Correcting for non-participation bias in health surveys using record-linkage, synthetic observations and pattern mixture modelling.
Surveys are key means of obtaining policy-relevant information not available from routine sources. Bias arising from non-participation is typically handled by applying weights derived from limited socio-demographic characteristics. This approach neither captures nor adjusts for differences in health and related behaviours between participants and non-participants within categories. We addressed non-participation bias in alcohol consumption estimates using novel methodology applied to 2003 Scottish Health Survey responses record-linked to prospective administrative data. Differences were identified in socio-demographic characteristics, alcohol-related harm (hospitalisation or mortality) and all-cause mortality between survey participants and, from unlinked administrative sources, the contemporaneous general population of Scotland. These were used to infer the number of non-participants within each subgroup defined by socio-demographics and health outcomes. Synthetic observations for non-participants were then generated, missing only alcohol consumption. Weekly alcohol consumption values among synthetic non-participants were multiply imputed under missing at random and missing not at random assumptions. Relative to estimates adjusted using previously derived weights, the obtained mean weekly alcohol intake estimates were up to 59% higher among men and 16% higher among women, depending on the assumptions imposed. This work demonstrates the universal value of multiple imputation-based methodological advancement incorporating administrative health data over routine weighting procedures.


Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells.
An 11-year-old girl presented with a papulovesicular rash and severe respiratory distress 5 weeks after receiving varicella vaccine. Restriction fragment length-polymorphism analysis of virus isolated from an endotracheal-tube aspirate and from bronchoalveolar lavage revealed that this patient's illness was due to the Oka vaccine strain of varicella. An extensive immunologic analysis failed to identify a known diagnostic entity to explain her susceptibility to this attenuated vaccine strain. Analysis of her lymphocytes on separate occasions, months after recovery from her illness, revealed a profound deficiency of natural killer T (NKT) cells and of NKT-cell activity, suggesting that NKT cells contribute to host defense against varicella virus.


Dual autonomous mitochondrial cell death pathways are activated by Nix/BNip3L and induce cardiomyopathy.
Dysregulation of programmed cell death due to abnormal expression of Bcl-2 proteins is implicated in cancer, neurodegenerative diseases, and heart failure. Among Bcl-2 family members, BNip proteins uniquely stimulate cell death with features of both apoptosis and necrosis. Localization of these factors to mitochondria and endoplasmic reticulum (ER) provides additional complexity. Previously, we observed regulation of intracellular calcium stores by reticular Nix. Here, we report effects of Nix targeting to mitochondria or ER on cell death pathways and heart failure progression. Nix-deficient fibroblasts expressing mitochondrial-directed or ER-directed Nix mutants exhibited similar cytochrome c release, caspase activation, annexin V and TUNEL labeling, and cell death. ER-Nix cells, but not mitochondrial-Nix cells, showed dissipation of mitochondrial inner membrane potential, Deltapsi(m), and were protected from cell death by cyclosporine A or ppif ablation, implicating the mitochondrial permeability transition pore (MPTP). ER-Nix cells were not protected from death by caspase inhibition or combined ablation of Bax and Bak. Combined inhibition of caspases and the MPTP fully protected against Nix-mediated cell death. To determine the role of the dual pathways in heart failure, mice conditionally overexpressing Nix or Nix mutants in hearts were created. Cardiomyocte death caused by mitochondrial- and ER-directed Nix was equivalent, but ppif ablation fully protected only ER-Nix. Thus, Nix stimulates dual autonomous death pathways, determined by its subcellular localization. Mitochondrial Nix activates Bax/Bak- and caspase-dependent apoptosis, whereas ER-Nix activates Bax/Bak-independent, MPTP-dependent necrosis. Complete protection against programmed cell death mediated by Nix and related factors can be achieved by simultaneous inhibition of both pathways.


Electromagnetically induced transparency-like effect in a two-bus waveguides coupled microdisk resonator.
We observe theoretically and experimentally electromagnetically induced transparency (EIT)-like effect in a single microdisk resonator (MDR) evanescently coupled with two bus waveguides. This structure is modeled using transfer matrix method, and it is revealed that the EIT-like spectrum originates from the coherent interference between two nearby low-order whispering-gallery modes (WGMs) with comparable quality factors. The EIT-like properties have been investigated analytically with respect to coupling efficiency, round-trip power attenuation, as well as phase spacing between two resonances. The resonance spacing and mode coupling are adjustable by varying the effective indices of WGMs and waveguide mode. Consequently, fully integrated MDRs were fabricated in silicon. Resonant modes and coupling efficiency are studied in one-bus waveguide coupled MDRs. Finally, EIT-like resonance is observed in a two-bus waveguides coupled MDR of 3 μm in radius with a quality factor of 4,200 and central transmission larger than 0.65. The experimental results agree with our modeling well and show good internal consistency, confirming that two WGMs coupled in a point-to-point manner are required for EIT-like effect.


Magnesium and Human Health: Perspectives and Research Directions.
Magnesium is the fourth most abundant cation in the body. It has several functions in the human body including its role as a cofactor for more than 300 enzymatic reactions. Several studies have shown that hypomagnesemia is a common electrolyte derangement in clinical setting especially in patients admitted to intensive care unit where it has been found to be associated with increase mortality and hospital stay. Hypomagnesemia can be caused by a wide range of inherited and acquired diseases. It can also be a side effect of several medications. Many studies have reported that reduced levels of magnesium are associated with a wide range of chronic diseases. Magnesium can play important therapeutic and preventive role in several conditions such as diabetes, osteoporosis, bronchial asthma, preeclampsia, migraine, and cardiovascular diseases. This review is aimed at comprehensively collating the current available published evidence and clinical correlates of magnesium disorders.


Regulation of Expression of Renal Organic Anion Transporters OAT1 and OAT3 in a Model of Ischemia/Reperfusion Injury.
Recently, we gained evidence that impairment of rOat1 and rOat3 expression induced by ischemic acute kidney injury (AKI) is mediated by COX metabolites and this suppression might be critically involved in renal damage. (i) Basolateral organic anion uptake into proximal tubular cells after model ischemia and reperfusion (I/R) was investigated by fluorescein uptake. The putative promoter sequences from hOAT1 (SLC22A6) and hOAT3 (SCL22A8) were cloned into a reporter plasmid, transfected into HEK cells and (ii) transcriptional activity was determined after model ischemia and reperfusion as a SEAP reporter gen assay. Inhibitors or antagonists were applied with the beginning of reperfusion. By using inhibitors of PKA (H89) and PLC (U73122), antagonists of E prostanoid receptor type 2 (AH6809) and type 4 (L161,982), we gained evidence that I/R induced down regulation of organic anion transport is mediated by COX1 metabolites via E prostanoid receptor type 4. The latter signaling was confirmed by application of butaprost (EP2 agonist) or TCS2510 (EP4 agonist) to control cells. In brief, the latter signaling was verified for the transcriptional activity in the reporter gen assay established. Therein, selective inhibitors for COX1 (SC58125) and COX2 (SC560) were also applied. Our data show (a) that COX1 metabolites are involved in the regulation of renal organic anion transport(ers) after I/R via the EP4 receptor and (b) that this is due to transcriptional regulation of the respective transporters. As the promoter sequences cloned were of human origin and expressed in a human renal epithelial cell line we (c) hypothesize that the regulatory mechanisms described after I/R is meaningful for humans as well.


Activity of a specific inhibitor, gefitinib (Iressa, ZD1839), of epidermal growth factor receptor in refractory non-small-cell lung cancer.
Gefitinib (Iressa(TM), ZD1839) is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Phase I studies showed that it is well tolerated, with evidence of tumor regression in patients with advanced non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the antitumor activity and tolerability of gefitinib in a series of patients with previously treated, advanced NSCLC, as a part of a compassionate use program. To be eligible, all patients were required to have histologically or cytologically proven advanced or metastatic NSCLC, prior chemotherapy with at least one cisplatin-containing chemotherapy regimen or contraindication to cytotoxic drugs, Eastern Cooperative Oncology Group performance status < or =2, and adequate hematological, renal and hepatic parameters. All patients provided signed informed consent. Patient re-evaluation was performed every 4-6 weeks. Seventy-three consecutive patients were enrolled. Response rate, including complete and partial response, was 9.6%; an additional 43.8% of patients achieved stable disease, for an overall disease control of 53.4%. EGFR1 status was evaluated by immunocytochemistry in 25 patients. According to EGFR1 immunoreactivity all responses were observed with medium/strong imunoreactivity while three out of four responses were observed in high expressive patients. Median survival for all patients was 4 months while it reached 6 months for patients with disease control. The 1-year survival rate was 13.1% for the entire series and 23.2% for patients with disease control. Non-hematological toxicity was generally mild. Gefitinib has promising activity with a good toxicity profile in patients with progressive NSCLC who have received one or two prior chemotherapy regimens. A possible relationship within response and EGFR1 expression is suggested.


Cystatin C and measures of physical function in elderly adults: the Health, Aging, and Body Composition (HABC) Study.
Most studies of the relation between kidney function and physical function have been conducted in persons with advanced kidney disease and have used creatinine-based measures of kidney function. Cystatin C concentration is a measure of kidney function that is independent of muscle mass, unlike creatinine. Using baseline data on 3,043 elderly adults from the Health, Aging, and Body Composition Study (Blacks and Whites recruited from Pittsburgh, Pennsylvania, and Memphis, Tennessee, in 1997-1998), the authors examined the cross-sectional association between cystatin C level and performance on several tests of physical function. After adjustment for demographic and lifestyle variables, chronic health conditions, and inflammation, each standard-deviation (0.34 mg/liter) increase in cystatin C concentration was associated with 1.32 odds (95% confidence interval (CI): 1.20, 1.46) of not completing a 400-m walk, a 10.9-second (95% CI: 8.1, 13.8) slower 400-m walk time, a 0.11-point (95% CI: 0.09, 0.13) reduction in lower extremity performance score, a 1.12-kg (95% CI: 0.83, 1.40) lower grip strength, and a 4.7-nm (95% CI: 3.5, 5.9) lower knee extension strength. In contrast, when kidney function was measured by estimated glomerular filtration rate, the association of kidney function with physical function was only evident below 60 ml/minute/1.73 m2. In these older adults, mild decrements in kidney function, as measured by cystatin C concentration, were associated with poorer physical function.


Blood rheology, cardiovascular risk factors, and cardiovascular disease: the West of Scotland Coronary Prevention Study.
The West of Scotland Coronary Prevention Study (WOSCOPS) showed that pravastatin reduced the risk of coronary heart disease (CHD) events in 6,595 middle-aged hypercholesterolaemic men aged 45-64 years without prior myocardial infarction followed for an average of 4.9 years. We hypothesised prospectively (a) that baseline levels of haemorheological variables were related to baseline and incident CHD and to mortality; and (b) that reduction in lipoproteins by pravastatin would lower plasma and blood viscosity, a potential contributory mechanism to CHD events. We therefore studied plasma and blood viscosity, fibrinogen, haematocrit, and blood cell counts at baseline and 1 year. At baseline, plasma and blood viscosity were related to risk factors, CHD measures, and claudication. On univariate analysis, baseline levels of all rheological variables (except platelet count) were related to incident CHD; CHD mortality; and total mortality. On multivariate analysis including baseline CHD and risk factors, plasma and blood viscosity, haematocrit and white cell count each remained significantly associated with incident CHD; while fibrinogen remained an independent predictor of mortality (all p < 0.03). After one year, lipoprotein reduction by pravastatin was associated with significant reductions (about one quarter of a standard deviation) in plasma viscosity (mean difference 0.02 mPa.s, p <0.001) and in blood viscosity (mean difference 0.06 mPa.s, p<0.001), but was not associated with significant changes in other rheological variables. We therefore suggest that pravastatin therapy, which reduces elevated lipoproteins in hypercholesterolaemic men, may lower risks of CHD and mortality partly by lowering plasma and blood viscosity. Further studies are required to test this hypothesis.


Protective and aggravating effects of Nlrp3 inflammasome activation in IBD models: influence of genetic and environmental factors.
Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation due to dysregulation of the mucosal immune system. The cytokines IL-1β and IL-18 appear early in intestinal inflammation and their pro-forms are processed via the caspase-1-activating multiprotein complex, the Nlrp3 inflammasome. Previously, we reported that the uptake of dextran sodium sulfate (DSS) by macrophages activates the Nlrp3 inflammasome and that Nlrp3(-/-) mice are protected in the acute DSS colitis model. Of note, other groups have reported opposing effects in regards to DSS susceptibility in Nlrp3(-/-) mice. Recently, mice lacking inflammasomes were found to develop a distinct intestinal microflora. To reconcile the contradicting observations, we investigated the role of Nlrp3 deficiency in two different IBD models: acute DSS colitis and TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced colitis. In addition, we investigated the impact of the intestinal flora on disease severity by performing cohousing experiments of wild-type and Nlrp3(-/-) mice, as well as by antibiotic treatment. Nlrp3(-/-) mice treated with either DSS or TNBS exhibited attenuated colitis and lower mortality. This protective effect correlated with an increased frequency of CD103+ lamina propria dendritic cells expressing a tolerogenic phenotype in Nlrp3(-/-) mice in steady state conditions. Interestingly, after cohousing, Nlrp3(-/-) mice were as susceptible as wild-type mice, indicating that transmission of endogenous bacterial flora between the two mouse strains might increase susceptibility of Nlrp3(-/-) mice towards DSS-induced colitis. Accordingly, treatment with antibiotics almost completely prevented colitis in the DSS model. The composition of the intestinal microflora significantly influences disease severity in IBD models comparing wild-type and Nlrp3(-/-) mice. This observation may - at least in part - explain contradictory results concerning the role of the inflammasome in different labs. Further studies are required to define the role of the Nlrp3 inflammasome in noninflamed mucosa under steady state conditions and in IBD.


Mixed Meal and Intravenous L-Arginine Tests Both Stimulate Incretin Release Across Glucose Tolerance in Man: Lack of Correlation with β Cell Function.
The aims of this study were to 1. define the responses of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and peptide YY (PYY) to an oral meal and to intravenous L-arginine; and 2. examine correlation of enteroendocrine hormones with insulin secretion. We hypothesized a relationship between circulating incretin concentrations and insulin secretion. Subjects with normal glucose tolerance (NGT, n = 23), prediabetes (PDM, n = 17), or with type 2 diabetes (T2DM, n = 22) were studied twice, following a mixed test meal (470 kCal) (mixed meal tolerance test [MMTT]) or intravenous L-arginine (arginine maximal stimulation test [AST], 5 g). GLP-1 (total and active), PYY, GIP, glucagon, and β cell function were measured before and following each stimulus. Baseline enteroendocrine hormones differed across the glucose tolerance (GT) spectrum, T2DM generally >NGT and PDM. In response to MMTT, total and active GLP-1, GIP, glucagon, and PYY increased in all populations. The incremental area-under-the-curve (0-120 min) of analytes like total GLP-1 were often higher in T2DM compared with NGT and PDM (35-51%; P < 0.05). At baseline glucose, L-arginine increased total and active GLP-1 and glucagon concentrations in all GT populations (all P < 0.05). As expected, the MMTT and AST provoked differential glucose, insulin, and C-peptide responses across GT populations. Baseline or stimulated enteroendocrine hormone concentrations did not consistently correlate with either measure of β cell function. Both MMTT and AST resulted in insulin and enteroendocrine hormone responses across GT populations without consistent correlation between release of incretins and insulin, which is in line with other published research. If a defect is in the enteroendocrine/β cell axis, it is probably reduced response to rather than diminished secretion of enteroendocrine hormones.


Structural basis of FFAT motif-mediated ER targeting.
The FFAT motif is a targeting signal responsible for localizing a number of proteins to the cytosolic surface of the endoplasmic reticulum (ER) and to the nuclear membrane. FFAT motifs bind to members of the highly conserved VAP protein family, which are tethered to the cytoplasmic face of the ER by a C-terminal transmembrane domain. We have solved crystal structures of the rat VAP-A MSP homology domain alone and in complex with an FFAT motif. The co-crystal structure was used to design a VAP mutant that disrupts rat and yeast VAP-FFAT interactions in vitro. The FFAT binding-defective mutant also blocked function of the VAP homolog Scs2p in yeast. Finally, overexpression of the FFAT binding-defective VAP in COS7 cells dramatically altered ER morphology. Our data establish the structural basis of FFAT-mediated ER targeting and suggest that FFAT-targeted proteins play an important role in determining ER morphology.


Green tobacco sickness in children and adolescents.
Tobacco (Nicotiana tabacum) is cultivated in more than 100 countries, and in 2004, some 5.73 million metric tons dry weight of tobacco were grown worldwide. The top five tobacco producers forecast for 2004 are China (2.01 million metric tons; 35.1%), Brazil (757 thousand metric tons; 13.2%), India (598 thousand metric tons; 10.4%), United States (358 thousand metric tons; 6.2%), and Malawi (138 thousand metric tons; 2.4%). Together, these five countries account for two-thirds of worldwide tobacco production. Tobacco farming presents several hazards to those who cultivate and harvest the plant. Although some of these hazards, such as pesticide exposure and musculoskeletal trauma, are faced by workers in other types of agricultural production, tobacco production presents some unique hazards, most notably acute nicotine poisoning, a condition also known as green tobacco sickness (GTS). GTS is an occupational poisoning that can affect workers who cultivate and harvest tobacco. It occurs when workers absorb nicotine through the skin as they come into contact with leaves of the mature tobacco plant. GTS is characterized largely by nausea, vomiting, headache, muscle weakness, and dizziness. Historically, children have played a role in agricultural production in the United States, and they continue to do so today. This includes tobacco farming. The North American Guidelines for Children's Agricultural Tasks, a set of injury prevention guidelines prepared by the National Children's Center for Rural and Agricultural Health and Safety, lists GTS as one of several hazards children face when working on tobacco farms. Children 17 years of age and younger who work on U.S. tobacco farms come from three main groups: members of farm families, migrant youth laborers (primarily Latinos), and other hired local children. All three groups are at risk for GTS. Beyond the U.S., tobacco production using child labor is an emerging topic of concern in developing nations. An international movement, advocated by the Eliminating Child Labor in Tobacco Foundation, is underway to restrict child labor in tobacco production. GTS is a unique occupational poisoning associated with tobacco farming. We suspect that many public health practitioners, clinicians, advocates, and researchers are unaware of GTS among children and adolescents. In this article, we provide an overview of GTS among young people who work in tobacco, summarize reports documenting pediatric GTS cases, explain GTS etiology, and present three case studies of pediatric GTS in Kentucky. In addition, we discuss the need for expanded surveillance and prevention of GTS, both in the United States and globally.


Population DNA methylation studies in the Developmental Origins of Health and Disease (DOHaD) framework.
Epigenetic changes represent a potential mechanism underlying associations of early-life exposures and later life health outcomes. Population-based cohort studies starting in early life are an attractive framework to study the role of such changes. DNA methylation is the most studied epigenetic mechanism in population research. We discuss the application of DNA methylation in early-life population studies, some recent findings, key challenges and recommendations for future research. Studies into DNA methylation within the Developmental Origins of Health and Disease framework generally either explore associations between prenatal exposures and offspring DNA methylation or associations between offspring DNA methylation in early life and later health outcomes. Only a few studies to date have integrated prospective exposure, epigenetic and phenotypic data in order to explicitly test the role of DNA methylation as a potential biological mediator of environmental effects on health outcomes. Population epigenetics is an emerging field which has challenges in terms of methodology and interpretation of the data. Key challenges include tissue specificity, cell type adjustment, issues of power and comparability of findings, genetic influences, and exploring causality and functional consequences. Ongoing studies are working on addressing these issues. Large collaborative efforts of prospective cohorts are emerging, with clear benefits in terms of optimizing power and use of resources, and in advancing methodology. In the future, multidisciplinary approaches, within and beyond longitudinal birth and preconception cohorts will advance this complex, but highly promising, the field of research.


[The contributions of French-Canadian group to Optics].
For a number of years, optics, mainly in the area of diffraction, has been pursued with increasing vigor at Laval University. The present article summarizes the contributions of this French-Canadian group. After a brief historical outline, the following topics are surveyed: circular gratings, axially symmetrical diffraction patterns with both phase and amplitude variation, the factor of encircled energy and apodization, millimeter-wave optics, optical convolution, iterated diffraction in connection with beam waveguides and resonators, structure of focal region for wide angle systems, and holography.


Predicting Reactions to Psychedelic Drugs: A Systematic Review of States and Traits Related to Acute Drug Effects.
Psychedelic drugs are increasingly being incorporated into therapeutic contexts for the purposes of promoting mental health. However, they can also induce adverse reactions in some individuals, and it is difficult to predict before treatment who is likely to experience positive or adverse acute effects. Although consideration of setting and dosage as well as excluding individuals with psychotic predispositions has thus far led to a high degree of safety, it is imperative that researchers develop a more nuanced understanding of how to predict individual reactions. To this end, the current systematic review coalesced the results of 14 studies that included baseline states or traits predictive of the acute effects of psychedelics. Individuals high in the traits of absorption, openness, and acceptance as well as a state of surrender were more likely to have positive and mystical-type experiences, whereas those low in openness and surrender or in preoccupied, apprehensive, or confused psychological states were more likely to experience acute adverse reactions. Participant sex was not a robust predictor of drug effects, but 5-HT2AR binding potential, executive network node diversity, and rACC volume may be potential baseline biomarkers related to acute reactions. Finally, increased age and experience with psychedelics were individual differences related to generally less intense effects, indicating that users may become slightly less sensitive to the effects of the drugs after repeated usage. Although future well-powered, placebo-controlled trials directly comparing the relative importance of these predictors is needed, this review synthesizes the field's current understanding of how to predict acute reactions to psychedelic drugs.


Narrative text analysis of Kentucky tractor fatality reports.
Narrative information in fatality investigation reports contains data elements not routinely analyzed with coded occupational injury surveillance data. A narrative text analysis of 69 Kentucky Fatality Assessment and Control Evaluation (FACE) agricultural tractor fatality reports from 1994 to 2004 was performed. The FACE reports were developed using the National Institute for Occupational Safety and Health, Division of Safety Research-recommended FACE report format that incorporates Haddon's matrix. Haddon's matrix separates the fatal incident into three event phases and is used to develop points of intervention based on human, organizational, and environmental factors. A multivariate logistic regression analysis for association between identified exposure variables and the outcomes of interest was undertaken. The operation of a tractor with an attached bucket, muddy terrain, and being thrown from the tractor were independent risk factors for being declared "dead at the scene". A tractor rollover and operation of a tractor on a slope were independent risk factors for being "crushed" by a tractor. Narrative text analysis of FACE fatality investigation reports is a valuable tool for the identification of additional factors contributing to tractor fatalities that can inform farm safety training, identify new areas for agricultural interventions, and support the development of new agricultural engineering strategies.


RECOPE: How to succeed in bringing ideas from academia to market without compromising ingenuity.
Translation of biomedical technology originated in academia to the market is hindered by lack of consideration of market needs and commercialization pathways that leads academic research away from the market, leaving the public without long-awaited cures. Here we describe Reverse Conceptual Product Engineering (RECOPE), an approach applied in academic setting early in the course of the research project to facilitate biomedical research translation from bench to bedside. By using expertise of diverse set of biomedical professionals and trainees to solve a problem, RECOPE helps to make research goals more relevant to the society needs and translatable in a long-term perspective. Through the use of RECOPE one can critically reassess research design and translational potential and identify new market opportunities. RECOPE also provides for considerable educational opportunities to pre- and post-doctoral trainees. Adoption of RECOPE as a basic to for research design education will have a noticeable impact on academic research.


Defective survival and activation of thymocytes in transgenic mice expressing a catalytically inactive form of Ca2+/calmodulin-dependent protein kinase IV.
We have generated transgenic mice that express a catalytically inactive form of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) specifically in thymic T cells. The presence of this protein results in a markedly reduced thymic cellularity, although the distribution of the remaining cells is normal based on evaluation of the CD4 and CD8 cell surface antigens that are used to gauge T cell development. Isolated thymic T cells from the transgenic mice also show a dramatically decreased survival rate when evaluated in culture under conditions that do not favor activation. When challenged with an activating stimulus such as alpha-CD3 or a combination of phorbol ester plus ionophore, the cells are severely compromised in their ability to produce the cytokine interleukin-2 (IL-2). Reduction of IL-2 production is secondary to the inability to phosphorylate the cAMP response element binding protein, CREB, and induce expression of the immediate early genes such as Fos B that are required to transactivate the IL-2 promoter. Because transgene expression was regulated by the proximal promoter of the murine lck gene and this promoter is inactivated in T cells that exit the thymus, the mutant hCaMKIV is not present in peripheral T cells. Consequently, T lymphocytes present in the spleen can be activated normally in response to either stimulus mentioned above, demonstrating that the effects of the inactive CaMKIV on activation are reversible. Our results suggest that CaMKIV may represent a physiologically relevant CREB kinase in T cells and that the enzyme is also required to ensure normal expansion of T cells in the thymus. Whereas the pathway responsible for this latter role is yet to be elucidated, it is unlikely to include CREB phosphorylation.


Scientific Versus Experiential Evidence: Discourse Analysis of the Chronic Cerebrospinal Venous Insufficiency Debate in a Multiple Sclerosis Forum.
The vascular hypothesis of multiple sclerosis (MS), called chronic cerebrospinal venous insufficiency (CCSVI), and its treatment (known as liberation therapy) was immediately rejected by experts but enthusiastically gripped by patients who shared their experiences with other patients worldwide by use of social media, such as patient online forums. Contradictions between scientific information and lay experiences may be a source of distress for MS patients, but we do not know how patients perceive and deal with these contradictions. We aimed to understand whether scientific and experiential knowledge were experienced as contradictory in MS patient online forums and, if so, how these contradictions were resolved and how patients tried to reconcile the CCSVI debate with their own illness history and experience. By using critical discourse analysis, we studied CCSVI-related posts in the patient online forum of the German MS Society in a chronological order from the first post mentioning CCSVI to the time point when saturation was reached. For that time period, a total of 117 CCSVI-related threads containing 1907 posts were identified. We analyzed the interaction and communication practices of and between individuals, looked for the relation between concrete subtopics to identify more abstract discourse strands, and tried to reveal discourse positions explaining how users took part in the CCSVI discussion. There was an emotionally charged debate about CCSVI which could be generalized to 2 discourse strands: (1) the "downfall of the professional knowledge providers" and (2) the "rise of the nonprofessional treasure trove of experience." The discourse strands indicated that the discussion moved away from the question whether scientific or experiential knowledge had more evidentiary value. Rather, the question whom to trust (ie, scientists, fellow sufferers, or no one at all) was of fundamental significance. Four discourse positions could be identified by arranging them into the dimensions "trust in evidence-based knowledge," "trust in experience-based knowledge," and "subjectivity" (ie, the emotional character of contributions manifested by the use of popular rhetoric that seemed to mask a deep personal involvement). By critical discourse analysis of the CCSVI discussion in a patient online forum, we reconstruct a lay discourse about the evidentiary value of knowledge. We detected evidence criteria in this lay discourse that are different from those in the expert discourse. But we should be cautious to interpret this dissociation as a sign of an intellectual incapability to understand scientific evidence or a naïve trust in experiential knowledge. Instead, it might be an indication of cognitive dissonance reduction to protect oneself against contradictory information.


Management of postmenopausal osteoporosis.
Postmenopausal osteoporosis is associated with significant morbidity, mortality, reduction in quality of life, and increasing health care costs. It is estimated that 1.5 million women in the United States have one or more osteoporosis-related fractures annually. Fractures may occur at any site, but vertebral fractures are the most common. Longitudinal studies have demonstrated a decreased life expectancy associated with both vertebral and nonvertebral fractures. Once an initial fracture occurs, there is a fivefold increased risk of a second fracture within 1 year. The management of osteoporosis today incorporates multiple modalities of therapy. In addition to early detection, patient education, exercise, and nutritional supplementation, multiple therapeutic agents should be implemented early in an attempt to prevent initial and subsequent fractures. This article reviews currently approved modalities of therapy for the prevention and treatment of postmenopausal osteoporosis.


A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses.
Though there was initial interest in the use of psychedelic drugs for psychiatric treatment, bad outcomes and subsequent passage of the Substance Act of 1970, which placed psychedelic drugs in the Schedule I category, significantly limited potential progress. More recently, however, there has been renewal in interest and promise of psychedelic research. The purpose of this review is to highlight contemporary human studies on the use of select psychedelic drugs, such as psilocybin, LSD, MDMA and ayahuasca, in the treatment of various psychiatric illnesses, including but not limited to treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. The safety and efficacy as reported from human and animal studies will also be discussed. Accumulated research to date has suggested the potential for psychedelics to emerge as breakthrough therapies for psychiatric conditions refractory to conventional treatments. However, given the unique history and high potential for misuse with popular distribution, special care and considerations must be undertaken to safeguard their use as viable medical treatments rather than drugs of abuse.


Compartment syndrome and regional anaesthesia: Critical review.
Acute compartment syndrome (ACS) is a potential orthopaedic/traumatology emergency. Without prompt, precise diagnosis and immediate treatment with surgical decompressive fasciotomy it can lead to neurological dysfunction and disability. The role of regional anaesthesia (RA) in patients at risk for ACS/ and in those with developed ACS is controversial. The aim of this critical review was to answer the question, whether regional anaesthesia can delay the diagnosis. The authors use an evidence-based approach to discuss these high risk patients in considering RA as a method of choice for effective analgesia. To the date of data collection, there was no single case report identified where RA alone led to delay in ACS diagnosis and surgical treatment. In four clinical cases, epidural analgesia can be associated with delayed ACS diagnosis. Frequent clinical evaluation and breakthrough pain despite a functional RA in combination with intracompartment pressure measurement remains the keystone of recommended management for patients at risk of ACS.


Is there still a French eating model? A taxonomy of eating behaviors in adults living in the Paris metropolitan area in 2010.
Meal times in France still represent an important moment in everyday life. The model of three rigorously synchronized meals is still followed by a majority of people, while meal frequencies have flattened in other European or North-American countries. We aimed to examine the "French model" of eating behavior by identifying and characterizing distinct meal patterns. Analyses were based on data from the SIRS cohort, a representative survey of the adult population in the Paris area. A clustering algorithm was applied to meal variables (number, time, location, with whom the meal is usually shared and activities associated with meals). Regression models were used to investigate associations between patterns and socio-demographic, social environment and perceived food quality variables. Five different patterns were identified among 2994 participants. The first three types (prevalence 33%, 17% and 24%) followed a three-meal pattern, with differences in locations and social interactions mainly related to time constraints and age. More marked differences were observed in the remaining two types. In the fourth type (prevalence 13%), individuals ate one or two meals per day, often with an irregular schedule, at home and in front of the television. They frequently were unemployed and had lower income. Breakfast skipping, increased snacking and a low adherence to dietary guidelines suggested that this behavior might have health consequences. In the fifth type (12%), people also ate two meals or less per day, possibly with the same consequences on food quality. However, meals were often taken outside the home, in social settings, and individuals following this pattern were typically active, integrated, young people, suggesting that this pattern might be an adaptation to a modern urban lifestyle. While a majority of the population still follows the three-meal pattern, our analysis distinguished two other eating patterns associated with specific sociological profiles.


Hypertrophic peroneal tubercle with stenosing tenosynovitis: the results of surgical treatment.
A hypertrophic peroneal tubercle creates a stenotic tunnel which triggers a painful peroneal longus. The painful condition is rare, so delayed diagnosis frequently occurs. The purpose of this study was to retrospectively analyze the diagnosis and the functional results of this condition. A consecutive series of 6 patients with painful hypertrophy of the peroneal tubercle was surgically treated with simple resection of the peroneal tubercle and tenosynovectomy. There were 4 women and 2 men with a median age of 26 years. The clinical symptoms included a prominence at the lateral calcaneus with tenderness. The symptoms were exaggerated with ankle motion. X-ray and computed tomography scanning revealed a bony prominence at the lateral calcaneal cortex. An enlarged peroneal tubercle and stenosing tenosynovitis were found in all patients. The associated findings included a ganglion cyst in one patient, entrapment of a branch of the sural nerve in one patient, and skin callatosis with bursitis in one patient. After a median follow-up period of 35 months, all patients had achieved satisfactory functional results, which included freedom from pain, good peroneal muscle power, good range of motion of the foot, and no limitation in footwear. In summary, the clinical symptoms caused by a hypertrophic peroneal tubercle rarely occurred. However, the diagnosis could be made with careful clinical and radiographic examinations. The symptoms were successfully treated by the complete resection of the tubercle, tenosynovectomy, and early range of motion exercise of the hindfoot joints.


Lessons learned from the Global Polio Eradication Initiative: A roadmap for the international COVID-19 vaccination campaign.
The COVID-19 vaccine is lauded by many as one of the greatest accomplishments in modern medicine, with the potential to definitively contain the deadliest pandemic of the last century. With the vaccine rollout now underway in the developing world, a robust, methodical, and swift global distribution effort is required to ensure that it will be done in an equitable manner. Taking into account the vast geographic, socioeconomic, cultural, and political diversity of countries around the world, global vaccination efforts have historically required multifaceted, time consuming, and labor-intensive approaches to be effective. However, with over 33 years of experience from the Global Polio Eradication Initiative - an international health initiative aimed at eradicating poliomyelitis - the COVID-19 vaccination campaign does not have to be approached blindly. Using lessons learned from the Global Polio Eradication Initiative, this paper aims to identify the supply- and demand-side barriers to the success of the international COVID-19 vaccination effort, and ways each can be overcome. Most notably, health systems shortcomings, political and cultural messaging, and civil unrest and violent conflict serve as daunting obstacles to the success of the COVID-19 vaccination campaign. The Global Polio Eradication Initiative has been able to overcome many of these same obstacles with innovative strategies such as context-specific microplanning, robust health surveillance systems, and community-centered education and advocacy programs. Ultimately, while the Global Polio Eradication Initiative is still fighting the battle of polio eradication, it has provided a roadmap for the COVID-19 vaccination campaign to be executed in a more swift and equitable manner.


Clinical significance of connective tissue growth factor in hepatitis B virus-induced hepatic fibrosis.
To determine the utility of connective tissue growth factor (CCN2/CTGF) for assessing hepatic fibrosis in hepatitis B virus (HBV)-induced chronic liver diseases (CLD-B). Enzyme-linked immunosorbent assay was used to measure CCN2 in sera from 107 patients with chronic hepatitis B (CHB) and 39 patients with HBV-induced active liver cirrhosis and 30 healthy individuals. Liver samples from 31 patients with CHB, 8 patients with HBV-induced liver cirrhosis and 8 HBV carriers with normal liver histology were examined for transforming growth factor β-1 (TGF-β1) or CCN2 mRNA levels by in situ hybridization, and computer image analysis was performed to measure integrated optimal density (IOD) of CCN2 mRNA-positive cells in liver tissues. Histological inflammation grading and fibrosis staging were evaluated by H and E staining and Van Gieson's method. Serum CCN2 concentrations were, respectively, 4.0- or 4.9-fold higher in patients with CHB or active liver cirrhosis as compared to healthy individuals (P < 0.01). There was good consistency between the levels of CCN2 in sera and CCN2 mRNA expression in liver tissues (r = 0.87, P < 0.01). The levels of CCN2 in sera were increased with the enhancement of histological fibrosis staging in patients with CLD-B (r = 0.85, P < 0.01). Serum CCN2 was a reliable marker for the assessment of liver fibrosis, with areas under the receiver operating characteristic (ROC) curves (AUC) of 0.94 or 0.85 for, respectively, distinguishing normal liver controls from patients with F1 stage liver fibrosis or discriminating between mild and significant fibrosis. Detection of serum CCN2 in patients with CLD-B may have clinical significance for assessment of severity of hepatic fibrosis.


A sensitive high-temperature electrothermal atomic absorption analysis for Rb+ in erythrocytes and plasma of normal and hypertensive persons.
This method for determination of Rb+ in human plasma and erythrocytes by graphite-furnace atomic absorption spectrophotometry has a sensitivity of 29 nmol/L for plasma, 12 nmol/L for erythrocytes. The detection limit is 24 nmol/L for plasma, 4.8 nmol/L for erythrocytes. This assay is approximately 30-fold more sensitive than previously reported techniques involving atomic absorption spectrophotometry, enabling use of smaller samples. The rubidium signal is linear with concentration up to 1.2 mumol/L, and addition of other cations to the matrix produces only minor alterations in the Rb+ signal. We measured plasma and erythrocytic Rb+ concentrations in healthy subjects and in patients with untreated essential hypertension. In both, our values are similar to those previously reported for healthy individuals.


Opposite regulation of Gax homeobox expression by angiotensin II and C-type natriuretic peptide.
Growth arrest-specific homeobox (Gax) gene was isolated from rat aorta cDNA library and its expression was largely confined to the cardiovascular tissues. Gax gene was rapidly downregulated by platelet-derived growth factor in vascular smooth muscle cells (VSMCs) and overexpressed Gax was reported to reduce the neointimal thickening after balloon injury in vivo. We have demonstrated that angiotensin II (Ang II) stimulates vascular growth. In contrast, we also reported that C-type natriuretic peptide (CNP) is secreted from vascular endothelial cells to act as a novel endothelium-derived relaxing peptide and inhibits vascular growth via cGMP cascade. In the present study, we examined the effects of Ang II and CNP on Gax gene expression in VSMCs. In quiescent rat aortic VSMCs. Gax mRNA (2 3 kb) level became negligible 6 hours after the addition of Ang II (10(-6) mol/L). The inhibitory action of Ang II on Gax mRNA expression (ED50: 10(-11) mol/L) was almost completely blocked by an AT1R antagonist, CV11974. In contrast, CNP 10(-6) mol/L augmented Gax mRNA expression to exhibit 1.8-fold increase of the control 12 hours after the stimulation. This effect of CNP was mimicked by the addition of 8-bromoadenosine 3'-5'-cyclic monophosphate. The addition of C-ANF[4-23], an atrial natriuretic peptide-C receptor-specific agonist and devoid of stimulating cGMP production, exhibited no effect on Gax mRNA expression. Simultaneous administration of Ang II and CNP revealed that CNP (10(-6) mol/L) significantly attenuated the inhibitory action of Ang II (10(-10) mol/L) on Gax mRNA expression. These results suggest that Gax is a common transcription factor involved in the signaling pathway of vascular growth for Ang II and CNP and regulates the cell cycle and/or phenotype of VSMCs for vascular remodeling in hypertension and atherosclerosis.


Object-Part Attention Model for Fine-Grained Image Classification.
Fine-grained image classification is to recognize hundreds of subcategories belonging to the same basic-level category, such as 200 subcategories belonging to the bird, which is highly challenging due to large variance in the same subcategory and small variance among different subcategories. Existing methods generally first locate the objects or parts and then discriminate which subcategory the image belongs to. However, they mainly have two limitations: 1) relying on object or part annotations which are heavily labor consuming; and 2) ignoring the spatial relationships between the object and its parts as well as among these parts, both of which are significantly helpful for finding discriminative parts. Therefore, this paper proposes the object-part attention model (OPAM) for weakly supervised fine-grained image classification and the main novelties are: 1) object-part attention model integrates two level attentions: object-level attention localizes objects of images, and part-level attention selects discriminative parts of object. Both are jointly employed to learn multi-view and multi-scale features to enhance their mutual promotion; and 2) Object-part spatial constraint model combines two spatial constraints: object spatial constraint ensures selected parts highly representative and part spatial constraint eliminates redundancy and enhances discrimination of selected parts. Both are jointly employed to exploit the subtle and local differences for distinguishing the subcategories. Importantly, neither object nor part annotations are used in our proposed approach, which avoids the heavy labor consumption of labeling. Compared with more than ten state-of-the-art methods on four widely-used datasets, our OPAM approach achieves the best performance.


Oxidative stress response in Clostridium perfringens.
Clostridium perfringens, a strictly anaerobic bacterium, is able to survive when exposed to oxygen for short periods of time and exhibits a complex adaptive response to reactive oxygen species, both under aerobic and anaerobic conditions. However, this adaptive response is not completely understood. C. perfringens possesses specialized genes that might be involved in this adaptive process, such as those encoding superoxide dismutase (SOD), superoxide reductase and alkyl hydroperoxide reductase, but their contribution to the oxidative stress response and their control mechanisms are unknown. By a combination of functional complementation of Escherichia coli strains impaired in either SOD, alkyl hydroperoxide reductase (AhpC) or catalase activity (Cat), transcription analysis and characterization of mutants impaired in regulatory genes, it was concluded that: (i) the product of the sod gene is certainly essential to scavenge superoxide radicals, (ii) the ahpC gene, which is fully induced in all oxidative stress conditions, is probably involved in the scavenging of all intracellular peroxides, (iii) the three rubrerythrin (rbr) genes of C. perfringens do not encode proteins with in vivo H(2)O(2) reductase activity, and (iv) the two rubredoxin (rub) genes do not contribute to the hypothetical superoxide reductase activity, but are likely to belong to an electron transfer chain involved in energy metabolism.


Diagnostic and therapeutic role of laparoscopy in perforated peptic ulcer in the elderly patients.
The purpose of this study is to analyze the outcome of elderly patients with perforated peptic ulcer comparing laparoscopic treatment versus open approach. In our General and Emergency Surgery Unit in the last 3 years, 20 elderly patients with perforated peptic ulcer were performed. We considered elderly all patients over the age of 65 years (10 females and 10 males; the mean age was 75 years). 16 patients (80%) were submitted to laparoscopic repair with omentoplasty and 4 (20%) to open repair. The patients were classified using the Boye's score which influenced the choice of surgical treatment and the outcoEmergency Romame. The two groups were compared in terms of operative surgery times, complication rate, mortality and postoperative outcomes. Perforated peptic ulcer is a common abdominal disease that is treated by surgery. The potential advantages of laparoscopy, both in terms of diagnosis and therapy, are clear and the major advantages may be observed in cases with peritonitis secondary as a perforated peptic ulcer where laparoscopy allows the confirmation of the diagnosis, the identification of the position of the ulcer and the repair. With the age the risks of comorbidities increases multidisease syndrome. Elderly patients suffer from frailty syndrome. All these factors make the elderly patient a major challenge for a laparoscopy treatment. The laparoscopic approach is an effective method for treatment of perforated peptic ulcer in the elderly with a great diagnostic and therapeutic role. Nowadays more prospective randomized studies are needed to evaluate the effectiveness of laparoscopic versus open repair.


Melting Down Protein Stability: PAPS Synthase 2 in Patients and in a Cellular Environment.
Within the crowded and complex environment of the cell, a protein experiences stabilizing excluded-volume effects and destabilizing quinary interactions with other proteins. Which of these prevail, needs to be determined on a case-by-case basis. PAPS synthases are dimeric and bifunctional enzymes, providing activated sulfate in the form of 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for sulfation reactions. The human PAPS synthases PAPSS1 and PAPSS2 differ significantly in their protein stability as PAPSS2 is a naturally fragile protein. PAPS synthases bind a series of nucleotide ligands and some of them markedly stabilize these proteins. PAPS synthases are of biomedical relevance as destabilizing point mutations give rise to several pathologies. Genetic defects in PAPSS2 have been linked to bone and cartilage malformations as well as a steroid sulfation defect. All this makes PAPS synthases ideal to study protein unfolding, ligand binding, and the stabilizing and destabilizing factors in their cellular environment. This review provides an overview on current concepts of protein folding and stability and links this with our current understanding of the different disease mechanisms of PAPSS2-related pathologies with perspectives for future research and application.


Structured decomposition design of partial Mueller matrix polarimeters.
Partial Mueller matrix polarimeters (pMMPs) are active sensing instruments that probe a scattering process with a set of polarization states and analyze the scattered light with a second set of polarization states. Unlike conventional Mueller matrix polarimeters, pMMPs do not attempt to reconstruct the entire Mueller matrix. With proper choice of generator and analyzer states, a subset of the Mueller matrix space can be reconstructed with fewer measurements than that of the full Mueller matrix polarimeter. In this paper we consider the structure of the Mueller matrix and our ability to probe it using a reduced number of measurements. We develop analysis tools that allow us to relate the particular choice of generator and analyzer polarization states to the portion of Mueller matrix space that the instrument measures, as well as develop an optimization method that is based on balancing the signal-to-noise ratio of the resulting instrument with the ability of that instrument to accurately measure a particular set of desired polarization components with as few measurements as possible. In the process, we identify 10 classes of pMMP systems, for which the space coverage is immediately known. We demonstrate the theory with a numerical example that designs partial polarimeters for the task of monitoring the damage state of a material as presented earlier by Hoover and Tyo [Appl. Opt.46, 8364 (2007)10.1364/AO.46.008364APOPAI1559-128X]. We show that we can reduce the polarimeter to making eight measurements while still covering the Mueller matrix subspace spanned by the objects.


Intraoperative assessment of breast cancer specimens decreases cost and number of reoperations.
It is the aim of our study to determine if the assessment of intraoperative breast cancer margins leads to decreased incidence of repeat operations and decreased cost. We collected data prospectively from two hospitals in Austin, TX, University Medical Center at Brackenridge (UMCB) and Seton Northwest Hospital (SNW), over a 2-year period. Comparison was made to see if intraoperative margin assessment affected total surgical costs and need for reoperation. One hundred and seven cases met criteria for inclusion in the study (UMCB = 45, SNW = 62). Intraoperative margin assessment was used in zero cases at SNW (0%) and in 17 at UMCB (38%). Intraoperative assessment was used in 16 per cent of total cases. Sixty per cent of cases at SNW required subsequent return to the operating room. Twenty-four per cent of cases at UMCB required subsequent reoperation (P < 0.05). The average number of surgical interventions required was 1 ± 0.3 with intraoperative assessment, 2 ± 0.6 without, (P < 0.05). Total surgical costs were $15,341 ± $4,328 with intraoperative assessment and $22,013 ± $13,821 without (P < 0.05). Use of intraoperative margin assessment for breast cancer operations leads to both a decrease in reoperations as well as a decrease in total operative costs.


Rationale, development and implementation of the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest.
To describe the development, design and consequent scientific implications of the Resuscitation Outcomes Consortium (ROC) population-based registry; ROC Epistry-Cardiac Arrest. The ROC Epistry--Cardiac Arrest is designed as a prospective population-based registry of all Emergency Medical Services (EMSs)-attended 9-1-1 calls for patients with out-of-hospital cardiac arrest occurring in the geographical area described by the eight US and three Canadian regions. The dataset was derived by an North American interdisciplinary steering committee. Enrolled cases include individuals of all ages who experience cardiac arrest outside the hospital, with evaluation by organized EMS personnel and: (a) attempts at external defibrillation (by lay responders or emergency personnel), or chest compressions by organized EMS personnel; (b) were pulseless but did not receive attempts to defibrillate or CPR by EMS personnel. Selected data items are categorized as mandatory or optional and undergo revisions approximately every 12 months. Where possible all definitions are referenced to existing literature. Where a common definition did not exist one was developed. Optional items include standardized CPR process data elements. It is anticipated the ROC Epistry--Cardiac Arrest will enroll between approximately 9000 and 13,500 treated all rhythm arrests and 4000 and 5000 ventricular fibrillation arrests annually and approximately 8000 EMS-attended but untreated arrests. We describe the rationale, development, design and future implications of the ROC Epistry--Cardiac Arrest. This paper will serve as the reference for subsequent ROC manuscripts and for the common data elements captured in both ROC Epistry--Cardiac Arrest and the ROC trials.


Grima: A Distinct Emotion Concept?
People experience an unpleasant sensation when hearing a scratch on a board or plate. The present research focuses on this aversive experience known in Spanish as 'grima' with no equivalent term in English and German. We hypothesized that this aversive experience constitutes a distinctive, separate emotional concept. In Study 1, we found that the affective meaning of 'grima' was closer to disgust than to other emotion concepts. Thus, in Study 2 we explored the features of grima and compared them with disgust. As grima was reported to be predominantly elicited by certain auditory stimuli and associated with a distinctive physiological pattern, Study 3 used direct measures of physiological arousal to test the assumption of a distinctive pattern of physiological responses elicited by auditory stimuli of grima and disgust, and found different effects on heart rate but not on skin conductance. In Study 4, we hypothesized that only participants with an implementation intention geared toward down-regulating grima would be able to successfully weaken the grima- but not disgust- experience. Importantly, this effect was specific as it held true for the grima-eliciting sounds only, but did not affect disgust-related sounds. Finally, Study 5 found that English and German speakers lack a single accessible linguistic label for the pattern of aversive reactions termed by Spanish speaking individuals as 'grima', whereas the elicitors of other emotions were accessible and accurately identified by German, English, as well as Spanish speakers.


Engineering hierarchical nanostructures by elastocapillary self-assembly.
Surfaces coated with nanoscale filaments such as silicon nanowires and carbon nanotubes are potentially compelling for high-performance battery and capacitor electrodes, photovoltaics, electrical interconnects, substrates for engineered cell growth, dry adhesives, and other smart materials. However, many of these applications require a wet environment or involve wet processing during their synthesis. The capillary forces introduced by these wet environments can lead to undesirable aggregation of nanoscale filaments, but control of capillary forces can enable manipulation of the filaments into discrete aggregates and novel hierarchical structures. Recent studies suggest that the elastocapillary self-assembly of nanofilaments can be a versatile and scalable means to build complex and robust surface architectures. To enable a wider understanding and use of elastocapillary self-assembly as a fabrication technology, we give an overview of the underlying fundamentals and classify typical implementations and surface designs for nanowires, nanotubes, and nanopillars made from a wide variety of materials. Finally, we discuss exemplary applications and future opportunities to realize new engineered surfaces by the elastocapillary self-assembly of nanofilaments.


A transcriptional toolbox for exploring peripheral neuroimmune interactions.
Correct communication between immune cells and peripheral neurons is crucial for the protection of our bodies. Its breakdown is observed in many common, often painful conditions, including arthritis, neuropathies, and inflammatory bowel or bladder disease. Here, we have characterised the immune response in a mouse model of neuropathic pain using flow cytometry and cell-type-specific RNA sequencing (RNA-seq). We found few striking sex differences, but a very persistent inflammatory response, with increased numbers of monocytes and macrophages up to 3 1/2 months after the initial injury. This raises the question of whether the commonly used categorisation of pain into "inflammatory" and "neuropathic" is one that is mechanistically appropriate. Finally, we collated our data with other published RNA-seq data sets on neurons, macrophages, and Schwann cells in naive and nerve injury states. The result is a practical web-based tool for the transcriptional data mining of peripheral neuroimmune interactions. http://rna-seq-browser.herokuapp.com/.


The association of BMI status with adolescent preventive screening.
To examine the relationship between BMI status (normal, overweight, and obese) and preventive screening among adolescents at their last checkup. We used population-based data from the 2003-2007 California Health Interview Surveys, telephone interviews of adolescents aged 12 to 17 years with a checkup in the past 12 months (n = 9220). Respondents were asked whether they received screening for nutrition, physical activity, and emotional distress. BMI was calculated from self-reported height and weight: (1) normal weight or underweight (<85th percentile); (2) overweight (85th-94th percentile); and (3) obese (>95th percentile). Multivariate logistic regression models tested how screening by topic differed according to BMI status, adjusting for age, gender, income, race/ethnicity, and survey year. Screening percentages in the pooled sample (all 3 years) were higher for obese, but not overweight, adolescents for physical activity (odds ratio: 1.4; P < .01) and nutrition (odds ratio: 1.6; screening did not differ P < .01). Stratified analysis by year revealed higher screening for obese (versus normal-weight) adolescents for nutrition and physical activity in 2003 and for all 3 topics in 2005. However, by 2007, screening did not differ according to BMI status. Overall screening between 2003 and 2007 declined for nutrition (75%-59%; P < .01), physical activity (74%-60%; P < .01), and emotional distress (31%-24%; P < .01). Obese adolescents receive more preventive screening versus their normal-weight peers. Overweight adolescents do not report more screening, but standards of care dictate increased attention for this group. These results are discouraging amid a rise in pediatric obesity and new guidelines that recommend screening by BMI status.


Bone mineral density in prediabetic men.
There are many studies regarding the effects of insulin on bone metabolism and changes in bone mineral density (BMD) in the setting of diabetes. The effect of prediabetes on BMD is not known. A total of 802 men participated in the Korea Rural Genomic Cohort Study (in Geumsan County). According to the results of an oral glucose tolerance test, subjects were classified into normal, prediabetic, and diabetic categories. One hundred twenty-four subjects diagnosed with type 2 diabetes were excluded, leaving 678 subjects for the study inclusion. BMD was estimated with a quantitative ultrasonometer. The average BMD T scores of normal and prediabetic subjects were -1.34 ± 1.42 and -1.33 ± 1.30, respectively; there was no significant difference in the BMD T scores between these groups. The BMD T score was inversely associated with age and positively correlated with body weight, body mass index, total cholesterol, low density lipoprotein cholesterol, and HbA1c. On multiple linear regression analysis, low density lipoprotein cholesterol was the only statistically significant variable for prediabetes (β = 0.007, P = 0.005). On the stepwise regression analysis, age (β = -0.026, P < 0.001), the body mass index (β = 0.079, P < 0.001), and low density lipoprotein cholesterol (β = 0.004, P = 0.016) were significant variables for prediabetes. There was no significant difference in the BMD T score between the normal and prediabetic subjects. Further studies are needed regarding the association of fracture risk and changes in BMD with the development of overt diabetes.


Description of extended pre-harvest pig Salmonella surveillance-and-control programme and its estimated effect on food safety related to pork.
Salmonella in pork can be combated during pre- or post-harvest. For large slaughterhouses, post-harvest measures like decontamination might be cost-effective while this is less likely with small-to-medium sized slaughterhouses. In this study, pre-harvest measures might be more relevant. We describe an extended surveillance-and-control programme for Salmonella in finisher pigs, which, to establish equivalence to the Swedish control programme, is intended for implementation on the Danish island, Bornholm. The effect of the programme on food safety was estimated by analysing Salmonella data from pig carcasses originating from herds that would have qualified for the programme during 2006-2008. Food safety was interpreted as prevalence of Salmonella on carcasses as well as the estimated number of human cases of salmonellosis related to pork produced within the programme. Data from the Danish Salmonella programme were obtained from Bornholm. We used a simulation model developed to estimate the number of human cases based on the prevalence of Salmonella on carcass swabs. Herds are only accepted in the programme if they have one or less seropositive sample within the previous 6 months. In this way, the Salmonella load is kept to a minimum. The programme is not yet in operation and pigs that qualify for the programme are currently mixed at slaughter with those that do not qualify. Therefore, we had to assess the impact on the carcass prevalence indirectly. The prevalence of Salmonella in carcass swabs among qualifying herds was 0.46% for the 3 years as a whole, with 2006 as the year with highest prevalence. According to the simulation the expected number of human cases relating to pork produced within the programme was below 10. When the programme is in operation, an extra effect of separating pigs within the programme from those outside is expected to lower the prevalence of Salmonella even further.


Cross-border movement, economic development and malaria elimination in the Kingdom of Saudi Arabia.
Malaria at international borders presents particular challenges with regards to elimination. International borders share common malaria ecologies, yet neighboring countries are often at different stages of the control-to-elimination pathway. Herein, we present a case study on malaria, and its control, at the border between Saudi Arabia and Yemen. Malaria program activity reports, case data, and ancillary information have been assembled from national health information systems, archives, and other related sources. Information was analyzed as a semi-quantitative time series, between 2000 and 2017, to provide a plausibility framework to understand the possible contributions of factors related to control activities, conflict, economic development, migration, and climate. The malaria recession in the Yemeni border regions of Saudi Arabia is a likely consequence of multiple, coincidental factors, including scaled elimination activities, cross-border vector control, periods of low rainfall, and economic development. The temporal alignment of many of these factors suggests that economic development may have changed the receptivity to the extent that it mitigated against surges in vulnerability posed by imported malaria from its endemic neighbor Yemen. In many border areas of the world, malaria is likely to be sustained through a complex congruence of factors, including poverty, conflict, and migration.


Prevalence of psychiatric disorders in Norwegian 10-14-year-olds: Results from a cross-sectional study.
Youth mental health problems is the leading cause of disability worldwide and a major public health concern. Prevalence rates are needed for planning preventive interventions and health care services. We here report Norwegian prevalence estimates for youth mental disorders based on findings from the Bergen Child Study cohort. A web-based psychiatric interview; the Development and Well-Being Assessment, was completed by parents and teachers of 2,043 10-14-year-olds from the city of Bergen, Norway. Post-stratification weights were used to account for selective participation related to parental educational in the estimation of prevalence rates. Prevalence rates are presented for the whole sample and stratified by gender and age. The overall population weighted estimate suggests that 6.93% (95% CI 5.06-9.41) of the children met DSM-IV diagnostic criteria for one or more psychiatric disorders. There were no robust indications of age- or gender-related differences in the prevalence. 11.4% of the children fulfilled criteria for more than one diagnosis. The most common comorbid conditions were ADHD and disruptive disorders. The prevalence of psychiatric disorders was relatively low among Norwegian 10-14-year-olds, compared to published worldwide prevalence estimates. This is in line with estimates from prior studies from the Nordic countries. These findings raise important questions about the origins of different prevalence rates for psychiatric disorders between societies. The findings also illustrate the importance of locally driven epidemiological studies for planning preventative efforts and appropriately scaling mental health services to meet the need of the population.


Google Glass for documentation of medical findings: evaluation in forensic medicine.
Google Glass is a promising premarket device that includes an optical head-mounted display. Several proof of concept reports exist, but there is little scientific evidence regarding its use in a medical setting. The objective of this study was to empirically determine the feasibility of deploying Glass in a forensics setting. Glass was used in combination with a self-developed app that allowed for hands-free operation during autopsy and postmortem examinations of 4 decedents performed by 2 physicians. A digital single-lens reflex (DSLR) camera was used for image comparison. In addition, 6 forensic examiners (3 male, 3 female; age range 23-48 years, age mean 32.8 years, SD 9.6; mean work experience 6.2 years, SD 8.5) were asked to evaluate 159 images for image quality on a 5-point Likert scale, specifically color discrimination, brightness, sharpness, and their satisfaction with the acquired region of interest. Statistical evaluations were performed to determine how Glass compares with conventionally acquired digital images. All images received good (median 4) and very good ratings (median 5) for all 4 categories. Autopsy images taken by Glass (n=32) received significantly lower ratings than those acquired by DSLR camera (n=17) (region of interest: z=-5.154, P<.001; sharpness: z=-7.898, P<.001; color: z=-4.407, P<.001, brightness: z=-3.187, P=.001). For 110 images of postmortem examinations (Glass: n=54, DSLR camera: n=56), ratings for region of interest (z=-8.390, P<.001) and brightness (z=-540, P=.007) were significantly lower. For interrater reliability, intraclass correlation (ICC) values were good for autopsy (ICC=.723, 95% CI .667-.771, P<.001) and postmortem examination (ICC=.758, 95% CI .727-.787, P<.001). Postmortem examinations performed using Glass took 42.6 seconds longer than those done with the DSLR camera (z=-2.100, P=.04 using Wilcoxon signed rank test). The battery charge of Glass quickly decreased; an average 5.5% (SD 1.85) of its battery capacity was spent per postmortem examination (0.81% per minute or 0.79% per picture). Glass was efficient for acquiring images for documentation in forensic medicine, but the image quality was inferior compared to a DSLR camera. Images taken with Glass received significantly lower ratings for all 4 categories in an autopsy setting and for region of interest and brightness in postmortem examination. The effort necessary for achieving the objectives was higher when using the device compared to the DSLR camera thus extending the postmortem examination duration. Its relative high power consumption and low battery capacity is also a disadvantage. At the current stage of development, Glass may be an adequate tool for education. For deployment in clinical care, issues such as hygiene, data protection, and privacy need to be addressed and are currently limiting chances for professional use.


Magnetic-field-controlled reconfigurable semiconductor logic.
Logic devices based on magnetism show promise for increasing computational efficiency while decreasing consumed power. They offer zero quiescent power and yet combine novel functions such as programmable logic operation and non-volatile built-in memory. However, practical efforts to adapt a magnetic device to logic suffer from a low signal-to-noise ratio and other performance attributes that are not adequate for logic gates. Rather than exploiting magnetoresistive effects that result from spin-dependent transport of carriers, we have approached the development of a magnetic logic device in a different way: we use the phenomenon of large magnetoresistance found in non-magnetic semiconductors in high electric fields. Here we report a device showing a strong diode characteristic that is highly sensitive to both the sign and the magnitude of an external magnetic field, offering a reversible change between two different characteristic states by the application of a magnetic field. This feature results from magnetic control of carrier generation and recombination in an InSb p-n bilayer channel. Simple circuits combining such elementary devices are fabricated and tested, and Boolean logic functions including AND, OR, NAND and NOR are performed. They are programmed dynamically by external electric or magnetic signals, demonstrating magnetic-field-controlled semiconductor reconfigurable logic at room temperature. This magnetic technology permits a new kind of spintronic device, characterized as a current switch rather than a voltage switch, and provides a simple and compact platform for non-volatile reconfigurable logic devices.


Chronic effects of cannabis use on the human reward system: an fMRI study.
Cannabis is one of the most used drugs of abuse. It affects the brain reward system in animals, and has proven rewarding and addictive potential in humans. We used functional MRI to measure brain activity during reward anticipation in a monetary reward task. Long-term cannabis users were compared to healthy controls. An additional control group consisting of nicotine users was included. Cannabis users showed attenuated brain activity during reward anticipation in the nucleus accumbens compared to non-smoking controls, but not compared to smoking controls. Cannabis users showed decreased reward anticipation activity in the caudate nucleus, compared to both non-smoking and smoking controls. These data suggest that nicotine may be responsible for attenuated reward anticipation activity in the accumbens, but that differences in the caudate are associated with the use of cannabis. Our findings imply that chronic cannabis use as well as nicotine, may cause an altered brain response to rewarding stimuli.


Neurologist care in Parkinson disease: a utilization, outcomes, and survival study.
To investigate the utilization of neurologist providers in the treatment of patients with Parkinson disease (PD) in the United States and determine whether neurologist treatment is associated with improved clinical outcomes. This was a retrospective observational cohort study of Medicare beneficiaries with PD in the year 2002. Multilevel logistic regression was used to determine which patient characteristics predicted neurologist care between 2002 and 2005 and compare the age, race, sex, and comorbidity-adjusted annual risk of skilled nursing facility placement and hip fracture between neurologist- and primary care physician-treated patients with PD. Cox proportional hazards models were used to determine the adjusted 6-year risk of death using incident PD cases, stratified by physician specialty. More than 138,000 incident PD cases were identified. Only 58% of patients with PD received neurologist care between 2002 and 2005. Race and sex were significant demographic predictors of neurologist treatment: women (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.76-0.80) and nonwhites (OR 0.83, 95% CI 0.79-0.87) were less likely to be treated by a neurologist. Neurologist-treated patients were less likely to be placed in a skilled nursing facility (OR 0.79, 95% CI 0.77-0.82) and had a lower risk of hip fracture (OR 0.86, 95% CI 0.80-0.92) in logistic regression models that included demographic, clinical, and socioeconomic covariates. Neurologist-treated patients also had a lower adjusted likelihood of death (hazard ratio 0.78, 95% CI 0.77-0.79). Women and minorities with PD obtain specialist care less often than white men. Neurologist care of patients with PD may be associated with improved selected clinical outcomes and greater survival.


Medicinal properties of mangiferin, structural features, derivative synthesis, pharmacokinetics and biological activities.
The identification of biologically active and potentially therapeutically useful pharmacophores from natural products has been a long-term focus in the pharmaceutical industry. The recent emergence of a worldwide obesity and Type II diabetes epidemic has increased focus upon small molecules that can modulate energy metabolism, insulin sensitivity and fat biology. Interesting preliminary work done on mangiferin (MGF), the predominant constituent of extracts of the mango plant Mangifera indica L., portends potential for this pharmacophore as a novel parent compound for treating metabolic disorders. MGF is comprised of a C-glucosylated xanthone. Owing to the xanthone chemical structure, MGF has a redox active aromatic system and has antioxidant properties. MGF exerts varied and impressive metabolic effects in animals, improving metabolic disorders. For example we have discovered that MGF is a novel activator of the mammalian pyruvate dehydrogenase complex, leading to enhancement of carbohydrate utilization in oxidative metabolism, and leading to increased insulin sensitivity in animal models of obesity and insulin resistance. In addition, recent unbiased proteomics studies revealed that MGF upregulates proteins pivotal for mitochondrial bioenergetics and downregulates proteins controlling de novo lipogenesis in liver, helping to explain protective effects of MGF in prevention of liver steatosis. Several chemical studies have achieved synthesis of MGF, suggesting possible synthetic strategies to alter its chemical structure for development of structure-activity relationship (SAR) information. Ultimately, chemical derivatization studies could lead to the eventual development of novel therapeutics based upon the parent pharmacophore structure. Here we provide comprehensive review on chemical features of MGF, synthesis of its derivatives, its pharmacokinetics and biological activities.


Cell type-specific manipulation with GFP-dependent Cre recombinase.
There are many transgenic GFP reporter lines that allow the visualization of specific populations of cells. Using such lines for functional studies requires a method that transforms GFP into a molecule that enables genetic manipulation. We developed a method that exploits GFP for gene manipulation, Cre recombinase dependent on GFP (CRE-DOG), a split component system that uses GFP and its derivatives to directly induce Cre/loxP recombination. Using plasmid electroporation and AAV viral vectors, we delivered CRE-DOG to multiple GFP mouse lines, which led to effective recombination selectively in GFP-labeled cells. Furthermore, CRE-DOG enabled optogenetic control of these neurons. Beyond providing a new set of tools for manipulation of gene expression selectively in GFP(+) cells, we found that GFP can be used to reconstitute the activity of a protein not known to have a modular structure, suggesting that this strategy might be applicable to a wide range of proteins.


The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation.
Chronic infection and associated inflammation are key contributors to human carcinogenesis. Ulcerative colitis (UC) is an oxyradical overload disease and is characterized by free radical stress and colon cancer proneness. Here we examined tissues from noncancerous colons of ulcerative colitis patients to determine (a) the activity of two base excision-repair enzymes, AAG, the major 3-methyladenine DNA glycosylase, and APE1, the major apurinic site endonuclease; and (b) the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in UC colon epithelium undergoing elevated inflammation and MSI was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MSI. Our results are consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MSI in patients with UC and may extend to chronic inflammatory or other diseases with MSI of unknown etiology.


Saccharomyces cerevisiae SPT3 gene is required for transposition and transpositional recombination of chromosomal Ty elements.
Mutations in the Saccharomyces cerevisiae SPT3 gene have dramatic effects on the expression of Ty elements and genes adjacent to the element. The SPT3 gene is essential for Ty transposition, because transposition of chromosomal Ty elements ceased when the SPT3 gene was replaced with the frameshift mutation spt3-101. Presumably, the elimination of transposition was due to the effect of the SPT3 gene product on Ty transcription; the transcripts of chromosomal Ty elements were largely abolished in the spt3-101 strain (F. Winston, K. J. Durbin, and G. R. Fink, Cell 39:675-682, 1984). Ty transcription in an spt3-101 strain could be reestablished by introduction of the pGTyH3 plasmid, in which transcription of the Ty element TyH3 is under the control of the GAL1 promoter; these plasmid-derived Ty transcripts were SPT3-independent. Ty transposition resumed after galactose induction in spt3-101 strains containing the pGTyH3 plasmid. In spt3 mutants nearly all of the resulting transposition events derived from pGTyH3 plasmids and not from chromosomal elements.


Determination of the zebrafish forebrain: induction and patterning.
We report an analysis of forebrain determination and patterning in the zebrafish Danio rerio. In order to study these events, we isolated zebrafish homologs of two neural markers, odd-paired-like (opl), which encodes a zinc finger protein, and fkh5, which encodes a forkhead domain protein. At mid-gastrula, expression of these genes defines a very early pattern in the presumptive neurectoderm, with opl later expressed in the telencephalon, and fkh5 in the diencephalon and more posterior neurectoderm. Using in vitro explant assays, we show that forebrain induction has occurred even earlier, by the onset of gastrulation (shield stage). Signaling from the early gastrula shield, previously shown to be an organizing center, is sufficient for activation of opl expression in vitro. In order to determine whether the organizer is required for opl regulation, we removed from late blastula stage embryos either the presumptive prechordal plate, marked by goosecoid (gsc) expression, or the entire organizer, marked by chordin (chd) expression. opl was correctly expressed after removal of the presumptive prechordal plate and consistently, opl was correctly expressed in one-eyed pinhead (oep) mutant embryos, where the prechordal plate fails to form. However, after removal of the entire organizer, no opl expression was observed, indicating that this region is crucial for forebrain induction. We further show that continued organizer function is required for forebrain induction, since beads of BMP4, which promotes ventral fates, also prevented opl expression when implanted during gastrulation. Our data show that forebrain specification begins early during gastrulation, and that a wide area of dorsal mesendoderm is required for its patterning.


Impact of distracted driving on safety and traffic flow.
Studies have documented a link between distracted driving and diminished safety; however, an association between distracted driving and traffic congestion has not been investigated in depth. The present study examined the behavior of teens and young adults operating a driving simulator while engaged in various distractions (i.e., cell phone, texting, and undistracted) and driving conditions (i.e., free flow, stable flow, and oversaturation). Seventy five participants 16-25 years of age (split into 2 groups: novice drivers and young adults) drove a STISIM simulator three times, each time with one of three randomly presented distractions. Each drive was designed to represent daytime scenery on a 4 lane divided roadway and included three equal roadway portions representing Levels of Service (LOS) A, C, and E as defined in the 2000 Highway Capacity Manual. Participants also completed questionnaires documenting demographics and driving history. Both safety and traffic flow related driving outcomes were considered. A Repeated Measures Multivariate Analysis of Variance was employed to analyze continuous outcome variables and a Generalized Estimate Equation (GEE) Poisson model was used to analyze count variables. Results revealed that, in general more lane deviations and crashes occurred during texting. Distraction (in most cases, text messaging) had a significantly negative impact on traffic flow, such that participants exhibited greater fluctuation in speed, changed lanes significantly fewer times, and took longer to complete the scenario. In turn, more simulated vehicles passed the participant drivers while they were texting or talking on a cell phone than while undistracted. The results indicate that distracted driving, particularly texting, may lead to reduced safety and traffic flow, thus having a negative impact on traffic operations. No significant differences were detected between age groups, suggesting that all drivers, regardless of age, may drive in a manner that impacts safety and traffic flow negatively when distracted.


System for measuring oxygen consumption rates of mammalian cells in static culture under hypoxic conditions.
Estimating the oxygen consumption rates (OCRs) of mammalian cells in hypoxic environments is essential for designing and developing a three-dimensional (3-D) cell culture system. However, OCR measurements under hypoxic conditions are infrequently reported in the literature. Here, we developed a system for measuring OCRs at low oxygen levels. The system injects nitrogen gas into the environment and measures the oxygen concentration by an optical oxygen microsensor that consumes no oxygen. The developed system was applied to HepG2 cells in static culture. Specifically, we measured the spatial profiles of the local dissolved oxygen concentration in the medium, then estimated the OCRs of the cells. The OCRs, and also the pericellular oxygen concentrations, decreased nonlinearly as the oxygen partial pressure in the environment decreased from 19% to 1%. The OCRs also depended on the culture period and the matrix used for coating the dish surface. Using this system, we can precisely estimate the OCRs of various cell types under environments that mimic 3-D culture conditions, contributing crucial data for an efficient 3-D culture system design.


Cariologic aspects of xylitol and its use in chewing gum: a review.
Several studies indicate that xylitol is not metabolized to acids either in pure cultures of oral microorganisms in vitro or in dental plaque in vivo. Chronic consumption of xylitol-sweetened chewing gum resulted in reduction of dental plaque, suppression of mutans streptococci, and reduced adhesiveness of plaque. So far, four field studies with regimens including chewing gum and other xylitol-containing products and four clinical trials have been carried out. All of the latter studies showed that a daily intake of two to three pieces of xylitol gum resulted in a defined reduction of caries. There are indications that regular and prolonged use of xylitol chewing gum may have a caries-preventive effect.


Extracellular Matrix Stiffness Regulates Osteogenic Differentiation through MAPK Activation.
Mesenchymal stem cell (MSC) differentiation is regulated by the extracellular matrix (ECM) through activation of intracellular signaling mediators. The stiffness of the ECM was shown to be an important regulatory factor for MSC differentiation, and transcriptional coactivator with PDZ-binding motif (TAZ) was identified as an effector protein for MSC differentiation. However, the detailed underlying mechanism regarding the role of ECM stiffness and TAZ in MSC differentiation is not yet fully understood. In this report, we showed that ECM stiffness regulates MSC fate through ERK or JNK activation. Specifically, a stiff hydrogel matrix stimulates osteogenic differentiation concomitant with increased nuclear localization of TAZ, but inhibits adipogenic differentiation. ERK and JNK activity was significantly increased in cells cultured on a stiff hydrogel. TAZ activation was induced by ERK or JNK activation on a stiff hydrogel because exposure to an ERK or JNK inhibitor significantly decreased the nuclear localization of TAZ, indicating that ECM stiffness-induced ERK or JNK activation is important for TAZ-driven osteogenic differentiation. Taken together, these results suggest that ECM stiffness regulates MSC differentiation through ERK or JNK activation.


Platelet signalling networks: pathway perturbation demonstrates differential sensitivity of ADP secretion and fibrinogen binding.
Platelet signalling responses to single agonists have been identified previously. However, a model of the total platelet signalling network is still lacking. In order to gain insights into this network, we explored the effects of a range of platelet-function inhibitors in two independent assays of platelet function, namely fibrinogen binding and ADP secretion. In this study, we targeted the intracellular signalling molecules targeted intracellular signalling molecules, Syk and PI3K and targeted intracellular signalling molecules, Syk and PI3K, the prostaglandin synthesis enzyme cyclooxygenase, surface receptors for TxA(2) and ADP (P2Y1 and P2Y12) and the integrin cell adhesion molecule, αIIbβ3. We demonstrate that the platelet responses of fibrinogen binding and secretion can be differentially affected by the individual inhibitors permitting the generation of a model delineating novel regulatory links in the platelet signalling network. Importantly, the model illustrates the interconnections among portions that are traditionally studied as separate modules, promoting a more integrated view of the platelet.


Levels of Acculturation of Chinese Older Adults in the Greater Chicago Area - The Population Study of Chinese Elderly in Chicago.
Acculturation is a difficult process for minority older adults for a variety of reasons, including access and exposure to mainstream culture, competing ethnic identities, and linguistic ability and preference. There is a paucity of research regarding overall level of acculturation for Chinese older adults in the United States. This study aimed to provide an overall estimate of level of acculturation of Chinese older adults in the United States and to examine correlations between sociodemographic characteristics, self-reported health measures, and level of acculturation. Data were collected through the Population Study of Chinese Elderly in Chicago (PINE) study. This community-based participatory research study surveyed 3,159 Chinese older adults aged 60 and older. The PINE Study Acculturation Scale was used to assess level of acculturation in three dimensions: language preference, media use, and ethnic social relations. Mean acculturation level for all items was 15.3 ± 5.1, indicating low levels of acculturation. Older age, more offspring, lower income, fewer years living in the United States, lower overall health status, and lower quality of life were associated with lower levels of acculturation. Level of acculturation was low in Chinese older adults, and certain subsets of the population were more likely to have a lower level of acculturation. Future research should investigate causality and effects of level of acculturation.


Role of auxiliary beta1-, beta2-, and beta3-subunits and their interaction with Na(v)1.8 voltage-gated sodium channel.
The nociceptive C-fibers of the dorsal root ganglion express several sodium channel isoforms that associate with one or more regulatory beta-subunits (beta1-beta4). To determine the effects of individual and combinations of the beta-subunit isoforms, we co-expressed Nav1.8 in combination with these beta-subunits in Xenopus oocytes. Whole-cell inward sodium currents were recorded using the two-microelectrode voltage clamp method. Our studies revealed that the co-expression beta1 alone or in combination with other beta-subunits enhanced current amplitudes, accelerated current decay kinetics, and negatively shifted the steady-state curves. In contrast, beta2 alone and in combination with beta1 altered steady-state inactivation of Nav1.8 to more depolarized potentials. Co-expression of beta3 shifted steady-state inactivation to more depolarized potentials; however, combined beta1beta3 expression caused no shift in channel availability. The results in this study suggest that the functional behavior of Nav1.8 will vary depending on the type of beta-subunit that expressed under normal and disease states.


Investigation of the effects of alpha-tocopherol on the levels of Fe, Cu, Zn, Mn, and carbonic anhydrase in rats with bleomycin-induced pulmonary fibrosis.
This study was designed to examine the effects of vitamin E on the levels of Zn, Mn, Cu, Fe, and carbonic anhydrase in rats with bleomycininduced pulmonary fibrosis. Twenty-one male Wistar albino rats were randomly divided into three groups: bleomycin alone, bleomycin+vitamin E, and saline alone (control group). The bleomycin group was given 7.5 mg/kg body weight (single dose) bleomycin hydrochloride intratracheally. The bleomycin+vitamin E group was also instilled with bleomycin hydrochloride but received injections of alpha-tocopherol twice a week. The control group was treated with saline alone. Animals were sacrified 14 d after intratracheal instillation of bleomycin. Tissue Zn, Mn, Cu, Fe, and carbonic anhydrase activities were measured in the lung and liver. Lung Cu, Fe, and carbonic anhydrase activity increase in both experimental groups. Zn and Mn levels decreased, except for the Mn level in the bleomycin group. Liver Zn, Mn, and Cu levels decreased in both experimental groups compared to the control group, whereas Fe and carbonic anhydrase activity increased in comparison to the control group. However, the liver tissue Fe level decreased compared to the control group. In the histopathologic assesment of lung sections in the bleomycin+vitamin E group, partial fibrotic lesions were observed, but the histopathologic changes were much less severe compared to the bleomycin-treated group.