Computed tomographic evaluation of cerebral ventricular size in clinically normal calves.
To evaluate lateral ventricular size in clinically normal calves by use of computed tomography and to examine the relationships between ventricular height (Vh), ventricular area (VA), and ventricular volume (VV). 14 Holstein calves. Procedures-14 calves underwent computed tomography of the head with transverse images acquired from the rostral aspect of the frontal lobe continuing caudally to the level of the foramen magnum. Hemispheric height, Vh, VA, and hemispheric area were measured on images obtained at the level of the interventricular foramen. Ventricular volume was calculated by multiplying the sum of VAs measured on each transverse image by the total slice thickness. The left Vh-to-right Vh ratio was calculated to determine the degree of ventricular asymmetry, which was categorized as normal (ie, symmetric) to minimally asymmetric, mildly asymmetric, or severely asymmetric. Mean +/- SD values for Vh and the Vh-to-hemispheric height ratio were 4.96 +/- 1.56 mm and 7.47%, respectively. The mean VA was 114.29 +/- 47.68 mm(2), and the mean VV was 2,443.50 +/- 1,351.50 mm3. Normal to minimally asymmetric ventricles were identified in 13 calves, and mildly asymmetric ventricles were identified in 1 calf. Significant correlations were found between Vh and VA and between Vh and VV. These results establish reference values for ventricular size in clinically normal calves and suggest that Vh measurement may be a simple and useful technique for examining size of the cerebral ventricles in calves.


Liver stiffness measurement reliability and main determinants of point shear-wave elastography in patients with chronic liver disease.
Liver stiffness (LS) measured by transient elastography (TE) accurately predicts the severity of chronic liver diseases (CLD). Point quantification shear-wave elastography (pSWE) is a new technique incorporated into a conventional ultrasound system for measuring LS. We evaluated pSWE feasibility, reproducibility and diagnostic accuracy in consecutively recruited CLD patients who concomitantly underwent TE and liver biopsy. To evaluate pSWE feasibility, reproducibility and diagnostic accuracy in consecutively recruited CLD patients who concomitantly underwent TE and liver biopsy. Over 2 years 186 CLD patients (116 males, 132 viral hepatitis) consecutively underwent pSWE (10 valid measurements by ElastPQ) blindly performed by two raters. A further operator performed TE. Inter-observer agreement for pSWE was analysed by intraclass correlation coefficient (ICC) and correlated with histological liver fibrosis (METAVIR). Main determinants of pSWE were investigated by linear regression model. Three hundred and seventy-two (100%) reliable measurements were obtained by pSWE and 184 by TE (99%). LS was 8.1 ± 4.5 kPa for pSWE with the first rater and 8.0 ± 4.2 kPa with the second one vs. 8.8 ± 3.6 kPa for TE. pSWE ICC was 0.89 (95% CI 0.85-0.91), not influenced by age, sex, BMI, liver enzymes, liver aetiology. ICC increased over time with year 1 at 0.86 and 95% CI 0.81-0.90 vs. year 2 at 0.92 and 95% CI 0.87-0.95. Liver fibrosis was the only independent determinant of LS on pSWE. The AUROCs for diagnosing F ≥ 2, F ≥ 3 and F = 4 were 0.77, 0.85 and 0.88 for pSWE vs. 0.81, 0.88 and 0.94 for TE. After 1-year training they were 0.86, 0.94 and 0.91. Point quantification shear-wave elastography reliably and reproducibly evaluates liver stiffness, matching transient elastography for accuracy after a 1-year learning curve or 130 examinations.


Effects of health-system strengthening on under-5, infant, and neonatal mortality: 11-year provincial-level time-series analyses in Mozambique.
Knowledge of the relation between health-system factors and child mortality could help to inform health policy in low-income and middle-income countries. We aimed to quantify modifiable health-system factors and their relation with provincial-level heterogeneity in under-5, infant, and neonatal mortality over time in Mozambique. Using Demographic and Health Survey (2003 and 2011) and Multiple Indicator Cluster Survey (2008) data, we generated provincial-level time-series of child mortality in under-5 (ages 0-4 years), infant (younger than 1 year), and neonatal (younger than 1 month) age groups for 2000-10. We built negative binomial mixed models to examine health-system factors associated with changes in child mortality. Under-5 mortality rate was heterogeneous across provinces, with yearly decreases ranging from 11·1% (Nampula) to 1·9% (Maputo Province). Heterogeneity was greater for neonatal mortality rate, with only seven of 11 provinces showing significant yearly decreases, ranging from 13·6% (Nampula) to 4·2% (Zambezia). Health workforce density (adjusted rate ratio 0·94, 95% CI 0·90-0·98) and maternal and child health nurse density (0·96, 0·92-0·99) were both associated with reduced under-5 mortality rate, as were institutional birth coverage (0·94, 0·90-0·98) and government financing per head (0·80, 0·65-0·98). Higher population per health facility was associated with increased under-5 mortality rate (1·14, 1·02-1·28). Neonatal mortality rate was most strongly associated with institutional birth attendance, maternal and child nurse density, and overall health workforce density. Infant mortality rate was most strongly associated with institutional birth attendance and population per health facility. The large decreases in child mortality seen in Mozambique between 2000 and 2010 could have been partly caused by improvements in the public-sector health workforce, institutional birth coverage, and government health financing. Increased attention should be paid to service availability, because population per health facility is increasing across Mozambique and is associated with increased under-5 mortality. Investments in health information systems and new methods to track potentially increasing subnational health disparities are urgently needed. Doris Duke Charitable Foundation and Mozambican National Institute of Health.


Disintegration/dissolution profiles of copies of Fosamax (alendronate).
Poor quality has been reported for some generics and other copies of original products. We performed a pilot study to compare the disintegration/dissolution profiles of FOSAMAX (alendronate) 70 mg tablets with those of copies of FOSAMAX that were manufactured outside the United States. We used the standard United States Pharmacopeia (USP) disintegration method to evaluate FOSAMAX 70 mg tablets and 13 copies. At least 12 (n = 12) dosage units were tested for each product (except Fosmin, n = 10). The dissolution profiles of FOSAMAX and one representative copy were also compared. Nine copies (Osteomax, Defixal, Fosmin, Endronax, Osteomix, Genalmen, Fixopan, Osteoplus, and Fosval) disintegrated two- to ten-fold faster than FOSAMAX. Three other copies (Neobon, Regenesis, and Ostenan) disintegrated at least five-fold slower than FOSAMAX. Neobon is a softgel capsule, so special consideration was given to this different dosage form. One copy (Arendal) did not fall into either category but exhibited potentially large inter- and intra-lot variability. Dissolution of alendronate from Regenesis lagged behind that from FOSAMAX. Slower disintegration may reduce efficacy because bisphosphonates must be taken in the fasting state and contact with food or even certain beverages severely reduces bioavailability. Faster disintegration (or the use of gel-caps or other alterations to the drug formulation) could increase the risk of esophagitis, an adverse event associated with prolonged contact of the esophagus with bisphosphonates. These disintegration and dissolution results suggest that important differences may exist between FOSAMAX and its copies with regard to bioavailability, pharmacokinetics, and clinical efficacy and safety profiles. Additional testing is warranted to evaluate the pharmacokinetics and clinical safety of these copies.


The tumor suppressor adenomatous polyposis coli regulates T lymphocyte migration.
Adenomatous polyposis coli (APC) is a tumor suppressor whose mutations underlie familial adenomatous polyposis (FAP) and colorectal cancer. Although its role in intestinal epithelial cells is well characterized, APC importance in T cell biology is ill defined. APC regulates cytoskeleton organization, cell polarity, and migration in various cell types. Here, we address whether APC plays a role in T lymphocyte migration. Using a series of cell biology tools, we unveiled that T cells from FAP patients carrying APC mutations display impaired adhesion and motility in constrained environments. We further dissected the cellular mechanisms underpinning these defects in APC-depleted CEM T cell line that recapitulate the phenotype observed in FAP T cells. We found that APC affects T cell motility by modulating integrin-dependent adhesion and cytoskeleton reorganization. Hence, APC mutations in FAP patients not only drive intestinal neoplasms but also impair T cell migration, potentially contributing to inefficient antitumor immunity.


Juvenile pilocytic astrocytomas: CT and MR characteristics.
Thirty-seven cases of juvenile pilocytic astrocytoma were reviewed retrospectively to determine their CT and MR characteristics. All cases occurred in pediatric patients, except for one in a young adult. There was a propensity for tumors to be located around the third and fourth ventricles. On CT the tumors were all sharply demarcated and smoothly marginated and rarely had associated edema. The lesions tended to be round or oval. The tumor matrix was most often hypo- or isodense with marked enhancement. Cyst formation, either micro- or macrocystic or combined, was frequently observed, and tumor calcification occurred occasionally. On MR the tumors appeared hypo- or isointense on T1-weighted images and hyperintense on T2-weighted images. The radiologic appearances of juvenile pilocytic astrocytomas are quite characteristic. By using age of presentation, typical location, configuration, and enhancement patterns, the presurgical diagnosis of juvenile pilocytic astrocytoma can be made with a high index of confidence.


Systematic Review of Genetic Factors in the Etiology of Esophageal Squamous Cell Carcinoma in African Populations.
Background: Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is endemic in Sub-Saharan Africa, constituting a major health burden. It has the most divergence in cancer incidence globally, with high prevalence reported in East Asia, Southern Europe, and in East and Southern Africa. Its etiology is multifactorial, with lifestyle, environmental, and genetic risk factors. Very little is known about the role of genetic factors in ESCC development and progression among African populations. The study aimed to systematically assess the evidence on genetic variants associated with ESCC in African populations. Methods: We carried out a comprehensive search of all African published studies up to April 2019, using PubMed, Embase, Scopus, and African Index Medicus databases. Quality assessment and data extraction were carried out by two investigators. The strength of the associations was measured by odds ratios and 95% confidence intervals. Results: Twenty-three genetic studies on ESCC in African populations were included in the systematic review. They were carried out on Black and admixed South African populations, as well as on Malawian, Sudanese, and Kenyan populations. Most studies were candidate gene studies and included DNA sequence variants in 58 different genes. Only one study carried out whole-exome sequencing of 59 ESCC patients. Sample sizes varied from 18 to 880 cases and 88 to 939 controls. Altogether, over 100 variants in 37 genes were part of 17 case-control genetic association studies to identify susceptibility loci for ESCC. In these studies, 25 variants in 20 genes were reported to have a statistically significant association. In addition, eight studies investigated changes in cancer tissues and identified somatic alterations in 17 genes and evidence of loss of heterozygosity, copy number variation, and microsatellite instability. Two genes were assessed for both genetic association and somatic mutation. Conclusions: Comprehensive large-scale studies on the genetic basis of ESCC are still lacking in Africa. Sample sizes in existing studies are too small to draw definitive conclusions about ESCC etiology. Only a small number of African populations have been analyzed, and replication and validation studies are missing. The genetic etiology of ESCC in Africa is, therefore, still poorly defined.


New monoclonal/bi-specific antibodies: Reshaping transfusion medicine beyond replacement.
Since the first successful transfusion in 1818, Transfusion Medicine has evolved significantly. The advent of plasma fractionation and availability of recombinant products allowed for precision replacement therapy to treat many hematological conditions, such as hemophilia, thrombotic thrombocytopenic purpura, and hereditary angioedema. A deeper understanding of the pathophysiology underlying those conditions along with the development of safer monoclonal and bispecific antibodies is now offering safe and effective alternatives to the simple conventional approach of replacing a missing plasma protein. Many biologicals are already in wide clinical use in areas such as rheumatology, gastroenterology, and medical oncology. The introduction of novel therapeutic antibodies within the realm of Transfusion Medicine will likely reshape the field and challenge the role of local blood establishments as the gate-keepers of such therapies.


Training methods and analysis of races of a top level Paralympic swimming athlete.
Training methods for Paralympic swimmers must take into account different pathologies, competitions classes, athlete's individual circumstances and peculiar physical adaptation mechanisms, hence general guidelines cannot be found in literature. In this study we present a training program, implemented for the physical preparation of a top level Paralympic swimmer. The athlete under study, affected by infantile cerebral palsy within a clinical picture of a spastic tetraparesis, by the end of 2016 was holder of Italian, European, world and Paralympic titles in the 400-m freestyle competition, S6 class. The training macrocycle was structured in a 3-fold periodization (three mesocycles), in view of the preparation to three international competitions. The 4-month training mesocycles prior to each competition differed substantially in terms of mileage load, intensity and recovery times. The first mesocycle was characterized by a sizeable low-intensity mileage load, the second one was shifted to lower mileage load, carried out at middle-to-high intensity levels, the third one entailed increased effort intensity, counterbalanced by lower mileage load. In all cases, recovery times were balanced to obtain optimized performance through physical adaptation to training stimuli, keeping into account the physiopatological response. Tapering phases were adjusted to maximize performance at competition. As an assessment of the effectiveness of the training method, correspondence between chronometric and technical parameters in the three competitions and the respective mesocycle training programs was found. The results of the present study may support the development of training guidelines for athletes affected by upper motor neuron lesions.


Colonization of Germ-Free Piglets with Commensal Lactobacillus amylovorus, Lactobacillus mucosae, and Probiotic E. coli Nissle 1917 and Their Interference with Salmonella Typhimurium.
Non-typhoid Salmonellae are worldwide spread food-borne pathogens that cause diarrhea in humans and animals. Their multi-drug resistances require alternative ways to combat this enteric pathogen. Mono-colonization of a gnotobiotic piglet gastrointestinal tract with commensal lactobacilli Lactobacillus amylovorus and Lactobacillus mucosae and with probiotic E. coli Nissle 1917 and their interference with S. Typhimurium infection was compared. The impact of bacteria and possible protection against infection with Salmonella were evaluated by clinical signs, bacterial translocation, intestinal histology, mRNA expression of villin, claudin-1, claudin-2, and occludin in the ileum and colon, and local intestinal and systemic levels of inflammatory cytokines IL-8, TNF-α, and IL-10. Both lactobacilli colonized the gastrointestinal tract in approximately 100× lower density compare to E. coli Nissle and S. Typhimurium. Neither L. amylovorus nor L. mucosae suppressed the inflammatory reaction caused by the 24 h infection with S. Typhimurium. In contrast, probiotic E. coli Nissle 1917 was able to suppress clinical signs, histopathological changes, the transcriptions of the proteins, and the inductions of the inflammatory cytokines. Future studies are needed to determine whether prebiotic support of the growth of lactobacilli and multistrain lactobacilli inoculum could show higher protective effects.


Atl (atlastin) regulates mTor signaling and autophagy in Drosophila muscle through alteration of the lysosomal network.
atl atlastin; ALR autophagic lysosome reformation; ER endoplasmic reticulum; GFP green fluorescent protein; HSP hereditary spastic paraplegia; Lamp1 lysosomal associated membrane protein 1 PolyUB polyubiquitin; RFP red fluorescent protein; spin spinster; mTor mechanistic Target of rapamycin; VCP valosin containing protein.


The blood pressure buffering capacity of nitric oxide by comparison to the baroreceptor reflex.
To compare the contribution of nitric oxide (NO) to the buffering of short-term and circadian fluctuations of arterial blood pressure with that of the baroreceptor reflex, conscious foxhounds were subjected to continuous 24-h blood pressure recordings. A pressure transducer was placed into the lumen of the abdominal aorta. Telemetry recordings were done under control conditions, following blockade of NO formation by intravenous bolus injection of NG-nitro-L-arginine (L-NNA; 16.5 +/- 2 mg/kg body wt) and after total sinoaortic and cardiopulmonary denervation in five dogs each. L-NNA produced a sustained elevation of mean arterial pressure (MAP; 137.2 +/- 6.4 mmHg vs. control, 112.9 +/- 3.7 mmHg). After denervation, no significant increase of MAP was found (113.5 +/- 4.1 mmHg), but the standard deviation of the MAP histogram was significantly greater (22.5 +/- 3.1 vs. 10.6 +/- 0.9 mmHg, P < 0.05). Sequential spectral analysis showed that total power between 0 and 0.5 Hz was elevated more than twofold after L-NNA (P < 0.05). This was due primarily to increased power in the range above 0.1 Hz. After denervation, total power increased about three-fold (P < 0.05), almost exclusively occurring below 0.04 Hz. Power in the range above 0.2 Hz was diminished, although not significantly. It is concluded that in the conscious dog, NO, as well as the baroreceptor reflex, is an effective blood pressure buffer. NO is most effective above 0.1 Hz, whereas the baroreceptors primarily buffer fluctuations slower than 0.04 Hz.


Altered Dynamic Postural Stability and Joint Position Sense Following British Army Foot-Drill.
Impaired proprioceptive acuity negatively affects both joint position sense and postural control and is a risk factor for lower-extremity musculoskeletal injury in athletes and military personnel. British Army foot-drill is an occupational military activity involving cyclical high impact loading forces greater than those observed in athletes during high level plyometrics. Foot-drill may contribute to the high rates of lower-extremity overuse injuries observed in recruits during basic training. There is limited research investigating foot-drill specific injury risk factors in women, despite greater incidences of musculoskeletal injury reported in women (522 vs. 417 per 1,000 personnel, OR: 1.53) when compared to men during basic training. This study aimed to quantify changes in ankle joint proprioception and dynamic postural stability following a period of British Army foot-drill. Fourteen women of similar age to British Army female recruits underwent pre-post foot-drill measures of frontal plane ankle joint position sense (JPS) and dynamic postural stability using the dynamic postural stability index (DPSI). Passive ankle JPS was assessed from relative test angles of inversion 30% (IN30%) and eversion 30% (EV30%) and IN60% of participants range of motion using an isokinetic dynamometer. The DPSI and the individual stability indices (medio-lateral [MLSI], anterior-posterior [APSI], and vertical [VSI]) were calculated from lateral and forward jump-landing conditions using force plates. Foot-drill was conducted by a serving British Army drill instructor. Significantly greater absolute mean JPS error for IN30% and EV30% was observed post foot-drill (p ≤ 0.016, d ≥ 0.70). For both the lateral and forward jump-landing conditions, significantly greater stability index scores were observed for MLSI, APSI, and DPSI (p ≤ 0.017, d ≥ 0.52). Significantly greater JPS error and stability index scores are associated with the demands of British Army foot-drill. These results provide evidence that foot-drill negatively affects lower-extremity proprioceptive acuity in recruit age-matched women, which has implications for increased injury risk during subsequent military physical activity, occurring in a normal training cycle.


Contrasting genetic paths to morphological and physiological evolution.
The relative importance of protein function change and gene expression change in phenotypic evolution is a contentious, yet central topic in evolutionary biology. Analyzing 5,199 mouse genes with recorded mutant phenotypes, we find that genes exclusively affecting morphological traits when mutated (dubbed "morphogenes") are grossly enriched with transcriptional regulators, whereas those exclusively affecting physiological traits (dubbed "physiogenes") are enriched with channels, transporters, receptors, and enzymes. Compared to physiogenes, morphogenes are more likely to be essential and pleiotropic and less likely to be tissue specific. Morphogenes evolve faster in expression profile, but slower in protein sequence and gene gain/loss than physiogenes. Thus, morphological and physiological changes have a differential molecular basis; separating them helps discern the genetic mechanisms of phenotypic evolution.


Iridium-Based Multimetallic Nanoframe@Nanoframe Structure: An Efficient and Robust Electrocatalyst toward Oxygen Evolution Reaction.
Nanoframe electrocatalysts have attracted great interest due to their inherently high active surface area per a given mass. Although recent progress has enabled the preparation of single nanoframe structures with a variety of morphologies, more complex nanoframe structures such as a double-layered nanoframe have not yet been realized. Herein, we report a rational synthetic strategy for a structurally robust Ir-based multimetallic double-layered nanoframe (DNF) structure, nanoframe@nanoframe. By leveraging the differing kinetics of dual Ir precursors and dual transition metal (Ni and Cu) precursors, a core-shell-type alloy@alloy structure could be generated in a simple one-step synthesis, which was subsequently transformed into a multimetallic IrNiCu DNF with a rhombic dodecahedral morphology via selective etching. The use of single Ir precursor yielded single nanoframe structures, highlighting the importance of employing dual Ir precursors. In addition, the structure of Ir-based nanocrystals could be further controlled to DNF with octahedral morphology and CuNi@Ir core-shell structures via a simple tuning of experimental factors. The IrNiCu DNF exhibited high electrocatalytic activity for oxygen evolution reaction (OER) in acidic media, which is better than Ir/C catalyst. Furthermore, IrNiCu DNF demonstrated excellent durability for OER, which could be attributed to the frame structure that prevents the growth and agglomeration of particles as well as in situ formation of robust rutile IrO2 phase during prolonged operation.


Fat-to-Muscle Ratio: A New Anthropometric Indicator as a Screening Tool for Metabolic Syndrome in Young Colombian People.
Fat-to-muscle ratio has been proposed as an alternative approach for assessing body fat. The objective of this study was to explore fat-to-muscle ratio thresholds in metabolic syndrome (MetS) diagnosis; it was hypothesised that the fat-to-muscle ratio is a good predictive indicator of MetS in a large population of young Colombian adults. For this purpose, a cross-sectional study was conducted on 1416 subjects (66.6% female), aged from 18.1 to 25.1. As part of the study, measurements of the subjects' anthropometric indicators, serum lipid indices, blood pressure, and fasting plasma glucose were taken. Body composition was measured through bioelectrical impedance analysis (BIA). A new variable (ratio of fat mass to muscle mass, in kg) was calculated. Following the International Diabetes Federation (IDF) definition, MetS includes three or more metabolic abnormalities. Receiver operating characteristic (ROC) curves and logistic regression determined the discriminatory ability of the fat-to-muscle ratio to predict MetS. According to the IDF, the best fat-to-muscle ratio cut-off point for detecting MetS in men was 0.225 kg, with an area under the curve (AUC) of 0.83, sensitivity of 80%, and specificity of 70%. For women, the fat-to-muscle ratio cut-off point was 0.495 kg, the AUC was 0.88, and the sensitivity and specificity were 82% and 80%, respectively. In conclusion, our results showed that the fat-to-muscle ratio cut-off points from ROC analyses demonstrate good discriminatory power for detecting MetS in young Colombian adults.


Morphology, biometry, and taxonomy of freshwater and marine interstitial cyphoderia (cercozoa: euglyphida).
Good taxonomy is essential for ecological, biogeographical, and evolutionary studies of any group of organisms. Therefore, we performed detailed light- and scanning electron microscopy investigations on the shell ultrastructure and biometric analyses of the morphometric variability of five freshwater and marine interstitial testate amoebae of the genus Cyphoderia (C. trochus var. amphoralis, C. ampulla, C. margaritacea var. major, C. compressa, and C. littoralis), isolated from different populations in Bulgaria and Switzerland. Our aims were (1) to clarify the morphological characteristics of these taxa, and (2) to compare the morphology of a given taxon (C. ampulla) among different locations in Bulgaria and Switzerland as a first step towards an assessment of the geographical variation within a supposedly cosmopolitan taxon. Four of the studied taxa are characterized by a well-expressed main-size class and by a small size range of all the characters and can be defined as size-monomorphic species. Based on these results, the following systematic changes are proposed: C. major (Penard, 1891) n. comb. (Syn.: C. margaritacea var. major (Penard, 1891) and C. amphoralis (Wailes & Penard, 1911) n. comb. (Syn.: C. trochus var. amphoralis (Wailes & Penard, 1911)). However, we also show significant morphological variability between the Swiss and Bulgarian populations of C. ampulla, suggesting the possible existence of more than one taxon within this species. Further studies are required to assess (1) if these two morphologically different taxa represent individual species, (2) if so, if more species exist, and if this diversity is due to limited distribution ranges (endemism) or if several closely related taxa occur together in different geographical areas.


Network-assisted investigation of combined causal signals from genome-wide association studies in schizophrenia.
With the recent success of genome-wide association studies (GWAS), a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each single GWAS dataset and then implemented a discovery-evaluation strategy to identify module genes with consistent association signals. We validated the module genes in an independent dataset, and also examined them through meta-analysis of the related SNPs using multiple GWAS datasets. As a result, we identified 205 module genes with a joint effect significantly associated with schizophrenia; these module genes included a number of well-studied candidate genes such as DISC1, GNA12, GNA13, GNAI1, GPR17, and GRIN2B. Further functional analysis suggested these genes are involved in neuronal related processes. Additionally, meta-analysis found that 18 SNPs in 9 module genes had P(meta)<1 × 10⁻⁴, including the gene HLA-DQA1 located in the MHC region on chromosome 6, which was reported in previous studies using the largest cohort of schizophrenia patients to date. These results demonstrated our bi-directional network-based strategy is efficient for identifying disease-associated genes with modest signals in GWAS datasets. This approach can be applied to any other complex diseases/traits where multiple GWAS datasets are available.


Last appearance of Homo erectus at Ngandong, Java, 117,000-108,000 years ago.
Homo erectus is the founding early hominin species of Island Southeast Asia, and reached Java (Indonesia) more than 1.5 million years ago1,2. Twelve H. erectus calvaria (skull caps) and two tibiae (lower leg bones) were discovered from a bone bed located about 20 m above the Solo River at Ngandong (Central Java) between 1931 and 19333,4, and are of the youngest, most-advanced form of H. erectus5-8. Despite the importance of the Ngandong fossils, the relationship between the fossils, terrace fill and ages have been heavily debated9-14. Here, to resolve the age of the Ngandong evidence, we use Bayesian modelling of 52 radiometric age estimates to establish-to our knowledge-the first robust chronology at regional, valley and local scales. We used uranium-series dating of speleothems to constrain regional landscape evolution; luminescence, 40argon/39argon (40Ar/39Ar) and uranium-series dating to constrain the sequence of terrace evolution; and applied uranium-series and uranium series-electron-spin resonance (US-ESR) dating to non-human fossils to directly date our re-excavation of Ngandong5,15. We show that at least by 500 thousand years ago (ka) the Solo River was diverted into the Kendeng Hills, and that it formed the Solo terrace sequence between 316 and 31 ka and the Ngandong terrace between about 140 and 92 ka. Non-human fossils recovered during the re-excavation of Ngandong date to between 109 and 106 ka (uranium-series minimum)16 and 134 and 118 ka (US-ESR), with modelled ages of 117 to 108 thousand years (kyr) for the H. erectus bone bed, which accumulated during flood conditions3,17. These results negate the extreme ages that have been proposed for the site and solidify Ngandong as the last known occurrence of this long-lived species.


Methodology for randomized trials of patients with nonvariceal upper gastrointestinal bleeding: recommendations from an international consensus conference.
The aim of this document is to provide a methodological framework for the design, performance, analysis, interpretation, and communication of randomized trials that assess management of patients with nonvariceal upper gastrointestinal bleeding. Literature searches were performed and an iterative process with electronic and face-to-face meetings was used to achieve consensus among panel members as part of an International Consensus Conference on Nonvariceal Upper Gastrointestinal Bleeding. Recommendations of the panel include the following. Randomized trials must explicitly state their primary hypothesis. A nonmanipulable randomization schedule with concealed allocation should be used. Stratification (e.g., for age and stigmata of hemorrhage) may be considered, especially in smaller studies. The patient and personnel providing care or recording information should be blinded. Inclusion criteria should be overt bleeding with endoscopy performed within 24 h or less. One type of lesion (e.g., ulcer) should be studied with stigmata to be included predefined. Use of placebo/no therapy vs. active controls depends on current standard practice. Standardizing study and key non-study interventions should ensure uniform provision of interventions. Criteria for repeat endoscopy and subsequent interventions should be predefined. The primary end point should be further bleeding (persistent and recurrent bleeding) with primary assessment at 7 days; mortality, with primary assessment at 30 days, would be appropriate in very large trials. Sample size calculation based on assumptions regarding primary end point results with regard to study intervention and control must be provided, and all patients enrolled must be accounted for. In general, the primary population for analysis is all patients randomized, although a per-protocol population may be used if this is the more conservative approach (e.g., equivalence study).


Study protocol: ICONS: identifying continence options after stroke: a randomised trial.
Urinary incontinence following acute stroke is common, affecting between 40%-60% of people in hospital after a stroke. Despite the availability of clinical guidelines for urinary incontinence and urinary incontinence after stroke, national audit data suggest incontinence is often poorly managed. Conservative interventions (e.g. bladder training, pelvic floor muscle training and prompted voiding) have been shown to have some effect with participants in Cochrane systematic reviews, but have not had their effectiveness demonstrated with stroke patients. A cluster randomised controlled pilot trial designed to assess the feasibility of a full-scale cluster randomised trial and to provide preliminary evidence of the effectiveness and cost-effectiveness of a systematic voiding programme for the management of continence after stroke. Stroke services will be randomised to receive the systematic voiding programme, the systematic voiding programme plus supported implementation, or usual care. The trial aims to recruit at least 780 participants in 12 stroke services (4 per arm). The primary outcome is presence/absence of incontinence at six weeks post-stroke. Secondary outcomes include frequency and severity of incontinence, quality of life and cost-utility. Outcomes will be measured at six weeks, three months and (for participants recruited in the first three months) twelve months after stroke. Process data will include rates of recruitment and retention and fidelity of intervention delivery. An integrated qualitative evaluation will be conducted in order to describe implementation and assist in explaining the potential mediators and modifiers of the process. ISRCTN: ISRCTN08609907


Spatial risk analysis for the introduction and circulation of six arboviruses in the Netherlands.
Arboviruses are a growing public health concern in Europe, with both endemic and exotic arboviruses expected to spread further into novel areas in the next decades. Predicting where future outbreaks will occur is a major challenge, particularly for regions where these arboviruses are not endemic. Spatial modelling of ecological risk factors for arbovirus circulation can help identify areas of potential emergence. Moreover, combining hazard maps of different arboviruses may facilitate a cost-efficient, targeted multiplex-surveillance strategy in areas where virus transmission is most likely. Here, we developed predictive hazard maps for the introduction and/or establishment of six arboviruses that were previously prioritized for the Netherlands: West Nile virus, Japanese encephalitis virus, Rift Valley fever virus, tick-borne encephalitis virus, louping-ill virus and Crimean-Congo haemorrhagic fever virus. Our spatial model included ecological risk factors that were identified as relevant for these arboviruses by an earlier systematic review, including abiotic conditions, vector abundance, and host availability. We used geographic information system (GIS)-based tools and geostatistical analyses to model spatially continuous datasets on these risk factors to identify regions in the Netherlands with suitable ecological conditions for arbovirus introduction and establishment. The resulting hazard maps show that there is spatial clustering of areas with either a relatively low or relatively high environmental suitability for arbovirus circulation. Moreover, there was some overlap in high-hazard areas for virus introduction and/or establishment, particularly in the southern part of the country. The similarities in environmental suitability for some of the arboviruses provide opportunities for targeted sampling of vectors and/or sentinel hosts in these potential hotspots of emergence, thereby increasing the efficient use of limited resources for surveillance.


Patient directed self management of pain (PaDSMaP) compared to treatment as usual following total knee replacement: study protocol for a randomized controlled trial.
In 2009, 665 patients underwent total knee replacements (TKRs) at the Norfolk and Norwich University Hospitals NHS Foundation Trust (NNUH), representing nearly 1% of the national total. Pain control following the operation can be poor, and this can cause poor mobilization and potential long-term adverse events. Although high levels of pain are not associated with patient dissatisfaction, brief periods of pain may lead to neuronal remodeling and sensitization. Patient controlled oral analgesia (PCOA) may improve pain relief; however, the evidence to date has been inconclusive. Patient directed self management of pain (PaDSMaP) is a single center randomized controlled trial, which aims to establish if patient self-medication improves, or is equivalent to, treatment as usual and to create an educational package to allow implementation elsewhere. Patients eligible for a TKR will be recruited and randomized in the outpatient clinic. All patients will undergo their operations according to normal clinical practice but will be randomized into two groups. Once oral medication has commenced, one group will have pain relief administered by nursing staff in the usual way (treatment as usual; TAU), whilst the second group will self manage their pain medication (patient directed self management of pain; PaDSMaP). Those recruited for self-medication will undergo a training program to teach the use of oral analgesics according to the World Health Organization (WHO) pain cascade and how to complete the study documentation. The primary endpoint of the trial is the visual analogue scale (VAS) pain score at 3 days or discharge, whichever is sooner. The follow-up time is 6 weeks with a planned trial period of 3 years. The secondary objectives are satisfaction with the management of patient pain post-operatively whilst an inpatient after primary TKR; overall pain levels and pain on mobilization; satisfaction with pain management information provided; global outcomes, such as quality of life (QOL) and activities of daily living (ADLs); time to mobilization and whether time to mobilization is associated with frequency of adverse events, improvements in QOL, ADLs and pain at 6 weeks after the operation; incidence of adverse events; quantity and type of pain medications used whilst an inpatient; the acceptability of PaDSMaP and/or TAU protocols for patients and the healthcare professionals involved in their care; to investigate the health-related costs associated with a PaDSMaP system; and to estimate the cost-effectiveness of PaDSMaP compared to TAU. Current Controlled Trials ISRCTN: 10868989.


Changes in E2F5 intracellular localization in mouse and human choroid plexus epithelium with development.
The choroid plexus epithelium (CPe) is a specialized epithelium involved primarily in the production of cerebrospoinal fluid (CSF) which is important for maintaining an optimal homeostatic environment for the brain. Although, the physiology of the CPe is fairly well understood, its development has not been thoroughly studied. It has been recently shown that mice lacking functional transcription factors, E2F5, foxJ1 or p73, develop non-obstructive hydrocephalus likely due to CPe dysfunction. We have further studied their expression in the mouse and human developing CPe, focusing particularly on E2F5. We show here that in the mouse E2F5, foxJ1 and p73 transcripts are detectable as soon as the choroid plexuses form. E2F5 protein is also detected as soon as the choroid plexuses are morphologically apparent both in mouse and human, suggesting that its expression is regulated at the transcriptional level. E2F5 protein is down-regulated late in embryogenesis and this coincides with a change in its intracellular localization, from predominantly nuclear to cytoplasmic. The pattern of expression and intracellular localization of E2F5 in vivo does not appear to correlate with that of proliferating CPe cells, as indicated by protein cell nuclear antigen (PCNA) staining, but rather with their maturation, as changes in E2F5 localization from the nucleus to the cytoplasm parallel the morphological change from pseudostratified to cuboidal epithelium.


Variation in recorded child maltreatment concerns in UK primary care records: a cohort study using The Health Improvement Network (THIN) database.
To determine variation over time and between practices in recording of concerns related to abuse and neglect (maltreatment) in children's primary care records. Retrospective cohort study using a United Kingdom representative primary care database. 448 General Practices. In total 1,548, 972 children (<18 y) registered between 1995 and 2010. Change in annual incidence of one or more maltreatment-related codes per child year of registration. Variation between general practices measured as the proportion of registered children with one or more maltreatment-related codes during 3 years (2008-2010). From 1995-2010, annual incidence rates of any coded maltreatment-related concerns rose by 10.8% each year (95% confidence interval 10.5, 11.2; adjusted for sex, age and deprivation). In 2010 the rate was 9.5 per 1000 child years (95%CI: 9.3, 9.8), equivalent to a prevalence of 0.8% of all registered children in 2010. Across all practices, the median prevalence of children with any maltreatment-related codes in three years (2008 to 2010) was 0.9% (range 0%-13.4%; 11 practices (2.5%) had zero children with relevant codes in the same period). Once we accounted for sex, age, and deprivation, the prevalence for each practice was within two standard errors of the grand mean. General Practitioners (GPs) are far from disengaged from safeguarding children; they are consistently and increasingly recording maltreatment concerns. As these results are likely to underestimate the burden of maltreatment known to primary care, there is much scope for increasing recording in primary care records with implications for resources to respond to concerns about maltreatment. Interventions and policies should build on this evidence that the average GP in the UK is engaged in child safeguarding activity.


Implementation of a 4Pi-SMS super-resolution microscope.
The development of single-molecule switching (SMS) fluorescence microscopy (also called single-molecule localization microscopy) over the last decade has enabled researchers to image cell biological structures at unprecedented resolution. Using two opposing objectives in a so-called 4Pi geometry doubles the available numerical aperture, and coupling this with interferometric detection has demonstrated 3D resolution down to 10 nm over entire cellular volumes. The aim of this protocol is to enable interested researchers to establish 4Pi-SMS super-resolution microscopy in their laboratories. We describe in detail how to assemble the optomechanical components of a 4Pi-SMS instrument, align its optical beampath and test its performance. The protocol further provides instructions on how to prepare test samples of fluorescent beads, operate this instrument to acquire images of whole cells and analyze the raw image data to reconstruct super-resolution 3D data sets. Furthermore, we provide a troubleshooting guide and present examples of anticipated results. An experienced optical instrument builder will require ~12 months from the start of ordering hardware components to acquiring high-quality biological images.


A hybrid procedure for MSW generation forecasting at multiple time scales in Xiamen City, China.
Accurate forecasting of municipal solid waste (MSW) generation is crucial and fundamental for the planning, operation and optimization of any MSW management system. Comprehensive information on waste generation for month-scale, medium-term and long-term time scales is especially needed, considering the necessity of MSW management upgrade facing many developing countries. Several existing models are available but of little use in forecasting MSW generation at multiple time scales. The goal of this study is to propose a hybrid model that combines the seasonal autoregressive integrated moving average (SARIMA) model and grey system theory to forecast MSW generation at multiple time scales without needing to consider other variables such as demographics and socioeconomic factors. To demonstrate its applicability, a case study of Xiamen City, China was performed. Results show that the model is robust enough to fit and forecast seasonal and annual dynamics of MSW generation at month-scale, medium- and long-term time scales with the desired accuracy. In the month-scale, MSW generation in Xiamen City will peak at 132.2 thousand tonnes in July 2015 - 1.5 times the volume in July 2010. In the medium term, annual MSW generation will increase to 1518.1 thousand tonnes by 2015 at an average growth rate of 10%. In the long term, a large volume of MSW will be output annually and will increase to 2486.3 thousand tonnes by 2020 - 2.5 times the value for 2010. The hybrid model proposed in this paper can enable decision makers to develop integrated policies and measures for waste management over the long term.


Renal Artery Stent Outcomes: Effect of Baseline Blood Pressure, Stenosis Severity, and Translesion Pressure Gradient.
Multiple randomized clinical trials comparing renal artery stent placement plus medical therapy with medical therapy alone have not shown any benefit of stent placement. However, debate continues whether patients with extreme pressure gradients, stenosis severity, or baseline blood pressure benefit from stent revascularization. The study sought to test the hypothesis that pressure gradients, stenosis severity, and/or baseline blood pressure affects outcomes after renal artery stent placement. Using data from 947 patients with a history of hypertension or chronic kidney disease from the largest randomized trial of renal artery stent placement, the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) study, we performed exploratory analyses to determine if subsets of patients experienced better outcomes after stent placement than the overall cohort. We examined baseline stenosis severity, systolic blood pressure, and translesion pressure gradient (peak systolic and mean) and performed interaction tests and Cox proportional hazards analyses for the occurrence of the primary endpoint through all follow-up, to examine the effect of these variables on outcomes by treatment group. There were no statistically significant differences in outcomes based on the examined variables nor were there any consistent nonsignificant trends. Based on data from the CORAL randomized trial, there is no evidence of a significant treatment effect of the renal artery stent procedure compared with medical therapy alone based on stenosis severity, level of systolic blood pressure elevation, or according to the magnitude of the trans-stenotic pressure gradient. (Benefits of Medical Therapy Plus Stenting for Renal Atherosclerotic Lesions [CORAL]; NCT00081731).


UV light phototransduction activates transient receptor potential A1 ion channels in human melanocytes.
Human skin is constantly exposed to solar ultraviolet radiation (UVR), the most prevalent environmental carcinogen. Humans have the unique ability among mammals to respond to UVR by increasing their skin pigmentation, a protective process driven by melanin synthesis in epidermal melanocytes. The molecular mechanisms used by melanocytes to detect and respond to long-wavelength UVR (UVA) are not well understood. We recently identified a UVA phototransduction pathway in melanocytes that is mediated by G protein-coupled receptors and leads to rapid calcium mobilization. Here we report that in human epidermal melanocytes physiological doses of UVR activate a retinal-dependent current mediated by transient receptor potential A1 (TRPA1) ion channels. The TRPA1 photocurrent is UVA-specific and requires G protein and phospholipase C signaling, thus contributing to UVA-induced calcium responses to mediate downstream cellular effects and providing evidence for TRPA1 function in mammalian phototransduction. Remarkably, TRPA1 activation is required for the UVR-induced and retinal-dependent early increase in cellular melanin. Our results show that TRPA1 is essential for a unique extraocular phototransduction pathway in human melanocytes that is activated by physiological doses of UVR and results in early melanin synthesis.


C/EBP transcription factors mediate epicardial activation during heart development and injury.
The epicardium encapsulates the heart and functions as a source of multipotent progenitor cells and paracrine factors essential for cardiac development and repair. Injury of the adult heart results in reactivation of a developmental gene program in the epicardium, but the transcriptional basis of epicardial gene expression has not been delineated. We established a mouse embryonic heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered on CCAAT/enhancer binding protein (C/EBP) transcription factors. Disruption of C/EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function. These findings reveal a transcriptional basis for epicardial activation and heart injury, providing a platform for enhancing cardiac regeneration.


Can skills assessment on a virtual reality trainer predict a surgical trainee's talent in laparoscopic surgery?
A number of studies have investigated several aspects of feasibility and validity of performance assessments with virtual reality surgical simulators. However, the validity of performance assessments is limited by the reliability of such measurements, and some issues of reliability still need to be addressed. This study aimed to evaluate the hypothesis that test subjects show logarithmic performance curves on repetitive trials for a component task of laparoscopic cholecystectomy on a virtual reality simulator, and that interindividual differences in performance after considerable training are significant. According to kinesiologic theory, logarithmic performance curves are expected and an individual's learning capacity for a specific task can be extrapolated, allowing quantification of a person's innate ability to develop task-specific skills. In this study, 20 medical students at the University of Basel Medical School performed five trials of a standardized task on the LS 500 virtual reality simulator for laparoscopic surgery. Task completion time, number of errors, economy of instrument movements, and maximum speed of instrument movements were measured. The hypothesis was confirmed by the fact that the performance curves for some of the simulator measurements were very close to logarithmic curves, and there were significant interindividual differences in performance at the end of the repetitive trials. Assessment of perceptual motor skills and the innate ability of an individual with no prior experience in laparoscopic surgery to develop such skills using the LS 500 VR surgical simulator is feasible and reliable.


Drinking water in traditional Persian medicine: Do's and don'ts.
Water is the main component of our body and its balance is vital for maintaining normal physiology. Accordingly, adequate fluid intake in the daily diet is very important for a healthy life. Nevertheless, there is a controversy about what the suitable amount of water that we need to drink is. In this paper, we aimed to discuss this important issue based on the doctrine of traditional Persian medicine (TPM) and our clinical experience in a practical manner.


Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease.
Guidelines for the diagnosis and treatment of gastroesophageal reflux disease (GERD) were published in 1995 and updated in 1999. These and other guidelines undergo periodic review. Advances continue to be made in the area of GERD, leading us to review and revise previous guideline statements. GERD is defined as symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus. These guidelines were developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee, and approved by the Board of Trustees. Diagnostic guidelines address empiric therapy and the use of endoscopy, ambulatory reflux monitoring, and esophageal manometry in GERD. Treatment guidelines address the role of lifestyle changes, patient directed (OTC) therapy, acid suppression, promotility therapy, maintenance therapy, antireflux surgery, and endoscopic therapy in GERD. Finally, there is a discussion of the rare patient with refractory GERD and a list of areas in need of additional study.


Monitoring protein conformation along the pathway of chaperonin-assisted folding.
The GroEL/GroES chaperonin system mediates protein folding in the bacterial cytosol. Newly synthesized proteins reach GroEL via transfer from upstream chaperones such as DnaK/DnaJ (Hsp70). Here we employed single molecule and ensemble FRET to monitor the conformational transitions of a model substrate as it proceeds along this chaperone pathway. We find that DnaK/DnaJ stabilizes the protein in collapsed states that fold exceedingly slowly. Transfer to GroEL results in unfolding, with a fraction of molecules reaching locally highly expanded conformations. ATP-induced domain movements in GroEL cause transient further unfolding and rapid mobilization of protein segments with moderate hydrophobicity, allowing partial compaction on the GroEL surface. The more hydrophobic regions are released upon subsequent protein encapsulation in the central GroEL cavity by GroES, completing compaction and allowing rapid folding. Segmental chain release and compaction may be important in avoiding misfolding by proteins that fail to fold efficiently through spontaneous hydrophobic collapse.


Socioeconomic and racial/ethnic factors affecting non-fatal medically attended injury rates in US children.
Using a representative survey of US children, the purpose was to evaluate separate effects of socioeconomic and racial/ethnic factors, including access to care, on medically attended non-fatal injury rates. Multivariate linear regression models were used to determine associations between injuries and health care coverage (insurance or Medicaid), having a place to go for care, race/ethnicity, maternal education, number of adults and children in the household, poverty, and urbanicity. The 1988 Child Health Supplement to the National Health Interview Survey included questions on medically attended injuries, and their cause, location, and effects on the child. Injury categories included total, consequential, occurrence at home or school, falls, and being struck or cut. Lack of health care coverage was consistently associated with lower medically attended injury rates in non-Hispanic blacks or whites and Mexican-Americans, but affected total rates for each group differently due to unequal distribution of health care coverage. Injuries occurred about 40% more frequently to children and adolescents living in single adult households compared with two adult homes for all injury categories except for injuries occurring at school. Preventive interventions targeted to specific populations based on assumptions that poverty, lack of education, or minority status result in greater risks for injuries require a closer look. Efficient targeting should address underlying factors such as differences in exposures and environments associated with single adult homes or recreational activities. Data sources used to target high risk populations for interventions need to address bias due to access to care.


Microfluidic platform for monitoring Saccharomyces cerevisiae mutation accumulation.
Mutations in DNA have large-ranging consequences, from evolution to disease. Many mechanisms contribute to mutational processes such as dysfunctions in DNA repair pathways and exogenous or endogenous mutagen exposures. Model organisms and mutation accumulation (MA) experiments are indispensable to study mutagenesis. Classical MA is, however, time consuming and laborious. To fill the need for more efficient approaches to characterize mutational profiles, we have developed an innovative microfluidic-based system that automatizes MA culturing over many generations in budding yeast. This unique experimental tool, coupled with high-throughput sequencing, reduces by one order of magnitude the time required for genome-wide measurements of mutational profiles, while also parallelizing and simplifying the cell culture. To validate our approach, we performed microfluidic MA experiments on two different genetic backgrounds, a wild-type strain and a base-excision DNA repair ung1 mutant characterized by a well-defined mutational profile. We show that the microfluidic device allows for mutation accumulation comparable to the traditional method on plate. Our approach thus paves the way to massively-parallel MA experiments with minimal human intervention that can be used to investigate mutational processes at the origin of human diseases and to identify mutagenic compounds relevant for medical and environmental research.


Clinical Characteristics of Hospitalized Covid-19 Patients in New York City.
The coronavirus 2019 (Covid-19) pandemic is a global public health crisis, with over 1.6 million cases and 95,000 deaths worldwide. Data are needed regarding the clinical course of hospitalized patients, particularly in the United States. Demographic, clinical, and outcomes data for patients admitted to five Mount Sinai Health System hospitals with confirmed Covid-19 between February 27 and April 2, 2020 were identified through institutional electronic health records. We conducted a descriptive study of patients who had in-hospital mortality or were discharged alive. A total of 2,199 patients with Covid-19 were hospitalized during the study period. As of April 2 nd , 1,121 (51%) patients remained hospitalized, and 1,078 (49%) completed their hospital course. Of the latter, the overall mortality was 29%, and 36% required intensive care. The median age was 65 years overall and 75 years in those who died. Pre-existing conditions were present in 65% of those who died and 46% of those discharged. In those who died, the admission median lymphocyte percentage was 11.7%, D-dimer was 2.4 ug/ml, C-reactive protein was 162 mg/L, and procalcitonin was 0.44 ng/mL. In those discharged, the admission median lymphocyte percentage was 16.6%, D-dimer was 0.93 ug/ml, C-reactive protein was 79 mg/L, and procalcitonin was 0.09 ng/mL. This is the largest and most diverse case series of hospitalized patients with Covid-19 in the United States to date. Requirement of intensive care and mortality were high. Patients who died typically had pre-existing conditions and severe perturbations in inflammatory markers.


Anchoring 9,371 maize expressed sequence tagged unigenes to the bacterial artificial chromosome contig map by two-dimensional overgo hybridization.
Our goal is to construct a robust physical map for maize (Zea mays) comprehensively integrated with the genetic map. We have used a two-dimensional 24 x 24 overgo pooling strategy to anchor maize expressed sequence tagged (EST) unigenes to 165,888 bacterial artificial chromosomes (BACs) on high-density filters. A set of 70,716 public maize ESTs seeded derivation of 10,723 EST unigene assemblies. From these assemblies, 10,642 overgo sequences of 40 bp were applied as hybridization probes. BAC addresses were obtained for 9,371 overgo probes, representing an 88% success rate. More than 96% of the successful overgo probes identified two or more BACs, while 5% identified more than 50 BACs. The majority of BACs identified (79%) were hybridized with one or two overgos. A small number of BACs hybridized with eight or more overgos, suggesting that these BACs must be gene rich. Approximately 5,670 overgos identified BACs assembled within one contig, indicating that these probes are highly locus specific. A total of 1,795 megabases (Mb; 87%) of the total 2,050 Mb in BAC contigs were associated with one or more overgos, which are serving as sequence-tagged sites for single nucleotide polymorphism development. Overgo density ranged from less than one overgo per megabase to greater than 20 overgos per megabase. The majority of contigs (52%) hit by overgos contained three to nine overgos per megabase. Analysis of approximately 1,022 Mb of genetically anchored BAC contigs indicates that 9,003 of the total 13,900 overgo-contig sites are genetically anchored. Our results indicate overgos are a powerful approach for generating gene-specific hybridization probes that are facilitating the assembly of an integrated genetic and physical map for maize.


Addressing multimorbidity in evidence integration and synthesis.
To minimize bias, clinical practice guidelines (CPG) for managing patients with multiple conditions should be informed by well-planned syntheses of the totality of the relevant evidence by means of systematic reviews and meta-analyses. However, deficiencies along the entire evidentiary pathway hinder the development of evidence-based CPGs. Published reports of trials and observational studies often do not provide usable data on treatment effect heterogeneity, perhaps because their design, analysis and presentation is seldom geared towards informing on how multimorbidity modifies the effect of treatments. Systematic reviews and meta-analyses inherit all the limitations of their building blocks and introduce additional of their own, including selection biases at the level of the included studies, ecological biases, and analytical challenges. To generate recommendations to help negotiate some of the challenges in synthesizing the primary literature, so that the results of the evidence synthesis is applicable to the care of those with multiple conditions. Informal group process. We have built upon established general guidance, and provide additional recommendations specific to systematic reviews that could improve the CPGs for multimorbid patients. We suggest that following the additional recommendations is good practice, but acknowledge that not all proposed recommendations are of equal importance, validity and feasibility, and that further work is needed to test and refine the recommendations.


Molecular cloning, sequencing, and expression of the 36 kDa protein present in pars planitis. Sequence homology with yeast nucleopore complex protein.
Patients with active pars planitis have increased levels of a 36 kDa protein (p-36) in their circulation. The current studies were undertaken to determine the primary structure of this protein. A degenerate oligonucleotide probe based on the amino terminal sequence of p-36 was used to identify a clone from a human spleen cDNA library. The cDNA insert was subcloned into the EcoR1 site of pUC-19, and both strands were sequenced. Southern blot analysis was used to study the genomic hybridization pattern. p-36 cDNA was subcloned in a pSG5 expression vector, and the construct was used to transfect COS-7 cells. The cDNA sequence contained an open reading frame of 966 base pairs encoding a protein of 322 amino acids, an untranslated region of 322 base pairs, and 2693 base pairs at the 5' and 3' ends, respectively. The deduced amino acid sequence showed 96.8% identity with the carboxy-terminal region of a yeast nucleopore complex protein, nup 100. Southern blot analysis of human genomic DNA revealed a simple hybridization pattern. Transfection of p-36 cDNA in COS-7 cells resulted in the presence of p-36 mRNA and expression of protein. The 36 kDa protein (p-36) detected at increased levels in the blood of patients with active pars planitis was cloned from a human spleen cDNA library. Its deduced amino acid sequence is homologous with the carboxy-terminal region of a nucleopore complex protein. Thus, we refer to this protein as nup36.


Sex difference in the development of deoxycorticosterone-salt hypertension in the rat.
To investigate a possible sex difference in the development of deoxycorticosterone (DOC)-salt hypertension in rats, systolic blood pressure was measured over 6 weeks in unilaterally nephrectomized male and female rats with or without DOC-salt treatment. Throughout the treatment, systolic blood pressure was significantly lower in female than in male DOC-salt rats (at the end of the sixth week: 190 +/- 8 vs 163 +/- 7 mm Hg, p less than 0.05). The difference in blood pressure was also confirmed by the direct measurement of mean arterial pressure at the end of the experiment. The 24-hour urinary excretion of vasopressin was significantly higher in male control rats than in female control rats; however, no difference was observed between male and female DOC-salt rats, in which the urinary excretion of vasopressin was four to five times higher than in control rats. The plasma vasopressin concentration was higher in DOC-salt rats, but there were no differences between sexes. There were no differences in the metabolic clearance rate of vasopressin among the four groups of rats. This indicates that the elevated plasma vasopressin concentration in DOC-salt hypertensive rats is due to increased release of the hormone, rather than to impaired metabolism. Thus, although vasopressin plays a pivotal role in the pathogenesis of DOC-salt hypertension, the sexual dimorphism in this form of hypertension cannot be attributed to differences in the secretion, metabolism, or plasma concentration of vasopressin.


Role of depressive symptoms in the health-related quality of life of Venezuelan patients with rheumatoid arthritis. Results from a tertiary care center.
To examine the effect of depressive symptoms on health-related quality of life (HR-QoL) in Venezuelan patients with rheumatoid arthritis (RA). HR-QoL was assessed in a cross-sectional, single-center study of 212 consecutive Venezuelan patients with RA (1987 American College of Rheumatology criteria) using the Medical Outcomes Study Short Form (SF-36), which includes a Physical Composite Scale (PCS) and a Mental Composite Scale (MCS); depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Covariates included socio-demographics, comorbidities, disease characteristics, body mass index, and disability. Unadjusted and multivariable linear regression analysis were used to determine the effect of depressive symptoms on HR-QoL. Mean age was 50.2 years and 89.6% were female. Twenty-five percent of patients had depressive symptoms. In the multivariable regression analysis, the presence of depressive symptoms changed the mental SF-36 scores by - 4.81 (p = 0.0052) and the physical SF-36 scores by - 3.33 (p = 0.0527). Other factors significantly associated with scores on the PCS of the SF-36 were functional class, disability and job loss due to RA. The presence of depressive symptoms negatively affected the HR-QoL in our patients, with a predominant effect on the MCS of the SF-36. The PCS of the SF-36 was mainly affected by those symptoms related to the functional impairment and inflammatory activity of the disease. The routine assessment and early treatment of depressive symptoms, targeting mental and mood manifestations, may improve the HR-QoL and thus contribute to healthier outcomes in Venezuelan RA patients.


The spore photoproduct lyase repairs the 5S- and not the 5R-configured spore photoproduct DNA lesion.
The spore photoproduct lyase is a Fe-S/AdoMet DNA repair enzyme, which directly repairs spore lesions, induced by UV irradiation of spores, using an unknown radical mechanism. The air sensitive radical SAM enzyme was for the first time challenged with synthetically pure substrates. It was found that the enzyme recognizes a synthetic 5S-configured spore lesion without the central phosphodiester bond. The 5R-configured lesion is in contrast to current belief not a substrate.


The emerging role of the endocannabinoid system in cardiovascular disease.
Endocannabinoids are endogenous bioactive lipid mediators present both in the brain and various peripheral tissues, which exert their biological effects via interaction with specific G-protein-coupled cannabinoid receptors, the CB(1) and CB(2). Pathological overactivation of the endocannabinoid system (ECS) in various forms of shock and heart failure may contribute to the underlying pathology and cardiodepressive state by the activation of the cardiovascular CB(1) receptors. Furthermore, tonic activation of CB(1) receptors by endocannabinoids has also been implicated in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes, such as plasma lipid alterations, abdominal obesity, hepatic steatosis, inflammation, and insulin and leptin resistance. In contrast, activation of CB(2) receptors in immune cells exerts various immunomodulatory effects, and the CB(2) receptors in endothelial and inflammatory cells appear to limit the endothelial inflammatory response, chemotaxis, and inflammatory cell adhesion and activation in atherosclerosis and reperfusion injury. Here, we will overview the cardiovascular actions of endocannabinoids and the growing body of evidence implicating the dysregulation of the ECS in a variety of cardiovascular diseases. We will also discuss the therapeutic potential of the modulation of the ECS by selective agonists/antagonists in various cardiovascular disorders associated with inflammation and tissue injury, ranging from myocardial infarction and heart failure to atherosclerosis and cardiometabolic disorders.


Intraindividual comparison of high-spatial-resolution abdominal MR angiography at 1.5 T and 3.0 T: initial experience.
To prospectively compare three-dimensional (3D) contrast material-enhanced abdominal magnetic resonance (MR) angiography at 1.5 and 3.0 T intraindividually in healthy volunteers. After institutional review board approval and informed consent were obtained, 15 healthy male volunteers (age range, 24-41 years) underwent one abdominal 3D contrast-enhanced MR angiographic examination each at 1.5 and 3.0 T in random order. Fast 3D gradient-echo sequence with parallel imaging acceleration factor of three was used for MR angiography; acquired spatial resolutions were 1x0.8x1 mm3 (imaging time, 19 seconds) at 1.5 T and 0.9x0.8x0.9 mm3 (imaging time, 18 seconds) at 3.0 T. With the latter, volume of the 3D slab was 8% larger. At 1.5 T, 20-mL bolus of gadobenate dimeglumine was delivered at 2 mL/sec; at 3.0 T, 15-mL bolus was delivered at 2.5 mL/sec. Two blinded radiologists rated image quality of aorta and proximal renal arteries in consensus with five-point scale (4=very good, 0=nondiagnostic) according to sequence and in direct intraindividual comparison. Visibility of proximal and segmental renal arteries was rated with three-point scale (3=completely visible, 1=nonvisible). Signal-to-noise ratio (SNR) was determined with phantoms. For statistical analysis of the SNRs, t tests were used. All MR angiographic measurements were diagnostic. Median score for image quality at both field strengths was 4. Depiction of proximal renal arteries was rated 3 at both field strengths. The visibility of the distal renal arteries was better at 3.0 T (median score, 3) than at 1.5 T (median score, 2). With direct comparison, 3.0-T MR angiography was better in 14 of 15 cases; no field strength was preferred in the other case. Mean SNR was significantly (P<.001) higher at 3.0 T (17.8+/-0.09 [standard deviation]) than at 1.5 T (11.9+/-0.10). MR angiography at 3.0 T provided better vessel visibility and SNR than did that at 1.5 T, although voxel size and imaging time were reduced.


Dietary patterns in India: a systematic review.
Dietary patterns analysis is an emerging area of research. Identifying distinct patterns within a large dietary survey can give a more accurate representation of what people are eating. Furthermore, it allows researchers to analyse relationships between non-communicable diseases (NCD) and complete diets rather than individual food items or nutrients. However, few such studies have been conducted in developing countries including India, where the population has a high burden of diabetes and CVD. We undertook a systematic review of published and grey literature exploring dietary patterns and relationships with diet-related NCD in India. We identified eight studies, including eleven separate models of dietary patterns. Most dietary patterns were vegetarian with a predominance of fruit, vegetables and pulses, as well as cereals; dietary patterns based on high-fat, high-sugar foods and more meat were also identified. There was large variability between regions in dietary patterns, and there was some evidence of change in diets over time, although no evidence of different diets by sex or age was found. Consumers of high-fat dietary patterns were more likely to have greater BMI, and a dietary pattern high in sweets and snacks was associated with greater risk of diabetes compared with a traditional diet high in rice and pulses, but other relationships with NCD risk factors were less clear. This review shows that dietary pattern analyses can be highly valuable in assessing variability in national diets and diet-disease relationships. However, to date, most studies in India are limited by data and methodological shortcomings.


Nurse-Driven Interprofessional Rounds: Improving Care Coordination and Length of Stay.
Inpatient oncology units care for patients with some of the most complex medical conditions outside of the intensive care unit. These patients benefit from structured care coordination. Reduced ability to admit patients to oncology beds contributes to delays in specialty care. This quality improvement initiative established nurse-driven interprofessional rounds (IPRs) to reduce length of stay (LOS), improve discharge time of day, and enhance care coordination, patient flow, and access to care in the community. Care coordination during enhanced IPRs (eIPRs) included estimation of discharge dates, comparison of LOS to a standard geometric mean LOS, and discussion of clinical milestones and barriers to progression and discharge. Data analysis evaluated the effect of eIPRs on key outcomes. Although LOS variance was reduced by 15.8% and 44.1% in all-unit and hematology-oncology discharges, respectively, the results were not significant. Discharges by 2 pm improved significantly for all-unit and hematology-oncology populations, respectively. Patient flow measured by accepted patient transfers requesting hematology-oncology services improved significantly.


Diffusion of palliative care in nursing homes: lessons from the culture change movement.
Studies have found that nursing homes (NHs) that rely heavily on Medicaid funding are less likely to implement innovative approaches to care, such as palliative care (PC) or resident-centered approaches commonly referred to as "culture change" (CC). However, a nationally representative survey we previously conducted found that some high Medicaid facilities have implemented these innovative approaches. The purpose of this study was to identify the factors that enable some high Medicaid NHs to implement innovative approaches to care. We conducted telephone interviews with 16 NH administrators in four categories of facilities: 1) low PC and low CC, 2) low PC and high CC, 3) high PC and low CC, and 4) high PC and high CC. Interviews explored strategies used to overcome barriers to implementation and the resources needed for implementation. We had expected to find differences between low and high NHs but instead found differences in NHs' experiences with CC and PC. Since the time of our national survey in 2009-2010, most previously low CC NHs had implemented at least some CC practices; however, we did not find similar changes around PC. Administrators reported numerous ways in which they had received information and assistance from outside entities for implementing CC. This was not the case for PC where administrators reported relying exclusively and heavily on hospices for both their residents' PC needs and information related to PC. PC advocates could learn much from the CC model in which advocates have used multipronged efforts to institute reform.


Scalp recurrence of cholangiocarcinoma after curative hepatectomy: A report of two cases.
Cholangiocarcinomas are the second most common primary liver malignancies. The lymphatics are the common route of metastatic spread for cholangiocarcinomas. The most frequent sites of metastasis are the liver, abdominal lymph nodes, peritoneum and lungs. Cutaneous metastasis of cholangiocarcinoma is rare, and most commonly occurs following percutaneous biliary drainage. Brain or skull metastases from this tumor are uncommon. However, these rare metastatic lesions may occasionally be the first disease manifestation, although scalp recurrence following curative treatment is uncommon. We herein present the cases of two patients with cholangiocarcinoma, who were evaluated as resectable based on the criteria for cholangiocarcinoma resectability, and developed scalp recurrence following curative hepatectomy. Therefore, although scalp recurrence is a rare occurrence following curative treatment for cholangiocarcinoma, metastases should be included in the differential diagnosis.


Thalassemia Major and Priapism: A Case Report of an Adolescent.
Priapism is defined as a prolonged pathologic penile erection without sexual stimulation. In children, priapism secondary to sickle cell disease or hematological malignancy is a frequent condition. Appropriate treatment of priapism varies; the treatment is primarily etiological, conservative management. In the present report, we aimed to present a case of asplenic thalassemia major who developed priapism, improved with hydration and ibuprofen treatment. Clinicians should take into account that priapism can be encountered in patients with thalassemia major. To our knowledge this is the second publication reporting the association between thalassemia major and priapism in childhood.


Induction of malignant plasma cell proliferation by eosinophils.
The biology of the malignant plasma cells (PCs) in multiple myeloma (MM) is highly influenced by the bone marrow (BM) microenvironment in which they reside. More specifically, BM stromal cells (SCs) are known to interact with MM cells to promote MM cell survival and proliferation. By contrast, it is unclear if innate immune cells within this same space also actively participate in the pathology of MM. Our study shows for the first time that eosinophils (Eos) can contribute to the biology of MM by enhancing the proliferation of some malignant PCs. We first demonstrate that PCs and Eos can be found in close proximity in the BM. In culture, Eos were found to augment MM cell proliferation that is predominantly mediated through a soluble factor(s). Fractionation of cell-free supernatants and neutralization studies demonstrated that this activity is independent of Eos-derived microparticles and a proliferation-inducing ligand (APRIL), respectively. Using a multicellular in vitro system designed to resemble the native MM niche, SCs and Eos were shown to have non-redundant roles in their support of MM cell growth. Whereas SCs induce MM cell proliferation predominantly through the secretion of IL-6, Eos stimulate growth of these malignant cells via an IL-6-independent mechanism. Taken together, our study demonstrates for the first time a role for Eos in the pathology of MM and suggests that therapeutic strategies targeting these cells may be beneficial.


Predictors of childhood trajectories of overt and indirect aggression: An interdisciplinary approach.
The aim of this study was to advance our understanding of the development of aggression in boys and girls by testing a model combining insights from both evolutionary theory and developmental psychology. A sample of 744 children (348 girls) between six and 13 years old was recruited in schools with high deprivation indices. Half of the sample (N = 372; 40.1% girls) had received special educational services for behavioral and/or socio-emotional problems. Two trajectories for overt aggression and two trajectories for indirect aggression were identified and binomial logistic regressions were used to identify environmental predictors and sex-specific patterns of these trajectories. Results indicated that peer rejection predicted overt aggression and indirect aggression and that extraversion and male sex predicted overt aggression. The results also showed that interaction between parental practices and some child temperament traits predicted overt aggression (coercion and lack of supervision associated with extraversion or low effortful control) or indirect aggression (coercion and neglect associated with negative affect or low effortful control), and the absence of a father figure predicted high indirect aggression in girls.


Modulation of epidermal growth factor receptor phosphorylation by endogenously expressed gangliosides.
The effect of changing the ganglioside composition of Chinese hamster ovary K1 cells on the function of the epidermal growth factor receptor (EGFr) was examined by studying the signalling pathway generated after the binding of epidermal growth factor (EGF) both in cells depleted of glycosphingolipids by inhibiting glucosylceramide synthase activity and in cell lines expressing different gangliosides as the result of stable transfection of appropriate ganglioside glycosyltransferases. After stimulation with EGF, cells depleted of glycolipids showed EGFr phosphorylation and extracellular signal-regulated protein kinase 2 (ERK2) activity as parental cells expressing GM3 [ganglioside nomenclature follows Svennerholm (1963) J. Neurochem. 10, 613-623] or as transfected cells expressing mostly GM2 and GD1a as the result of stable transfection of UDP-GalNAc:LacCer/GM3/GD3 N-acetylgalactosaminyltransferase. However, cells stably transfected with CMP-NeuAc:GM3 sialyltransferase and expressing GD3 at the cell surface showed both decreased EGFr phosphorylation and ERK2 activation after stimulation with EGF. Results suggest that changes in the ganglioside composition of cell membranes might be important in the regulation of the EGF signal transduction.


Additive therapeutic effects of the liver extract preparation mixture adelavin-9 on interferon-beta treatment for chronic hepatitis C.
We previously reported that intravenous interferon-beta administration was effective in treating patients with chronic hepatitis C and that there was no significant correlation between the response to therapy and host in vitro immunoglobulin production. The aims of this study were to evaluate the additive effect of a liver extract preparation and flavin adenine dinucleotide mixture and to reevaluate the correlation. 65 patients with chronic hepatitis C received intravenously 6 million units of interferon-beta and 2 mL of a liver extract preparation and flavin adenine dinucleotide mixture. The results of this study were compared with those of our previous study, on interferon-beta monotherapy in 91 patients with chronic hepatitis C. In addition, peripheral blood mononuclear cells were obtained before interferon-beta administration and cultured. Immunoglobulin concentrations in their supernatants were measured and the correlation with the interferon response was evaluated. The virological end-of-treatment or sustained response occurred in 49 of 58 cases (84.5%), and 16 of 58 cases (27.6%), respectively. Biochemical end-of-treatment or sustained responses occurred in 22 of 58 cases (37.9%), and 30 of 58 cases (51.7%), respectively. These response rates were higher than those reported in our previous study of interferon monotherapy. Monovariate analysis indicated that the use of the liver extract preparation and flavin adenine dinucleotide mixture was a significant predictor of the virological end-of-treatment response and the sustained biochemical response, but by multivariate analysis these relationships were not significant. Immunoglobulin production was not correlated with the virological and biochemical responses. This study indicated that combination therapy with intravenous interferon-beta and the liver extract preparation and flavin adenine dinucleotide mixture was more effective than intravenous interferon-beta monotherapy. However, no correlation between the interferon response and in vitro immunoglobulin production was observed.


Effect of simvastatin on transforming growth factor beta-1-induced myofibroblast differentiation and collagen production in nasal polyp-derived fibroblasts.
Statins are the most commonly prescribed drugs for the treatment of hypercholesterolemia. Statins exert not only lipid-lowering but also other cellular effects, including antifibrotic properties. The purpose of this study was to determine the effect of simvastatin on transforming growth factor (TGF)-beta-1-induced myofibroblast differentiation and collagen production in nasal polyp-derived fibroblasts (NPDFs) and to verify the mechanism of the effect of simvastatin in TGF-beta-1-induced myofibroblast differentiation in NPDFs. NPDFs were pretreated with simvastatin with or without mevalonate or Y-27643 for 2 hours before induction by TGF-beta-1. The expression of alpha-smooth muscle actin (SMA) and collagen type IV mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of alpha-SMA protein was determined by immunofluorescent cytochemical staining. Total soluble collagen production was analyzed by the SirCol collagen dye-binding assay (Biocolor, Belfast, U.K.). Phosphorylation of Smad 2/3 was evaluated by Western blot analysis. In TGF-beta-1-induced NPDFs, simvastatin significantly inhibited the expressions of α-SMA and collagen type IV mRNA and reduced alpha-SMA and collagen protein levels. Pretreatment with mevalonate reversed the effect of simvastatin. The expression of alpha-SMA mRNA and protein was significantly decreased by pretreatment with Y-27632. The TGF-beta-1-induced expression of pSmad 2/3 protein was notably decreased by pretreatment with simvastatin. We showed that simvastatin inhibits TGF-beta-1-induced myofibroblast differentiation (expression of alpha-SMA) and collagen production in NPDFs and Rho/Rock and TGF-β/Smad signaling is involved as an underlying mechanism. The results of our study suggest that simvastatin is a possible candidate for the suppression of nasal polyp formation.


Local newspapers, community partnerships, and health improvement projects: their roles in a comprehensive community initiative.
To understand local media's role in a community health initiative, a content analysis of 1,709 paragraphs from 173 news articles and editorials was undertaken. The articles were from three local newspapers, one in each of three communities. Analyses focused on article content combined with reflective personal interviews with local campaign directors. Results suggest that local campaign staff can be successful using commercial media to achieve objectives. Surprisingly, most coverage was not about projects with observable and easily identifiable benefits for local residents, but rather partnerships among influential residents engaged in decision-making about such projects. We conclude that the politics of resource distribution is more newsworthy to local journalists than tangible topics like access to health information, insurance coverage, and service provision.


The molecular sociology of the cell.
Proteomic studies have yielded detailed lists of the proteins present in a cell. Comparatively little is known, however, about how these proteins interact and are spatially arranged within the 'functional modules' of the cell: that is, the 'molecular sociology' of the cell. This gap is now being bridged by using emerging experimental techniques, such as mass spectrometry of complexes and single-particle cryo-electron microscopy, to complement traditional biochemical and biophysical methods. With the development of integrative computational methods to exploit the data obtained, such hybrid approaches will uncover the molecular architectures, and perhaps even atomic models, of many protein complexes. With these structures in hand, researchers will be poised to use cryo-electron tomography to view protein complexes in action within cells, providing unprecedented insights into protein-interaction networks.


Alterations in white matter microstructure are associated with goal-directed upper-limb movement segmentation in children born extremely preterm.
Altered white matter microstructure is commonly found in children born preterm (PT), especially those born at an extremely low gestational age (GA). These children also commonly show disturbed motor function. This study explores the relation between white matter alterations and upper-limb movement segmentation in 41 children born PT (19 girls), and 41 children born at term (18 girls) at 8 years. The PT group was subdivided into extremely PT (E-PT; GA = 25-27 weeks, N = 10), very PT (V-PT; GA = 28-32 weeks, N = 13), and moderately PT (M-PT; GA = 33-35 weeks, N = 18). Arm/hand preference (preferred/non-preferred) was determined through object interactions and the brain hemispheres were designated accordingly. White matter alterations were assessed using diffusion tensor imaging in nine areas, and movement segmentation of the body-parts head, shoulder, elbow, and wrist were registered during a unimanual goal-directed task. Increased movement segmentation was demonstrated consistently on the preferred side in the E-PT group compared with the term born group. Also compared with the term born peers, the E-PT group demonstrated reduced fractional anisotropy (FA) in the cerebral peduncle (targeting the corticospinal tract) in the hemisphere on the non-preferred side and in the splenium of corpus callosum. In contrast, in the anterior internal capsule on the preferred side, the E-PT group had increased FA. Lower FA in the cerebral peduncle, but higher FA in the anterior internal capsule, was associated with increased movement segmentation across body-parts in a contralateral manner. The results suggest that impaired development of sensorimotor tracts in E-PT children could explain a sub-optimal spatiotemporal organization of upper-limb movements. Hum Brain Mapp 38:5051-5068, 2017. © 2017 Wiley Periodicals, Inc.


The angiopoietin/Tie2 axis mediates malignant pleural effusion formation.
Angiopoietins and their receptor, Tie2, participate in angiogenesis, regulation of vascular permeability, and inflammation, all central to the pathogenesis of malignant pleural effusions (MPEs). In the present study, we aimed to examine the role of the angiopoietin/Tie2 axis in MPE pathogenesis. MPE was induced by intrapleural injection of murine adenocarcinoma cells in C57BL/6 mice. Animals were given twice-weekly intraperitoneal injections of 40 mg/kg MuTekdeltaFc or vehicle. MuTekdeltaFc is a soluble Tie2 (sTie2) receptor that binds murine angiopoietins thereby disrupting their interaction with Tie2 receptors expressed on tissues. Animals were killed on day 14. Angiopoietin/Tie2 axis blockade significantly reduced pleural fluid volume and pleural tumor foci. The mean +/- SEM pleural fluid volumes were 617 +/- 48 microl and 316 +/- 62 microl for the control and treated groups, respectively (P = .001), whereas the mean +/- SEM tumor foci were 7.3 +/- 1.0 and 3.0 +/- 0.52 for the control and treated groups, respectively (P = .001). In addition, tumor-associated cachexia, tumor angiogenesis, pleural vascular permeability, recruitment of inflammatory cells to the pleural cavity, and local elaboration of vascular endothelial growth factor and interleukin 6 were also downregulated, and tumor cell apoptosis was induced in animals treated with the inhibitor. Our results indicate that the angiopoietin/Tie2 axis is an important component of MPE pathogenesis. Further studies are required to determine whether therapeutic interventions targeting this pathway could be beneficial for patients with MPE.


Evaluating the Ability of Economic Models of Diabetes to Simulate New Cardiovascular Outcomes Trials: A Report on the Ninth Mount Hood Diabetes Challenge.
The cardiovascular outcomes challenge examined the predictive accuracy of 10 diabetes models in estimating hard outcomes in 2 recent cardiovascular outcomes trials (CVOTs) and whether recalibration can be used to improve replication. Participating groups were asked to reproduce the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program. Calibration was performed and additional analyses assessed model ability to replicate absolute event rates, hazard ratios (HRs), and the generalizability of calibration across CVOTs within a drug class. Ten groups submitted results. Models underestimated treatment effects (ie, HRs) using uncalibrated models for both trials. Calibration to the placebo arm of EMPA-REG OUTCOME greatly improved the prediction of event rates in the placebo, but less so in the active comparator arm. Calibrating to both arms of EMPA-REG OUTCOME individually enabled replication of the observed outcomes. Using EMPA-REG OUTCOME-calibrated models to predict CANVAS Program outcomes was an improvement over uncalibrated models but failed to capture treatment effects adequately. Applying canagliflozin HRs directly provided the best fit. The Ninth Mount Hood Diabetes Challenge demonstrated that commonly used risk equations were generally unable to capture recent CVOT treatment effects but that calibration of the risk equations can improve predictive accuracy. Although calibration serves as a practical approach to improve predictive accuracy for CVOT outcomes, it does not extrapolate generally to other settings, time horizons, and comparators. New methods and/or new risk equations for capturing these CV benefits are needed.


Effect of recombinant human growth hormone on cellular sodium metabolism.
1. The effect of treatment with recombinant human growth hormone on urinary sodium excretion, total body water, the renin-angiotensin system and erythrocyte sodium metabolism was investigated in 16 adults with growth hormone deficiency. 2. Total body water was determined by isotopic dilution, and erythrocyte electrolyte contents were analysed using flame photometry. The rate of sodium influx and the efflux rate constant of sodium were calculated from values of 22Na in erythrocytes in vitro. 3. One week of treatment with recombinant human growth hormone caused a decrease in urinary sodium excretion in 9/10 patients and an increase in erythrocyte sodium content. Total body water, plasma renin activity, angiotensin II concentration and transmembrane sodium transport were unaltered. 4. Six months of treatment with recombinant human growth hormone caused significant increases in total body water, erythrocyte sodium content and sodium transmembrane influx. Plasma renin activity tended to increase, whereas blood pressure and serum sodium and potassium concentrations remained unchanged. After 6 months on recombinant human growth hormone total body water showed a significant negative correlation with plasma renin activity. 5. The enhanced erythrocyte sodium transport, if this reflects what happens in the renal tubular cell, combined with a decrease in urinary sodium excretion, during treatment with recombinant human growth hormone could indicate an increase in tubular sodium reabsorption induced by the hormone. An increased plasma renin activity associated with the lack of blood pressure rise would reinforce sodium and water retention.


Ocean warming-acidification synergism undermines dissolved organic matter assembly.
Understanding the influence of synergisms on natural processes is a critical step toward determining the full-extent of anthropogenic stressors. As carbon emissions continue unabated, two major stressors--warming and acidification--threaten marine systems on several scales. Here, we report that a moderate temperature increase (from 30°C to 32°C) is sufficient to slow--even hinder--the ability of dissolved organic matter, a major carbon pool, to self-assemble to form marine microgels, which contribute to the particulate organic matter pool. Moreover, acidification lowers the temperature threshold at which we observe our results. These findings carry implications for the marine carbon cycle, as self-assembled marine microgels generate an estimated global seawater budget of ~1016 g C. We used laser scattering spectroscopy to test the influence of temperature and pH on spontaneous marine gel assembly. The results of independent experiments revealed that at a particular point, both pH and temperature block microgel formation (32°C, pH 8.2), and disperse existing gels (35°C). We then tested the hypothesis that temperature and pH have a synergistic influence on marine gel dispersion. We found that the dispersion temperature decreases concurrently with pH: from 32°C at pH 8.2, to 28°C at pH 7.5. If our laboratory observations can be extrapolated to complex marine environments, our results suggest that a warming-acidification synergism can decrease carbon and nutrient fluxes, disturbing marine trophic and trace element cycles, at rates faster than projected.