[Quality of socioeconomic and demographic data in relation to infant mortality in the Brazilian Mortality Information System (1996/2001)].
This study aimed to evaluate the quality of socioeconomic and demographic data in the Brazilian Mortality Information System (SIM), in relation to infant mortality. The article assesses the system's potential for monitoring inequalities in infant mortality in various States in the country. Accessibility, timeliness, methodological clarity, incompleteness, and consistency were explored as quality indicators. Selected variables were: race, birth weight, gestational age, medical care, parity, and maternal schooling, age, and occupation. The study also reviewed the system's working documentation and the scientific literature on infant mortality. Proportions of data incompleteness were calculated by region and State, identifying factors that might influence (in)completeness using logistic regression. Despite the database's accessibility and the relevance of most of its variables, the system has serious quality problems: confusing instructions in the information manual concerning missing data, misclassification of maternal occupation, lack of data on the informant's race/ethnicity, and high proportions of incomplete information. The system does not appear to be a reliable source for monitoring, evaluating, and planning measures to minimize infant health inequalities.


Differential profiling of breast cancer plasma proteome by isotope-coded affinity tagging method reveals biotinidase as a breast cancer biomarker.
Breast cancer is one of the leading causes of women's death worldwide. It is important to discover a reliable biomarker for the detection of breast cancer. Plasma is the most ideal source for cancer biomarker discovery since many cells cross-communicate through the secretion of soluble proteins into blood. Plasma proteomes obtained from 6 breast cancer patients and 6 normal healthy women were analyzed by using the isotope-coded affinity tag (ICAT) labeling approach and tandem mass spectrometry. All the plasma samples used were depleted of highly abundant 6 plasma proteins by immune-affinity column chromatography before ICAT labeling. Several proteins showing differential abundance level were selected based on literature searches and their specificity to the commercially available antibodies, and then verified by immunoblot assays. A total of 155 proteins were identified and quantified by ICAT method. Among them, 33 proteins showed abundance changes by more than 1.5-fold between the plasmas of breast cancer patients and healthy women. We chose 5 proteins for the follow-up confirmation in the individual plasma samples using immunoblot assay. Four proteins, alpha1-acid glycoprotein 2, monocyte differentiation antigen CD14, biotinidase (BTD), and glutathione peroxidase 3, showed similar abundance ratio to ICAT result. Using a blind set of plasmas obtained from 21 breast cancer patients and 21 normal healthy controls, we confirmed that BTD was significantly down-regulated in breast cancer plasma (Wilcoxon rank-sum test, p = 0.002). BTD levels were lowered in all cancer grades (I-IV) except cancer grade zero. The area under the receiver operating characteristic curve of BTD was 0.78. Estrogen receptor status (p = 0.940) and progesterone receptor status (p = 0.440) were not associated with the plasma BTD levels. Our study suggests that BTD is a potential serological biomarker for the detection of breast cancer.


Elimination of Chromosomal Island SpyCIM1 from Streptococcus pyogenes Strain SF370 Reverses the Mutator Phenotype and Alters Global Transcription.
Streptococcus pyogenes chromosomal island M1 (SpyCIM1) integrates by site-specific recombination into the 5' end of DNA mismatch repair (MMR) gene mutL in strain SF370SmR, blocking transcription of it and the downstream operon genes. During exponential growth, SpyCIM1 excises from the chromosome and replicates as an episome, restoring mutL transcription. This process is reversed in stationary phase with SpyCIM1 re-integrating into mutL, returning the cells to a mutator phenotype. Here we show that elimination of SpyCIM1 relieves this mutator phenotype. The downstream MMR operon genes, multidrug efflux pump lmrP, Holliday junction resolution helicase ruvA, and DNA base excision repair glycosylase tag, are also restored to constitutive expression by elimination of SpyCIM1. The presence of SpyCIM1 alters global transcription patterns in SF370SmR. RNA sequencing (RNA-Seq) demonstrated that loss of SpyCIM1 in the SpyCIM1 deletion mutant, CEM1Δ4, impacted the expression of over 100 genes involved in virulence and metabolism both in early exponential phase, when the SpyCIM1 is episomal, as well as at the onset of stationary phase, when SpyCIM1 has reintegrated into mutL. Among these changes, the up-regulation of the genes for the antiphagocytic M protein (emm1), streptolysin O (slo), capsule operon (hasABC), and streptococcal pyrogenic exotoxin (speB), are particularly notable. The expression pattern of the MMR operon confirmed our earlier observations that these genes are transcribed in early exponential phase but silenced as stationary phase is approached. Thus, the direct role of SpyCIM1 in causing the mutator phenotype is confirmed, and further, its influence upon the biology of S. pyogenes was found to impact multiple genes in addition to the MMR operon, which is a novel function for a mobile genetic element. We suggest that such chromosomal islands are a remarkable evolutionary adaptation to promote the survival of its S. pyogenes host cell in changing environments.


Target specificity among canonical nuclear poly(A) polymerases in plants modulates organ growth and pathogen response.
Polyadenylation of pre-mRNAs is critical for efficient nuclear export, stability, and translation of the mature mRNAs, and thus for gene expression. The bulk of pre-mRNAs are processed by canonical nuclear poly(A) polymerase (PAPS). Both vertebrate and higher-plant genomes encode more than one isoform of this enzyme, and these are coexpressed in different tissues. However, in neither case is it known whether the isoforms fulfill different functions or polyadenylate distinct subsets of pre-mRNAs. Here we show that the three canonical nuclear PAPS isoforms in Arabidopsis are functionally specialized owing to their evolutionarily divergent C-terminal domains. A strong loss-of-function mutation in PAPS1 causes a male gametophytic defect, whereas a weak allele leads to reduced leaf growth that results in part from a constitutive pathogen response. By contrast, plants lacking both PAPS2 and PAPS4 function are viable with wild-type leaf growth. Polyadenylation of SMALL AUXIN UP RNA (SAUR) mRNAs depends specifically on PAPS1 function. The resulting reduction in SAUR activity in paps1 mutants contributes to their reduced leaf growth, providing a causal link between polyadenylation of specific pre-mRNAs by a particular PAPS isoform and plant growth. This suggests the existence of an additional layer of regulation in plant and possibly vertebrate gene expression, whereby the relative activities of canonical nuclear PAPS isoforms control de novo synthesized poly(A) tail length and hence expression of specific subsets of mRNAs.


Effects of squalene/squalane on dopamine levels, antioxidant enzyme activity, and fatty acid composition in the striatum of Parkinson's disease mouse model.
Active oxygen has been implicated in the pathogenesis of Parkinson's disease (PD); therefore, antioxidants have attracted attention as a potential way to prevent this disease. Squalene, a natural triterpene and an intermediate in the biosynthesis of cholesterol, is known to have active oxygen scavenging activities. Squalane, synthesized by complete hydrogenation of squalene, does not have active oxygen scavenging activities. We examined the effects of oral administration of squalene or squalane on a PD mouse model, which was developed by intracerebroventricular injection of 6-hydroxydopamine (6-OHDA). Squalene administration 7 days before and 7 days after one 6-OHDA injection prevented a reduction in striatal dopamine (DA) levels, while the same administration of squalane enhanced the levels. Neither squalene nor squalane administration for 7 days changed the levels of catalase, glutathione peroxidase, or superoxide dismutase activities in the striatum. Squalane increased thiobarbituric acid reactive substances, a marker of lipid peroxidation, in the striatum. Both squalane and squalene increased the ratio of linoleic acid/linolenic acid in the striatum. These results suggest that the administration of squalene or squalane induces similar changes in the composition of fatty acids and has no effect on the activities of active oxygen scavenging enzymes in the striatum. However, squalane increases oxidative damage in the striatum and exacerbates the toxicity of 6-OHDA, while squalene prevents it. The effects of squalene or squalane treatment in this model suggest their possible uses and risks in the treatment of PD.


Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): A randomized, placebo-controlled trial.
The primary aim of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) is to determine whether the favourable effects of inhibition of the sodium glucose co-transporter 2 (SGLT2) on blood glucose, blood pressure and body weight are accompanied by protection against adverse renal outcomes. CANVAS-R is a prospective, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes with a history or high risk of cardiovascular events. Patients were randomly assigned to once-daily placebo or canagliflozin 100 mg (with optional uptitration to 300 mg) for a planned average of 2.5 years of follow-up. The primary outcome is kidney disease progression, defined by class change in albuminuria. The two secondary outcomes are the composite of hospitalized heart failure or cardiovascular death, and cardiovascular death alone. Effects on end-stage renal disease and a range of other outcomes will also be explored. A total of 5812 participants were recruited at 422 sites in 24 countries between January 2014 and May 2015. The mean baseline age was 64 years, mean duration of diabetes was 14 years, mean glycated haemoglobin level was 8.3% and mean body mass index was 32 kg/m2 . Of these participants, 37% were women, 71% had a history of cardiovascular disease, 22.3% had microalbuminuria and 8.7% had macroalbuminuria. The mean baseline estimated glomerular filtration rate was 76 mL/min/1.73 m2 . The study will have at least 90% power ( P = .05) to detect a 22% or greater reduction in the risk of progression of albuminuria. The trial should define the potential renoprotective effect of canagliflozin and will provide additional important new data about its effects on vascular outcomes, death and kidney failure.


The role of academic health centres in improving health equity: a systematic review.
Purpose Academic health centres (AHCs) are organisations that pursue a "tripartite" mission to deliver high-quality care to patients, undertake clinical and laboratory research, and train future health professionals. The last decade has seen a global spread of AHC models and a growing interest in the role of AHCs in addressing health system equity. The purpose of this paper is to synthesise and critically appraise the evidence on the role of AHCs in improving health equity. Design/methodology/approach Peer-reviewed and grey literature published in English between 2000 and 2016 were searched. Articles that identified AHCs as the primary unit of analysis and that also addressed health equity concepts in relation to the AHC's activity or role were included. Findings In total, 103 publications met the inclusion criteria of which 80 per cent were expert opinion. Eight descriptive themes were identified through which health equity concepts in relation to AHCs were characterised, described and operationalised: population health, addressing health disparities, social determinants of health, community engagement, global health, health system reform, value-based and accountable financing models, and role clarification/recalibration. There was consensus that AHCs can and should address health disparities, but there is a lack of empirical evidence to show that AHCs have a capacity to contribute to health equity goals or are demonstrating this contribution. Originality/value This review highlights the relevance of health equity concepts in discussions about the role and missions of AHCs. Future research should improve the quality of the evidence base by empirically examining health equity strategies and interventions of AHCs in multiple countries and contexts.


Activation of serum response element-regulated genes by lysophosphatidic acid.
Lysophosphatidic acid (LPA) is an important constituent of serum and shares its mitogenic activity. Serum induction of several genes is regulated, at least in part, by sequences related to the c-fos serum response element (SRE). A Rat-2 fibroblast cell line containing the beta-galactosidase reporter gene under SRE control was treated with LPA. Lysophosphatidic acid induced a time- and dose-dependent increase in beta-galactosidase activity. After 5 hours of treatment with 1-oleoyl-LPA a 3-fold increase in beta-galactosidase activity was observed. In contrast, endogenous alkaline phosphatase activity did not change in parallel with the beta-galactosidase activity indicating that the induction was specific. Various LPAs with different acyl groups in the sn-1 position induced beta-galactosidase activity with a rank order potency of 1-oleoyl-LPA > 1-palmitoyl-LPA > or = 1-myristoyl-LPA > 1-stearoyl-LPA. Phosphatidic acid was approximately equal to 1-stearoyl-LPA. Neither the calcium ionophore (A23187) nor 12-O-tetradecanoylphorbol 13-acetate, induced beta-galactosidase activity. These data suggest that LPA may exert some of its effects by regulation of SRE controlled genes.


Equivalence of Family Functioning and Externalizing in Adolescent Substance Users of Different Race/Ethnicity.
Brief Strategic Family Therapy (BSFT) for Adolescent Drug Abuse clinical trial of 480 adolescents boys and girls age 12 to 17 and their parents was designed to maximize the chance that a sufficient number of Hispanic and Black adolescents would be included to allow valid subgroup comparisons. Examination of measurement invariance is an important step to ensure valid analysis. Two construct areas important to the analysis of trial results, adolescent problem behaviors and family functioning showed a high degree of measurement invariance, which allowed valid comparisons of mean baseline differences across groups. Results showed that Black families had significantly higher initial levels of family functioning and lower levels of adolescent externalizing than either Hispanic or White non-Hispanic families. This pattern is consistent with an increased likelihood of referral of Black adolescents with more severe problems to restricted setting rather than to outpatient drug abuse treatment. This possibility highlights the importance of considering differing baseline characteristics of subgroups prior to assessing differential treatment effectiveness to prevent confounding.


Developing the Australasian Hepatology Association's consensus-based guidelines for the nursing care of patients with liver disease.
Abstract Purpose: Hepatology nursing is an emerging speciality. To define best practice, the Australasian Hepatology Association (AHA) developed consensus-based guidelines for the nursing care of patients with liver disease. Using the Delphi technique, six rounds of consultation were conducted with Australian hepatology nurses and non-nursing hepatology professionals. Input was captured through face-to-face and electronic communication and questionnaires. The experts' opinions were collated and consensus on the delivery of hepatology nursing care was achieved. In total, 90 consensus guidelines were developed. The principles underpinning the Guidelines include patient-centred care, non-discriminatory practice, cultural competence, collaboration and partnership and working within own scope of practice. Internationally, the AHA Guidelines are the first to document a consensus on the scope of hepatology nursing practice. The Guidelines reflect the expansion of hepatology nursing, from viral hepatitis to caring for patients with advanced liver disease and hepatocellular carcinoma, and provides a framework for future nursing practice.


Core-shell biopolymer nanoparticles produced by electrostatic deposition of beet pectin onto heat-denatured beta-lactoglobulin aggregates.
The purpose of this study was to produce and characterize core-shell biopolymer particles based on electrostatic deposition of an anionic polysaccharide (beet pectin) onto amphoteric protein aggregates (heat-denatured beta-lactoglobulin [beta-lg]). Initially, the optimum conditions for forming stable protein particles were established by thermal treatment (80 degrees C for 15 min) of 0.5 wt% beta-lg solutions at different pH values (3 to 7). After heating, stable submicron-sized (d=100 to 300 nm) protein aggregates could be formed in the pH range from 5.6 to 6. Core-shell biopolymer particles were formed by mixing a suspension of protein aggregates (formed by heating at pH 5.8) with a beet pectin solution at pH 7 and then adjusting the pH to values where the beet pectin is adsorbed (< pH 6). The impact of pH (3 to 7) and salt concentration (0 to 250 mM NaCl) on the properties of the core-shell biopolymer particles formed was then established. The biopolymer particles were stable to aggregation from pH 4 to 6, but aggregated at lower pH values because they had a relatively small -potential. The biopolymer particles remained intact and stable to aggregation up to 250 mM NaCl at pH 4, indicating that they had good salt stability. The core-shell biopolymer particles prepared in this study may be useful for encapsulation and delivery of bioactive food components or as substitutes for lipid droplets.


Prevalence of HIV Infection among U.S. Hodgkin lymphoma cases.
Hodgkin lymphoma is uncommon in the U.S. general population; however, Hodgkin lymphoma risk is elevated in people with human immunodeficiency virus (HIV) infection. Thus, despite the low HIV prevalence in the United States, the HIV epidemic may have contributed substantially to the general population burden of Hodgkin lymphoma. We used data from 14 U.S. cancer registries in the Surveillance, Epidemiology, and End Results Program that recorded HIV status of Hodgkin lymphoma cases at diagnosis during 2000 to 2010. We computed the HIV prevalence in Hodgkin lymphoma cases by demographic and tumor characteristics, the proportion of deaths among Hodgkin lymphoma cases because of HIV, and 5-year mortality by HIV status. Of 22,355 Hodgkin lymphoma cases, 848 (3.79%) were HIV infected at diagnosis. HIV prevalence in Hodgkin lymphoma cases was greater among males than females (6.0% vs. 1.2%). Among males, HIV prevalence was greatest among 40- to 59-year-olds (14.2%), non-Hispanic blacks (16.9%), Hispanics (9.9%), and among cases of lymphocyte-depleted (15.1%), and mixed cellularity Hodgkin lymphoma (10.5%). Eight percent of male and 1.5% of female Hodgkin lymphoma cases died from HIV. Five-year mortality was two-fold higher in HIV-infected Hodgkin lymphoma cases (36.9% vs. 17.5%). In the United States, a substantial proportion of lymphocyte-depleted and mixed cellularity Hodgkin lymphoma cases and Hodgkin lymphoma cases among non-Hispanic black, Hispanic, and middle-aged men are HIV infected. In addition, HIV is an important cause of death among Hodgkin lymphoma cases. Clinicians should be aware of the high prevalence of HIV in certain subgroups of patients with Hodgkin lymphoma and routine HIV testing should be recommended for all patients presenting with Hodgkin lymphoma.


Evaluation of methods for the estimation of threshold concentrations by the skin prick test.
The allergen dose-response curve is flat; thus, small changes in wheal size reflect large differences in skin sensitivity. The sensitivity as measured by provocation tests is given by the threshold concentration that causes symptoms and/or objective signs. The threshold concentrations differ by several magnitudes between the most and the least sensitive individuals clinically allergic to the same allergen. Variation in technique can be minimized by relating allergen responses to that to histamine. The aim here is to present and validate simple methods for estimation of the skin sensitivity given as the concentration inducing a wheal of the same size as that with the positive reference, 10 mg/ml of histamine HCl, in the same patient. Data from previously reported trials on the biological equilibration of allergen extracts were used to document a method to calculate the concentration of allergen required to induce a wheal of the same size as that with 10 mg/ml of histamine dihydrochloride in the same patient, and to validate the methods using the parallel line bioassay as the gold standard. The validated methods correlated well with the results obtained using the gold standard method and provide results of skin prick testing based on threshold concentrations of allergen. The validated methods reduce the error of differences in testing techniques and make it possible to report skin sensitivity at threshold concentrations. A simple method to be used in clinical practice and a method suitable to describe changes in skin reactivity over time or during treatment are proposed.


Abdominal compartment syndrome.
Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are frequently encountered in critically ill patients and carry a high morbidity and mortality risk. Despite these facts, IAH/ACS are still overlooked by many physicians and therefore timely diagnosis is not made and treatment is often inadequate. All clinicians should be aware of the risk factors predicting IAH/ACS, the profound implications and derangements on all organ systems, the clinical presentation, the appropriate measurement of intra-abdominal pressure to detect IAH/ACS and the current treatment options for these detrimental syndromes. This comprehensive review provides knowledge about known facts, unresolved issues and future directions for research to improve patient survival and long-term outcome.


The Effect of Foam Rolling of the Hamstrings on Proprioception at the Knee and Hip Joints.
The purpose of this study was to determine the acute effect of hamstring foam rolling on proprioception at the knee and hip joints. Twenty-five participants completed two proprioceptive tests on separate days, in a random order. The joint position matching test used no visual feedback. Participants were verbally guided to a target lunge position, which was maintained for six seconds while right hip and knee angles were recorded. After rest, participants reproduced this position without guidance for six seconds. Three trials were completed at baseline, and zero, 10, and 20 minutes post-intervention. In the force matching test, participants completed three trials with feedback about force output from a graph, and three trials without. They gradually applied knee flexion force against the dynamometer until reaching target force output. This test was also completed at baseline, and zero, 10, and 20 minutes post-intervention. A significant main effect was found for absolute knee position matching error (F(1.97, 47.36), p = 0.004). No significant differences were found between post-intervention values at zero and 10 minutes, zero and 20 minutes, or 10 and 20 minutes for absolute hip position matching error or absolute knee force matching error at zero, 10, or 20 minutes (p > 0.05). Foam rolling improved knee joint position sense for at least 20 minutes post-intervention, and did not decrease hip joint position sense or knee joint force sense. This indicates that foam rolling may be used immediately prior to exercise without the risk of injury due to proprioceptive deficits.


SHRIMP uranium-lead dating of diagenetic xenotime in siliciclastic sedimentary rocks
Diagenetic xenotime is common in siliciclastic sedimentary rocks, where it starts to form on detrital zircon shortly after sediment deposition. It is possible to estimate the age of sedimentary rocks by in situ uranium-lead analysis of that xenotime. Two Proterozoic sandstone units from northwestern Australia, previously constrained to the age interval of 1790 to 750 million years ago, have diagenetic xenotime ages of 1704 +/- 7 and 1704 +/- 14 million years ago. This method has potential for dating sedimentary sequences of all ages but should be especially valuable for refining the Precambrian time scale.


Applying Resilience Promotion Training Among Special Forces Police Officers.
Police Special Forces (a.k.a. special weapons and tactics [SWAT]) officers are tasked with responding to the most critical situations, including incidents that require specialized skills and equipment beyond typical policing activities. In this study, we tested the feasibility of applying Arnetz and colleagues' resilience promotion training that was developed for patrol officers to SWAT team officers (n = 18). The resilience promotion training program included psychoeducation focused on police stress and resilience, and the practice of resilience promotion techniques (controlled breathing and imagery) while listening to audio-recorded critical incident scenarios. The aims of this study were to (a) examine if a resilience training program was relevant and accepted by SWAT team officers and (b) assess participants' physiological stress responses (heart rate, respiration) during the resilience training sessions to note if there were improvements in stress responding over time. Our findings revealed that participants were able to significantly reduce their average heart rate and improve their ability to engage in controlled respiration (i.e., breathing) during simulated critical incidents over the course of the 5-day training. Improvements in stress responding were observed even when the critical incident scenarios became more graphic. Results suggest that an intervention to reduce stress responses of SWAT officers to critical incident scenarios works in a simulated training setting. Translation of these findings to real-world occupational hazards is a recommended next step.


Gene therapy in transplantation.
In transplantation, gene therapy strategies to prolong graft survival involve gene transfer and expression of immunomodulatory or graft-protecting molecules. The local production of immunosuppressive molecules has the potential to reduce their systemic side effects, and to increase their bioavailability and hence their therapeutic efficiency. Ex vivo gene transfer enables manipulation prior to engraftment. Vectors have now been developed that can optimally transfer the relevant genes to various cells, tissues and organs. The elimination of genetically modified cells can even be time-controlled by prodrug administration in suicide gene therapy systems. Gene transfer to stem cells may eventually lead to accelerated tissue repair and regeneration. In addition, xenotransplantation and organ cloning techniques have the potential to resolve the current shortage of donor organs.


Incidence and risk factors associated with hypoglycemia among patients with chronic kidney disease: A systematic review.
Hypoglycemia is a common complication in patients with chronic kidney disease (CKD), more so if they have diabetes as well. The occurrence of hypoglycemia in CKD is associated with considerable morbidity and mortality, both of which are treatable and preventable. This review summarizes the incidence and risk factors associated with hypoglycemia among patients with CKD. The meta-analysis was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A search was done on PubMed, EMBASE, SCOPUS, Cochrane Library, Google Scholar, and Cumulative Index to Nursing and Allied Health Literature for cohort studies in English published between January 2000 and August 2019 using search terms related to hypoglycemia (low blood sugar), chronic kidney disease (chronic renal failure OR renal failure), and incidence (risk OR epidemiology OR risk factors). Summary measures were calculated using random-effects model. A total of 5 studies involving 311,817 persons were included in the meta-analysis. The pooled incidence of hypoglycemia in patients with CKD was 0.188 (confidence interval [CI] = 0.097-0.287). The incidence of hypoglycemia was significantly higher in patients with CKD than in patients without CKD (Relative risk [RR] = 1.89, 95% CI = 1.86-1.92, P < 0.0001). No heterogeneity was reported between the studies (I2 = 0%, P > 0.05), and publication bias was also found. Females, patients who had diabetes mellitus of long duration, and those on antidiabetic drugs such as insulin and sulfonylureas were at risk of developing hypoglycemia in CKD as per narrative review. The incidence of hypoglycemia in patients with CKD is high. Therefore, there is need to closely monitor affected individuals so that appropriate management protocols could be set up. Further probing of various risk factors for hypoglycemia in CKD patients is necessary for early detection and initiation of timely preventive and curative measures.


Stress Effects in Vowel Perception as a Function of Language-Specific Vocabulary Patterns.
Evidence from spoken word recognition suggests that for English listeners, distinguishing full versus reduced vowels is important, but discerning stress differences involving the same full vowel (as in mu- from music or museum) is not. In Dutch, in contrast, the latter distinction is important. This difference arises from the relative frequency of unstressed full vowels in the two vocabularies. The goal of this paper is to determine how this difference in the lexicon influences the perception of stressed versus unstressed vowels. All possible sequences of two segments (diphones) in Dutch and in English were presented to native listeners in gated fragments. We recorded identification performance over time throughout the speech signal. The data were here analysed specifically for patterns in perception of stressed versus unstressed vowels. The data reveal significantly larger stress effects (whereby unstressed vowels are harder to identify than stressed vowels) in English than in Dutch. Both language-specific and shared patterns appear regarding which vowels show stress effects. We explain the larger stress effect in English as reflecting the processing demands caused by the difference in use of unstressed vowels in the lexicon. The larger stress effect in English is due to relative inexperience with processing unstressed full vowels.


Comparison of the Analgesic Effect of Sufentanil versus Fentanyl in Intravenous Patient-Controlled Analgesia after Total Laparoscopic Hysterectomy: A Randomized, Double-blind, Prospective Study.
Background: Fentanyl is one of the most widely used opioids for intravenous patient-controlled analgesia (IV-PCA). Sufentanil, a fentanyl analog, is suitable for postoperative pain control because it has no active metabolites and shows a higher therapeutic index and lower frequency of respiratory suppression than fentanyl. This study aimed to compare the two opioids for postoperative pain relief on the basis of analgesic efficacy, adverse effects, and patient satisfaction. Methods: Sixty-four patients undergoing total laparoscopic hysterectomy were randomly allocated into a fentanyl group (n = 31) or a sufentanil group (n = 33). The patients received 50-μg fentanyl or 10-μg sufentanil before induction of anesthesia and 5 minutes after uterine incision during surgery in the fentanyl and sufentanil group, respectively. After arriving at the post-anesthesia care unit (PACU), verbal pain score (VPS) and sedation score were assessed. IV-PCA (fentanyl 1250 μg or sufentanil 250 μg with ondansetron 8 mg; total volume, 60 ml) was connected and continued for 48 h postoperatively. Postoperative pain was evaluated by using the numeric rating scale (NRS; at rest/during cough) at 6, 12, 24, 36, and 48 hours after surgery. The cumulative PCA consumption, patient satisfaction scores, and adverse effects were measured. Results: In the PACU, VPS was significantly higher and rescue fentanyl consumption was higher in the fentanyl group than in the sufentanil group, while the sedation score and adverse effects were comparable between the groups. No significant differences were observed in the NRS scores for pain (at rest/during cough) in the ward over 48 hours postoperatively, but the cumulative PCA consumption was significantly higher in the fentanyl group (47.4 ± 9.9 ml vs. 36.2 ± 14.6 ml, P = 0.01). There were no significant intergroup differences in patient satisfaction score and the incidence of adverse effects in the ward, except for a higher incidence of dry mouth in the fentanyl group. Conclusions: In comparison with fentanyl, sufentanil showed comparable analgesic efficacy and safety with less analgesic consumption (under a potency ratio of 1:5) in IV-PCA after total laparoscopic hysterectomy. Therefore, we suggest that sufentanil can be a useful alternative to fentanyl for IV-PCA.


Renal gene and protein expression signatures for prediction of kidney disease progression.
Although chronic kidney disease (CKD) is common, only a fraction of CKD patients progress to end-stage renal disease. Molecular predictors to stratify CKD populations according to their risk of progression remain undiscovered. Here we applied transcriptional profiling of kidneys from transforming growth factor-beta1 transgenic (Tg) mice, characterized by heterogeneity of kidney disease progression, to identify 43 genes that discriminate kidneys by severity of glomerular apoptosis before the onset of tubulointerstitial fibrosis in 2-week-old animals. Among the genes examined, 19 showed significant correlation between mRNA expression in uninephrectomized left kidneys at 2 weeks of age and renal disease severity in right kidneys of Tg mice at 4 weeks of age. Gene expression profiles of human orthologs of the 43 genes in kidney biopsies were highly significantly related (R(2) = 0.53; P < 0.001) to the estimated glomerular filtration rates in patients with CKD stages I to V, and discriminated groups of CKD stages I/II and III/IV/V with positive and negative predictive values of 0.8 and 0.83, respectively. Protein expression patterns for selected genes were successfully validated by immunohistochemistry in kidneys of Tg mice and kidney biopsies of patients with IgA nephropathy and CKD stages I to V, respectively. In conclusion, we developed novel mRNA and protein expression signatures that predict progressive renal fibrosis in mice and may be useful molecular predictors of CKD progression in humans.


[Accumulation of respiratory diseases among employees at a recently established refuse sorting plant].
An increasing number of plants for re-use of refuse have been constructed in Denmark in recent years. The Kaastrup Plant near Skive was opened in spring 1986. The plant accepts household rubbish and industrial refuse separately. The refuse is sorted by machine (industrial refuse is sorted partially manually) and in a large partially open machine plant, refuse is converted into fuel pellets. During a period of eight months, eight out of 15 employees developed respiratory symptoms. In seven, bronchial asthma was diagnosed and chronic bronchitis in one person. Four had initial symptoms of the organic dust toxic syndrome. After further six months, another case of occupationally-conditioned asthma occurred in the plant. Only two out of nine had previously had asthma or atopic disease. The investigation did not reveal any evidence of type-I allergy. Six out of nine had specific precipitating antibodies to refuse while all had negative RAST tests to this. In spring 1989, from six to eighteen months after the onset of the symptoms, six had still dyspnoea on exertion and three had positive histamine-provocation tests and seven out of nine had left the plant. Occupational medical measurements revealed dust concentrations of 8.1 mg/cubic millimeter in September 1986 and total germs of up to 3 x 10(9) cfu/cubic meter. Construction of the plant involved considerable contact with the refuse on account of the cleansing processes and open systems and it was reconstructed in the course of 1987/1988 so that the hygienic conditions are now acceptable.(ABSTRACT TRUNCATED AT 250 WORDS)


Development and application of in vivo expression technology (IVET) for analysing microbial gene expression in complex environments.
Establishing the mechanisms by which microbes interact with their environment, including eukaryotic hosts, is a major challenge that is essential for the economic utilisation of microbes and their products. Techniques for determining global gene expression profiles of microbes, such as microarray analyses, are often hampered by methodological restraints, particularly the recovery of bacterial transcripts (RNA) from complex mixtures and rapid degradation of RNA. A pioneering technology that avoids this problem is In Vivo Expression Technology (IVET). IVET is a 'promoter-trapping' methodology that can be used to capture nearly all bacterial promoters (genes) upregulated during a microbe-environment interaction. IVET is especially useful because there is virtually no limit to the type of environment used (examples to date include soil, oomycete, a host plant or animal) to select for active microbial promoters. Furthermore, IVET provides a powerful method to identify genes that are often overlooked during genomic annotation, and has proven to be a flexible technology that can provide even more information than identification of gene expression profiles. A derivative of IVET, termed resolvase-IVET (RIVET), can be used to provide spatio-temporal information about environment-specific gene expression. More recently, niche-specific genes captured during an IVET screen have been exploited to identify the regulatory mechanisms controlling their expression. Overall, IVET and its various spin-offs have proven to be a valuable and robust set of tools for analysing microbial gene expression in complex environments and providing new targets for biotechnological development.


Treatment of Cartilage Defects With the Matrix-Induced Autologous Chondrocyte Implantation Cookie Cutter Technique.
Focal cartilage defects lead to significant pain and disability, prompting the development of various options for biologic restoration of the articular surface. Although each technique and biologic implant provides various advantages and associated limitations, matrix-induced autologous chondrocyte implantation (MACI) has gained popularity given promising long-term results. We present a technique for the facile implantation of MACI membranes using cookie cutter instrumentation to aid in defect debridement and graft preparation. The technique described allows for efficient operative workflow while ensuring the creation of vertical, stable defect edges and a form-fitting MACI membrane in a readily implemented fashion.


Hybrid upconversion nanomaterials for optogenetic neuronal control.
Nanotechnology-based approaches offer the chemical control required to develop precision tools suitable for applications in neuroscience. We report a novel approach employing hybrid upconversion nanomaterials, combined with the photoresponsive ion channel channelrhodopsin-2 (ChR2), to achieve near-infrared light (NIR)-mediated optogenetic control of neuronal activity. Current optogenetic methodologies rely on using visible light (e.g. 470 nm blue light), which tends to exhibit high scattering and low tissue penetration, to activate ChR2. In contrast, our approach enables the use of 980 nm NIR light, which addresses the short-comings of visible light as an excitation source. This was facilitated by embedding upconversion nanomaterials, which can convert NIR light to blue luminescence, into polymeric scaffolds. These hybrid nanomaterial scaffolds allowed for NIR-mediated neuronal stimulation, with comparable efficiency as that of 470 nm blue light. Our platform was optimized for NIR-mediated optogenetic control by balancing multiple physicochemical properties of the nanomaterial (e.g. size, morphology, structure, emission spectra, concentration), thus providing an early demonstration of rationally-designing nanomaterial-based strategies for advanced neural applications.


Clinical and Histologic Features of Lichenoid Mucocutaneous Eruptions Due to Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Immunotherapy.
Antagonist antibodies to programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have shown remarkable activity in multiple tumor types. Recent US Food and Drug Administration approval of such agents for advanced melanoma, non-small cell lung cancer, and renal cell carcinoma has hastened the need to better characterize their unique toxicity profiles. To provide a clinical and pathologic description of the lichenoid mucocutaneous adverse effects seen in patients receiving anti-PD-1/PD-L1 treatment. Patients with advanced cancer who were referred to dermatology at Yale-New Haven Hospital, a tertiary care hospital, after developing cutaneous adverse effects while receiving an anti-PD-1 or PD-L1 antibody therapy either as monotherapy or in combination with another agent were identified. Medical records from 2010 to 2015 and available skin biopsy specimens were retrospectively reviewed. Patient demographic characteristics, concurrent medications, therapeutic regimen, type of disease, previous oncologic therapies, clinical morphology of cutaneous lesions, treatment of rash, peripheral blood eosinophil count, tumor response, and skin histologic characteristics if biopsies were available. Patients were 13 men and 7 women, with a mean (range) age of 64 (46-86) years. The majority of cases (16 [80%]) had a clinical morphology consisting of erythematous papules with scale in a variety of distributions. Biopsies were available from 17 patients; 16 (94%) showed features of lichenoid interface dermatitis. Eighteen patients were treated with topical corticosteroids, and only 1 patient required discontinuation of anti-PD-1/PD-L1 therapy. Only 4 of 20 patients (20%) developed peripheral eosinophilia. Sixteen patients (80%) were concurrently taking medications that have been previously reported to cause lichenoid drug eruptions. Papular and nodular eruptions with scale, as well as mucosal erosions, with lichenoid features on histologic analysis were a distinct finding seen with anti-PD-1/PD-L1 therapies and were generally manageable with topical steroids. Concurrent medications may play a role in the development of this cutaneous adverse effect.


Changing the culture of academic medicine: the C-Change learning action network and its impact at participating medical schools.
The culture of academic medicine has been described as hierarchical, competitive, and not highly supportive of female or minority faculty. In response to this, the authors designed the Learning Action Network (LAN), which was part of the National Initiative on Gender, Culture and Leadership in Medicine (C-Change). The LAN is a five-school consortium aimed at changing the organizational culture of its constituent institutions. The authors selected LAN schools to be geographically diverse and representative of U.S. medical schools. Institutional leaders and faculty representatives from constituent schools met twice yearly for four years (2006-2010), forming a cross-institutional learning community. Through their quarterly listing of institutional activities, schools reported a wide array of actions. Most common were increased faculty development and/or mentoring, new approaches to communication, and adoption of new policies and procedures. Other categories included data collection/management, engagement of key stakeholders, education regarding gender/diversity, and new/expanded leadership positions. Through exit interviews, most participants reported feeling optimistic about maintaining the momentum of change. However, some, especially in schools with leadership changes, expressed uncertainty. Participants reported that they felt that the LAN enabled, empowered, facilitated, and/or caused the reported actions.For others who might want to work toward changing the culture of academic medicine, the authors offer several lessons learned from their experiences with C-Change. Most notably, people, structures, policies, and reward systems must be put into place to support cultural values, and broad-based support should be created in order for changes to persist when inevitable transitions in leadership occur.


Therapeutic significance of a D-dimer cut-off level of >3 µg/ml in colorectal cancer patients treated with standard chemotherapy plus bevacizumab.
The risk of venous thromboembolism has been reported to increase when receiving bevacizumab. Many cancer patients are reported to have elevated D-dimer levels. It is not clear what D-dimer level might indicate an increased risk of venous thromboembolism in the colorectal cancer patients treated with bevacizumab-containing chemotherapy. The D-dimer levels and any event concurrent with an elevated D-dimer level were evaluated in patients receiving bevacizumab. The D-dimer cut-off level was determined using the receiver-operating characteristic analysis. The selection criteria were as follows: histologically proven metastatic and unresectable colorectal adenocarcinoma; no prior chemotherapy containing bevacizumab; D-dimer test performed repetitively on the baseline and during bevacizumab administration; no venous thromboembolism identified at the baseline; and enhanced computed tomographic scan performed every 2 months. Sixty-nine patients were included. The chemotherapy regimens with bevacizumab included the regimen of 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), the regimen of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), and leucovorin-modulated 5-fluorouracil. The median baseline D-dimer level was 1.2 µg/ml. The appropriate D-dimer cut-off level was 3 µg/ml with the negative predictive value of 98% and relative risk of 6.9. Twenty-one of 69 patients showed elevated D-dimer levels of >3 µg/ml, with 11 patients for unknown reasons, 6 with tumor progression, 3 with venous thromboembolism and 1 with sepsis. In the remaining 48 patients whose D-dimer levels were ≤3 µg/ml, only one patient developed a venous thromboembolism. A D-dimer cut-off level of 3 µg/ml might be a useful indicator level to exclude venous thromboembolism or show an increased risk for venous thromboembolism in colorectal cancer patients treated with bevacizumab-containing chemotherapy.


Electron-phonon interactions and the intrinsic electrical resistivity of graphene.
We present a first-principles study of the temperature- and density-dependent intrinsic electrical resistivity of graphene. We use density-functional theory and density-functional perturbation theory together with very accurate Wannier interpolations to compute all electronic and vibrational properties and electron-phonon coupling matrix elements; the phonon-limited resistivity is then calculated within a Boltzmann-transport approach. An effective tight-binding model, validated against first-principles results, is also used to study the role of electron-electron interactions at the level of many-body perturbation theory. The results found are in excellent agreement with recent experimental data on graphene samples at high carrier densities and elucidate the role of the different phonon modes in limiting electron mobility. Moreover, we find that the resistivity arising from scattering with transverse acoustic phonons is 2.5 times higher than that from longitudinal acoustic phonons. Last, high-energy, optical, and zone-boundary phonons contribute as much as acoustic phonons to the intrinsic electrical resistivity even at room temperature and become dominant at higher temperatures.


The Decline in Diffuse Support for National Politics: The Long View on Political Discontent in Britain.
This research note considers how to track long-term trajectories of political discontent in Britain. Many accounts are confined to using either survey data drawn from recent decades or imperfect behavioral measures such as voting or party membership as indicators of political disengagement. We instead develop an approach that provides the long view on political disaffection. We first consider time-series data available from repeated survey measures. We next replicate historic survey questions to observe change in public opinion relative to earlier points in time. Finally, we use Stimson's (1991) dyad-ratios algorithm to construct an over-time index of political discontent that combines data from multiple poll series. This reveals rising levels of political discontent for both specific and diffuse measures of mass opinion. Our method and findings offer insights into the rising tide of disillusionment afflicting many contemporary democracies.


Estimation of segregation and linkage parameters in simulated data. I. Segregation analyses with different ascertainment schemes.
We report the results of a simulation study designed to assess the capability of segregation analysis to detect Mendelian transmission and to estimate genetic model parameters for complex qualitative traits, characterized by heritability in the range 0.20-0.45 and low heterozygote penetrance. The pedigree analysis package, PAP, was used to perform the analyses. For all data sets, models of no transmission could be rejected. In most cases, models of Mendelian transmission could not be rejected; however, several samples approached significance levels. When Mendelian transmission was assumed, reasonably good parameter estimates were obtained, although heterozygote penetrances were often overestimated. Different sampling schemes were imposed on the simulated data in order to examine the extent of information loss with the reduction in sample size. One of these strategies (a sequential sampling scheme) appears to have resulted in critical loss of information in some cases.


Efficacy of artesunate plus chloroquine for the treatment of uncomplicated malaria in children in Burkina Faso: a double-blind, randomized, controlled trial.
Chloroquine (CQ)-resistant Plasmodium falciparum is compromising malaria control in Africa. Combining artesunate (AS) with standard antimalarial drugs increases cure rates and may delay drug resistance. We compared the safety and efficacy of CQ alone and CQ combined with AS (CQ-AS) for treating uncomplicated P. falciparum malaria in Burkina Faso between August 1999 and August 2000. Chloroquine (25 mg/kg over 3 d) combined with AS or placebo (4 mg/kg/d for 3 d) was administered to 300 children aged 6 to 59 months in a randomized, double-blind study. Follow-up extended over 28 d. No adverse drug reactions were recorded. By day 14, parasites were cleared in 120/147 (81.6%) CQ AS-treated children compared with 53/143 (37.1%) CQ-treated children (odds ratio [OR] = 7.55, 95% CI 4.27-13.43, P < 0.001). Corresponding rates for day 28 were 71/145 (49.0%) vs. 27/142 (19.0%) (OR= 4.09, 95% CI 2.33-7.21, P < 0.001). Children who received CQ-AS had significantly faster parasite and fever clearance. Despite the beneficial effects of adding AS, the high failure rate at day 28 of CQ-AS precludes its use as the first-line regimen for treating CQ-resistant P. falciparum in Burkina Faso.


p56lck interacts via its src homology 2 domain with the ZAP-70 kinase.
p56lck, a member of the src family of protein tyrosine kinases, is an essential component in T cell receptor (TCR) signal transduction. p56lck contains a src homology 2 (SH2) domain found in a number of proteins involved in intracellular signaling. SH2 domains have been implicated in protein-protein interactions by binding to sequences in target proteins containing phosphorylated tyrosine. Using an in vitro assay, we have studied specific binding of tyrosine-phosphorylated proteins to a recombinant p56lck SH2 domain. In nonactivated Jurkat cells, two tyrosine-phosphorylated proteins were detected. Stimulation with anti-CD3 monoclonal antibodies induced the binding of seven additional tyrosine-phosphorylated proteins to the SH2 domain of p56lck. We have identified the zeta-associated tyrosine kinase, ZAP-70, as one of these proteins. Evidence suggests that binding of ZAP-70 to p56lck SH2 is direct and not mediated by zeta. The significance of this interaction was further investigated in vivo. p56lck could be coprecipitated with the zeta/ZAP-70 complex and conversely, ZAP-70 was detected in p56lck immunoprecipitates of activated Jurkat cells. The physical association of p56lck and ZAP-70 during activation supports the recently proposed functional cooperation of these two tyrosine kinases in TCR signaling.


Testosterone supplementation therapy for older men: potential benefits and risks.
Serum testosterone levels decline gradually and progressively with aging in men. Many manifestations associated with aging in men, including muscle atrophy and weakness, osteoporosis, reduced sexual functioning, and increased fat mass, are similar to changes associated with testosterone deficiency in young men. These similarities suggest that testosterone supplementation may prevent or reverse the effects of aging. A MEDLINE search was performed to identify studies of testosterone supplementation therapy in older men. A structured, qualitative review was performed of placebo-controlled trials that included men aged 60 and older and evaluated one or more physical, cognitive, affective, functional, or quality-of-life outcomes. Studies focusing on patients with severe systemic diseases and hormone deficiencies related to specific diseases were excluded. In healthy older men with low-normal to mildly decreased testosterone levels, testosterone supplementation increased lean body mass and decreased fat mass. Upper and lower body strength, functional performance, sexual functioning, and mood were improved or unchanged with testosterone replacement. Variable effects on cognitive function were reported, with improvements in some cognitive domains (e.g., spatial, working, and verbal memory). Testosterone supplementation improved exercise-induced coronary ischemia in men with coronary heart disease, whereas angina pectoris was improved or unchanged. In a few studies, men with low testosterone levels were more likely to experience improvements in lumbar bone mineral density, self-perceived functional status, libido, erectile function, and exercise-induced coronary ischemia with testosterone replacement than men with less marked testosterone deficiency. No major unfavorable effects on lipids were reported, but hematocrit and prostate specific antigen levels often increased. Based on these results, testosterone supplementation cannot be recommended at this time for older men with normal or low-normal testosterone levels and no clinical manifestations of hypogonadism. However, testosterone replacement may be warranted in older men with markedly decreased testosterone levels, regardless of symptoms, and in men with mildly decreased testosterone levels and symptoms or signs suggesting hypogonadism. The long-term safety and efficacy of testosterone supplementation remain uncertain. Establishment of evidence-based indications will depend on further demonstrations of favorable clinical outcomes and symptomatic, functional, and quality-of-life benefits in carefully performed, long-term, randomized, placebo-controlled clinical trials.


A randomised trial of intracavitary electrocardiography versus surface landmark measurement for central venous access device placement.
Malpositioned central venous access devices (CVADs) can lead to significant patient injury including central vein thrombosis and dysrhythmias. Intra-cavitary electrocardiography (IC ECG) has been recommended by peak professional bodies as an accurate alternative for bedside CVAD insertion, to reduce risk of malposition and allowing immediate use of the device. Our objective was to compare the effect of IC ECG on CVAD malposition compared to traditional institutional practice for CVAD placement. Randomised controlled trial of IC ECG CVAD insertion verses traditional CVAD insertion (surface landmark measurement with post insertion x ray). Patient recruitment was from December 2016 to July 2018. The setting was a 900-bed tertiary referral hospital based in South Western Sydney, Australia. Three hundred and forty-four adult patients requiring CVAD insertion for intravenous therapy, were enrolled and randomly allocated (1:1 ratio) to either IC-ECG (n = 172) or traditional (n = 172) CVAD insertion. Our primary outcome of interest was the rate of catheters not requiring repositioning after insertion (ready for use). Secondary outcomes were comparison of procedure time and cost. Of the 172 patients allocated to the IC ECG method, 170 (99%) were ready for use immediately compared to 139 of the 172 (81%) in the traditional insertion group (difference, 95% confidence interval (CI): 18%, 11.9-24.1%). The total procedure time was mean 15 min (SD 8 min) for IC ECG and mean 36 min (SD 17 min) for traditional CVAD insertion (difference-19.9 min (95% CI-14.6 to -34.4). IC ECG guided CVAD insertion had a cost reduction of AUD $62.00 per procedure. Using IC-ECG resulted in nearly no requirement for post-insertion repositioning of CVADs resulting in savings in time and cost and virtually eliminating the need for radiographic confirmation. This trial is registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). The registration number is ACTRN12620000919910.


Do extra compulsory physical education lessons mean more physically active children--findings from the childhood health, activity, and motor performance school study Denmark (The CHAMPS-study DK).
Primarily, this study aims to examine whether children attending sports schools are more active than their counterpart attending normal schools. Secondary, the study aims to examine if physical activity (PA) levels in specific domains differ across school types. Finally, potential modifications by status of overweight/obesity and poor cardio-respiratory fitness are examined. Participants were from the first part of the CHAMPS-study DK, which included approximately 1200 children attending the 0th - 6th grade. At the sports schools, the mandatory physical education (PE) program was increased from 2 to 6 weekly lessons over a 3-year period. Children attending normal schools were offered the standard 2 PE lessons. PA was assessed at two different occasions with the GT3X ActiGraph accelerometer, once during winter in 2009/10 and once during summer/fall in 2010. Leisure time organized sports participation was quantified by SMS track. Based on baseline values in 2008, we generated a high-BMI and a low-cardio-respiratory fitness for age and sex group variable. There were no significant differences in PA levels during total time, PE, or recess between children attending sports schools and normal schools, respectively. However, children, especially boys, attending sports schools were more active during school time than children attending normal schools (girls: β=51, p=0.065; boys: β=113, p<0.001). However, in the leisure time during weekdays children who attended sports schools were less active (girls: β=-41, p=0.004; boys: β=-72, p<0.001) and less involved in leisure time organized sports participation (girls: β=-0.4, p=0.016; boys: β=-0.2, p=0.236) than children who attended normal schools. Examination of modification by baseline status of overweight/obesity and low cardio-respiratory fitness indicated that during PE low fit girls in particular were more active at sports schools. No differences were revealed in overall PA levels between children attending sports schools and normal schools. Sports schools children were more active than normal schools children during school time, but less active during leisure time. In girls, less organized sports participation at least partly explained the observed differences in PA levels during leisure time across school types. Baseline status of cardio-respiratory fitness modified school type differences in PA levels during PE in girls.


Using Z Boson Events to Study Parton-Medium Interactions in Pb-Pb Collisions.
The spectra measurements of charged hadrons produced in the shower of a parton originating in the same hard scattering with a leptonically decaying Z boson are reported in lead-lead nuclei (Pb-Pb) and proton-proton (pp) collisions at a nucleon-nucleon center-of-mass energy of 5.02 TeV. Both Pb-Pb and pp data sets are recorded by the CMS experiment at the LHC and correspond to an integrated luminosity of 1.7 nb^{-1} and 320 pb^{-1}, respectively. Hadronic collision data with one reconstructed Z boson candidate with the transverse momentum p_{T}>30 GeV/c are analyzed. The Z boson constrains the initial energy and direction of the associated parton. In heavy ion events, azimuthal angular distributions of charged hadrons with respect to the direction of a Z boson are sensitive to modifications of the in-medium parton shower and medium response. compared to reference data from pp interactions, the results for central Pb-Pb collisions indicate a modification of the angular correlations. The measurements of the fragmentation functions and p_{T} spectra of charged particles in Z boson events, which are sensitive to medium modifications of the parton shower longitudinal structure, are also reported. Significant modifications in central Pb-Pb events compared to the pp reference data are also found for these observables.


Abundance, natural infection with trypanosomes, and food source of an endemic species of triatomine, Panstrongylus howardi (Neiva 1911), on the Ecuadorian Central Coast.
The elimination of domestic triatomines is the foundation of Chagas disease control. Regional initiatives are eliminating introduced triatomine species. In this scenario, endemic triatomines can occupy the ecological niches left open and become a threat to long-term Chagas disease control efforts. This study determined the abundance, colonization, and Trypanosoma cruzi infection rate of the endemic Panstrongylus howardi in 10 rural communities located in Ecuador's Manabí Province. In total, 518 individuals of P. howardi were collected. Infestation indices of 1.4% and 6.6% were found in the domestic and peridomestic environments, respectively. We determined a T. cruzi infection rate of 53.2% (N = 47) in this species. P. howardi has a high capacity to adapt to different habitats, especially in the peridomicile. This implies a considerable risk of transmission because of the frequency of intradomicile invasion. Therefore, this species needs to be taken into account in Chagas control and surveillance efforts in the region.


Olfactory cues are sufficient to elicit social approach behaviors but not social transmission of food preference in C57BL/6J mice.
Mouse models for the study of autistic-like behaviors are increasingly needed to test hypotheses about the causes of autism, and to evaluate potential treatments. Both the automated three-chambered social approach test and social transmission of food preference have been proposed as mouse behavioral assays with face validity to diagnostic symptoms of autism, including aberrant reciprocal social interactions and impaired communication. Both assays measure aspects of normal social behavior in the mouse. However, little is known regarding the salient cues present in each assay that elicit normal social approach and communication. To deconstruct the critical components, we focused on delivering discrete social and non-social olfactory and visual cues within the context of each assay. Results indicate that social olfactory cues were sufficient to elicit normal sociability in the three-chambered social approach test. On social transmission of food preference, isolated social olfactory cues were sufficient to induce social investigation, but not sufficient to induce food preference. These findings indicate that olfactory cues are important in mouse social interaction, but that additional sensory cues are necessary in certain situations. The present evidence that both the three-chambered social approach assay and the social transmission of food preference assay require socially relevant cues to elicit normal behavior supports the use of these two assays to investigate autism-related behavioral phenotypes in mice.


Transition-to-U.S. Practice Experiences of Internationally Educated Nurses: An Integrative Review.
Internationally educated nurses (IENs) are an important part of the U.S. nursing workforce. Optimizing their transition-to-practice (TTP) experiences in the United States is crucial for ensuring high-quality patient and IENs' outcomes. The purpose of this integrative review is to analyze and synthesize the current evidence surrounding IEN TTP experiences in the United States from 2000 to 2018 to inform improvements in TTP. Eighteen studies were included. TTP was defined through IENs' description of facilitators and barriers of the transition process and presented in seven themes. Two themes were facilitators: support from family and nursing colleagues, and perceptions of self-efficacy. The remaining five themes were barriers: (a) the stigma associated with educational preparation, (b) communication and language, (c) differences in culture, (d) differences in nursing practice, and (e) legal issues. Findings are important for improving TTP programs. Further research focusing on the outcomes of transition programs is needed to inform policymaking surrounding IEN recruitment and retention.


Interprofessional education in the Arabic-speaking Middle East: Perspectives of pharmacy academics.
The current status of interprofessional education (IPE) in Arabic Middle Eastern countries is largely unexamined and there is a need to assess IPE and collaborative practice in these countries. As faculty attitudes towards IPE are believed to be one of the main factors that affect the successful integration of IPE into the different healthcare curricula, this article aims to explore the attitudes and views of pharmacy academics in Arabic-speaking Middle Eastern countries towards IPE and collaborative practice. The findings from this article are part of a larger study investigating pharmacy's perspectives of IPE and collaborative practice in Qatar and the Middle East. An online survey which included three validated scales was used to gather information from pharmacy academics at 89 pharmacy schools in 14 countries. The response rate was 107 out of 334 (32%) and the majority of the respondents were from Jordan, Qatar, Lebanon, and Saudi Arabia. Statistical analysis was completed descriptively as well as inferentially using a series of independent t-tests. Overall pharmacy academics had positive attitudes towards IPE. The majority of the respondents, 90.8% (n = 99), perceived IPE to be important. Age, likelihood to engage in IPE, and years of IPE experience were the factors that were related to faculty members' attitudes towards IPE. Highly perceived barriers for implementing IPE included cultural challenges for each profession, scheduling common courses, and activities in addition to limited resources. The study findings indicated that pharmacy academics in the Middle East are ready to pursue IPE. These results can serve as impetus for implementing IPE in Middle Eastern countries.


Central crime computer project draws mixed reviews.
After committing a crime in Ohio, an offender from California, for example, may flee to Florida, having profitably disposed of his stolen goods in still another State. With all the marvels of modern transportation, all this can and does occur while the police pore over the fresh traces at the crime scene. To solve crime in the space-age tempo of today's society demands that law enforcement officers have available immediately the facts of crime whenever or wherever they are likely to confront suspected elements of it.


Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions.
Atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intra-epithelial lesions (LSIL) are minor lesions of the cervical epithelium, detectable by cytological examination of cells collected from the surface of the cervix of a woman.Usually, women with ASCUS and LSIL do not have cervical (pre-) cancer, however a substantial proportion of them do have underlying high-grade cervical intra-epithelial neoplasia (CIN, grade 2 or 3) and so are at increased risk for developing cervical cancer. Therefore, accurate triage of women with ASCUS or LSIL is required to identify those who need further management.This review evaluates two ways to triage women with ASCUS or LSIL: repeating the cytological test, and DNA testing for high-risk types of the human papillomavirus (hrHPV) - the main causal factor of cervical cancer. Main objective To compare the accuracy of hrHPV testing with the Hybrid Capture 2 (HC2) assay against that of repeat cytology for detection of underlying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+) in women with ASCUS or LSIL. For the HC2 assay, a positive result was defined as proposed by the manufacturer. For repeat cytology, different cut-offs were used to define positivity: Atypical squamous cells of undetermined significance or worse (ASCUS+), low-grade squamous intra-epithelial lesions or worse (LSIL+) or high-grade squamous intra-epithelial lesions or worse (HSIL+).Secondary objective To assess the accuracy of the HC2 assay to detect CIN2+ or CIN3+ in women with ASCUS or LSIL in a larger group of reports of studies that applied hrHPV testing and the reference standard (coloscopy and biopsy), irrespective whether or not repeat cytology was done. We made a comprehensive literature search that included the Cochrane Register of Diagnostic Test Accuracy Studies; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (through PubMed), and EMBASE (last search 6 January 2011). Selected journals likely to contain relevant papers were handsearched from 1992 to 2010 (December). We also searched CERVIX, the bibliographic database of the Unit of Cancer Epidemiology at the Scientific Institute of Public Health (Brussels, Belgium) which contains more than 20,000 references on cervical cancer.More recent searches, up to December 2012, targeted reports on the accuracy of triage of ASCUS or LSIL with other HPV DNA assays, or HPV RNA assays and other molecular markers. These searches will be used for new Cochrane reviews as well as for updates of the current review. Studies eligible for inclusion in the review had to include: women presenting with a cervical cytology result of ASCUS or LSIL, who had undergone both HC2 testing and repeat cytology, or HC2 testing alone, and were subsequently subjected to reference standard verification with colposcopy and colposcopy-directed biopsies for histologic verification. The review authors independently extracted data from the selected studies, and obtained additional data from report authors.Two groups of meta-analyses were performed: group I concerned triage of women with ASCUS, group II concerned women with LSIL. The bivariate model (METADAS-macro in SAS) was used to assess the absolute accuracy of the triage tests in both groups as well as the differences in accuracy between the triage tests. The pooled sensitivity of HC2 was significantly higher than that of repeat cytology at cut-off ASCUS+ to detect CIN2+ in both triage of ASCUS and LSIL (relative sensitivity of 1.27 (95% CI 1.16 to 1.39; P value < 0.0001) and 1.23 (95% CI 1.06 to 1.4; P value 0.007), respectively. In ASCUS triage, the pooled specificity of the triage methods did not differ significantly from each other (relative specificity: 0.99 (95% CI 0.97 to 1.03; P value 0.98)). However, the specificity of HC2 was substantially, and significantly, lower than that of repeat cytology in the triage of LSIL (relative specificity: 0.66 (95% CI 0.58 to 0.75) P value < 0.0001). HPV-triage with HC2 can be recommended to triage women with ASCUS because it has higher accuracy (significantly higher sensitivity, and similar specificity) than repeat cytology. When triaging women with LSIL, an HC2 test yields a significantly higher sensitivity, but a significantly lower specificity, compared to a repeat cytology. Therefore, practice recommendations for management of women with LSIL should be balanced, taking local circumstances into account.


Impairments in part-whole representations of objects in two cases of integrative visual agnosia.
How complex multipart visual objects are represented perceptually remains a subject of ongoing investigation. One source of evidence that has been used to shed light on this issue comes from the study of individuals who fail to integrate disparate parts of visual objects. This study reports a series of experiments that examine the ability of two such patients with this form of agnosia (integrative agnosia; IA), S.M. and C.R., to discriminate and categorize exemplars of a rich set of novel objects, "Fribbles", whose visual similarity (number of shared parts) and category membership (shared overall shape) can be manipulated. Both patients performed increasingly poorly as the number of parts required for differentiating one Fribble from another increased. Both patients were also impaired at determining when two Fribbles belonged in the same category, a process that relies on abstracting spatial relations between parts. C.R., the less impaired of the two, but not S.M., eventually learned to categorize the Fribbles but required substantially more training than normal perceivers. S.M.'s failure is not attributable to a problem in learning to use a label for identification nor is it obviously attributable to a visual memory deficit. Rather, the findings indicate that, although the patients may be able to represent a small number of parts independently, in order to represent multipart images, the parts need to be integrated or chunked into a coherent whole. It is this integrative process that is impaired in IA and appears to play a critical role in the normal object recognition of complex images.


The calcium channel alpha2delta-2 subunit partitions with CaV2.1 into lipid rafts in cerebellum: implications for localization and function.
The accessory alpha2delta subunits of voltage-gated calcium channels are highly glycosylated transmembrane proteins that interact with calcium channel alpha1 subunits to enhance calcium currents. We compared the membrane localization and processing of native cerebellar alpha2delta-2 subunits with alpha2delta-2 stably expressed in tsA-201 cells. We identified that alpha2delta-2 is completely concentrated in cholesterol-rich microdomains (lipid rafts) in cerebellum, in which it substantially colocalizes with the calcium channel alpha1 subunit CaV2.1, although CaV2.1 is also present in the Triton X-100-soluble fraction. In tsA-201 cells, unlike cerebellum, alpha2delta-2 is not completely proteolytically processed into alpha2-2 and delta-2. However, this processing is more complete in the lipid raft fraction of tsA-201 cells, in which alpha2delta-2 also colocalizes with CaV2.1. Cholesterol depletion of intact cells disrupted their lipid rafts and enhanced CaV2.1/alpha2delta-2/beta4 currents. Furthermore, alpha2delta-2 coimmunoprecipitates with lipid raft-associated proteins of the stomatin family. The apparent affinity of alpha2delta-2 for its ligand gabapentin is increased markedly in the cholesterol-rich microdomain fractions, in both cerebellum and the stable alpha2delta-2 cell line. In contrast, alpha2delta-2 containing a point mutation (R282A) has a much lower affinity for gabapentin, and this is not enhanced in the lipid raft fraction. This R282A mutant alpha2delta-2 shows reduced functionality in terms of enhancement of CaV2.1/beta4 calcium currents, suggesting that the integrity of the gabapentin binding site may be important for normal functioning of alpha2delta-2. Together, these results indicate that both alpha2delta-2 and CaV2.1 are normally associated with cholesterol-rich microdomains, and this influences their functionality.


Experimental evidence that female rhesus macaques (Macaca mulatta) perceive variation in male facial masculinity.
Among many primate species, face shape is sexually dimorphic, and male facial masculinity has been proposed to influence female mate choice and male-male competition by signalling competitive ability. However, whether conspecifics pay attention to facial masculinity has only been assessed in humans. In a study of free-ranging rhesus macaques, Macaca mulatta, we used a two-alternative look-time experiment to test whether females perceive male facial masculinity. We presented 107 females with pairs of images of male faces-one with a more masculine shape and one more feminine-and recorded their looking behaviour. Females looked at the masculine face longer than at the feminine face in more trials than predicted by chance. Although there was no overall difference in average look-time between masculine and feminine faces across all trials, females looked significantly longer at masculine faces in a subset of trials for which the within-pair difference in masculinity was most pronounced. Additionally, the proportion of time subjects looked toward the masculine face increased as the within-pair difference in masculinity increased. This study provides evidence that female macaques perceive variation in male facial shape, a necessary condition for intersexual selection to operate on such a trait. It also highlights the potential impact of perceptual thresholds on look-time experiments.


Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats.
Watermelon is rich in L-citrulline, an effective precursor of L-arginine. This study was conducted to determine whether dietary supplementation with watermelon pomace juice could ameliorate the metabolic syndrome in the Zucker diabetic fatty (ZDF) rat, an animal model of noninsulin-dependent diabetes mellitus. Nine-week-old ZDF rats were assigned randomly to receive drinking water containing 0% (control) or 0.2% L-arginine (as 0.24% L-arginine-HCl), 63% watermelon pomace juice, 0.01% lycopene, or 0.05% citrus pectin (n = 6 per treatment). At the end of the 4-wk supplementation period, blood samples, aortic rings, and hearts were obtained for biochemical and physiological analyses. Feed or energy intakes did not differ among the 5 groups of rats. However, dietary supplementation with watermelon pomace juice or L-arginine increased serum concentrations of arginine; reduced fat accretion; lowered serum concentrations of glucose, free fatty acids, homocysteine, and dimethylarginines; enhanced GTP cyclohydrolase-I activity and tetrahydrobiopterin concentrations in the heart; and improved acetylcholine-induced vascular relaxation. Compared with the control, dietary supplementation with lycopene or citrus pectin did not affect any measured parameter. These results provide the first evidence to our knowledge for a beneficial effect of watermelon pomace juice as a functional food for increasing arginine availability, reducing serum concentrations of cardiovascular risk factors, improving glycemic control, and ameliorating vascular dysfunction in obese animals with type-II diabetes.


Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial): study protocol for a randomized controlled trial.
Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months). This is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography-computed tomography (PET-CT). The primary endpoint is overall survival at 24 months, with secondary endpoints including response rate, progression-free survival, and quality of life. The planned sample size is 78 patients throughout five years. Patients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint. ClinicalTrials.gov registration number: NCT01785316 (registered 1 February 2013). EudraCT registration number: 2013-000564-29.


Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130.
The interleukin-6 (IL-6) signal is transduced through membrane-anchored gp130, which is associated with IL-6 receptor (IL-6R) in the presence of IL-6. Soluble forms of gp130 (sgp130) with molecular weights of 90 and 110 Kd were found in human serum. In the presence of recombinant IL-6 (rIL-6), serum sgp130 were capable of associating with serum sIL-6R. By the sandwich enzyme-linked immunosorbent assay, healthy human sera was shown to contain 390 +/- 72 ng/mL of sgp130. A mouse pro-B-cell line-derived transfectant, BAF-130, expressing human gp130 was used to examine the function of serum sgp130. When supplemented with rIL-6, human serum induced DNA synthesis in BAF-130 cells, whereas the serum deprived of sIL-6R did not. In contrast, the DNA synthesis induced in BAF-130 cells by rIL-6-supplemented serum was increased when the serum was deprived of sgp130. These results indicated that serum sgp130 could negatively regulate the IL-6 signal. Recently, gp130 has been shown to be involved in the signaling processes of oncostatin M, leukemia inhibitory factor, and ciliary neurotropic factor, in addition to those of IL-6. Recombinant sgp130 showed inhibitory effect on the biologic function of such cytokines. This work implies physiologic roles of naturally produced serum sgp130 in modulating signals through gp130.


Baclofen suppression of cocaine self-administration: demonstration using a discrete trials procedure.
We have previously reported that rats display a circadian pattern of cocaine self-administration if access to drug is limited to 10-min discrete trials that are separated by at least 20 min. In the present study, the pattern of cocaine intake (1.5 mg/kg per injection) was studied in two large groups of animals that were maintained on different 12-h light/dark cycles (3 a.m. to 3 p.m. versus 10 a.m. to 10 p.m.). Regardless of the time of light onset, a circadian pattern of cocaine self-administration was observed. Maximum cocaine intake occurred during the final 6 h of the dark period and was followed by a relative abstinence period during the light phase. This highly predictable pattern of drug taking behavior provided an opportunity to explore the effect of baclofen, a GABAB agonist, on the initiation of self-administration behavior. In two separate studies, acute treatment with baclofen (1.25-5.0 mg/kg) was shown to suppress cocaine intake for at least 4 h. Baclofen had no significant effect on responding for food reinforcement. Previous results have indicated that baclofen appears to reduce specifically the motivation to respond for cocaine. Together, these data suggest that baclofen should be considered as a possible pharmacotherapeutic agent in cocaine addiction.


Vps11 and Vps18 of Vps-C membrane traffic complexes are E3 ubiquitin ligases and fine-tune signalling.
In response to extracellular signals, many signalling proteins associated with the plasma membrane are sorted into endosomes. This involves endosomal fusion, which depends on the complexes HOPS and CORVET. Whether and how their subunits themselves modulate signal transduction is unknown. We show that Vps11 and Vps18 (Vps11/18), two common subunits of the HOPS/CORVET complexes, are E3 ubiquitin ligases. Upon overexpression of Vps11/Vps18, we find perturbations of ubiquitination in signal transduction pathways. We specifically demonstrate that Vps11/18 regulate several signalling factors and pathways, including Wnt, estrogen receptor α (ERα), and NFκB. For ERα, we demonstrate that the Vps11/18-mediated ubiquitination of the scaffold protein PELP1 impairs the activation of ERα by c-Src. Thus, proteins involved in membrane traffic, in addition to performing their well-described role in endosomal fusion, fine-tune signalling in several different ways, including through ubiquitination.


ATP-dependent chromatin remodeling in neural development.
Recent advances have revealed that modification of chromatin structure is an important determinant of cell fate and function. DNA methylation and covalent modifications of histone tails contribute to changes in chromatin architectures, either enhancing or repressing gene expression. Another mechanism underlying the modification of chromatin structure relies on the activity of the SWI/SNF-related ATP-dependent chromatin remodeling complexes that control the accessibility of DNA sequences to transcription factors. There is increasing evidence that ATP-dependent chromatin remodeling complexes based on the alternative DNA-dependent ATPases, Brg1 and Brm, plays essential roles during neural development in both vertebrates and invertebrates. This remodeling complex has dedicated functions at different stages of neural development that appear to arise by combinatorial assembly of its subunits.


Dalangtan Playa (Qaidam Basin, NW China): Its microbial life and physicochemical characteristics and their astrobiological implications.
Dalangtan Playa is the second largest salt playa in the Qaidam Basin, north-western China. The hyper saline deposition, extremely arid climate and high UV radiation make Dalangtan a Mars analogue both for geomorphology and life preservation. To better understand microbial life at Dalangtan, both culture-dependent and culture-independent methods were examined and simultaneously, environment conditions and the evaporitic mineral assemblages were investigated. Ten and thirteen subsurface samples were collected along a 595-cm deep profile (P1) and a 685-cm deep profile (P2) respectively, and seven samples were gathered from surface sediments. These samples are composed of salt minerals, minor silicate mineral fragments and clays. The total bacterial cell numbers are (1.54±0.49) ×10(5) g-1 for P1 and (3.22±0.95) ×10(5) g-1 for P2 as indicated by the CAtalyzed Reporter Deposition- Fluorescent in situ Hybridization (CARD-FISH). 76.6% and 75.7% of the bacteria belong to Firmicutes phylum respectively from P1 and P2. In total, 47 bacteria and 6 fungi were isolated from 22 subsurface samples. In contrast, only 3 bacteria and 1 fungus were isolated from 3 surface samples. The isolated bacteria show high homology (≥97%) with members of the Firmicutes phylum (47 strains, 8 genera) and the Actinobacteria phylum (3 strains, 2 genera), which agrees with the result of CARD-FISH. Isolated fungi showed ≥98% ITS1 homology with members of the phylum Ascomycota. Moisture content and TOC values may control the sediments colonization. Given the deliquescence of salts, evaporites may provide refuge for microbial life, which merits further investigation. Halotolerant and spore-forming microorganisms are the dominant microbial groups capable of surviving under extreme conditions. Our results offer brand-new information on microbial biomass in Dalangtan Playa and shed light on understanding the potential microbial life in the dried playa or paleo-lakes on Mars.


Effect of incremental levels of L-lysine and determination of the limiting amino acids in low crude protein corn-soybean meal diets for broilers.
Research was conducted to determine the level of l-Lys that can be included in corn-soybean meal (C-SBM) diets for broilers before an amino acid (AA) beyond Met, Lys, Thr, or Gly becoming limiting and to determine the order of limiting AA in low CP C-SBM diets. All experiments were conducted with Ross 708 broilers (0 to 18 d of age) in brooder batteries. Treatments contained 7 or 8 replicates with 6 birds per replicate. In all experiments, a control C-SBM diet containing no l-Lys.HCl and a similar diet [positive control (PC) + Gly] with supplemental Gly to provide 2.32% total dietary Gly + Ser were fed. All diets were formulated to contain 1.26% total Lys. All diets with added l-Lys.HCl contained supplemental Gly to provide 2.32% total dietary Gly + Ser. In experiment 1, l-Lys.HCl was added to the diets at 0.02% increments from 0.15 to 0.27%. Compared with the PC + Gly diet, there were no negative effects (P > 0.10) of supplemental Lys on ADG, ADFI, or G:F. In experiment 2, l-Lys.HCl was added to the diets at 0.05% increments from 0.25 to 0.60%. Compared with the PC + Gly diet, ADG and G:F were decreased (P < 0.03) in broilers fed diets containing greater than 0.30% l-Lys.HCl but not (P > 0.10) in the 0.25% l-Lys.HCl diet. In experiment 3, l-Lys.HCl was added to the diets at 0.05% increments from 0.20 to 0.30%. Daily gain was decreased (P < 0.03) in broilers fed 0.30% l-Lys.HCl but not in those fed 0.20 or 0.25% l-Lys.HCl. In experiment 4, the order of limiting AA was determined in a C-SBM diet containing 0.45% L-Lys.HCl. In addition to the PC and PC + Gly diets, diets consisted of a negative control (NC) diet with 0.45% l-Lys.HCl, NC + 0.247% Ile, NC + 0.484% l-Arg.HCl, NC + 0.249% Val, and all possible 2- and l-way combinations of all 3 AA. Compared with the NC diet, addition of Arg and the combination of Arg and the other AA increased ADG and ADFI, indicating that Arg was the limiting AA in this diet. Experiment 5 was conducted in an identical manner to experiment 4 except the diets with the added AA contained the same ratio of corn to soybean meal that is present in a diet with 0.25% l-Lys.HCl. The results of experiment 5 suggest that Arg and Val are equaling limiting in a diet with 0.25% l-Lys.HCl. In summary, 0.25% l-Lys.HCl can be added to C-SBM diets supplemented with Met, Thr, and Gly with no negative effects on growth performance, and Arg and Val are equaling limiting (after Met, Thr, Lys, and Gly) in diets containing 0.25% l-Lys.HCl.


Bruton's tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor alpha production.
Lipopolysaccharide (LPS), a product of Gram-negative bacteria, is potent mediator of tumor necrosis factor (TNF)alpha production by myeloid/macrophage cells. Inhibitors capable of blocking the signaling events that result in TNF alpha production could provide useful therapeutics for treating septic shock and other inflammatory diseases. Broad spectrum tyrosine inhibitors are known to inhibit TNF alpha production, however, no particular family of tyrosine kinases has been shown to be essential for this process. Here we show that the Bruton's tyrosine kinase (Btk)-deficient mononuclear cells from X-linked agammaglobulinemia patients have impaired LPS-induced TNF alpha production and that LPS rapidly induces Btk kinase activity in normal monocytes. In addition, adenoviral overexpression of Btk in normal human monocytes enhanced TNF alpha production. We examined the role of Btk in TNF alpha production using luciferase reporter adenoviral constructs and have established that overexpression of Btk results in the stabilization of TNF alpha mRNA via the 3' untranslated region. Stimulation with LPS also induced the activation of related tyrosine kinase, Tec, suggesting that the Tec family kinases are important components for LPS-induced TNF alpha production. This study provides the first clear evidence that tyrosine kinases of the Tec family, in particular Btk, are key elements of LPS-induced TNF alpha production and consequently may provide valuable therapeutic targets for intervention in inflammatory conditions.


Unique knowledge, unique skills, unique role: Aboriginal and Torres Strait Islander Health Workers in Queensland, Australia.
Aboriginal and Torres Strait Islander Health Workers (A&TSIHWs) are a professional cadre of Australian health workers typically located in primary care clinics. The role is one of only two that is 'identified'- that is, it must be occupied by an Aboriginal and/or Torres Strait Islander person - and holds specific responsibilities in relation to advocating for facility-level cultural safety. However, lack of understanding of the distinctive skills, scope and value associated with the A&TSIHW role remains pervasive in the broader health workforce. Positioned to represent the perspective of those working as A&TSIHWs, and drawing on 83 in-depth interviews with A&TSIHWs and others, this qualitative study reports on the core functions and distinctive orientation of the role, and seeks to articulate its distinctive value in the modern Queensland health service. Findings highlight the multifaceted (generalist) nature of the A&TSIHW role, which comprises three core functions: health promotion, clinical service and cultural brokerage. Underpinning these cross-cutting functions, is the role's unique orientation, defined by client-centredness and realised through Indigenous strengths based ways of knowing, being and doing. The findings highlight how the A&TSIHW role is one of the only mechanisms through which Aboriginal and Torres Strait Islander knowledge can be brought to bear on context-specific adaptations to routine health service practices; and through which the impacts of lack of cultural or self-awareness among some non-Indigenous health professionals can be mitigated. The complexity of such work in a government health system where a dominant biomedical culture defines what is valued and therefore resourced, is under-recognised and undervalued and contributes to pressures and stress that are potentially threatening the role's long-term viability.


Mechanism of antiviral drug resistance of vaccinia virus: identification of residues in the viral DNA polymerase conferring differential resistance to antipoxvirus drugs.
The acyclic nucleoside phosphonate (ANP) family of drugs shows promise as therapeutics for treating poxvirus infections. However, it has been questioned whether the utility of these compounds could be compromised through the intentional genetic modification of viral sequences by bioterrorists or the selection of drug resistance viruses during the course of antiviral therapy. To address these concerns, vaccinia virus (strain Lederle) was passaged 40 times in medium containing an escalating dose of (S)-1-[3-hydroxy-2-(phosphonomethoxypropyl)-2,6-diaminopurine [(S)-HPMPDAP], which selected for mutant viruses exhibiting a approximately 15-fold-increased resistance to the drug. (S)-HPMPDAP-resistant viruses were generated because this compound was shown to be one of the most highly selective and effective ANPs for the treatment of poxvirus infections. DNA sequence analysis revealed that these viruses encoded mutations in the E9L (DNA polymerase) gene, and marker rescue studies showed that the phenotype was produced by a combination of two (A684V and S851Y) substitution mutations. The effects of these mutations on drug resistance were tested against various ANPs, both separately and collectively, and compared with E9L A314T and A684V mutations previously isolated using selection for resistance to cidofovir, i.e., (S)-1-[3-hydroxy-2-(phosphonomethoxypropyl)cytosine]. These studies demonstrated a complex pattern of resistance, although as a general rule, the double-mutant viruses exhibited greater resistance to the deoxyadenosine than to deoxycytidine nucleotide analogs. The S851Y mutant virus exhibited a low level of resistance to dCMP analogues but high-level resistance to dAMP analogues and to 6-[3-hydroxy-2-(phosphonomethoxy)propoxy]-2,4-diaminopyrimidine, which is considered to mimic the purine ring system. Notably, (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-3-deazaadenine retained marked activity against most of these mutant viruses. In vitro studies showed that the A684V mutation partially suppressed a virus growth defect and mutator phenotype created by the S851Y mutation, but all of the mutant viruses still exhibited a variable degree of reduced virulence in a mouse intranasal challenge model. Infections caused by these drug-resistant viruses in mice were still treatable with higher concentrations of the ANPs. These studies have identified a novel mechanism for the development of mutator DNA polymerases and provide further evidence that antipoxviral therapeutic strategies would not readily be undermined by selection for resistance to ANP drugs.


The International Classification of Functioning, Disability and Health (ICF) Core Sets: application to a postmenopausal woman with rheumatoid arthritis and osteoporosis of the spine.
The International Classification of Functioning, Disability and Health (ICF) framework facilitates systematic assessment of functioning across four components. ICF Core Sets are proposed to be beneficial for clinicians in multidisciplinary care settings because they provide a common language for communication. A clinical vignette of a postmenopausal woman with rheumatoid arthritis (RA) and a non-traumatic vertebral fracture is presented to discuss how the ICF Core Sets for RA and osteoporosis (OP) can be helpful in structuring clinical decisions. To demonstrate how condition-specific ICF Core Sets can be used to evaluate and treat women with two comorbidities, each component of the ICF Core Sets is compared across conditions and integrated into clinical decision-making. Topics covered include: exercise tolerance, urinary continence, bone mass, fear of falling, and environmental factors. The benefits of thorough communication with the client and a common language across healthcare disciplines are highlighted as the potential benefits of the ICF framework; however, limitations to uptake of the ICF in clinical practice are also addressed.