in May 1998 at Raytheon/Santa Barbara Remote Sensing (SBRS). This comparison was conducted in support of the calibration of the Moderate Resolution Imaging Spectroradiometer (MODIS) and the Landsat 7 Enhanced Thematic Mapper Plus (ETM+) instruments. The radiometric scale assigned to the Spherical Integrating Source (SIS100) by SBRS was validated through a comparison with radiometric measurements made by a number of stable, well-characterized transfer radiometers from the National Institute of Standards and Technology (NIST), the National Aeronautics and Space Administration's Goddard Space Flight Center (NASA's GSFC), and the University of Arizona Optical Sciences Center (UA). The measured radiances from the radiometers differed by ±3 % in the visible to near infrared when compared to the SBRS calibration of the sphere, and the overall agreement was within the combined uncertainties of the individual measurements. In general, the transfer radiometers gave higher values than the SBRS calibration in the near infrared and lower values in the blue. The measurements of the radiometers differed by ±4 % from 800 nm to 1800 nm compared to the SBRS calibration of the sphere, and the overall agreement was within the combined uncertainties of the individual measurements for wavelengths less than 2200 nm. The results of the radiometric measurement comparison presented here supplement the results of previous measurement comparisons on the integrating sphere sources used to calibrate the Multi-angle Imaging SpectroRadiometer (MISR) at NASA's Jet Propulsion Laboratory (JPL), Pasadena, CA and the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) at NEC Corporation, Yokohama, Japan.


Parietal neurons related to memory-guided hand manipulation.
1. We recorded activity of the hand-manipulation-task-related neurons in the posterolateral bank of the anterior intraparietal sulcus (area AIP) of the monkey parietal cortex during a delayed hand manipulation task. 2. We examined mainly the object-type visual-dominant and visual-and-motor neurons that responded to the sight of objects for manipulation. The majority of these neurons (32 of 48) showed sustained activity during the delay period in the dark before manipulation of preferred objects. 3. Six visual-and-motor neurons showed set-related activity before the hand manipulation in the dark, so that their delay period activity was likely to be related to motor preparation. 4. The delay period activity of 18 visual-dominant and visual-and-motor neurons without set-related activity was likely to represent spatial features of objects, because the majority of the neurons showed the same selectivity in the shape and/or orientation during object fixation and the delay period. 5. Of these 18 neurons, 10 showed sustained activity in the dark after brief illumination of objects during a light-interrupted fixation task, suggesting that they store the short-term memory of objects without the intention to remember. 6. The results suggest that the visual memory of three-dimensional features of objects is likely to be incorporated in area AIP and to be used for the guidance of hand manipulation.


Atomic scale reversible opto-structural switching of few atom luminescent silver clusters confined in LTA zeolites.
Luminescent silver clusters (AgCLs) stabilized inside partially Ag exchanged Na LTA zeolites show a remarkable reversible on-off switching of their green-yellowish luminescence that is easily tuned by a hydration and dehydration cycle, making them very promising materials for sensing applications. We have used a unique combination of photoluminescence (PL), UV-visible-NIR Diffuse Reflectance (DRS), X-ray absorption fine structure (XAFS), Fourier Transform-Infrared (FTIR) and electron spin resonance (ESR) spectroscopies to unravel the atomic-scale structural changes responsible for the reversible optical behavior of the confined AgCLs in LTA zeolites. Water coordinated, diamagnetic, tetrahedral AgCLs [Ag4(H2O)4]2+ with Ag atoms positioned along the axis of the sodalite six-membered rings are at the origin of the broad and intense green-yellowish luminescence in the hydrated sample. Upon dehydration, luminescent [Ag4(H2O)4]2+ clusters are transformed into non-luminescent (dark), diamagnetic, octahedral AgCLs [Ag6(OF)14]2+ with Ag atoms interacting strongly with zeolite framework oxygen (OF) of the sodalite four-membered rings. This highly responsive on-off switching reveals that besides quantum confinement and molecular-size, coordinated water and framework oxygen ligands strongly affect the organization of AgCLs valence electrons and play a crucial role in the opto-structural properties of AgCLs.


Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial.
Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828. 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]). These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis. Novartis Pharmaceuticals.


Impact of Screening on Breast Cancer Mortality: The UK Program 20 Years On.
With changes in diagnosis, treatment, and management of breast cancer since the mammography screening trials, there is a need to evaluate contemporary breast screening programs. A case-control study was set up to assess the current impact of attendance in the English Breast Screening Program on breast cancer mortality. Cancer registry cases who died from primary breast cancer ages 47 to 89 years in London in 2008 to 2009 (869 women) were matched to 1 or 2 general population controls (1,642 women) with no diagnosis of breast cancer at the time of the case's diagnosis, who were alive at the case's death. Cases and controls were matched for date of birth and screening area, and had been invited to breast screening at least once prior to the case's diagnosis. ORs were estimated using conditional logistic regression. Self-selection bias was addressed using contemporaneous attendance at the cervical screening program. Sensitivity analyses were undertaken to assess the likely effect of lead time bias. Attendance at breast screening resulted in a breast cancer mortality reduction of 39% [OR, 0.61; 95% confidence interval (CI), 0.44-0.85] after self-selection correction. Attendance in the last 3 years prior to diagnosis resulted in a 60% mortality reduction (OR, 0.40; 95% CI, 0.31-0.51). Lead time bias effects were negligible. Our results suggest that community breast screening programs provide their expected benefit in terms of reducing the risk of breast cancer death among women participating. Mammography is an important tool for reducing breast cancer mortality and its impact could be increased by encouraging regular attendance.


Does SLE widen or narrow race/ethnic disparities in the risk of five co-morbid conditions? Evidence from a community-based outpatient care system.
The heterogeneous spectrum of systemic lupus erythematosus (SLE) often presents with secondary complications such as cardiovascular disease (CVD), infections and neoplasms. Our study assessed whether the presence of SLE independently increases or reduces the disparities, accounting for the already higher risk of these outcomes among racial/ethnic minority groups without SLE. We defined a cohort using electronic health records data (2005-2016) from a mixed-payer community-based outpatient setting in California serving patients of diverse racial/ethnic backgrounds. The eligible population included adult patients with SLE and matched non-SLE patients (≥18 years old). SLE was the primary exposure. The following outcomes were identified: pneumonia, other infections, CVD and neoplasms. For each racial/ethnic group, we calculated the proportion of incident co-morbidities by SLE exposure, followed by logistic regression for each outcome with SLE as the exposure. We evaluated interaction on the additive and multiplicative scales by calculating the relative excess risk due to interaction and estimating the cross-product term in each model. We identified 1036 SLE cases and 8875 controls. The incidence for all outcomes was higher among the SLE exposed. We found little difference in the odds of the outcomes associated with SLE across racial/ethnic groups, even after multivariable adjustment. This finding was consistent on the multiplicative and additive scales. We demonstrated that SLE status does not independently confer substantial interaction or heterogeneity by race/ethnicity toward the risk of pneumonia, other infections, CVD or neoplasms. Further studies in larger datasets are necessary to validate this novel finding.


Increasing Migration, Diverging Communities: Changing Character of Migrant Streams in Rural Thailand.
This paper studies how increasing migration changes the character of migrant streams in sending communities. Cumulative causation theory posits that past migration patterns determine future flows, as prior migrants provide resources, influence, or normative pressures that make individuals more likely to migrate. The theory implies exponentially increasing migration flows that are decreasingly selective. Recent research identifies heterogeneity in the cumulative patterns and selectivity of migration in communities. We propose that this heterogeneity may be explained by individuals' differential access to previously accumulated migration experience. Multi-level, longitudinal data from 22 rural Thai communities allow us to measure the distribution of past experience as a proxy for its accessibility to community members. We find that migration becomes a less-selective process as migration experience accumulates, and migrants become increasingly diverse in socio-demographic characteristics. Yet, selectivity within migrant streams persists if migration experience is not uniformly distributed among, and hence not equally accessible to, all community members. The results confirm that the accumulation and distribution of prior migrants' experiences distinctly shape future migration flows, and may lead to diverging cumulative patterns in communities over time.