Text summarization as a decision support aid.
PubMed data potentially can provide decision support information, but PubMed was not exclusively designed to be a point-of-care tool. Natural language processing applications that summarize PubMed citations hold promise for extracting decision support information. The objective of this study was to evaluate the efficiency of a text summarization application called Semantic MEDLINE, enhanced with a novel dynamic summarization method, in identifying decision support data. We downloaded PubMed citations addressing the prevention and drug treatment of four disease topics. We then processed the citations with Semantic MEDLINE, enhanced with the dynamic summarization method. We also processed the citations with a conventional summarization method, as well as with a baseline procedure. We evaluated the results using clinician-vetted reference standards built from recommendations in a commercial decision support product, DynaMed. For the drug treatment data, Semantic MEDLINE enhanced with dynamic summarization achieved average recall and precision scores of 0.848 and 0.377, while conventional summarization produced 0.583 average recall and 0.712 average precision, and the baseline method yielded average recall and precision values of 0.252 and 0.277. For the prevention data, Semantic MEDLINE enhanced with dynamic summarization achieved average recall and precision scores of 0.655 and 0.329. The baseline technique resulted in recall and precision scores of 0.269 and 0.247. No conventional Semantic MEDLINE method accommodating summarization for prevention exists. Semantic MEDLINE with dynamic summarization outperformed conventional summarization in terms of recall, and outperformed the baseline method in both recall and precision. This new approach to text summarization demonstrates potential in identifying decision support data for multiple needs.


Stomach content analyses of the threadfin anglerfish Lophiodes spilurus (Lophiiformes: Lophiidae) associated with deepwater shrimp fisheries from the central Pacific of Costa Rica.
Our knowledge of deepwater ecosystems along the Pacific of Central America is extremely limited. We analyzed the diet composition of 200 adult specimens of Lophiodes spilurus ranging in size from 7.8 to 17.8 cm total length (TL). Samples were obtained from deep bottom trawls (depth: 105-238 m) along the central Pacific of Costa Rica. We calculated the percentage of number (% N), weight (% W), and occurrence (% O) of each food item encountered in the stomachs; based on this information, the Index of Relative Importance (IR) was calculated. Moreover, we estimated diet overlap for three different size classes (<10.1, 10.1-15.0 and > 15.1 cm TL). The results revealed exclusively two groups of benthic prey items: crustaceans (30%) and teleost fish (70%) in their diet. The most frequent preys were pandalid shrimps Plesionika trispinus (% O = 17) and the fathom mora Physiculus rastrelliger (% O = 12). The greatest diversity and frequency of abundance of food items was observed in intermediate-sized individuals (10.1-15.0 cm TL). Small-sized L. spilurus (< 10.1 cm TL) fed mainly on teleost fish, while larger (> 15.0 cm TL) preyed on large-sized stomatopods and teleost fish. There was a clear diet overlap between small and intermediate-sized L. spilurus (p < 0.05). However, differences in diet-overlap were not detected in small and large-sized individuals or intermediate and large-sized specimens (p > 0.05). Our results suggest that L. spilurus feeds exclusively on crustaceans (Decapoda and Stomatopoda) and benthic teleost fish along the Pacific of Costa Rica. While small and large-sized individuals showed a more pronounced selectivity for certain prey items, the high diversity of benthic prey items observed in intermediate-sized specimens suggest a more opportunistic foraging behavior.


Benchmarking organic micropollutants in wastewater, recycled water and drinking water with in vitro bioassays.
Thousands of organic micropollutants and their transformation products occur in water. Although often present at low concentrations, individual compounds contribute to mixture effects. Cell-based bioassays that target health-relevant biological endpoints may therefore complement chemical analysis for water quality assessment. The objective of this study was to evaluate cell-based bioassays for their suitability to benchmark water quality and to assess efficacy of water treatment processes. The selected bioassays cover relevant steps in the toxicity pathways including induction of xenobiotic metabolism, specific and reactive modes of toxic action, activation of adaptive stress response pathways and system responses. Twenty laboratories applied 103 unique in vitro bioassays to a common set of 10 water samples collected in Australia, including wastewater treatment plant effluent, two types of recycled water (reverse osmosis and ozonation/activated carbon filtration), stormwater, surface water, and drinking water. Sixty-five bioassays (63%) showed positive results in at least one sample, typically in wastewater treatment plant effluent, and only five (5%) were positive in the control (ultrapure water). Each water type had a characteristic bioanalytical profile with particular groups of toxicity pathways either consistently responsive or not responsive across test systems. The most responsive health-relevant endpoints were related to xenobiotic metabolism (pregnane X and aryl hydrocarbon receptors), hormone-mediated modes of action (mainly related to the estrogen, glucocorticoid, and antiandrogen activities), reactive modes of action (genotoxicity) and adaptive stress response pathway (oxidative stress response). This study has demonstrated that selected cell-based bioassays are suitable to benchmark water quality and it is recommended to use a purpose-tailored panel of bioassays for routine monitoring.


Contribution of nonesterified fatty acids to mitogen-activated protein kinase activation in human skeletal muscle during endurance exercise.
Mitogen-activated protein kinase (MAPK) pathways are activated in skeletal muscle during endurance exercise, but the upstream molecular events are incompletely resolved. As an increase in plasma nonesterified fatty acids (NEFA) is a common feature of long-lasting exercise, the authors tested the hypothesis that NEFA contribute to the activation of MAPK during endurance exercise. Acipimox was used before and during endurance exercise to prevent the elevation of plasma NEFA levels in healthy subjects and patients with diabetes. In 2 separate studies, healthy subjects cycled for 2 hr and patients with diabetes for 1 hr at 50% Wmax. In control conditions, plasma NEFA concentrations increased from 0.35 to 0.90 mM during exercise in healthy subjects and from 0.55 to 0.70 mM in patients with diabetes (p < .05). Phosphorylation states of extracellularly regulated kinase 1 and 2 (ERK1/2), p38, and c-Jun NH2-terminal kinases (JNK) were significantly increased after exercise in the vastus lateralis in both groups. Acipimox blocked the increase in plasma NEFA concentrations and almost completely repressed any rise in ERK1/2 and p38 but not in JNK. In conclusion, the data support a role for plasma NEFA in the activation of p38 and ERK1/2 in skeletal-muscle tissue of healthy and diabetic subjects during endurance exercise. Further investigation will be required to determine the molecular link between NEFA and MAPK activation during exercise in human skeletal muscle.


Novel serum biomarker candidates for liver fibrosis in hepatitis C patients.
Liver biopsy is currently the gold standard for assessing liver fibrosis, and no reliable noninvasive diagnostic approach is available. Therefore a suitable serologic biomarker of liver fibrosis is urgently needed. We used a proteomics method based on 2-dimensional gel electrophoresis to identify potential fibrosis biomarkers. Serum samples from patients with varying degrees of hepatic scarring induced by infection with the hepatitis C virus (HCV) were analyzed and compared with serum from healthy controls. We observed the most prominent differences when we compared serum samples from cirrhotic patients with healthy control serum. Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) fragments, alpha1 antichymotrypsin, apolipoprotein L1 (Apo L1), prealbumin, albumin, paraoxonase/arylesterase 1, and zinc-alpha2-glycoprotein were decreased in cirrhotic serum, whereas CD5 antigen-like protein (CD5L) and beta2 glycoprotein I (beta2GPI) were increased. In general, alpha2 macroglobulin (a2M) and immunoglobulin components increased with hepatic fibrosis, whereas haptoglobin and complement components (C3, C4, and factor H-related protein 1) decreased. Novel proteins associated with HCV-induced fibrosis included ITIH4 fragments, complement factor H-related protein 1, CD5L, Apo L1, beta2GPI, and thioester-cleaved products of a2M. Assessment of hepatic scarring may be performed with a combination of these novel fibrosis biomarkers, thus eliminating the need for liver biopsy. Further evaluation of these candidate markers needs to be performed in larger patient populations. Diagnosis of fibrosis during early stages will allow early treatment, thereby preventing fibrosis progression.


Challenges in imaging assessment following liver stereotactic body radiotherapy: pitfalls to avoid in clinical practice.
Stereotactic body radiotherapy (SBRT) is increasingly used in the management of unresectable liver metastases and hepatocellular carcinoma (HCC) as it allows delivery of high-dose conformal radiotherapy with limited toxicities. However, it may be difficult to differentiate viable tumour from radiotherapy-related changes after SBRT. The imaging changes observed after SBRT may also differ from those observed following conventionally fractionated radiotherapy. Hence, we aim to review the imaging changes that occur within the tumour and adjacent normal liver after SBRT which may help to identify local relapse in clinical practice.


The Role of Toll-Like Receptors in the Production of Cytokines by Human Lung Macrophages.
The Toll-like receptor (TLR) family is involved in the recognition of and response to microbial infections. These receptors are expressed in leukocytes. TLR stimulation induces the production of proinflammatory cytokines and chemokines. Given that human lung macrophages (LMs) constitute the first line of defense against inhaled pathogens, the objective of this study was to investigate the expression and function of TLR subtypes in this cell population. Human primary LMs were obtained from patients undergoing surgical resection. The RNA and protein expression levels of TLRs, chemokines, and cytokines were assessed after incubation with subtype-selective agonists. In human LMs, the TLR expression level varied from one subtype to another. Stimulation with subtype-selective agonists induced an intense, concentration- and time-dependent increase in the production of chemokines and cytokines. TLR4 stimulation induced the strongest effect, whereas TLR9 stimulation induced a much weaker response. The stimulation of TLRs in human LMs induces intense cytokine and chemokine production, a characteristic of the proinflammatory M1 macrophage phenotype.


The Efficacy and Safety of Hydroxychloroquine in Patients with COVID-19: A Multicenter National Retrospective Cohort.
Hydroxychloroquine (HCQ) is an antimalarial drug that received worldwide news and media attention in the treatment of patients with coronavirus disease 2019 (COVID-19). This drug was used on the basis of its antimicrobial and antiviral properties despite lack of definite evidence of clinical efficacy. In this study, we aim to assess the efficacy and safety of using HCQ in treatment of patients with COVID-19 who were admitted in acute care hospitals in Bahrain. We conducted a retrospective cohort study on a random sample of patients admitted with COVID-19 between 24 February and 31 July 2020. The study was conducted in four acute care COVID-19 hospitals in Bahrain. Data was extracted from the medical records. The primary endpoint was the requirement of non-invasive ventilation, intubation, or death. Secondary endpoint was length of hospitalization for survivors. Three methods of analysis were used to control for confounding factors: logistic multivariate regression, propensity score adjusted regression, and matched propensity score analysis. A random sample of 1571 patients were included, 440 of whom received HCQ (treatment group) and 1131 did not receive it (control group). Our results showed that HCQ did not have a significant effect on primary outcomes due to COVID-19 infection when compared to controls after adjusting for confounders (OR 1.43, 95% CI 0.85-2.37, P = 0.17). Co-administration of azithromycin had no effect on primary outcomes (OR 2.7, 95% CI 0.82-8.85, P = 0.10). HCQ was associated with increased risk of hypoglycemia (OR 10.9, 95% CI 1.72-69.49, P = 0.011) and diarrhea (OR 2.8, 95% CI 1.4-5.5, P = 0.003), but not QT prolongation (OR 1.92, 95% CI 0.95-3.9, P = 0.06) or cardiac arrhythmia (OR 1.06, 95% CI 0.55-2.05, P = 0.85). Our results showed no significant beneficial effect of using hydroxychloroquine on the outcome of patients with COVID-19. Moreover, the risk of hypoglycemia due to hydroxychloroquine would possess a significant risk for out-of-hospital use.


Central Obesity and Visceral Adipose Tissue Are Not Associated With Incident Atherosclerotic Cardiovascular Disease Events in Older Men.
Background Visceral adipose tissue ( VAT ) and other measures of central obesity predict incident atherosclerotic cardiovascular disease ( ASCVD ) events in middle-aged individuals, but these associations are less certain in older individuals age 70 years and older. Our objective was to estimate the associations of VAT and the android-gynoid fat mass ratio, another measure of central obesity, with incident ASCVD events among a large cohort of older men. Methods and Results Two thousand eight hundred ninety-nine men (mean [ SD ] age 76.3 [5.5] years) enrolled in the Outcomes of Sleep Disorders in Older Men study had rigorous adjudication of incident ASCVD events (myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke). We used proportional hazards models to estimate the hazard ratios for incident ASCVD per SD increase of VAT or android-gynoid fat mass ratio (measured at baseline with dual-energy absorptiometry), adjusted for age, race, education, systolic blood pressure, smoking status, oxidized low-density lipoprotein level, treatment for hypertension, statin use, aspirin use, presence of diabetes mellitus, and study enrollment site. Over a mean ( SD ) follow-up period of 7.9 (3.4) years, 424 men (14.6%) had an incident ASCVD event. Neither VAT nor android-gynoid fat mass ratio were associated with incident ASCVD events, either unadjusted or after multivariable-adjustment (hazard ratios [95% confidence interval ] per SD increase 1.02 [0.92-1.13] and 1.05 [0.95-1.17], respectively). Conclusions Central adipose tissue, as measured by VAT or android-gynoid fat mass ratio, was not associated with incident ASCVD events in this study of older men.


Untwisting of the DNA helix stimulates the endonuclease activity of Bacillus subtilis Nth at AP sites.
Bacterial nucleoid associated proteins play a variety of roles in genome maintenance and dynamics. Their involvement in genome packaging, DNA replication and transcription are well documented but it is still unclear whether they play any specific roles in genome repair. We discovered that untwisting of the DNA double helix by bacterial non-specific DNA binding proteins stimulates the activity of a repair endonuclease of the Nth/MutY family involved in abasic site removal during base excision repair. The essential Bacillus subtilis primosomal gene dnaD, coding for a protein with DNA-untwisting activity, is in the same operon with nth and the promoter activity of this operon is transiently stimulated by H(2)O(2). Consequently, dnaD mRNA levels persist high upon treatment with H(2)O(2) compared to the reduced mRNA levels of the other essential primosomal genes dnaB and dnaI, suggesting that DnaD may play an important role in DNA repair in addition to its essential role in replication initiation. Homologous Nth repair endonucleases are found in nearly all organisms, including humans. Our data have wider implications for DNA repair as they suggest that genome associated proteins that alter the superhelicity of the DNA indirectly facilitate base excision repair mediated by repair endonucleases of the Nth/MutY family.


Evaluation of the psychometric properties of the phlebitis and infiltration scales for the assessment of complications of peripheral vascular access devices.
To prevent complications from peripheral vascular access device (PVAD) therapy, the Infusion Nurses Society (INS) developed 2 scales to measure the extent and severity of phlebitis and infiltration in PVADs. This study evaluated the psychometric properties of these scales to validate them with respect to their interrater reliability, concurrent validity, feasibility, and acceptability. A total of 182 patients at 2 sites were enrolled, and 416 observations of PVAD sites were made. Two nurses independently rated each PVAD site for the presence or absence of phlebitis and/or infiltration by using the INS scales. The interrater reliability was calculated, as was the agreement of the observed versus charted incidence of phlebitis and infiltration (concurrent validity) and the ease of use of the scales (feasibility, acceptability). Interrater reliability for both the Phlebitis and Infiltration scales and concurrent validity were found to be statistically significant (P < .05). The study nurses reported the scales to be easy to use, taking an average of 1.3 minutes to complete both. The importance of valid measures for use in research cannot be underestimated. The INS Phlebitis and Infiltration scales have been shown to be easy to use, valid, and reliable scales.


Congener-dependent conformations of isolated rhamnolipids at the vacuum-water interface: A molecular dynamics simulation.
Molecular dynamics simulation can be used to differentiate between the adsorption properties of rhamnolipid congeners at a vacuum-water interface. Adsorption of five congeners with differing alkyl chains (two C10 chains, two C14 chains or mixed C14C10 and C10C14), number of rhamnose rings (mono- or di-) and carboxyl group charge (non-ionic or anionic) are simulated at the vacuum-water interface. All rhamnolipids adsorb in the interfacial region with rhamnose and carboxyl groups closer to the water phase, and alkyl chains closer to the vacuum phase, but with differing adsorbed conformations. Headgroups of uncharged congeners show two preferred conformations, closed and partially open. Di-rhamnolipid has a low proportion of closed conformation, due to the steric constraints of the second pyranose ring. Charged congeners show strong preference for closed headgroup conformations. For rhamnolipids with equal alkyl chains lengths (C10C10, C14C14) the distribution of alkyl chain tilt angles is similar for both. Where chain lengths are unequal (C14C10, C10C14) one chain has a greater tendency to tilt towards the water phase (>90°). The order parameter of the alkyl chains shows they are disordered at the interface. Together, these results show congener-dependent adsorbed conformation differences suggesting they will have differing surface-active properties at vacuum-water and oil-water interfaces.


The evolutionary impact of invasive species.
Since the Age of Exploration began, there has been a drastic breaching of biogeographic barriers that previously had isolated the continental biotas for millions of years. We explore the nature of these recent biotic exchanges and their consequences on evolutionary processes. The direct evidence of evolutionary consequences of the biotic rearrangements is of variable quality, but the results of trajectories are becoming clear as the number of studies increases. There are examples of invasive species altering the evolutionary pathway of native species by competitive exclusion, niche displacement, hybridization, introgression, predation, and ultimately extinction. Invaders themselves evolve in response to their interactions with natives, as well as in response to the new abiotic environment. Flexibility in behavior, and mutualistic interactions, can aid in the success of invaders in their new environment.


Synthesis and characterization of phosphorescent two-coordinate copper(i) complexes bearing diamidocarbene ligands.
The photophysical properties of four, two-coordinate, linear diamidocarbene copper(i) complexes, [(DAC)2Cu][BF4] (1), (DAC)CuOSiPh3 (2), (DAC)CuC6F5 (3) and (DAC)Cu(2,4,6-Me3C6H2) (4) (DAC = 1,3-bis(2,4,6-trimethylphenyl)-5,5-dimethyl-4,6-diketopyrimidinyl-2-ylidene) have been investigated. Complex 1 shows a high photoluminescence quantum efficiency (ΦPL) in both the solid state (ΦPL = 0.85) and in CH2Cl2 solution (ΦPL = 0.65). The emission band of 1, both as a crystalline solid and in solution, is narrow (fwhm = 2300 cm-1) relative to the emission bands of 2 (fwhm = 2900 cm-1) and 3 (fwhm = 3700 cm-1). Complexes 2 and 3 are each brightly luminescent in the solid state (ΦPL = 0.62 and 0.18, respectively), but markedly less so in CH2Cl2 solution (ΦPL = 0.03 and <0.01, respectively). Complex 4 is not emissive in either the solid state or in solution. Phosphorescence of 1 in CH2Cl2 solution shows negligible quenching by oxygen in CH2Cl2 solution. This insensitivity to quenching is attributed to the excited state redox potential being insufficient for electron transfer to oxygen.


Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women.
High amounts of sedentary behaviour have been associated with increased risks of several chronic conditions and mortality. However, it is unclear whether physical activity attenuates or even eliminates the detrimental effects of prolonged sitting. We examined the associations of sedentary behaviour and physical activity with all-cause mortality. We did a systematic review, searching six databases (PubMed, PsycINFO, Embase, Web of Science, Sport Discus, and Scopus) from database inception until October, 2015, for prospective cohort studies that had individual level exposure and outcome data, provided data on both daily sitting or TV-viewing time and physical activity, and reported effect estimates for all-cause mortality, cardiovascular disease mortality, or breast, colon, and colorectal cancer mortality. We included data from 16 studies, of which 14 were identified through a systematic review and two were additional unpublished studies where pertinent data were available. All study data were analysed according to a harmonised protocol, which categorised reported daily sitting time and TV-viewing time into four standardised groups each, and physical activity into quartiles (in metabolic equivalent of task [MET]-hours per week). We then combined data across all studies to analyse the association of daily sitting time and physical activity with all-cause mortality, and estimated summary hazard ratios using Cox regression. We repeated these analyses using TV-viewing time instead of daily sitting time. Of the 16 studies included in the meta-analysis, 13 studies provided data on sitting time and all-cause mortality. These studies included 1 005 791 individuals who were followed up for 2-18·1 years, during which 84 609 (8·4%) died. Compared with the referent group (ie, those sitting <4 h/day and in the most active quartile [>35·5 MET-h per week]), mortality rates during follow-up were 12-59% higher in the two lowest quartiles of physical activity (from HR=1·12, 95% CI 1·08-1·16, for the second lowest quartile of physical activity [<16 MET-h per week] and sitting <4 h/day; to HR=1·59, 1·52-1·66, for the lowest quartile of physical activity [<2·5 MET-h per week] and sitting >8 h/day). Daily sitting time was not associated with increased all-cause mortality in those in the most active quartile of physical activity. Compared with the referent (<4 h of sitting per day and highest quartile of physical activity [>35·5 MET-h per week]), there was no increased risk of mortality during follow-up in those who sat for more than 8 h/day but who also reported >35·5 MET-h per week of activity (HR=1·04; 95% CI 0·99-1·10). By contrast, those who sat the least (<4 h/day) and were in the lowest activity quartile (<2·5 MET-h per week) had a significantly increased risk of dying during follow-up (HR=1·27, 95% CI 1·22-1·31). Six studies had data on TV-viewing time (N=465 450; 43 740 deaths). Watching TV for 3 h or more per day was associated with increased mortality regardless of physical activity, except in the most active quartile, where mortality was significantly increased only in people who watched TV for 5 h/day or more (HR=1·16, 1·05-1·28). High levels of moderate intensity physical activity (ie, about 60-75 min per day) seem to eliminate the increased risk of death associated with high sitting time. However, this high activity level attenuates, but does not eliminate the increased risk associated with high TV-viewing time. These results provide further evidence on the benefits of physical activity, particularly in societies where increasing numbers of people have to sit for long hours for work and may also inform future public health recommendations. None.


Comparing Self-Reported Sugar Intake With the Sucrose and Fructose Biomarker From Overnight Urine Samples in Relation to Cardiometabolic Risk Factors.
Studies on sugar intake and its link to cardiometabolic risk show inconsistent results, partly due to dietary misreporting. Cost-effective and easily measured nutritional biomarkers that can complement dietary data are warranted. Measurement of 24-h urinary sugars is a biomarker of sugar intake, but there are knowledge gaps regarding the use of overnight urine samples. We aim to compare (1) overnight urinary sucrose and fructose measured with liquid chromatography-tandem mass spectrometry, (2) self-reported sugar intake measured with web-based 4-day food records, (3) their composite measure, and (4) these different measures' (1-3) cross-sectional associations with cardiometabolic risk factors in 991 adults in the Malmö Offspring Study (18-69 years, 54% women). The correlations between the reported intakes of total sugar, added sugar and sucrose was higher for urinary sucrose than fructose, and the correlations for the sum or urinary sucrose and fructose (U-sugars) varied between r≈0.2-0.3 (P < 0.01) in men and women. Differences in the direction of associations were observed for some cardiometabolic risk factors between U-sugars and reported added sugar intake, as well as between the sexes. In women, U-sugars, but not reported added sugar intake, were positively associated with systolic and diastolic blood pressure and fasting glucose. Both U-sugars and added sugar were positively associated with BMI and waist circumference in women, whereas among men, U-sugars were negatively associated with BMI and waist circumference, and no association was observed for added sugar. The composite measure of added sugars and U-sugars was positively associated with BMI, waist circumference and systolic blood pressure and negatively associated with HDL cholesterol in women (P < 0.05). Conclusively, we demonstrate statistically significant, but not very high, correlations between reported sugar intakes and U-sugars. Results indicate that overnight urinary sugars may be used as a complement to self-reported dietary data when investigating associations between sugar exposure and cardiometabolic risk. However, future studies are highly needed to validate the overnight urinary sugars as a biomarker because its use, instead of 24-h urine, facilitates data collection.


Initialization independent clustering with actively self-training method.
The results of traditional clustering methods are usually unreliable as there is not any guidance from the data labels, while the class labels can be predicted more reliable by the semisupervised learning if the labels of partial data are given. In this paper, we propose an actively self-training clustering method, in which the samples are actively selected as training set to minimize an estimated Bayes error, and then explore semisupervised learning to perform clustering. Traditional graph-based semisupervised learning methods are not convenient to estimate the Bayes error; we develop a specific regularization framework on graph to perform semisupervised learning, in which the Bayes error can be effectively estimated. In addition, the proposed clustering algorithm can be readily applied in a semisupervised setting with partial class labels. Experimental results on toy data and real-world data sets demonstrate the effectiveness of the proposed clustering method on the unsupervised and the semisupervised setting. It is worthy noting that the proposed clustering method is free of initialization, while traditional clustering methods are usually dependent on initialization.


XRCC1 Arg194Trp and Arg399Gln polymorphisms and arsenic methylation capacity are associated with urothelial carcinoma.
The association between DNA repair gene polymorphisms and bladder cancer has been widely studied. However, few studies have examined the correlation between urothelial carcinoma (UC) and arsenic or its metabolites. The aim of this study was to examine the association between polymorphisms of the DNA repair genes, XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln, with urinary arsenic profiles and UC. To this end, we conducted a hospital-based case-control study with 324 UC patients and 647 age- and gender-matched non-cancer controls. Genomic DNA was used to examine the genotype of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln by PCR-restriction fragment length polymorphism analysis (PCR-RFLP). Urinary arsenic profiles were measured by high performance liquid chromatography (HPLC) linked with hydride generator and atomic absorption spectrometry. The XRCC1 399 Gln/Gln and 194 Arg/Trp and Trp/Trp genotypes were significantly related to UC, and the odds ratio (OR) and 95% confidence interval (95%CI) were 1.68 (1.03-2.75) and 0.66 (0.48-0.90), respectively. Participants with higher total urinary arsenic levels, a higher percentage of inorganic arsenic (InAs%) and a lower percentage of dimethylarsinic acid (DMA%) had a higher OR of UC. Participants carrying XRCC1 risk diplotypes G-C/G-C, A-C/A-C, and A-T/G-T, and who had higher total arsenic levels, higher InAs%, or lower DMA% compared to those with other XRCC1 diplotypes had a higher OR of UC. Our results suggest that the XRCC1 399 Gln/Gln and 194 Arg/Arg DNA repair genes play an important role in poor arsenic methylation capacity, thereby increasing the risk of UC in non-obvious arsenic exposure areas.


Killer B lymphocytes: the evidence and the potential.
Immune regulation plays a critical role in controlling potentially dangerous inflammation and maintaining health. The Fas ligand/Fas receptor axis has been studied extensively as a mechanism of killing T cells and other cells during infections, autoimmunity, and cancer. FasL expression has been primarily attributed to activated T cells and NK cells. Evidence has emerged that B lymphocytes can express FasL and other death-inducing ligands, and can mediate cell death under many circumstances. Among B cell subsets, the expression of both Fas ligand and IL-10 is highest on the CD5(+) B cell population, suggesting that CD5(+) B cells may have a specialized regulatory function. The relevance of killer B cells to normal immune regulation, disease pathogenesis, and inflammation is discussed.


A method for evaluating chemical selectivity of agonists for glutamate receptor channels incorporated in liposomes based on an agonist-induced ion flux measured by ion-selective electrodes.
A new method for evaluating chemical selectivity of agonists for the NMDA subtype of glutamate receptor (GluR) channels is described. The method is based on the magnitude of Ca2+ release from GluR-incorporated liposomes, which is measured by a Ca2+ ion-selective electrode with a thin-layer mode. The partially purified GluRs from rat whole brain were reconstituted into Ca2+-loaded liposomes. Small aliquots (each 50 microl) of the proteoliposomes, in the presence of an antagonist DNQX for blocking non-NMDA subtype, were subjected to potentiometric measurements of Ca2+ release under stimulation by three kinds of agonists, i.e. NMDA, L-glutamate and L-CCG-IV. The amount of the Ca2+ ion flux through the GluR channel induced by the agonists was found to increase in the order of NMDA < L-glutamate < L-CCG-IV, which was consistent with that of binding affinity of the agonists toward the NMDA subtype. However, the range of selectivity of the relevant agonists was much smaller compared with results based on binding affinities. The present method provides physiologically more relevant values for the agonist selectivity of GluRs as compared to that of the conventional binding assay in the sense that the selectivity is based on the very magnitude of Ca2+ flux through the NMDA receptor, i.e. the extent of signal transduction by a given agonist. The evaluation of agonist selectivity based on Na+ release was also investigated by using a Na+ ion-selective electrode, but agonist-induced Na+ release was not detected, because of low permeability of Na+ through the NMDA subtype.


Guidance to 2018 good practice: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma.
Mobile Airways Sentinel NetworK (MASK) belongs to the Fondation Partenariale MACVIA-LR of Montpellier, France and aims to provide an active and healthy life to rhinitis sufferers and to those with asthma multimorbidity across the life cycle, whatever their gender or socio-economic status, in order to reduce health and social inequities incurred by the disease and to improve the digital transformation of health and care. The ultimate goal is to change the management strategy in chronic diseases. MASK implements ICT technologies for individualized and predictive medicine to develop novel care pathways by a multi-disciplinary group centred around the patients. Include patients, health care professionals (pharmacists and physicians), authorities, patient's associations, private and public sectors. MASK is deployed in 23 countries and 17 languages. 26,000 users have registered. MASK is participating in EU projects (POLLAR: impact of air POLLution in Asthma and Rhinitis, EIT Health, DigitalHealthEurope, Euriphi and Vigour). (i) Adherence to treatment is the major problem of allergic disease, (ii) Self-management strategies should be considerably expanded (behavioural), (iii) Change management is essential in allergic diseases, (iv) Education strategies should be reconsidered using a patient-centred approach and (v) Lessons learnt for allergic diseases can be expanded to chronic diseases.


Bayesian Brains without Probabilities.
Bayesian explanations have swept through cognitive science over the past two decades, from intuitive physics and causal learning, to perception, motor control and language. Yet people flounder with even the simplest probability questions. What explains this apparent paradox? How can a supposedly Bayesian brain reason so poorly with probabilities? In this paper, we propose a direct and perhaps unexpected answer: that Bayesian brains need not represent or calculate probabilities at all and are, indeed, poorly adapted to do so. Instead, the brain is a Bayesian sampler. Only with infinite samples does a Bayesian sampler conform to the laws of probability; with finite samples it systematically generates classic probabilistic reasoning errors, including the unpacking effect, base-rate neglect, and the conjunction fallacy.


An oligotrophic deep-subsurface community dependent on syntrophy is dominated by sulfur-driven autotrophic denitrifiers.
Subsurface lithoautotrophic microbial ecosystems (SLiMEs) under oligotrophic conditions are typically supported by H2 Methanogens and sulfate reducers, and the respective energy processes, are thought to be the dominant players and have been the research foci. Recent investigations showed that, in some deep, fluid-filled fractures in the Witwatersrand Basin, South Africa, methanogens contribute <5% of the total DNA and appear to produce sufficient CH4 to support the rest of the diverse community. This paradoxical situation reflects our lack of knowledge about the in situ metabolic diversity and the overall ecological trophic structure of SLiMEs. Here, we show the active metabolic processes and interactions in one of these communities by combining metatranscriptomic assemblies, metaproteomic and stable isotopic data, and thermodynamic modeling. Dominating the active community are four autotrophic β-proteobacterial genera that are capable of oxidizing sulfur by denitrification, a process that was previously unnoticed in the deep subsurface. They co-occur with sulfate reducers, anaerobic methane oxidizers, and methanogens, which each comprise <5% of the total community. Syntrophic interactions between these microbial groups remove thermodynamic bottlenecks and enable diverse metabolic reactions to occur under the oligotrophic conditions that dominate in the subsurface. The dominance of sulfur oxidizers is explained by the availability of electron donors and acceptors to these microorganisms and the ability of sulfur-oxidizing denitrifiers to gain energy through concomitant S and H2 oxidation. We demonstrate that SLiMEs support taxonomically and metabolically diverse microorganisms, which, through developing syntrophic partnerships, overcome thermodynamic barriers imposed by the environmental conditions in the deep subsurface.


Using a Data-Driven Approach to Estimate Second-Language Proficiency From Brain Activation: A Functional Near-Infrared Spectroscopy Study.
While non-invasive brain imaging has made substantial contributions to advance human brain science, estimation of individual state is becoming important to realize its applications in society. Brain activations were used to classify second-language proficiencies. Participants in functional near-infrared spectroscopy (fNIRS) experiment were 20/20 native Japanese speakers with high/low English abilities and 19/19 native English speakers with high/low Japanese abilities. Their cortical activities were measured by functional near-infrared spectroscopy while they were conducting Japanese/English listening comprehension tests. The data-driven method achieved classification accuracy of 77.5% in the case of Japanese speakers and 81.9% in the case of English speakers. The informative features predominantly originated from regions associated with language function. These results bring an insight of fNIRS neuroscience and its applications in society.


The Indiana Chronic Disease Management Program's impact on medicaid claims: a longitudinal, statewide evaluation.
: Disease management programs have grown in popularity over the past decade as a strategy to curb escalating healthcare costs for persons with chronic diseases. : To evaluate the effect of the Indiana Chronic Disease Management Program (ICDMP) on the longitudinal changes in Medicaid claims statewide. : Phased implementation of a chronic disease management program in 3 regions of the state. Fourteen repeated cohorts of Medicaid members were drawn over a period of 3.5 years and the trends in claims were evaluated using a repeated measures model. : A total of 44,218 Medicaid members with diabetes and/or congestive heart failure in 3 geographic regions in Indiana. : Across all 3 regions and both disease classes, we found a flattening of cost trends between the pre- and post-ICDMP-initiation periods. This change in the slopes was significant for all of the models except for congestive heart failure in southern Indiana. Thus, the average per member claims paid was increasing at a faster rate before ICDMP but slowed once the program was initiated. To distinguish shorter and longer-term effects related to ICDMP, we estimated annual slopes within the pre- and post-ICDMP- time periods. A similar pattern was found in all regions: claims were increasing before ICDMP, flattened in the years around program initiation, and remained flat in the final year of follow-up. : This analysis shows that the trend in average total claims changed significantly after the implementation of ICDMP, with a decline in the rate of increase in claims paid observed for targeted Medicaid program populations across the state of Indiana.


Platelet-derived HMGB1 is a critical mediator of thrombosis.
Thrombosis and inflammation are intricately linked in several major clinical disorders, including disseminated intravascular coagulation and acute ischemic events. The damage-associated molecular pattern molecule high-mobility group box 1 (HMGB1) is upregulated by activated platelets in multiple inflammatory diseases; however, the contribution of platelet-derived HMGB1 in thrombosis remains unexplored. Here, we generated transgenic mice with platelet-specific ablation of HMGB1 and determined that platelet-derived HMGB1 is a critical mediator of thrombosis. Mice lacking HMGB1 in platelets exhibited increased bleeding times as well as reduced thrombus formation, platelet aggregation, inflammation, and organ damage during experimental trauma/hemorrhagic shock. Platelets were the major source of HMGB1 within thrombi. In trauma patients, HMGB1 expression on the surface of circulating platelets was markedly upregulated. Moreover, evaluation of isolated platelets revealed that HMGB1 is critical for regulating platelet activation, granule secretion, adhesion, and spreading. These effects were mediated via TLR4- and MyD88-dependent recruitment of platelet guanylyl cyclase (GC) toward the plasma membrane, followed by MyD88/GC complex formation and activation of the cGMP-dependent protein kinase I (cGKI). Thus, we establish platelet-derived HMGB1 as an important mediator of thrombosis and identify a HMGB1-driven link between MyD88 and GC/cGKI in platelets. Additionally, these findings suggest a potential therapeutic target for patients sustaining trauma and other inflammatory disorders associated with abnormal coagulation.


The Burden of Subthreshold Posttraumatic Stress Disorder in World Trade Center Responders in the Second Decade After 9/11.
To characterize the prevalence, risk and protective correlates, and clinical characteristics associated with probable subthreshold posttraumatic stress disorder (PTSD) in police and nontraditional (eg, construction workers) World Trade Center (WTC) responders a median of 12.2 years after September 11, 2001. A total of 4,196 WTC responders, monitored via the WTC Health Program, completed a web-based survey between 2012 and 2014 assessing a range of variables, including demographics, WTC exposures, medical and psychiatric comorbidities, and mental health services use. The sample included 2,029 police responders and 2,167 nontraditional responders. Current (past-month) probable WTC-related PTSD level (none, subthreshold, or full PTSD) was assessed based on DSM-IV criteria using the PTSD Checklist-Specific Stressor version (PCL-S). The prevalence of current probable full and subthreshold WTC-related PTSD in police responders was 9.3% and 17.5%, respectively, and in nontraditional responders was 21.9% and 24.1%, respectively. Risk and protective correlates for subthreshold PTSD included post-9/11 medical comorbidities and traumatic events (odds ratios [ORs] = 1.1-1.2). Clinical characteristics included elevated rates of comorbid depression (OR = 3.2 and 3.9 for subthreshold PTSD and 17.2 and 30.3 for full PTSD for nontraditional and police responders, respectively). Among responders with subthreshold PTSD, police were more likely to have accessed mental health services and utilized a greater variety of treatments than nontraditional responders. Overall, 26.8% of police and 46.0% of nontraditional responders met criteria for probable WTC-related full or subthreshold PTSD an average of 12 years after 9/11. Probable subthreshold PTSD, which is not typically assessed in clinical settings, was more prevalent than probable full PTSD and was associated with significantly elevated rates of psychiatric comorbidities, functional impairment, and reduced quality of life. These findings underscore the importance of assessing, monitoring, and possibly treating subthreshold PTSD in WTC and other disaster responders.


Systemic Acyl-CoA:cholesterol acyltransferase inhibition reduces inflammation and improves vascular function in hypercholesterolemia.
Circulating lipids may initiate and progress atherosclerosis by causing vascular inflammation. Monocytes and tissue macrophages are involved and regulate lipid metabolism in the vascular wall through acetylation of cholesterol by acyl-CoA:cholesterol acyltransferase (ACAT). ACAT inhibition reduces atherosclerosis in animal models by mechanisms that may be independent of their effects on circulating lipids. Because endothelial dysfunction is an important factor in atherosclerosis, we tested the hypothesis that systemic ACAT inhibition would improve endothelial function in hypercholesterolemic humans and assessed its effects on circulating lipids and markers of systemic inflammation. We studied 21 hypercholesterolemic subjects in a double-blind, randomized-crossover, placebo-controlled trial with assessments of circulating lipids, markers of inflammation, resistance-vessel endothelial function (with venous occlusion plethysmography), and conduit-vessel vasoreactivity (brachial artery flow-mediated dilation at baseline and after placebo or treatment with avasimibe 750 mg QDS for 8 weeks. There was a small change in total cholesterol with treatment (326+/-25 to 311+/-22 mg/dL, P=0.04). Circulating tumor necrosis factor-alpha was significantly reduced (4.0+/-0.3 to 3.6+/-0.2 pg/mL, P=0.02); resistance vessel responses to acetylcholine, bradykinin, and verapamil were significantly enhanced; and responses to nitroglycerin and conduit-vessel vasoreactivity were unchanged after ACAT inhibition. Systemic ACAT inhibition reduces circulating tumor necrosis factor-alpha levels in hypercholesterolemic subjects and improves resistance-vessel endothelial function, with small effects on circulating cholesterol. This may be a novel therapeutic strategy to target vascular inflammation and endothelial dysfunction in atherosclerosis.


Transcranial Doppler and rCBF compared in carotid endarterectomy.
In eight patients undergoing carotid endarterectomy, the mean velocity and an index of pulse amplitude in the middle cerebral artery were monitored continuously by transcranial doppler ultrasound. rCBF was measured by intracarotid injection of 133 Xenon shortly before and at the time of the carotid artery occlusion, and again a few minutes after carotid flow was reestablished. Comparison of the mean velocity in the MCA and the cortical convexity rCBF revealed relatively little hysteresis in their relationship from prior to after the occlusion. There was however, considerable variability in this relationship among patients. Both the rCBF and the velocity decreased substantially at occlusion in three cases, neither changed very much in three. While in two, though the rCBF decreased significantly, the velocity did not change. The index of pulse amplitude was somewhat more sensitive to the occlusion, decreasing in the seven cases in which it was recorded, including one in which the rCBF did not change.


Optical quantal analysis of synaptic transmission in wild-type and rab3-mutant Drosophila motor axons.
Synaptic transmission from a neuron to its target cells occurs via neurotransmitter release from dozens to thousands of presynaptic release sites whose strength and plasticity can vary considerably. We report an in vivo imaging method that monitors real-time synaptic transmission simultaneously at many release sites with quantal resolution. We applied this method to the model glutamatergic system of the Drosophila melanogaster larval neuromuscular junction. We find that, under basal conditions, about half of release sites have a very low release probability, but these are interspersed with sites with as much as a 50-fold higher probability. Paired-pulse stimulation depresses high-probability sites, facilitates low-probability sites, and recruits previously silent sites. Mutation of the small GTPase Rab3 substantially increases release probability but still leaves about half of the sites silent. Our findings suggest that basal synaptic strength and short-term plasticity are regulated at the level of release probability at individual sites.


Transforming ligands into transcriptional regulators: building blocks for bifunctional molecules.
The human body is comprised of several hundred distinct cell types that all share a common genomic template. This diversity arises from regulated expression of individual genes. The first critical step in this process is transcription and is governed by a large number of transcription factors. Small molecules that can alter transcription hold tremendous utility as chemical probes and therapeutics. To fully realize their potential, however, artificial transcription factors must be able to orchestrate protein recruitment at gene promoters just like their natural counterparts. This tutorial review surveys the discovery of small ligands (drug-like molecules and short peptides) that bind transcriptional coregulatory proteins, and thus comprise one of the two essential characteristics of a transcription factor. By joining these ligands to DNA-targeting moieties, one can construct a bifunctional molecule that recruits its protein target to specific genes and controls gene transcription.


Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis.
Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK.


Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases.
CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information, which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared with a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86%), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12%) and rarely in the bone (3%). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84% cases, with a diffuse pattern only in 23% of cases, whereas nuclear WT1 was seen in 92%. A CIC-DUX4 fusion was detected in 57% of cases, with either DUX4 on 4q35 (35%) or on 10q26 in 25 (22%) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43%, which was significantly lower than the 77% 5-year survival in the control Ewing sarcoma group (P=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared with Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors distinct from Ewing sarcoma.


Tubular early endosomal networks in AtT20 and other cells.
Using horseradish peroxidase (HRP) as a fluid-phase endocytic tracer, we observed through the electron microscope numerous tubular endosomes with a diameter of 30-50 nm and lengths of greater than 2 microns in thick sections (0.2-0.5 microns) of AtT20 cells. These tubular endosomes are multibranching and form local networks but not a single reticulum throughout the cytoplasm. They are sometimes in continuity with vesicular endosomal structures but have not been observed in continuity with AtT20 cell late endosomes. Tubular endosomal networks are not uniformly distributed throughout the cytoplasm, but are particularly abundant in growth cones, in patches below the plasma membrane of the cell body, and surrounding the centrioles and microtubule organizing center (MTOC). Tubular endosomes at all these locations receive HRP within the first 5 min of endocytosis but approximately 30 min of endocytosis are required to load the tubular endosomal networks with HRP so that their full extent can be visualized in the electron microscope. After 10 min of endocytosis, complete unloading occurs within 30 min of chase, but between 30 and 60 min are required to chase out all the tracer from the tubular endosomes loaded to steady state during 60 min endocytosis of 10 mg/ml HRP. In interphase cells, neither the loading nor unloading of tubular endosomes depends on microtubules but in cells blocked in mitosis by depolymerization of the mitotic spindle with nocodazole, HRP does not chase out of tubular endosomes. The thread-like shape of tubular endosomes is not dependent on microtubules. Furthermore, HRP is delivered to AtT20 tubular endosomes at 20 degrees C. All these properties indicate that AtT20 cell tubular endosomes are an early endocytic compartment distinct from late endosomes. Tubular endosomes like those in AtT20 cells have been seen in cells of the following lines: PC12, HeLa, Hep2, Vero, MDCK I and II, CCL64, RK13, and NRK; they are particularly abundant in the first three lines. In contrast, tubular endosomes are sparse in 3T3 and BHK21 cells. The tubular endosomes we have observed appear to be identical to the endosomal reticulum observed in the living Hep2 cells by Hopkins, C. R., A. Gibson, H. Shipman, and K. Miller. 1990.


Nonbismuth concomitant quadruple therapy for Helicobacter pylori eradication in Chinese regions: A meta-analysis of randomized controlled trials.
To evaluate the applicability of nonbismuth concomitant quadruple therapy for Helicobacter pylori (H. pylori) eradication in Chinese regions. A systematic review and meta-analysis of randomized controlled trials was performed to evaluate the efficacy of nonbismuth concomitant quadruple therapy between sequential therapy or triple therapy for H. pylori eradication in Chinese regions. The defined Chinese regions include China, Hong Kong, Taiwan, and Singapore. The primary outcome was the H. pylori eradication rate; the secondary outcome was the compliance with therapy. The PubMed, Embase, Scopus, and Cochrane databases were searched for studies published in the period up to March 2016 with no language restriction. We reviewed six randomized controlled trials and 1616 patients. In 3 trials comparing concomitant quadruple therapy with triple therapy, the H. pylori eradication rate was significantly higher for 7-d nonbismuth concomitant quadruple therapy than for 7-d triple therapy (91.2% vs 77.9%, risk ratio = 1.17, 95%CI: 1.09-1.25). In 3 trials comparing quadruple therapy with sequential therapy, the eradication rate was not significant between groups (86.9% vs 86.0%). However, higher compliance was achieved with concomitant therapy than with sequential therapy. The H. pylori eradication rate was higher for nonbismuth concomitant quadruple therapy than for triple therapy. Moreover, higher compliance was achieved with nonbismuth concomitant quadruple therapy than with sequential therapy. Thus, nonbismuth concomitant quadruple therapy should be the first-line treatment in Chinese regions.


Comparative evaluation of cefadroxil and cephalexin in children and adolescents with pyodermas. Cefadroxil Once Daily Pyoderma Study Group.
This randomized, multicenter study compared the safety and efficacy of cefadroxil with that of cephalexin for the treatment of pyodermas in children and adolescents (1-18 years of age). Cefadroxil was given as a single oral daily dose of 30 mg/kg, and cephalexin 30 mg/kg/day was given in two divided doses. The maximum daily dose for both drugs was 1 gm, and treatment was administered for 10 days. Clinical and bacteriologic evaluations were made on days 4 or 5 during therapy and 2 to 4 days after therapy was completed. Of the 462 patients enrolled in the study, 156 patients in the cefadroxil group and 133 patients in the cephalexin group were evaluable. Staphylococcus aureus (56% of isolates) and Streptococcus pyogenes (39% of isolates) were isolated most frequently. The bacteriologic response was statistically greater in the patients treated with cefadroxil than in those treated with cephalexin (96% versus 89%; P = 0.042). A satisfactory clinical response was reported in 147 (94%) cefadroxil-treated patients and 122 (92%) cephalexin-treated patients (P = 0.476). The overall effective response to treatment was significantly higher with cefadroxil than with cephalexin (94% versus 86%; P = 0.024). Compliance with 9 or 10 days of therapy was similar in both treatment groups, although there was a difference between the two treatment groups with respect to completion of medication regimen: 95% of patients taking cefadroxil once daily--versus 65% of patients taking cephalexin twice daily--took 100% of their medication (P < 0.0001). Adverse events were infrequent and mild. The results of this study demonstrate that once-daily cefadroxil offers greater bacteriologic eradication and a better overall effective response than twice-daily cephalexin for the treatment of pyodermas caused by gram-positive pathogens in children and adolescents.


MtENOD11 gene activation during rhizobial infection and mycorrhizal arbuscule development requires a common AT-rich-containing regulatory sequence.
The MtENOD11 gene from the model legume Medicago truncatula is transcriptionally activated both in response to Sinorhizobium meliloti Nod factors and throughout infection of root tissues by the nitrogen-fixing microsymbiont. To identify the regulatory sequences involved in symbiosis-related MtENOD11 expression, a series of promoter deletions driving the beta-glucuronidase reporter gene were analyzed in transgenic M. truncatula roots. These studies have revealed that distinct regulatory regions are involved in infection-related MtENOD11 expression compared with preinfection (Nod factor-mediated) expression. In particular, the 257-bp promoter sequence immediately upstream from the start codon is sufficient for infection-related expression, but is unable to drive gene transcription in response to the Nod factor elicitor. This truncated promoter is also sufficient to confer MtENOD11 expression during both the arbuscular mycorrhizal (AM) association and the parasitic interaction with root-knot nematodes. Site-directed mutagenesis further showed that a previously identified nodule-specific AT-rich motif is required for high-level MtENOD11 expression during S. meliloti infection as well as during AM colonization. However, mutation of this motif does not affect gene expression associated with nematode-feeding sites. Taken together, these results suggest a close link between regulatory mechanisms controlling transcriptional early nodulin gene activation during both rhizobial and AM root endosymbioses.


Validation of the FibroTest biochemical markers score in assessing liver fibrosis in hepatitis C patients.
Determining the stage of fibrosis by liver biopsy is important in managing patients with hepatitis C virus infection. We investigated the predictive value of the proprietary FibroTest score to accurately identify significant fibrosis in Australian hepatitis C patients. Serum obtained from 125 confirmed hepatitis C patients before antiviral therapy was analyzed for haptoglobin, alpha(2)-macroglobulin, apolipoprotein A1, bilirubin, and gamma-glutamyltransferase activity, and the FibroTest score was computed. Liver fibrosis pathology was staged according to a defined system on a scale of F0 to F4. We used predictive values and a ROC curve to assess the accuracy of FibroTest scores. The prevalence of significant fibrosis defined by liver biopsy was 0.38. The most useful single test for predicting significant fibrosis was serum alpha(2)-macroglobulin (cutoff value, 2.52 g/L; sensitivity, 75%; specificity, 67%). The negative predictive value of a FibroTest score <0.1 was 85%, and the positive predictive value of a score >0.6 was 78%. Although 33 of the 125 patients had FibroTest scores <0.1 and were therefore deemed unlikely to have fibrosis, 6 (18%) had significant fibrosis. Conversely, of the 24 patients with scores >0.6 who were likely to have significant fibrosis, 5 (21%) had mild fibrosis. Of the 125 patients in the cohort, 57 (46%) could have avoided liver biopsy, but discrepant results were recorded in 11 of those 57 (19%). The FibroTest score could not accurately predict the presence or absence of significant liver fibrosis.


Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome.
The HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the retinal phenotype of a HANAC mouse model. Heterozygous mutant mice displayed both a thinning of the basement membrane in retinal blood vessels and in Bruch's membrane resulting in vascular leakage. Homozygous mice had additional vascular changes, including greater vessel coverage and tortuosity. This greater tortuosity was associated to higher expression levels of vascular endothelial growth factor (VEGF). These major changes to the blood vessels were correlated with photoreceptor dysfunction and degeneration. The neuronal damage was associated with reactive gliosis in astrocytes and Müller glial cells, and by the migration of microglial cells into the outer retina. This study illustrates how vascular changes can trigger neuronal degeneration in a new model of HANAC syndrome that can be used to further study dysfunctions of neurovascular coupling. This study provides a phenotypic analysis of a novel mouse model of HANAC syndrome focusing on the retinal aspect. It recapitulates most of the aspects of the human disease and is therefore a great tool to study and to address this condition.


Beyond the Literal Meaning of Words in Children with Klinefelter Syndrome: Two Case Studies.
Literature on children with Klinefelter Syndrome (KS) points to general linguistic difficulties in both comprehension and production among other cognitive functions, and in the majority of cases, these coexist with an intellectual level within the norms. In these conditions, children having language delay generally engage in language therapy and are systematically monitored across ages. In this article, we present the profiles of two children with KS (47, XXY), aged 9.1 (Child S) and 13 (Child D), whose language development was assessed as adequate at age 3, and for this reason, did not receive any language treatment. At the present stage, their IQ, as measured by Wechsler Scales (Child S: 92; Child D: 101), is within the norm, but they both present marked weaknesses in pragmatic skills such as figurative language comprehension. The analysis of these two cases points to the need to go beyond global indexes of verbal abilities, as the same global index may mask a wide diversification of individual profiles. In addition, this study underlines the importance of monitoring the developmental trajectories of children like Child D and Child S, because weaknesses in pragmatic skills that are relevant for both academic achievement and social adaptation could emerge at later stages.


Exposure-response relations of alpha-amylase sensitisation in British bakeries and flour mills.
To describe the levels of exposure to fungal alpha-amylase in British bakeries and flour mills, and to describe the relation between exposure to alpha-amylase and sensitisation to fungal alpha-amylase. 495 personal flour dust samples were taken in seven British bakeries and flour mills and analysed for alpha-amylase with an immunoassay. Workers at the sites were asked to fill out questionnaires on work related symptoms, smoking history, and work history, and they were skin prick tested with common allergens and fungal alpha-amylase to assess sensitisation. Exposure to high concentrations of alpha-amylase occur in a few areas of British bakeries and flour mills, and there can be considerable differences in exposures to alpha-amylase between sites and between exposure groups, and even within similar exposure groups from different sites. Exposure to the highest concentrations of alpha-amylase was found in the dispensing and mixing areas of the bakeries (geometric mean (GM) 39.7 ng/m3). Exposure to alpha-amylase showed only a moderate correlation with concentrations of dust (r = 0.42) and flour aeroallergen (r = 0.46). The results also showed a relation between exposure to alpha-amylase and sensitisation to fungal alpha-amylase (prevalence ratio (PR) for medium exposure 3.9, 95% confidence interval (95% CI) 0.8 to 20.2, PR for high exposure 9.9, 95% CI 2.8 to 34.6) compared with the low exposure category). Atopic subjects had an increased risk of sensitisation, but this was not significant. This study suggests that exposure to alpha-amylase is a considerable health risk in British bakeries and flour mills. A small proportion of workers are exposed to alpha-amylase at concentrations that result in high rates of sensitisation. A reduction in exposure to alpha-amylase is likely to reduce this risk.


Recent trends and patterns in HIV-1 transmitted drug resistance in the United Kingdom.
Transmission of drug-resistant HIV-1 has decreased in the UK since the early 2000s. This analysis reports recent trends and characteristics of transmitted drug resistance (TDR) in the UK from 2010 to 2013. Resistance tests conducted in antiretroviral treatment (ART)-naïve individuals between 2010 and 2013 were analysed for the presence of transmitted drug resistance mutations (TDRMs), defined as any mutations from a modified 2009 World Health Organization surveillance list, or a modified 2013 International Antiviral Society-USA list for integrase tests. Logistic regression was used to examine associations between demographics and the prevalence of TDRMs. TDRMs were observed in 1223 (7.5%) of 16 425 individuals; prevalence declined from 8.1% in 2010 to 6.6% in 2013 (P = 0.02). The prevalence of TDRMs was higher among men who have sex with men (MSM) compared with heterosexual men and women (8.7% versus 6.4%, respectively) with a trend for decreasing TDRMs among MSM (P = 0.008) driven by a reduction in nucleoside reverse transcriptase inhibitor (NRTI)-related mutations. The most frequently detected TDRMs were K103N (2.2%), T215 revertants (1.6%), M41L (0.9%) and L90M (0.7%). Predicted phenotypic resistance to first-line ART was highest to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) rilpivirine and efavirenz (6.2% and 3.4%, respectively) but minimal to NRTIs, including tenofovir, and protease inhibitors (PIs). No major integrase TDRMs were detected among 101 individuals tested while ART-naïve. We observed a decrease in TDRMs in recent years. However, this was confined to the MSM population and rates remained stable in those with heterosexually acquired HIV infection. Resistance to currently recommended first-line ART, including integrase inhibitors, remained reassuringly low.


Characterization of monoclonal antibodies for rapid identification of Actinomyces naeslundii in clinical samples.
The purpose of this study was to generate highly specific serological reagents for the quantitative identification of Actinomyces naeslundii in clinical samples, in particular dental plaque. Balb/c mice were immunized with pasteurized human A. naeslundii strains representing different genospecies and serotypes. Ten hybrid cell lines secreting monoclonal antibodies reactive with A. naeslundii were isolated and characterized. Antibody specificity was determined by indirect immunofluo-rescence and enzyme-linked immunosorbent assay using strains from 59 species and by immunofluorescence analyses of supragingival plaque from 10 gingivitis patients. Nine monoclonal antibodies reacted selectively with A. naeslundii, whereas one additionally bound to Actinomyces israelii. They recognized at least nine different epitopes with characteristic expression patterns among the test strains. Six clusters of antigenically unique or closely related strains could be distinguished. Clusters 1, 4, and 5 represented by 12, 18, and 5 strains, respectively, comprised over 80% of the A. naeslundii strains tested. All reference strains for genospecies 1 grouped with cluster 1. Strains associated with genospecies 2 fell into clusters 4 and 5. Tests with mutant strains indicated that three monoclonal antibodies recognize type 2 and one type 1 fimbriae of genospecies 2. Only four isolates grouped with clusters 2 and 3 characterized by the expression of cluster-specific antigens. Interestingly, cluster 2 and 3 bacteria were markedly more abundant in vivo than indicated by their sparse representation in our strain collection. Overall, all but one of the new monoclonal antibodies should prove of value for the serological classification and rapid quantitative determination of A. naeslundii in clinical samples.


Abrupt light transitions in illuminance and correlated colour temperature result in different temporal dynamics and interindividual variability for sensation, comfort and alertness.
Detailed insights in both visual effects of light and effects beyond vision due to manipulations in illuminance and correlated color temperature (CCT) are needed to optimize study protocols as well as to design light scenarios for practical applications. This study investigated temporal dynamics and interindividual variability in subjective evaluations of sensation, comfort and mood as well as subjective and objective measures of alertness, arousal and thermoregulation following abrupt transitions in illuminance and CCT in a mild cold environment. The results revealed that effects could be uniquely attributed to changes in illuminance or CCT. No interaction effects of illuminance and CCT were found for any of these markers. Responses to the abrupt transitions in illuminance and CCT always occurred immediately and exclusively amongst the subjective measures. Most of these responses diminished over time within the 45-minute light manipulation. In this period, no responses were found for objective measures of vigilance, arousal or thermoregulation. Significant interindividual variability occurred only in the visual comfort evaluation in response to changes in the intensity of the light. The results indicate that the design of dynamic light scenarios aimed to enhance human alertness and vitality requires tailoring to the individual to create visually comfortable environments.


Sources of superoxide radicals involved in the pathogenesis of diethyldithiocarbamate-induced gastric antral ulcer in rats.
The production of superoxide radicals as a result of decreased Cu,Zn-superoxide dismutase activity is considered to be the most important factor in the pathogenesis of diethyldithiocarbamate (DDC)-induced gastric antral ulcers in rats. The aim of the present study was to identify possible sources of superoxide radicals and the role of platelet-activating factor (PAF) in DDC-induced ulcer formation. Groups of rats were pretreated with a drug or antiserum before DDC (800 mg/kg) administration. The size of the DDC-induced gastric antral ulcers was measured. Pretreatment with anti-rat polymorphonuclear leukocyte serum or CV-3988 (a specific antagonist of PAF) 20 mg/kg significantly reduced the size of DDC-induced gastric antral ulcers. The results confirmed that superoxide radicals play an important role in the pathogenesis of DDC-induced gastric ulcer in rats and suggested that NADPH (reduced nicotinamide-adenine dinucleotide phosphate) oxidase in PAF-activated polymorphonuclear leukocytes may be involved in the generation of these radicals.


A large-scale RNAi screen identifies Deaf1 as a regulator of innate immune responses in Drosophila.
Innate immune signalling pathways are evolutionarily conserved between invertebrates and vertebrates. The analysis of NF-kappaB signalling in Drosophila has contributed important insights into how organisms respond to infection. Nevertheless, significant gaps remain in our understanding of how the activation of intracellular signalling elicits specific transcriptional programs. Here we report a genome-wide RNA interference survey for transcription factors that are required for Toll-dependent immune responses. In addition to the NF-kappaB homologs Dif, Dorsal and factors of the general transcription machinery, we identified Deformed Epidermal Autoregulatory Factor 1 (Deaf1) to be required for the expression of the Toll target gene Drosomycin in cultured cells and in Drosophila in vivo. We show that Deaf1 is required for the survival of flies after fungal, but not E. coli, infection. We determine that Deaf1 acts downstream of the NF-kappaB factors Dorsal and Dif. These results indicate that Deaf1 is an important contributor to innate immune responses in vivo.


Homoleptic versus Heteroleptic Formation of Mononuclear Fe(II) Complexes with Tris-Imine Ligands.
We show a marked tendency of Fe(II) to form heteroleptic [Fe(L)(L')](ClO4)2 complexes from pairs of chelating tris-imine 3bpp, tpy, or 2bbp ligands. New synthetic avenues for spin crossover research become thus available, here illustrated with three new heteroleptic compounds with differing magnetic behaviors: [Fe(H4L1)(Cl-tpy)](ClO4)2·C3H6O (1), [Fe(H2L3)(Me3bpp)](ClO4)2·C3H6O (2), [Fe(H4L1)(2bbp)](ClO4)2·3C3H6O (3). Structural studies demonstrate that 1 is in the low-spin (LS) state up to 350 K, while complexes 2 and 3 are, by contrast, in the high-spin (HS) state down to 2 K, as corroborated through magnetic susceptibility measurements. Upon exposure to the atmosphere, the latter exhibits the release of three molecules of acetone per complex, turning into the solvent-free analogue [Fe(H4L1)(2bbp)](ClO4)2 (3a), through a single-crystal-to-single-crystal transformation. This guest extrusion process is accompanied by a spin switch, from HS to LS.


Utility of serial urinary cytology in the initial evaluation of the patient with microscopic hematuria.
We determine the utility of serial urinary cytologies in patients presenting with microscopic hematuria who were evaluated with upper and lower urinary tract studies to rule out a malignancy. Two hundred and thirty-seven patients with the diagnosis of microscopic hematuria were evaluated at an inner-city tertiary care hospital. Of these 239 patients, 182 patients had 405 cytologies obtained as part of their evaluation for hematuria. In addition, all patients had their lower urinary tract and upper tract thoroughly evaluated. Two hundred and seventy four cytology samples were read as normal, 104 (26%) as atypia, 7 (2%) as suspicious/malignant, and 20 (5%) as unsatisfactory. Seventeen patients (9.3%) had biopsy confirmed bladder cancer. Of these 17 patients, 2 had normal cytology, 11 had atypia, and 5 had suspicious/malignant. No patient had a positive cytology and a negative biopsy. Overall the number of hematuric patients harboring bladder cancer was small (7%). Cytology #1 detected 4 cases of cancer, cytology #2 detected an additional case and cytology #3 did not detect any additional cancers. Because of this low prevalence of bladder cancer in patients presenting with microscopic hematuria and the low sensitivity of detecting bladder cancers, the utility of urinary cytology in the initial evaluation of patients with hematuria may be minimal. The exact role of urinary cytology in the evaluation of hematuria is unknown.


SQT1, which encodes an essential WD domain protein of Saccharomyces cerevisiae, suppresses dominant-negative mutations of the ribosomal protein gene QSR1.
QSR1 is an essential Saccharomyces cerevisiae gene, which encodes a 60S ribosomal subunit protein required for joining of 40S and 60S subunits. Truncations of QSR1 predicted to encode C-terminally truncated forms of Qsr1p do not substitute for QSR1 but do act as dominant negative mutations, inhibiting the growth of yeast when expressed from an inducible promoter. The dominant negative mutants exhibit a polysome profile characterized by 'half-mer' polysomes, indicative of a subunit joining defect like that seen in other qsr1 mutants (D. P. Eisinger, F. A. Dick, and B. L. Trumpower, Mol. Cell. Biol. 17:5136-5145, 1997.) By screening a high-copy yeast genomic library, we isolated several clones containing overlapping inserts of a novel gene that rescues the slow-growth phenotype of the dominant negative qsr1 truncations. The suppressor of qsr1 truncation mutants, SQT1, is an essential gene, which encodes a 47.1-kDa protein containing multiple WD repeats and which interacts strongly with Qsr1p in a yeast two-hybrid system. SQT1 restores growth and the "half-mer" polysome profile of the dominant negative qsr1 mutants to normal, but it does not rescue temperature-sensitive qsr1 mutants or the original qsr1-1 missense allele. In yeast cell lysates, Sqt1p fractionates as part of an oligomeric protein complex that is loosely associated with ribosomes but is distinct from known eukaryotic initiation factor complexes. Loss of SQT1 function by down regulation from an inducible promoter results in formation of half-mer polyribosomes and decreased Qsr1p levels on free 60S subunits. Sqt1p thus appears to be involved in a late step of 60S subunit assembly or modification in the cytoplasm.


Knowledge and Perceptions of Pharmacy Students in Qatar on Anti-Doping in Sports and on Sports Pharmacy in Undergraduate Curricula.
Objective. To assess pharmacy students' knowledge and perceptions of doping and anti-doping in sports and to explore the curricular needs for undergraduate pharmacy in the field of sports pharmacy. Methods. A cross-sectional, descriptive, web-based survey of pharmacy students was conducted at Qatar University College of Pharmacy from March to May 2014. Data were analyzed using descriptive and inferential statistics. Results. Eighty respondents completed the online survey (80% response rate). Sixty percent were unaware of the World Anti-Doping Agency, and 85% were unaware of the International Pharmaceutical Federation's statement on the pharmacist's role in anti-doping. Students' knowledge score regarding the prohibited status of drugs that may be used by athletes was around 50%. Fourth-year pharmacy students had significantly higher knowledge scores than the other groups of students. Respondents acknowledged the important role of health care professionals, including pharmacists, as advisors on the safe and effective use of drugs in sports. Ninety percent of the students supported the inclusion of sports pharmacy in the curriculum. Conclusion. Pharmacy students indicated a strong desire to play a role in doping prevention and ensure safe and rational use of drugs among athletes. They suggested requiring an education and training strategy for sports pharmacy in undergraduate pharmacy curricula.


Artificial light at night, in interaction with spring temperature, modulates timing of reproduction in a passerine bird.
The ecological impact of artificial light at night (ALAN) on phenological events such as reproductive timing is increasingly recognized. In birds, previous experiments under controlled conditions showed that ALAN strongly advances gonadal growth, but effects on egg-laying date are less clear. In particular, effects of ALAN on timing of egg laying are found to be year-dependent, suggesting an interaction with climatic conditions such as spring temperature, which is known have strong effects on the phenology of avian breeding. Thus, we hypothesized that ALAN and temperature interact to regulate timing of reproduction in wild birds. Field studies have suggested that sources of ALAN rich in short wavelengths can lead to stronger advances in egg-laying date. We therefore tested this hypothesis in the Great Tit (Parus major), using a replicated experimental set-up where eight previously unlit forest transects were illuminated with either white, green, or red LED light, or left dark as controls. We measured timing of egg laying for 619 breeding events spread over six consecutive years and obtained temperature data for all sites and years. We detected overall significantly earlier egg-laying dates in the white and green light vs. the dark treatment, and similar trends for red light. However, there was a strong interannual variability in mean egg-laying dates in all treatments, which was explained by spring temperature. We did not detect any fitness consequence of the changed timing of egg laying due to ALAN, which suggests that advancing reproduction in response to ALAN might be adaptive.


Geographic information systems and the environmental risk of schistosomiasis in Bahia, Brazil.
A geographic information system was constructed using maps of regional environmental features, Schistosoma mansoni prevalence in 30 representative municipalities, and snail distribution in Bahia, Brazil to study the spatial and temporal dynamics of infection and to identify environmental factors that influence the distribution of schistosomiasis. Results indicate that population density and the duration of annual dry period are the most important determinants of prevalence of schistosomiasis in the areas selected for study. Maximum rainfall, total precipitation during three consecutive months, annual maximum or minimum temperatures, and diurnal temperature difference were not shown to be significant factors influencing S. mansoni prevalence in local populations or distribution of snail hosts. Prevalence of the disease was highest in the coastal areas of the state. Higher prevalence tended to occur in areas with latossolo soil type and transitional vegetation.


The influence of playful activities on children's anxiety during the preoperative period at the outpatient surgical center.
To verify the influence of playful activities during the preoperative period on the anxiety of children participating in the therapeutic recreation project conducted at the outpatient surgical center of Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil. The modified Yale Preoperative Anxiety Scale (mYPAS) was administered to 50 children between 5 and 12 years of age undergoing medical procedures at the outpatient surgical center. The children were divided in two groups: recreation group (individuals who participated in playful interventions in the recreation room) and control group (individuals who did not participate in playful interventions). Anxiety was measured using the mYPAS at two different moments: soon after the individuals arrived at the outpatient surgical center (minute 0) and 15 minutes after the first measurement. The results showed that soon after arriving at the outpatient surgical center, the patients did not have significant differences regarding anxiety, showing high values. However, after 15 minutes waiting or undergoing intervention, the children in the recreation group had reduced anxiety levels and those in the control group remained anxious. During the preoperative period, children who participate in playful activities in the recreation room have their anxiety reduced in comparison with those that only stay in the preoperative holding area for at least 15 minutes.


Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography.
In standard reference sources, the incidence of coronary artery disease (CAD) in patients with atrial fibrillation (AF) ranged between 24 and 46.5%. Since then, the incidence of cardiovascular risk factors (CRF) has increased and modern treatment strategies ("pill in the pocket") are only applicable to patients without structural heart disease. The aim of this study was to investigate the incidence and severity of CAD in patients with AF. From January 2005 until December 2009, we included 261 consecutive patients admitted to hospital with paroxysmal, persistent or permanent AF in this prospective study. All patients underwent coronary angiography and the Framingham risk score (FRS) was calculated. Patients with previously diagnosed or previously excluded CAD were excluded. The overall incidence of CAD in patients presenting with AF was 34%; in patients >70 years, the incidence of CAD was 41%. The incidence of patients undergoing a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) was 21%. Patients with CAD were older (73±8 years vs 68±10 years, p = 0.001), had significantly more frequent hypercholesterolemia (60% vs 30%, p<0.001), were more frequent smokers (26% vs 13%, p = 0.017) and suffered from angina more often (37% vs 2%, p<0.001). There was a significant linear trend among the FRS categories in percentage and the prevalence of CAD and PCI/CABG (p<0.0001). The overall incidence of CAD in patients presenting with AF was relatively high at 34%; the incidence of PCI/CABG was 21%. Based upon increasing CRF in the western world, we recommend a careful investigation respecting the FRS to either definitely exclude or establish an early diagnosis of CAD--which could contribute to an early and safe therapeutic strategy considering type Ic antiarrhythmics and oral anticoagulation.


Service quality as measured by service fit and mortality among public mental health system service recipients.
Service fit, defined as consistency between mental health services judged needed and services received was measured for a random sample of service recipients in a public mental health system (N = 6588). A variant of small area analysis was used to measure the relationship between catchment area mortality rates from natural causes, suicide, and medicolegal causes and area fit scores for a variety of services. We tested the theory-based hypothesis that service fit would predict interarea variations in mortality better than simple measures of amount of service prescribed and received. We also tested the hypothesis that, controlling for relevant demographic and clinical factors, fit would be protective for mortality from all causes. Findings supported the first hypothesis. With respect to the second, service fit for only certain services was protective. Housing and clubhouses services were particularly protective, suggesting the importance of services providing social support.


Rapid microbiologic and pharmacologic evaluation of experimental compounds against Mycobacterium tuberculosis.
The assessment of physiochemical and pharmacological properties at early stages of drug discovery can accelerate the conversion of hits and leads into candidates for further development. A strategy for streamlined evaluation of compounds against Mycobacterium tuberculosis in the early preclinical stage is presented in this report. As a primary assay to rapidly select experimental compounds with sufficient in vitro activity, the growth inhibition microtiter plate assay was devised as an alternative to current methods. This microdilution plate assay is a liquid culture method based on spectrophotometric readings of the bacillary growth. The performance of this method was compared to the performance of two established susceptibility methods using clinical available tuberculosis (TB) drugs. Data generated from all three assays were similar for all of the tested compounds. A second simple bioassay was devised to assess the oral bioavailability of compounds prior to extensive in vivo efficacy testing. The bioassay estimates drug concentrations in collected serum samples by a microdilution MIC plate method using M. tuberculosis. In the same assay, the MIC of the compound is also determined in the presence of 10% mouse serum as an indication of protein binding. The method was validated using different clinically available TB drugs, and results are discussed in this report. With these methodological advances, screening of compounds against tuberculosis in the preclinical phase will be rapid, can be adapted to semi-high-throughput screening, and will add relevant physicochemical and basic pharmacological criteria to the decision process of drug discovery.


Species-specific oligonucleotide probe for detection of Bonamia exitiosa (Haplosporidia) using in situ hybridisation assay.
Bonamiosis is a disease affecting various oyster species and causing oyster mass mortalities worldwide. The protozoans Bonamia exitiosa and B. ostreae (Haplosporidia) are included in the list of notifiable diseases of the World Organisation for Animal Health as the causative agents of this disease. Although the geographic range of both species was considered different for years, both species are now known to co-occur in some European areas affecting the same host, Ostrea edulis, which strengthens the need of species-specific methods to unequivocally identify the species of Bonamia. An oligonucleotide probe for specific detection of B. exitiosa (BEX_ITS) was designed to be used in in situ hybridisation (ISH) assays. ISH assay with BEX_ITS probe showed species-specificity and more sensitivity than traditional histology to visualise the parasite inside host tissue. ISH assay showed that the oyster gonad was the area where the parasite was most frequently located, and was the exclusive organ of infection in some oysters. A recommendation arising from the study is that more than 1 organ (including gonad and gills) should be used for PCR-based diagnosis of B. exitiosa, to maximise the sensitivity.


Osteogenesis imperfecta. Radiographic classification, natural history, and treatment of spinal deformities.
The natural history of the radiographic changes associated with osteogenesis imperfecta was recorded for sixty-four patients. Detailed clinical data regarding spinal deformities were available for forty-three patients. The patients could be placed in six well defined groups on the basis of a cluster of radiographic changes. The radiographic criteria used to classify patients who had osteogenesis imperfecta included the shape, dimensions, and appearance of the long bones; the presence of a trefoil pelvis and protrusio acetabuli; and the shape of the vertebrae. Patients can be classified more accurately if the dynamic nature of the radiographic changes is appreciated. Patients who had Type-A disease, a mild form of osteogenesis imperfecta, maintained the contours of the vertebrae. Most had straight long bones except for five patients who had mild bowing. Patients who had Type-B disease had bowed long bones with wide cortices. The pelvis had a normal contour. The vertebral bodies were biconcave, and kyphosis and scoliosis developed. Patients who had Type-C disease had thin, bowed long bones, and protrusio acetabuli developed around the age of ten years. Patients who had Type-D disease had the same findings as those who had Type-C disease, with the additional finding of cystic changes around the knee by the age of five years. The physes closed early, and the cysts disappeared around the age of fifteen. Patients who had Type-C or D disease had development of severe spinal deformities. Patients who had Type-E disease were totally dependent functionally, and spinal deformities developed at a very early age. The long bones appeared to have no cortex. Patients who had Type-F disease had complete disruption of the ribs, which was incompatible with survival. The natural history of scoliosis in the patients who had Type-B, C, D, or E disease was one of progression of the curve. Bracing used in the treatment of scoliosis in one patient who had Type-E disease and five patients who had Type-C disease was unsuccessful. Arthrodesis of the spine prevented progression of the spinal deformities in patients who had Type-A disease, but the results of the operation were variable in the remaining types of the disease.


Evaluation of carbonic anhydrase and paraoxonase inhibition activities and molecular docking studies of highly water-soluble sulfonated phthalocyanines.
The investigation of carbonic anhydrase and paraoxonase enzyme inhibition properties of water-soluble zinc and gallium phthalocyanine complexes ( 1 and 2 ) are reported for the first time. The binding of p-sulfonylphenoxy moieties to the phthalocyanine structure favors excellent solubilities in water, as well as providing an inhibition effect on carbonic anhydrase (CA) I and II isoenzymes and paraoxonase (PON1) enzyme. According to biological activity results, both complexes inhibited hCA I, hCA II, and PON1. Whereas 1 and 2 showed moderate hCA I and hCA II (off-target cytosolic isoforms) inhibitory activity (Ki values of 26.09 µM and 43.11 µM for hCA I and 30.95 µM and 33.19 µM for hCA II, respectively), they exhibited strong PON1 (associated with high-density lipoprotein [HDL]) inhibitory activity (Ki values of 0.37 µM and 0.27 µM, respectively). The inhibition kinetics were analyzed by Lineweaver-Burk double reciprocal plots. It revealed that 1 and 2 were noncompetitive inhibitors against PON1, hCA I, and hCA II. These complexes can be more advantageous than other synthetic CA and PON inhibitors due to their water solubility. Docking studies were carried out to examine the interactions between hCA I, hCA II, and PON1 inhibitors and metal complexes at a molecular level and to predict binding energies.


Quantitative and qualitative ST segment monitoring during and after percutaneous transluminal coronary angioplasty.
Patients who undergo elective percutaneous transluminal coronary angioplasty (PTCA) provide a unique human model, with fully defined coronary anatomy and known sites and periods of coronary occlusion. High-resolution, quantitative ST segment monitoring during PTCA procedures allows characterization of the first moments of coronary occlusion, as well as the effect of interventions intended to reduce ischemia during occlusion. Data from more than 1,000 coronary occlusions are reviewed in this presentation. Intracoronary interventions during acute myocardial infarction (MI) and elective PTCA create a potentially unstable coronary nidus through their therapeutic effect. Angiographic evidence of the anatomic appearance remains the "gold standard" for real-time assessment of success although angiography has limited ability to identify the 2-4% of patients who suffer morbidity or mortality in the coronary care unit (CCU) after an apparently successful intervention. Standard CCU monitoring of patient symptoms and rhythms underestimates transient ischemic activity in 87% of patients who experience ischemia after interventions. The capabilities of real-time multilead ST segment monitoring are reviewed from 8,331 hours of monitoring in 338 patients after intracoronary interventions. The documentation of persistent ischemia after angiographically successful PTCA and the clinical potential of qualitative patient-specific, coronary site-specific, precordial "fingerprinting" for identification of high-risk patients before or in the absence of anginal symptoms are discussed.