Functional links between the fusion peptide-proximal polar segment and membrane-proximal region of human immunodeficiency virus gp41 in distinct phases of membrane fusion.
The binding of CD4 and chemokine receptors to the gp120 attachment glycoprotein of human immunodeficiency virus triggers refolding of the associated gp41 fusion glycoprotein into a trimer of hairpins with a 6-helix bundle (6HB) core. These events lead to membrane fusion and viral entry. Here, we examined the functions of the fusion peptide-proximal polar segment and membrane-proximal Trp-rich region (MPR), which are exterior to the 6HB. Alanine substitution of Trp(666), Trp(672), Phe(673), and Ile(675) in the MPR reduced entry by up to 120-fold without affecting gp120-gp41 association or cell-cell fusion. The L537A polar segment mutation led to the loss of gp120 from the gp120-gp41 complex, reduced entry by approximately 10-fold, but did not affect cell-cell fusion. Simultaneous Ala substitution of Leu(537) with Trp(666), Trp(672), Phe(673), or Ile(675) abolished entry with 50-80% reductions in cell-cell fusion. gp120-gp41 complexes of fusion-defective double mutants were resistant to soluble CD4-induced shedding of gp120, suggesting that their ability to undergo receptor-induced conformational changes was compromised. Consistent with this idea, a representative mutation, L537A/W666A, led to an approximately 80% reduction in lipophilic fluorescent dye transfer between gp120-gp41-expressing cells and receptor-expressing targets, indicating a block prior to the lipid-mixing phase. The L537A/W666A double mutation increased the chymotrypsin sensitivity of the polar segment in a trimer of hairpins model, comprising the 6HB core, the polar segment, and MPR linked N-terminally to maltose-binding protein. The data indicate that the polar segment and MPR of gp41 act synergistically in forming a fusion-competent gp120-gp41 complex and in stabilizing the membrane-interactive end of the trimer of hairpins.


Association Between Giving Birth During the Early Coronavirus Disease 2019 (COVID-19) Pandemic and Serious Maternal Morbidity.
To evaluate whether delivering during the early the coronavirus disease 2019 (COVID-19) pandemic was associated with increased risk of maternal death or serious morbidity from common obstetric complications compared with a historical control period. This was a multicenter retrospective cohort study with manual medical-record abstraction performed by centrally trained and certified research personnel at 17 U.S. hospitals. Individuals who gave birth on randomly selected dates in 2019 (before the pandemic) and 2020 (during the pandemic) were compared. Hospital, health care system, and community risk-mitigation strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in response to the early COVID-19 pandemic are described. The primary outcome was a composite of maternal death or serious morbidity from common obstetric complications, including hypertensive disorders of pregnancy (eclampsia, end organ dysfunction, or need for acute antihypertensive therapy), postpartum hemorrhage (operative intervention or receipt of 4 or more units blood products), and infections other than SARS-CoV-2 (sepsis, pelvic abscess, prolonged intravenous antibiotics, bacteremia, deep surgical site infection). The major secondary outcome was cesarean birth. Overall, 12,133 patients giving birth during and 9,709 before the pandemic were included. Hospital, health care system, and community SARS-CoV-2 mitigation strategies were employed at all sites for a portion of 2020, with a peak in modifications from March to June 2020. Of patients delivering during the pandemic, 3% had a positive SARS-CoV-2 test result during pregnancy through 42 days postpartum. Giving birth during the pandemic was not associated with a change in the frequency of the primary composite outcome (9.3% vs 8.9%, adjusted relative risk [aRR] 1.02, 95% CI 0.93-1.11) or cesarean birth (32.4% vs 31.3%, aRR 1.02, 95% CI 0.97-1.07). No maternal deaths were observed. Despite substantial hospital, health care, and community modifications, giving birth during the early COVID-19 pandemic was not associated with higher rates of serious maternal morbidity from common obstetric complications. ClinicalTrials.gov, NCT04519502.


Variance analysis as a tool to predict the mechanism underlying synaptic plasticity.
The strength of synaptic transmission onto a neuron depends on the number of functional vesicle release sites (N), the probability of vesicle release (Pr), and the quantal size (Q). Statistical tools based on the quantal model of synaptic transmission can be used to acquire information on which of these parameters is the source of plasticity. However, quantal analysis depends on assumptions that may not be met at central synapses. We examined the merit of quantal analysis to extract the mechanisms underlying synaptic plasticity by applying binomial statistics on the variance in amplitude of postsynaptic currents evoked at Schaffer collateral-CA1 (Sc-CA1) synapses in mouse hippocampal slices. We extend this analysis by combining the conventional inverse square of the coefficient of variation (1/CV2) with the variance-to-mean ratio (VMR). This method can be used to assess the relative, but not absolute, contribution of N, Pr and Q to synaptic plasticity. The changes in 1/CV2 and VMR values correctly reflect experimental modifications of N, Pr and Q at Sc-CA1 synapses. While the 1/CV2 depends on N and Pr, but is independent of Q, the VMR is dependent on Pr and Q, but not on N. Combining both allows for a rapid assessment of the mechanism underlying synaptic plasticity without the need for additional electrophysiological experiments. Combining the 1/CV2 with the VMR allows for a reliable prediction of the relative contribution of changes in N, Pr and Q to synaptic plasticity.


Different agglomeration properties of PC61BM and PC71BM in photovoltaic inks - a spin-echo SANS study.
Fullerene derivatives are used in a wide range of applications including as electron acceptors in solution-processable organic photovoltaics. We report agglomeration of fullerene derivatives in optically opaque solutions of PC61BM and PC71BM, with concentrations ranging from 30 mg mL-1 up to 90 mg mL-1, in different solvents with relevance to organic photovoltaics, using a novel neutron scattering technique, Spin-Echo Small Angle Neutron Scattering (SESANS). From SESANS, agglomerates with correlation lengths larger than 1 μm are found in some PC61BM solutions, in contrast no agglomerates are seen in PC71BM solutions. These results clearly show that PC71BM is fundamentally more soluble than PC61BM in the solvents commonly used in photovoltaic inks and corroborating similar observations previously achieved using other experimental techniques. Computer models are presented to study the energetics of solution and agglomeration of both species, ascribing the difference to a kinetic effect probably related to the larger anisotropy of PC71BM. Also, this work showcases the power of SESANS to probe agglomerates of fullerene derivatives in completely opaque solutions for agglomerates of the order of one to several microns.


Neutrophil elastase inhibitor improves postoperative clinical courses after thoracic esophagectomy.
Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase (NE), and is effective in acute lung injury associated with systemic inflammatory response syndrome (SIRS). The effect of Sivelestat for postoperative clinical courses after transthoracic esophagectomy was investigated. Consecutive patients with carcinoma of the thoracic esophagus who underwent transthoracic esophagectomy between 2003 and 2004 were assigned to the Sivelestat-treated group (n = 18), and those between 1998 and 2003 were assigned to the control group (n = 25). The morbidity rate, duration of postoperative SIRS, mechanical ventilation, and intensive care unit (ICU) stay, and the sum of the sequential organ failure assessment scores at all time points after the operation were compared. Serum NE activities and serum concentrations of TNF-alpha, IL-1beta, IL-6, and high mobility group box chromosomal protein 1 (HMGB1) were measured. Postoperative complications developed in three patients in the control group, and one in the Sivelestat-treated group. The durations of SIRS, mechanical ventilation, and ICU stay were significantly shorter in the Sivelestat-treated group. Even in patients without complications, the durations of mechanical ventilation, and ICU stay were also significantly shorter, and the arterial oxygen pressure/fraction of inspired oxygen ratio at postoperative day 1 was significantly higher in the Sivelestat-treated group. Serum NE activities and serum concentrations of IL-1beta, IL-6, and HMGB1 were significantly suppressed in the Sivelestat-treated group. Postoperative Sivelestat treatment after transthoracic esophagectomy improves the condition of SIRS and postoperative clinical courses, even in patients without complications.


Magnetization transfer ratio may be a surrogate of spongiform change in human prion diseases.
Human prion diseases are fatal neurodegenerative disorders caused by misfolding of the prion protein. There are no useful biomarkers of disease progression. Cerebral cortex spongiform change, one of the classical pathological features of prion disease, resolves in prion-infected transgenic mice following prion protein gene knockout. We investigated the cross-sectional, longitudinal and post-mortem cerebral magnetization transfer ratios as a surrogate for prion disease pathology. Twenty-three prion disease patients with various prion protein gene mutations and 16 controls underwent magnetization transfer ratio and conventional magnetic resonance imaging at 1.5 T. For each subject, whole-brain, white and grey matter magnetization transfer ratio histogram mean, peak height, peak location, and magnetization transfer ratio at 25th, 50th and 75th percentile were computed and correlated with several cognitive, functional and neuropsychological scales. Highly significant associations were found between whole brain magnetization transfer ratio and prion disease (P < 0.01). Additionally, highly significant correlations were found between magnetization transfer ratio histogram parameters and clinical, functional and neuropsychological scores (P < 0.01). Longitudinally, decline in the Clinician's Dementia Rating scale was correlated with decline in magnetization transfer ratio. To investigate the histological correlates of magnetization transfer ratio, formalin-fixed cerebral and cerebellar hemispheres from 19 patients and six controls underwent magnetization transfer ratio imaging at 1.5 T, with mean magnetization transfer ratio calculated from six regions of interest, and findings were followed-up in six variant Creutzfeldt-Jakob disease cases with 9.4 T high-resolution magnetization transfer imaging on frontal cortex blocks, with semi-quantitative histopathological scoring of spongiosis, astrocytosis and prion protein deposition. Post-mortem magnetization transfer ratios was significantly lower in patients than controls in multiple cortical and subcortical regions, but not frontal white matter. Measurements (9.4 T) revealed a significant and specific negative correlation between cortical magnetization transfer ratios and spongiosis (P = 0.02), but not prion protein deposition or gliosis. The magnetic resonance imaging measurement of magnetization transfer ratios may be an in vivo surrogate for spongiform change and has potential utility as a therapeutic biomarker in human prion disease.


A new electron-methanol molecule pseudopotential and its application for the solvated electron in methanol.
A new electron-methanol molecule pseudopotential is developed and tested in the present paper. The formal development of the potential is based on quantum mechanical calculations on the electron-methanol molecule model in the static exchange approximation. The computational model includes a steep confining potential that keeps the otherwise unbound excess electron in the vicinity of the methanol molecule. Using the Phillips-Kleinman theorem we introduce a smooth pseudowave function of the excess electron with the exact eigenenergy and correct asymptotic behavior. The nonlocal potential energy operator of the model Hamiltonian is then replaced to a local potential that reproduces the ground-state properties of the excess electron satisfactorily. The pseudopotential is then optimized in an analytically simple functional form to fit this approximate local potential in conjunction with the point charges and the geometry of a classical, all-site methanol-methanol interaction potential. Of the adjustable parameters, the parameters for the carbon and the methyl hydrogen atoms are optimized, while those for the oxygen and the hydroxyl hydrogen are taken from a previous electron-water molecule pseudopotential. A polarization term is added to the potential a posteriori. The polarization parameters are chosen to reproduce the experimental position of the optical absorption spectrum of an excess electron in mixed quantum-classical molecular dynamics simulations. The energetic, structural and spectroscopic properties of the solvated electron in a methanol bath are simulated at 300 K and compared with previous solvated electron simulations and available experimental data.


Altered intra-nuclear organisation of heterochromatin and genes in ICF syndrome.
The ICF syndrome is a rare autosomal recessive disorder, the most common symptoms of which are immunodeficiency, facial anomalies and cytogenetic defects involving decondensation and instability of chromosome 1, 9 and 16 centromeric regions. ICF is also characterised by significant hypomethylation of the classical satellite DNA, the major constituent of the juxtacentromeric heterochromatin. Here we report the first attempt at analysing some of the defining genetic and epigenetic changes of this syndrome from a nuclear architecture perspective. In particular, we have compared in ICF (Type 1 and Type 2) and controls the large-scale organisation of chromosome 1 and 16 juxtacentromeric heterochromatic regions, their intra-nuclear positioning, and co-localisation with five specific genes (BTG2, CNN3, ID3, RGS1, F13A1), on which we have concurrently conducted expression and methylation analysis. Our investigations, carried out by a combination of molecular and cytological techniques, demonstrate the existence of specific and quantifiable differences in the genomic and nuclear organisation of the juxtacentromeric heterochromatin in ICF. DNA hypomethylation, previously reported to correlate with the decondensation of centromeric regions in metaphase described in these patients, appears also to correlate with the heterochromatin spatial configuration in interphase. Finally, our findings on the relative positioning of hypomethylated satellite sequences and abnormally expressed genes suggest a connection between disruption of long-range gene-heterochromatin associations and some of the changes in gene expression in ICF. Beyond its relevance to the ICF syndrome, by addressing fundamental principles of chromosome functional organisation within the cell nucleus, this work aims to contribute to the current debate on the epigenetic impact of nuclear architecture in development and disease.


Use of transabdominal ultrasound-guided transjugular portal vein puncture on radiation dose in transjugular intrahepatic portosystemic shunt formation.
Transjugular intrahepatic portosystemic shunt (TIPS) creation is used to treat portal hypertension complications. Often the most challenging and time-consuming step in the procedure is the portal vein (PV) puncture. TIPS procedures are associated with prolonged fluoroscopy time and high patient radiation exposures. We measured the impact of transabdominal ultrasound guidance for PV puncture on duration of fluoroscopy time and dose. We retrospectively analyzed the radiation dose for all TIPS performed over a four-year period with transabdominal ultrasound guidance for PV puncture (n=212, with 210 performed successfully and data available for 206); fluoroscopy time, dose area product (DAP) and skin dose were recorded. Mean fluoroscopy time was 12 min 9 s (SD, ±14 min 38 s), mean DAP was 40.3±73.1 Gy·cm2, and mean skin dose was 404.3±464.8 mGy. Our results demonstrate that ultrasound-guided PV puncture results in low fluoroscopy times and radiation doses, which are markedly lower than the only published dose reference levels.


Chinese older adults' Internet use for health information.
Technological advancement benefits Internet users with the convenience of social connection and information search. This study aimed at investigating the predictors of Internet use to search for online health information among Chinese older adults. The Technology Acceptance Model (TAM) was applied to examine the predictiveness of perceived ease of use, perceived usefulness, and attitudes toward Internet use on behavioral intention to search for health information online. Ninety-eight Chinese older adults were recruited from an academic institute for older people and community centers. Frequency of Internet use and physical and psychological health were also assessed. Results showed that perceived ease of use and attitudes significantly predicted behavioral intention of Internet use. The potential influences of traditional Chinese values and beliefs in health were also discussed.


IFN-I inducible miR-3614-5p targets ADAR1 isoforms and fine tunes innate immune activation.
Regulation of innate immune responses is essential for maintenance of immune homeostasis and development of an appropriate immunity against microbial infection. We show here that miR-3614-5p, product of the TRIM25 host gene, is induced by type I interferon (IFN-I) in several human non-immune and immune cell types, in particular in primary myeloid cells. Studies in HeLa cells showed that miR-3614-5p represses both p110 and p150 ADAR1 and reduces constitutive and IFN-induced A-to-I RNA editing. In line with this, activation of innate sensors and expression of IFN-β and the pro-inflammatory IL-6 are promoted. MiR-3614-5p directly targets ADAR1 transcripts by binding to one specific site in the 3'UTR. Moreover, we could show that endogenous miR-3614-5p is associated with Ago2 and targets ADAR1 in IFN-stimulated cells. Overall, we propose that, by reducing ADAR1, IFN-I-induced miR-3614-5p contributes to lowering the activation threshold of innate sensors. Our findings provide new insights into the role of miR-3614-5p, placing it as a potential fine tuner of dsRNA metabolism, cell homeostasis and innate immunity.


Salivary proteomics in bisphosphonate-related osteonecrosis of the jaw.
The objective of this study was to identify differentially expressed salivary proteins in bisphosphonate-related osteonecrosis of the jaw (BRONJ) patients that could serve as biomarkers for BRONJ diagnosis. Whole saliva obtained from 20 BRONJ patients and 20 controls were pooled within groups. The samples were analyzed using iTRAQ-labeled two-dimensional liquid chromatography-tandem mass spectrometry. Overall, 1340 proteins were identified. Of these, biomarker candidates were selected based on P-value (<0.001), changes in protein expression (≥1.5-fold increase or decrease), and unique peptides identified (≥2). Three comparisons made between BRONJ and control patients identified 200 proteins to be differentially expressed in BRONJ patients. A majority of these proteins were predicted to have a role in drug metabolism and immunological and dermatological diseases. Of all the differentially expressed proteins, we selected metalloproteinase-9 and desmoplakin for further validation. Immunoassays confirmed increased expression of metalloproteinase-9 in individual saliva (P = 0.048) and serum samples (P = 0.05) of BRONJ patients. Desmoplakin was undetectable in saliva. However, desmoplakin levels tended to be lower in BRONJ serum than controls (P = 0.157). Multiple pathological reactions are involved in BRONJ development. One or more proteins identified by this study may prove to be useful biomarkers for BRONJ diagnosis. The role of metalloproteinase-9 and desmoplakin in BRONJ requires further investigation.


Sleep duration and depressive symptoms: a gene-environment interaction.
We used quantitative genetic models to assess whether sleep duration modifies genetic and environmental influences on depressive symptoms. Participants were 1,788 adult twins from 894 same-sex twin pairs (192 male and 412 female monozygotic [MZ] pairs, and 81 male and 209 female dizygotic [DZ] pairs] from the University of Washington Twin Registry. Participants self-reported habitual sleep duration and depressive symptoms. Data were analyzed using quantitative genetic interaction models, which allowed the magnitude of additive genetic, shared environmental, and non-shared environmental influences on depressive symptoms to vary with sleep duration. Within MZ twin pairs, the twin who reported longer sleep duration reported fewer depressive symptoms (ec = -0.17, SE = 0.06, P < 0.05). There was a significant gene × sleep duration interaction effect on depressive symptoms (a'c = 0.23, SE = 0.08, P < 0.05), with the interaction occurring on genetic influences that are common to both sleep duration and depressive symptoms. Among individuals with sleep duration within the normal range (7-8.9 h/night), the total heritability (h2) of depressive symptoms was approximately 27%. However, among individuals with sleep duration within the low (< 7 h/night) or high (≥ 9 h/night) range, increased genetic influence on depressive symptoms was observed, particularly at sleep duration extremes (5 h/night: h2 = 53%; 10 h/night: h2 = 49%). Genetic contributions to depressive symptoms increase at both short and long sleep durations.


Women's freedom of movement and participation in psychosocial support groups: qualitative study in northern India.
Depression, the world's leading cause of disability, disproportionately affects women. Women in India, one of the most gender unequal countries worldwide, face systemic gender disadvantage that significantly increases the risk of common mental disorders. This study's objective was to examine the factors influencing women's participation in psychosocial support groups, within an approach where community members work together to collectively strengthen their community's mental health. This community-based qualitative study was conducted from May to July 2016, across three peri-urban sites in Dehradun district, Uttarakhand, Northern India. Set within an NGO-run mental health project, data were collected through focus group discussions with individuals involved in psychosocial support groups including women with psychosocial disabilities as well as caregivers (N = 10, representing 59 women), and key informant interviews (N = 8) with community members and mental health professionals. Data were analyzed using a thematic analysis approach. The principal barrier to participating in psychosocial support groups was restrictions on women's freedom of movement. Women in the community are not normally permitted to leave home, unless going to market or work, making it difficult for women to leave their home to participate in the groups. The restrictions emanated from the overall community's attitude toward gender relations, the women's own internalized gender expectations, and most significantly, the decision-making power of husbands and mothers-in-law. Other factors including employment and education shaped women's ability to participate in psychosocial support groups; however, the role of these additional factors must be understood in connection to a gender order limiting women's freedom of movement. Mental health access and gender inequality are inseparable in the context of Northern India, and women's mental health cannot be addressed without first addressing underlying gender relations. Community-based mental health programs are an effective tool and can be used to strengthen communities collectively; however, attention towards the gender constraints that restrict women's freedom of movement and their ability to access care is required. To our knowledge, this is the first study to clearly document and analyze the connection between access to community mental health services in South Asia and women's freedom of movement.


The Benefit of Combining Neuronal Feedback and Feed-Forward Control for Robustness in Step Down Perturbations of Simulated Human Walking Depends on the Muscle Function.
It is often assumed that the spinal control of human locomotion combines feed-forward central pattern generation with sensory feedback via muscle reflexes. However, the actual contribution of each component to the generation and stabilization of gait is not well understood, as direct experimental evidence for either is difficult to obtain. We here investigate the relative contribution of the two components to gait stability in a simulation model of human walking. Specifically, we hypothesize that a simple linear combination of feedback and feed-forward control at the level of the spinal cord improves the reaction to unexpected step down perturbations. In previous work, we found preliminary evidence supporting this hypothesis when studying a very reduced model of rebounding behaviors. In the present work, we investigate if the evidence extends to a more realistic model of human walking. We revisit a model that has previously been published and relies on spinal feedback control to generate walking. We extend the control of this model with a feed-forward muscle activation pattern. The feed-forward pattern is recorded from the unperturbed feedback control output. We find that the improvement in the robustness of the walking model with respect to step down perturbations depends on the ratio between the two strategies and on the muscle to which they are applied. The results suggest that combining feed-forward and feedback control is not guaranteed to improve locomotion, as the beneficial effects are dependent on the muscle and its function during walking.


Nucleation of cracks in a brittle sheet.
We use molecular dynamics to study the nucleation of cracks in a two-dimensional material without pre-existing cracks. We study models with zero and nonzero shear moduli. In both situations, the time required for crack formation obeys an Arrhenius law, from which the energy barrier and prefactor are extracted for different system sizes. For large systems, the characteristic time of rupture is found to decrease with system size, in agreement with classical Weibull theory. In the case of zero shear modulus, the energy opposing rupture is identified with the breakage of a single atomic bond. In the case of nonzero shear modulus, thermally activated fracture can only be studied within a reasonable time at very high strains. In this case, the energy barrier is much higher compared to the zero shear modulus case. This barrier is understood within adiabatic simulations.


Global efforts in structural genomics.
A worldwide initiative in structural genomics aims to capitalize on the recent successes of the genome projects. Substantial new investments in structural genomics in the past 2 years indicate the high level of support for these international efforts. Already, enormous progress has been made on high-throughput methodologies and technologies that will speed up macromolecular structure determinations. Recent international meetings have resulted in the formation of an International Structural Genomics Organization to formulate policy and foster cooperation between the public and private efforts.


Three-dimensional printing of drug-eluting implants: preparation of an antimicrobial polylactide feedstock material.
The aim of the present work was to investigate the potential of three-dimensional (3D) printing as a manufacturing method for products intended for personalized treatments by exploring the production of novel polylactide-based feedstock materials for 3D printing purposes. Nitrofurantoin (NF) and hydroxyapatite (HA) were successfully mixed and extruded with up to 30% drug load with and without addition of 5% HA in polylactide strands, which were subsequently 3D-printed into model disc geometries (10 × 2 mm). X-ray powder diffraction analysis showed that NF maintained its anhydrate solid form during the processing. Release of NF from the disks was dependent on the drug loading in a concentration-dependent manner as a higher level of released drug was observed from disks with higher drug loads. Disks with 30% drug loading were able to prevent surface-associated and planktonic growth of Staphylococcus aureus over a period of 7 days. At 10% drug loading, the disks did not inhibit planktonic growth, but still inhibited surface-associated growth. Elemental analysis indicated the presence of microdomains of solid drug supporting the observed slow and partial drug release. This work demonstrates the potential of custom-made, drug-loaded feedstock materials for 3D printing of pharmaceutical products for controlled release.


Binding of α,α-disubstituted amino acids to arginase suggests new avenues for inhibitor design.
Arginase is a binuclear manganese metalloenzyme that hydrolyzes L-arginine to form L-ornithine and urea, and aberrant arginase activity is implicated in various diseases such as erectile dysfunction, asthma, atherosclerosis, and cerebral malaria. Accordingly, arginase inhibitors may be therapeutically useful. Continuing our efforts to expand the chemical space of arginase inhibitor design and inspired by the binding of 2-(difluoromethyl)-L-ornithine to human arginase I, we now report the first study of the binding of α,α-disubstituted amino acids to arginase. Specifically, we report the design, synthesis, and assay of racemic 2-amino-6-borono-2-methylhexanoic acid and racemic 2-amino-6-borono-2-(difluoromethyl)hexanoic acid. X-ray crystal structures of human arginase I and Plasmodium falciparum arginase complexed with these inhibitors reveal the exclusive binding of the L-stereoisomer; the additional α-substituent of each inhibitor is readily accommodated and makes new intermolecular interactions in the outer active site of each enzyme. Therefore, this work highlights a new region of the protein surface that can be targeted for additional affinity interactions, as well as the first comparative structural insights on inhibitor discrimination between a human and a parasitic arginase.


Critical role of the matricellular protein SPARC in mediating erythroid progenitor cell development in zebrafish.
Sparc (osteonectin) is a multifunctional matricellular glycoprotein expressed by many differentiated cells. Members of this family mediate cell-matrix interactions rather than acting as structural components of the extracellular matrix (ECM); therefore, they can influence many remodelling events, including haematopoiesis. We have investigated the role of sparc in embryonic haematopoiesis using a morpholino antisense oligonucleotide-based knockdown approach. Knockdown of sparc function resulted in specific erythroid progenitor cell differentiation defects that were highlighted by changes in gene expression and morphology, which could be rescued by injection of sparc mRNA. Furthermore, a comparison of blood phenotypes of sparc and fgfs knockdowns with similar defects and the sparc rescue of the fgf21 blood phenotype places sparc downstream of fgf21 in the genetic network regulating haematopoiesis in zebrafish. These results establish a role for an ECM protein (Sparc) as an important regulator of embryonic haematopoiesis during early development in zebrafish.


Effects of ultraviolet irradiation on the physicochemical and functional properties of gum arabic.
The impact of ultraviolet (UV) irradiation on the physicochemical and functional properties of gum arabic was investigated. Gum arabic samples were exposed to UV irradiation for 30, 60, 90, and 120 min; gum arabic was also treated with formaldehyde for comparison. Molecular weight analysis using gel permeation chromatography indicated that no significant changes occurred on the molecular structure on the samples exposed to UV irradiation. Free amino group analysis indicated that mild UV irradiation (30 min) could induce cross-linking on gum arabic; this result was comparable with that of samples treated with formaldehyde. However, viscosity break down was observed for samples exposed to UV irradiation for longer times (90 and 120 min). All irradiated and formaldehyde-treated samples exhibited better emulsification properties than unirradiated samples. These results indicate that UV-irradiated gum arabic could be a better emulsifier than the native (unmodified) gum arabic and could be exploited commercially.


Modulation of the gut microbiota with antibiotic treatment suppresses whole body urea production in neonatal pigs.
We examined whether changes in the gut microbiota induced by clinically relevant interventions would impact the bioavailability of dietary amino acids in neonates. We tested the hypothesis that modulation of the gut microbiota in neonatal pigs receiving no treatment (control), intravenously administered antibiotics, or probiotics affects whole body nitrogen and amino acid turnover. We quantified whole body urea kinetics, threonine fluxes, and threonine disposal into protein, oxidation, and tissue protein synthesis with stable isotope techniques. Compared with controls, antibiotics reduced the number and diversity of bacterial species in the distal small intestine (SI) and colon. Antibiotics decreased plasma urea concentrations via decreased urea synthesis. Antibiotics elevated threonine plasma concentrations and turnover, as well as whole body protein synthesis and proteolysis. Antibiotics decreased protein synthesis rate in the proximal SI and liver but did not affect the distal SI, colon, or muscle. Probiotics induced a bifidogenic microbiota and decreased plasma urea concentrations but did not affect whole body threonine or protein metabolism. Probiotics decreased protein synthesis in the proximal SI but not in other tissues. In conclusion, modulation of the gut microbiota by antibiotics and probiotics reduced hepatic ureagenesis and intestinal protein synthesis, but neither altered whole body net threonine balance. These findings suggest that changes in amino acid and nitrogen metabolism resulting from antibiotic- or probiotic-induced shifts in the microbiota are localized to the gut and liver and have limited impact on whole body growth and anabolism in neonatal piglets.


FHL2 regulates the resolution of tissue damage in chronic inflammatory arthritis.
We analysed the role of the adaptor molecule four-and-a-half Lin11, Isl-1 & Mec-3 (LIM) domain protein 2 (FHL2) in the activation of fibroblast-like synoviocytes in human rheumatoid arthritis (RA) and tumour necrosis factor α (TNFα)-dependent animal models of the disease. Synovial tissues of patients with RA and osteoarthritis (OA) as well as hind paw sections from arthritic human TNFα transgenic (hTNFtg) mice and synovial fibroblasts from these were analysed. The effects of cytokines on the expression of FHL2 and disease-relevant matrixmetalloproteases (MMPs) were determined. Analyses of human tissue specimens from patients treated with anti-TNFα as well as anti-TNFα treatment of hTNFtg mice were performed to substantiate the TNFα effects on FHL2 levels. FHL2(-/-) mice and hTNFtg mice (with constitutive or inducible transgene expression) were crossbred to generate TNFα overexpressing FHL2-deficient animals. Signalling pathways were analysed in cells from these mice and in human cells after knock down of FHL2 by western blot. FHL2 levels were higher in RA than in OA and in hTNFtg than in wild-type mice. Surprisingly, while transforming growth factor (TGF)β-induced FHL2 expression, TNFα suppressed FHL2. In vivo, anti-TNFα treatment led to higher FHL2 levels both in RA patients and hTNFtg mice. The loss of FHL2 increased joint destruction in hTNFtg mice, which was accompanied by elevated MMP-13. In vitro, TNFα-mediated MMP-13 was significantly higher in FHL2(-/-) cells and after knock down of FHL2, which was caused by prolonged p38 MAPK activation. These data suggest that FHL2 serves as a protective factor and that, rather than promoting the pathology, the upregulation of FHL2 in RA occurs in frame of a regenerative attempt.


belladonna/(Ihx2) is required for neural patterning and midline axon guidance in the zebrafish forebrain.
Some of the earliest axon pathways to form in the vertebrate forebrain are established as commissural and retinal axons cross the midline of the diencephalon and telencephalon. To better understand axon guidance in the forebrain, we characterized the zebrafish belladonna (bel) mutation, which disrupts commissural and retinal axon guidance in the forebrain. Using a positional cloning strategy, we determined that the bel locus encodes zebrafish Lhx2, a lim-homeodomain transcription factor expressed in the brain, eye and fin buds. We show that bel(Ihx2) function is required for patterning in the ventral forebrain and eye, and that loss of bel function leads to alterations in regulatory gene expression, perturbations in axon guidance factors, and the absence of an optic chiasm and forebrain commissures. Our analysis reveals new roles for Ihx2 in midline axon guidance, forebrain patterning and eye morphogenesis.


Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice.
Secreted factors FGF8 and WNT1 are essential either for the inductive activity of the isthmus organizer or for the regionalization of the midbrain-hindbrain boundary (MHB). However, transcriptional regulation of these secreted factors during development remains to be elucidated. Here we show that the LIM homeobox gene Lmx1b is expressed in the anterior embryo as early as E7.5 and its expression becomes progressively restricted to the isthmus at E9.0. Analysis of gene expression in the MHB of the mutant embryos showed that many genes were lost by E9.5. In the MHB of Lmx1b-/- embryos, the expression of Fgf8, which normally occurs at the 4-somite stage, was completely absent, whereas Wnt1 was downregulated before the 4-somite stage. Moreover, transcription factors En1 and Pax2 were also downregulated prior to the 4-somite stage, whereas Gbx2 downregulation occurred at the 4-somite stage. By contrast, Otx2 and Pax6 expression was not affected in Lmx1b-/- embryos. The requirement of specific Lmx1b expression in the MHB was further confirmed by Wnt1-Cre-mediated region-specific conditional knockout of Lmx1b. As a result of these molecular defects, the development of the tectum and cerebellum was severely impaired in Lmx1b-/- mice. Taken together, our results indicate that Lmx1b plays an essential role in the development of the tectum and cerebellum by regulating expression of Fgf8, Wnt1 and several isthmus-related transcription factors in the MHB, and is a crucial component of a cross-regulatory network required for the induction activity of the isthmic organizer in the MHB.


The all-fiber cladding-pumped Yb-doped gain-switched laser.
Gain-switching is an alternative pulsing technique of fiber lasers, which is power scalable and has a low complexity. From a linear stability analysis of rate equations the relaxation oscillation period is derived and from it, the pulse duration is defined. Good agreement between the measured pulse duration and the theoretical prediction is found over a wide range of parameters. In particular we investigate the influence of an often present length of passive fiber in the cavity and show that it introduces a finite minimum in the achievable pulse duration. This minimum pulse duration is shown to occur at longer active fibers length with increased passive length of fiber in the cavity. The peak power is observed to depend linearly on the absorbed pump power and be independent of the passive fiber length. Given these conclusions, the pulse energy, duration, and peak power can be estimated with good precision.


Temperature-sensitive beta-lactam-tolerant mutants of Escherichia coli.
Seven temperature-sensitive penicillin-tolerant mutants of Escherichia coli strain LD5 (thi lysA dapD) were isolated and characterized. Treatment with beta-lactams caused lysis of the mutants at 30 degrees C. Although growth of the mutants at 42 degrees C was inhibited by beta-lactams, no lysis occurred. The mutants were also slightly tolerant to D-cycloserine at 42 degrees C but lysed readily when deprived of diaminopimelate or when treated with moenomycin. The minimum inhibitory concentrations of various antibiotics were the same for the mutants and their parent. The mutations conferring penicillin tolerance were phenotypically suppressed in the presence of a variety of compounds which may act as chaotropic or antichaotropic agents. No defects in penicillin-binding proteins and peptidoglycan hydrolases were detected. Temperature-resistant revertants of the mutants were no longer tolerant to penicillin-induced autolysis at 42 degrees C. The mutations in five isolates were localized to the 56 to 61 min region of the E. coli linkage map and to the 44 to 51 min region in the case of two other isolates.


Functional magnetic resonance imaging in medicine and physiology.
Magnetic resonance imaging (MRI) is a well-established diagnostic tool that provides detailed information about macroscopic structure and anatomy. Recent advances in MRI allow the noninvasive spatial evaluation of various biophysical and biochemical processes in living systems. Specifically, the motion of water can be measured in processes such as vascular flow, capillary flow, diffusion, and exchange. In addition, the concentrations of various metabolites can be determined for the assessment of regional regulation of metabolism. Examples are given that demonstrate the use of functional MRI for clinical and research purposes. This development adds a new dimension to the application of magnetic resonance to medicine and physiology.


Prospective Changes in the Distribution of Movement Behaviors Are Associated With Bone Health in the Elderly According to Variations in their Frailty Levels.
Frailty is associated with poor bone health and osteoporosis, and physical activity (PA) is one of the best treatments for both pathologies in older adults. Nonetheless, because daily time is limited, how the time is distributed during the waking hours is critical. The waking hours are spent according to different movement behaviors: sedentary behaviors (SB), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA). The aim of this study was to use compositional data analyses to examine the effects of the change in movement behaviors on bone health during aging in older people, related to the changes in their frailty levels. We analyzed 227 older people aged 65 to 94 (125 women and 102 men) over a 4-year period. Movement behaviors were assessed using accelerometry. Both bone mineral density (BMD) and bone mineral content (BMC) were determined using bone densitometry. The Frailty Trait Scale was used to divide the sample by frailty level evolution during aging. The R statistical system was used for the compositional data analysis and, in addition, all models were adjusted for several covariates. The changes in the distribution of all movement behaviors within a waking hour period were significantly associated with spine and femoral neck BMD changes in the subgroup with a positive change in frailty level and spine BMC in the subgroup with no change in frailty level (p ≤ .05). Likewise, MVPA relative to the change in other movement behaviors was also associated in both subgroups with higher BMD and BMC, respectively, in the same body areas (p ≤ .05). No significant associations were found in the negative change in frailty level subgroup. Older people who achieved a positive change in frailty level during a 4-year period showed higher BMD changes compared to those with no changes or increases in their frailty level. Therefore, increasing MVPA relative to the change in the other movement behaviors during a 4-year period could perhaps produce bone health improvements in the elderly that do not worsen their frailty level. © 2020 American Society for Bone and Mineral Research.


Deletion of FoxN1 in the thymic medullary epithelium reduces peripheral T cell responses to infection and mimics changes of aging.
Aging increases susceptibility to infection, in part because thymic involution culminates in reduced naïve T-lymphocyte output. Thymic epithelial cells (TECs) are critical to ensure normal maturation of thymocytes and production of peripheral T cells. The forkhead-class transcription factor, encoded by FoxN1, regulates development, differentiation, and function of TECs, both in the prenatal and postnatal thymus. We recently showed that expression of FoxN1, by keratin 14 (K14)-expressing epithelial cells is essential for maintenance of thymic medullary architecture, and deletion of FoxN1 in K14 promoter-driven TECs inhibited development of mature TECs and reduced the number of total thymocytes. These findings are reminiscent of changes observed during normal thymic aging. In the current report, we compared the effects of K14-driven FoxN1 deletion on peripheral T cell function in response to influenza virus infection with those associated with normal aging in a mouse model. FoxN1-deleted mice had reduced numbers of peripheral CD62L+CD44- naïve T-cells. In addition, during influenza infection, these animals had reduced antigen-specific CD8+ T-cell and IgG responses to influenza virus, combined with increased lung injury, weight loss and mortality. These findings paralleled those observed in aged wild type mice, providing the first evidence that K14-mediated FoxN1 deletion causes changes in T-cell function that mimic those in aging during an immune response to challenge with an infectious agent.


Blunt splenic trauma in children.
Splenic trauma in 96 patients over an 11-year period is reviewed. Almost 80% of injuries resulted from motor vehicle accidents in which the patients was a pedestrian, and over 80% of patients sustained multiple injuries. Splenic injury was confirmed by isotope scanning at laparotomy. Non-operative management was feasible in 87.5% of the children, with no mortality or morbidity. In patients requiring surgery, splenic salvage was possible in 75%.


The Adult Cardiac Anesthesiology Section of STS Adult Cardiac Surgery Database: 2020 Update on Quality and Outcomes.
The Society of Cardiovascular Anesthesiologists, in partnership with The Society of Thoracic Surgeons, has developed the Adult Cardiac Anesthesiology Section of the Adult Cardiac Surgery Database. The goal of this landmark collaboration is to advance clinical care, quality, and knowledge, and to demonstrate the value of cardiac anesthesiology in the perioperative care of cardiac surgical patients. Participation in the Adult Cardiac Anesthesiology Section has been optional since its inception in 2014 but has progressively increased. Opportunities for further growth and improvement remain. In this first update report on quality and outcomes of the Adult Cardiac Anesthesiology Section, we present an overview of the clinically significant anesthesia and surgical variables submitted between 2015 and 2018. Our review provides a summary of quality measures and outcomes related to the current practice of cardiothoracic anesthesiology. We also emphasize the potential for addressing high-impact research questions as data accumulate, with the overall goal of elucidating the influence of cardiac anesthesiology contributions to patient outcomes within the framework of the cardiac surgical team.


The importance of measuring dynamic visual acuity.
In their everyday life, people interact with different objects, static as well as those in motion. However, dynamic acuity is rarely checked in medical examinations, even those preceding the issue of driving license. In order for driving to be safe, good eyesight or good correction with visual aids is imperative. Beside good eyesight, drivers also have to have good reflexes and short reaction span. The aim of this study was to compare dynamic and static visual acuity in order to observe how they vary among individuals. Twenty female and male participants, 65 years of age, took part in the study and the comparison was made with the results provided by 20 20-year old participants. Dynamic acuity was tested using the Landolt-ring optotype which was simulating movement velocity of 72 km/h. T-test demonstrated the presence of a statistically significant difference between dynamic and static acuity among the participants from 62 to 68 years of age (t = 15.852; df = 39; p < 0.01). Within the same group, dynamic acuity (mean = 0.887; std. deviation = 0.297) proved to be significantly worse than static acuity (mean = 1.40; std. deviation = 0.317). By comparing the results measured within the older group of participants with those measured in the younger group, it was shown that there exists a statistically significant difference (t = 0.275; df = 58; p < 0,05) between the older and younger group in their dynamic binocular acuity with correction. Younger participants had better dynamic binocular acuity with correction (mean = 1.063; std. deviation = 0.259) than the older participants (mean = 0.884; std. deviation = 0.298). The differences between dynamic and static acuity and its degradation in the older age groups have to be taken into account when issuing driving licenses. The future of research lies within the study of correlation between the age and acuity in order that the results can be applied in practice.


Oncology training programs: are we doing comparative effectiveness research justice?
Comparative effectiveness research (CER) is defined as an assessment of all available options for a specific medical condition, with intent to estimate effectiveness in specific subpopulations. Medical professionals must receive training in CER, including its general goals, the 'toolbox' necessary to perform CER and its design. Oncologic training programs are currently not doing justice to CER: a rationale for conducting CER has been proposed, funding from the US government is available, but encouragement from oncologic residencies and fellowships is minimal. Encouragement to train oncologic physicians in CER is limited by a few factors, including inadequate emphasis on evidence weighing, and no explicit mention of factors key to CER in the Accreditation Council for Graduate Medical Education guidelines. As residency program requirements transition to milestone-based curricula and evaluations, explicit recommendations regarding CER and patient-centered outcomes research should be implemented for all programs. Upper level trainees who have reached milestones related to CER will be competitive applicants for research funding.


Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas.
High epidermal growth factor receptor (EGFR) gene copy number is associated with poor prognosis in lung cancer, but such findings have not been reported for HNSCC. A better understanding of the EGFR pathway may improve the use of EGFR inhibitors in HNSCC. EGFR status was analyzed in 86 tumor samples from 82 HNSCC patients by fluorescent in situ hybridization (FISH) to determine EGFR gene copy number, by polymerase chain reaction and direct sequencing for activating mutations, and by DNA microarray and immunohistochemistry for RNA and protein expression. The results were associated with patient characteristics and clinical end points. Forty-three (58%) of 75 samples with FISH results demonstrated EGFR high polysomy and/or gene amplification (FISH positive). The FISH-positive group did not differ from the FISH-negative group with respect to age, sex, race, tumor grade, subsites and stage, or EGFR expression by analyses of RNA or protein. No activating EGFR mutations were found. However, the FISH-positive group was associated with worse progression-free and overall survival (P < .05 and P < .01, respectively; log-rank test). When microarray data were interrogated using the FISH results as a supervising parameter, ECop (which is known to coamplify with EGFR and regulate nuclear factor-kappa B transcriptional activity) had higher expression in FISH-positive tumors. High EGFR gene copy number by FISH is frequent in HNSCC and is a poor prognostic indicator. Additional investigation is indicated to determine the biologic significance and implications for EGFR inhibitor therapies in HNSCC.


Cannabinoid 1 receptors are expressed by nerve growth factor- and glial cell-derived neurotrophic factor-responsive primary sensory neurones.
Expression of the cannabinoid 1 (CB1) receptor and its regulation were studied in the different nociceptive and non-nociceptive sub-populations of cultured primary sensory neurones of adult rats. Bandairaea simplicifolia isolectin B4 (IB4) binding and calcitonin gene-related peptide (CGRP) immunostaining were used to distinguish between the glial cell-derived neurotrophic factor (GDNF)- and nerve growth factor (NGF)-responsive nociceptive and the non-nociceptive primary sensory neurones while a specific CB1 receptor antibody was used to study the expression of the CB1 receptor protein. About half of the total number of primary sensory neurones (47+/-3.2%) cultured for 1 day in the presence of both neurotrophic factors (50 ng/ml each) showed CB1 receptor-like immunostaining, whereas 21.8+/-3.3% and 32.7+/-5.6% of the neurones showed CGRP-like immunopositivity and IB4 binding, respectively. A proportion of the CB1 receptor-like immunopositive neurones was immunostained for CGRP (31.7+/-5%) and IB4 (48.2%+/-7.5), with a minimal (1%) co-expression of CGRP and IB4 binding. About a fifth of the CB1 receptor-like immunopositive neurones did not show either CGRP-like immunostaining or IB4 binding. To find out whether CB1 receptor expression in nociceptive primary sensory neurones is regulated by GDNF or NGF, cultures were grown in the presence or absence of the neurotrophic factors for 7 days. Vanilloid receptor 1 (VR1) immunostaining was used as a control marker to monitor the effect of the neurotrophins. In cultures maintained in the presence of both factors (50 ng/ml each) 51+/-2.6% and 42.4+/-1.2% of the cells showed CB1 receptor-like and VR1-like immunostaining, respectively. In cultures grown for 7 days in the absence of either of the neurotrophic factors the relative number of VR1-like immunopositive cells decreased to 13.4+/-2.7%, whereas the relative number of CB1 receptor-like immunopositive neurones was unchanged (50.6+/-1.1%). Our data suggest that the CB1 receptor is expressed in all of the three major sub-populations of primary sensory neurones and that the CB1 receptor expression is not regulated by either NGF or GDNF.


Effective delivery of stem cells using an extracellular matrix patch results in increased cell survival and proliferation and reduced scarring in skin wound healing.
Wound healing is one of the most complex biological processes and occurs in all tissues and organs of the body. In humans, fibrotic tissue, or scar, hinders function and is aesthetically unappealing. Stem cell therapy offers a promising new technique for aiding in wound healing; however, current findings show that stem cells typically die and/or migrate from the wound site, greatly decreasing efficacy of the treatment. Here, we demonstrate effectiveness of a stem cell therapy for improving wound healing in the skin and reducing scarring by introducing stem cells using a natural patch material. Adipose-derived stromal cells were introduced to excisional wounds created in mice using a nonimmunogenic extracellular matrix (ECM) patch material derived from porcine small-intestine submucosa (SIS). The SIS served as an attractive delivery vehicle because of its natural ECM components, including its collagen fiber network, providing the stem cells with a familiar structure. Experimental groups consisted of wounds with stem cell-seeded patches removed at different time points after wounding to determine an optimal treatment protocol. Stem cells delivered alone to skin wounds did not survive post-transplantation as evidenced by bioluminescence in vivo imaging. In contrast, delivery with the patch enabled a significant increase in stem cell proliferation and survival. Wound healing rates were moderately improved by treatment with stem cells on the patch; however, areas of fibrosis, indicating scarring, were significantly reduced in wounds treated with the stem cells on the patch compared to untreated wounds.


The short-term effects of various oral care methods in dependent elderly: comparison between toothbrushing, tongue cleaning with sponge brush and wiping on oral mucous membrane by chlorhexidine.
To explore the short-term effects from toothbrushing, tongue cleaning with sponge brush and wiping on oral mucous membrane by chlorhexidine. Numerous reports have been seen in recent years proving the effectiveness of mouth cleaning with a toothbrush for the prevention of respiratory infections among the dependent elderly. However, the short-term effects from each oral care method have not yet been clarified. Hence, an investigation was conducted by having each subject independently perform various oral care methods for five consecutive days. The subjects consisted of 12 assistance-dependent elderly who have difficulties with tooth brushing by themselves, have 10 or more residual teeth and are not yet using plate dentures. After the pre-intervention examination, each of the following oral care methods were performed on the same subject on an approximately three week basis: 1) Tooth brushing 2) Tongue cleaning with sponge brush 3) Wiping on oral mucous with sponge brush by chlorhexidine. Each method was performed independently, once a day for 5 consecutive days and the subjects were reexamined on the sixth day for comparative verification. Consequently, toothbrushing decreased the plaque index and gingival index significantly and an improvement of oral malodour was also acknowledged (p < 0.01). Tongue cleaning with a sponge brush decreased the tongue coat score significantly (p < 0.05) and oral malodour was also improved (p < 0.01). Wiping on oral mucous with a sponge brush soaked in chlorhexidine significantly decreased opportunistic infections in the pharynx region (p < 0.05). It was suggested that the use of not only a toothbrush but also chlorhexidine gluconate may be indicated for dependent elderly people in whom pathogens of opportunistic infection are detected.


Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and meta-analysis.
In patients with suspected lower extremity deep vein thrombosis (DVT), compression ultrasound (CUS) is typically the initial test to confirm or exclude DVT. Patients with an initial negative CUS result often require repeat CUS after 5 to 7 days. Whole-leg CUS may exclude proximal and distal DVT in a single evaluation. To determine the risk of venous thromboembolism after withholding anticoagulation in patients with suspected lower extremity DVT following a single negative whole-leg CUS result. MEDLINE, EMBASE, CINAHL, LILACS, Cochrane, and Health Technology Assessments databases were searched for articles published from January 1970 through November 2009. Supplemental searches were performed of Internet resources, reference lists, and by contacting content experts. Included studies were randomized controlled trials and prospective cohort studies of patients with suspected DVT and a negative whole-leg CUS result who did not receive anticoagulant therapy, and were followed up at least 90 days for venous thromboembolism events. Two authors independently reviewed and extracted data regarding a single positive or negative whole-leg CUS result, occurrence of venous thromboembolism during follow-up, and study quality. Seven studies were included totaling 4731 patients with negative whole-leg CUS examinations who did not receive anticoagulation. Of these, up to 647 patients (13.7%) had active cancer and up to 725 patients (15.3%) recently underwent a major surgery. Most participants were identified from an ambulatory setting. Venous thromboembolism or suspected venous thromboembolism-related death occurred in 34 patients (0.7%), including 11 patients with distal DVT (32.4%); 7 patients with proximal DVT (20.6%); 7 patients with nonfatal pulmonary emboli (20.6%); and 9 patients (26.5%) who died, possibly related to venous thromboembolism. Using a random-effects model with inverse variance weighting, the combined venous thromboembolism event rate at 3 months was 0.57% (95% confidence interval, 0.25%-0.89%). Withholding anticoagulation following a single negative whole-leg CUS result was associated with a low risk of venous thromboembolism during 3-month follow-up.


The accuracy of portable ultrasonography to diagnose fractures in an austere environment.
Previous literature has shown the ability of ultrasonography technology to accurately assess orthopedic pathology. Over the past two decades, the use of ultrasound in the prehospital setting has become an important tool for triage, diagnosis, and treatment, especially in austere and remote environments that lack appropriate radiography capability and logistical support. The purpose of our study was to assess the accuracy of ultrasound in the austere, combat environment for diagnosis of orthopedic fracture. We conducted a longitudinal, prospective, observational study on patients presenting with suspected closed fractures using a digital handheld ultrasound device. All patients presenting with suspected fracture underwent an ultrasound examination by a board-certified emergency medicine physician credentialed in emergency ultrasonography. Patients were then categorized into ultrasound-positive and ultrasound-negative groups. A total of 44 subjects underwent ultrasound examination for suspected fractures. There were initially 12 (27%) positive and 32 (73%) negative scans. Of the initial 12 positive scans, ten had a true fracture verified by plain radiography. Ultrasonography yielded an overall sensitivity of 100% and a specificity of 94%. Only four patients with an initial negative ultrasound scan continued to have clinical symptoms for more than three days and were found to have no evidence of fracture by radiograph. Our data show that use of ultrasound by an experienced clinician in the austere environment can be performed accurately and can possibly prevent unnecessary evacuations for suspected fractures requiring radiographic verification. The purpose of our study was to assess the accuracy of ultrasound examination in the austere, combat environment for diagnosis of orthopedic fracture.


Lesion enhancement in radio-frequency spoiled gradient-echo imaging: theory, experimental evaluation, and clinical implications.
To investigate the lesser lesion conspicuity after gadolinium contrast infusion with radio-frequency spoiled gradient-echo (SPGR) sequences relative to conventional T1-weighted spin-echo techniques. The influences of repetition time, echo time, and flip angle on spin-echo and SPGR signal were studied with mathematical modeling of the image signal amplitude for concentrations of gadopentetate dimeglumine solute from 0 to 10 mM. Predictions of signal strength were verified in vitro by imaging of a doped water phantom. The effects of standard (0.1 mmol/kg) and high-dose (0.3 mmol/kg) gadoteridol on spin-echo and SPGR images were also investigated in three patients. The measured amplitude of undoped water and the rate of increase of doped water signal with increasing gadopentetate concentration (slope) for spin-echo 600/11/1/90 degrees (repetition time/echo time/excitations/flip angle) and SPGR (600/11/190 degrees) were similar and exceeded those of SPGR (35/5/145 degrees). Greater increases in SPGR doped water signal and its slope were produced by increasing TR than by varying echo-time or flip angle. The subjective lesion conspicuity and measured lesion contrast at 0.3 mmol/kg were greater with spin-echo (600/11/1/90 degrees) than with SPGR (35/5/145 degrees) in all three patients; the measured lesion enhancement was similar for both techniques in two patients and decreased for SPGR in the third patient. The phantom studies suggest that the short repetition time of 35 msec, typically used in clinical SPGR imaging, is largely responsible for a reduced signal amplitude and a diminished rate of increase of signal with increasing gadopentetate concentration, relative to spin-echo. Phantom and clinical studies suggest that the dose of paramagnetic agent required to achieve SPGR lesion conspicuity with short repetition time comparable with spin-echo would have to be higher than the dose in current clinical use.


A pilot investigation of quality of life and lung function following choral singing in cancer survivors and their carers.
The diagnosis of cancer creates a wide range of social and emotional problems to patients and carers. However, delivering effective psychological, emotional, and social support remains a challenge. This pilot study evaluated quality of life (QoL) and lung function before and after three months of choral singing in cancer survivors and their carers. At baseline, 30 cancer survivors and their carers, mean (standard deviation) age 60 (10), completed questions about QoL (SF-36), anxiety and depression, and the multidimensional fatigue score. Lung function was measured by spirometry, and respiratory musclestrength (maximal inspiratory pressure, MIP; maximal expiratory pressure, MEP) was also measured. Assessments were repeated after three months of singing in the choir, and 10 participants completed semi-structured interviews to explore their experience of the choir. After three months of choral singing, 20 subjects repeated the assessments. Several domains of the SF-36 improved, including vitality, social functioning, mental health, and bodily pain. There was also a trend of reduced anxiety and depression, despite no change in fatigue. Spirometric measures of lung function were unchanged; however, there was a trend of increased MEP. Themes from the interviews revealed that the choir provided a focus, so the future participants felt uplifted and had greater confidence and self-esteem. This pilot project provides preliminary data which suggest choral singing may improve QoL and depression, despite no physiological change in cancer survivors and their carers. Choral groups offer a support mechanism applicable to cancer patients, carers, and supporters, and may be relevant to other chronic conditions. Further research examining the efficacy of this intervention in a larger controlled study is warranted.


Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation.
Sleep and wakefulness are governed by both the suprachiasmatic nuclei of the hypothalamus (SCN), and a sleep homeostatic process; however, the interaction of these control systems is not well understood. From rodent studies it has been assumed that the SCN promote neither wake nor sleep but gate the homeostatic sleep-promoting process. Yet in humans sleep tendency is lowest during the later waking hours of the day, and sleep duration can be predicted because of the precise circadian timing of waking. Thus in primates, the SCN could assure sleep-wake cycle consolidation by actively promoting or facilitating wakefulness. To evaluate this hypothesis, we examined the sleep-wake and sleep-stage patterns of intact and SCN-lesioned (SCNx) squirrel monkeys maintained in constant light. This diurnal primate has consolidated sleep and wake patterns more similar to man than rodents. Sleep-wake, sleep stages, brain temperature, and drinking circadian rhythms were eliminated, and total sleep time was significantly increased (4.0 hr, P < 0.01) in SCNx monkeys. However, total times in deeper stages of non-rapid eye movement (non-REM; e.g., delta sleep) and REM sleep were not significantly affected by SCN lesions. Increased total sleep time was associated with a reduction in subjective day wake consolidation, as evidenced by substantially shorter wake bout lengths in SCNx monkeys (15 +/- 6 min) as compared to intact monkeys (223 +/- 10 min; P < 0.0001, ANOVA). These findings show that the SCN influence the regulation of daily total wake and sleep times, and implicate an alternative sleep-wake regulatory model in which an SCN-dependent process actively facilitates the initiation and maintenance of wakefulness and opposes homeostatic sleep tendency during the subjective day in diurnal primates.


Morbidity Pattern, Availability and Utilization of Health Services: A Study among the Male Youth (15-24 Years) Living in the Slums.
Youth is considered as a healthy period but their health is greatly influenced by the hostile living conditions in the slums. When this is accompanied by poor health infrastructure, health risk escalates multiple times. The objective was (1) to study the health problems of the male youth living in the slums and (2) to study the availability and utilization of health services for the male youth living in the slums. Study design: Cross-sectional study. Study population: Male youth (15-24 years). Study settings: Four urban slums of Amritsar city. Study period: January 1, 2017-December 31, 2017. Sample size: One thousand male youths. Inclusion criteria: Male youth (15-24 years) with consent. Exclusion criteria: Male youth (15-24 years) not given consent, not available at home on the third repeat visit, and mentally unstable or deaf or dumb. The morbidity pattern showed that 47.5% suffered from any disease during the past 3 months and 3.3% were hospitalized in the past 1 year. Majority of the cases were due to diseases of the respiratory system and gastrointestinal system. Private health sectors including chemist shops were utilized more in case of both outpatient (88.9%) and inpatient services (57.6%) as compared to public health sector. The private health facilities were within 500 m from majority (89.6%) of households in the slums of Amritsar city. Primary health care needs to be strengthened in the slums. Effective and easily accessible health-care services should be provided by the government at the doorsteps of slum households. The Information Education Communication/Behavior Change Communication activities regarding disease prevention should be strengthened to promote and protect good health.


Infertility evaluation and treatment among women in the United States.
To examine the characteristics of women seeking infertility evaluation and treatment. Cross-sectional survey based on in-person interviews, followed by two-step hurdle analysis. Not applicable. 4,558 married or cohabitating women ages 25 to 44 years. None. Likelihood of seeking a preliminary infertility evaluation and of seeking infertility treatment once evaluated, and the treatment type provided. Of 623 women (13.7%) who reported seeking an infertility evaluation, 328 reported undergoing subsequent infertility treatment. Age at marriage, marital status, education, health insurance status, race/ethnicity, and religion were associated with the likelihood of seeking infertility evaluation. For example, the predicted probability that a non-white woman who married at age 25 will seek evaluation was 12%. This probability increased to 34% for white women with a graduate degree who had married at age 30. Among women who were evaluated, income, employment status, and ethnicity correlated strongly with the likelihood of seeking infertility treatment. Infertility drug therapy was the most frequent treatment used, and reproductive surgery and in vitro fertilization (IVF) were used the least often. The use of infertility services is not random. Understanding the sociodemographic factors correlated with use may assist new couples with family planning. Roughly 50% of the women evaluated for infertility progressed to treatment, and only a small proportion were treated with more advanced assisted reproductive technologies such as in vitro fertilization. Future research aimed at improving access to effective health-care treatments within the boundaries of affordability is warranted.


Maternal postnatal depression and children's growth and behaviour during the early years of life: exploring the interaction between physical and mental health.
To assess the association between maternal postnatal depression and child behaviour problems and child growth at age 2 years. This was a longitudinal birth cohort study in Johannesburg, South Africa. Primary analysis on the 'Birth to Twenty' cohort was performed for the association between maternal postnatal depression and child behaviour problems (n=1035) and growth (n=891) at age 2 and subgroup analyses (n=635) were carried out to assess the role of poor child growth in this association. Main outcome measures were the association between maternal postpartum depression (measured at 6 months postnatally using the Pitt depression inventory) and child behaviour problems (Richman child behaviour scale) and child growth at age 2 years. Maternal postnatal depression was significantly associated with child behaviour problems at age 2, independent of socioeconomic status (beta=0.353, p value=0.015). There was some evidence that children of depressed mothers were also at increased risk for having stunted growth, compared to non-depressed mothers (OR 1.61 (95% CI 1.02 to 2.56). The association between postnatal depression and child behavioural problems was significantly mediated by the stunted growth of the child (beta=0.294, p value=0.111). Maternal postnatal depression is associated with later child behaviour problems independent of the socioeconomic status of the family. This association is mediated by the child's growth, demonstrating the importance of considering a child's physical and mental health together.


Scoliosis in chickens: responsiveness of severity and incidence to dietary copper.
The severity and incidence of spinal lesions were manipulated in a line of chickens susceptible to scoliosis by varying their dietary intake of copper. A decrease in expression of the lesion was related to increased intake of copper. The change in expression, however, appeared to be related only indirectly to the defects in collagen cross-linking, maturation, and deposition known to be associated with dietary copper deficiency. Thus, a dietary constituent in the range of normal intakes may act as an environmental factor in the expression of scoliosis.


Jejunal Cancer with WRN Mutation Identified from Next-Generation Sequencing: A Case Study and Minireview.
Small bowel cancer is a rare, gastrointestinal cancer originating from the small intestines. Carcinogenesis in the jejunum, the middle segment of the small intestines, occurs less commonly than in the duodenum and ileum. Despite the increasing incidences globally, the cancer is still poorly understood, which includes lack of pathological understanding and etiological reasoning, as it seems to exhibit both similarities and differences with other types of cancers. A 76-year-old Asian man was presented with abdominal pain, which was later attributed to an adenocarcinoma in the jejunum. Initial immunoreactive staining results found no connections to colorectal cancer. The microsatellite instability test was further examined by immunohistochemistry which revealed them to be wild-type. From our exome-capture sequencing results, mutations of WRN may be important as they represent the only genetic defect in this jejunal cancer. The patient has since undergone surgical resection of his cancer and is currently being treated with chemotherapy. The pathology, genomic markers, and treatments are described along with literature review.


The VISA-A questionnaire: a valid and reliable index of the clinical severity of Achilles tendinopathy.
There is no disease specific, reliable, and valid clinical measure of Achilles tendinopathy. To develop and test a questionnaire based instrument that would serve as an index of severity of Achilles tendinopathy. Item generation, item reduction, item scaling, and pretesting were used to develop a questionnaire to assess the severity of Achilles tendinopathy. The final version consisted of eight questions that measured the domains of pain, function in daily living, and sporting activity. Results range from 0 to 100, where 100 represents the perfect score. Its validity and reliability were then tested in a population of non-surgical patients with Achilles tendinopathy (n = 45), presurgical patients with Achilles tendinopathy (n = 14), and two normal control populations (total n = 87). The VISA-A questionnaire had good test-retest (r = 0.93), intrarater (three tests, r = 0.90), and interrater (r = 0.90) reliability as well as good stability when compared one week apart (r = 0.81). The mean (95% confidence interval) VISA-A score in the non-surgical patients was 64 (59-69), in presurgical patients 44 (28-60), and in control subjects it exceeded 96 (94-99). Thus the VISA-A score was higher in non-surgical than presurgical patients (p = 0.02) and higher in control subjects than in both patient populations (p<0.001). The VISA-A questionnaire is reliable and displayed construct validity when means were compared in patients with a range of severity of Achilles tendinopathy and control subjects. The continuous numerical result of the VISA-A questionnaire has the potential to provide utility in both the clinical setting and research. The test is not designed to be diagnostic. Further studies are needed to determine whether the VISA-A score predicts prognosis.


Prognostic value of three different methods of MGMT promoter methylation analysis in a prospective trial on newly diagnosed glioblastoma.
Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O(6)-methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide. Hence, the MGMT status is widely determined in most clinical trials and frequently requested in routine diagnostics of glioblastoma. Since various different techniques are available for MGMT promoter methylation analysis, a generally accepted consensus as to the most suitable diagnostic method remains an unmet need. Here, we assessed methylation-specific polymerase chain reaction (MSP) as a qualitative and semi-quantitative method, pyrosequencing (PSQ) as a quantitative method, and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a semi-quantitative method in a series of 35 formalin-fixed, paraffin-embedded glioblastoma tissues derived from patients treated in a prospective clinical phase II trial that tested up-front chemoradiotherapy with dose-intensified temozolomide (UKT-05). Our goal was to determine which of these three diagnostic methods provides the most accurate prediction of progression-free survival (PFS). The MGMT promoter methylation status was assessable by each method in almost all cases (n = 33/35 for MSP; n = 35/35 for PSQ; n = 34/35 for MS-MLPA). We were able to calculate significant cut-points for the continuous methylation signals at each CpG site analysed by PSQ (range, 11.5 to 44.9%) and at one CpG site assessed by MS-MLPA (3.6%) indicating that a dichotomisation of continuous methylation data as a prerequisite for comparative survival analyses is feasible. Our results show that, unlike MS-MLPA, MSP and PSQ provide a significant improvement of predicting PFS compared with established clinical prognostic factors alone (likelihood ratio tests: p<0.001). Conclusively, taking into consideration prognostic value, cost effectiveness and ease of use, we recommend pyrosequencing for analyses of MGMT promoter methylation in high-throughput settings and MSP for clinical routine diagnostics with low sample numbers.


Polymorphism of the polyketide synthase gene phID in biocontrol fluorescent pseudomonads producing 2,4-diacetylphloroglucinol and comparison of PhID with plant polyketide synthases.
Many biocontrol fluorescent pseudomonads can protect plants from soilborne fungal pathogens through production of the antifungal secondary metabolite 2,4-diacetylphloroglucinol (Phl). One of the phl biosynthetic genes, phlD, encodes a polyketide synthase similar to plant chalcone synthases. Here, restriction analysis of phlD from 39 Phl+ biocontrol fluorescent pseudomonads yielded seven different banding patterns. The gene was sequenced in seven strains, representing the different restriction patterns. Cluster analysis of phlD restriction data or phlD sequences indicated that phlD polymorphism was high, and two main clusters were obtained when predicted PhlD sequences were compared. When the seven PhlD sequences were studied with those of other procaryotic polyketide synthases (gram-positive bacteria) and plant chalcone synthases, however, Phl+ pseudomonads, gram-positive bacteria, and plants clustered separately. Yet, sequence analysis of active site regions for PhlD and plant chalcone synthases revealed that PhlD can be considered a member of the chalcone synthase family, which may be interpreted as convergent evolution of key enzymes involved in secondary metabolism. For the 39 Phl+ pseudomonads, a relationship was found among phlD restriction patterns, phylogenetic groups defined by 16S rDNA restriction analysis (confirmed by 16S rDNA sequencing), and production levels of Phl in vitro.


Traveler's diarrhea: epidemiology and impact on visitors to Fortaleza, Brazil.
To assess the epidemiology and impact of traveler's diarrhea (TD) among visitors to the city of Fortaleza, Ceará, Brazil, as part of a global study on TD carried out in four countries. Within a cross-sectional survey, questionnaires were completed by departing travelers at the Fortaleza airport between March 1997 and February 1998. The questions inquired about demographics, duration of stay, reason for their visit, pretravel health advice they had received, risky food and beverage consumption while in Fortaleza, and quality of life during the visit to Fortaleza in relation to having or not having contracted TD. A total of 12,499 questionnaires were analyzed. The most common reason that the visitors gave for their travel to Fortaleza was a holiday (60.3%). The total diarrhea attack rate was 13.4%. Younger people (< 36 years) had significantly higher TD attack rates than did older persons. Using a logistic regression model, we investigated the visitors' risk factors, including age, gender, length of stay, and trip's purpose. According to that analysis, characteristics that are slightly predictive of TD are gender, length of stay, and visiting as a tourist rather than for some other purpose. Characteristics that protect against contracting TD include being older and traveling for business rather than for some other reason. Of those who were incapacitated by TD, the mean duration of the impairment was 42 hours. TD affected the travel plans and activities of many of the visitors to Fortaleza. Further, although aware of the health risks, the majority of those travelers did not avoid all potentially contaminated food or beverage items. Given this pattern of behavior, future efforts to combat TD may have to depend on such other alternative strategies as new vaccines.


Freshwater fishes of northern Australia.
Northern Australia is biologically diverse and of national and global conservation signicance. Its ancient landscape contains the world's largest area of savannah ecosystem in good ecological condition and its rivers are largely free-flowing. Agriculture, previously confined largely to open range-land grazing, is set to expand in extent and to focus much more on irrigated cropping and horticulture. Demands on the water resources of the region are thus, inevitably increasing. Reliable information is required to guide and inform development and help plan for a sustainable future for the region which includes healthy rivers that contain diverse fish assemblages. Based on a range of information sources, including the outcomes of recent and extensive new field surveys, this study maps the distribution of the 111 freshwater fishes (excluding elasmobranches) and 42 estuarine vagrants recorded from freshwater habitats of the region. We classify the habitat use and migratory biology of each species. This study provides a comprehensive assessment of the diversity and distribution of fishes of the region within a standardised nomenclatural framework. In addition, we summarise the outcomes of recent phylogeographic and phylogenetic research using molecular technologies to identify where issues of taxonomy may need further scrutiny. The study provides an informed basis for further research on the spatial arrangement of biodiversity and its relationship to environmental factors (e.g. hydrology), conservation planning and phylogentic variation within individual taxa.


Phenotypic variability in unicellular organisms: from calcium signalling to social behaviour.
Historically, research has focused on the mean and often neglected the variance. However, variability in nature is observable at all scales: among cells within an individual, among individuals within a population and among populations within a species. A fundamental quest in biology now is to find the mechanisms that underlie variability. Here, we investigated behavioural variability in a unique unicellular organism, Physarum polycephalum. We combined experiments and models to show that variability in cell signalling contributes to major differences in behaviour underpinning some aspects of social interactions. First, following thousands of cells under various contexts, we identified distinct behavioural phenotypes: 'slow-regular-social', 'fast-regular-social' and 'fast-irregular-asocial'. Second, coupling chemical analysis and behavioural assays we found that calcium signalling is responsible for these behavioural phenotypes. Finally, we show that differences in signalling and behaviour led to alternative social strategies. Our results have considerable implications for our understanding of the emergence of variability in living organisms.


Ecological Momentary Assessment of Bipolar Disorder Symptoms and Partner Affect: Longitudinal Pilot Study.
The World Health Organization ranks bipolar disorder (BD) as the 7th leading cause of disability. Although the effects on those with BD are well described, less is reported on the impact of BD on cohabiting partners or any interactions between the two; this requires in vivo data collection measured each day over several months. We set out to demonstrate the utility of ecological momentary assessment with BD couples measured using yoked smartphone apps. When randomly prompted over time, we assumed distinct patterns of association would emerge between BD symptoms (both depression and hypo/mania) and partner mood (positive and negative affect). For this pilot study, we recruited an international sample of young and older adults with BD and their cohabiting partners where available. Both participants and partners downloaded separate apps onto their respective smartphones. Within self-specified "windows of general availability," participants with BD were randomly prompted to briefly report symptoms of depression and hypo/mania (ie, BDSx), positive and negative mood (ie, POMS-15; partners), and any important events of the day (both). The partner app was yoked to the participant app so that the former was prompted roughly 30 minutes after the participant with BD or the next morning if outside the partner's specified availability. Four couples provided 312 matched BD symptom and partner mood responses over an average of 123 days (range 65-221 days). Both were GPS- and time-stamped (mean 3:11 hrs between questionnaires, SD 4:51 hrs). Total depression had a small but significant association with positive (r=-.14; P=.02) and negative partner affect (r=.15; P=.01]. Yet total hypo/mania appeared to have no association with positive partner affect (r=-.01; P=.87); instead, negative partner affect was significantly correlated with total hypo/mania (r=.26; P=.01). However, when we look specifically at BD factors, we see that negative partner affect is associated only with affrontive symptoms of hypo/mania (r=.38; P=.01); elation or loss of insight appears unrelated to either positive (r=.10; P=.09) or negative partner affect (r=.02; P=.71). Yet affrontive symptoms of hypo/mania were significantly correlated with negative affect, but only when couples were together (r=.41; P=.01), not when apart (r=.22; P=.12). That is, these angry interpersonal symptoms of hypo/mania appear to be experienced most negatively by spouses when couples are together. These initial findings demonstrate the utility of in vivo ambulatory data collection in longitudinal mental health research. Preliminary analyses suggest different BD symptoms are associated with negative and positive partner mood. These negative effects appear greater for hypo/mania than depressive symptoms, but proximity to the person with BD is important.


Alkylsulfanylphenyl derivatives of cytosine and 7-deazaadenine nucleosides, nucleotides and nucleoside triphosphates: synthesis, polymerase incorporation to DNA and electrochemical study.
Aqueous Suzuki-Miyaura cross-coupling reactions of halogenated nucleosides, nucleotides and nucleoside triphosphates derived from 5-iodocytosine and 7-iodo-7-deazaadenine with methyl-, benzyl- and tritylsufanylphenylboronic acids gave the corresponding alkylsulfanylphenyl derivatives of nucleosides and nucleotides. The modified nucleoside triphosphates were incorporated into DNA by primer extension by using Vent(exo-) polymerase. The electrochemical behaviour of the alkylsulfanylphenyl nucleosides indicated formation of compact layers on the electrode. Modified nucleotides and DNA with incorporated benzyl- or tritylsulfanylphenyl moieties produced signals in [Co(NH(3))(6)](3+) ammonium buffer, attributed to the Brdička catalytic response, depending on the negative potential applied. Repeated constant current chronopotentiometric scans in this medium showed increased Brdička catalytic response, which suggests the deprotection of the alkylsulfanyl derivatives to free thiols under the conditions.


Tamsulosin for benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate which can result in bothersome lower urinary tract symptoms. The treatment goal for men with BPH is to relieve these bothersome symptoms. This systematic review assessed the effects of tamsulosin in the treatment of lower urinary tract symptoms (LUTS) compatible with BPH. Trials were searched in computerized general and specialized databases (MEDLINE, EMBASE, Cochrane Library), by checking bibliographies, and by contacting manufacturers and researchers. Trials were eligible if they (1) randomized men with BPH to receive tamsulosin in comparison with placebo, other BPH medications or surgical interventions and (2) included clinical outcomes such as urologic symptom scales, symptoms, or urodynamic measurements, and (3) had a treatment duration of 30 days or longer. Eligibility was assessed by at least two independent observers. Information on patients, interventions, and outcomes were extracted by at least two independent reviewers using a standard form. The main outcome measure for comparing the effectiveness of tamsulosin with placebo, medical or surgical interventions was the change in urologic symptom scale scores. Secondary outcomes included changes in urinary flow measures (peak urine flow rate). The main outcome measure for adverse effects was the number of men reporting adverse effects. Fourteen studies involving 4,122 subjects met inclusion criteria. Study duration ranged from 4-26 weeks, and no placebo-controlled study lasted longer than 13 weeks. The mean age of subjects was 64 years. Baseline symptom scores and urine flow rates demonstrated that men had moderate LUTS. Tamsulosin improved symptoms and peak urine flow relative to placebo. The weighted mean differences (WMD) for mean change from baseline for the Boyarsky symptom score for 0.4 mg and 0.8 mg doses of tamsulosin relative to placebo were -1.1 points (95% CI = -1.49, -0.72; 12% improvement) and -1.6 points (95% CI = -2.3, -1.0; 16% improvement), respectively. The WMD for mean change from baseline in peak urine flow were 1.1 mL/sec (95% CI = 0.59, 1.51) and 1.1 mL/sec (95% CI= 0.65, 1.48) for 0.4 mg and 0.8 mg, respectively. Tamsulosin (0.2 mg-0.4 mg) was as effective as other alpha antagonists and the phytotherapeutic agent Permixon in improving symptoms and flow rates though the doses of all alpha-antagonists studied may not have been optimal. Discontinuations from treatment for any reason and discontinuations "due to adverse events" were similar in the low dose tamsulosin (0.2 mg) and placebo groups but increased to 16% in trials utilizing a 0.8 mg dose of tamsulosin. Low dose tamsulosin was generally well tolerated although not all the trials reported specific adverse events. The most frequently reported adverse events that were significantly greater than placebo included dizziness, rhinitis and abnormal ejaculation. Adverse effects increased markedly as tamsulosin dosing increased, and were reported in 75% of men receiving the 0.8 mg dose. Men receiving a 0.2 mg dose tamsulosin were less likely to discontinue treatment compared to men receiving terazosin. Tamsulosin provided a small to moderate improvement in urinary symptoms and flow compared to men receiving placebo in men with BPH. Effectiveness was similar to other alpha antagonists and increased only slightly with higher doses. Long term effectiveness and ability to reduce complications due to BPH progression could not be determined. Adverse effects were generally mild but their frequency, including withdrawals, increased substantially with the higher doses that are generally available for treatment.


Superoscillatory diffraction-free beams.
It is theoretically shown that by superimposing diffraction-free solutions of the Helmholtz equation, one can construct localized diffraction-free beams that pass through predetermined points on subwavelength distances. These beams are based on the phenomenon of superoscillations and thus do not contain any evanescent waves. The effect of an aperture and noise is examined in specific examples where truncated beams with λ/3 subwavelength features can propagate into the far field.


Autophagy, inflammation and innate immunity in inflammatory myopathies.
Autophagy has a large range of physiological functions and its dysregulation contributes to several human disorders, including autoinflammatory/autoimmune diseases such as inflammatory myopathies (IIMs). In order to better understand the pathogenetic mechanisms of these muscular disorders, we sought to define the role of autophagic processes and their relation with the innate immune system in the three main subtypes of IIM, specifically sporadic inclusion body myositis (sIBM), polymyositis (PM), dermatomyositis (DM) and juvenile dermatomyositis (JDM). We found that although the mRNA transcript levels of the autophagy-related genes BECN1, ATG5 and FBXO32 were similar in IIM and controls, autophagy activation in all IIM subgroups was suggested by immunoblotting results and confirmed by immunofluorescence. TLR4 and TLR3, two potent inducers of autophagy, were highly increased in IIM, with TLR4 transcripts significantly more expressed in PM and DM than in JDM, sIBM and controls, and TLR3 transcripts highly up-regulated in all IIM subgroups compared to controls. Co-localization between autophagic marker, LC3, and TLR4 and TLR3 was observed not only in sIBM but also in PM, DM and JDM muscle tissues. Furthermore, a highly association with the autophagic processes was observed in all IIM subgroups also for some TLR4 ligands, endogenous and bacterial HSP60, other than the high-mobility group box 1 (HMGB1). These findings indicate that autophagic processes are active not only in sIBM but also in PM, DM and JDM, probably in response to an exogenous or endogenous 'danger signal'. However, autophagic activation and regulation, and also interaction with the innate immune system, differ in each type of IIM. Better understanding of these differences may lead to new therapies for the different IIM types.


Relationship characteristics associated with sexual risk behavior among MSM in committed relationships.
Understanding situations that increase HIV risk among men who have sex with men (MSM) requires consideration of the context in which risky behaviors occur. Relationships are one such context. This study examines the presence and predictors of unprotected anal intercourse (UAI) in the past 3 months among 566 MSM couples. A majority of couples allowed sex with outside partners. Overall, 65% of the sample engaged in UAI with primary partner, including nearly half of discordant couples. Positive relationship factors, such as attachment and intimacy, were associated with an increased likelihood of UAI with primary partner. Meanwhile, 22% of the sample engaged in at least one episode of UAI with an outside partner, half of whom were discordant or unknown HIV status outside partners. Higher levels of HIV-specific social support, equality, and sexual agreement investment were significantly associated with a decreased likelihood of engaging in UAI with a discordant or unknown HIV status outside partner. HIV-positive men in discordant relationships had two and one half times the odds of having UAI with a discordant or unknown HIV status outside partner as their HIV-negative partners. Many MSM in relationships, including some in serodiscordant ones, engage in UAI with primary partners. Potential explanations include relationship closeness, relationship length, and agreement type. In addition, relationship context appears to have a differential impact upon UAI with primary and outside partners, implying that prevention messages may need to be tailored for different types of couples. Prevention efforts involving MSM couples must take into account relationship characteristics as couples balance safer sex and HIV risk with intimacy and pleasure.