Assessment of mucosal immunity to HIV-1.
A key gap in the development and evaluation of HIV-1 vaccines is insufficient knowledge with regard to sampling techniques and assessment of mucosal immune responses required for early prevention and inhibition of viral dissemination. In an attempt to start bridging this gap, the EUROPRISE network of scientists working on HIV-1 vaccine and microbicide research organized a workshop with the aim to review the types of mucosal responses/biomarkers currently measured in mucosal immunology and to define how the mucosal responses/biomarkers are measured and/or the assays and sampling methods used. The Workshop addressed two critical questions: first whether, with current knowledge, it would be possible to define a consensus set of mucosal sampling methods to facilitate cross-species comparisons and ensure standardized implementation in clinical trials; second to determine the remaining challenges (technical and logistical) and their possible solutions for assessing mucosal responses to HIV-1 vaccines.


The combination effect of vitamin K and vitamin D on human bone quality: a meta-analysis of randomized controlled trials.
Previous studies did not draw a consistent conclusion about the effects of vitamin K combined with vitamin D on human skeletal quality. A comprehensive search on Web of Science, PubMed, Embase and the Cochrane Library (from 1950 to February 2020) and bibliographies of relevant articles was undertaken, with the meta-analysis of eight randomized controlled trials (RCTs) including a total of 971 subjects. Vitamin K combined with vitamin D significantly increased the total bone mineral density (BMD): the pooled effect size was 0.316 [95% CI (confidence interval), 0.031 to 0.601]. A significant decrease in undercarboxylated osteocalcin (-0.945, -1.113 to -0.778) can be observed with the combination of vitamin K and D. Simultaneously, subgroup analysis showed that K2 or vitamin K (not specified) supplement was less than 500 μg d-1, which when combined with vitamin D can significantly increase the total BMD compared with the control group fed a normal diet or the group with no treatment (0.479, 0.101 to 0.858 and 0.570, 0.196 to 0.945). The combination of vitamin K and D can significantly increase the total BMD and significantly decrease undercarboxylated osteocalcin, and a more favorable effect is expected when vitamin K2 is used.


Migration and invasion of NSCLC suppressed by the downregulation of Src/focal adhesion kinase using single, double and tetra domain anti- CEACAM6 antibodies.
Carcinoembryonic antigen-related cell adhesion molecules 6 (CEACAM6) is a cell adhesion receptor. Expression of CEACAM6 in non-small cell lung cancer (NSCLC) associated with tumor progression and metastatic condition via Src/FAK signaling pathway. We established three anti-CEACAM6 antibodies with valences, which were designed to be monomeric sdAb, bivalent sdAb (2Ab), and tetravalent sdAb (4Ab). The anti-CEACAM6 antibodies can be used to target CEACAM6 overexpressing NSCLC. Anti-CEACAM6 antibodies, sdAb, 2Ab and 4Ab, were modified with different valency via protein engineering. sdAb and multivalent sdAbs (2Ab & 4Ab) were expressed and purified from E.coli and CHO cells, respectively. We compared the effect of anti-CEACAM6 antibodies with doxorubicin in NSCLC cell line both in vitro and in vivo. The 4Ab showed significant effect on cell viability. In addition, A549 cells treated with 2Ab and 4Ab inhibited the invasion and migration. In western blot, the 2Ab and 4Ab showed significant inhibition of phospho FAK domain Ty397 that is essential for activation of Src kinase family. Meanwhile, overall protein analysis revealed that 2Ab and 4Ab potently inhibited the phosphorylation of pSRC, pERK, pFAK, pAKT, MMP-2, MMP-9 and N-cadherin. Anti-tumor effect was observed in an A549 NSCLC xenograft model treated with 2Ab or 4Ab compared with doxorubicin. Confocal analysis showed higher targeting ability of 4Ab than that of 2Ab at 4 h incubation. Our data suggests that 2Ab and 4Ab inhibits EMT-mediated migration and invasion via suppression of Src/FAK signaling, which exhibits therapeutic efficiency for NSCLC treatment.


Hydrogels for sustained delivery of biologics to the back of the eye.
Hydrogels are water-laden polymer networks that have been used for myriad biological applications. By controlling the chemistry through which a hydrogel is constructed, a wide range of chemical and physical properties can be accessed, making them an attractive class of biomaterials. In this review, we cover the application of hydrogels for sustained delivery of biologics to the back of the eye. In adapting hydrogels to this purpose, success is dependent on careful consideration of material properties, route of administration, means of injection, and control of drug efflux, all of which are addressed. We also provide a perspective on clinical and chemistry, manufacturing and controls (CMC) considerations that are integral to the development of an ocular hydrogel delivery system.


In vivo expression of Helicobacter pylori virulence genes in patients with gastritis, ulcer, and gastric cancer.
The best-studied Helicobacter pylori virulence factor associated with development of peptic ulcer disease or gastric cancer (GC) rather than asymptomatic nonatrophic gastritis (NAG) is the cag pathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host epithelial cells. Here we used real-time reverse transcription-PCR (RT-PCR) to measure the in vivo expression of genes on the cagPAI and of other virulence genes in patients with NAG, duodenal ulcer (DU), or GC. In vivo expression of H. pylori virulence genes was greater overall in gastric biopsy specimens of patients with GC than in those of patients with NAG or DU. However, since in vitro expression of cagA was not greater in H. pylori strains from patients with GC than in those from patients with NAG or DU, increased expression in GC in vivo is likely a result of environmental conditions in the gastric mucosa, though it may in turn cause more severe pathology. Increased expression of virulence genes in GC may represent a stress response to elevated pH or other environmental conditions in the stomach of patients with GC, which may be less hospitable to H. pylori colonization than the acidic environment in patients with NAG or DU.


Late first-trimester invasive prenatal diagnosis: results of an international randomized trial.
To assess, in a randomized trial, the safety and accuracy of amniocentesis and transabdominal chorionic villus sampling (CVS) performed at 11-14 weeks of gestation, given that this time frame is increasingly relevant to early trisomy screening. We compared amniocentesis with CVS from 77 to 104 days of gestation in a randomized trial in a predominantly advanced maternal age population. Before randomization, the feasibility of both procedures was confirmed by ultrasonography, and experienced operators performed sampling under ultrasound guidance; conventional cytogenetic analysis was employed. The primary outcome measure was a composite of fetal loss plus preterm delivery before 28 weeks of gestation in cytogenetically normal pregnancies. We randomized 3,775 women into 2 groups (1,914 to CVS; 1,861 to amniocentesis), which were comparable at baseline. More than 99.6% had the assigned procedure, and 99.9% were followed through delivery. In contrast to previous thinking, in the cytogenetically normal cohort (n = 3,698), no difference in primary study outcome was observed: 2.1% (95% confidence interval 1.5, 2.8) for CVS and 2.3% (95% confidence interval, 1.7, 3.1) for amniocentesis. However, spontaneous losses before 20 weeks and procedure-related, indicated terminations combined were increased in the amniocentesis group (P =.07, relative risk 1.74). We found a 4-fold increase in the rate of talipes equinovarus after amniocentesis (P =.02) overall and in week 13 (P =.03, relative risk = 4.65), but data were insufficient to determine this risk in week 14. Amniocentesis at 13 weeks carries a significantly increased risk of talipes equinovarus compared with CVS and also suggests an increase in early, unintended pregnancy loss. I


Differences in Tsimane children's growth outcomes and associated determinants as estimated by WHO standards vs. within-population references.
Anthropometric measures are commonly converted to age stratified z-scores to examine variation in growth outcomes in mixed-age and sex samples. For many study populations, z-scores will differ if calculated from World Health Organization (WHO) growth standards or within-population references. The specific growth reference used may influence statistical estimates of growth outcomes and their determinants, with implications for biological inference. We examined factors associated with growth outcomes in a sample of 152 Tsimane children aged 0-36 months. The Tsimane are a subsistence-scale population in the Bolivian Amazon with high rates of infectious disease and growth faltering. To examine the influence of growth reference on statistical inferences, we constructed multiple plausible models from available infant, maternal, and household attributes. We then ran identical models for height-for-age (HAZ), weight-for-age (WAZ), and weight-for-height (WHZ), with z-scores alternately calculated from WHO and robust Tsimane Lambda-Mu-Sigma growth curves. The distribution of WHO relative to Tsimane HAZ scores was negatively skewed, reflecting age-related increases in lower HAZ. Standardized coefficients and significance levels generally agreed across WHO and Tsimane models, although the strength and significance of specific terms varied in some models. Age was strongly, negatively associated with HAZ and WAZ in nearly all WHO, but not Tsimane models, resulting in consistently higher R2 estimates. Age and weaning effects were confounded in WHO models. Biased estimates of determinants associated with WHO HAZ may be more extreme in small samples and for variables that are strongly age-patterned. Additional methodological considerations may be warranted when applying WHO standards to within-population studies, particularly for populations with growth patterns known to systematically deviate from those of the WHO reference sample.


Asymmetric cortical surface area and morphology changes in mesial temporal lobe epilepsy with hippocampal sclerosis.
To date, magnetic resonance imaging (MRI)-based studies of the cerebral cortex in mesial temporal lobe epilepsy (MTLE) have focused primarily on investigating cortical volume and thickness. However, volume is a composite of surface area and thickness, each reflecting distinct neurobiologic and genetic processes. The goal of this study was to investigate cerebral cortex (1) surface area, (2) surface geometric distortion, and (3) thickness in MTLE with hippocampal sclerosis (HS). Seventy patients with "sporadic" unilateral MTLE + HS and 40 healthy controls underwent T(1) -weighted MRI. Processing MR images using an automated cortical surface reconstruction method (FreeSurfer), we quantified cortical surface area, surface geometric distortion (metric distortion), and thickness at each vertex across the entire cortex. Differences between patients and controls were determined using generalized linear models. Separate linear regression models were employed to assess the relationship between cortical surface area and hippocampal volume as well as a series of important clinical features of the condition. We detected an asymmetric reduction in cortical surface area, predominantly in ipsilateral mesial and anterior temporal lobe subregions, of patients with MTLE + HS. Changes in surface geometric features were also evident and closely mirrored surface area patterns. In contrast, cortical thinning appeared dispersed across the cortex bilaterally. The regression models revealed that ipsilateral hippocampal volume was a significant predictor of temporal lobe surface area changes. Our findings indicate that contraction in surface area, rather than cortical thinning, explains ipsilateral mesial and anterior temporal lobe atrophy in patients with MTLE with HS. Furthermore, the alterations in surface geometry indicate folding abnormality involving the same regions. Cortical surface changes may represent sequelae of the disease or deviant cortical development.


Myocardial protection for cardiac surgery: the nursing perspective.
The advancement of myocardial protection techniques is considered to be the most instrumental in achieving successful cardiac surgical outcomes. Although many issues complicate the efficacy of myocardial protection, warm cardioplegia is instituted more often as a better myocardial protection method for patients undergoing cardiac surgery. Understanding differences in patient response between warm and cold cardioplegia is essential for development of appropriate nursing intervention strategies and prevention of postoperative complications. Advanced practice nurses in cardiac surgical settings must continue to evaluate metabolic, functional, and hemodynamic variations of patients with different cardioplegia for positive patient outcomes.


A flow sensing model for mesenchymal stromal cells using morphogen dynamics.
The differentiation of mesenchymal stromal cells has been shown to be affected by many parameters such as morphogens, flow rate, medium viscosity, and shear stress when exposed to fluid flow. The mechanism by which these cells sense their environment is still under intense discussion. In particular, during flow chamber experiments, it is difficult to interpret the interplay of the above-mentioned parameters in the process of cell differentiation. In this work, we tested the hypothesis that the competition between diffusion and advection of paracrine morphogens could explain the dependency of the cell differentiation to the above-mentioned parameters. To evaluate this hypothesis, we developed a numerical model simulating a simplified version of the advection-diffusion-reaction of morphogens secreted by the cells within a flow chamber. The model predicted a sharp transition in the fraction of receptors bound to the morphogen. This transition was characterized by a new, dimensionless number depending on flow rate, flow viscosity, flow chamber dimensions, and morphogen decay rate. We concluded that the competition between diffusion and advection of paracrine morphogens can act as a probe for the cells to sense their pericellular environment.


Logic model framework for considering the inputs, processes and outcomes of a healthcare organisation-research partnership.
The published literature provides few insights regarding how to develop or consider the effects of knowledge co-production partnerships in the context of delivery system science. To describe how a healthcare organisation-university-based research partnership was developed and used to design, develop and implement a practice-integrated decision support tool for patients with a physician recommendation for colorectal cancer screening. Instrumental case study. Data were ascertained from project documentation records and semistructured questionnaires sent to 16 healthcare organisation leaders and staff, research investigators and research staff members. Using a logic model framework, we organised the key inputs, processes and outcomes of a healthcare organisation-university-based research partnership. In addition to pragmatic researchers, partnership inputs included a healthcare organisation with a supportive practice environment and an executive-level project sponsor, a mid-level manager to serve as the organisational champion and continual access to organisational employees with relevant technical, policy and system/process knowledge. During programme design and implementation, partnership processes included using project team meetings, standing organisational meetings and one-on-one consultancies to provide platforms for shared learning and problem solving. Decision-making responsibility was shared between the healthcare organisation and research team. We discuss the short-term outcomes of the partnership, including how the partnership affected the current research team's knowledge and health system initiatives. Using a logic model framework, we have described how a healthcare organisation-university-based research team partnership was developed. Others interested in developing, implementing and evaluating knowledge co-production partnerships in the context of delivery system science projects can use the experiences to consider ways to develop, implement and evaluate similar co-production partnerships.


Association between antibody titers and protection against influenza virus infection within households.
Previous studies have established that antibody titer measured by the hemagglutination-inhibiting (HAI) assay is correlated with protection against influenza virus infection, with an HAI titer of 1:40 generally associated with 50% protection. We recruited index cases with confirmed influenza virus infection from outpatient clinics, and followed up their household contacts for 7-10 days to identify secondary infections. Serum samples collected from a subset of household contacts were tested by HAI and microneutralization (MN) assays against prevalent influenza viruses. We analyzed the data using an individual hazard-based transmission model that adjusted for age and vaccination history. Compared to a reference group with antibody titers <1:10, we found that HAI titers of 1:40 against influenza A(H1N1) and A(H3N2) were associated with 31% (95% confidence interval [CI], 13%-46%) and 31% (CI, 1%-53%) protection against polymerase chain reaction (PCR)-confirmed A(H1N1) and A(H3N2) virus infection, respectively, while an MN titer of 1:40 against A(H3N2) was associated with 49% (95% CI, 7%-81%) protection against PCR-confirmed A(H3N2) virus infection. An HAI titer of 1:40 was associated with substantially less than 50% protection against PCR-confirmed influenza virus infection within households, perhaps because of exposures of greater duration or intensity in that confined setting.


Regulation of Na+ excretion and arterial blood pressure by purinergic signalling intrinsic to the distal nephron: consequences and mechanisms.
Discretionary control of Na(+) excretion is a key component of the regulation of arterial blood pressure in mammals. Sodium excretion is fine-tuned in the aldosterone-sensitive distal nephron by the activity of the epithelial Na(+) channel (ENaC). Here, ENaC functions as a final effector of the renin-angiotensin-aldosterone system (RAAS) during negative feedback control of blood pressure. Mutations affecting ENaC activity and abnormal regulation of this channel affect blood pressure through pathological changes to Na(+) excretion. Recent evidence demonstrates that powerful signalling pathways function in parallel with the RAAS to modulate ENaC activity and blood pressure. An inclusive paradigm is emerging with respect to regulation of blood pressure where ENaC serves as a critical point of convergence for several important signalling systems that affect renal Na(+) excretion. A robust inhibitory purinergic signalling system intrinsic to the distal nephron dynamically regulates ENaC through paracrine ATP signalling via the metabotropic P2Y2 purinergic receptor to properly match urinary Na(+) excretion to dietary Na(+) intake. This enables blood pressure to be maintained within a normal range despite broad changes in dietary Na(+) consumption. Loss of purinergic inhibition of ENaC increases blood pressure by causing inappropriate Na(+) excretion. In contrast, stimulation of the P2Y2 receptor promotes natriuresis and a decrease in blood pressure. Such observations identify purinergic signalling in the distal nephron as possibly causative, when dysfunctional, for certain forms of elevated blood pressure, and as a possible therapeutic target for the treatment of elevated blood pressure particularly that associated with salt sensitivity.


Electrochemically assisted solid based extraction techniques: a review.
The complexity of the matrices of the analytes from a biological sample or environmental origin can disturb the separation and data analysis steps. Thus, the major incentive of recent research trends in environmental and bioanalysis research is to achieve faster, simpler, inexpensive, and more environmental-friendly sample preparation techniques. Application of auxiliary energies is one of the efficient strategies to reach the aforementioned purposes. Among these, application of electrical driving force in different extraction techniques has found remarkable consideration in recent years attributed to its ability in control of different properties of an extraction system such as selectivity, clean-up, rate, and efficiency by imposition of a variable potential difference. This review attempts to explain the principles of electrically assisted solid based extraction techniques as well as different roles of electrical field in these methods in more details. Also, advantages, disadvantages, and limitations of these techniques are discussed providing coherent information and useful insights for future researches.


Cellular phenotype recognition for high-content RNA interference genome-wide screening.
Genome-wide, cell-based screens using high-content screening (HCS) techniques and automated fluorescence microscopy generate thousands of high-content images that contain an enormous wealth of cell biological information. Such screens are key to the analysis of basic cell biological principles, such as control of cell cycle and cell morphology. However, these screens will ultimately only shed light on human disease mechanisms and potential cures if the analysis can keep up with the generation of data. A fundamental step toward automated analysis of high-content screening is to construct a robust platform for automatic cellular phenotype identification. The authors present a framework, consisting of microscopic image segmentation and analysis components, for automatic recognition of cellular phenotypes in the context of the Rho family of small GTPases. To implicate genes involved in Rac signaling, RNA interference (RNAi) was used to perturb gene functions, and the corresponding cellular phenotypes were analyzed for changes. The data used in the experiments are high-content, 3-channel, fluorescence microscopy images of Drosophila Kc167 cultured cells stained with markers that allow visualization of DNA, polymerized actin filaments, and the constitutively activated Rho protein Rac(V12). The performance of this approach was tested using a cellular database that contained more than 1000 samples of 3 predefined cellular phenotypes, and the generalization error was estimated using a cross-validation technique. Moreover, the authors applied this approach to analyze the whole high-content fluorescence images of Drosophila cells for further HCS-based gene function analysis.


Effect of nutrient and selective inhibitor amendments on methane oxidation, nitrous oxide production, and key gene presence and expression in landfill cover soils: characterization of the role of methanotrophs, nitrifiers, and denitrifiers.
Methane and nitrous oxide are both potent greenhouse gasses, with global warming potentials approximately 25 and 298 times that of carbon dioxide. A matrix of soil microcosms was constructed with landfill cover soils collected from the King Highway Landfill in Kalamazoo, Michigan and exposed to geochemical parameters known to affect methane consumption by methanotrophs while also examining their impact on biogenic nitrous oxide production. It was found that relatively dry soils (5% moisture content) along with 15 mg NH (4) (+) (kg soil)(-1) and 0.1 mg phenylacetylene(kg soil)(-1) provided the greatest stimulation of methane oxidation while minimizing nitrous oxide production. Microarray analyses of pmoA showed that the methanotrophic community structure was dominated by Type II organisms, but Type I genera were more evident with the addition of ammonia. When phenylacetylene was added in conjunction with ammonia, the methanotrophic community structure was more similar to that observed in the presence of no amendments. PCR analyses showed the presence of amoA from both ammonia-oxidizing bacteria and archaea, and that the presence of key genes associated with these cells was reduced with the addition of phenylacetylene. Messenger RNA analyses found transcripts of pmoA, but not of mmoX, nirK, norB, or amoA from either ammonia-oxidizing bacteria or archaea. Pure culture analyses showed that methanotrophs could produce significant amounts of nitrous oxide, particularly when expressing the particulate methane monooxygenase (pMMO). Collectively, these data suggest that methanotrophs expressing pMMO played a role in nitrous oxide production in these microcosms.


Comparison of multiple methods to measure maternal fat mass in late gestation.
Measurements of maternal fat mass (FM) are important for studies of maternal and fetal health. Common methods of estimating FM have not been previously compared in pregnancy with measurements using more complete body composition models. The goal of this pilot study was to compare multiple methods that estimate FM, including 2-, 3- and 4-compartment models in pregnant women at term, and to determine how these measures compare with FM by dual-energy X-ray absorptiometry (DXA) 2 wk postpartum. Forty-one healthy pregnant women with prepregnancy body mass index (in kg/m(2)) 19 to 46 underwent skinfold thickness (SFT), bioelectrical impedance analysis (BIA), body density (Db) via air displacement plethysmography (ADP), and deuterium dilution of total body water (TBW) with and without adjustments for gestational age using van Raaij (VRJ) equations at 37-38 wk of gestation and 2 wk postpartum to derive 8 estimates of maternal FM. Deming regression analysis and Bland-Altman plots were used to compare methods of FM assessment. Systematic differences in FM estimates were found. Methods for FM estimates from lowest to highest were 4-compartment, DXA, TBW(VRJ), 3-compartment, Db(VRJ), BIA, air displacement plethysmography body density, and SFT ranging from a mean ± SD of 29.5 ± 13.2 kg via 4-compartment to 39.1 ± 11.7 kg via SFT. Compared with postpartum DXA values, Deming regressions revealed no substantial departures from trend lines in maternal FM in late pregnancy for any of the methods. The 4-compartment method showed substantial negative (underestimating) constant bias, and the air displacement plethysmography body density and SFT methods showed positive (overestimating) constant bias. ADP via Db(VRJ)and 3-compartment methods had the highest precision; BIA had the lowest. ADP that uses gestational age-specific equations may provide a reasonable and practical measurement of maternal FM across a spectrum of body weights in late pregnancy. SFT would be acceptable for use in larger studies. This trial was registered at clinicaltrials.gov as NCT02586714.


Molecular diversity of structure and function of the voltage-gated Na+ channels.
A variety of different isoforms of voltage-sensitive Na+ channels have now been identified. The recent three-dimensional analysis of Na+ channels has unveiled a unique and unexpected structure of the Na+ channel protein. Na+ channels can be classified into two categories on the basis of their amino acid sequence, Nav1 isoforms currently comprising nine highly homologous clones and Nax that possesses structure diverging from Nav1, especially in several critical functional motifs. Although the functional role of Nav1 isoforms is primarily to form an action potential upstroke in excitable cells, recent biophysical studies indicate that some of the Nav1 isoforms can also influence subthreshold electrical activity through persistent or resurgent Na+ currents. Nav1.8 and Nav1.9 contain an amino acid sequence common to tetrodotoxin resistant Na+ channels and are localized in peripheral nociceptors. Recent patch-clamp experiments on dorsal root ganglion neurons from Nav1.8-knock-out mice unveiled an additional tetrodotoxin-resistant Na+ current. The demonstration of its dependence on Nav1.9 provides evidence for a specialized role of Nav1.9, together with Nav1.8, in pain sensation. Although Nax has not been successfully expressed in an exogenous system, recent investigations using relevant native tissues combined with gene-targeting have disclosed their unique "concentration"-sensitive but not voltage-sensitive roles. In this context, these emerging views of novel functions mediated by different types of Na+ channels are reviewed, to give a perspective for future research on the expanding family of Na+ channel clones.


Vy-PER: eliminating false positive detection of virus integration events in next generation sequencing data.
Several pathogenic viruses such as hepatitis B and human immunodeficiency viruses may integrate into the host genome. These virus/host integrations are detectable using paired-end next generation sequencing. However, the low number of expected true virus integrations may be difficult to distinguish from the noise of many false positive candidates. Here, we propose a novel filtering approach that increases specificity without compromising sensitivity for virus/host chimera detection. Our detection pipeline termed Vy-PER (Virus integration detection bY Paired End Reads) outperforms existing similar tools in speed and accuracy. We analysed whole genome data from childhood acute lymphoblastic leukemia (ALL), which is characterised by genomic rearrangements and usually associated with radiation exposure. This analysis was motivated by the recently reported virus integrations at genomic rearrangement sites and association with chromosomal instability in liver cancer. However, as expected, our analysis of 20 tumour and matched germline genomes from ALL patients finds no significant evidence for integrations by known viruses. Nevertheless, our method eliminates 12,800 false positives per genome (80× coverage) and only our method detects singleton human-phiX174-chimeras caused by optical errors of the Illumina HiSeq platform. This high accuracy is useful for detecting low virus integration levels as well as non-integrated viruses.


Ceftaroline Resistance by Clone-Specific Polymorphism in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus.
A total of 281 nonduplicated Staphylococcus aureus blood isolates were collected from January to May 2017 from eight hospitals in South Korea to investigate the epidemiological traits of ceftaroline resistance in methicillin-resistant S. aureus (MRSA). Cefoxitin-disk diffusion tests and the mecA gene PCR revealed that 56.6% (159/281) of the S. aureus isolates were MRSA, and most belonged to ST5 (50.3%, 80/281) and ST72 (41.5%, 66/281). Of the MRSA isolates, 44.0% (70/159) were nonsusceptible to ceftaroline (MIC ≥ 2 mg/liter), whereas all of the methicillin-susceptible S. aureus isolates were susceptible to the drug. Eight amino acid substitutions in penicillin-binding protein 2a (PBP2a), including four (L357I, E447K, I563T, and S649A) in the penicillin-binding domain (PBD) and four (N104K, V117I, N146K, and A228V) in the non-PBD (nPBD) of PBP2a, were associated with ceftaroline resistance. The accumulation of substitutions in PBP2a resulted in the elevation of ceftaroline MICs: one substitution at 1 to 2 mg/liter, two or three substitutions at 2 to 4 mg/liter, and five substitutions at 4 or 16 mg/liter. Ceftaroline resistance in MRSA might be the result of clone-specific PBP2a polymorphism, along with substitutions both in PBD and nPBD, and the elevated ceftaroline MICs were associated with the substitution sites and accumulation of substitutions.


Double Hole-Lump Interaction between Halogen Atoms.
In this paper a theoretical study has been carried out to investigate the nature of the unusual halogen-halogen contacts in the complexes R-X···X-R (with R = -H, -Cl, -F and X = Cl, Br, I). AIM, NBO, and MEP analyses have been used to characterize X···X interactions. Formation of the unusual X···X interactions leads to a significant increase of electron charge density in the bonding region between the two halogen atoms. The geometry and stability of these complexes is mainly due to electrostatic interactions lump(X1) → hole(X2) and lump(X2) → hole(X1) [or equivalently [VS,min(X1) → VS,max(X2) and VS,min(X2) → VS,max(X1)] and the charge transfers LP(X1) → σ*(R-X2) and LP(X2) → σ*(R-X1). In other words, these findings suggest that the electrostatic interactions and the charge transfer play a substantial role in determining the optimal geometry of these complexes, as in conventional halogen bonds, even though the dispersion term is the most important attractive term for all the complexes studied here, save one.


Modification of the existing maximum residue levels for potassium phosphonates in flowering brassica, Chinese cabbages, kales and spinaches.
In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Tilco-Alginure GmbH submitted a request to the competent national authority in Germany to modify the existing maximum residue levels (MRL) for the active substance potassium phosphonates in flowering brassica, Chinese cabbages, kales and spinaches. The data submitted in support of the request were found to be sufficient to derive MRL proposals for all the crops under assessment. Adequate analytical methods for enforcement are available to control residues of potassium phosphonates in the crops under assessment. Based on the risk assessment results, EFSA concluded that the long-term intake of residues resulting from the use of potassium phosphonates according to the reported agricultural practices is unlikely to present a risk to consumer health. The consumer risk assessment shall be regarded as indicative and a more realistic intake assessment will be performed in the framework of the MRL review for potassium phosphonates. The reliable end points, appropriate for use in regulatory risk assessment are presented.


Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair.
In human cells, efficient global genomic repair of DNA damage induced by ultraviolet radiation requires the p53 tumor suppressor, but the mechanism has been unclear. The p48 gene is required for expression of an ultraviolet radiation-damaged DNA binding activity and is disrupted by mutations in the subset of xeroderma pigmentosum group E cells that lack this activity. Here, we show that p48 mRNA levels strongly depend on basal p53 expression and increase further after DNA damage in a p53-dependent manner. Furthermore, like p53(-/-) cells, xeroderma pigmentosum group E cells are deficient in global genomic repair. These results identify p48 as the link between p53 and the nucleotide excision repair apparatus.


Circulating miRNAs as potential biomarkers in Alzheimer's disease.
Several micro(mi)RNA are deregulated in brain, cerebrospinal fluid (CSF), and serum/plasma from patients with Alzheimer's disease (AD). The aim of the study was to profile circulating miRNAs in serum as non-invasive biomarkers for AD, correlating them with those identified in CSF, the biological fluid which better reflects biochemical changes occurring during pathological processes in the brain and may provide a robust indicator of AD-related disease pathogenesis thanks to the evidence of low amyloid and high levels of tau and hyperphosphorylated tau. Using a two-step analysis (array and validation through real-time PCR), a down-regulation (mean fold change ± SEM) of miR-125b (0.415 ± 0.11 versus 1.381 ± 0.36, p = 0.009), miR-23a (0.111 ± 0.03 versus 0.732 ± 0.14, p < 0.001), and miR-26b (0.414 ± 0.11 versus 1.353 ± 0.39, p < 0.01), out of 84 tested, was shown in serum from 22 AD patients compared with 18 non-inflammatory and 8 inflammatory neurological controls (NINDCs and INDCs) and 10 patients with frontotemporal dementia. Significant down-regulation of miR-125b and miR-26b was also confirmed in CSF from AD patients versus NINDCs (miR-125b: 0.089 ± 0.03 versus 0.230 ± 0.08, p < 0.001; miR-26b: 0.217 ± 0.06 versus 1.255 ± 0.29, p < 0.001, mean fold change ± SEM, respectively), whereas data were not replicated for miR-23a. In serum, miR-125b had an AUC of 0.82 to distinguish AD from NINDCs (95% CI: 0.65-0.98, p = 0.005). In conclusion, we demonstrated that cell-free miR-125b serum levels are decreased in serum from patients with AD as compared with NINDC and distinguish between AD and NINDCs with an accuracy of 82%.


Ovarian cancer: screening, treatment, and followup.
To provide physicians with a current consensus on screening, prevention, diagnosis, and treatment of ovarian cancer. A non-Federal, nonadvocate, 14-member consensus panel representing the fields of gynecologic, medical, and radiation oncology, obstetrics/gynecology, and biostatistics; 25 experts in obstetrics/gynecology and gynecologic, medical, and radiation oncology who presented data to the consensus panel; and a conference audience of approximately 500. The literature was searched through Medline and an extensive bibliography of references was produced for the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given priority over clinical anecdotal experience. The panel, answering predefined consensus questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. The panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. There is no evidence available yet that the current screening modalities of CA 125 and transvaginal ultrasonography can be effectively used for widespread screening to reduce mortality from ovarian cancer nor that their use will result in decreased rather than increased morbidity and mortality. Women with stage IA grade 1 and IB grade 1 ovarian cancer do not require postoperative adjuvant therapy. Many remaining stage I patients do require chemotherapy. Subsets of stage I must be fully defined and ideal treatment determined. Women with stages II, III, and IV epithelial ovarian cancer (other than low malignant potential tumors) should receive postoperative chemotherapy.


Synergistic effect of tocotrienol-rich fraction (TRF(25)) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans.
Tocotrienols exert hypocholesterolemic action in humans and animals. Lovastatin is widely used for that purpose. Both agents work by suppressing the activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase through different mechanisms, post-transcriptional vs competitive inhibition. A human study with 28 hypercholesterolemic subjects was carried out in 5 phases of 35 days each, to check the efficacy of tocotrienol-rich fraction (TRF(25)) of rice bran alone and in combination with lovastatin. After placing subjects on the American Heart Association (AHA) Step-1 diet (phase II), the subjects were divided into two groups, A and B. The AHA Step-1 diet was continued in combination with other treatments during phases III to V. Group A subjects were given 10 mg lovastatin, 10 mg lovastatin plus 50 mg TRF(25), 10 mg lovastatin plus 50 mg alpha-tocopherol per day, in the third, fourth, and fifth phases, respectively. Group B subjects were treated exactly to the same protocol except that in the third phase, they were given 50 mg TRF(25) instead of lovastatin.The TRF(25) or lovastatin plus AHA Step-1 diet effectively lower serum total cholesterol (14%, 13%) and LDL-cholesterol (18%, 15% P < 0.001), respectively, in hypercholesterolemic subjects. The combination of TRF(25) and lovastatin plus AHA Step-1 diet significantly reduces of these lipid parameters of 20% and 25% (P < 0.001) in these subjects. Substitution of TRF(25) with alpha-tocopherol produces insignificant changes when given with lovastatin. Especially significant is the increase in the HDL/LDL ratio to 46% in group (A) and 53% (P < 0.002) in group (B). These results are consistent with the synergistic effect of these two agents. None of the subjects reported any side-effects throughout the study of 25-weeks. In the present study, the increased effectiveness of low doses of tocotrienols (TRF(25)) as hypocholesterolemic agents might be due to a minimum conversion to alpha-tocopherol. The report also describes in vivo the conversion of gamma-[4-3H]-, and [14C]-desmethyl (d-P(21)-T3) tocotrienols to alpha-tocopherol.


The role of immediate and final goals in action planning: an fMRI study.
To interact effectively with our environment, we need to specify the intended outcomes (goals) of our actions. In this process, immediate goals and final goals can be regarded as different levels within a hierarchically organized system for action planning: immediate goals and movement details are selected to accomplish more remote goals. Behavioral studies support this notion of different levels of action planning, but the neurophysiological basis remains unclear. Using fMRI, we examined the neural correlates of preparing object manipulations based on either the desired end-state (the final goal) or the initial movement towards a target (the immediate goal). Subjects had to insert an object (consisting of a large and a small cube) into one of two corresponding large and small slots. The subjects were cued on either which slot to fill (Final Goal trials) or which object part to grasp (Immediate Goal trials). These actions required similar movements, but different planning. During Final Goal trials, there was differential preparatory activity along the superior frontal gyrus (bilaterally) and in left inferior parietal cortex. Immediate Goal trials evoked differential activity in occipito-parietal and occipito-temporal cortex. These findings support the notion that actions can be planned at different levels. We show that different fronto-parietal circuits plan the same action, by a relative emphasis on either selecting a sequence of movements to achieve a desired end-state, or selecting movements spatially compatible with given object properties.


The development of prospective memory across adolescence: an event-related potential analysis.
Prospective memory (PM) is an important cognitive function vital for day-to-day functioning. Although there has been extensive research into the decline of PM in older adulthood, little is known about its developmental trajectory throughout adolescence, a time of important brain maturation. In the present study, the development of PM was examined in 85 participants across the following groups: 12 to 13-year-olds (n = 19), 14 to 15-year-olds (n = 21), 16 to 17-year-olds (n = 19), and 18 to 19-year-olds (n = 26). A 30-cue (30 min) event-based PM task (with font-color stimuli as PM cues and a lexical-decision task as the ongoing task) was used while recording Event-Related Potentials (ERPs). The well-established neural correlates of PM, the N300 and parietal positivity, were examined across the age groups. In addition, hierarchical multiple regressions were used to examine the unique contribution of executive functioning measures (viz., the Self-Ordered Pointing Task [SOPT], the Stroop task, and Trail Making Test [TMT]) on the ERP components of PM (after controlling for age). First, the established components of ERPs associated with prospective remembering (i.e., N300 and parietal positivity) were detected for each age group. Second, although there were no significant age- group differences on the amplitude of the N300, the amplitude of the parietal positivity was found to be different between the 12 to 13-year-olds and 18 to 19-year-olds (viz., the 12 to 13-year-olds had the highest amplitude). Third, for the contribution of executive functioning measures on the amplitude of the ERP components of PM, the regression on the N300 was not significant, however, the SOPT beta weights were significant predictors of the amplitude of the parietal positivity. This relationship was found to be specific for the central and right electrode region. These findings are discussed within the context of brain development and executive functioning along with particular task demands, which may contribute to age-related PM differences across adolescence. Moreover, the findings suggest that cognitive processes associated with parietal positivity may continue to develop across adolescence.


Effect of Patient Portal Reminders Sent by a Health Care System on Influenza Vaccination Rates: A Randomized Clinical Trial.
Influenza vaccination rates across the US are low. Because few practices send patient reminders for influenza vaccination, a scalable patient reminder system is needed. To evaluate the effect of patient reminders sent via a health care system's electronic health record patient portal on influenza vaccination rates. This pragmatic, 4-arm randomized clinical trial was performed from October 1, 2018, to March 31, 2019, across the UCLA (University of California, Los Angeles) health care system. A total of 164 205 patients in 52 primary care practices who had used the patient portal within 12 months were included. Patients due for an influenza vaccine were sent a letter via the patient portal of the health care system reminding them about the importance of influenza vaccination, safety of the vaccine, and morbidity associated with influenza. Patients were randomized within primary care practices to 1 of 4 study groups (no reminder [n = 41 070] vs 1 reminder [n = 41 055], 2 reminders [n = 41 046], or 3 reminders [n = 41 034]). The primary outcome was receipt of 1 or more influenza vaccines as documented in the electronic health record, which was supplemented with influenza vaccination data from external sources (eg, pharmacies). Secondary outcomes were influenza vaccination rates among subgroups and influenza vaccinations self-reported by patients in reply to the portal-based query as having been received elsewhere. A total of 164 205 patients (mean [SD] age, 46.2 [19.6] years; 95 779 [58.3%] female) were randomly allocated to 1 of the 4 study arms. In the primary analysis across all ages and not including patient self-reported vaccinations in reply to portal reminders, influenza vaccination rates were 37.5% for those receiving no reminders, 38.0% for those receiving 1 reminder (P = .008 vs no reminder), 38.2% for those receiving 2 reminders (P = .03 vs no reminder), and 38.2% for those receiving 3 reminders (P = .02 vs no reminder). In the secondary analysis not including patient self-reported vaccinations, among adults aged 18 to 64 years (vaccination rates: 32.0% in the control group, 32.8% in the 1-reminder group, 32.8% in the 2-reminder group, and 32.8% in the 3-reminder group; P = .001), male patients (vaccination rates: 37.3% vs 38.3%, 38.6%, and 38.8%; P = .001), non-Hispanic patients (vaccination rates: 37.6% vs 38.2%, 38.3%, and 38.2%; P = .004), and those who were not vaccinated in the prior 2 years (vaccination rates: 15.3% vs 15.9%, 16.3%, and 16.1%; P < .001), vaccination rates were higher in the portal reminder groups than in the control group; the findings in these 3 subgroups mirrored the findings in the entire population. When self-reported vaccinations received elsewhere were included, influenza vaccination rates were 1.4 to 2.9 percentage points higher in the portal reminder groups, with a dose-response effect (0 reminders: 15 537 [37.8%]; 1 reminder: 16 097 [39.2%]; 2 reminders: 16 426 [40.0%]; and 3 reminders: 16 714 [40.7%]; P < .001). Generic patient portal reminders were effective in minimally increasing influenza vaccination rates, but more intensive or more targeted patient motivational strategies appear to be needed. ClinicalTrials.gov Identifier: NCT03666026.


Social participation as an indicator of successful aging: an overview of concepts and their associations with health.
Objectives Social participation has generated a wealth of research in gerontology, but the concept suffers from a lack of conceptual clarity that renders it difficult to define and measure. This means that research on social participation is difficult to compare directly. The aim of the present study was to draw the literature on social participation in older adults together to inform health services researchers seeking to investigate social participation as an indicator of successful aging. Methods A narrative review of studies investigating the association between social participation and health in adults aged 65 years and older was conducted. Results Three concepts of social participation (i.e. social connections, informal social participation and volunteering) were defined, their measurement instruments described and evidence of their associations with health explored. All three concepts have demonstrated associations with an array of health indicators. Prospective studies reveal that social participation at baseline is positively associated with mental and physical health. Conclusion A model of social participation on health is presented, showing the evidence that all three concepts contribute to the association between social participation and health through their shared mechanisms of social support and social cohesion with the wider community. Using an instrument that can be separated into these three distinct concepts will assist health services researchers to determine the relative effect of each form of participation on the health of older adults. What is known about the topic? Social participation has generated a wealth of research in gerontology. The scope of the literature on social participation is broad and the concepts diverse. For this reason, most previous systematic reviews have been unable to comprehensively assess the effect of all concepts of social participation on health. This means the research on social participation is difficult to compare directly, and indicators of social participation in older adults are difficult for policy makers to select. What does this paper add? This paper overviews the three concepts of social participation, their methods of measurement and their associations with health in older adults. We present a model of social participation that incorporates all three concepts of social participation and their effects on health. We argue that the use of a measure that can be segmented into each of the three forms of social participation will predict more of the variance in health outcomes than any measure on its own. What are the implications for practitioners? Enhancing the social participation of older adults is a key factor in successful aging that many older adults value. However, many service provision organisations tend to focus on meeting the specific physical needs of clients, rather than targeting services that connect older adults with their community. Targeting social participation may present one of the greatest opportunities to improve older adults' general health, and will also generate societal benefits by increasing community contributions from this group. Selecting an indicator of social participation that measures each of the three concepts overviewed in this paper will enable policy makers to identify the areas in which social interventions for older adults will have the most effect.


Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT.
We report the outcome of 229 patients who received an allograft for myeloma with reduced-intensity conditioning (RIC) regimens from 33 centers within the European Group for Blood and Marrow Transplantation (EBMT). The median age was 52 years and 64% were male. Conditioning regimens were heterogeneous, but most were fludarabine based and T cell depleted with antithymocyte globulin or alemtuzumab. Transplantation-related mortality (TRM) at 1 year was 22%. The 3-year overall survival (OS) and progression-free survival (PFS) were 41% and 21%, respectively. Adverse OS was associated with chemoresistant disease (relative risk [RR], 2.9), more than 1 prior transplantation (RR, 2.0), and male patients with female donors (RR, 1.45). Adverse PFS was associated with chemoresistance (RR, 2.4) and alemtuzumab (RR, 1.8). TRM was increased with female-to-male donation (RR, 2.5) and transplantation more than 1 year from diagnosis (RR, 2.3). Grades II to IV acute graft-versus-host disease (aGvHD) occurred in 31%. Chronic GvHD was associated with better OS and PFS and were 84% and 46% for limited, 58% and 30% for extensive, and 29% and 12% in its absence suggesting that a graft-versus-myeloma effect is important. While RIC is feasible, heavily pretreated patients and patients with progressive disease do not benefit.


Transaminase-Mediated Amine Borrowing via Shuttle Biocatalysis.
Shuttle catalysis has emerged as a useful methodology for the reversible transfer of small functional groups, such as CO and HCN, and goes far beyond transfer hydrogenation chemistry. While a biocatalytic hydrogen-borrowing methodology is well established, the biocatalytic borrowing of alternative functional groups has not yet been realized. Herein, we present a new concept of amine borrowing via biocatalytic shuttle catalysis, which has no counterpart in chemo-shuttle catalysis and allows efficient intermolecular amine shuttling to generate reactive intermediates in situ. By coupling this dynamic exchange with an irreversible downstream step to displace the reaction equilibrium in the forward direction, high conversion to target products can be achieved. We showcase the potential of this amine-borrowing methodology using a biocatalytic equivalent of both the Knorr-pyrrole synthesis and Pictet-Spengler reaction.


Inhibition of activation of transcription factor AP-1 by CD28 signalling in human T-cells.
Co-stimulation of T-lymphocytes by T-cell receptor (TcR) occupancy and activation of the CD28 surface molecule results in enhanced proliferation and interleukin 2 (IL-2) production. The increase in IL-2 gene expression triggered by CD28 involves a kappa B-like sequence in the 5'-regulatory region of the IL-2 promoter, called CD28-responsive element. Stimulation of T-cells by agonistic anti-CD28 antibodies in conjunction with phorbol 12-myristate 13-acetate (PMA)- or TcR-derived signals induces the enhanced activation of the transcription factor NF-kappa B. Here we report that CD28 engagement, however, exerts opposite effects on the transcription factor AP-1. Whereas anti-CD28 together with PMA increased the DNA binding and trans-activation activity of NF-kappa B, PMA-induced activation of AP-1 was significantly suppressed. The inhibitory effect exerted by anti-CD28 was observed at the level of DNA binding as well as in functional reporter-gene assays. These results suggest that the two transcription factors are independently regulated and may perform different functions during T-cell activation.


Vibrational structure of the formyl group on heme a. Implications on the properties of cytochrome c oxidase.
Resonance Raman spectra have been recorded for heme a derivatives in which the oxygen atom of the formyl group has been isotopically labeled and for Schiff base derivatives of heme a in which the Schiff base nitrogen has been isotopically labeled. The 14N-15N isotope shift in the C = N stretching mode of the Schiff base is close to the theoretically predicted shift for an isolated C = N group for both the ferric and ferrous oxidation states and in both aqueous and nonaqueous solutions. In contrast, the 16O-18O isotope shift of the C = O stretching mode of the formyl group is significantly smaller than that predicted for an isolated C = O group and is also dependent on whether the environment is aqueous or nonaqueous. This differences between the theoretically predicted shifts and the observed shifts are attributed to coupling of the C = O stretching mode to as yet unidentified modes of the heme. The complex behavior of the C = O stretching vibration precludes the possibility of making simple interpretations of frequency shifts of this mode in cytochrome c oxidase.


Short-term smoking reduction is associated with reduction in measures of lower respiratory tract inflammation in heavy smokers.
The beneficial effect of short-term smoking reduction in reducing lower respiratory tract inflammation was assessed in 15 healthy heavy smokers. All underwent fibreoptic bronchoscopy and bronchoalveolar lavage and were then treated with at least 20 mg of nicotine gum daily. Self-reported cigarette consumption decreased from 50.7 +/- 2.3 to 18.8 +/- 1.5 (p less than 0.001) cigarettes daily, and expired CO decreased from 48.5 +/- 2.5 to 27.3 +/- 2.5 ppm (p less than 0.001). After two months, repeat bronchoscopy and bronchoalveolar lavage revealed that bronchial inflammation, as assessed by direct inspection, neutrophilia of bronchial lavage fluid, and the number of alveolar macrophages, the number of alveolar neutrophils and the concentration of neutrophil elastase alpha 1-antiprotease complex in alveolar lavage fluid, had improved significantly. The present study suggests that smoking reduction may be associated with an improvement in lower respiratory tract inflammation in heavy smokers and may, if persistent, be an alternative for smokers who cannot, or do not wish, to quit.


Inhibitory Plasticity: Balance, Control, and Codependence.
Inhibitory neurons, although relatively few in number, exert powerful control over brain circuits. They stabilize network activity in the face of strong feedback excitation and actively engage in computations. Recent studies reveal the importance of a precise balance of excitation and inhibition in neural circuits, which often requires exquisite fine-tuning of inhibitory connections. We review inhibitory synaptic plasticity and its roles in shaping both feedforward and feedback control. We discuss the necessity of complex, codependent plasticity mechanisms to build nontrivial, functioning networks, and we end by summarizing experimental evidence of such interactions.


Health Behavior Change and Complementary Medicine Use: National Health Interview Survey 2012.
Background and objectives: Complementary and alternative medicine (CAM) use has been associated with preventive health behaviors. However, the role of CAM use in patients' health behaviors remains unclear. This study aimed to determine the extent to which patients report that CAM use motivates them to make changes to their health behaviors. Materials and Methods: This secondary analysis of 2012 National Health Interview Survey data involved 10,201 CAM users living in the United States who identified up to three CAM therapies most important to their health. Analyses assessed the extent to which participants reported that their CAM use motivated positive health behavior changes, specifically: eating healthier, eating more organic foods, cutting back/stopping drinking alcohol, cutting back/quitting smoking cigarettes, and/or exercising more regularly. Results: Overall, 45.4% of CAM users reported being motivated by CAM to make positive health behavior changes, including exercising more regularly (34.9%), eating healthier (31.4%), eating more organic foods (17.2%), reducing/stopping smoking (16.6% of smokers), or reducing/stopping drinking alcohol (8.7% of drinkers). Individual CAM therapies motivated positive health behavior changes in 22% (massage) to 81% (special diets) of users. People were more likely to report being motivated to change health behaviors if they were: aged 18-64 compared to those aged over 65 years; of female gender; not in a relationship; of Hispanic or Black ethnicity, compared to White; reporting at least college education, compared to people with less than high school education; without health insurance. Conclusions: A sizeable proportion of respondents were motivated by their CAM use to undertake health behavior changes. CAM practices and practitioners could help improve patients' health behavior and have potentially significant implications for public health and preventive medicine initiatives; this warrants further research attention.


Quantity and quality of randomized controlled trials published by Indian physiotherapists.
Randomized controlled trials (RCTs) are considered as the gold standard evidence for determining efficacy of interventions. Physiotherapeutic interventions are essential in the management of various conditions. However, information on the quantity and quality of RCTs published by Indian physiotherapists is largely unknown. Therefore, the primary objective of this study was to review the RCTs published by Indian physiotherapists for analyzing publication trend and its quality. Medline database was searched for eligible RCTs published by Indian physiotherapists between the years 2000 and 2013. We performed quantitative analysis of RCTs including type of participants, area of focus in physiotherapy, clinical condition and geographical location of first author's affiliation and analyzed the methodological quality and reporting of RCTs using Physiotherapy Evidence Database (PEDro) scale and consolidated standards of reporting trials (CONSORTs) key criterion statement, respectively. A total of 45 RCTs have been published by Indian physiotherapists. The common conditions investigated in the trials were low back pain (16.3%), followed by diabetes (6.7%) and chronic obstructive pulmonary disease (6.7%). The mean score of PEDro is 5.5 (standard deviation: 1.2). Trial registration (3 [7%]) and sample size calculation (28.9%) are the most common CONSORT items not reported in the trials. RCTs published by Indian physiotherapists is gradually increasing in numbers and the methodological qualities of studies are fair. However, there is substantial scope for improvement in conducting and reporting trials. In the future, Indian physiotherapists should focus more on conditions such as stroke, asthma, and others, which have a larger burden of illness among Indian population.


Validation of reference genes for quantitative real-time PCR studies in the dentate gyrus after experimental febrile seizures.
Quantitative real-time PCR (qPCR) is a commonly used technique to quantify gene expression levels. Validated normalization is essential to obtain reliable qPCR data. In that context, normalizing to multiple reference genes has become the most popular method. However, expression of reference genes may vary per tissue type, developmental stage and in response to experimental treatment. It is therefore imperative to determine stable reference genes for a specific sample set and experimental model. The present study was designed to validate potential reference genes in hippocampal tissue from rats that had experienced early-life febrile seizures (FS). To this end, we applied an established model in which FS were evoked by exposing 10-day old rat pups to heated air. One week later, we determined the expression stability of seven frequently used reference genes in the hippocampal dentate gyrus. Gene expression stability of 18S rRNA, ActB, GusB, Arbp, Tbp, CycA and Rpl13A was tested using geNorm and Normfinder software. The ranking order of reference genes proposed by geNorm was not identical to that suggested by Normfinder. However, both algorithms indicated CycA, Rpl13A and Tbp as the most stable genes, whereas 18S rRNA and ActB were found to be the least stably expressed genes. Our data demonstrate that the geometric averaging of at least CycA, Rpl13A and Tbp allows reliable interpretation of gene expression data in this experimental set-up. The results also show that ActB and 18S rRNA are not suited as reference genes in this model.


Hierarchical levels of representation in language prediction: The influence of first language acquisition in highly proficient bilinguals.
Language comprehension is largely supported by predictive mechanisms that account for the ease and speed with which communication unfolds. Both native and proficient non-native speakers can efficiently handle contextual cues to generate reliable linguistic expectations. However, the link between the variability of the linguistic background of the speaker and the hierarchical format of the representations predicted is still not clear. We here investigate whether native language exposure to typologically highly diverse languages (Spanish and Basque) affects the way early balanced bilingual speakers carry out language predictions. During Spanish sentence comprehension, participants developed predictions of words the form of which (noun ending) could be either diagnostic of grammatical gender values (transparent) or totally ambiguous (opaque). We measured electrophysiological prediction effects time-locked both to the target word and to its determiner, with the former being expected or unexpected. Event-related (N200-N400) and oscillatory activity in the low beta-band (15-17Hz) frequency channel showed that both Spanish and Basque natives optimally carry out lexical predictions independently of word transparency. Crucially, in contrast to Spanish natives, Basque natives displayed visual word form predictions for transparent words, in consistency with the relevance that noun endings (post-nominal suffixes) play in their native language. We conclude that early language exposure largely shapes prediction mechanisms, so that bilinguals reading in their second language rely on the distributional regularities that are highly relevant in their first language. More importantly, we show that individual linguistic experience hierarchically modulates the format of the predicted representation.


Adjuvant endocrine therapy in postmenopausal breast cancer.
Adjuvant endocrine therapy with tamoxifen has a clearly established benefit in postmenopausal women with resected early breast cancer that expresses the estrogen receptor and/or progesterone receptor. Whereas there is a vast and long experience with tamoxifen, the major focus of clinical trials over the past 6 years has involved the study of the third-generation aromatase inhibitors. Recently published data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, which involved only postmenopausal women and is the largest adjuvant trial ever conducted, has demonstrated superior efficacy for anastrozole over tamoxifen alone or in combination with anastrozole. These data have engendered a great deal of discussion as to whether they provide a sufficient basis for changing the standard of practice in terms of choice of agent. Currently, a case can be made that further maturation of the ATAC trial is necessary and that tamoxifen should remain the standard of endocrine adjuvant therapy for most women, with anastrozole being used in those with a contraindication or intolerance to tamoxifen. However, close attention must be paid to new information as it develops not only related to efficacy but also to other end organ effects.


[Trends in the teaching of epidemiology in Brazil].
The teaching of epidemiology in Brazil began in the 1920s and has always been connected to public health. The 1970s witnessed an expansion in the number of graduate-level courses in epidemiology. The 1980s were characterized by "social epidemiology," which incorporated the social sciences and their methods into epidemiology; the second half of the decade was marked by the development of biostatistical techniques. Currently, the definition of guidelines for the teaching of epidemiology in Brazil depends on careful reflection regarding a number of issues, among which are the reformulation or elimination of medical residency programs in preventive medicine, social medicine, and collective health; the creation of masters and doctoral programs exclusively in epidemiology; the conflict between a theoretical emphasis and a technical emphasis; and the development of strategies to strengthen new instructional groups that are being created in teaching institutions in less developed regions of the country. A positive trend is that teaching institutions are working more closely with health services, both for training personnel and for providing technical support in planning, organizing, and evaluating health programs. Regarding the teaching of health service professionals, successful training depends on how well teachers can provide in-service training that ties students' learning to real work situations, where the application of theories can be understood in the natural context of real problems.


Antigenic Variation in the Lyme Spirochete: Insights into Recombinational Switching with a Suggested Role for Error-Prone Repair.
The Lyme disease spirochete, Borrelia burgdorferi, uses antigenic variation as a strategy to evade the host's acquired immune response. New variants of surface-localized VlsE are generated efficiently by unidirectional recombination from 15 unexpressed vls cassettes into the vlsE locus. Using algorithms to analyze switching from vlsE sequencing data, we characterize a population of over 45,000 inferred recombination events generated during mouse infection. We present evidence for clustering of these recombination events within the population and along the vlsE gene, a role for the direct repeats flanking the variable region in vlsE, and the importance of sequence homology in determining the location of recombination, despite RecA's dispensability. Finally, we report that non-templated sequence variation is strongly associated with recombinational switching and occurs predominantly at the 5' end of conversion tracts. This likely results from an error-prone repair mechanism operational during recombinational switching that elevates the mutation rate > 5,000-fold in switched regions.


Giant pituitary adenomas: role of radiotherapy.
Between 1970 and 1989, 31 patients with a diagnosis of giant pituitary adenoma were referred to the London Regional Cancer Center. Giant pituitary adenoma was defined in terms of extension in excess of 40 mm from the midpoint of the jugum sphenoidale. The diagnosis was made surgically in 30 patients and clinically in one. Tumor extent and dimensions were obtained from operative reports and/or radiological scans computed tomography or magnetic resonance imaging. Mean follow-up was 8 years. Initial treatment consisted of surgery alone (4 patients), radiotherapy alone (2 patients) and combined surgery-radiotherapy (25 patients). One patient underwent a needle biopsy for histological confirmation and was grouped with the radiotherapy alone subset. Four of the six patients who received single modality treatment failed initial treatment (three surgery and one radiation). In contrast only 3 of the 25 patients treated with combined surgery-post-operative radiotherapy progressed despite the fact that all patients had gross residual disease post-operatively and that 43% of these patients received radiotherapy based on the post-operative rather than the pre-operative tumor extent. With subsequent salvage, overall tumor control amongst the 31 patients was 93.5%. Complications in general were minimal although one acromegalic patient sustained a unilateral internal capsular cerebrovascular accident year post treatment. In summary, combined modality treatment with initial surgical debulking followed by radiotherapy in the dose range of 4500-5000 cGy over 25 fractions yields tumor control rates in giant pituitary adenomas similar to those of smaller pituitary adenomas without undue morbidity.


Characterization of a supercontinuum generated from a photonic crystal fiber and its application to coherent Raman spectroscopy.
The temporal and spectral profiles of supercontinuum radiation generated from a photonic crystal fiber are evaluated with a polarization-gate frequency-resolved optical gating technique. The supercontinuum is then applied to coherent inverse Raman spectroscopy. A stimulated Raman signal of cyclohexane is observed as an induced absorption signal with an instantaneous response. The Raman signal has a peak at a slight negative delay time, which is explained by perturbed Raman-induced coherence.


Life history patterns shape energy allocation among fishes on coral reefs.
Although critically important, the link between animal life histories and ecosystem energetics is seldom explored. In the pursuit of ecological simplification, ecosystem properties are typically described by models based on static counts, where organisms are aggregated into trophic- or size-based groups. Consequently, output is often based on an assumption that larger group biomass equals greater energetic contribution. Here, we modelled the individual growth of over 58,000 fishes from 74 genera within a coral reef ecosystem to investigate the role and importance of taxon-specific life histories to the division, spatial distribution and relative contribution of biomass production within 14 coral reef fish families. Rank changes among families in standing biomass to biomass production indicated that small cryptic families (e.g. Gobiidae and Blenniidae) exhibit collective growth potentials equal to or exceeding those of many other common families composed of individuals with body-sizes 1-3 orders of magnitude larger. Remaining at high risk of predation throughout their lives as a consequence of their small size, these cryptic fishes also provide a constant food resource and supply of reproductive energy to coral reefs throughout the year. Enhanced further by the strength and diversity of their trophic relationships within food webs, the highly productive nature of these small cryptic fishes suggests they make a substantial contribution to the flow of energy in coral reef ecosystems via predatory pathways. It appears that life histories leave a strong imprint on ecosystem energy fluxes and illustrate the importance of incorporating taxon-specific features when assigning values to key ecosystem processes.


Embryonic stem cell-derived glial precursors as a vehicle for sulfamidase production in the MPS-IIIA mouse brain.
Pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, have generated much excitement about their prospects for use in cell transplantation therapies. This is largely attributable to their virtually unlimited growth potential, their ability to be precisely genetically altered in culture, and their utility for forming differentiated cell populations with potential clinical applications. Lysosomal storage diseases such as Sanfilippo syndrome (MPS-IIIA) represent ideal candidate diseases for the evaluation of cell therapies in the central nervous system (CNS). These diseases exhibit widespread pathology yet result from a single gene deficiency, in the case of Sanfilippo syndrome the lysosomal enzyme sulfamidase. The aim of this study was to investigate mouse embryonic stem (ES) cell-derived glial precursor cells as a vehicle for sulfamidase delivery in the MPS-IIIA mouse brain. In this study we have created a mouse ES cell line genetically modified to stably express and secrete high levels of human sulfamidase and a protocol for the in vitro derivation of large numbers glial precursors from ES cells. Differentiation of sulfamidase-expressing ES cells resulted in cell populations with sustained secretion of high levels of sulfamidase, comprised primarily of glial precursor cells with minor contaminants of other neural cell phenotypes but not residual pluripotent cells. CNS implantation studies demonstrated that ES cell-derived glial precursor cells formed using this differentiation method were able to engraft and survive for at least 12 weeks following implantation. The percentage of engraftment was quantified in different regions of the brain in 2-, 4-, and 8-week-old normal and MPS-IIIA mice. No teratomas were observed in any of the cell-transplanted animals. The results of this study support the further investigation of sulfamidase-expressing glial precursor cells as a vehicle for delivery of deficient enzyme into the CNS of MPS-IIIA mice.


Biochemical characterization of rolledSem, an activated form of Drosophila mitogen-activated protein kinase.
The rolled (rl) gene of Drosophila encodes a homologue of vertebrate mitogen-activated protein kinases. Genetic analyses have shown that the gain-of-function mutation rolledSevenmaker (rlSem) is sufficient to activate developmental pathways controlled by distinct receptor tyrosine kinases, such as Sevenless, Torso, and the Drosophila epidermal growth factor receptor homologue. Here we show that mutant RlSem protein, immunoprecipitated from transiently transfected COS cells, exhibits a moderate increase in kinase activity compared with wild-type Rl protein. Time course studies revealed that RlSem is more active than Rl following short term as well as prolonged treatment with epidermal growth factor. Interestingly, a more pronounced difference in kinase activity is observed when the proteins are immunoprecipitated from extracts of Drosophila rl and rlSem larvae. In fact, the kinase activity of RlSem from larvae extracts is comparable to the kinase activity of larvae expressing either an activated Sevenless receptor or an activated Raf kinase. We also demonstrate that Dsor1, which has been placed upstream of rl genetically, is able to phosphorylate and activate Rl in vitro.


Educational inequalities and premature mortality: the Cuba Prospective Study.
Although socioeconomic status is a major determinant of premature mortality in many populations, the impact of social inequalities on premature mortality in Cuba, a country with universal education and health care, remains unclear. We aimed to assess the association between educational level and premature adult mortality in Cuba. The Cuba Prospective Study (a cohort study) enrolled 146 556 adults aged 30 years and older from the general population in five provinces from Jan 1, 1996, to Nov 24, 2002. Participants were followed up until Jan 1, 2017, for cause-specific mortality. Deaths were identified through linkage to the Cuban Public Health Ministry's national mortality records. Cox regression models yielded rate ratios (RRs) for the effect of educational level (a commonly used measure for social status) on mortality at ages 35-74 years, with assessment for the mediating effects of smoking, alcohol consumption, and BMI. A total of 127 273 participants aged 35-74 years were included in the analyses. There was a strong inverse association between educational level and premature mortality. Compared with a university education, men who did not complete primary education had an approximately 60% higher risk of premature mortality (RR 1·55, 95% CI 1·40-1·72), while the risk was approximately doubled in women (1·96, 1·81-2·13). Overall, 28% of premature deaths could be attributed to lower education levels. Excess mortality in women was primarily due to vascular disease, while vascular disease and cancer were equally important in men. 31% of the association with education in men and 18% in women could be explained by common modifiable risk factors, with smoking having the largest effect. This study highlights the value of understanding the determinants of health inequalities in different populations. Although many major determinants lie outside the health system in Cuba, this study has identified the diseases and risk factors that require targeted public health interventions, particularly smoking. UK Medical Research Council, British Heart Foundation, Cancer Research UK, CDC Foundation (with support from Amgen).


A real-time comparison between direct control, sequential pattern recognition control and simultaneous pattern recognition control using a Fitts' law style assessment procedure.
Pattern recognition (PR) based strategies for the control of myoelectric upper limb prostheses are generally evaluated through offline classification accuracy, which is an admittedly useful metric, but insufficient to discuss functional performance in real time. Existing functional tests are extensive to set up and most fail to provide a challenging, objective framework to assess the strategy performance in real time. Nine able-bodied and two amputee subjects gave informed consent and participated in the local Institutional Review Board approved study. We designed a two-dimensional target acquisition task, based on the principles of Fitts' law for human motor control. Subjects were prompted to steer a cursor from the screen center of into a series of subsequently appearing targets of different difficulties. Three cursor control systems were tested, corresponding to three electromyography-based prosthetic control strategies: 1) amplitude-based direct control (the clinical standard of care), 2) sequential PR control, and 3) simultaneous PR control, allowing for a concurrent activation of two degrees of freedom (DOF). We computed throughput (bits/second), path efficiency (%), reaction time (second), and overshoot (%)) and used general linear models to assess significant differences between the strategies for each metric. We validated the proposed methodology by achieving very high coefficients of determination for Fitts' law. Both PR strategies significantly outperformed direct control in two-DOF targets and were more intuitive to operate. In one-DOF targets, the simultaneous approach was the least precise. The direct control was efficient in one-DOF targets but cumbersome to operate in two-DOF targets through a switch-depended sequential cursor control. We designed a test, capable of comprehensively describing prosthetic control strategies in real time. When implemented on control subjects, the test was able to capture statistically significant differences (p < 0.05) in control strategies when considering throughputs, path efficiencies and reaction times. Of particular note, we found statistically significant (p < 0.01) improvements in throughputs and path efficiencies with simultaneous PR when compared to direct control or sequential PR. Amputees could readily achieve the task; however a limited number of subjects was tested and a statistical analysis was not performed with that population.


Reflex cardiorespiratory responses to pulmonary vascular congestion.
The purpose of these studies was to determine the reflex responses of the cardiovascular system and central inspiratory activity caused by pulmonary vascular congestion. We used a canine preparation in which the left lung was isolated in situ and could be exposed to a variety of stimuli, including distension of the pulmonary capillaries with blood, without direct mechanical or chemical alterations on the circulation. We found that lung expansion to 30 cmH2O and stimulation of nerve endings of the left lung with capsaicin caused pronounced transient reflex bradycardia (-30 to -50 beats/min) and hypotension (-25 to -40 mmHg) and caused reflex cessation of inspiratory activity. Pressurizing the left pulmonary vessels by injecting blood in volumes sufficient to raise pulmonary transcapillary pressures to 30 mmHg caused no changes in heart rate, systemic arterial pressure, or inspiratory muscle activity. These results lead us to conclude that pulmonary vascular congestion does not stimulate pulmonary C-fibers or any other nerve endings to such a degree as to cause detectable changes in blood pressure, heart rate, or central inspiratory activity. Morphometric analysis revealed distended capillaries engorged with blood, but the alveolar wall surface area was not increased which raises the possibility that expansion of the alveolar membrane may be needed to mechanically initiate the C-fiber reflex.


Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Children and Adolescents: A Systematic Review.
The current rapid worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection justifies the global effort to identify effective preventive strategies and optimal medical management. While data are available for adult patients with coronavirus disease 2019 (COVID-19), limited reports have analyzed pediatric patients infected with SARS-CoV-2. To evaluate currently reported pediatric cases of SARS-CoV-2 infection. An extensive search strategy was designed to retrieve all articles published from December 1, 2019, to March 3, 2020, by combining the terms coronavirus and coronavirus infection in several electronic databases (PubMed, Cochrane Library, and CINAHL), and following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Retrospective cross-sectional and case-control studies, case series and case reports, bulletins, and national reports about the pediatric SARS-CoV-2 infection were included. The risk of bias for eligible observational studies was assessed according to the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline. A total of 815 articles were identified. Eighteen studies with 1065 participants (444 patients were younger than 10 years, and 553 were aged 10 to 19 years) with confirmed SARS-CoV-2 infection were included in the final analysis. All articles reflected research performed in China, except for 1 clinical case in Singapore. Children at any age were mostly reported to have mild respiratory symptoms, namely fever, dry cough, and fatigue, or were asymptomatic. Bronchial thickening and ground-glass opacities were the main radiologic features, and these findings were also reported in asymptomatic patients. Among the included articles, there was only 1 case of severe COVID-19 infection, which occurred in a 13-month-old infant. No deaths were reported in children aged 0 to 9 years. Available data about therapies were limited. To our knowledge, this is the first systematic review that assesses and summarizes clinical features and management of children with SARS-CoV-2 infection. The rapid spread of COVID-19 across the globe and the lack of European and US data on pediatric patients require further epidemiologic and clinical studies to identify possible preventive and therapeutic strategies.


Josephson effect in fermionic superfluids across the BEC-BCS crossover.
The Josephson effect is a macroscopic quantum phenomenon that reveals the broken symmetry associated with any superfluid state. Here we report on the observation of the Josephson effect between two fermionic superfluids coupled through a thin tunneling barrier. We show that the relative population and phase are canonically conjugate dynamical variables throughout the crossover from the molecular Bose-Einstein condensate (BEC) to the Bardeen-Cooper-Schrieffer (BCS) superfluid regime. For larger initial excitations from equilibrium, the dynamics of the superfluids become dissipative, which we ascribe to the propagation of vortices through the superfluid bulk. Our results highlight the robust nature of resonant superfluids.


The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms.
Our previous studies have identified berberine (BBR), an alkaloid isolated from the Chinese herb huanglian, as a unique cholesterol-lowering drug that upregulates hepatic low density lipoprotein receptor (LDLR) expression through a mechanism of mRNA stabilization. Here, we demonstrate that the root extract of goldenseal, a BBR-containing medicinal plant, is highly effective in upregulation of liver LDLR expression in HepG2 cells and in reducing plasma cholesterol and low density lipoprotein cholesterol (LDL-c) in hyperlipidemic hamsters, with greater activities than the pure compound BBR. By conducting bioassay-driven semipurifications, we demonstrate that the higher potency of goldenseal is achieved through concerted actions of multiple bioactive compounds in addition to BBR. We identify canadine (CND) and two other constituents of goldenseal as new upregulators of LDLR expression. We further show that the activity of BBR on LDLR expression is attenuated by multiple drug resistance-1 (MDR1)-mediated efflux from liver cells, whereas CND is resistant to MDR1. This finding defines a molecular mechanism for the higher activity of CND than BBR. We also provide substantial evidence to show that goldenseal contains natural MDR1 antagonist(s) that accentuate the upregulatory effect of BBR on LDLR mRNA expression. These new findings identify goldenseal as a natural LDL-c-lowering agent, and our studies provide a molecular basis for the mechanisms of action.


Impact of influenza vaccination on seasonal mortality in the US elderly population.
Observational studies report that influenza vaccination reduces winter mortality risk from any cause by 50% among the elderly. Influenza vaccination coverage among elderly persons (> or =65 years) in the United States increased from between 15% and 20% before 1980 to 65% in 2001. Unexpectedly, estimates of influenza-related mortality in this age group also increased during this period. We tried to reconcile these conflicting findings by adjusting excess mortality estimates for aging and increased circulation of influenza A(H3N2) viruses. We used a cyclical regression model to generate seasonal estimates of national influenza-related mortality (excess mortality) among the elderly in both pneumonia and influenza and all-cause deaths for the 33 seasons from 1968 to 2001. We stratified the data by 5-year age group and separated seasons dominated by A(H3N2) viruses from other seasons. For people aged 65 to 74 years, excess mortality rates in A(H3N2)-dominated seasons fell between 1968 and the early 1980s but remained approximately constant thereafter. For persons 85 years or older, the mortality rate remained flat throughout. Excess mortality in A(H1N1) and B seasons did not change. All-cause excess mortality for persons 65 years or older never exceeded 10% of all winter deaths. We attribute the decline in influenza-related mortality among people aged 65 to 74 years in the decade after the 1968 pandemic to the acquisition of immunity to the emerging A(H3N2) virus. We could not correlate increasing vaccination coverage after 1980 with declining mortality rates in any age group. Because fewer than 10% of all winter deaths were attributable to influenza in any season, we conclude that observational studies substantially overestimate vaccination benefit.


Viscoelastic response to repeated static stretching in the human hamstring muscle.
The purpose of this study was (1) to evaluate the reproducibility of a new method of measuring passive resistance to stretch in the human hamstring muscle group, in vivo, using a test re-test protocol and 2) to examine the effect of repeated stretches. Passive resistance offered by the hamstring muscle group during knee extension was measured in 10 subjects as knee flexion moment (Nm) using a KinCom dynamometer. The knee was passively extended at 5 deg/s to the final position where it remained stationary for 90 s (static phase). EMG of the hamstring muscle was also measured. The test re-test protocol included 2 tests (tests 1 and 2) administered 1 h apart. On a separate occasion 5 consecutive static stretches were administered (stretches 1-5) separted by 30 s. Stretch 6 was administered one hour after stretch 5. In the static phase passive resistance did not differ between test 1 and test 2. Resistance declined in both tests 1 and 2, whereas EMG activity remained unchanged. The decline in resistance was significant up to 45 s. For the repeated stretches there was an effect of time (90 s) and stretch (1-5) with a significant interaction i.e., resistance diminished with stretches, and the 90-s decline was less as more stretches were performed. Passive resistance in stretch 6 was lower than in stretch 1. The present study has demonstrated a reliable method for studying resistance to stretch of the human hamstring muscle group. A viscoelastic response of the human hamstring muscle was shown. With 5 repeated stretches, resistance to stretch diminished and each stretch exibited a viscoelastic response, albeit less with each subsequent stretch. The effect of 5 repeated stretches was significant 1 h later.


Early Colonoscopy in Hospitalized Patients With Acute Lower Gastrointestinal Bleeding: A Nationwide Analysis.
Performing colonoscopy within 24 h of presentation to the hospital is the accepted standard of care for patients with an acute lower gastrointestinal bleed (LGIB). Previous studies have failed to demonstrate the benefit of early colonoscopy (EC) on mortality. In this study, we wanted to see if there was a change in inpatient deaths (primary outcome), length of stay (LOS), and hospitalization charges (TOTCHG) (secondary outcomes) with EC compared to previous studies. Adults diagnosed with LGIB were identified using the International Classification of Disease 10th Revision codes from the National Inpatient Sample database for 2016 to 2019. EC was defined as the procedure performed within 24 h of hospitalization. Delayed colonoscopy (DC) was defined as a procedure performed after 24 h of presentation. The patient population was divided into EC and DC groups, and the effects of several covariates on outcomes were measured using binary logistic and multivariate regression analysis. Inverse probability treatment weighting (IPTW) was performed to adjust for confounding covariates. There were 1,549,065 cases diagnosed with LGIB, of which 285,165 cases (18.4%) received a colonoscopy. A total of 107,045 (6.9%) patients received early colonoscopies. EC was associated with decreased inpatient deaths (0.9% in EC, and 1.4% in DC, P < 0.001). However, upon IPTW, this difference was not present. EC was associated with a decreased LOS (median 3 days vs. 5 days, P < 0.001) and TOTCHG (median $32,037 vs. $44,092, P < 0.001). Weekend admissions (WA) were associated with fewer EC (31.6% in WA, and 39.5% in non-WA, P < 0.001). WA did not affect inpatient deaths. EC was not associated with decreased inpatient deaths. There was no difference in endoscopic interventions in both EC and DC groups. The difference in inpatient deaths observed between the two groups was not evident upon adjusting the results for confounders. EC was associated with a decreased LOS, and TOTCHG in patients with LGIB.


Current and predicted trends in the production, consumption and trade of live animals and their products.
Changes in livestock production, driven by both demand- and supply-side factors, have been significant worldwide. Though historically the developed world was a large supplier of meat and livestock for the developing world, the developing world has rapidly increased production and is meeting more of its growing domestic demand. Many regions of the developing world, however, do not produce enough currently to meet their domestic demand and continue to import more than they produce. There are exceptions, such as Brazil, Thailand, the People's Republic of China and India, where growth in livestock production has been rapid. It is anticipated that in the future many of the developing countries will increase domestic production to meet growing domestic demand. By 2030, beef will probably still be the most significant meat import of developing countries and milk will have more than doubled as a net export of the developed world.


Cytoprotective Effects of Melatonin Against Amitriptyline-Induced Toxicity in Isolated Rat Hepatocytes.
Amitriptyline, one of the commonly used tricyclic antidepressants, caused rare but severe hepatotoxicity in patients who received it continuously. Previous findings showed that the intermediate metabolites of amitriptyline produced by CYP450 are involved in hepatic injury. Melatonin is an antiaging and antioxidant hormone synthesized from pineal gland. The aim of present study was to evaluate the protective role of melatonin in an in vitro model of isolated rat hepatocytes. Markers such as cell viability, reactive oxygen species formation, lipid peroxidation, mitochondrial membrane potential, and hepatocytes glutathione content were evaluated every 60 minutes for 180 minutes. Present results indicated that administration of 1mM of melatonin effectively reduced the cell death, ROS formation and lipid peroxidation, mitochondrial membrane potential collapse, and reduced cellular glutathione content caused by amitriptyline. Our results indicated that melatonin is an effective antioxidant in preventing amitriptyline-induced hepatotoxicity. We recommend further in vivo animal and clinical trial studies on the hepatoprotective effects of melatonin in patients receiving amitriptyline.


Epidermal growth factor receptor ectodomain in the urine of patients with squamous cell carcinoma.
In this study we determined the levels of the epidermal growth factor receptor (EGFR) in the urine of patients with squamous cell carcinoma compared to levels in the urine of normal volunteers and patients with nonsquamous cell carcinoma. A 24-h urine specimen was collected from 50 normal volunteers, 50 patients with nonsquamous cell carcinoma, and 42 patients with squamous cell carcinoma. An ELISA using mAbs to the external domain of the EGFR was used to measure levels of the receptor in the urine samples. Measurement of the EGFR ectodomain in the 24-h urine specimens showed detectable levels in 15 (36%) of 42 squamous cell carcinoma patients compared to 3 (6%) of 50 controls and 8 (16%) of 50 nonsquamous patients. It was also observed that 10 (53%) of 19 patients with metastatic squamous cell carcinoma had detectable EGFR ectodomain levels compared to 5 (22%) of 23 squamous cell patients with localized disease. Thus, we concluded that the EGFR ectodomain was detectable in the urine in a significantly higher number of patients with squamous cell carcinoma than normal volunteers or patients with nonsquamous cell carcinoma.