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International audience; Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1(+/-) mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1(+/-) mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.

Human exposure to toluene diisocyanate (TDI) occurs mainly through inhalation of vapors in occupational settings where TDI is produced or used, but dermal exposure to TDI is also possible during some operations. Because of a recent epidemiology study reporting a possible association with lung cancer risk in workers with potential dermal exposure to TDI, we evaluated the evidence from epidemiological, toxicological, and toxicokinetic studies to assess whether it is likely that dermal exposure to TDI can cause human respiratory cancers. We found that the reported associations with respiratory cancers in the epidemiology studies do not support TDI as a causal factor, as there are other explanations that are more likely than causation, such as confounding by smoking and low socioeconomic status. Experimental animal and genotoxicity studies indicate that the carcinogenic potential of TDI depends on its conversion to toluene diamine (TDA), and there is no evidence of systemic availability of TDA after dermal or inhalation exposure to TDI. Also, systemic uptake of TDI is very low after dermal exposure, and any absorbed TDI is more likely to react with biomolecules on or below the skin surface than to form TDA. Even if some TDA formation occurred after dermal exposure to TDI, TDA does not induce respiratory tract tumors in experimental animals after either dermal or oral exposure. We conclude that the available evidence indicates that dermal TDI exposure does not cause respiratory cancers in humans. Keywords: Carcinogenicity, Dermal exposure, Diisocyanates, Polyurethane foam, Respiratory cancer, Toluene diisocyanate

To determine whether evidence indicates that short-term exposure to ambient concentrations of ozone in the United States can affect asthma severity, we systematically reviewed published controlled human exposure, epidemiology, and animal toxicity studies. The strongest evidence for a potential causal relationship came from epidemiology studies reporting increased emergency department visits and hospital admissions for asthma following elevated ambient ozone concentrations. However, while controlled exposure studies reported lung function decrements and increased asthma symptoms following high ozone exposures 160-400 parts per billion [ppb]), epidemiology studies evaluating similar outcomes reported less consistent results. Animal studies showed changes in pulmonary function at high ozone concentrations (> 500ppb), although there is substantial uncertainty regarding the relevance of these animal models to human asthma. Taken together, the weight of evidence indicates that there is at least an equal likelihood that either explanation is true, i.e., the strength of the evidence for a causal relationship between short-term exposure to ambient ozone concentrations and asthma severity is "equipoise and above."

Context US EPA proposed a Reference Concentration for Libby amphibole asbestos based on the premise that pleural plaques are adverse and cause lung function deficits. Objective We conducted a systematic review to evaluate whether there is an association between pleural plaques and lung function and ascertain whether results were dependent on the method used to identify plaques. Methods Using the PubMed database, we identified studies that evaluated pleural plaques and lung function. We assessed each study for quality, then integrated evidence and assessed associations based on the Bradford Hill guidelines. We also compared the results of HRCT studies to those of X-ray studies. Results We identified 16 HRCT and 36 X-ray studies. We rated six HRCT and 16 X-ray studies as higher quality based on a risk-of-bias analysis. Half of the higher quality studies reported small but statistically significant mean lung function decrements associated with plaques. None of the differences were clinically significant. Many studies had limitations, such as inappropriate controls and/or insufficient adjustment for confounders. There was little consistency in the direction of effect for the most commonly reported measurements. X-ray results were more variable than HRCT results. Pleural plaques were not associated with changes in lung function over time in longitudinal studies. Conclusion The weight of evidence indicates that pleural plaques do not impact lung function. Observed associations are most likely due to unidentified abnormalities or other factors.

Arsenic (As) can exist in the environment in several different forms, each having unique chemical characteristics that influence its toxicity and potential for human and ecological exposure. Within the last decade or so, the focus on speciated As (both the inorganic and organic forms) and its potential toxicity has led to an increased availability of data on speciated As in different food types. To gain an understanding of these developments and the current science, we evaluated the state of knowledge regarding As speciation in food and calculated the average levels of several species of As measured in food. Because inorganic arsenic (inAs) is considered the most toxicologically important form of As, we focused our analysis on papers presenting information on total inAs and speciated inAs (inAs 3 + or inAs 5 + ). We also evaluated speciated As forms ( e.g. , monomethylarsonic and dimethylarsinic acid) when presented with inAs information. Publications were drawn from the peer-reviewed literature and reports by authoritative health agencies. While a great deal of speciation data were identified, including over 6500 unique inAs data points, unclear study methodology and inconsistencies between studies introduced uncertainty into the analysis of these data. Despite these limitations, our analysis demonstrates that inAs in foods can vary widely by type and even by sample, with mean inAs concentrations ranging from undetectable (in milk) to 11,000 μg/kg (in seaweed/algae). We found a high percentage of non-measurable As in many food types, suggesting that the limits of detection of speciated As must be considered to accurately estimate dietary As exposure. The applicability of our analysis is limited by the inconsistencies and uncertainties in the available data; calculations of inAs dietary intake should be tailored to the study population of interest and should consider study quality.

We conducted a weight-of-evidence (WoE) analysis to assess whether the current body of research supports a causal relationship between long-term ozone exposure (defined by EPA as at least 30 days in duration) at ambient levels and cardiovascular (CV) effects. We used a novel WoE framework based on the United States Environmental Protection Agency's National Ambient Air Quality Standards causal framework for this analysis. Specifically, we critically evaluated and integrated the relevant epidemiology and experimental animal data and classified a causal determination based on categories proposed by the Institute of Medicine's 2008 report, Improving the Presumptive Disability Decision-making Process for Veterans. We found that the risks of CV effects are largely null across human and experimental animal studies. The few positive associations reported in studies of CV morbidity and mortality are very small in magnitude, mainly reported in single-pollutant models, and likely attributable to bias, chance, or confounding. The few positive effects in experimental animal studies were observed mainly in ex vivo studies at high exposures, and even the in vivo findings are not likely relevant to humans. The available data also do not support a biologically plausible mechanism for the effects of ozone on the CV system. Overall, the current WoE provides no convincing case for a causal relationship between long-term exposure to ambient ozone and adverse effects on the CV system in humans, but the limitations of the available studies preclude definitive conclusions regarding a lack of causation; thus, we categorize the strength of evidence for a causal relationship between long-term exposure to ozone and CV effects as "below equipoise."

There is a relatively large body of research on the potential cardiovascular (CV) effects associated with short-term ozone exposure (defined by EPA as less than 30 days in duration). We conducted a weight-of-evidence (WoE) analysis to assess whether it supports a causal relationship using a novel WoE framework adapted from the US EPA's National Ambient Air Quality Standards causality framework. Specifically, we synthesized and critically evaluated the relevant epidemiology, controlled human exposure, and experimental animal data and made a causal determination using the same categories proposed by the Institute of Medicine report Improving the Presumptive Disability Decision-making Process for Veterans ( IOM 2008). We found that the totality of the data indicates that the results for CV effects are largely null across human and experimental animal studies. The few statistically significant associations reported in epidemiology studies of CV morbidity and mortality are very small in magnitude and likely attributable to confounding, bias, or chance. In experimental animal studies, the reported statistically significant effects at high exposures are not observed at lower exposures and thus not likely relevant to current ambient ozone exposures in humans. The available data also do not support a biologically plausible mechanism for CV effects of ozone. Overall, the current WoE provides no convincing case for a causal relationship between short-term exposure to ambient ozone and adverse effects on the CV system in humans, but the limitations of the available studies preclude definitive conclusions regarding a lack of causation. Thus, we categorize the strength of evidence for a causal relationship between short-term exposure to ozone and CV effects as "below equipoise."

The discovery of small non-coding microRNAs has revealed novel mechanisms of post-translational regulation of gene expression, the implications of which are still incompletely understood. We focused on microRNA 21 (miR-21), which is expressed in cardiac valve endothelium during development, in order to better understand its mechanistic role in cardiac valve development. Using a combination of in vivo gene knockdown in zebrafish and in vitro assays in human cells, we show that miR-21 is necessary for proper development of the atrioventricular valve (AV). We identify pdcd4b as a relevant in vivo target of miR-21 and show that protection of pdcd4b from miR-21 binding results in failure of AV development. In vitro experiments using human pulmonic valve endothelial cells demonstrate that miR-21 overexpression augments endothelial cell migration. PDCD4 knockdown alone was sufficient to enhance endothelial cell migration. These results demonstrate that miR-21 plays a necessary role in cardiac valvulogenesis, in large part due to an obligatory downregulation of PDCD4.

Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia. Here we show that SGK1 directly regulates NaV1.5 channel function, and genetic inhibition of SGK1 in a zebrafish model of inherited long QT syndrome rescues the long QT phenotype. Using computer-aided drug discovery coupled with in vitro kinase assays, we identified a novel class of SGK1 inhibitors. Our lead SGK1 inhibitor (5377051) selectively inhibits SGK1 in cultured cardiomyocytes, and inhibits phosphorylation of an SGK1-specific target as well as proliferation in the prostate cancer cell line, LNCaP. Finally, 5377051 can reverse SGK1’s effects on NaV1.5 and shorten the action potential duration in induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a patient with a gain-of-function mutation in Nav 1.5 (Long QT3 syndrome). Our data suggests that SGK1 inhibitors warrant further investigation in the treatment of cardiac arrhythmias.

Study Design Clinical measurement, cross-sectional. Background Quadriceps deficits are common in individuals with knee joint impairments and impact functional and quality-of-life outcomes. Quadriceps strength symmetry influences clinical decisions after knee injury. Isometric electromechanical dynamometry (ISO-ED) is the gold standard for measuring symmetry, but is not available in all clinical settings. Objectives To compare concurrent validity of handheld dynamometry and 1-repetition-maximum leg press, knee extension from 90° to 0°, and knee extension from 90° to 45° to that of ISO-ED in identifying meaningful quadriceps strength deficits. Methods Fifty-six participants with knee joint impairments completed ISO-ED and 4 alternative measures of quadriceps strength symmetry in a single session. Absolute agreement of alternative measures with ISO-ED was calculated with intraclass correlation coefficients (ICCs). Clinical agreement values at thresholds of 80% and 90% symmetry were compared between the alternatives and ISO-ED. Results Knee extension from 90° to 45° (ICC = 0.67) and handheld dynamometry (ICC = 0.70) had the greatest ICCs. Clinical agreement was also best for these measures for 80% symmetry (κ = 0.56 and 0.55, respectively) and 90% symmetry (κ = 0.19 and 0.33, respectively). Conclusion Handheld dynamometry and 1-repetition-maximum testing of knee extension from 90° to 45° are fair alternatives, although symmetry is typically overestimated. Receiver operating characteristic analysis identified alternative measure thresholds that correlated with the 80% and 90% symmetry thresholds on the ISO-ED. Clinicians should use more stringent symmetry values for these alternative tests to increase the probability that individuals have a minimum ISO-ED symmetry of 80% or 90%. J Orthop Sports Phys Ther 2017;47(2):97-107. doi:10.2519/jospt.2017.6651.

Changes in the peptide and MHC molecules have been extensively examined for how they alter T cell activation, but many fewer studies have examined the TCR. Structural studies of how TCR differences alter T cell specificity have focused on broad variation in the CDR3 loops. However, changes in the CDR1 and 2 loops can also alter TCR recognition of pMHC. In this study we focus on two mutations in the CDR1α loop of the TCR that increased the affinity of a TCR for agonist Hb(64-76)/I-E(k) by increasing the on-rate of the reaction. These same mutations also conferred broader recognition of altered peptide ligands. TCR transgenic mice expressing the CDR1α mutations had altered thymic selection, as most of the T cells were negatively selected compared to T cells expressing the wildtype TCR. The few T cells that escaped negative selection and were found in the periphery were rendered anergic, thereby avoiding autoimmunity. T cells with the CDR1α mutations were completely deleted in the presence of Hb(64-76) as an endogenous peptide. Interestingly, the wildtype T cells were not eliminated, identifying a threshold affinity for negative selection where a 3-fold increase in affinity is the difference between incomplete and complete deletion. Overall, these studies highlight how small changes in the TCR can increase the affinity of TCR:pMHC but with the consequences of skewing selection and producing an unresponsive T cell.

In 1989, the U.S. Army Engineer Research and Development Center and Crafco, Inc., initiated a research effort to develop improved materials and processes for sealing joints in portland cement concrete pavements. Objectives were to develop specifications for improved hot-applied, jet fuel–resistant (JFR) and non–jet fuel–resistant (non-JFR) sealants and to determine the impact of installation configuration on field performance. The laboratory phase identified desired sealant properties, evaluated sealants for those properties, and developed sealants with improved low-temperature and aging properties. The field phase was installed in June 1991 at Fairchild Air Force Base, Washington, to determine performance of developed sealants compared with standard sealants and to determine whether performance could be improved by changing installation geometry. Thirteen sealants were installed. The field study documented installation and evaluations at 6 and 12 months. After study completion, the installations were monitored several additional times. Detailed papers were prepared after 5 and 10 years. At 10 years, some sealants had greater than a 10-year life. In 2011, the installations reached 20 years of age. The JFR sections had been replaced, and non-JFR sections were still intact and were evaluated in April 2012. Results of the 21-year evaluation are presented. One silicone sealant and the improved non-JFR sealant achieved a 21-year life. Results also show that the flush-fill installation geometry increased life of the hot-applied asphalt sealants by more than 50% compared with the standard recessed configuration and should be considered for joint sealant installations.

Inorganic arsenic (iAs) in drinking water varies geographically and is prevalent worldwide. While exposures in the US are generally low, there are some areas with higher levels of naturally occurring iAs (potentially >100μg/L) where residents rely on unregulated drinking water wells. Much of the evidence on the association between iAs and cancer comes from epidemiological studies conducted in South American and Asian populations. These populations have generally been exposed to much higher levels of iAs and have differing underlying characteristics, both of which make comparing them to Western populations difficult. A key question is whether and how one should extrapolate from these high exposure studies to estimate cancer risk at lower exposures. We conducted an independent analysis to determine the most appropriate cancer endpoints, studies, and models to support an oral carcinogenicity assessment of iAs, taking into consideration factors that affect the apparent potency of iAs across geographically and culturally distinct populations. We identified bladder and lung cancer as high-priority endpoints and used meta-regression to pool data across studies from different regions of the world to derive oral cancer slope factors (CSFs) and unit risks (excess risk per μg/L) for iAs based on the background risks of bladder and lung cancer in the US. We also calculated concentrations of iAs in water that are not likely to result in cancer risk above what is considered acceptable by the United States Environmental Protection Agency (US EPA). While we derived these factors assuming a linear, no-threshold relationship between iAs and cancer risk, we also evaluated the shape of the dose-response curves and assessed the evidence for overall nonlinearity. Overall, we found that the incremental risks of bladder and lung cancer associated with iAs were relatively low. The sensitivity analyses we conducted suggested that populations with relatively high iAs exposures appeared to drive the pooled cancer risk estimates, but many of our other tested assumptions did not substantially alter these estimates. Finally, we found that the mode of action evidence supports there being a threshold, but making a robust quantitative demonstration of a threshold using epidemiological data is difficult. When considered in the context of typical exposure levels in the US, our potency estimates indicate that iAs-induced cancer risk is much lower than observed bladder and lung cancer incidences. This suggests that the low iAs levels to which much of the general US population is exposed likely do not result in substantial additional cancer risk. Keywords: Inorganic arsenic, Meta-regression, Dose-response, Cancer slope factor, Bladder cancer, Lung cancer

Research suggests that exposure to ambient particulate matter (PM) may be associated with lung cancer; however, no mode of action (MoA) for this has been established. We applied a weight-of-evidence (WoE) approach to evaluate recent evidence from four realms of research (controlled human exposure, epidemiology, animal, and in vitro) to determine whether the overall evidence supports one or more MoAs by which PM could cause lung cancer. We evaluated three general MoAs: DNA damage and repair; other genotoxic effects, including mutagenicity and clastogenicity; and gene expression, protein expression, and DNA methylation. After assessing individual study quality, we evaluated the strength of the evidence within as well as across disciplines using a modified set of Bradford Hill considerations. We conclude that the overall WoE indicates it is plausible that PM of various size fractions may cause direct DNA damage, but the evidence is insufficient regarding the alternative MoAs we evaluated. More research is needed to determine whether DNA damage can lead to downstream events and, ultimately, lung cancer.

Proper atrioventricular canal (AVC) patterning and subsequent valvulogenesis is a complex process, and defects can result in disease or early death. The zebrafish Danio rerio has become a useful model system for studying AVC development, and much progress has been made in dissecting out the critical steps. Here, we review the recent advances in the field and highlight the cellular and molecular changes observed during zebrafish AVC development.

Oral candidosis is the most common fungal infection encountered in general dental practice. It manifests in a variety of clinical presentations which may mimic more sinister diseases, and can occasionally be refractory to treatment requiring the attention of an oral medicine specialist. Management of oral candidosis should always include a thorough investigation of underlying predisposing conditions, as the disease often presents when the patient is systemically compromised. This update highlights the pathogenesis, clinical presentation, and management strategies of oral Candidal lesions commonly encountered in dental practice.

Background: It is not clear whether naltrexone is effective in reducing alcohol consumption among patients with clinically significant mood symptoms and whether naltrexone favorably interacts with antidepressant medications when they are co-prescribed. Methods: This study reflects a secondary analysis of the first 13 weeks of VA CSP #425, a study that evaluated the efficacy of naltrexone 50 mg/d in 627 alcohol dependent military veterans receiving Twelve Step Facilitation therapy at 20 VA Medical Centers. This study included patients with comorbid mood and anxiety disorders, providing they did not need treatment for these comorbid conditions at the time of study entry. Sixty patients developed sufficiently severe mood symptoms while on study medication that they required antidepressant treatment. This analysis evaluated whether the efficacy of naltrexone and placebo was influenced by the prescription of antidepressant medications to some study patients for their mood and anxiety symptoms. Results: In patients randomized to placebo (n = 209), prescription of antidepressants was associated with a significantly higher percentage of drinking days (lsmean = 24.4, se = 4.85 vs. lsmean = 12.9, se = 1.69, p = 0.02). Although the group of patients receiving naltrexone (n = 418) was larger than the group assigned to placebo, there were no significant differences in drinking-related outcomes in the groups who did or did not receive antidepressants (lsmean = 11.5, se = 1.18 vs. lsmean = 12.9, se = 1.69, p = 0.47). Among the group of patients receiving antidepressants, naltrexone prescription was associated with a reduction in the percent drinking days compared to placebo [lsmean = 10.1, se = 3.47 vs. lsmean = 24.4, se = 4.85, F(1,556) = 5.84, p = 0.02]. Conclusions: Further investigation will be needed to determine whether naltrexone is efficacious among depressed alcohol dependent patients and whether naltrexone and antidepressant medications show interactive efficacy for treating alcohol dependence.

Approaches for the systematic review and evaluation of chemical toxicity are currently being reconsidered, with a specific focus on the evaluation of individual studies and their integration into the overall body of evidence. This renewed interest has arisen, in part, as a result of several prominent reviews of these approaches by special committees of the National Research Council (NRC), among others. We conducted a critical evaluation of several available frameworks for evaluating study quality. We assessed the criteria separately for human, animal, and in vitro studies as well as for systematic reviews. We then evaluated commonalities across disciplines. We also considered the potential implications of applying criteria frameworks and how they bear on fundamental risk assessment questions. We found that the available frameworks within each discipline differed in terms of their intended purpose and level of guidance for decision making. All the frameworks across disciplines shared common themes, however, including the adequate reporting of specific details of study conditions and design/protocol, selection and randomization of study groups (where applicable), outcome assessment methods and applicability (e.g., validity and reliability), avoidance of selective reporting, and the consideration of potential confounders or bias. We identified the most informative study quality considerations, which will enable researchers to implement more objective and standardized methods for evaluating studies and, ultimately, improve risk assessment methods.

Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. Recent data demonstrates a critical role for the serum and glucocorticoid regulated kinase-1 (SGK1) by modulation of INa in the heart, by regulating the voltage-gated sodium channel NaV1.5. To better understand and pharmacologically probe the significance of SGK1 in cardiac dysrhythmias, we have used computer aided drug discovery (CADD) to identify small molecule inhibitors of SGK1. Expression of a constitutively active form of SGK1 (SGK1-CA) increased INa (1.7 fold, p Using CADD partnered with iterative empirical screens we identified several hit chemical scaffolds. Our lead compound inhibits the phosphorylation of the SGK1 target gene, GSK3-β in a dose dependent manner in cardiomyocytes (CMs) expressing SGK1-CA at the lowest effective concentration of 0.5μM. There was no significant inhibition of AKT dependent phosphorylation of GSK3-β up to a concentration of 50μM, demonstrating specificity of the inhibitor for SGK1. Incubation of bkd zebrafish mutants with the inhibitor rescued the 2:1 AV block in a dose dependent manner (60% rescue with 45μM, p < 0.05). Acute application of the inhibitor dramatically inhibited INa with either expression of SGK1-CA (90.8% reduction, p We conclude SGK1 activity regulates INa and speculate that structure activity relationship (SAR) derivatives of our lead compound might have a role in treatment of human cardiac arrhythmias.

The US Environmental Protection Agency (EPA) recently concluded that there is likely to be a causal relationship between short-term (< 30 days) ozone exposure and cardiovascular (CV) effects; however, biological mechanisms to link transient effects with chronic cardiovascular disease (CVD) have not been established. Some studies assessed changes in circulating levels of biomarkers associated with inflammation, oxidative stress, coagulation, vasoreactivity, lipidology, and glucose metabolism after ozone exposure to elucidate a biological mechanism. We conducted a weight-of-evidence (WoE) analysis to determine if there is evidence supporting an association between changes in these biomarkers and short-term ozone exposure that would indicate a biological mechanism for CVD below the ozone National Ambient Air Quality Standard (NAAQS) of 75 parts per billion (ppb). Epidemiology findings were mixed for all biomarker categories, with only a few studies reporting statistically significant changes and with no consistency in the direction of the reported effects. Controlled human exposure studies of 2 to 5 hours conducted at ozone concentrations above 75 ppb reported small elevations in biomarkers for inflammation and oxidative stress that were of uncertain clinical relevance. Experimental animal studies reported more consistent results among certain biomarkers, although these were also conducted at ozone exposures well above 75 ppb and provided limited information on ozone exposure-response relationships. Overall, the current WoE does not provide a convincing case for a causal relationship between short-term ozone exposure below the NAAQS and adverse changes in levels of biomarkers within and across categories, but, because of study limitations, they cannot not provide definitive evidence of a lack of causation.

Single stage en bloc abdominoperineal resection and sacrectomy, with a myocutaneous flap closure is a relatively uncommon procedure. Our case study of a 77 year old man with a locally invasive rectal adenocarcinoma highlights the complex intraoperative management of such a patient.

Background : The diagnosis of giant cell arteritis (GCA) is often confirmed by an early temporal artery (TA) biopsy of adequate length. Treatment of this condition with high-dose corticosteroids may be associated with significant morbidity, including osteo­porosis. Aim: To audit current management of patients with suspected GCA at Auckland Healthcare, a large teaching hospital. Methods: We performed a retrospective chart review of all TA biopsies from January 1996 to June 2000. A total of 117 biopsies from 111 patients was audited. Of these patients, 37/111 (33%) had a final clinical diagnosis of GCA (GCA patients). The areas of interest for audit were waiting time for TA biopsy, length of sample, initial corticosteroid therapy and osteo­porosis prophylaxis. Results: The mean waiting time for biopsy for all patients was 5.6 days (range 0−42 days). This time varied from 9.3 days for rheumatology patients to 2.6 days for ophthalmology patients (P = 0.003). Only 44/117 (37.6%) specimens measured more than 10 mm. For GCA patients, the median initial oral prednisone dose was 60 mg/day. Osteoporosis prophylaxis was prescribed in 24/37 (65%) GCA patients, most commonly cyclical etidronate. Conclusions: There is significant variation in the management of GCA within our institution. This audit has highlighted several areas where improvement could be made, particularly in streamlining the process of obtaining TA biopsy and in promoting the use of osteoporosis prophylaxis. (Intern Med J 2002; 32: 315−319)

In 1989, the U.S. Army Engineer Research and Development Center and Crafco, Inc., initiated a research effort to develop improved materials and processes for sealing and resealing joints in portland cement concrete pavements. The objectives of the research were to develop specification limits for improved field performance of hot-applied, jet-fuel-resistant (JFR) and non-jet-fuel-resistant (non-JFR) sealants and obtain field data to determine the field performance of different sealants and installation configurations. The research effort was divided into a laboratory phase and a field phase. The laboratory phase focused on identifying ideal properties that a hot-applied non-JFR and hot-applied JFR sealant should possess, evaluating commercially available sealants to determine if they exhibited those properties, and developing improved hot-applied materials that would exhibit as many of those properties as feasible. The field phase was initiated in June 1991 at Fairchild Air Force Base near Spokane, Washington. The focus of this effort was to determine the field performance of field-molded sealants (including improved materials versus commercially available sealants) and possible improvements in field performance by changing the sealant installation geometry. Thirteen different field-molded sealants were installed, and their field performance was monitored at different times over 10 years. The evaluations indicated that two of the hot-applied, asphalt-based sealants, four of the silicone-based sealants, and one of the coal tar–based sealants had life expectancies of greater than 10 years. The improved JFR and non-JFR sealants exhibited better field performance than the standard hot-applied sealants included in the evaluation.

Introduction: Long QT syndrome (LQTS) is caused by delayed ventricular repolarization and is a cause of sudden death. In a recent chemical screen with an in vivo zebrafish model of LQTS-type 2, we identified 2-methoxy-N-[4-methylphenyl] benzamide (2MMB), which shortens the ventricular action potential (Figure A). Methods: We initially used a zebrafish LQT2 model to perform a structure-activity relationship (SAR) study with 50 substituted benzanilide derivatives. We generated a human LQT-type 1 embryonic stem cell (hESC) model with a bi-allelic disruption of KCNQ1 in the hESC H7 line using CRISPR. KCNQ1-/- hESC-derived cardiomyocytes (hESC-CM) were electrophysiologically characterized and used to perform secondary structure activity studies for a subset of benzanilide derivatives (Figure A). Results: We observed a range of biological activities among the 50 analogs tested in the zebrafish assay, including several compounds with no activity and several that were more potent than 2MMB. Genetically engineered LQT1 hESC-CMs had diminished IKs current (Figure B) and prolonged action potentials that significantly shortened upon 2MMB treatment (Figure C). SAR studies in the LQT1 hESC-CMs confirmed improved potency for two of the compounds and lack of activity for one. A single discrepancy existed for a compound without activity in our zebrafish assay but significantly shortened action potentials in hESC-CMs. Conclusions: We report the use of a physiologically faithful genetically engineered LQT1 hESC line for therapeutic discovery in LQTS. Inclusion of hESC-CMs in future studies may complement animal testing by enabling direct screening on disease specific human tissue.

Mitral valve prolapse (MVP) is a common disease affecting nearly 1 in 40 individuals. It is the leading surgical indication for mitral valve regurgitation. Despite a clear heritable component, the genetic etiology of non-syndromic MVP has remained elusive. Individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of a previously linked interval on chromosome 11. We found a novel missense mutation in DCHS1, the human homologue of the Drosophila cell polarity gene dachsous (ds) that segregates with MVP in the family. The familial mutation reduced protein stability in zebrafish and cultured cells. Morpholino knockdown of zebrafish dachsous1b yielded a regurgitant atrioventricular canal defect that could be rescued by wild-type human DCHS1 but not by mRNA with the familial mutation. Adult haploinsufficient Dchs1 mice had anatomic and functional prolapse of thickened, elongated leaflets recapitulating the human MVP phenotype. Dchs1 haploinsufficiency was associated with developmental defects in valve shape, cell migration and patterning during fetal morphogenesis, suggesting cell polarity as a previously unrecognized facet of valve morphogenesis. Studies of downstream changes identified increased MAP kinase activities and α-SMA+ cells (myofibroblasts) in the valves preceding myxomatous degeneration; these suggest potential future directions for blunting disease progression. Additional genetic studies identified a second family with a DCHS1 mutation and a significantly increased burden of novel DCHS1 mutations in sporadic MVP cases Interdisciplinary studies strongly support DCHS1 as the first identified disease-causing gene for non-syndromic MVP and suggest potential mechanisms for modifying disease natural history.

The possibility of an association between inorganic arsenic (iAs) exposure and cardiovascular outcomes has received increasing attention in the literature over the past decade. The United States Environmental Protection Agency (US EPA) is currently revising its Integrated Risk Assessment System (IRIS) review of iAs, and one of the non-cancer endpoints of interest is cardiovascular disease (CVD). Despite the increased interest in this area, substantial gaps remain in the available information, particularly regarding the mechanism of action (MOA) by which iAs could cause or exacerbate CVD. Few studies specifically address the plausibility of an association between iAs and CVD at the low exposure levels which are typical in the United States (i.e., below 100 μg As/L in drinking water). We have conducted a review and evaluation of the animal, mechanistic, and human data relevant to the potential MOAs of iAs and CVD. Specifically, we evaluated the most common proposed MOAs, which include disturbance of endothelial function and hepatic dysfunction. Our analysis of the available evidence indicates that there is not a well-established MOA for iAs in the development or progression of CVD. Few human studies of the potential MOAs have addressed plausibility at low doses and the applicability of extrapolation from animal studies to humans is questionable. However, the available evidence indicates that regardless of the specific MOA, the effects of iAs on physiological processes at the cellular level appear to operate via a threshold mechanism. This finding is consistent with the lack of association of CVD with iAs exposure in humans at levels below 100 μg/L, particularly when considering important exposure and risk modifiers such as nutrition and genetics. Based on this analysis, we conclude that there are no data supporting a linear dose-response relationship between iAs and CVD, indicating this relationship has a threshold.

Objective: This article examines the perceived helpfulness of treatment components in comprehensive interdisciplinary pain management programs as they relate to cost. Design: Patient satisfaction results assessed by the Treatment Helpfulness Questionnaire (THQ) and treatment costs were compared for 309 subjects at three comprehensive interdisciplinary chronic pain management centers. All subjects completed the THQ immediately after treatment, and follow-up data were gathered 3 to 6 months after the end of treatment at two of the three centers. Results: Ratings of treatment helpfulness were not found to be related to either demographic or medical variables. Mean THQ ratings for many treatment modalities did differ significantly between centers, but subjects at all centers generally gave higher THQ ratings to psychological and educational therapies than to physical therapy and medical modalities both at posttreatment and at follow-up evaluations. More costly treatments generally did not receive higher ratings than less costly ones. THQ ratings tended to decline modestly from posttreatment to follow-up evaluations. Conclusions: For the selected population of patients undergoing comprehensive interdisciplinary pain management, educational and psychological approaches received high ratings of helpfulness at a relatively low cost. Further research is needed to address whether comparative patient satisfaction data can be used at pain centers to produce improved outcomes at reduced costs.

Ballistic experiments have been performed using aluminum spheres against 10-mm rolled homogenous armour (RHA), MARS270, MARS300, and titanium alloy plates to investigate the influence of the plugging mechanism on material properties. The experiments have measured the threshold for plug mass and velocity as well as the recovered aluminum sphere mass over a range of velocities. Some of the experiments have been simulated using the in-house second generation Eulerian hydrocode GRIM. The calculations feature advanced material algorithms derived from interrupted tensile testing techniques and a triaxial failure model derived from notched tensile tests over a range of strain rates and temperatures. The effect of mesh resolution on the results has been investigated and understood. The simulation results illustrate the importance of the constitutive model in the shear localization process and the subsequent plugging phenomena. The stress triaxiality is seen as the dominant feature in controlling the onset and subsequent propagation of the crack leading to the shear plug. The simulations have demonstrated that accurate numerics coupled with accurate constitutive and fracture algorithms can successfully reproduce the observed experimental features. However, extrapolation of the fracture data leads to the simulations overpredicting the plug damage. The reasons for this are discussed.

A newly developed digital image-analysis method was used to characterize the morphological characteristics of coarse aggregates. Regression analyses found that the imaging morphological characteristics of coarse aggregates correlated well with results of other indirect characterization tests such as the test method for index of particle shape and texture (ASTM D 3398); the test method for uncompacted void content of coarse aggregate as influenced by particle shape, surface texture, and grading (modified ASTM C 1252); and the test method for unit weight and voids in aggregate test (ASTM C 29). The imaging morphological characteristics of coarse aggregates also correlated well to the effects of coarse-aggregate properties on hot-mix asphalt concrete mixtures. This research offers a new approach for evaluating coarse-aggregate characteristics of asphalt-concrete mixtures and demonstrates use of an emerging technology for pavement engineering.

Portland cement concrete (PCC) began to be used as a surface or wearing course for pavements in the United States in the early 1900s. The joint sealant or filler materials used during this early construction period were typically sand, tar paper, coal-tar pitch, asphaltic compounds, or wooden blocks. Material specifications for these early joint filler materials were nonexistent. The main emphasis of pavement construction during this period was to "get the country out of the mud" [1], not to provide a long lasting flexible joint sealant material to protect the pavement structure. In the early 1940s, pavement engineers began to concentrate on the construction of the joints in rigid pavements and the materials used to seal those joints. It was during this time period that elastomeric materials (generally an asphalt-based material modified with crumb rubber) began to be developed for use in pavement joints and the first material specifications were developed to provide a means of quality control. As user requirements changed (i.e., materials resistant to fuel spill-age, etc.), new materials (typically polymer modified and/or extended coal-tar materials) were introduced and new material specifications were developed. New formulations have continued to be introduced with individual material specifications eventually being developed for each sealant. Typical base materials used today for pavement joint sealing include asphalt-rubber, modified coal-tar, polysulfide, polyurethane, silicone, and polychloroprene. Improvements have been made to the sealant formulations but the current material specifications have hindered innovation because they are typically material specific and generally do not directly correlate to sealant field performance. A review of the history of joint sealant material specifications, current specifications, and potential techniques that may be included in material specifications of the future to provide a more direct correlation between laboratory evaluation and field performance is presented.

Preformed pavement polychloroprene compression seals were analyzed using dynamic shear rheology and numerical analysis to assess the feasibility of using these techniques to develop an improved methodology for designing and characterizing preformed seals, as well as predicting their field performance. The investigation consisted of three phases: (1) dynamic shear rheological analysis of unaged and aged polychloroprene materials to obtain material property input for numerical analysis; (2) numerical analysis of one preformed compression seal web design; and (3) numerical analysis verification through laboratory compression tests of unaged and aged seal materials. The investigational results indicate advanced material modeling capabilities of finite-element analysis coupled with the material properties obtained through dynamic shear rheological analysis and provide a significant capability to explore seal performance variations resulting from different joint seal geometries, material compositions, and aging characteristics. The techniques investigated accurately described the deformation of the seal and provided force-displacement relationships, including relaxation with time and stiffening with age. Additional minor refinements in the techniques developed through this investigation would result in a powerful design and field performance predictive model.

Background and objective The primary aim of this intervention was to improve oxygen prescribing in accordance with the 2008 British Thoracic Society guidelines for the prescription of emergency oxygen in adults. Methods Eight final year medical students reviewed the drug charts of all patients admitted to the respiratory ward on a daily basis in order to collect data on five audit questions: (1) Has oxygen (O2) been prescribed? (2) Has an O2 target saturation level been indicated? (3) Has O2 been prescribed as an ‘as required’ (PRN) or ‘continuous therapy’? (4) Has the prescription been signed? (5) Has O2 been signed for in every drug round since the original prescription? Following an initial audit cycle an educational poster was distributed to all clinical staff via email and hard copies of the poster were placed strategically throughout the ward before its effectiveness was measured. Results During the pre-intervention phase, compliance with all five measures varied from 0 to 25%. There was an increase in the variation in compliance after the poster intervention to 14–44%; however, this masked better overall compliance with all five investigative questions with figures of 44%, 39% and 42% being recorded in three of the four post-intervention days. Overall there was increased compliance with four of the five audit questions. Indeed compliance with question 3 rose from 14% to 83%. Conclusions The poster intervention was marginally effective while also showing that students can improve prescribing in a clinical setting.

A reduced size antiresonant antenna for underground object detection is presented. The reduced size antenna is shown to provide improved differential impedance properties to that of a full size antiresonant dipole while providing a factor of eight reduction in the maximum dimension of the antenna.

Objective: To investigate the toxicity of bupropion hydrochloride in deliberate selfpoisoning in adults and accidental ingestion by children. Design and setting: Prospective study of cases identified from calls to the New South Wales Poisons Information Centre (NSW PIC), with follow-up through hospital medical records. Participants: Patients with bupropion poisoning managed in hospital, about whom the NSW PIC was contacted for advice, from 1 November 2000 to 31 July 2001 (59 adults and 10 children). Main outcome measures: Clinical effects, adverse outcomes (including seizures and death) and treatment. Results: 45 of the 59 adults were followed up (76%), 19 of whom had taken bupropion alone. Major clinical effects of bupropion included sinus tachycardia (83%), hypertension (56%), seizures (37%), gastrointestinal symptoms (37%) and agitation (32%). Seizures were dose-dependent, with those having seizures ingesting a significantly higher median dose (P = 0.02). All seizures were brief and self-limiting. 29 patients received decontamination therapy. 10 patients required pharmacological sedation, 10 were admitted to intensive care and six were intubated. None died. Eight of 10 accidental ingestions by children were followed up (80%); one child had symptoms (vomiting and hallucinations). Conclusions: Bupropion overdose caused significant clinical effects in adults, but few

The changes in input impedance for a simple antenna or transmission line located over a soil containing a conducting object are examined near antiresonance. The near-field coupling of the underground object to the antenna or transmission line is investigated using the complex Poynting vector in order to identify the contribution of traveling and/or standing waves.

Shoulder dystocia is an obstetric emergency with raised neonatal morbidity including brachial plexus injury. With much litigation the Clinical Negligence Scheme for Trusts (CNST) advise minimum standards for documentation.

The cell dynamics associated with induction of peripheral T cell tolerance remain largely undefined. In this study, an in vivo model was adapted to two-photon microscopy imaging, and T cell behavior was analyzed on tolerogen-induced modulation. FcγR-deficient (FcγR−/−) mice were unable to resist or alleviate experimental allergic encephalomyelitis when treated with Ig-myelin oligodendrocyte glycoprotein (MOG) tolerogen, an Ig carrying the MOG35–55 peptide. However, when FcγR+/+ dendritic cells (DCs) are adoptively transferred into FcγR−/− mice, uptake and presentation of Ig-MOG occurs and the animals were able to overcome experimental allergic encephalomyelitis. We then fluorescently labeled FcγR+/+ DCs and 2D2 MOG-specific TCR-transgenic T cells, transferred them into FcγR−/− mice, administered Ig-MOG, and analyzed both T cell–DC contact events and T cell motility. The results indicate that tolerance takes place in lymphoid organs, and surprisingly, the T cells do not become anergic but instead have a Th2 phenotype. The tolerant Th2 cells displayed reduced motility after tolerogen exposure similar to Th1 cells after immunization. However, the Th2 cells had higher migration speeds and took longer to exhibit changes in motility. Therefore, both Th1 immunity and Th2 tolerance alter T cell migration on Ag recognition, but the kinetics of this effect differ among the subsets.

When utilizing an antenna over ground as a near-field probe for detecting underground conducting objects, maximizing the variation in the antenna input impedance due to the buried object is the primary concern. Using the example of a horizontal dipole and a buried cylinder, significant variation in the dipole input impedance is obtained by carefully positioning the antiresonant dipole to excite the dominant cylinder resonance.

Background— Genetic long QT (LQT) syndrome is a life-threatening disorder caused by mutations that result in prolongation of cardiac repolarization. Recent work has demonstrated that a zebrafish model of LQT syndrome faithfully recapitulates several features of human disease, including prolongation of ventricular action potential duration, spontaneous early afterdepolarizations, and 2:1 atrioventricular block in early stages of development. Because of their transparency, small size, and absorption of small molecules from their environment, zebrafish are amenable to high-throughput chemical screens. We describe a small-molecule screen using the zebrafish KCNH2 mutant breakdance to identify compounds that can rescue the LQT type 2 phenotype. Methods and Results— Zebrafish breakdance embryos were exposed to test compounds at 48 hours of development and scored for rescue of 2:1 atrioventricular block at 72 hours in a 96-well format. Only compounds that suppressed the LQT phenotype in 3 of 3 fish were considered hits. Screen compounds were obtained from commercially available small-molecule libraries (Prestwick and Chembridge). Initial hits were confirmed with dose-response testing and time-course studies. Optical mapping with the voltage-sensitive dye di-4 ANEPPS was performed to measure compound effects on cardiac action potential durations. Screening of 1200 small molecules resulted in the identification of flurandrenolide and 2-methoxy-N-(4-methylphenyl) benzamide (2-MMB) as compounds that reproducibly suppressed the LQT phenotype. Optical mapping confirmed that treatment with each compound caused shortening of ventricular action potential durations. Structure activity studies and steroid receptor knockdown suggest that flurandrenolide functions via the glucocorticoid signaling pathway. Conclusions— Using a zebrafish model of LQT type 2 syndrome in a high-throughput chemical screen, we have identified 2 compounds, flurandrenolide and the novel compound 2-MMB, as small molecules that rescue the zebrafish LQT type 2 syndrome by shortening the ventricular action potential duration. We provide evidence that flurandrenolide functions via the glucocorticoid receptor–mediated pathway. These 2 molecules and future discoveries from this screen should yield novel tools for the study of cardiac electrophysiology and may lead to novel therapeutics for human LQT patients.

Oral candidosis is the most common fungal infection encountered in general dental practice. It manifests in a variety of clinical presentations which may mimic more sinister diseases, and can occasionally be refractory to treatment requiring the attention of an oral medicine specialist. Management of oral candidosis should always include a thorough investigation of underlying predisposing conditions, as the disease often presents when the patient is systemically compromised. This update highlights the pathogenesis, clinical presentation, and management strategies of oral Candidal lesions commonly encountered in dental practice.

Background and Aims: Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption. Consequences of iron overload include organ dysfunction, cirrhosis and hepatocellular carcinoma. Although phlebotomy is the standard of care, it is contraindicated in patients with severe heart disease or anemia, venous access may be difficult and compliance can be variable. The once-daily, oral iron chelator, deferasirox (Exjade®) may provide an alternative treatment. Results of the 6-month core trial were previously reported; 6-month extension data are reportedhere.Methods: Patients with HFE C282Y homozygous HH with serum ferritin (SF) 300–2000 ng/mL, transferrin saturation ≥45% and no known history of cirrhosis were enrolled in this dose-escalation study (deferasirox 5, 10 and 15 mg/kg/day). This multicenter study comprised a core and extension phase (both 24 weeks). The primary endpoint was the incidence and severity of adverse events (AEs). Secondary endpoints included change in SF. Results: 49 patients were enrolled (33 men, 16 women; mean age 50.6 years; mean 3.1 years since HH diagnosis) and received deferasirox 5 (n = 11), 10 (n = 15) or 15 mg/kg/day (n = 23). 37 (75.5%) patients completed the core trial. Of 26 patients whoentered the extension, 23 (88.5%) completed 48 weeks. The most common reasons for discontinuation were AEs, mainly in the 10 and 15 mg/kg/day cohorts. Overall, AEs were dose dependent, including diarrhea, headache and nausea (n = 18, n = 10 and n = 8 in the core and n = 1, n = 1, n = 0 in the extension, respectively). Throughout 48weeks in the 15 mg/kg/day cohort, six patients experienced ALT >3 x baseline and > upper limit of normal (ULN), and eight patients had serum creatinine ≥33% above baseline and >ULN on two consecutive occasions. SF declined in all cohorts; median reduction was 63.5%, 74.8% and 74.1% in the 5, 10 and 15 mg/kg/day cohorts, respectively; in all cohorts, median SF was