The FKBP5-gene in depression and treatment response--an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Cohort.
In a recent study of several antidepressant drugs in hospitalized, non-Hispanic White patients, Binder et al. reported association of markers located within the FKBP5 gene with treatment response after 2 and 5 weeks. Individuals homozygous for the TT-genotype at one of the markers (rs1360780) reported more depressive episodes and responded better to antidepressant treatment. There was no association between markers in FKBP5 and disease. The present study aimed at studying the associated FKBP5 markers in the ethnically diverse Sequenced Treatment Alternatives to Relieve Depression (STAR*D) sample of non-hospitalized patients treated with citalopram. We used clinical data and DNA samples from 1809 outpatients with non-psychotic major depressive disorder (DSM-IV criteria), who received up to 14 weeks of citalopram. A subset of 1523 patients of White non-Hispanic or Black race was matched with 739 control subjects for a case-control analysis. The markers rs1360780 and rs4713916 were genotyped on the Illumina platform. TaqMan-assay was used for marker rs3800373. In the case-control analysis, marker rs1360780 was significantly associated with disease status in the White non-Hispanic sample after correction for multiple testing. A significant association was also found between rs4713916 and remission. Markers rs1360780 and rs4713916 were in strong linkage disequilibrium in the White non-Hispanic but not in the Black population. There was no significant difference in the number of previous episodes of depression between genotypes at any of the three markers. These results indicate that FKBP5 is an important target for further studies of depression and treatment response.


Ovalbumin messenger RNA of chick oviduct: partial characterization, estrogen dependence, and translation in vitro.
A rapidly-labeled RNA fraction can be isolated from hen oviduct polysomes that has characteristics of the messenger RNA (mRNA) for the cell-specific protein, ovalbumin. This RNA, which sediments in the 8-17S region of sucrose gradients, possesses properties suggestive of the presence of a polyadenylic acid sequence and can be translated with fidelity in a cell-free protein synthesizing system derived from rabbit reticulocytes. The identity of the protein product as ovalbumin is confirmed by three methods, and translation of ovalbumin mRNA is shown to be dependent both on amount of exogenous mRNA and incubation time. Both rate and extent of ovalbumin synthesis is enhanced by the addition of a protein extract from ribosomes that contains peptide chain initiation factors. Finally, the presence of this specific mRNA is shown to be estrogen-dependent: it is induced by estrogen administration to immature chicks, disappears upon cessation of estrogen treatment, and can be reinduced by a single injection of estrogen to chicks that have been pretreated with estrogen and then withdrawn from the hormone.


Phagocytosis of M. paratuberculosis fails to activate expression of NADH dehydrogenase and nucleolin-related protein in bovine macrophages.
Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) is a facultative intracellular bacterium and causal agent of Johne's disease in cattle. Following phagocytosis, M. paratuberculosis resides and replicates in macrophage phagosomes that fail to mature. Differential display reverse transcription polymerase chain reaction (DDRT-PCR) was used as a high throughput initial screen to begin to test the hypothesis that macrophage gene expression patterns would be differentially affected by M. paratuberculosis when compared to readily degraded bacteria or non-degradable latex beads. Gene expression profiles from immortalized bovine macrophage cells (BOMAC) exposed to M. paratuberculosis were compared to gene expression profiles for BOMAC cells exposed to Escherichia coli, latex beads or PBS. Amplicons representing genes specifically activated or repressed during M. paratuberculosis phagocytosis were cloned for further investigation. Northern blot hybridizations preformed using DDRT-PCR-derived amplicons 3-1-4, 5-2-10, 5-4-2 and 4-1-6 confirmed stimuli dependent differential gene expression. Expression pattern observed for amplicon 3-1-4 represents genes that are up-regulated following phagocytosis of E. coli or latex beads, but not M. paratuberculosis. Amplicon 5-2-10 exhibited a pattern of expression representative of genes that are up-regulated strongly following phagocytosis of E. coli or latex beads but only moderately following M. paratuberculosis phagocytosis. Expression pattern of the gene for amplicon 5-4-2 was representative of genes that are specifically suppressed following M. paratuberculosis phagocytosis, while the amplicon 4-1-6 gene expression pattern represented genes that are generally suppressed following phagocytosis of any of the three stimuli. DNA sequencing and Genbank database analysis of these amplicons revealed that amplicon 3-1-4, whose expression failed to activate following M. paratuberculosis phagocytosis, had high levels of similarity to a Rattus norvegicus nucleolin-related protein (NRP). Amplicon 5-2-10, which increased expression moderately following M. paratuberculosis phagocytosis, was a near perfect match to bovine nicotinamide adenine dinucleotide dehydrogenase (FNADH dehydrogenase) subunit 1 (ND1). Failure to activate these two genes at levels observed following phagocytosis of either E. coli or latex beads may uncover new mechanisms for the survival of M. paratuberculosis within bovine macrophage cells.


Phylogeny of lichen- and non-lichen-forming omphalinoid mushrooms and the utility of testing for combinability among multiple data sets.
As an initial step toward developing a model system to study requirements for and consequences of transitions to mutualism, the phylogeny of a group of closely related lichenized and nonlichenized basidiomycetes (Omphalina) was reconstructed. The phylogenetic analyses are based on four data sets representing different regions of the nuclear ribosomal repeat unit (ITS1, 5.8S, ITS2, and 25S) obtained from 30 species of Omphalina and related genera. The resulting phylogenetic trees from each of these four data sets, when analyzed separately, were not identical. Testing for the combinability of these four data sets suggested that they could not be combined in their entirety. The removal of ambiguous alignments and saturated sites was sufficient, after reapplying the combinability test on the pruned data sets, to explain the topological discrepancies. In this process, the first of two complementary tests developed by Rodrigo et al. (1993, N.Z. J. Bot. 31:257-268) to assess whether two data sets are the result of the same phylogenetic history was found to be biased, rejecting the combinability of two data sets even when they are samples of the same phylogenetic history. Combining the four pruned data sets yielded phylogenies that suggest the five lichen-forming species of Omphalina form a monophyletic group. The sister group to this symbiotic clade consists mostly of dark brown Omphalina species intermixed with species from the genera Arrhenia and Phaeothellus. The genera Omphalina and Gerronema are shown to be polyphyletic. The lichen-forming species O. ericetorum and the nonmutualistic species O. velutipes, O. epichysium, and O. sphagnicola are the best candidates for experimental work designed to gain a better understanding of mechanisms involved in symbiotic interactions and the role symbiosis has played in the evolution of fungi.


Higher Protein Intake Is Associated with Higher Lean Mass and Quadriceps Muscle Strength in Adult Men and Women.
The impact of dietary protein intake on lower extremity lean mass and strength in community-dwelling adult Americans is not fully understood. The objective was to determine the associations between total protein (TP), animal protein (AP), and plant protein (PP) intakes and lean mass of the legs and quadriceps muscle strength. We further examined whether the associations with quadriceps strength may be explained by lean mass of the legs. This cross-sectional study included men (n = 1166) and women (n = 1509) from the Framingham Offspring Cohort in Massachusetts. Protein intake in grams per day was measured in either 1995-1998 or 1998-2001. Leg lean mass and isometric quadriceps strength, both in kilograms, were measured in 1996-2001. Multilinear regression models estimated adjusted least squares means of each of the muscle measures by quartile categories of protein intake, adjusting for relevant confounders and covariates. Mean age was 59 ± 9 y (range: 29-86 y) and TP intake was 80 ± 27 g/d in men and 76 ± 26 g/d in women. In men and women, leg lean mass was higher in participants in the highest quartiles of TP and AP intake compared with those in the lowest quartiles of intake [least squares means (kg): TP-17.6 vs. 17.1 in men, P-trend: 0.005, and 11.7 vs. 11.4 in women, P-trend: 0.006; AP-17.6 vs. 17.1 in men, P-trend: 0.002, and 11.7 vs. 11.4 in women, P-trend: 0.003]. PP intake was not associated with lean mass in either sex. In men and women, quadriceps strength was higher in participants in the highest quartile of PP intake compared with those in the lowest quartile [least squares means (kg): 22.9 vs. 21.7 in men, P-trend: 0.01, and 19.0 vs. 18.2 in women, P-trend: 0.01]; this association was no longer significant after adjustment for fruit and vegetable intake (P-trend: 0.06 in men and 0.10 in women). Although no significant association was observed for AP intake in either sex, nonsignificant protective trends were observed for TP intake (P-trend: 0.08 in men and 0.10 in women). Our findings suggest that maintaining adequate protein intake with age may help preserve muscle mass and strength in adult men and women. Dietary protein types may differentially affect muscle mass and strength. Whether PP is a marker of dietary quality or has a direct effect on muscle strength (independent of lean mass) needs to be further clarified.


Conservation implications of a lack of relationship between baseline glucocorticoids and fitness in a wild passerine.
The application of physiological measures to conservation monitoring has been gaining momentum and, while a suite of physiological traits are available to ascertain disturbance and condition in wildlife populations, glucocorticoids (i.e., GCs; cortisol and corticosterone) are the most heavily employed. The interpretation of GC levels as sensitive indicators of population change necessitates that GCs and metrics of population persistence are linked. However, the relationship between GCs and fitness may be highly context-dependent, changing direction, or significance, depending on the GC measure, fitness metric, life history stage, or other intrinsic and extrinsic contexts considered. We examined the relationship between baseline plasma corticosterone (CORT) levels measured at two periods of the breeding season and three metrics of fitness (offspring quality, reproductive output, and adult survival) in female Tree Swallows (Tachycineta bicolor). Specifically, we investigated whether (1) a relationship between baseline CORT metrics and fitness exists in our population, (2) whether the inclusion of energetic contexts, such as food availability, reproductive investment, or body mass, could alter or improve the strength of the relationship between CORT and fitness, and (3) whether energetic contexts could better predict fitness compared to CORT metrics. Importantly, we investigated these relationships in both natural conditions and under an experimental manipulation of foraging profitability (feather clipping) to determine the influence of an environmental constraint on GC-fitness relationships. We found a lack of relationship between baseline CORT and both short- and long-term metrics of fitness in control and clipped birds. In contrast, loss in body mass over reproduction positively predicted reproductive output (number of chicks leaving the nest) in control birds; however, the relationship was characterized by a low R2 (5%), limiting the predictive capacity, and therefore the application potential, of such a measure in a conservation setting. Our results stress the importance of ground-truthing GC-fitness relationships and indicate that baseline GCs will likely not be easily employed as conservation biomarkers across some species and life history stages. Given the accumulating evidence of temporally dynamic, inconsistent, and context-dependent GC-fitness relationships, placing effort towards directly measuring fitness traits, rather than plasma GC levels, will likely be more worthwhile for many conservation endeavours.


Development of an engineered bioluminescent reporter phage for the sensitive detection of viable Salmonella typhimurium.
Because foodborne illnesses continuously threaten public health, rapid and sensitive detection of pathogens in food has become an important issue. As an alternative to time-consuming and laborious conventional detection methods, a technique using recombinant reporter phages has been developed. Here, we developed an advanced bioluminescent reporter phage SPC32H-CDABE by inserting a bacterial luxCDABE operon into the Salmonella temperate phage SPC32H genome. Whole SPC32H genome sequencing enabled the selection of nonessential genes, which can be replaced with approximately 6-kb luxCDABE operon, which provides both luciferase (LuxAB) and its substrate, fatty aldehyde, as generated by fatty acid reductase (LuxCDE). Thus, the SPC32H-CDABE detection assay is simpler and more efficient compared to the luxAB-based assay because the substrate addition step is excluded. At least 20 CFU/mL of pure S. Typhimurium culture was detectable using SPC32H-CDABE within 2 h, and the signals increased proportionally to the number of cells contaminated in lettuce, sliced pork, and milk. These results thereby demonstrate that this phage successfully detects live Salmonella without appreciable interference from food components. Furthermore, the presented data suggest that SPC32H-CDABE represents a promising easy-to-use diagnostic tool for the detection of Salmonella contamination in food.


The nature and correlates of paid and unpaid work among service users of London Community Mental Health Teams.
Aims. Little is known about how the rates and characteristics of mental health service users in unpaid work, training and study compare with those in paid employment. Methods. From staff report and patient records, 1353 mental health service users of seven Community Mental Health Teams in two London boroughs were categorized as in paid work, unpaid vocational activity or no vocational activity. Types of work were described using Standard Occupational Classifications. The characteristics of each group were reported and associations with vocational status were explored. Results. Of the sample, 5.5% were in paid work and 12.7% were in unpaid vocational activity, (including 5.3% in voluntary work and 8.1% in study or training). People in paid work were engaged in a broader range of occupations than those in voluntary work and most in paid work (58.5%) worked part-time. Younger age and high educational attainment characterized both groups. Having sustained previous employment was most strongly associated with being in paid work. Conclusions. Rates of vocational activity were very low. Results did not suggest a clear clinical distinction between those in paid and unpaid activity. The motivations for and functions of unpaid work need further research.


Aqueous olanexidine versus aqueous povidone-iodine for surgical skin antisepsis on the incidence of surgical site infections after clean-contaminated surgery: a multicentre, prospective, blinded-endpoint, randomised controlled trial.
Surgical site infection (SSI) is the most common problem after surgery. Although several guidelines have indicated the efficacy of antiseptics, such as chlorhexidine-alcohol and povidone-iodine, in reducing SSI rate, the optimal recommendation is still not established. Olanexidine might have higher bactericidal activity than other antiseptic agents. However, no randomised study has evaluated the efficacy and safety of olanexidine over conventional antiseptics. We compared the effect of aqueous olanexidine and aqueous povidone-iodine on the incidence of SSI following clean-contaminated surgery. This was a multicentre, prospective, randomised, blinded-endpoint superiority trial for surgical skin antisepsis in clean-contaminated gastrointestinal and hepatobiliary pancreatic surgeries in four Japanese hospitals. Patients aged 20 years or older who underwent elective clean-contaminated wound surgery were randomly assigned in a 1:1 replacement ratio using a computer-generated block randomisation. Patients were randomly assigned to surgical skin antisepsis with an aqueous formulation of 1·5% olanexidine or surgical skin antisepsis with an aqueous formulation of 10% povidone-iodine before surgery. We used olanexidine in a ready-to-use applicator, and povidone-iodine was administered by a brush or by compression using pliers. Both antiseptics were applied from the papilla with a cranial limit and to the upper thigh with a caudal limit. The antiseptics were allowed to dry for 3 min, and then surgery started. Participants, some investigators, and data analysts were masked to treatment allocation. Participant enrolment was done by non-masked investigators. The primary outcome was 30-day SSI assessed in the intention-to-treat population. The surgical wound site of each participant was observed daily. After discharge, participants underwent at least one outpatient visit within 30 days after surgery. This trial is registered with University hospital Medical Information Network, 000031560. Between June 10, 2018, and April 18, 2019, 883 patients were assessed for eligibility. 587 patients were eligible and 294 received olanexidine and 293 received aqueous povidone-iodine before surgery. 30-day SSI occurred in 19 (7%) patients in the olanexidine group and 39 patients (13%) patients in the povidone-iodine group (adjusted risk difference -0·069; 90% CI -0·109 to -0·029; adjusted risk ratio [RR] 0·48, 90% CI 0·30 to 0·74; p=0·002). Five patients (2%) in the olanexidine group and five (2%) in the povidone-iodine group developed adverse skin reactions (adjusted RR 0·99, 95% CI 0·29 to 3·40; p=1·00). Olanexidine significantly reduced the occurrence of overall SSI and superficial incisional SSI compared with aqueous povidone-iodine in clean-contaminated surgery. Our results indicate that olanexidine might have a role to prevent SSI in patients who undergo clean-contaminated surgeries. Keio University and Ohyama Health Foundation.


Revisiting the classification of curtoviruses based on genome-wide pairwise identity.
Members of the genus Curtovirus (family Geminiviridae) are important pathogens of many wild and cultivated plant species. Until recently, relatively few full curtovirus genomes have been characterised. However, with the 19 full genome sequences now available in public databases, we revisit the proposed curtovirus species and strain classification criteria. Using pairwise identities coupled with phylogenetic evidence, revised species and strain demarcation guidelines have been instituted. Specifically, we have established 77 % genome-wide pairwise identity as a species demarcation threshold and 94 % genome-wide pairwise identity as a strain demarcation threshold. Hence, whereas curtovirus sequences with >77 % genome-wide pairwise identity would be classified as belonging to the same species, those sharing >94 % identity would be classified as belonging to the same strain. We provide step-by-step guidelines to facilitate the classification of newly discovered curtovirus full genome sequences and a set of defined criteria for naming new species and strains. The revision yields three curtovirus species: Beet curly top virus (BCTV), Spinach severe surly top virus (SpSCTV) and Horseradish curly top virus (HrCTV).


To denoise or to cluster, that is not the question: optimizing pipelines for COI metabarcoding and metaphylogeography.
The recent blooming of metabarcoding applications to biodiversity studies comes with some relevant methodological debates. One such issue concerns the treatment of reads by denoising or by clustering methods, which have been wrongly presented as alternatives. It has also been suggested that denoised sequence variants should replace clusters as the basic unit of metabarcoding analyses, missing the fact that sequence clusters are a proxy for species-level entities, the basic unit in biodiversity studies. We argue here that methods developed and tested for ribosomal markers have been uncritically applied to highly variable markers such as cytochrome oxidase I (COI) without conceptual or operational (e.g., parameter setting) adjustment. COI has a naturally high intraspecies variability that should be assessed and reported, as it is a source of highly valuable information. We contend that denoising and clustering are not alternatives. Rather, they are complementary and both should be used together in COI metabarcoding pipelines. Using a COI dataset from benthic marine communities, we compared two denoising procedures (based on the UNOISE3 and the DADA2 algorithms), set suitable parameters for denoising and clustering, and applied these steps in different orders. Our results indicated that the UNOISE3 algorithm preserved a higher intra-cluster variability. We introduce the program DnoisE to implement the UNOISE3 algorithm taking into account the natural variability (measured as entropy) of each codon position in protein-coding genes. This correction increased the number of sequences retained by 88%. The order of the steps (denoising and clustering) had little influence on the final outcome. We highlight the need for combining denoising and clustering, with adequate choice of stringency parameters, in COI metabarcoding. We present a program that uses the coding properties of this marker to improve the denoising step. We recommend researchers to report their results in terms of both denoised sequences (a proxy for haplotypes) and clusters formed (a proxy for species), and to avoid collapsing the sequences of the latter into a single representative. This will allow studies at the cluster (ideally equating species-level diversity) and at the intra-cluster level, and will ease additivity and comparability between studies.


Deep Sequencing of Cell-Free Peripheral Blood DNA as a Reliable Method for Confirming the Diagnosis of Myelodysplastic Syndrome.
Demonstrating the presence of myelodysplastic syndrome (MDS)-specific molecular abnormalities can aid in diagnosis and patient management. We explored the potential of using peripheral blood (PB) cell-free DNA (cf-DNA) and next-generation sequencing (NGS). We performed NGS on a panel of 14 target genes using total nucleic acid extracted from the plasma of 16 patients, all of whom had confirmed diagnoses for early MDS with blasts <5%. PB cellular DNA from the same patients was sequenced using conventional Sanger sequencing and NGS. Deep sequencing of the cf-DNA identified one or more mutated gene(s), confirming the diagnosis of MDS in all cases. Five samples (31%) showed abnormalities in cf-DNA by NGS that were not detected by Sanger sequencing on cellular PB DNA. NGS of PB cell DNA showed the same findings as those of cf-DNA in four of five patients, but failed to show a mutation in the RUNX1 gene that was detected in one patient's cf-DNA. Mutant allele frequency was significantly higher in cf-DNA compared with cellular DNA (p = 0.008). These data suggest that cf-DNA when analyzed using NGS is a reliable approach for detecting molecular abnormalities in MDS and should be used to determine if bone marrow aspiration and biopsy are necessary.


Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease.
A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit β-amyloid peptide (Aβ) formation in Alzheimer's disease (AD). ADAM10 also plays a critical role in regulating functional membrane proteins at the synapse. Using human hippocampal homogenates, we found that ADAM10 removal from the plasma membrane was mediated by clathrin-dependent endocytosis. Additionally, we identified the clathrin adaptor AP2 as an interacting partner of a previously uncharacterized atypical binding motif in the ADAM10 C-terminal domain. This domain was required for ADAM10 endocytosis and modulation of its plasma membrane levels. We found that the ADAM10/AP2 association was increased in the hippocampi of AD patients compared with healthy controls. Long-term potentiation (LTP) in hippocampal neuronal cultures induced ADAM10 endocytosis through AP2 association and decreased surface ADAM10 levels and activity. Conversely, long-term depression (LTD) promoted ADAM10 synaptic membrane insertion and stimulated its activity. ADAM10 interaction with the synapse-associated protein-97 (SAP97) was necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced changes in spine morphogenesis. These data identify and characterize a mechanism controlling ADAM10 localization and activity at excitatory synapses that is relevant to AD pathogenesis.


Aerobic granular sludge treating high strength citrus wastewater: Analysis of pH and organic loading rate effect on kinetics, performance and stability.
In the present paper, the feasibility of citrus wastewater treatment with aerobic granular sludge sequencing batch reactors (AGSBR) was investigated. Two AGSBRs (named R1 and R2, respectively) were operated for 90 days under different organic loading rates (OLR) and pH in two experimental periods. The OLR ranged approximately between 3.0 kg TCOD m-3d-1 and 7 kg TCOD m-3d-1 during Period I, whereas between 7 kg TCOD m-3d-1 and 15 kg TCOD m-3d-1 during Period II. pH was maintained at 7.0 and 5.5 in R1 and R2, respectively. The results revealed that under high OLR and unbalanced feast/famine regime (Period I), the development of fast-growing microorganisms (fungi and filamentous bacteria) was favoured in both reactors, resulting in granular sludge instability. An extended famine phase and a proper balancing between feast and famine periods (Period II) were favourable for the development of bacteria with low growth rates (0.05 d-1) thus enhancing the granules stability. To the benefit of granular sludge stability and effluent quality, the length of the feast period should not exceed 25% of cycle length. Moreover, under OLR lower than 7 kg TCOD m-3d-1 the removal efficiency of total chemical oxygen demand (TCOD) was approximately 90% in R1 and R2 and no side effects on the organic carbon removal performance related to the pH were observed. In contrast, at higher OLR a significant decrease in the removal efficiency (from 90% to less than 75%) was observed in R2. Results revealed also that under low pH, hydrolysis of proteins occurred and a decrease in the biological kinetic rates proportionally to the applied OLR was observed.


A PROCESS OF PRIORITIZING TOPICS FOR HEALTH TECHNOLOGY ASSESSMENT IN KAZAKHSTAN.
The aim of this study was to develop criteria for the prioritization of topics for health technology assessment (HTA) in the healthcare system of Kazakhstan. Initial proposals for criteria were suggested through consultation with Ministry of Health (MoH) policy areas. These were refined through a workshop attended by HTA department staff, persons from medical universities and research institutes, and MoH policy makers. The workshop included discussion on methods used in international HTA practice. Opinions of participants on selection of criteria from those specified in a review of prioritization processes were used to define a list for inclusion in an instrument for routine use. A scoring system was established in later discussion. Selected criteria for HTA prioritization were burden of disease, availability of alternative technology, clinical effectiveness, economic efficiency, budget impact, and ethical, legal, and/or psychosocial aspects. For each criterion, a health technology under consideration is given a score from 3 (High) to 1 (Low). The total score determines whether the technology is of high to medium priority or of low priority. Determination of priorities for assessment, using the instrument, should be carried out by an expert group appointed by the MoH. The process was applied in 2014 to a selection of topics, and three health technologies were chosen for full assessments. Criteria for prioritization have evolved with development of the HTA program in Kazakhstan. A method for HTA prioritization has been developed that is easy to apply, requires comparatively few resources, and is compatible with processes required by the MoH.


Stronger Is Better: The Impact of Upper Body Strength in Double Poling Performance.
The purpose of the present study was to compare time results from a roller-skiing double poling (DP) time trial with different physiological variables, muscular strength variables, and DP characteristics in both male and female young competitive skiers with the same relative training background. In order to do this, 28 (16 women and 12 men) well-trained 16-25-year-old cross-country skiers from three Norwegian high schools for skiers, as well as local high performance competitive skiers from the South-East of Norway were recruited to participate in the study. All participants were tested for; maximal oxygen uptake in running, Peak oxygen uptake in DP, lactate threshold in DP, DP economy, time to voluntary exhaustion in DP, force analyses in DP, one repetition maximum and power output in pulldown, and leg press and a time trial during DP roller skiing. The results expressed strong correlations between roller skiing time trial performance and maximal strength in pull-down, both independent (r xy = -0.83, p < 0.01) and dependent (r xy-z = -0.50, p < 0.02) of sex. Higher maximal upper body strength was related to higher DP peak forces (PF) (r xy = 0.78, p < 0.02), lower DP frequency (r xy = -0.71, p < 0.01), and shorter DP contact time (CT) (r xy = -0.48, p < 0.02). The practical implications of the present study is to acknowledge maximal upper body strength as a performance determining factor in DP. This point at the importance of including maximal strength training in cross-country skiers training programs.


Photonic-to-plasmonic mode converter.
A novel photonic-to-plasmonic mode converter for efficiently converting a silicon strip waveguide mode to a gap surface plasmon polariton (SPP) of a metallic slot structure is proposed. A conversion efficiency of more than 85% is found for metallic slots with a slot size of 30-50 nm. Calculations show that high conversion efficiencies can be achieved for various cladding materials with refractive indices of 1.44, 1.6, and 1.7. The optical 1 dB bandwidth of the converter is around 200 nm. The proposed mode converter shows a good tolerance with respect to fabrication errors, and it requires a simple fabrication procedure only.


How the Local Environment of Functional Sites Regulates Protein Function.
Proteins form complex biological machineries whose functions in the cell are highly regulated at both the cellular and molecular levels. Cellular regulation of protein functions involves differential gene expressions, post-translation modifications, and signaling cascades. Molecular regulation, on the other hand, involves tuning an optimal local protein environment for the functional site. Precisely how a protein achieves such an optimal environment around a given functional site is not well understood. Herein, by surveying the literature, we first summarize the various reported strategies used by certain proteins to ensure their correct functioning. We then formulate three key physicochemical factors for regulating a protein's functional site, namely, (i) its immediate interactions, (ii) its solvent accessibility, and (iii) its conformational flexibility. We illustrate how these factors are applied to regulate the functions of free/metal-bound Cys and Zn sites in proteins.


Impact of Digoxin on Mortality in Patients With Atrial Fibrillation Stratified by Heart Failure: Findings From Gulf Survey of Atrial Fibrillation Events in the Middle East.
The use of digoxin in patients having atrial fibrillation (AF) with or without heart failure (HF) is not without controversy. The aim of this study was to examine the impact of digoxin therapy on mortality stratified by HF. Gulf Survey of Atrial Fibrillation Events was a prospective, multinational, observational registry of consecutive patients with AF recruited from the emergency department of 23 hospitals in 6 countries in the Middle East. Patients were recruited between October 2009 and June 2010 and followed up for 1 year after enrollment. Analyses were performed using univariate and multivariate statistical techniques. The study included a total of 1962 patients with AF, with an overall mean age of 56 ± 16 years, and 52% (n = 1026) were males. At hospital discharge, digoxin was prescribed in 36% (n = 709) of the patients, whereas HF was present in 27% (n = 528) of the cohort. A total of 225 (12.1%) patients died during the 12-month follow-up period after discharge (5.3% [n = 104] were lost to follow-up). Patients with HF were consistently associated with higher mortality at 1 month (5.1% vs 2.1%; P < .001), 6 months (17.2% vs 5.0%; P < 0.001), and 12 months (24.3% vs 7.6%; P < .001) when compared to those without HF. When stratified by HF, digoxin therapy was associated with significantly higher mortality in those without HF at 6 months (8.7% vs 3.7%; adjusted odds ratio (aOR), 5.07; P < .001) and 12 months (12.3% vs 6.0%; aOR, 4.22; P < .001) but not in those with HF (6 months: 18.6% vs 14.7%; aOR, 1.62; P = .177 and 12 months: 25.4% vs 22.4%; aOR, 1.37; P = .317). In patients with AF and HF, digoxin did not offer any survival advantages. However, in those without HF, digoxin therapy was, in fact, associated with significantly higher long-term mortality.


Clinical aspects of reactive oxygen and nitrogen species.
Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.


Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.
To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women. Open label, randomised controlled trial. Denmark, 1990-93. 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone. In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years. The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction. At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer. After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke. ClinicalTrials.gov NCT00252408.


Investigation of Aspergillus fumigatus biofilm formation by various "omics" approaches.
In the lung, Aspergillus fumigatus usually forms a dense colony of filaments embedded in a polymeric extracellular matrix called biofilm (BF). This extracellular matrix embeds and glues hyphae together and protects the fungus from an outside hostile environment. This extracellular matrix is absent in fungal colonies grown under classical liquid shake conditions (PL), which were historically used to understand A. fumigatus pathobiology. Recent works have shown that the fungus in this aerial grown BF-like state exhibits reduced susceptibility to antifungal drugs and undergoes major metabolic changes that are thought to be associated to virulence. These differences in pathological and physiological characteristics between BF and liquid shake conditions suggest that the PL condition is a poor in vitro disease model. In the laboratory, A. fumigatus mycelium embedded by the extracellular matrix can be produced in vitro in aerial condition using an agar-based medium. To provide a global and accurate understanding of A. fumigatus in vitro BF growth, we utilized microarray, RNA-sequencing, and proteomic analysis to compare the global gene and protein expression profiles of A. fumigatus grown under BF and PL conditions. In this review, we will present the different signatures obtained with these three "omics" methods. We will discuss the advantages and limitations of each method and their complementarity.


Current updates on laboratory techniques for the diagnosis of male reproductive failure.
The incidence of male reproductive failure leading to infertility, whether due to delayed parenthood, environmental issues, genetic factors, drugs, etc., is increasing throughout the world. The diagnosis and prognosis of male subfertility have become a challenge. While the basic semen assessment has been performed for many years, a number of studies question the value of the traditional semen characteristics. This is partly due to inadequate methods and standardization, limited knowledge of technical requirements for quality assurance, and an incomplete understanding of what clinical information a semen assessment can provide. Laboratories currently performing semen and endocrine assessment show great variability. The World Health Organization (WHO) manual for the evaluation of semen has been the core of andrology and fertility evaluation that has helped in further development of this field over many years. These include the physical appearance of the ejaculate, assessments of sperm count, motility, vitality, morphology, and functional aspects of the sperm and semen sample. These tests also include male endocrine profile, biochemical evaluation of the semen, detection of antisperm antibodies in serum, the use of computer-aided sperm analysis (CASA), sperm DNA integrity, and its damage due to oxidative stress. Assisted reproductive techniques (e.g., IVF, ICSI) have shown great success but are too expensive. Further development in this field with newer techniques and extensive training/instructions can improve accuracy and reduce variability, thus maintaining the quality and standards of such an evaluation. There is an urgent need to have standardized training centers and increased awareness in this area of men's health for reproductive success.


Proper care for the dying: a critical public issue.
The ability of the medical profession to sustain life, or more appropriately, to prolong dying, in patients with terminal illness, creates a most complex and controversial situation for all involved: the patient, if mentally alert; the patient's family; and the medical care team including physicians, nurses and attendants. This situation is especially complex in large acute care hospitals where medical and nursing students, residents and house officers receive advanced medical training. A major problem, prolonging the dying of the terminally ill, with its medical, legal, ethical and economic complexities now confronts American society. The problem is particularly acute in teaching hospitals, in which one finds a disproportionate number of terminally ill patients. The ability to work at these questions as a community rather than as adversaries will determine much about the ability of the health care system to respect the dignity and autonomy of those who seek aid and comfort when faced with serious illness and impending death. Better communication between the physicians, health care providers, the lawyers and ethicists must be developed in order to solve these problems. Over the next ten years society and our elected representatives will be making very demanding decisions about the use of the health dollar. One possible way to prevent increasing costs is to reach significant agreement on the proper care of the dying. Proper care for the dying is being considered, discussed, and evaluated by very thoughtful people. It is not governments which should decide who is to live or who is to die. There is the serious problem of the 'slippery slope' to euthanasia by omission if cost containment becomes the major force in formulating policy on the proper care of the dying.


Mitral regurgitation surgery in patients with ischemic cardiomyopathy and ischemic mitral regurgitation: factors that influence survival.
The treatment of patients with ischemic cardiomyopathy and concomitant mitral regurgitation can be challenging and is associated with reduced long-term survival. It is unclear how mitral valve repair versus replacement affects subsequent outcome. Therefore, we conducted this study to understand the predictors of mortality and to delineate the role of mitral valve repair versus replacement in this high-risk population. From 1993 to 2007, 431 patients (mean age, 70 ± 9 years) with ischemic cardiomyopathy (left ventricular ejection fraction ≤ 45%) and significant ischemic mitral regurgitation (>2) were identified. Patients (44) with concomitant mitral stenosis were excluded from the analysis. A homogeneous group of 387 patients underwent combined coronary artery bypass grafting and mitral valve surgery, mitral valve repair in 302 (78%) and mitral valve replacement in 85 (22%). Uni- and multivariate analyses were performed on the entire cohort, and the predictors of mortality were identified in 2 distinct risk phases. Furthermore, we specifically examined the impact of mitral valve repair versus replacement by comparing 2 propensity-matched subgroups. Follow-up was 100% complete (median, 3.6 years; range, 0-15 years). Overall 1-, 5-, and 10-year survivals were 82.7%, 55.2%, and 24.3%, respectively, for the entire group. The risk factors for an increased mortality within the first year of surgery included previous coronary artery bypass grafting (hazard ratio = 3.39; P < .001), emergency/urgent status (hazard ratio = 2.08; P = .007), age (hazard ratio = 1.5; P = .03), and low left ventricular ejection fraction (hazard ratio = 1.31; P = .026). Thereafter, only age (hazard ratio = 1.58; P < .001), diabetes (hazard ratio = 2.5; P = .001), and preoperative renal insufficiency (hazard ratio = 1.72; P = .025) were predictive. The status of mitral valve repair versus replacement did not influence survival, and this was confirmed by comparable survival in propensity-matched analyses. Survival after combined coronary artery bypass grafting and mitral valve surgery in patients with ischemic cardiomyopathy (left ventricular ejection fraction ≤ 45%) and mitral regurgitation is compromised and mostly influenced by factors related to the patient's condition at the time of surgery. The specifics of mitral valve repair versus replacement did not seem to affect survival.


Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA.
Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.


The Management of Myelomeningocele Study: full cohort 30-month pediatric outcomes.
Previous reports from the Management of Myelomeningocele Study demonstrated that prenatal repair of myelomeningocele reduces hindbrain herniation and the need for cerebrospinal fluid shunting, and improves motor function in children with myelomeningocele. The trial was stopped for efficacy after 183 patients were randomized, but 30-month outcomes were only available at the time of initial publication in 134 mother-child dyads. Data from the complete cohort for the 30-month outcomes are presented here. Maternal and 12-month neurodevelopmental outcomes for the full cohort were reported previously. The purpose of this study is to report the 30-month outcomes for the full cohort of patients randomized to either prenatal or postnatal repair of myelomeningocele in the original Management of Myelomeningocele Study. Eligible women were randomly assigned to undergo standard postnatal repair or prenatal repair <26 weeks gestation. We evaluated a composite of mental development and motor function outcome at 30 months for all enrolled patients as well as independent ambulation and the Bayley Scales of Infant Development, Second Edition. We assessed whether there was a differential effect of prenatal surgery in subgroups defined by: fetal leg movements, ventricle size, presence of hindbrain herniation, gender, and location of the myelomeningocele lesion. Within the prenatal surgery group only, we evaluated these and other baseline parameters as predictors of 30-month motor and cognitive outcomes. We evaluated whether presence or absence of a shunt at 1 year was associated with 30-month motor outcomes. The data for the full cohort of 183 patients corroborate the original findings of Management of Myelomeningocele Study, confirming that prenatal repair improves the primary outcome composite score of mental development and motor function (199.4 ± 80.5 vs 166.7 ± 76.7, P = .004). Prenatal surgery also resulted in improvement in the secondary outcomes of independent ambulation (44.8% vs 23.9%, P = .004), WeeFIM self-care score (20.8 vs 19.0, P = .006), functional level at least 2 better than anatomic level (26.4% vs 11.4%, P = .02), and mean Bayley Scales of Infant Development, Second Edition, psychomotor development index (17.3% vs 15.1%, P = .03), but does not affect cognitive development at 30 months. On subgroup analysis, there was a nominally significant interaction between gender and surgery, with boys demonstrating better improvement in functional level and psychomotor development index. For patients receiving prenatal surgery, the presence of in utero ankle, knee, and hip movement, absence of a sac over the lesion and a myelomeningocele lesion of ≤L3 were significantly associated with independent ambulation. Postnatal motor function showed no correlation with either prenatal ventricular size or postnatal shunt placement. The full cohort data of 30-month cognitive development and motor function outcomes validate in utero surgical repair as an effective treatment for fetuses with myelomeningocele. Current data suggest that outcomes related to the need for shunting should be counseled separately from the outcomes related to distal neurologic functioning.


Mild Cognitive Impairment and Dementia Show Contrasting Associations with Risk of Cancer.
To investigate and to compare the relation between dementia and cancer with the association between mild cognitive impairment (MCI) and cancer. A total of 13,207 persons from the Rotterdam Study were followed between 1990 and 2013 for the onset of dementia and cancer (sample 1). Between 2002 and 2005, a subset of 5,181 persons underwent extensive cognitive testing for MCI and subsequently were followed up for cancer until 2013 (sample 2). We used Cox proportional hazard models to determine the association between dementia and cancer, and MCI and cancer. In sample 1, 1,404 patients were diagnosed with dementia, and 2,316 developed cancer (63 among dementia cases). Dementia was associated with a decreased risk of cancer (hazard ratio [HR] 0.53; 95% CI 0.41-0.68). In sample 2, 513 persons were diagnosed with MCI and 670 persons developed cancer (81 among MCI cases). In contrast to individuals with dementia, those with MCI tended to have an increased risk of cancer (HR 1.25; 95% CI 0.99-1.58). We found that persons with MCI tended to have an increased risk of cancer, whereas those with dementia have a decreased risk. These findings call into question a biological explanation for the inverse link between dementia and cancer, thereby suggesting the presence of methodological bias.


Current and Future Burden of Chronic Nonmalignant Liver Disease.
Disease burden is an important indicator of the state of health of a population. It can be measured as the frequency (eg, incidence and prevalence) of a condition or its effects including fatal and non-fatal health loss from disease (eg, disability-adjusted life years) as well as the financial costs (eg, direct healthcare costs and indirect healthcare expenditures related to lost income because of premature death). Accurate disease burden information is essential for policy-making such as prioritization of health interventions and allocation of resources. Chronic liver disease (CLD) causes substantial health and economic burden in the United States, where nearly 2 million deaths annually are attributable to CLD. In the recent past, overall mortality rate of CLD has been increasing. Viral hepatitis and alcoholic liver disease are thought to be the most common etiologies of chronic liver diseases. More recently, the prevalence of nonalcoholic fatty liver disease is rapidly increasing, and nonalcoholic steatohepatitis has become a leading indication for liver transplantation. In this article, we assemble available data on the burden of CLD in the United States, focusing on nonmalignant complications, whereas the impact on mortality and healthcare expenses of hepatocellular carcinoma, an important consequence of CLD, is discussed elsewhere.


Single-Molecule Imaging Reveals How Mre11-Rad50-Nbs1 Initiates DNA Break Repair.
DNA double-strand break (DSB) repair is essential for maintaining our genomes. Mre11-Rad50-Nbs1 (MRN) and Ku70-Ku80 (Ku) direct distinct DSB repair pathways, but the interplay between these complexes at a DSB remains unclear. Here, we use high-throughput single-molecule microscopy to show that MRN searches for free DNA ends by one-dimensional facilitated diffusion, even on nucleosome-coated DNA. Rad50 binds homoduplex DNA and promotes facilitated diffusion, whereas Mre11 is required for DNA end recognition and nuclease activities. MRN gains access to occluded DNA ends by removing Ku or other DNA adducts via an Mre11-dependent nucleolytic reaction. Next, MRN loads exonuclease 1 (Exo1) onto the free DNA ends to initiate DNA resection. In the presence of replication protein A (RPA), MRN acts as a processivity factor for Exo1, retaining the exonuclease on DNA for long-range resection. Our results provide a mechanism for how MRN promotes homologous recombination on nucleosome-coated DNA.


Complications of chronic suppurative otitis media: a retrospective review.
The purpose of this study was to review our patients with complications of chronic suppurative otitis media (CSOM) and compare with literature. This retrospective study was performed over 10 years in our tertiary referral university hospital. During this period 4,630 patients with CSOM were admitted to the department and 906 patients underwent a surgery. From the records of the 4,630 patients, 121 patients (2.6%) with complications were identified. Of the 906 CSOM patients that underwent a surgery, 511 had cholesteatoma, and 395 had granulation and/or polyp tissue. Ninety-four of 511 (18.4%) patients with cholesteatoma and 27 of 395 (6.8%) patients with granulation and/or polyp tissue had a complication. Of the 121 complicated CSOM patients, 57 extracranial (47.1%) and 37 intracranial (30.6%). Multiple combined complications were occurred in 27 (22.3%) patients. The mastoid abscess was the commonest extracranial complication (28.3%); it was followed by labyrinthitis (9%), facial nerve paralysis (8.4%), and Bezold's abscess (1.3%). The most common intracranial complication was lateral sinus thrombophlebitis (19.5%), followed by perisigmoid sinus abscess (13.5%), meningitis (9%), brain abscess (6.5%), and extradural abscess (4.5%). Most frequent intraoperative finding of complicated CSOM patients was cholesteatoma, with the exception of patients with facial nerve paralysis. There was no mortality in any of our patients. The additional morbidities were recorded in 25 patients (20.6%). In this study, we emphasize the importance of an accurate and early diagnosis, followed by adequate surgical therapy and a multidisciplinary approach.


[Characterization of assistance among philanthropic hospitals in Brazil].
To characterize the Brazilian philanthropic hospital network and its relation to the public and private sectors of the Sistema Unico de Saude (SUS) [Brazilian Unified Health System]. This is a descriptive study that took into consideration the geographic distribution, number of beds, available biomedical equipment, health care complexity as well as the productive and consumer profiles of philanthropic hospitals. It is based on a sample of 175 hospitals, within a universe of 1,917, involving 102 distinct institutions. Among these, there were 66 Brazilian Unified Health System (SUS) inpatient care providers with less than 599 beds randomly included in this study. Twenty-six of the twenty-seven SUS inpatient care providers with at least 599 beds, as well as ten institutions which do not provide their services to SUS, were also included. This is a cross-sectional study and the data was obtained in 2001. Data collection was conducted by trained researchers, who applied a questionnaire in interviews with the hospital's managers. Within the random sample, 81.2% of the hospitals are located in cities outside of metropolitan areas, and 53.6% of these are the only hospitals within their municipalities. Basic clinical hospitals, without ICUs, predominate within the random sample (44.9%). Among the individual hospitals of the large philanthropic institutions and the special hospitals, the majority -- 53% and 60% respectively -- are level II general hospitals, a category of greater complexity. It was verified that complexity of care was associated to hospital size, being that hospitals with the greatest complexity are situated predominantly in the capitals. Given the importance of the philanthropic hospital sector within the SUS [Unified Health System] in Brazil, this paper identifies some ways of formulating appropriate health policies adjusted to the specificities of its different segments.


A comparison of cranial fluctuating asymmetry between the two sexes in a Joseon Dynasty population of Korea.
Cranial fluctuating asymmetry (FA) has been used to examine developmental stress levels in various populations. In bioarchaeological studies, developmental stress can be an important factor for inferring standard of living in a population. However, the crania of a Joseon Dynasty population have only been studied in terms of its morphological characteristics. In this regard, the cranial FA of the two sexes from a Joseon Dynasty population of Korea were compared here for examining their aspects of living conditions in relation to developmental stress and socio-cultural factors. In this study, 77 individuals (39 males and 38 females) who belong to the 15th to the early-20th centuries from Seoul and Gyeonggi province in Korea were investigated. Nineteen three-dimensional landmarks on the vault and basicranium were collected using MicroScribe G2X. The coordinate data were aligned into a common coordinate plane by Procrustes least-squares superimposition. Procrustes ANOVA was adopted to evaluate FA at a population level. The FA of males and females were compared with t-test using SPSS 18. There was statistically insignificant difference in FA between the two sexes in the Joseon Dynasty population. The result was interpreted to reflect both relatively high developmental stress and sex-related discrimination in the population. It was postulated that relatively high developmental stress could increase difference in FA between the two sexes in the prenatal term compared to the postnatal term because sex-related discrimination cannot be practiced before birth and males have lower stress resistance than females. Then, the difference between the two sexes in the cranial FA could be decreased during postnatal development related to sex-related discrimination, resulting in insignificant FA difference of the two sexes in spite of high developmental stress of the Joseon Dynasty population. The results will be useful for comparing and reconstructing living conditions of ancient Korean populations.


Emotional, Cognitive and Self-Enhancement Processes in Aggressive Behavior After Interpersonal Rejection and Exclusion.
The relationship between exclusion or rejection and aggression is already well documented, but there is still a debate about the mechanisms that underlie this effect. In two studies we focused on the propensity to react aggressively (readiness for aggression) on the bases of emotional, cognitive or self-enhancement (personality-immanent) processes. In both studies we first measured readiness for aggression and then ego-depleted participants. Next, in Study 1 we excluded participants (n = 96) using an online ball throwing game and measured displaced aggressive behavior - intensity and duration of an unpleasant noise administrated to a stranger. In Study 2 participants (n = 140) were rejected by a peer on the basis of an interview that they gave and then could retaliate by reducing peer's chance for getting a job. The results show that exclusion effect on displaced aggression was moderated by cognitive readiness for aggression, while rejection effect on retaliatory aggression was shaped by emotional and personality-immanent readiness for aggression as well as ego-depletion. The results were discussed in light of the strength model of self-control by Baumeister, Vohs, and Tice (2007).


Immunohistochemical study of amoeboid microglial cells in fetal rat brain.
The present study examined the expression of different antigens in amoeboid microglial cells (AMC) in fetal rat brain extending from 12 to 20 d postconception (E12-E20) using a panel of monoclonal antibodies which recognised the major histocompatibility complex (MHC) class I (OX-18) and class II (OX-6) antigens, leucocyte common antigen (OX-1), CD4 receptor (OX-35), complement type 3 receptor (OX-42) or macrophage antigens of unknown function (ED1 and ED2). Of the above-mentioned antigens, ED1 and ED2-labelled AMC were observed in the neuroepithelia as early as embryonic day 12 (E12); other antigens were not detected at this stage. At E14, except for MHC class I antigen, all other antigens were expressed by AMC distributed predominantly in the developing white matter. At E16, AMC in the intermediate zone lateral to the striatum were endowed with all the above-mentioned antigens including MHC class I. At E18, the immunoreactivities of AMC stained with OX-6, OX-18, OX-35 and OX-42 antigens were noticeably reduced when compared with those cells at E16. At E20, amoeboid microglial cells exhibited full complement of antigen expression similar to those cells at E16; some of the labelled cells emitted a variable number of cytoplasmic processes. It is suggested that the successive and differential expression of various macrophage related antigens on AMC in fetal brain is related to the specific requirement of local environment in different stages of development.


Mechanical property and microstructural variations for recast low-gold alloy.
Using polystyrene plastic patterns meeting the dimensional requirements of ANSI/ADA specification no. 5, tension test specimens were recast multiple times from a popular Type III gold (46%) alloy. The alloy was melted by electrical heating in a graphite crucible and four conditions were compared: new alloy and alloy cast two, three, and four times (n = 4). After casting, age-hardened specimens were loaded at an elongation rate of 0.5 mm/min until failure, and the stress-strain plots were recorded. Values of yield strength, tensile strength, and percentage elongation for the specimen groups were analyzed by one-way analysis of variance, followed by the Student-Newman-Keuls multiple range test. Significant decreases (P < .01) in yield strength and percentage elongation occurred with recasting, although there were no significant differences (P > .05) in tensile strength. Scanning electron microscope examination revealed that the number of casting defects increased with remelting, and that their presence dominates the tensile fracture process. The variation in mechanical properties of the alloy with remelting was attributed to these casting defects.


Alternative payment models lead to strategic care coordination workforce investments.
Care coordination is generally viewed as a key to success for health systems seeking to adapt to a range of new value-based payment policies. This study explores care coordination staffing in four health systems participating in new payment models, including Medicaid payment reform and Accountable Care Organizations. Comparative case study design is used to describe models of care coordination. Analysis of 43 semi-structured interviews with leadership, clinicians, and care coordination staff at four health systems engaged in value-based contracts. Each of the sites engaged in significant task shifting of low-complexity care coordination activities to licensed practical nurses, medical assistants, and other unlicensed personnel freeing up registered nurses and social workers for more complex patients. Few have care coordination experience, requiring a significant investment in on-the-job training. Payment reform is leading to a greater investment in the care coordination workforce. However, demonstrating the return on investment remains a challenge.


Quality Evaluation Scores are no more Reliable than Gestalt in Evaluating the Quality of Emergency Medicine Blogs: A METRIQ Study.
Construct: We investigated the quality of emergency medicine (EM) blogs as educational resources. Online medical education resources such as blogs are increasingly used by EM trainees and clinicians. However, quality evaluations of these resources using gestalt are unreliable. We investigated the reliability of two previously derived quality evaluation instruments for blogs. Sixty English-language EM websites that published clinically oriented blog posts between January 1 and February 24, 2016, were identified. A random number generator selected 10 websites, and the 2 most recent clinically oriented blog posts from each site were evaluated using gestalt, the Academic Life in Emergency Medicine (ALiEM) Approved Instructional Resources (AIR) score, and the Medical Education Translational Resources: Impact and Quality (METRIQ-8) score, by a sample of medical students, EM residents, and EM attendings. Each rater evaluated all 20 blog posts with gestalt and 15 of the 20 blog posts with the ALiEM AIR and METRIQ-8 scores. Pearson's correlations were calculated between the average scores for each metric. Single-measure intraclass correlation coefficients (ICCs) evaluated the reliability of each instrument. Our study included 121 medical students, 88 EM residents, and 100 EM attendings who completed ratings. The average gestalt rating of each blog post correlated strongly with the average scores for ALiEM AIR (r = .94) and METRIQ-8 (r = .91). Single-measure ICCs were fair for gestalt (0.37, IQR 0.25-0.56), ALiEM AIR (0.41, IQR 0.29-0.60) and METRIQ-8 (0.40, IQR 0.28-0.59). The average scores of each blog post correlated strongly with gestalt ratings. However, neither ALiEM AIR nor METRIQ-8 showed higher reliability than gestalt. Improved reliability may be possible through rater training and instrument refinement.


IWTomics: testing high-resolution sequence-based 'Omics' data at multiple locations and scales.
With increased generation of high-resolution sequence-based 'Omics' data, detecting statistically significant effects at different genomic locations and scales has become key to addressing several scientific questions. IWTomics is an R/Bioconductor package (integrated in Galaxy) that, exploiting sophisticated Functional Data Analysis techniques (i.e. statistical techniques that deal with the analysis of curves), allows users to pre-process, visualize and test these data at multiple locations and scales. The package provides a friendly, flexible and complete workflow that can be employed in many genomic and epigenomic applications. IWTomics is freely available at the Bioconductor website (http://bioconductor.org/packages/IWTomics) and on the main Galaxy instance (https://usegalaxy.org/). Supplementary data are available at Bioinformatics online.


Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients.
The role of intensive insulin therapy in medical surgical intensive care patients remains unclear. The objective of this study was to examine the effect of intensive insulin therapy on mortality in medical surgical intensive care unit patients. Randomized controlled trial. Tertiary care intensive care unit. Medical surgical intensive care unit patients with admission blood glucose of > 6.1 mmol/L or 110 mg/dL. A total of 523 patients were randomly assigned to receive intensive insulin therapy (target blood glucose 4.4-6.1 mmol/L or 80-110 mg/dL) or conventional insulin therapy (target blood glucose 10-11.1 mmol/L or 180-200 mg/dL). The primary end point was intensive care unit mortality. Secondary end points included hospital mortality, intensive care unit and hospital length of stay, mechanical ventilation duration, the need for renal replacement therapy and packed red blood cells transfusion, and the rates of intensive care unit acquired infections as well as the rate of hypoglycemia (defined as blood glucose < or = 2.2 mmol/L or 40 mg/dL). There was no significant difference in intensive care unit mortality between the intensive insulin therapy and conventional insulin therapy groups (13.5% vs. 17.1%, p = 0.30). After adjustment for baseline characteristics, intensive insulin therapy was not associated with mortality difference (adjusted hazard ratio 1.09, 95% confidence interval 0.70-1.72). Hypoglycemia occurred more frequently with intensive insulin therapy (28.6% vs. 3.1% of patients; p < 0.0001 or 6.8/100 treatment days vs. 0.4/100 treatment days; p < 0.0001). There was no difference between the intensive insulin therapy and conventional insulin therapy in any of the other secondary end points. Intensive insulin therapy was not associated with improved survival among medical surgical intensive care unit patients and was associated with increased occurrence of hypoglycemia. Based on these results, we do not advocate universal application of intensive insulin therapy in intensive care unit patients. Current Controlled Trials registry (ISRCTN07413772) http://www.controlled-trials.com/ISRCTN07413772/07413772; 2005.


Patterns of care and persistence after incident elevated blood pressure.
Screening for hypertension in children occurs during routine care. When blood pressure (BP) is elevated in the hypertensive range, a repeat measurement within 1 to 2 weeks is recommended. The objective was to assess patterns of care after an incident elevated BP, including timing of repeat BP measurement and likelihood of persistently elevated BP. This retrospective study was conducted in 3 health care organizations. All children aged 3 through 17 years with an incident elevated BP at an outpatient visit during 2007 through 2010 were identified. Within this group, we assessed the proportion who had a repeat BP measured within 1 month of their incident elevated BP and the proportion who subsequently met the definition of hypertension. Multivariate analyses were used to identify factors associated with follow-up BP within 1 month of initial elevated BP. Among 72,625 children and adolescents in the population, 6108 (8.4%) had an incident elevated BP during the study period. Among 6108 with an incident elevated BP, 20.9% had a repeat BP measured within 1 month. In multivariate analyses, having a follow-up BP within 1 month was not significantly more likely among individuals with obesity or stage 2 systolic elevation. Among 6108 individuals with an incident elevated BP, 84 (1.4%) had a second and third consecutive elevated BP within 12 months. Whereas >8% of children and adolescents had an incident elevated BP, the great majority of BPs were not repeated within 1 month. However, relatively few individuals subsequently met the definition of hypertension.


Inward-Rectifying K+ Channels in Root Hairs of Wheat (A Mechanism for Aluminum-Sensitive Low-Affinity K+ Uptake and Membrane Potential Control).
K+ is the most abundant cation in cells of higher plants, and it plays vital roles in plant growth and development. Extensive studies on the kinetics of K+ uptake in roots have shown that K+ uptake is mediated by at least two transport mechanisms, one with a high and one with a low affinity for K+. However, the precise molecular mechanisms of K+ uptake from soils into root epidermal cells remain unknown. In the present study we have pursued the biophysical identification and characterization of mechanisms of K+ uptake into single root hairs of wheat (Triticum aestivum L.), since root hairs constitute an important site of nutrient uptake from the soil. These patch-clamp studies showed activation of a large inward current carried by K+ ions into root hairs at membrane potentials more negative than -75 mV. This K+ influx current was mediated by hyperpolarization-activated K+-selective ion channels, with a selectivity sequence for monovalent cations of K+ > Rb+ [almost equal to] NH4+ >> Na+ [almost equal to] Li+ > Cs+. Kinetic analysis of K+ channel currents yielded an apparent K+ equilibrium dissociation constant (Km) of [almost equal to]8.8 mM, which closely correlates to the major component of low-affinity K+ uptake. These channels did not inactivate during prolonged stimulation and would thus enable long-term K+ uptake driven by the plasma membrane proton-extruding pump. Aluminum, which is known to inhibit cation uptake at the root epidermis, blocked these inward-rectifying K+ channels with half-maximal current inhibition at [almost equal to]8 [mu]M free Al3+. Aluminum block of K+ channels at these Al3+ concentrations correlates closely to Al3+ phytotoxicity. It is concluded that inward-rectifying K+ channels in root hairs can function as both a physiologically important mechanism for low-affinity K+ uptake and as regulators of membrane potential. The identification of this mechanism is a major step toward a detailed molecular characterization of the multiple components involved in K+ uptake, transport, and membrane potential control in root epidermal cells.


Actinobacillus pleuropneumoniae induces SJPL cell cycle arrest in G2/M-phase and inhibits porcine reproductive and respiratory syndrome virus replication.
Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogens in the swine industry and causes important economic losses. No effective antiviral drugs against it are commercially available. We recently reported that the culture supernatant of Actinobacillus pleuropneumoniae, the porcine pleuropneumonia causative agent, has an antiviral activity in vitro against PRRSV in SJPL cells. Objectives of this study were (i) to identify the mechanism behind the antiviral activity displayed by A. pleuropneumoniae and (ii) to characterize the active molecules present in the bacterial culture supernatant. Antibody microarray analysis was used in order to point out cellular pathways modulated by the A. pleuropneumoniae supernatant. Subsequent, flow cytometry analysis and cell cycle inhibitors were used to confirm antibody microarray data and to link them to the antiviral activity of the A. pleuropneumoniae supernatant. Finally, A. pleuropneumoniae supernatant characterization was partially achieved using mass spectrometry. Using antibody microarray, we observed modulations in G2/M-phase cell cycle regulation pathway when SJPL cells were treated with A. pleuropneumoniae culture supernatant. These modulations were confirmed by a cell cycle arrest at the G2/M-phase when cells were treated with the A. pleuropneumoniae culture supernatant. Furthermore, two G2/M-phase cell cycle inhibitors demonstrated the ability to inhibit PRRSV infection, indicating a potential key role for PRRSV infection. Finally, mass spectrometry lead to identify two molecules (m/z 515.2 and m/z 663.6) present only in the culture supernatant. We demonstrated for the first time that A. pleuropneumoniae is able to disrupt SJPL cell cycle resulting in inhibitory activity against PRRSV. Furthermore, two putative molecules were identified from the culture supernatant. This study highlighted the cell cycle importance for PRRSV and will allow the development of new prophylactic or therapeutic approaches against PRRSV.


Prescription patterns of general practitioners in peshawar, pakistan.
To find out prescription patterns of general practitioners in Peshawar. Cross-sectional survey of drug prescriptions was done at six major hospitals and pharmacies of Peshawar between April and May 2011. A total of 1097 prescriptions that included 3640 drugs, were analyzed to assess completeness, average number of drugs, prescription frequency of various drug classes, and number of brands prescribed. No prescription contained all essential components of a prescription. Legibility was poor in 58.5% prescriptions. Physician's name and registration number were not mentioned in 89% and 98.2% prescriptions respectively. Over 78% prescriptions did not have diagnosis or indication mentioned. Dosage, duration of use, signature of physician and directions for taking drugs were not written in 63.8%, 55.4%, 18.5% and 10.9% of prescriptions respectively. On average each prescription included 3.32 drugs. Most frequently prescribed drug classes included analgesics (61.7%), anti-infective agents (57.2%), multi-vitamins (37.8%) and gastrointestinal drugs (34.4%). We found 206, 130, 105 and 101 different brands of anti-infective agents, gastrointestinal drugs, analgesics and multivitamins being prescribed. We observed a high number of average drugs per prescription mostly using brand names, and over-prescription of analgesics, antimicrobials, multivitamins and anti-ulcer drugs. Quality of written prescriptions was poor in terms of completeness.


Characterization of functional domains of the su(Hw) protein that mediate the silencing effect of mod(mdg4) mutations.
The suppressor of Hairy-wing [su(Hw)] protein represses enhancer function in a unidirectional fashion: enhancers segregated from the promoter by the su(Hw) binding region are rendered inactive. whereas those in the same domain are unaffected. In the case of the gypsy-induced y2 allele, the repressive effect of su(Hw) is rendered bidirectional in mod(mdg4) mutant flies, and all enhancers of the affected gene become inactive. This silencing of enhancer elements might be due to exposure of specific domains of su(Hw) when the mod(mdg4) protein is absent. Two of three regions of su(Hw) that are located adjacent to the leucine zipper motif and are conserved across Drosophila species are necessary for both the unidirectional and bidirectional repression of transcription by su(Hw). In contrast, two acidic domains that are dispensable for the unidirectional repression of enhancer elements are critical for the bidirectional silencing of enhancer activity observed in mutants lacking functional mod(mdg4) protein.


ant(6)-I Genes Encoding Aminoglycoside O-Nucleotidyltransferases Are Widely Spread Among Streptomycin Resistant Strains of Campylobacter jejuni and Campylobacter coli.
Thermotolerant Campylobacter species C. jejuni and C. coli are actually recognized as the major bacterial agent responsible for food-transmitted gastroenteritis. The most effective antimicrobials against Campylobacter are macrolides and some, but not all aminoglycosides. Among these, susceptibility to streptomycin is reduced by mutations in the ribosomal RPSL protein or by expression of ANT(6)-I aminoglycoside O-nucleotidyltransferases. The presence of streptomycin resistance genes was evaluated among streptomycin-resistant Campylobacter isolated from humans and animals by using PCR with degenerated primers devised to distinguish ant(6)-Ia, ant(6)-Ib and other ant-like genes. Genes encoding ANT(6)-I enzymes were found in all possible combinations with a major fraction of the isolates carrying a previously described ant-like gene, distantly related and belonging to the new ant(6)-I sub-family ant(6)-Ie. Among Campylobacter isolates, ant(6)-Ie was uniquely found functional in C. coli, as shown by gene transfer and phenotype expression in Escherichia coli, unlike detected coding sequences in C. jejuni that were truncated by an internal frame shift associated to RPSL mutations in streptomycin resistant strains. The genetic relationships of C. coli isolates with ANT(6)-Ie revealed one cluster of strains presented in bovine and humans, suggesting a circulation pathway of Campylobacter strains by consuming contaminated calf meat by bacteria expressing this streptomycin resistance element.


Citizen science: A new perspective to advance spatial pattern evaluation in hydrology.
Citizen science opens new pathways that can complement traditional scientific practice. Intuition and reasoning often make humans more effective than computer algorithms in various realms of problem solving. In particular, a simple visual comparison of spatial patterns is a task where humans are often considered to be more reliable than computer algorithms. However, in practice, science still largely depends on computer based solutions, which inevitably gives benefits such as speed and the possibility to automatize processes. However, the human vision can be harnessed to evaluate the reliability of algorithms which are tailored to quantify similarity in spatial patterns. We established a citizen science project to employ the human perception to rate similarity and dissimilarity between simulated spatial patterns of several scenarios of a hydrological catchment model. In total, the turnout counts more than 2500 volunteers that provided over 43000 classifications of 1095 individual subjects. We investigate the capability of a set of advanced statistical performance metrics to mimic the human perception to distinguish between similarity and dissimilarity. Results suggest that more complex metrics are not necessarily better at emulating the human perception, but clearly provide auxiliary information that is valuable for model diagnostics. The metrics clearly differ in their ability to unambiguously distinguish between similar and dissimilar patterns which is regarded a key feature of a reliable metric. The obtained dataset can provide an insightful benchmark to the community to test novel spatial metrics.


RS-predictor: a new tool for predicting sites of cytochrome P450-mediated metabolism applied to CYP 3A4.
This article describes RegioSelectivity-Predictor (RS-Predictor), a new in silico method for generating predictive models of P450-mediated metabolism for drug-like compounds. Within this method, potential sites of metabolism (SOMs) are represented as "metabolophores": A concept that describes the hierarchical combination of topological and quantum chemical descriptors needed to represent the reactivity of potential metabolic reaction sites. RS-Predictor modeling involves the use of metabolophore descriptors together with multiple-instance ranking (MIRank) to generate an optimized descriptor weight vector that encodes regioselectivity trends across all cases in a training set. The resulting pathway-independent (O-dealkylation vs N-oxidation vs Csp(3) hydroxylation, etc.), isozyme-specific regioselectivity model may be used to predict potential metabolic liabilities. In the present work, cross-validated RS-Predictor models were generated for a set of 394 substrates of CYP 3A4 as a proof-of-principle for the method. Rank aggregation was then employed to merge independently generated predictions for each substrate into a single consensus prediction. The resulting consensus RS-Predictor models were shown to reliably identify at least one observed site of metabolism in the top two rank-positions on 78% of the substrates. Comparisons between RS-Predictor and previously described regioselectivity prediction methods reveal new insights into how in silico metabolite prediction methods should be compared.


Long-rains crops, short-rains crops, permanent crops and fruit crops: The 'hidden' multiple season-cropping system for adaptation to rain variability by smallholder farms.
To adapt is to survive. However, sub-Saharan Africa, although highly dependent on agriculture, is vulnerable, most affected, with low-adaptive capacity. Luckily, the region is blessed with inherent adaptation-related strengths that are within reach, to counteract uncertainty in climatic patterns which are expected to continue well into the future. One such strength is a bimodal rainfall pattern that avails the 'hidden' multiple season-cropping systems that have the potential to produce four types of crops in a single plot in a single year: short-rains crops, long-rains crops, permanent crops and fruit crops. Despite burgeoning literature on adaptation, the impact of multiple season-cropping systems has not been adequately investigated. This study applies a novel approach to measure its impact on productivity of more than 10,000 smallholder plots using an endogenous switching regression framework. The study finds that plots that adopt multiple season-cropping systems produce higher quantities, earn more crop revenue, and are less likely to be affected by rainfall variability in comparison to plots that engage in single season-cropping systems. As the fight against climate change continues, there is need to move the needle on adaptation and consider strategies that are within reach. The multiple season-cropping systems provide this opportunity and emphasises the benefit of engaging in agriculture throughout the year and producing long-rains, short rains, permanent and fruits crops.


A mono-acyl phospholipid (20:1 lyso-PS) activates Toll-Like Receptor 2/6 hetero-dimer.
Toll-like receptor 2 (TLR2) is an important pattern recognition receptor on the surface of host immune cells that binds a variety of ligands that are released by microorganisms as well as by damaged or dying host cells. According to the current concept, TLR2/1 and TLR2/6 heterodimers are activated by tri- or di-acylated ligands, respectively. However, also mono-acyl phospholipid containing lipid fractions derived from parasites, were reported to be able to activate TLR2. In order to provide conclusive evidence for the TLR2 activating capacity of mono-acyl phospholipids derived from pathogens, we developed a biosynthetic method to enzymatically convert commercially available phospholipids into several mono-acyl-phospholipid variants that were examined for their TLR2 activating capacity. These investigations demonstrated that 1-(11Z-eicosenoyl)-glycero-3-phosphoserine 20:1 (20:1 lyso-PS) is a true agonist of the TLR2/6 heterodimer and that its polar headgroup as well as the length of the acyl chain are crucial for TLR2 activation. In silico modelling further confirmed 20:1 mono-acyl PS as a ligand for TLR2/6 heterodimer, as this predicted that multiple hydrogen bonds are formed between the polar headgroup of 20:1 mono-acyl PS and amino acid residues of both TLR2 and TLR6. Future studies can now be performed to further assess the functions of 20:1 lyso-PS as an immunological mediator, because this enzymatic method enables its preparation in larger quantities than is possible by isolation from the parasite that naturally produces this compound, Schistosoma mansoni, the source of the original discovery (Van der Kleij et al., 2002).


Trends in the Prevalence and Disparity in Cognitive Limitations of Americans 55-69 Years Old.
To determine whether the prevalence of cognitive limitation (CL) among Americans ages 55 to 69 years changed between 1998 and 2014, and to assess the trends in socioeconomic disparities in CL among groups defined by race/ethnicity, education, income, and wealth. Logistic regression using 1998-2014 data from the biennial Health and Retirement Study, a nationally representative data set. CL is defined as a score of 0-11 on a 27-point cognitive battery of items focused on memory. Socioeconomic status (SES) measures are classified as quartiles. In models controlling for age, gender, and previous cognitive testing, we find no significant change over time in the overall prevalence of CL, widening disparities in limitation by income and, in some cases, wealth, and improvements among non-Hispanic whites but not other racial/ethnic groups. Among people 55-69, rates of CL are many times higher for groups with lower SES than those with higher SES, and recent trends show little indication that the gaps are narrowing.


Testing multiple coordination constraints with a novel bimanual visuomotor task.
The acquisition of a new bimanual skill depends on several motor coordination constraints. To date, coordination constraints have often been tested relatively independently of one another, particularly with respect to isofrequency and multifrequency rhythms. Here, we used a new paradigm to test the interaction of multiple coordination constraints. Coordination constraints that were tested included temporal complexity, directionality, muscle grouping, and hand dominance. Twenty-two healthy young adults performed a bimanual dial rotation task that required left and right hand coordination to track a moving target on a computer monitor. Two groups were compared, either with or without four days of practice with augmented visual feedback. Four directional patterns were tested such that both hands moved either rightward (clockwise), leftward (counterclockwise), inward or outward relative to each other. Seven frequency ratios (3∶1, 2∶1, 3∶2, 1∶1, 2∶3. 1∶2, 1∶3) between the left and right hand were introduced. As expected, isofrequency patterns (1∶1) were performed more successfully than multifrequency patterns (non 1∶1). In addition, performance was more accurate when participants were required to move faster with the dominant right hand (1∶3, 1∶2 and 2∶3) than with the non-dominant left hand (3∶1, 2∶1, 3∶2). Interestingly, performance deteriorated as the relative angular velocity between the two hands increased, regardless of whether the required frequency ratio was an integer or non-integer. This contrasted with previous finger tapping research where the integer ratios generally led to less error than the non-integer ratios. We suggest that this is due to the different movement topologies that are required of each paradigm. Overall, we found that this visuomotor task was useful for testing the interaction of multiple coordination constraints as well as the release from these constraints with practice in the presence of augmented visual feedback.


Systematic difference between blood pressure readings caused by cuff type.
In this study we determine whether blood pressure readings using a cuff of fixed size systematically differed from readings made with a triple-bladder cuff (Tricuff) that automatically adjusts bladder width to arm circumference and assessed subsequent clinical and epidemiological effects. Blood pressure was measured with a standard cuff or a Tricuff in 454 patients visiting an outpatient clinic in the Seychelles (Indian Ocean). Overall means of within-individual standard cuff-Tricuff differences in systolic and diastolic blood pressures were examined in relation to arm circumference and sex. The standard cuff-Tricuff difference in systolic and diastolic blood pressures increased monotonically with circumference (from 4.7 +/- 0.8/3.2 +/- 0.7 mm Hg for arm circumference of 30 to 31 cm to 10.0 +/- 1.1/8.0 +/- 0.9 mm Hg for arm circumference > or = 36 cm) and was larger in women than men. Multivariate linear regression indicated independent effects of arm circumference and sex. Forty percent of subjects with a diastolic blood pressure of > or = 95 mm Hg measured with a standard cuff had values less than 95 mm Hg measured with a Tricuff. Extrapolation to the entire population of the Seychelles decreased the prevalence of blood pressure greater than or equal to 160/95 mm Hg by 11.5% and 24.0% in men and women, respectively, aged 35 to 64 years. The age-adjusted effect of body mass index on systolic and diastolic blood pressures decreased twofold using blood pressure readings made with a Tricuff instead of a standard cuff.(ABSTRACT TRUNCATED AT 250 WORDS)


Prenatal mercury concentration is associated with changes in DNA methylation at TCEANC2 in newborns.
Human exposure to the widespread environmental contaminant mercury is a known risk factor for common diseases such as cancer, cardiovascular disease and neurological disorders through poorly characterized mechanisms. Evidence suggests mercury exposure may alter DNA methylation levels, but to date, the effects in early life on a genome-wide scale have not been investigated. A study sample of 141 newborns was recruited in Baltimore, MD, USA and total mercury and methylmercury were measured in cord blood samples. We quantified genome-wide DNA methylation data using CHARM 2.0, an array-based method, and used region-finding analyses to identify concentration-associated differentially methylated regions (DMRs). To test for replication of these identified DMRs in the pilot, or Vanguard, phase of the National Children's Study (NCS), we compared bisulfite-pyrosequenced DNA at candidate regions from 85 whole cord blood samples with matched first trimester maternal mercury concentration measures. Total mercury concentration was associated with methylation at DMRs inside ANGPT2 and near PRPF18 genes [false discovery rate (FDR) < 0.05], as well as DMRs near FOXD2 and within TCEANC2 (FDR< 0.1) genes. Methylmercury concentration was associated with an overlapping DMR within TCEANC2 (FDR< 0.05). In NCS replication analyses, methylation levels at three of four cytosine-guanine DNA dinucleotides (CpG sites) within the TCEANC2 DMR were associated with total mercury concentration (P < 0.05), and this association was diminished after adjusting for estimated cell proportions. Evidence for an association between mercury and DNA methylation at the TCEANC2 region was found, which may represent a mercury-associated shift in cord blood cell composition or a change in methylation within blood cell types. Further confirmatory studies are needed.


Coexistence of urinary incontinence and major depressive disorder with health-related quality of life in older Americans with and without cancer.
This study evaluates the prevalence and factors associated with major depressive disorder (MDD) in a population of cancer survivors and the impact of co-occurring MDD and urinary incontinence (UI) on health-related quality of life (HRQOL). The prevalence of MDD risk among cancer survivors (breast, prostate, bladder, colorectal, lung, and endometrial/uterine cancers) and those without cancer was estimated using the Surveillance, Epidemiology and End Results Program-Medicare Health Outcomes Survey (SEER-MHOS) linked database (n = 9,282 with cancer/n = 289,744 without cancer). Risk for MDD was measured using three items from the Diagnostic Interview Schedule, and HRQOL was measured by the SF-36. UI was defined as self-reported leakage of urine causing a problem in previous 6 months. Factors associated with MDD were investigated using logistic regression, and the impact of co-occurring MDD and UI on HRQOL scores was determined using linear regression. The prevalence of MDD risk ranged from 19.2 % for prostate to 34.1 % for lung. Lung cancer diagnosis was associated with risk of MDD. Being ≥5 years from diagnosis was associated with decreased risk of MDD (prevalence odds ratio (POR) = 0.82, 95 % confidence interval (95 % CI) 0.71, 0.95). The coexistence of both UI and MDD was associated with a decrease across HRQOL subscales; including 40 points on role-emotional (RE) score. Cancer survivors reporting co-occurrence of UI and MDD experienced significant decrements in HRQOL. Understanding the combined effect of UI and MDD may help clinicians to better recognize and alleviate their effects on cancer survivors' HRQOL.


The role of the ocean in the global atmospheric budget of acetone.
Acetone is one of the most abundant carbonyl compounds in the atmosphere and it plays an important role in atmospheric chemistry. The role of the ocean in the global atmospheric acetone budget is highly uncertain, with past studies reaching opposite conclusions as to whether the ocean is a source or sink. Here we use a global 3-D chemical transport model (GEOS-Chem) simulation of atmospheric acetone to evaluate the role of air-sea exchange in the global budget. Inclusion of updated (slower) photolysis loss in the model means that a large net ocean source is not needed to explain observed acetone in marine air. We find that a simulation with a fixed seawater acetone concentration of 15 nM based on observations can reproduce the observed global patterns of atmospheric concentrations and air-sea fluxes. The Northern Hemisphere oceans are a net sink for acetone while the tropical oceans are a net source. On a global scale the ocean is in near-equilibrium with the atmosphere. Prescribing an ocean concentration of acetone as a boundary condition in the model assumes that ocean concentrations are controlled by internal production and loss, rather than by air-sea exchange. An implication is that the ocean plays a major role in controlling atmospheric acetone. This hypothesis needs to be tested by better quantification of oceanic acetone sources and sinks.


Apoptosis-inducing effects of Morinda citrifolia L. and doxorubicin on the Ehrlich ascites tumor in Balb-c mice.
Morinda citrifolia L. (Noni) is a herbal remedy with promising anti-cancer properties. However, its effects on various cancers are to be investigated to make a firm conclusion before implementing it into the clinical practice. Therefore, we investigated the cytotoxic potential of noni on Ehrlich ascites tumor grown in female Balb-c mice and also combined it with a potent anti-cancer agent, doxorubicin. One group received noni only (n = 8), another one doxorubicin (n = 8), and the other one noni + doxorubicin (n = 8) for 14 days after the inoculation of cells. The control group (n = 7) received 0.9% NaCl only. We found that short and long diameters of the tumor tissues were about 40-50% smaller, compared to those in control group. This anti-growth effect resulted from the induction of apoptosis, which was confirmed by the positive results from the Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) analysis and the active caspase-3 cells in tissues. Apoptosis also confirmed by caspase-cleaved cytokeratin 18 elevation in serum of the treated groups. Further, the proliferation was decreased, which was immunohistochemically shown by the PCNA staining. We conclude that noni may be useful in the treatment of breast cancer either on its own or in combination with doxorubicin. Further studies are warranted to assess the dosage and safety of using noni fruit juice in conjuction with anti-cancer drugs against breast cancer.