Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19 disease.
Some people with SARS-CoV-2 infection remain asymptomatic, whilst in others the infection can cause mild to moderate COVID-19 disease and COVID-19 pneumonia, leading some patients to require intensive care support and, in some cases, to death, especially in older adults. Symptoms such as fever or cough, and signs such as oxygen saturation or lung auscultation findings, are the first and most readily available diagnostic information. Such information could be used to either rule out COVID-19 disease, or select patients for further diagnostic testing. To assess the diagnostic accuracy of signs and symptoms to determine if a person presenting in primary care or to hospital outpatient settings, such as the emergency department or dedicated COVID-19 clinics, has COVID-19 disease or COVID-19 pneumonia. On 27 April 2020, we undertook electronic searches in the Cochrane COVID-19 Study Register and the University of Bern living search database, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. Studies were eligible if they included patients with suspected COVID-19 disease, or if they recruited known cases with COVID-19 disease and controls without COVID-19. Studies were eligible when they recruited patients presenting to primary care or hospital outpatient settings. Studies including patients who contracted SARS-CoV-2 infection while admitted to hospital were not eligible. The minimum eligible sample size of studies was 10 participants. All signs and symptoms were eligible for this review, including individual signs and symptoms or combinations. We accepted a range of reference standards including reverse transcription polymerase chain reaction (RT-PCR), clinical expertise, imaging, serology tests and World Health Organization (WHO) or other definitions of COVID-19. Pairs of review authors independently selected all studies, at both title and abstract stage and full-text stage. They resolved any disagreements by discussion with a third review author. Two review authors independently extracted data and resolved disagreements by discussion with a third review author. Two review authors independently assessed risk of bias using the QUADAS-2 checklist. Analyses were descriptive, presenting sensitivity and specificity in paired forest plots, in ROC (receiver operating characteristic) space and in dumbbell plots. We did not attempt meta-analysis due to the small number of studies, heterogeneity across studies and the high risk of bias. We identified 16 studies including 7706 participants in total. Prevalence of COVID-19 disease varied from 5% to 38% with a median of 17%. There were no studies from primary care settings, although we did find seven studies in outpatient clinics (2172 participants), and four studies in the emergency department (1401 participants). We found data on 27 signs and symptoms, which fall into four different categories: systemic, respiratory, gastrointestinal and cardiovascular. No studies assessed combinations of different signs and symptoms and results were highly variable across studies. Most had very low sensitivity and high specificity; only six symptoms had a sensitivity of at least 50% in at least one study: cough, sore throat, fever, myalgia or arthralgia, fatigue, and headache. Of these, fever, myalgia or arthralgia, fatigue, and headache could be considered red flags (defined as having a positive likelihood ratio of at least 5) for COVID-19 as their specificity was above 90%, meaning that they substantially increase the likelihood of COVID-19 disease when present. Seven studies carried a high risk of bias for selection of participants because inclusion in the studies depended on the applicable testing and referral protocols, which included many of the signs and symptoms under study in this review. Five studies only included participants with pneumonia on imaging, suggesting that this is a highly selected population. In an additional four studies, we were unable to assess the risk for selection bias. These factors make it very difficult to determine the diagnostic properties of these signs and symptoms from the included studies. We also had concerns about the applicability of these results, since most studies included participants who were already admitted to hospital or presenting to hospital settings. This makes these findings less applicable to people presenting to primary care, who may have less severe illness and a lower prevalence of COVID-19 disease. None of the studies included any data on children, and only one focused specifically on older adults. We hope that future updates of this review will be able to provide more information about the diagnostic properties of signs and symptoms in different settings and age groups. The individual signs and symptoms included in this review appear to have very poor diagnostic properties, although this should be interpreted in the context of selection bias and heterogeneity between studies. Based on currently available data, neither absence nor presence of signs or symptoms are accurate enough to rule in or rule out disease. Prospective studies in an unselected population presenting to primary care or hospital outpatient settings, examining combinations of signs and symptoms to evaluate the syndromic presentation of COVID-19 disease, are urgently needed. Results from such studies could inform subsequent management decisions such as self-isolation or selecting patients for further diagnostic testing. We also need data on potentially more specific symptoms such as loss of sense of smell. Studies in older adults are especially important.


Mechanism of gastric emptying through the pyloric sphincter: a human study.
The current view holds that gastric emptying is effected by the force of the antral peristaltic wave squeezing food particles through pyloric sphincter resistance. Whether this is accomplished by a reflex action was investigated. The study comprised 12 healthy volunteers (age: 42.2+/-10.6 years). A balloon-tipped and a manometric tube were introduced into the stomach. Pressure responses in the proximal stomach, pyloric antrum, and pyloric sphincter to distension of the proximal stomach and of the antrum were recorded. Pyloric sphincter distension was induced to test its effect on antral and proximal stomach pressure. These tests were repeated in nine men after separately anesthetizing the pyloric antrum and sphincter. Distension of the proximal stomach produced no pressure changes in the proximal stomach, pyloric antrum, or sphincter (p>0.05). Antral distension effected a significant rise in antral pressure, but not in the proximal stomach. Significant sphincter pressure decrease occurred only with antral distension volumes >50 ml. Pyloric sphincter distension produced a significant rise in antral pressure, but not in the proximal stomach. Sphincteric or antral anesthetization produced no pressure changes in the pyloric sphincter, antrum, or proximal stomach. Pyloric sphincter relaxation upon antral distension implies a reflex relationship the authors call the "antro-sphincteric inhibitory reflex". Pyloric sphincter distension effected antral contraction, which is suggested to be a reflex in nature and which they term the "sphinctero-antral excitatory reflex". It is postulated that these two reflexes act to churn and transport gastric contents to the duodenum.


Secure Authentication for Remote Patient Monitoring with Wireless Medical Sensor Networks.
There is broad consensus that remote health monitoring will benefit all stakeholders in the healthcare system and that it has the potential to save billions of dollars. Among the major concerns that are preventing the patients from widely adopting this technology are data privacy and security. Wireless Medical Sensor Networks (MSNs) are the building blocks for remote health monitoring systems. This paper helps to identify the most challenging security issues in the existing authentication protocols for remote patient monitoring and presents a lightweight public-key-based authentication protocol for MSNs. In MSNs, the nodes are classified into sensors that report measurements about the human body and actuators that receive commands from the medical staff and perform actions. Authenticating these commands is a critical security issue, as any alteration may lead to serious consequences. The proposed protocol is based on the Rabin authentication algorithm, which is modified in this paper to improve its signature signing process, making it suitable for delay-sensitive MSN applications. To prove the efficiency of the Rabin algorithm, we implemented the algorithm with different hardware settings using Tmote Sky motes and also programmed the algorithm on an FPGA to evaluate its design and performance. Furthermore, the proposed protocol is implemented and tested using the MIRACL (Multiprecision Integer and Rational Arithmetic C/C++) library. The results show that secure, direct, instant and authenticated commands can be delivered from the medical staff to the MSN nodes.


Surgery, palliative care, and the American College of Surgeons.
Since the late 1990s, the American College of Surgeons (ACS) has increasingly recognized and advocated palliative care for patients and their families with serious, critical, and terminal illness under surgical care. The college has been the primary catalyst for the recognition of palliative care in the field of surgery in the U.S. and abroad, primarily through educational efforts directed at practicing surgeons and surgeons in training. Roughly 15 years ago a group of surgeons from the fellowship of the college coalesced and then spearheaded these initiatives with invaluable support and advice from leading non-surgeon pioneers of palliative care. This group is now titled, the Committee on Surgical Palliative Care (CSPC). The CSPC's mission is to incorporate the precepts and techniques of palliative care into surgical clinical practice, education, research, and advocacy. This report chronicles the contributions the ACS has made to the evolution of surgical palliative care and details the formation of its CSPC and its role in shaping surgical palliative care today.


SU-E-I-91: Development of a Compact Radiographic Simulator Using Microsoft Kinect.
Radiographic simulator system is useful for learning radiographic techniques and confirmation of positioning before x-ray irradiation. Conventional x-ray simulators have drawbacks in cost and size, and are only applicable to situations in which position of the object does not change. Therefore, we have developed a new radiographic simulator system using an infrared-ray based three-dimensional shape measurement device (Microsoft Kinect). We made a computer program using OpenCV and OpenNI for processing of depth image data obtained from Kinect, and calculated the exact distance from Kinect to the object by calibration. Theobject was measured from various directions, and positional relationship between the x-ray tube and the object was obtained. X-ray projection images were calculated by projecting x-rays onto the mathematical three-dimensional CT data of a head phantom with almost the same size. The object was rotated from 0 degree (standard position) through 90 degrees in increments of 10 degrees, and the accuracy of the measured rotation angle values was evaluated. In order to improve the computational time, the projection image size was changed (512*512, 256*256, and 128*128). The x-ray simulation images corresponding to the radiographic images produced by using the x-ray tube were obtained. The three-dimensional position of the object was measured with good precision from 0 to 50 degrees, but above 50 degrees, measured position error increased with the increase of the rotation angle. The computational time and image size were 30, 12, and 7 seconds for 512*512, 256*256, and 128*128, respectively. We could measure the three-dimensional position of the object using properly calibrated Kinect sensor, and obtained projection images at relatively high-speed using the three-dimensional CTdata. It was suggested that this system can be used for obtaining simulated projection x-ray images before x-ray exposure by attaching this device onto an x-ray tube.


The genome of a subterrestrial nematode reveals adaptations to heat.
The nematode Halicephalobus mephisto was originally discovered inhabiting a deep terrestrial aquifer 1.3 km underground. H. mephisto can thrive under conditions of abiotic stress including heat and minimal oxygen, where it feeds on a community of both chemolithotrophic and heterotrophic prokaryotes in an unusual ecosystem isolated from the surface biosphere. Here we report the comprehensive genome and transcriptome of this organism, identifying a signature of adaptation: an expanded repertoire of 70 kilodalton heat-shock proteins (Hsp70) and avrRpt2 induced gene 1 (AIG1) proteins. The expanded Hsp70 genes are transcriptionally induced upon growth under heat stress, and we find that positive selection is detectable in several members of this family. We further show that AIG1 may have been acquired by horizontal gene transfer (HGT) from a rhizobial fungus. Over one-third of the genes of H. mephisto are novel, highlighting the divergence of this nematode from other sequenced organisms. This work sheds light on the genomic basis of heat tolerance in a complete subterrestrial eukaryotic genome.


Frequency and isostericity of RNA base pairs.
Most of the hairpin, internal and junction loops that appear single-stranded in standard RNA secondary structures form recurrent 3D motifs, where non-Watson-Crick base pairs play a central role. Non-Watson-Crick base pairs also play crucial roles in tertiary contacts in structured RNA molecules. We previously classified RNA base pairs geometrically so as to group together those base pairs that are structurally similar (isosteric) and therefore able to substitute for each other by mutation without disrupting the 3D structure. Here, we introduce a quantitative measure of base pair isostericity, the IsoDiscrepancy Index (IDI), to more accurately determine which base pair substitutions can potentially occur in conserved motifs. We extract and classify base pairs from a reduced-redundancy set of RNA 3D structures from the Protein Data Bank (PDB) and calculate centroids (exemplars) for each base combination and geometric base pair type (family). We use the exemplars and IDI values to update our online Basepair Catalog and the Isostericity Matrices (IM) for each base pair family. From the database of base pairs observed in 3D structures we derive base pair occurrence frequencies for each of the 12 geometric base pair families. In order to improve the statistics from the 3D structures, we also derive base pair occurrence frequencies from rRNA sequence alignments.


Reproduction of Heterodera schachtii Schmidt on Resistant Mustard, Radish, and Sugar Beet Cultivars.
The reproduction of a Wyoming population of Heterodera schachtii was determined for resistant trap crop radish (Raphanus sativus) and mustard (Sinapis alba) cultivars, and resistant and susceptible sugar beet (Beta vulgaris) cultivars in a greenhouse (21 degrees C/16 degrees C) and a growth chamber study (25 degrees C). Oil radish cultivars also were field tested in 2000 and 2001. In the greenhouse study, reproduction was suppressed similarly by the resistant sugar beet cultivar Nematop and all trap crop cultivars (P </= 0.05). In the growth chamber study, the radish cultivars were superior to most of the mustard cultivars in reducing nematode populations. All trap crops showed less reproduction than Nematop (P </= 0.05). In both studies, Nematop and all trap crops had lower Pf than susceptible sugar beet cultivars HH50 and HM9155 (P </= 0.05). In field studies, Rf values of radish cultivars decreased with increasing Pi of H. schachtii (r(2) = 0.59 in 2000 and r(2) = 0.26 in 2001). In 2000, trap crop radish cv. Colonel (Rf = 0.89) reduced nematode populations more than cv. Adagio (Rf = 4.67) and cv. Rimbo (Rf = 13.23) (P </= 0.05) when Pi was lower than 2.5 H. schachtii eggs and J2/cm(3) soil. There were no differences in reproductive factors for radish cultivars in 2001 (P </= 0.05); Rf ranged from 0.23 for Adagio to 1.31 for Commodore for all Pi.


Estrogen-dependent, extrahepatic synthesis of vitellogenin in male vertebrates: A mini-review.
In the last years, the hormonal balance is threatened by the interferences of substances with hormone-like action (endocrine disruptor chemicals, EDCs) that may harm animal reproduction. Most EDCs are resistant to environmental degradation and are considered ubiquitous contaminants. EDCs may have synthetic or natural origins. Pesticides used in intensive agriculture contain large amounts of chemicals with estrogenic properties, such as the alkylphenol nonylphenol (NP). Besides, animal feeding operations are important sources of natural estrogen metabolites introduced into the environment through manure application in organic farming. In both cases, EDCs can reach animals, including humans particularly at risk due to their position in the food chain. This is the reason for which it is important to use terrestrial vertebrates as sentinels in soil biomonitoring programmes. Today, the most validated biomarker of estrogenic exposure is the expression in male liver of the vitellogenin (VTG), an estrogen-dependent glycolipophosphoprotein naturally expressed only in the liver of oviparous females during the reproductive season. This report summarizes the data available on the EDC-dependent expression and the synthesis of VTG in male vertebrates, highlighting our latest studies that demonstrate the ability of testis and epididymis of the lacertid Podarcis sicula to synthesize VTG following estrogenic exposure. These findings provide, for the first time, evidence on an extrahepatic expression and synthesis of VTG in a terrestrial vertebrate and lay the groundwork for a new value of the VTG as a biomarker of environmental contamination. In addition, the results open a new scenario on the role of VTG in cells other than oocytes.


Cortical brain malformations: effect of clinical, neuroradiological, and modern genetic classification.
Malformations of cortical development (MCDs) are a major source of handicap. Much progress in understanding the genetic causes has been made recently. The number of affected children in whom a molecularly confirmed diagnosis can be made is unclear. To evaluate the etiology of MCDs in children and the effect of a combined radiological, clinical, and syndrome classification. A case series of 113 children with a radiological diagnosis of MCD from January 1, 1992, to January 1, 2006. The Erasmus Medical Center-Sophia Children's Hospital, a secondary and tertiary referral center. Patients with MCD underwent a complete radiological, clinical, and neurological assessment and testing for known genes involved in the pathogenesis of MCD as appropriate for their phenotype. We established an etiological diagnosis in 45 of 113 cases (40%). For 21 patients (19%), this included molecular and/or genetic confirmation (Miller-Dieker syndrome; LIS1, DCX, FLNA, EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism). In 17 (15%), a syndrome with an unknown genetic defect was diagnosed. In 7 patients (6%), we found evidence of a gestational insult. Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history with multiple affected persons (12 patients), or consanguineous parents (7 patients). In our cohort, combining diagnostic molecular testing with clinical, radiological, and genetic classification; syndrome identification; and family study provided a diagnosis in 40% of the cases of MCD. This contributes to the possibility of prenatal diagnosis and improved patient treatment and disease management.


Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment.
The transcriptional activation by SRY-type high mobility group box 9 (SOX9) and the transforming growth factor beta (TGF-beta) signals are necessary for chondrogenic differentiation. We have previously shown that CREB-binding protein (CBP/p300) act as an important SOX9 co-activator during chondrogenesis. In the present study, we investigated the relationship between TGF-beta-dependent Smad2/3 signaling pathways and the SOX9-CBP/p300 transcriptional complex at the early stage of chondrogenesis. Overexpressed Smad3 strongly induced the primary chondrogenesis of human mesenchymal stem cells. In addition, Smad3 enhanced the transcriptional activity of SOX9 and the expression of alpha1(II) collagen gene (COL2A1), and small interference RNA against Smad3 (si-Smad3) inhibited them. We observed that Smad2/3 associated with Sox9 in a TGF-beta-dependent manner and formed the transcriptional complexes with SOX9 on the enhancer region of COL2A1. Interestingly, the association between Sox9 and CBP/p300 was increased by Smad3 overexpression and was suppressed by si-Smad3. Our findings indicate that Smad3 has a stronger potential to stimulate the SOX9-dependent transcriptional activity by modulating the interaction between SOX9 and CBP/p300, rather than Smad2. This study suggests that the Smad3 pathway presents a key role for the SOX9-dependent transcriptional activation in primary chondrogenesis.


TheCellVision.org: A Database for Visualizing and Mining High-Content Cell Imaging Projects.
Advances in genome engineering and high throughput imaging technologies have enabled genome-scale screens of single cells for a variety of phenotypes, including subcellular morphology and protein localization. We constructed TheCellVision.org, a freely available and web-accessible image visualization and data browsing tool that serves as a central repository for fluorescence microscopy images and associated quantitative data produced by high-content screening experiments. Currently, TheCellVision.org hosts ∼575,590 images and associated analysis results from two published high-content screening (HCS) projects focused on the budding yeast Saccharomyces cerevisiae TheCellVision.org allows users to access, visualize and explore fluorescence microscopy images, and to search, compare, and extract data related to subcellular compartment morphology, protein abundance, and localization. Each dataset can be queried independently or as part of a search across multiple datasets using the advanced search option. The website also hosts computational tools associated with the available datasets, which can be applied to other projects and cell systems, a feature we demonstrate using published images of mammalian cells. Providing access to HCS data through websites such as TheCelllVision.org enables new discovery and independent re-analyses of imaging data.


The association between point-of-sale displays and youth smoking susceptibility.
According to tobacco industry documents, tobacco displays within the retail environment assume a much greater importance with the loss of other marketing channels. The impact of these displays upon young people and their future intentions to smoke (susceptibility) is, therefore, of significant interest to public health. A cross-sectional in-home survey was conducted in 2008 with young people (N = 1,401) aged 11-16 years, recruited from across the United Kingdom. We examine the salience of and attraction to cigarette displays at point-of-sale (POS), among youth, and whether this is associated with susceptibility. We concentrate exclusively on the 956 never-smokers. Logistic regression, controlling for known risk factors of youth smoking, found that noticing cigarette displays was associated with higher levels of susceptibility (odds ratio [OR] = 1.77, p < .05) and greater attraction to displays was associated with higher susceptibility (OR = 1.07, p < .001). It is difficult, if not impossible, to safeguard young people from exposure to displays of tobacco at POS. That these displays were associated with increased susceptibility suggests that moves to place tobacco out of sight in the United Kingdom, and elsewhere, are justified.


Mechanism of neuronal versus endothelial cell uptake of Alzheimer's disease amyloid beta protein.
Alzheimer's disease (AD) is characterized by significant neurodegeneration in the cortex and hippocampus; intraneuronal tangles of hyperphosphorylated tau protein; and accumulation of beta-amyloid (Abeta) proteins 40 and 42 in the brain parenchyma as well as in the cerebral vasculature. The current understanding that AD is initiated by the neuronal accumulation of Abeta proteins due to their inefficient clearance at the blood-brain-barrier (BBB), places the neurovascular unit at the epicenter of AD pathophysiology. The objective of this study is to investigate cellular mechanisms mediating the internalization of Abeta proteins in the principle constituents of the neurovascular unit, neurons and BBB endothelial cells. Laser confocal micrographs of wild type (WT) mouse brain slices treated with fluorescein labeled Abeta40 (F-Abeta40) demonstrated selective accumulation of the protein in a subpopulation of cortical and hippocampal neurons via nonsaturable, energy independent, and nonendocytotic pathways. This groundbreaking finding, which challenges the conventional belief that Abeta proteins are internalized by neurons via receptor mediated endocytosis, was verified in differentiated PC12 cells and rat primary hippocampal (RPH) neurons through laser confocal microscopy and flow cytometry studies. Microscopy studies have demonstrated that a significant proportion of F-Abeta40 or F-Abeta42 internalized by differentiated PC12 cells or RPH neurons is located outside of the endosomal or lysosomal compartments, which may accumulate without degradation. In contrast, BBME cells exhibit energy dependent uptake of F-Abeta40, and accumulate the protein in acidic cell organelle, indicative of endocytotic uptake. Such a phenomenal difference in the internalization of Abeta40 between neurons and BBB endothelial cells may provide essential clues to understanding how various cells can differentially regulate Abeta proteins and help explain the vulnerability of cortical and hippocampal neurons to Abeta toxicity.


Context-dependency of the relation between left ventricular mass and AGT gene variants.
In the European Project on Genes in Hypertension (EPOGH), we investigated in three populations to what extent in a family-based study, left ventricular mass (LVM) was associated with the C-532T and G-6A polymorphisms in the angiotensinogen (AGT) gene. We randomly recruited 221 nuclear families (384 parents and 440 offspring) in Cracow (Poland), Novosibirsk (Russia), and Mirano (Italy). Echocardiographic LVM was indexed to body surface area, adjusted for covariables, and subjected to multivariate analyses, using generalized estimating equations and quantitative transmission disequilibrium tests in a population-based and family-based approach, respectively. We found significant differences between the two Slavic centres and Mirano in left ventricular mass index (LVMI) (94.9 vs 80.4 g/m2), sodium excretion (229 vs 186 mmol/day), and the prevalence of the AGT -6A (55.7 vs 40.6%) and -532T (16.8 vs 9.4%) alleles. In population-based as well as in family-based analyses, we observed positive associations of LVMI and mean wall thickness (MWT) with the -532T allele in Slavic, but not in Italian male offspring. Furthermore, in Slavic male offspring, LVMI and MWT were significantly higher in carriers of the -532T/-6A haplotype than in those with the -532C/-6G or -532C/-6A allele combinations. In women, LVMI was neither associated with single AGT gene variants nor with the haplotypes (0.19 < P <0.98). In Slavic offspring carrying the AGT -532C/-6G or -532C/-6A haplotypes, LVMI significantly increased with higher sodium excretion (+3.5 g/m2/100 mmol; P=0.003), whereas such association was not present in -532T/-6A haplotype carriers (P-value for interaction 0.04). We found a positive association between LVMI and the AGT -532T allele due to increased MWT. This relation was observed in Slavic male offspring. It was therefore dependent on gender, age and ecogenetic context, and in addition it appeared to be modulated by the trophic effects of salt intake on LVM.


The dead ringer/retained transcriptional regulatory gene is required for positioning of the longitudinal glia in the Drosophila embryonic CNS.
The Drosophila dead ringer (dri, also known as retained, retn) gene encodes a nuclear protein with a conserved DNA-binding domain termed the ARID (AT-rich interaction domain). We show here that dri is expressed in a subset of longitudinal glia in the Drosophila embryonic central nervous system and that dri forms part of the transcriptional regulatory cascade required for normal development of these cells. Analysis of mutant embryos revealed a role for dri in formation of the normal embryonic CNS. Longitudinal glia arise normally in dri mutant embryos, but they fail to migrate to their final destinations. Disruption of the spatial organization of the dri-expressing longitudinal glia accounts for the mild defects in axon fasciculation observed in the mutant embryos. Consistent with the late phenotypes observed, expression of the glial cells missing (gcm) and reversed polarity (repo) genes was found to be normal in dri mutant embryos. However, from stage 15 of embryogenesis, expression of locomotion defects (loco) and prospero (pros) was found to be missing in a subset of LG. This suggests that loco and pros are targets of DRI transcriptional activation in some LG. We conclude that dri is an important regulator of the late development of longitudinal glia.


Analysis of video fluoroscopic swallowing study in patients with vocal cord paralysis.
We reviewed the findings of a video fluoroscopic swallowing study (VFSS) of 28 patients with vocal cord paralysis (VCP) who complained of swallowing difficulties. VFSSs were performed with thick and thin liquid using modified Logemann methods. The patients were grouped according to whether their VCP was of central or peripheral origin, and the VFSS findings of the groups were compared. The patients showed oral phase dysfunction and pharyngeal dysfunction, especially when the cause was of central origin. Oral phase abnormalities were found in 13 patients and pharyngeal phase abnormalities were found in all patients, including penetration in 20 patients and aspiration in 14 patients. Improper lip closure (LC) and bolus formation (BF) and a delay in triggering pharyngeal swallow (TPS) and upper esophageal sphincter release (UESR) were significantly more frequent in patients with central VCP. With thin-liquid swallowing, pharyngeal transit time (PTT) and pharyngeal delay time (PDT) were significantly more prolonged in central VCP. The results suggest that the delay in triggering and poor coordination of swallowing were profound in patients with central VCP, but dysfunction in peripheral VCP may originate from poor pharyngeal movement.


Proinflammatory cytokines, fibrinolytic system enzymes, and biochemical indices in children with infectious para-pneumonic effusions.
In children, pleural empyema is a recognized complication of severe pneumonia and is characterized by loculated effusions with fibrin septations. The aim of this study was to evaluate the relationship between proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6], intrapleural fibrinolytic system enzymes [tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1)], and common biochemical indices during pleural infection. Children with pneumonia complicated by para-pneumonic effusions were enrolled into our study and underwent real-time chest sonography. The patients were divided into 3 groups by ultrasound using a recognized staging system of pleural effusions. Staging of progressive pleural infection was used to correlate with the characteristics of pleural effusions. The correlation of various pleural variables with the formation of complicated para-pneumonic effusions (CPE) was performed and pleural variables for predicting subsequent intervention procedures were also analyzed. A total of 57 patients were enrolled in the present study. Univariate analysis revealed that the amounts of biochemical indices (pH, glucose, lactate dehydrogenase), proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), and fibrinolytic system enzymes (tPA, PAI-1) were significantly different with the progressive stages of para-pneumonic effusions (Ptrend < 0.05). For all proinflammatory cytokines, a positive correlation was found with lactate dehydrogenase and PAI-1, whereas a negative correlation was found with pH, glucose, and tPA. Moreover, these cytokines were also significantly correlated with PAI-1 in both non-CPE and CPE. The pleural fluid findings of IL-1beta (> or =50 pg/mL), PAI-1 (> or =1252 ng/mL), and pH (< or =7.30) were the most significant predictive factors for subsequent intervention procedures (P < 0.001). The increased release of proinflammatory cytokines in pleural fluid caused by bacteria may result in an imbalance of the fibrinolytic system, which can subsequently lead to fibrin deposition and intervention procedures.


Definitive fossil evidence for the extant avian radiation in the Cretaceous.
Long-standing controversy surrounds the question of whether living bird lineages emerged after non-avian dinosaur extinction at the Cretaceous/Tertiary (K/T) boundary or whether these lineages coexisted with other dinosaurs and passed through this mass extinction event. Inferences from biogeography and molecular sequence data (but see ref. 10) project major avian lineages deep into the Cretaceous period, implying their 'mass survival' at the K/T boundary. By contrast, it has been argued that the fossil record refutes this hypothesis, placing a 'big bang' of avian radiation only after the end of the Cretaceous. However, other fossil data--fragmentary bones referred to extant bird lineages--have been considered inconclusive. These data have never been subjected to phylogenetic analysis. Here we identify a rare, partial skeleton from the Maastrichtian of Antarctica as the first Cretaceous fossil definitively placed within the extant bird radiation. Several phylogenetic analyses supported by independent histological data indicate that a new species, Vegavis iaai, is a part of Anseriformes (waterfowl) and is most closely related to Anatidae, which includes true ducks. A minimum of five divergences within Aves before the K/T boundary are inferred from the placement of Vegavis; at least duck, chicken and ratite bird relatives were coextant with non-avian dinosaurs.


Rice Distillers Dried Grain Is a Promising Ingredient as a Partial Replacement of Plant Origin Sources in the Diet for Juvenile Red Seabream (Pagrus major).
This study was designed to test the effects of dietary distillers dried grain (DDG) level on the growth performance, feed utilization, body composition and antioxidant activity of juvenile red seabream (Pagrus major). Six isonitrogenous and isocaloric diets were formulated to contain 0%, 5%, 10%, 15%, 20%, and 25% DDG from rice (designated as DDG0, DDG5, DDG10, DDG15, DDG20, and DDG25), respectively. Juvenile red seabream averaging 10.1±0.05 g were randomly distributed into 400-L tanks in a flow through systems. Three replicate groups of fish were fed one of the experimental diets to visual satiation two times a day for 10 weeks. Survival, weight gain, feed efficiency, protein efficiency ratio and hepatosomatic index of fish were not affected by dietary DDG levels (p>0.05). Proximate and amino acid composition of whole body in juvenile red seabream were not affected by dietary DDG levels (p>0.05). Plasma content of total protein, glucose, cholesterol, glutamic-pyruvic transaminase, phospholipid and triglyceride were not affected by dietary DDG levels (p>0.05). 1, 1-Diphenyl-2-picryl-hydrazyl radical and alkyl radical scavenging activities in plasma and liver of fish were not affected by dietary DDG levels (p>0.05). The results of this experiment suggest that DDG has the potential to replace plant origin ingredients such as wheat flour and corn gluten meal and could be used up to 25% in diet without incurring negative effects on the growth performance of juvenile red seabream.


Registered nurses' use of research findings in the care of older people.
To describe registered nurses' reported use of research in the care of older people and to examine associations between research use and factors related to the elements: the communication channels, the adopter and the social system. Research use among registered nurses working in hospital settings has been reported in many studies. Few studies, however, have explored the use of research among registered nurses working in the care of older people. A cross-sectional survey. In eight municipalities, all registered nurses (n = 210) working in older people care were invited to participate (response rate 67%). The Research Utilisation Questionnaire was adopted. Questions concerning the work organisation and research-related resources were sent to the Community Chief Nurse at each municipality. Descriptive statistics and logistic regression were applied. The registered nurses reported a relatively low use of research findings in daily practice, despite reporting a positive attitude to research. The registered nurses reported lack of access to research reports at the work place and that they had little support from unit managers and colleagues. Registered nurses working in municipalities with access to research-related resources reported more use of research than registered nurses without resources. The factors 'Access to research findings at work place', 'Positive attitudes to research' and 'Nursing programme at university level' were significantly associated with research use. There is a great potential to increase registered nurses' use of research findings in the care of older people. Factors which were linked to the communication channels and the adopter were associated with research use. Strategies to enhance research use should focus on access to and adequate training in using information sources, increased knowledge on research methodology and nursing science and a supportive organisation.


Prognosis for ecosystem recovery following rodent eradication and seabird restoration in an island archipelago.
Invasive species are widespread and can have devastating effects on biota, especially insular biota. Invasive species eradications are increasingly employed to promote island recovery to preinvasion states. However, it remains unclear if additional restoration actions may be required on islands that were once heavily reliant on seabird guano for ecosystem functions. Active seabird augmentation has been suggested as necessary to exact ecosystem recovery on contemporary timescales in some cases. I use two experiments on offshore islands in Cook Strait, New Zealand, to test the hypothesis that seabird restoration will restore island ecosystem functioning following invasive rodent removal. The first is a small-scale single-island fertilization experiment that simulates seabird recovery. This experiment tested the recovery potential of offshore islands and was used to infer the density of seabirds needed to elicit ecosystem recovery. The second is a large-scale natural experiment that takes advantage of eight islands with differing rodent eradication and seabird restoration histories. I compared ecosystem functioning variables (delta 15N, C:N ratios in soil, plants, and spiders, as well as arthropod abundance and diversity) on two islands that had rodents eradicated and two islands undergoing seabird augmentation with two control islands (never invaded by rodents) and two positive control islands (currently invaded by rodents). The results suggest that islands do have the potential for recovery given nutrient amendments, but that islands with rodents eradicated and islands undergoing seabird augmentation have not recovered most of their ecosystem function. Finer, intra-island analysis showed that seabird restoration projects have the potential to speed the recovery process, but that the projects on the studied seabird restoration islands were not advanced enough to produce island-wide recovery. The results suggest that high seabird densities (5-10 burrows/m2) are needed to promote recovery to never-invaded control levels. Seabird augmentation, through chick translocation and/or social facilitation with decoys, vocalization playbacks, and/or mirrors can supplement passive seabird recovery on islands where seabirds have been extirpated or extremely reduced by invasive predators. Such restoration efforts may be necessary to promote ecosystem recovery on contemporary timescales.


Clinical applications of herbal medicines for anxiety and insomnia; targeting patients with bipolar disorder.
Patients with bipolar disorder frequently continue to experience residual anxiety and insomnia between mood episodes. In real-world practice, patients increasingly self-prescribe alternative medicines. We reviewed case reports, open-label, and placebo-controlled trials investigating the use of herbal medicines to treat anxiety and insomnia, and discussed their potential applications for bipolar disorder. Eleven herbal medicines that have been studied in human subjects are included in this review. Mechanisms of action, efficacy, side effects, and drug-drug interactions are discussed. Based on currently available evidence, valerian seems to be the most promising candidate for insomnia and anxiety in bipolar disorder. Adjunctive herbal medicines may have the potential to alleviate these symptoms and improve the outcomes of standard treatment, despite limited evidence. Physicians need to have a more in-depth understanding of the evidence of benefits, risks, and drug interactions of alternative treatments.


Hatching strategies in monogenean (platyhelminth) parasites that facilitate host infection.
In parasites, environmental cues may influence hatching of eggs and enhance the success of infections. The two major endoparasitic groups of parasitic platyhelminths, cestodes (tapeworms) and digeneans (flukes), typically have high fecundity, infect more than one host species, and transmit trophically. Monogeneans are parasitic flatworms that are among the most host specific of all parasites. Most are ectoparasites with relatively low fecundity and direct life cycles tied to water. They infect a single host species, usually a fish, although some are endoparasites of amphibians and aquatic chelonian reptiles. Monogenean eggs have strong shells and mostly release ciliated larvae, which, against all odds, must find, identify, and infect a suitable specific host. Some monogeneans increase their chances of finding a host by greatly extending the hatching period (possible bet-hedging). Others respond to cues for hatching such as shadows, chemicals, mechanical disturbance, and osmotic changes, most of which may be generated by the host. Hatching may be rhythmical, larvae emerging at times when the host is more vulnerable to invasion, and this may be combined with responses to other environmental cues. Different monogenean species that infect the same host species may adopt different strategies of hatching, indicating that tactics may be more complex than first thought. Control of egg assembly and egg-laying, possibly by host hormones, has permitted colonization of frogs and toads by polystomatid monogeneans. Some monogeneans further improve the chances of infection by attaching eggs to the host or by retaining eggs on, or in, the body of the parasite. The latter adaptation has led ultimately to viviparity in gyrodactylid monogeneans.


Cemented or Uncemented Hemiarthroplasty for Femoral Neck Fracture? Data from the Norwegian Hip Fracture Register.
A displaced femoral neck fracture in patients older than 70 years is a serious injury that influences the patient's quality of life and can cause serious complications or death. Previous national guidelines and a Cochrane review have recommended cemented fixation for arthroplasty to treat hip fractures in older patients, but data suggest that these guidelines are inconsistently followed in many parts of the world; the effects of that must be better characterized. The purpose of this study was to evaluate a large group of patients in the Norwegian Hip Fracture Register to investigate whether the fixation method in hemiarthroplasty is associated with (1) the risk of reoperation; (2) the mortality rate; and (3) patient-reported outcome measures (PROMs). Longitudinally maintained registry data from the Norwegian Hip Fracture Register with high completeness (93%) and near 100% followup of deaths were used for this report. From 2005 to 2017, 104,993 hip fractures were registered in the Norwegian Hip Fracture Register. Fractures other than intracapsular femoral neck fractures and operative methods other than bipolar hemiarthroplasty, such as osteosynthesis or THA, were excluded. The selection bias risk on using cemented or uncemented hemiarthroplasty is small in Norway because the decision is usually regulated by tender processes at each hospital and not by surgeon. A total of 7539 uncemented hemiarthroplasties (70% women, mean age, 84 years [SD 6] years) and 22,639 cemented hemiarthroplasties (72% women, mean age, 84 years [SD 6] years) were eligible for analysis. Hazard risk ratio (HRR) on reoperation and mortality was calculated in a Cox regression model adjusted for age, sex, comorbidities (according to the American Society of Anesthesiologists classification), cognitive function, surgical approach, and duration of surgery. At 12 months postoperatively, 65% of patients answered questionnaires regarding pain and quality of life, the results of which were compared between the fixation groups. A higher overall risk of reoperation for any reason was found after uncemented hemiarthroplasty (HRR, 1.5; 95% CI, 1.4-1.7; p < 0.001) than after cemented hemiarthroplasty. When assessing reoperations for specific causes, higher risks of reoperation because of periprosthetic fracture (HRR, 5.1; 95% CI, 3.5-7.5; p < 0.001) and infection (HRR, 1.2; 95% CI, 1.0-1.5; p = 0.037) were found for uncemented hemiarthroplasty than for cemented procedures. No differences were found in the overall mortality rate after 1 year (HRR, 1.0; 95% CI, 0.9-1.0; p = 0.12). Hemiarthroplasty fixation type was not associated with differences in patients' pain (19 versus 20 for uncemented and cemented hemiarthroplasties respectively, p = 0.052) or quality of life (EuroQol [EQ]-VAS score 64 versus 64, p = 0.43, EQ5D index score 0.64 versus 0.63, p = 0.061) 1 year after surgery. Our study found that the fixation method was not associated with differences in pain, quality of life, or the 1-year mortality rate after hemiarthroplasty. Uncemented hemiarthroplasties should not be used when treating elderly patients with hip fractures because there is an increased reoperation risk.Level of Evidence Level III, therapeutic study.


Pathogenic homozygous variant in POMK gene is the cause of prenatally detected severe ventriculomegaly in two Lithuanian families.
Biallelic pathogenic variants in POMK gene are associated with two types of dystroglycanopathies: limb-girdle muscular dystrophy-dystroglycanopathy, type C12 (MDDGC12), and congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A12 (MDDGA12). These disorders are very rare and have been previously reported in 10 affected individuals. We present two unrelated Lithuanian families with prenatally detected hydrocephalus due to a homozygous nonsense variant in the POMK. The first signs of hydrocephalus in the affected fetuses became evident at 15 weeks of gestation and rapidly progressed, thus these clinical features are compatible with a diagnosis of MDDGA12. The association between pathogenic POMK variants and macrocephaly and severe hydrocephalus has been previously reported only in two families. Clinical and molecular findings presented in this report highlight congenital hydrocephalus as a distinct feature of POMK related disorders and a differentiator from other dystroglycanopathies. These findings further extend the spectrum of MDDGA12 syndrome.


Elastostatic reversibility in thermally formed bulk metallic glasses: nanobeam diffraction fluctuation electron microscopy.
The unparalleled shaping ability of bulk metallic glasses can revolutionize commercial products having multi-length scale features with a processing time of several minutes. Despite the widespread shaping ability of these polymer-like multicomponent alloys, thermoplastic forming (TPF) can severely degrade the intrinsic properties, particularly when complex stress states are activated. The present work emphasizes the importance of elastostatic loading (ESL) which not only fully reverses deteriorated room temperature plasticity originating under TPF or post-cryostatic conditions, but also activates a rejuvenation mechanism by rendering an extended resistance against strain softening. Furthermore, the reduction in the supercooled liquid region and crystallization enthalpy measured by differential scanning calorimetry are found to be temporary, and can be fully reversed to the initial condition. HRTEM imaging of the samples are performed with an imaging spherical aberration corrector. Individual nanobeam diffraction patterns obtained by the fluctuation electron microscopy (FEM) measurements are acquired using a scanning transmission electron microscope with a probe size of 1.2 nm from a 10 × 10 raster, yielding 100 diffraction patterns. The normalized variance of a series of nanodiffraction patterns of the post-elastostatically loaded sample reveals a height decrease in the first broad peak of normalized intensity variance V(k) suggesting modifications in the medium-range structural order which in turn dramatically restores the mechanical and thermal properties. Overall, the combination of TPF and post-ESL treatment in advanced glassy metals can open a new avenue for ultra-high mechanical and thermal performance micro- and nanomechanical devices for biosensors, MOSFETs and robotics.


Safety monitoring of the intravenous immunoglobulin preparation Intratect® in primary and secondary immunodeficiencies: a prospective non-interventional study.
To better characterize the risk profile of the intravenous immunoglobulin (IVIG) Intratect®, a non-interventional study was undertaken to systematically collect large-scale safety information under real-life conditions in patients with primary and secondary immunodeficiency. Secondary objectives were data on treatment modalities. A prospective, non-interventional study was performed at 95 centers. RESULTS of an interim analysis are reported here. Intratect® (50 g/L) was administered at the physician's discretion. Data were captured from patients with different causes of immunodeficiency (61.5% with malignancy) at routine clinic visits, with a particular focus on the frequency and causality of adverse events. 1,313 patients were followed for a median of 294 days. At study entry, 836 patients (63.7%) were receiving therapy, most frequently IVIG treatment (37.2%). In total, 21,995 Intratect® infusions were documented (median 11 infusions per patient, median dose 200 mL). Median serum IgG level increased from 5.78 (interquartile range 3.70, 8.87) g/L at month 1 to 6.58 (4.82, 9.48) g/mL at month 12. Altogether, 689 adverse events were collected, irrespective of causality. From these, 225 (32.7%) were assessed as related to Intratect® and thus considered suspected adverse drug reactions (ADRs). Thus, the ADR rate was 1.0% per infusion. Seven ADRs (7/225, 3.1%) were graded serious. In all cases, the patients had recovered or were recovering at the time of reporting. Use of Intratect® for immunoglobulin substitution in primary and secondary immunodeficiency under real-life conditions is associated with a low rate of suspected ADRs. Serious ADRs are rare and manageable.


Simple and cost-effective fabrication of size-tunable zinc oxide architectures by multiple size reduction technique.
We present a simple size reduction technique for fabricating 400 nm zinc oxide (ZnO) architectures using a silicon master containing only microscale architectures. In this approach, the overall fabrication, from the master to the molds and the final ZnO architectures, features cost-effective UV photolithography, instead of electron beam lithography or deep-UV photolithography. A photosensitive Zn-containing sol-gel precursor was used to imprint architectures by direct UV-assisted nanoimprint lithography (UV-NIL). The resulting Zn-containing architectures were then converted to ZnO architectures with reduced feature sizes by thermal annealing at 400 °C for 1 h. The imprinted and annealed ZnO architectures were also used as new masters for the size reduction technique. ZnO pillars of 400 nm diameter were obtained from a silicon master with pillars of 1000 nm diameter by simply repeating the size reduction technique. The photosensitivity and contrast of the Zn-containing precursor were measured as 6.5 J cm-2 and 16.5, respectively. Interesting complex ZnO patterns, with both microscale pillars and nanoscale holes, were demonstrated by the combination of dose-controlled UV exposure and a two-step UV-NIL.


The combined effects of the expansion of primary health care and conditional cash transfers on infant mortality in Brazil, 1998-2010.
I examined the combined effects of access to primary care through the Family Health Program (FHP) and conditional cash transfers from the Bolsa Familia Program (BFP) on postneonatal infant mortality (PNIM) in Brazil. I employed longitudinal ecological analysis using panel data from 4583 Brazilian municipalities from 1998 to 2010, totaling 54 253 observations. I estimated fixed-effects ordinary least squares regressions models with PNIM rate as the dependent variable and FHP, BFP, and their interactions as the main independent variables of interest. The association of higher FHP coverage with lower PNIM became stronger as BFP coverage increased. At the means of all other variables, when BFP coverage was 25%, predicted PNIM was 5.24 (95% confidence interval [CI] = 4.95, 5.53) for FHP coverage = 0% and 3.54 (95% CI = 2.77, 4.31) for FHP coverage = 100%. When BFP coverage was 60%, predicted PNIM was 4.65 (95% CI = 4.36, 4.94) when FHP coverage = 0% and 1.38 (95% CI = 0.88, 1.89) when FHP coverage = 100%. The effect of the FHP depends on the expansion of the BFP. For impoverished, underserved populations, combining supply- and demand-side interventions may be necessary to improve health outcomes.


Reproductive performance links to fine-scale spatial patterns of female grey seal relatedness.
Fine-scale spatial patterns of female relatedness throughout the established grey seal breeding colony of North Rona, Scotland, were investigated by accurate mapping and spatially explicit analyses of a large sample (n = 262) of mothers using variation at nine microsatellite DNA loci. Local spatial autocorrelation analyses identified locations where seals were more highly related to the colony than average. These locations were also areas where the more successful females bred, were occupied first during each breeding season, were centrally placed locations of preferred habitat types and were likely to be the locations which were the first to be colonized historically. Mothers occupying such sites achieved higher than average pup growth rates, suggesting a founder fitness benefit.


Ambit-Tautomer: An Open Source Tool for Tautomer Generation.
We present a new open source tool for automatic generation of all tautomeric forms of a given organic compound. Ambit-Tautomer is a part of the open source software package Ambit2. It implements three tautomer generation algorithms: combinatorial method, improved combinatorial method and incremental depth-first search algorithm. All algorithms utilize a set of fully customizable rules for tautomeric transformations. The predefined knowledge base covers 1-3, 1-5 and 1-7 proton tautomeric shifts. Some typical supported tautomerism rules are keto-enol, imin-amin, nitroso-oxime, azo-hydrazone, thioketo-thioenol, thionitroso-thiooxime, amidine-imidine, diazoamino-diazoamino, thioamide-iminothiol and nitrosamine-diazohydroxide. Ambit-Tautomer uses a simple energy based system for tautomer ranking implemented by a set of empirically derived rules. A fine-grained output control is achieved by a set of post-generation filters. We performed an exhaustive comparison of the Ambit-Tautomer Incremental algorithm against several other software packages which offer tautomer generation: ChemAxon Marvin, Molecular Networks MN.TAUTOMER, ACDLabs, CACTVS and the CDK implementation of the algorithm, based on the mobile H atoms listed in the InChI. According to the presented test results, Ambit-Tautomer's performance is either comparable to or better than the competing algorithms. Ambit-Tautomer module is available for download as a Java library, a command line application, a demo web page or OpenTox API compatible Web service.


In situ observation of self-assembly of sugars and surfactants from nanometres to microns.
The hierarchical self-assembly of sugar and surfactant molecules into hollow tubular microstructures was characterized in situ with high resolution small-angle X-ray scattering spanning more than three orders of magnitude of spatial scales. Scattering profiles reveal that aqueous host-guest inclusion complexes self-assemble into multiple equally spaced curved bilayers forming a collection of concentric hollow cylinders. Scattering data can be described by a simple theoretical model of the microtubes. The interlamellar distance was found to be surprisingly large. Moreover, we report that the multi-walled structure of the microtubes swells as the concentration or the temperature is varied.


Dengue virus-induced autoantibodies bind to plasminogen and enhance its activation.
Dengue virus infection can lead to life-threatening dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) in patients. Abnormal activation of the coagulation and fibrinolysis system is one of the hallmarks associated with DHF/DSS patients. However, the mechanisms that cause pathology in DHF/DSS patients are still unclear. Because conversion of plasminogen (Plg) to plasmin (Plm) is the first step in the activation of fibrinolysis, Abs against Plg found in DHF/DSS patients may be important. Therefore, to investigate the specificity, function, and possible origin of these Abs, we generated several Plg cross-reactive mAbs from DENV-immunized mice. An IgG mAb, 6H11, which recognizes an epitope associated with a dengue envelope protein, demonstrated a high level of cross-reactivity with Plg. The 6H11 Ab was further characterized with regard to its effect on Plg activation. Using Plm-specific chromogenic substrate S-2251, we found that mAb 6H11 demonstrated serine protease activity and could convert Plg directly to Plm. The serine protease activity of mAb 6H11 was further confirmed using serine protease chromogenic substrate S-2288. In addition, we found several Plg cross-reactive mAbs that could enhance urokinase-induced Plg activation. Lastly, mAb 6H11 could induce Plm activity and increase the level of D-dimer (a fibrin degradation product) in both human and mouse platelet-poor plasma. Taken together, these data suggest DENV-induced Plg cross-reactive Abs may enhance Plg conversion to Plm, which would be expected to contribute to hyperfibrinolysis in DHF/DSS patients.


Indicators of food and water security in an Arctic Health context--results from an international workshop discussion.
In August 2012, a literature search with the aim of describing indicators on food and water security in an Arctic health context was initialized in collaboration between the Arctic Human Health Expert Group, SDWG/AHHEG and the AMAP (Arctic Monitoring and Assessment Programme within the Arctic Council) Human Health Assessment Group, AMAP/HHAG. In December 2012, workshop discussions were performed with representatives from both of these organizations, including 7 Arctic countries. The aim of this article is to describe the workshop discussions and the rational for the 12 indicators selected and the 9 rejected and to discuss the potential feasibility of these. Advantages and disadvantages of candidate indicators were listed. Informative value and costs for collecting were estimated separately on a 3-level scale: low, medium and high. Based on these reviews, the final selection of promoted and rejected indicators was performed and summarized in tables. Among 10 suggested indicators of food security, 6 were promoted: healthy weight, traditional food proportion in diet, monetary food costs, non-monetary food accessibility, food-borne diseases and food-related contaminants. Four were rejected: per-person dietary energy supply, food security modules, self-estimated food safety and healthy eating. Among 10 suggested indicators of water security, 6 were promoted: per-capita renewable water, accessibility of running water, waterborne diseases, drinking-water-related contaminants, authorized water quality assurance and water safety plans. Four were rejected: water consumption, types of water sources, periodic water shortages and household water costs.


Air monitoring for illegal drugs including new psychoactive substances: A review of trends, techniques and thermal degradation products.
The detection of illicit psychotropic substances in both indoor and outdoor air is a challenging analytical discipline, and the data from such investigation may provide intelligence in a variety of fields. Applications of drug monitoring in air include providing data on national and international drug consumption trends, as monitored by organisations such as the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and the United Nations Office on Drugs and Crime (UNODC). Air monitoring enables mapping of illicit drug manufacturing, dealing or consumption in cities and the identification of emergent compounds including the recent proliferation of new psychoactive substances (NPS). The rapid spread of NPS has changed the global drug market with greater diversity and dynamic spread of such compounds over several nations. This review provides an up to date analysis of key thematic areas within this analytical discipline. The process of how illicit psychotropic substances spread from emission sources to the atmosphere is considered alongside the sampling and analytical procedures involved. Applications of the technique applied globally are reviewed with studies ranging from the analysis of individual dwellings through to major international air-monitoring campaigns providing evidence on global drug trends. Finally, we consider thermal breakdown products of illicit psychotropic substances including NPS that are released upon heating, combustion or vaping and related potential for exposure to these compounds in the air.


Coenzyme Q10 treatment in infertile men with idiopathic asthenozoospermia: a placebo-controlled, double-blind randomized trial.
To evaluate the effectiveness of coenzyme Q(10) treatment in improving semen quality in men with idiopathic infertility. Placebo-controlled, double-blind randomized trial. Andrology Unit, Department of Internal Medicine, Polytechnic University of Marche, Italy. Sixty infertile patients (27-39 years of age) with the following baseline sperm selection criteria: concentration >20 x 10(6)/mL, sperm forward motility <50%, and normal sperm morphology >30%; 55 patients completed the study. Patients underwent double-blind therapy with coenzyme Q(10), 200 mg/day, or placebo; the study design was 1 month of run-in, 6 months of therapy or placebo, and 3 months of follow-up. Variations in semen parameters used for patient selection and variations of coenzyme Q(10) and ubiquinol concentrations in seminal plasma and spermatozoa. Coenzyme Q(10) and ubiquinol increased significantly in both seminal plasma and sperm cells after treatment, as well as spermatozoa motility. A weak linear dependence among the relative variations, baseline and after treatment, of seminal plasma or intracellular coenzyme Q(10) and ubiquinol levels and kinetic parameters was found in the treated group. Patients with a lower baseline value of motility and levels of coenzyme Q(10) had a statistically significant higher probability to be responders to the treatment. The exogenous administration of coenzyme Q(10) increases the level of the same and ubiquinol in semen and is effective in improving sperm kinetic features in patients affected by idiopathic asthenozoospermia.


Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin.
The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.


Responding to inequities: gorillas try to maintain their competitive advantage during play fights.
Humans respond to unfair situations in various ways. Experimental research has revealed that non-human species also respond to unequal situations in the form of inequity aversions when they have the disadvantage. The current study focused on play fights in gorillas to explore for the first time, to our knowledge, if/how non-human species respond to inequities in natural social settings. Hitting causes a naturally occurring inequity among individuals and here it was specifically assessed how the hitters and their partners engaged in play chases that followed the hitting. The results of this work showed that the hitters significantly more often moved first to run away immediately after the encounter than their partners. These findings provide evidence that non-human species respond to inequities by trying to maintain their competitive advantages. We conclude that non-human primates, like humans, may show different responses to inequities and that they may modify them depending on if they have the advantage or the disadvantage.


In silico structure-based design of a potent and selective small peptide inhibitor of protein tyrosine phosphatase 1B, a novel therapeutic target for obesity and type 2 diabetes mellitus: a computer modeling approach.
Protein Tyrosine Phosphatase 1B (PTP1B) has been shown to be a negative regulator of insulin signaling by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor. Recent gene knockout studies in mice have shown the mice to have increased insulin sensitivity and improved glucose tolerance. Furthermore, these mice also exhibited a resistance to diet induced obesity. Inhibitors of PTP1B would have the potential of enhancing insulin action by prolonging the phosphorylated state of the insulin receptor. In addition, recent clinical studies have shown that the haplotype ACTTCAG0 of the PTPN1 gene, which encodes PTP1B, is a major risk contributor to type 2 diabetes mellitus (T2DM). Thus, there is compelling evidence that small molecule inhibitors of PTP1B may be effective in treating insulin resistance at an early stage, thereby leading to a prevention strategy for T2DM and obesity. Based on the crystal structure of the complex of PTP1B with a known inhibitor, we have identified a tetrapeptide inhibitor with the sequence WKPD. Docking calculations indicate that this peptide is as potent as the existing inhibitors. Moreover, the peptide is also found to be selective for PTP1B with a greatly reduced potency against other biologically important protein tyrosine phosphatases such as PTP-LAR, Calcineurin, and the highly homologous T-Cell Protein Tyrosine Phosphatase (TCPTP). Thus the designed tetrapeptide is a suitable lead compound for the development of new drugs against type 2 diabetes and obesity.


Structure of an aliphatic amidase from Geobacillus pallidus RAPc8.
The amidase from Geobacillus pallidus RAPc8, a moderate thermophile, is a member of the nitrilase superfamily and catalyzes the conversion of amides to the corresponding carboxylic acids and ammonia. It shows both amide-hydrolysis and acyl-transfer activities and also exhibits stereoselectivity for some enantiomeric substrates, thus making it a potentially important industrial catalyst. The crystal structure of G. pallidus RAPc8 amidase at a resolution of 1.9 A was solved by molecular replacement from a crystal belonging to the primitive cubic space group P4(2)32. G. pallidus RAPc8 amidase is homohexameric in solution and its monomers have the typical nitrilase-superfamily alpha-beta-beta-alpha fold. Association in the hexamer preserves the eight-layered alpha-beta-beta-alpha:alpha-beta-beta-alpha structure across an interface which is conserved in the known members of the superfamily. The extended carboxy-terminal tail contributes to this conserved interface by interlocking the monomers. Analysis of the small active site of the G. pallidus RAPc8 amidase suggests that access of a water molecule to the catalytic triad (Cys, Glu, Lys) side chains would be impeded by the formation of the acyl intermediate. It is proposed that another active-site residue, Glu142, the position of which is conserved in the homologues, acts as a general base to catalyse the hydrolysis of this intermediate. The small size of the substrate-binding pocket also explains the specificity of this enzyme for short aliphatic amides and its asymmetry explains its enantioselectivity.


Mitogen-activated protein kinase (MAPK) activation by butylated hydroxytoluene hydroperoxide: implications for cellular survival and tumor promotion.
The mitogen-activated protein kinase (MAPK) cascade plays an important role in carcinogenic development. Herein, we show that the skin tumor promoter butylated hydroxytoluene hydroperoxide (BHTOOH) stimulates a rapid and potent (14- to 20-fold) activation of extracellular signal-regulated kinase (ERK) in vivo and in cultured mouse keratinocytes. BHTOOH also moderately (5-fold) activated c-jun-N-terminal kinase, and 38-kDa MAPK-related protein in these same cells. N-acetylcysteine and o-phenanthroline abolished ERK activation by BHTOOH, consistent with a requirement for metal-dependent formation of reactive intermediates. Indeed, 4-CD3-BHTOOH, an analogue that generates less of the metabolite BHT-quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone) and fewer tumors in vivo, accordingly exhibited diminished potency for activating ERK. ERK activation by BHTOOH was inhibited by suramin, and by expression of dominant-negative Ras-N-17 in PC12 cells, suggesting overlap between the pathways for BHTOOH and growth factor signaling. Induction of MAPK-dependent genes c-fos and MAPK phosphatase-1 by BHTOOH was also blocked by Ras-N-17 expression. Moreover, expression of Ras-N-17 or kinase-defective MAPK kinase (MEK) diminished cell survival following BHTOOH exposure. Similarly, pretreatment with suramin or the MEK inhibitor PD098059 also potentiated the toxicity of BHTOOH. On the other hand, expression of constitutively active MEK enhanced cell survival. Thus, we demonstrate that the MAPK cascade is critical to the cellular response to BHTOOH. This study suggests a functional role for MAPK activation in tumor promotion stimulated by oxidants and other agents.


Profiling embryonic stem cell differentiation by MALDI TOF mass spectrometry: development of a reproducible and robust sample preparation workflow.
MALDI TOF mass spectrometry (MS) is widely used to characterise and biotype bacterial samples, but a complementary method for profiling of mammalian cells is still underdeveloped. Current approaches vary dramatically in their sample preparation methods and are not suitable for high-throughput studies. In this work, we present a universal workflow for mammalian cell MALDI TOF MS analysis and apply it to distinguish ground-state naïve and differentiating mouse embryonic stem cells (mESCs), which can be used as a model for drug discovery. We employed a systematic approach testing many parameters to evaluate how efficiently and reproducibly each method extracted unique mass features from four different human cell lines. These data enabled us to develop a unique mammalian cell MALDI TOF workflow involving a freeze-thaw cycle, methanol fixing and a CHCA matrix to generate spectra that robustly phenotype different cell lines and are highly reproducible in peak identification across replicate spectra. We applied our optimised workflow to distinguish naïve and differentiating populations using multivariate analysis and reproducibly identify unique features. We were also able to demonstrate the compatibility of our optimised method for current automated liquid handling technologies. Consequently, our MALDI TOF MS profiling method enables identification of unique features and robust phenotyping of mESC differentiation in under 1 hour from culture to analysis, which is significantly faster and cheaper when compared with conventional methods such as qPCR. This method has the potential to be automated and can in the future be applied to profile other cell types and expanded towards cellular MALDI TOF MS screening assays.


DNA supercoiling during ATP-dependent DNA translocation by the type I restriction enzyme EcoAI.
Type I restriction enzymes cleave DNA at non-specific sites far from their recognition sequence as a consequence of ATP-dependent DNA translocation past the enzyme. During this reaction, the enzyme remains bound to the recognition sequence and translocates DNA towards itself simultaneously from both directions, generating DNA loops, which appear to be supercoiled when visualised by electron microscopy. To further investigate the mechanism of DNA translocation by type I restriction enzymes, we have probed the reaction intermediates with DNA topoisomerases. A DNA cleavage-deficient mutant of EcoAI, which has normal DNA translocation and ATPase activities, was used in these DNA supercoiling assays. In the presence of eubacterial DNA topoisomerase I, which specifically removes negative supercoils, the EcoAI mutant introduced positive supercoils into relaxed plasmid DNA substrate in a reaction dependent on ATP hydrolysis. The same DNA supercoiling activity followed by DNA cleavage was observed with the wild-type EcoAI endonuclease. Positive supercoils were not seen when eubacterial DNA topoisomerase I was replaced by eukaryotic DNA topoisomerase I, which removes both positive and negative supercoils. Furthermore, addition of eukaryotic DNA topoisomerase I to the product of the supercoiling reaction resulted in its rapid relaxation. These results are consistent with a model in which EcoAI translocation along the helical path of closed circular DNA duplex simultaneously generates positive supercoils ahead and negative supercoils behind the moving complex in the contracting and expanding DNA loops, respectively. In addition, we show that the highly positively supercoiled DNA generated by the EcoAI mutant is cleaved by EcoAI wild-type endonuclease much more slowly than relaxed DNA. This suggests that the topological changes in the DNA substrate associated with DNA translocation by type I restriction enzymes do not appear to be the trigger for DNA cleavage.


Cognitive behavioral treatment for childhood anxiety disorders: long-term effects on anxiety and secondary disorders in young adulthood.
The present study's aim was to examine the long-term effects (8 to 13 years post-treatment; M = 9.83 years; SD = 1.71) of the most widely used treatment approaches of exposure-based cognitive behavioral treatment for phobic and anxiety disorders in children and adolescents (i.e., group treatment and two variants of individual treatment). An additional aim was to compare the relative long-term efficacy of the treatment approaches. At long-term follow-up, participants (N = 67) were between 16 and 26 years of age (M = 19.43 years, SD = 3.02). Primary outcome was the targeted anxiety disorder and targeted symptoms. Secondary outcomes were other disorders and symptoms not directly targeted in the treatments including (1) other anxiety disorders and symptoms, (2) depressive disorders and symptoms, and (3) substance use disorders and symptoms. Long-term remission for anxiety disorders and symptoms targeted in the treatments was evident 8 to 13 years post-treatment. Long-term remission also was found for the secondary outcomes. There were more similarities than differences in the long-term gains when comparing the treatment approaches. Consistent with past research, the study's findings provide further evidence that the short-term benefits of exposure-based CBT for childhood phobic and anxiety disorders using both group and individual treatment may extend into the critical transition years of young adulthood.


The preference of tryptophan for membrane interfaces: insights from N-methylation of tryptophans in gramicidin channels.
To better understand the structural and functional roles of tryptophan at the membrane/water interface in membrane proteins, we examined the structural and functional consequences of Trp --> 1-methyl-tryptophan substitutions in membrane-spanning gramicidin A channels. Gramicidin A channels are miniproteins that are anchored to the interface by four Trps near the C terminus of each subunit in a membrane-spanning dimer. We masked the hydrogen bonding ability of individual or multiple Trps by 1-methylation of the indole ring and examined the structural and functional changes using circular dichroism spectroscopy, size exclusion chromatography, solid state (2)H NMR spectroscopy, and single channel analysis. N-Methylation causes distinct changes in the subunit conformational preference, channel-forming propensity, single channel conductance and lifetime, and average indole ring orientations within the membrane-spanning channels. The extent of the local ring dynamic wobble does not increase, and may decrease slightly, when the indole NH is replaced by the non-hydrogen-bonding and more bulky and hydrophobic N-CH(3) group. The changes in conformational preference, which are associated with a shift in the distribution of the aromatic residues across the bilayer, are similar to those observed previously with Trp --> Phe substitutions. We conclude that indole N-H hydrogen bonding is of major importance for the folding of gramicidin channels. The changes in ion permeability, however, are quite different for Trp --> Phe and Trp --> 1-methyl-tryptophan substitutions, indicating that the indole dipole moment and perhaps also ring size and are important for ion permeation through these channels.


TORCs: transducers of regulated CREB activity.
The cAMP responsive factor CREB stimulates gene expression, following its phosphorylation at Ser133, via recruitment of the coactivator CBP. In certain cell types, CREB also functions as a constitutive activator, although the underlying mechanisms are not understood. Here, we characterize a conserved family of coactivators, designated TORCs, for Transducers of Regulated CREB activity, that enhances CRE-dependent transcription via a phosphorylation-independent interaction with the bZIP DNA binding/dimerization domain of CREB. TORC recruitment does not appear to modulate CREB DNA binding activity, but rather enhances the interaction of CREB with the TAF(II)130 component of TFIID following its recruitment to the promoter. Remarkably, in certain mucoepidermoid carcinomas, a chromosomal translocation fuses the CREB binding domain of TORC1 to the Notch coactivator Mastermind (MAML2). As expression of the TORC1-MAML2 chimera strongly induced target gene expression via CREB, our results reveal a mechanism by which CREB stimulates transcription in normal and transformed cells.


Bayesian design and analysis of external pilot trials for complex interventions.
External pilot trials of complex interventions are used to help determine if and how a confirmatory trial should be undertaken, providing estimates of parameters such as recruitment, retention, and adherence rates. The decision to progress to the confirmatory trial is typically made by comparing these estimates to pre-specified thresholds known as progression criteria, although the statistical properties of such decision rules are rarely assessed. Such assessment is complicated by several methodological challenges, including the simultaneous evaluation of multiple endpoints, complex multi-level models, small sample sizes, and uncertainty in nuisance parameters. In response to these challenges, we describe a Bayesian approach to the design and analysis of external pilot trials. We show how progression decisions can be made by minimizing the expected value of a loss function, defined over the whole parameter space to allow for preferences and trade-offs between multiple parameters to be articulated and used in the decision-making process. The assessment of preferences is kept feasible by using a piecewise constant parametrization of the loss function, the parameters of which are chosen at the design stage to lead to desirable operating characteristics. We describe a flexible, yet computationally intensive, nested Monte Carlo algorithm for estimating operating characteristics. The method is used to revisit the design of an external pilot trial of a complex intervention designed to increase the physical activity of care home residents.


Polarization Transfer from Ligands Hyperpolarized by Dissolution Dynamic Nuclear Polarization for Screening in Drug Discovery.
Nuclear magnetic resonance (NMR) spectroscopy is a valuable technique for ligand screening, because it exhibits high specificity toward chemical structure and interactions. Dissolution dynamic nuclear polarization (DNP) is a recent advance in NMR methodology that enables the creation of non-equilibrium spin states, which can dramatically increase NMR sensitivity. Here, the transfer of such spin polarization from hyperpolarized ligand to protein is observed. Mixing hyperpolarized benzamidine with the serine protease trypsin, a "fingerprint" of enhanced protein signals is observed, which shows a different intensity profile than the equilibrium NMR spectrum of the protein, but coincides closely to the frequency profile of a saturation transfer difference (STD) NMR experiment. The DNP experiment benefits from hyperpolarization and enables observation of all frequencies in a single, rapid experiment. Based on these merits, it is an interesting alternative to the widely used STD experiment for identification of protein-ligand interactions.


Evaluation of prevalence's of pfdhfr and pfdhps mutations in Angola.
Malaria is the major cause of morbidity and mortality in Angola. The most vulnerable groups to Plasmodium falciparum infection are pregnant women and children under five years of age. The use of an intermittent preventive treatment (IPT) with sulphadoxine/pyrimethamine (SP) in pregnant women was introduced in Angola in 2006 by the National Malaria Control Programme, and currently this strategy has been considered to be used for children malaria control. Considering the previous wide use of SP combination in Angola, together to the reported cases of SP treatment failure it is crucial the evaluation of the prevalence of five mutations in pfdhfr and pfdhps genes associated to P. falciparum resistance to SP before the introduction of S/P IPT in children. The study was conducted in five provinces, with different transmission intensities: Huambo, Cabinda, Uíge, Kwanza Norte, and Malanje. The detection of the mutations in pfdhfr and pfdhps genes was carried out in 452 P. falciparum blood samples by PCR RFLP. For pfdhfr gene, 90,3% of the samples carried the mutation 51I, with 7.5% of mixed infections; 51% carried wild type allele 59C, with 29.2% mixed infections and; 99.1% of isolates harboured the mutant allele 108N. Concerning, pfdhps gene, 83,1% were mutant type 437G with 11% mixed infections , while 87% of the studied isolates were wild type for codon 540. This is the first representative epidemiological study of the whole Angola country on the prevalence of the genotypes associated with SP chemoresistance. A high frequency of individual mutations in both genes (51I and 108N in pfdhfr, and 437G in pfdhps) was found, besides a low prevalence of the quintuple mutation. The data showed that the implementation IPT using SP in children needs to be reviewed.


Ozone exposure during the early postnatal period alters the timing and pattern of alveolar growth and development in nonhuman primates.
Exposure to oxidant air pollutants in early childhood, with ozone as the key oxidant, has been linked to significant decrements in pulmonary function in young adults and exacerbation of airway remodeling in asthma. Development of lung parenchyma in rhesus monkeys is rapid during the first 2 years of life (comparable to the first 6 years in humans). Our hypothesis is that ozone inhalation during infancy alters alveolar morphogenesis. We exposed infant rhesus monkeys biweekly to 5, 8 hr/day, cycles of 0.5 ppm ozone with or without house dust mite allergen from 1 to 3 or 1 to 6 months of age. Monkeys were necropsied at 3 and 6 months of age. A morphometric approach was used to quantify changes in alveolar volume and number, the distribution of alveolar size, and capillary surface density per alveolar septa. Quantitative real time PCR was used to measure the relative difference in gene expression over time. Monkeys exposed to ozone alone or ozone combined with allergen had statistically larger alveoli that were less in number at 3 months of age. Alveolar capillary surface density was also decreased in the ozone exposed groups at 3 months of age. At 6 months of age, the alveolar number was similar between treatment groups and was associated with a significant rise in alveolar number from 3 to 6 months of age in the ozone exposed groups. This increase in alveolar number was not associated with any significant increase in microvascular growth as measured by morphometry or changes in angiogenic gene expression. Inhalation of ozone during infancy alters the appearance and timing of alveolar growth and maturation. Understanding the mechanism involved with this altered alveolar growth may provide insight into the parenchymal injury and repair process that is involved with chronic lung diseases such as severe asthma and COPD.


Modification of the release characteristics of estradiol encapsulated in PLGA particles via surface coating.
Drug-loaded poly(lactide-co-glycolide) particles (100-4500 nm in diameter) were prepared via the electrospraying method. An extensive study was then carried out to determine the parameters affecting the release profile of estradiol (the drug or active pharmaceutical ingredient) in order to facilitate minimum initial burst release of estradiol. The three most important factors affecting estradiol release were identified as: particle size, coating of the particles with chitosan/gelatin and the concentration of the coating agent. It was shown that coating the particles with chitosan significantly reduced the burst and initial release without affecting the subsequent release profile. This work demonstrates a powerful method of generating drug-loaded polymeric particles with modified release behavior and control over the initial release phase. The surface-modified particles may be useful in controlled therapeutic delivery systems to minimize undesirable side effects.


Exposure to organic solvents and personality.
Although cognitive and neuropsychological changes have been found after high cumulative exposures to solvents, it is not clear whether such exposures are associated with personality characteristics. To study this two groups of British and Chinese dockyard painters who had been heavily exposed to paint solvents have been investigated. 260 Male dockyard painters in the United Kingdom, 539 local community controls, 109 Chinese dockyard painters, and 255 dockyard controls completed the Eysenck personality questionnaire, neuroticism (N) and social conformity or dissimulation (L) scales. The non-parametric Kruskal-Wallis test was used to evaluate differences in scores of personality traits between painters and controls. Adjusted relative risks for painters having high N and L scores were calculated in a Breslow-Cox regression analysis, and exposure-response relations were examined in multivariate logistic regression analysis. Non-parametric Spearman's correlation was used to examine relations between previously determined neuropsychological symptoms and personality. Both British and Chinese data showed that mean neuroticism scores of painters were significantly higher than controls, whereas scores of social conformity did not differ. Relative risk of being a painter increased significantly with increasing N scores, but L scores showed no such trend. In a case-control analysis, there were significant exposure-response relations for the N score. In the United Kingdom the odds ratios (ORs) (95% confidence interval (95% CI), were 2.03 (0.79 to 5.22) for 1-4 years of exposure, 2.38 (0.82 to 6.91) for 5-9 years, 7.05 (1.27 to 39.25) for 10-14 years, and 1.76 (0.63 to 4.89) for 15-41 years. In the Chinese painters, ORs were 4.66 (1.38 to 15.75) for 2-14 years, 10.03 (2.96 to 34.04) for 15-18 years, and 13.56 (3.78 to 48.59) for 19-43 years. Neuroticism was significantly positively related to neuropsychological symptoms in all subjects. Social conformity showed no association with neuropsychological symptoms in British painters and a negative relation among the Chinese painters. Increasing symptoms suggesting neuroticism seemed to relate to the duration of painting whereas scores for social conformity and dissimulation did not. The relation between exposure time and response suggests that increased neuroticism may be caused by long term occupational exposure to organic solvents.


Single dose dipyrone (metamizole) for acute postoperative pain in adults.
Dipyrone (metamizole) is a nonsteroidal anti-inflammatory drug used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in other countries because of an association with life-threatening blood disorders. This review replaces a 2010 Cochrane review that has been withdrawn. To assess the analgesic efficacy and associated adverse events of single dose dipyrone for moderate to severe acute postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and LILACS to 11 August 2015; the Oxford Pain Relief Database; two clinical trial registries; and the reference lists of articles. We included randomised, double-blind, placebo-controlled trials of single dose dipyrone for relief of established moderate to severe postoperative pain in adults. We accepted oral, rectal, intramuscular, and intravenous routes of administration. Two review authors independently considered studies for inclusion in the review, assessed risk of bias, and extracted data. We used summed total pain relief or pain intensity difference (TOTPAR or SPID) over four to six hours to calculate the number of participants achieving at least 50% pain relief. From derived results, we calculated the risk ratio and number needed to treat for an additional beneficial outcome (NNT), with 95% confidence intervals (CI), for one participant to experience at least 50% pain relief over four to six hours compared to placebo. We looked at use of rescue medication and time to use of rescue medication as additional measures of efficacy. We also looked for information on adverse events and withdrawals. We included eight studies, involving 809 participants, comparing oral dipyrone 500 mg (143 participants), oral dipyrone 1000 mg (57 participants), and intramuscular dipyrone 2000 mg (35 participants) with placebo (236 participants). In addition to placebo, all studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen; 338 participants). Seven studies used the oral route of administration, and one study used the intramuscular route. The mean age ranged from 23 to 62 years. Six studies included both men and women, and two studies included only women. All the studies were small, but were otherwise of moderate to good quality.Over 70% of participants experienced our primary outcome of at least 50% pain relief over four to six hours with oral dipyrone 500 mg compared to 30% with placebo (five studies, 288 participants; NNT 2.4 (95% CI 1.8 to 3.1)) (moderate quality evidence). There were insufficient data to assess other doses or routes of administration of dipyrone.Fewer participants needed rescue medication within four to six hours with dipyrone 500 mg than with placebo (7% with dipyrone versus 34% with placebo; four studies, 248 participants) (low quality evidence).The data on numbers of participants experiencing any adverse event was inconsistently reported and no analysis was possible. No serious adverse events or adverse event withdrawals were reported (very low quality evidence).There were too few data to compare dipyrone directly with other active treatments. Based on very limited information, a single dose of dipyrone 500 mg provides good pain relief to about 70% of people treated, compared to about 30% with placebo. For every five people given dipyrone 500 mg, two people would experience this level of pain relief over four to six hours who would not have done with placebo, and fewer people would need rescue medication.We were unable to compare dipyrone directly with other active treatments, or to assess the effects of different doses or routes of administration, or the number of participants experiencing adverse events, because of insufficient data and inadequate reporting.


Case management and supportive treatment for patients with Crimean-Congo hemorrhagic fever.
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne infection which has been increasing in Turkey and European countries since the year 2000. The disease is particularly endemic in the Middle East and in some African countries. It is also seen in European countries as a travel infection. Patients with confirmed diagnosis are usually hospitalized for monitoring, while patients with good overall condition may be monitored on an outpatient basis. Hospitals that manage CCHF should have easy access to a blood bank, and tertiary care hospitals must have a well-equipped intensive care unit. Strict blood and body fluid control precautions should be started on admission to limit CCHF exposure. The follow-up period for each patient is determined based on individual clinical status and laboratory values. Since there is no specific antiviral treatment for CCHF, supportive treatment is essential. This review highlights some of the major features of case monitoring and supportive treatment in CCHF.


Inhibition of growth and guanylate cyclase activity of an undifferentiated prostate adenocarcinoma by an extract of the balsam pear (Momordica charantia abbreviata).
We have recently described the presence of a guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 22.214.171.124] inhibitor (GCI) in an aqueous extract of the balsam pear (Momordica charantia abbreviata). Because the guanylate cyclase-cyclic GMP system is though to be involved in cell growth, DNA and RNA synthesis, and possible malignant transformation, we examined the effect of the aqueous extract containing GCI on an undifferentiated adenocarcinoma of the rat prostate and concanavalin-A-stimulated [3H]thymidine incorporation into cultured splenic lymphocytes, a process thought to be mediated by cyclic GMP. The results demonstrate that the extract of the balsam pear blocks both the growth of the rat prostatic adencarcinoma in vitro and [3H]thymidine incorporation into DNA. DNA histograms from flow cytometry indicated that the extract containing GCI inhibited in the G2 + M phase of the cell cycle, a presumed locus of cyclic GMP effects. In addition, guanylate cyclase activity was significantly greater in the tumor than normal prostate tissue and was decreased by the extract containing GCI. Cyclic GMP levels in the tumor in culture wer also decreased by addition of the extract. It remains to be determined whether or not the anti-tumor agent and GCI are the same substance.