Mycobacterium avium paratuberculosis and the etiology of Crohn's disease: a review of the controversy from the clinician's perspective.
Mycobacterium avium paratuberculosis (MAP) is an obligate intracellular organism that has frequently been associated with Crohn's disease (CD). Because CD is a chronic inflammatory condition, many researchers have speculated that an infectious agent must be the cause of CD. MAP has often been proposed to be one such agent; however, despite considerable research, the evidence remains inconclusive. Higher levels of MAP have been found in the tissues and blood of CD patients than in controls, forming the foundation for much of the research into the role of MAP in CD and the primary argument in support of a causative role for MAP in CD. MAP is a slow-growing and fastidious organism that is difficult to grow in culture and, therefore, challenging to detect in patients. As a result, there has been variability in the results of studies attempting to detect the presence of MAP in CD patients, and considerable controversy over whether this organism has a causative role in the etiology of CD. Two main hypotheses exist with respect to the role of MAP in CD. The first is that MAP is a principal cause of CD, while the second is that MAP is more prevalent because of the immune dysfunction seen in CD but does not play a causative role. Clinicians are often faced with questions regarding the role of this organism and the need to treat it. The present article attempts to provide an overview of the controversy including the nature of the mycobacterium, the difficulty in detecting it, the use of antimycobacterial agents to treat it and the effect of immunosuppressive agents - all from a clinician's perspective. Although the role of MAP in CD remains controversial and an area of considerable research, it is currently only of academic interest because there is no clinically useful test to identify the presence of the organism, and no evidence to support the use of antibiotics to eradicate it for the treatment of CD.


The global market for ADHD medications.
Little is known about the global use and cost of medications for attention deficit hyperactivity disorder (ADHD). Global use of ADHD medications rose threefold from 1993 through 2003, whereas global spending (2.4 billion US dollars in 2003) rose ninefold, adjusting for inflation. Per capita gross domestic product (GDP) robustly predicted use across countries, but the United States, Canada, and Australia showed significantly higher-than-predicted use. Use and spending grew in both developed and developing countries, but spending growth was concentrated in developed countries, which adopted more costly, long-acting formulations. Promoting optimal prescription and monitoring should be a priority.


Evaluation of an AI system for the automated detection of glaucoma from stereoscopic optic disc photographs: the European Optic Disc Assessment Study.
To evaluate the performance of a deep learning based Artificial Intelligence (AI) software for detection of glaucoma from stereoscopic optic disc photographs, and to compare this performance to the performance of a large cohort of ophthalmologists and optometrists. A retrospective study evaluating the diagnostic performance of an AI software (Pegasus v1.0, Visulytix Ltd., London UK) and comparing it with that of 243 European ophthalmologists and 208 British optometrists, as determined in previous studies, for the detection of glaucomatous optic neuropathy from 94 scanned stereoscopic photographic slides scanned into digital format. Pegasus was able to detect glaucomatous optic neuropathy with an accuracy of 83.4% (95% CI: 77.5-89.2). This is comparable to an average ophthalmologist accuracy of 80.5% (95% CI: 67.2-93.8) and average optometrist accuracy of 80% (95% CI: 67-88) on the same images. In addition, the AI system had an intra-observer agreement (Cohen's Kappa, κ) of 0.74 (95% CI: 0.63-0.85), compared with 0.70 (range: -0.13-1.00; 95% CI: 0.67-0.73) and 0.71 (range: 0.08-1.00) for ophthalmologists and optometrists, respectively. There was no statistically significant difference between the performance of the deep learning system and ophthalmologists or optometrists. The AI system obtained a diagnostic performance and repeatability comparable to that of the ophthalmologists and optometrists. We conclude that deep learning based AI systems, such as Pegasus, demonstrate significant promise in the assisted detection of glaucomatous optic neuropathy.


A qualitative study of experiences with and perceptions regarding long-acting injectable antipsychotics: part II-physician perspectives.
In many countries, including Canada, a small proportion of people with psychotic disorders receive long-acting injectable (LAI) antipsychotics (APs), despite their demonstrated effectiveness and possible advantages for improving adherence rates. Attitudes regarding LAIs among physicians may influence their prescribing practices and thereby contribute to the underuse of LAIs. Here, we report on a qualitative study of perceptions and attitudes toward LAIs among psychiatrists in Canada. Focus groups were conducted with 24 psychiatrists in 4 Canadian provinces. The focus groups inquired about experiences with and attitudes toward LAI APs. The sessions were audiotaped and transcribed verbatim, and transcripts were coded using a hybrid process of deductive and inductive methods. A brief pre-focus group questionnaire was administered. The pre-focus group questionnaires indicated that psychiatrists in our study prescribed the oral formulation of APs most of the time and had limited experience with LAIs. The focus groups yielded 4 main themes: limited knowledge about and experience with LAIs; attitudes toward LAIs (beliefs about negative perceptions of patients regarding LAIs, personal bias against needles, and consensus about some advantages of LAIs); prescribing practices around LAIs (generally seen as a last-resort option for patients with a history of nonadherence); and pragmatic barriers to using LAIs (for example, cost, storage, and staffing). Several factors may be contributing to the underuse of LAIs and the continuing stigmatized and coercive image of LAIs. Psychiatrists may benefit from better education about LAIs, and from self-examination of their attitudes to LAIs and their prescribing practices.


Urkinase: structure of acetate kinase, a member of the ASKHA superfamily of phosphotransferases.
Acetate kinase, an enzyme widely distributed in the Bacteria and Archaea domains, catalyzes the phosphorylation of acetate. We have determined the three-dimensional structure of Methanosarcina thermophila acetate kinase bound to ADP through crystallography. As we previously predicted, acetate kinase contains a core fold that is topologically identical to that of the ADP-binding domains of glycerol kinase, hexokinase, the 70-kDa heat shock cognate (Hsc70), and actin. Numerous charged active-site residues are conserved within acetate kinases, but few are conserved within the phosphotransferase superfamily. The identity of the points of insertion of polypeptide segments into the core fold of the superfamily members indicates that the insertions existed in the common ancestor of the phosphotransferases. Another remarkable shared feature is the unusual, epsilon conformation of the residue that directly precedes a conserved glycine residue (Gly-331 in acetate kinase) that binds the alpha-phosphate of ADP. Structural, biochemical, and geochemical considerations indicate that an acetate kinase may be the ancestral enzyme of the ASKHA (acetate and sugar kinases/Hsc70/actin) superfamily of phosphotransferases.


Molecular characterization of a novel hepatitis E virus (HEV) strain obtained from a wild boar in Japan that is highly divergent from the previously recognized HEV strains.
Although a consensus classification system for hepatitis E virus (HEV) genotypes is currently unavailable, HEV variants (JBOAR135-Shiz09 and wbJOY_06) from wild boars (Sus scrofa leucomystax) have provisionally been classified into two novel genotypes (5 and 6). While performing a survey of HEV infections among 566 wild boars that were captured in Japan between January 2010 and August 2013, we found 24 boars (4.2%) with ongoing HEV infections: 13 had genotype 3 HEV, 10 had genotype 4 HEV and the remaining boar possessed a novel HEV variant (designated wbJNN_13). The entire wbJNN_13 genome comprised 7247 nucleotides excluding the poly(A) tail, and was highly divergent from known genotype 1 to 4 HEV isolates derived from humans, swine, wild boars, deer, mongoose and rabbits by 22.4-28.2%, JBOAR135-Shiz09 and wbJOY_06 by 19.6-21.9% and rat, ferret, bat and avian HEV isolates by 40.9-46.1% over the entire genome. Phylogenetic trees confirmed that wbJNN_13 is distantly related to all known HEV isolates. A Simplot analysis revealed no significant recombination among the existing HEV strains. These results indicate the presence of at least three genetic lineages of presumably boar-indigenous HEV strains. Further studies to fully understand the extent of the genomic heterogeneity of HEV variants infecting wild boars are warranted.


Lipid-Lowering Agents in Older Individuals: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
The efficacy of lipid-lowering agents on patient-important outcomes in older individuals is unclear. We included randomized trials that enrolled individuals aged 65 years or older and that included at least 1 year of follow-up.Pairs of reviewers selected and appraised the trials. We included 23 trials that enrolled 60,194 elderly patients. For primary prevention, statins reduced the risk of coronary artery disease [CAD; relative risk (RR): 0.79, 95% CI: 0.68 to 0.91] and myocardial infarction (MI; RR: 0.45, 95% CI: 0.31 to 0.66) but not all-cause or cardiovascular mortality or stroke. These effects were imprecise in patients with diabetes, but there was no significant interaction between diabetes status and the intervention effect. For secondary prevention, statins reduced all-cause mortality (RR: 0.80, 95% CI: 0.73 to 0.89), cardiovascular mortality (RR: 0.68, 95% CI: 0.58 to 0.79), CAD (RR: 0.68, 95% CI: 0.61 to 0.77), MI (RR: 0.68, 95% CI: 0.59 to 0.79), and revascularization (RR: 0.68, 95% CI: 0.61 to 0.77). Intensive (vs less-intensive) statin therapy reduced the risk of CAD and heart failure. Niacin did not reduce the risk of revascularization, and fibrates did not reduce the risk of stroke, cardiovascular mortality, or CAD. High-certainty evidence supports statin use for secondary prevention in older individuals. Evidence for primary prevention is less certain. Data in older individuals with diabetes are limited; however, no empirical evidence has shown a significant difference based on diabetes status.


Incidence of switching to second-line antiretroviral therapy and associated factors in children with HIV: an international cohort collaboration.
Estimates of incidence of switching to second-line antiretroviral therapy (ART) among children with HIV are necessary to inform the need for paediatric second-line formulations. We aimed to quantify the cumulative incidence of switching to second-line ART among children in an international cohort collaboration. In this international cohort collaboration study, we pooled individual patient-level data for children younger than 18 years who initiated ART (two or more nucleoside reverse-transcriptase inhibitors [NRTI] plus a non-NRTI [NNRTI] or boosted protease inhibitor) between 1993 and 2015 from 12 observational cohort networks in the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. Patients who were reported to be horizontally infected with HIV and those who were enrolled in trials of treatment monitoring, switching, or interruption strategies were excluded. Switch to second-line ART was defined as change of one or more NRTI plus either change in drug class (NNRTI to protease inhibitor or vice versa) or protease inhibitor change, change from single to dual protease inhibitor, or addition of a new drug class. We used cumulative incidence curves to assess time to switching, and multivariable proportional hazards models to explore patient-level and cohort-level factors associated with switching, with death and loss to follow-up as competing risks. At the data cutoff of Sept 16, 2015, 182 747 children with HIV were included in the CIPHER dataset, of whom 93 351 were eligible, with 83 984 (90·0%) from sub-Saharan Africa. At ART initiation, the median patient age was 3·9 years (IQR 1·6-6·9) and 82 885 (88·8%) patients initiated NNRTI-based and 10 466 (11·2%) initiated protease inhibitor-based regimens. Median duration of follow-up after ART initiation was 26 months (IQR 9-52). 3883 (4·2%) patients switched to second-line ART after a median of 35 months (IQR 20-57) of ART. The cumulative incidence of switching at 3 years was 3·1% (95% CI 3·0-3·2), but this estimate varied widely depending on the cohort monitoring strategy, from 6·8% (6·5-7·2) in settings with routine monitoring of CD4 (CD4% or CD4 count) and viral load to 0·8% (0·6-1·0) in settings with clinical only monitoring. In multivariable analyses, patient-level factors associated with an increased likelihood of switching were male sex, older age at ART initiation, and initial NNRTI-based regimen (p<0·0001). Cohort-level factors that increased the likelihood of switching were higher-income country (p=0·0017) and routine or targeted monitoring of CD4 and viral load (p<0·0001), which was associated with a 166% increase in likelihood of switching compared with CD4 only monitoring (subdistributional hazard ratio 2·66, 95% CI 2·22-3·19). Our global paediatric analysis found wide variations in the incidence of switching to second-line ART across monitoring strategies. These findings suggest the scale-up of viral load monitoring would probably increase demand for paediatric second-line ART formulations. International AIDS Society-CIPHER.


CAST: An automated segmentation and tracking tool for the analysis of transcriptional kinetics from single-cell time-lapse recordings.
Fluorescence and bioluminescence time-lapse imaging allows to investigate a vast range of cellular processes at single-cell or even subcellular resolution. In particular, time-lapse imaging can provide uniquely detailed information on the fine kinetics of transcription, as well as on biological oscillations such as the circadian and cell cycles. However, we face a paucity of automated methods to quantify time-lapse imaging data with single-cell precision, notably throughout multiple cell cycles. We developed CAST (Cell Automated Segmentation and Tracking platform) to automatically and robustly detect the position and size of cells or nuclei, quantify the corresponding light signals, while taking into account both cell divisions (lineage tracking) and migration events. We present here how CAST analyzes bioluminescence data from a short-lived transcriptional luciferase reporter. However, our flexible and modular implementation makes it easily adaptable to a wide variety of time-lapse recordings. We exemplify how CAST efficiently quantifies single-cell gene expression over multiple cell cycles using mouse NIH3T3 culture cells with a luminescence expression driven by the Bmal1 promoter, a central gene of the circadian oscillator. We further illustrate how such data can be used to quantify transcriptional bursting in conditions of lengthened circadian period, revealing thereby remarkably similar bursting signature compared to the endogenous circadian condition despite marked period lengthening. In summary, we establish CAST as novel tool for the efficient segmentation, signal quantification, and tracking of time-lapse images from mammalian cell culture.


Effects of sociodemographic characteristics, illness process, and social support on the levels of perceived quality of life in veterans.
Quality of life is a broad, complex, multidimensional concept incorporating psychological, sociopsychological, economic, philosophical, social, cultural, and spiritual dimensions. As accompanying or even constituting the concept of quality life, social support (empathic, informational, instrumental, and reassurance support) has not been studied. This study sought to determine the effects of sociodemographic characteristics, illness process, and type of social support on the quality of life levels of veterans hospitalized in a rehabilitation center. Seventy-nine veterans were involved in the study. None of the sociodemographic characteristics of the veterans correlated with the quality of life of the veterans except housing conditions. The perceived quality of life scores of the veterans who needed psychological help were lower than those of their counterparts (p < 0.01). The quality of life scores of the veterans were not different from those of the average Turkish population, but veterans who had not received any type of social support had lower quality of life scores (3.74 vs. 4.70). Veterans who had empathic, informational, and reassurance social support had higher quality of life scores than did those who did not have these types of social support. Having tangible social support did not change the quality of life scores. Our findings indicate that social support has a greater impact on the perceived quality of life than sociodemographic and medical factors among the veterans.


High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor.
Epidermal growth factor (EGF) receptors contribute to the development of malignant glioma. Here we considered the possible implication of the EGFR ligand epiregulin (EREG) in glioma development in relation to the activity of the unfolded protein response (UPR) sensor IRE1α. We also examined EREG status in several glioblastoma cell lines and in malignant glioma. Expression and biological properties of EREG were analyzed in human glioma cells in vitro and in human tumor xenografts with regard to the presence of ErbB proteins and to the blockade of IRE1α. Inactivation of IRE1α was achieved by using either the dominant-negative strategy or siRNA-mediated knockdown. EREG was secreted in high amounts by U87 cells, which also expressed its cognate EGF receptor (ErbB1). A stimulatory autocrine loop mediated by EREG was evidenced by the decrease in cell proliferation using specific blocking antibodies directed against either ErbB1 (cetuximab) or EREG itself. In comparison, anti-ErbB2 antibodies (trastuzumab) had no significant effect. Inhibition of IRE1α dramatically reduced EREG expression both in cell culture and in human xenograft tumor models. The high-expression rate of EREG in U87 cells was therefore linked to IRE1α, although being modestly affected by chemical inducers of the endoplasmic reticulum stress. In addition, IRE1-mediated production of EREG did not depend on IRE1 RNase domain, as neither the selective dominant-negative invalidation of the RNase activity (IRE1 kinase active) nor the siRNA-mediated knockdown of XBP1 had significant effect on EREG expression. Finally, chemical inhibition of c-Jun N-terminal kinases (JNK) using the SP600125 compound reduced the ability of cells to express EREG, demonstrating a link between the growth factor production and JNK activation under the dependence of IRE1α. EREG may contribute to glioma progression under the control of IRE1α, as exemplified here by the autocrine proliferation loop mediated in U87 cells by the growth factor through ErbB1.


Overview on health research ethics in Egypt and North Africa.
Developing countries, including Egypt and North African countries, need to improve their quality of research by enhancing international cooperation and exchanges of scientific information, as well as competing for obtaining international funds to support research activities. Research must comply with laws and other requirements for research that involves human subjects. The purpose of this article is to overview the status of health research ethics in Egypt and North African countries, with reference to other Middle Eastern countries. The EU and North African Migrants: Health and Health Systems project (EUNAM) has supported the revision of the status of health research ethics in Egypt and North African countries, by holding meetings and discussions to collect information about research ethics committees in Egypt, and revising the structure and guidelines of the committees, as well as reviewing the literature concerning ethics activities in the concerned countries. This overview has revealed that noticeable efforts have been made to regulate research ethics in certain countries in the Middle East. This can be seen in the new regulations, which contain the majority of protections mentioned in the international guidelines related to research ethics. For most of the internationally registered research ethics committees in North African countries, the composition and functionality reflect the international guidelines. There is growing awareness of research ethics in these countries, which extends to teaching efforts to undergraduate and postgraduate medical students.


Implementing developmental screening and referrals: lessons learned from a national project.
To assess the degree to which a national sample of pediatric practices could implement American Academy of Pediatrics (AAP) recommendations for developmental screening and referrals, and to identify factors that contributed to the successes and shortcomings of these efforts. In 2006, the AAP released a policy statement on developmental surveillance and screening that included an algorithm to aid practices in implementation. Simultaneously, the AAP launched a 9-month pilot project in which 17 diverse practices sought to implement the policy statement's recommendations. Quantitative data from chart reviews were used to calculate rates of screening and referral. Qualitative data on practices' implementation efforts were collected through semistructured telephone interviews and inductively analyzed to generate key themes. Nearly all practices selected parent-completed screening instruments. Instrument selection was frequently driven by concerns regarding clinic flow. At the project's conclusion, practices reported screening more than 85% of patients presenting at recommended screening ages. They achieved this by dividing responsibilities among staff and actively monitoring implementation. Despite these efforts, many practices struggled during busy periods and times of staff turnover. Most practices were unable or unwilling to adhere to 3 specific AAP recommendations: to implement a 30-month visit; to administer a screen after surveillance suggested concern; and to submit simultaneous referrals both to medical subspecialists and local early-intervention programs. Overall, practices reported referring only 61% of children with failed screens. Many practices also struggled to track their referrals. Those that did found that many families did not follow through with recommended referrals. A diverse sample of practices successfully implemented developmental screening as recommended by the AAP. Practices were less successful in placing referrals and tracking those referrals. More attention needs to be paid to the referral process, and many practices may require separate implementation systems for screening and referrals.


Metabolism of antiparkinson agent dopazinol by rat liver microsomes.
Metabolism of dopazinol (DZ) by liver microsomes from control and phenobarbital- and 3-methylcholanthrene-treated rats has been investigated. Liver microsomes from control and treated rats metabolized DZ to N-despropyl-DZ (39-53% of total metabolites); 8-hydroxy-DZ, a catechol metabolite (32-39%); and 5- or 6-hydroxy-DZ (12-20%). The last metabolite was identified as its dehydration product 5,6-dehydro-DZ. N-Dealkylation was favored only slightly over catechol formation (ratio = 1.2) by liver microsomes from control and phenobarbital-treated rats, whereas with liver microsomes from 3-methylcholanthrene-treated rats, N-dealkylation predominated (ratio = 1.7). Liver microsomes from control rats metabolized DZ at a rate of 0.86 nmol/nmol cytochrome P-450/min. Pretreatment of rats with phenobarbital or 3-methylcholanthrene stimulated rates of metabolism by 2.4- and 3-fold, respectively. Metabolism of DZ was inhibited by SKF 525-A, methimazole, and thiobenzamide. SKF 525-A completely inhibited metabolism of DZ, while methimazole and thiobenzamide, two alternate substrates of the microsomal flavin-containing monooxygenase (MFMO) inhibited N-dealkylation only. These results indicated that while the cytochrome P-450-dependent monooxygenase is the primary enzyme system in DZ oxidation, the MFMO also catalyzes the N-dealkylation reaction. The catechol metabolite was converted to isomeric O-methylated derivatives in approximately 1:1 ratio by purified catechol-O-methyl transferase or 105,000g liver cytosol. The late eluting isomer was 8-methoxy-DZ.


Age-related impairment of human T lymphocytes' activation: specific differences between CD4(+) and CD8(+) subsets.
The relevance of physiological immune aging is of great interest with respect to determining disorders with pathologic immune function in aging individuals. In recent years, the relevance of changes in peripheral lymphocytes in age-associated neurologic diseases has become more evident. Due to the lack of immunological studies, covering more than one event after mitogenic activation, we envisaged a new concept in the present study, aiming to investigate several events, starting from T cell receptor (TCR) ligation up to T cell proliferation. In addition, we addressed the question whether changes are present in the subsets (CD4, CD8) with aging. Phosphorylation of tyrosine residues declines with increasing age in CD4(+) cells. Fewer levels of CD69 positive cells after 4 h mitogenic activation, altered expression of cytokines (IL2, IFN-gamma and TNF-alpha; 22 h) and lower proliferation (72 h) were determined in aging. Moreover, it could be shown that CD8(+) lymphocytes react more effectively to mitogenic stimulation with reference to CD69 expression and proliferation in both age groups (<35 and >60 years old). These data indicate that T cell activation, mediated by TCR engagement, is significantly impaired in aging and both subsets are affected. However, bypassing the TCR does not fully restore T cell function, indicating that there are more mechanisms involved than impaired signal transduction through TCR only. The results will be discussed in relation to their relevance in neurodegenerative and psychiatric disorders.


Titin-based modulation of active tension and interfilament lattice spacing in skinned rat cardiac muscle.
The effect of titin-based passive tension on Ca2+ sensitivity of active tension and interfilament lattice spacing was studied in skinned rat ventricular trabeculae by measuring the sarcomere length (SL)-dependent change in Ca2+ sensitivity and performing small angle X-ray diffraction studies. To vary passive tension, preparations were treated with trypsin at a low concentration (0.31 mug/ml) for a short period (13 min) at 20 degrees C, that resulted in approximately 40% degradation of the I-band region of titin, with a minimal effect on A-band titin. We found that the effect of trypsin on titin-based passive tension was significantly more pronounced immediately after stretch than at steady state, 30 min after stretch (i.e., trypsin has a greater effect on viscosity than on elasticity of passive cardiac muscle). Ca2+ sensitivity was decreased by trypsin treatment at SL 2.25 microm, but not at SL 1.9 microm, resulting in marked attenuation of the SL-dependent increase in Ca2+ sensitivity. The SL-dependent change in Ca2+ sensitivity was significantly correlated with titin-based passive tension. Small-angle X-ray diffraction experiments revealed that the lattice spacing expands after trypsin treatment, especially at SL 2.25 microm, providing an inverse linear relationship between the lattice spacing and Ca2+ sensitivity. These results support the view that titin-based passive tension promotes actomyosin interaction and that the mechanism includes interfilament lattice spacing modulation.


Astaxanthin protects against early burn-wound progression in rats by attenuating oxidative stress-induced inflammation and mitochondria-related apoptosis.
Burn-wound progression can occur in the initial or peri-burn area after a deep burn injury. The stasis zone has a higher risk of deterioration mediated by multiple factors but is also considered salvageable. Astaxanthin (ATX), which is extracted from some marine organisms, is a natural compound with a strong antioxidant effect that has been reported to attenuate organ injuries caused by traumatic injuries. Hence, we investigated the potential effects of ATX on preventing early burn-wound progression. A classic "comb" burn rat model was established in this study for histological and biological assessments, which revealed that ATX, particularly higher doses, alleviated histological deterioration in the stasis zone. Additionally, we observed dose-dependent improvements in oxidative stress and the release of inflammatory mediators after ATX treatment. Furthermore, ATX dose-dependently attenuated burn-induced apoptosis in the wound areas, and this effect was accompanied by increases in Akt and Bad phosphorylation and a downregulation of cytochrome C and caspase expression. In addition, the administration of Ly 294002 further verified the effect of ATX. In summary, we demonstrated that ATX protected against early burn-wound progression in a rat deep-burn model. This protection might be mediated by the attenuation of oxidative stress-induced inflammation and mitochondria-related apoptosis.


Visit frequency for essential hypertension: observed associations.
Data from the British Department of Health and Social Services Hypertension Care Computing Project were analyzed to study determinants of visit frequency in hypertension management. The 457 patients from five general practices made 7974 visits between 1971 and 1985 resulting in 7391 intervals on which evaluation could be based. The mean interval between visits was 113 days (SD = 110 days) with a median interval of 91 days. Visit interval was influenced by level of blood pressure and length of time in follow-up. For diastolic pressures less than 104 mmHg the mean visit interval was 4 months, contrasting with 2 months for diastolic pressures greater than 130 mmHg. Visit intervals became longer with increasing length of time in follow-up, independent of level of blood pressure. Shorter intervals reflected initial management and getting the blood pressure reduced; longer intervals may reflect patients' failure to keep scheduled appointments. Between practices, mean visit intervals ranged from 99 to 193 days (median 72 to 164 days). These differences were reduced after adjustment for length of time the patients had been in follow-up. Patient age, sex, body mass index, and the presence of angina pectoris were not associated with visit interval. The analyses illustrate how process and outcome may be linked in ambulatory care practice as a means of determining rational guidelines for optimal utilization of health services.


Differential impact of combined antiretroviral therapy on the survival of italian patients with specific AIDS-defining illnesses.
A decrease in HIV-related mortality and morbidity has been observed since 1996 in most developed countries as a consequence of the extensive use of combined antiretroviral therapies. The purpose of this study was to investigate whether combined antiretroviral therapies had a differential impact on the survival of patients with different AIDS-defining illnesses (ADIs). In total, 35,318 persons representing all the adults with AIDS (PWAs) diagnosed in Italy from January 1, 1990 to August 31, 1998 were studied. Actuarial life tables and the Kaplan-Meier method were used to estimate the cumulative probability of survival; the multivariate Cox proportional hazards model was used to estimate adjusted relative hazard of death (RH). Among PWAs diagnosed after 1995, the proportion of survivors 24 months after diagnosis was more than doubled (66%) compared with that of PWAs diagnosed before the end of 1995 (31%). Significantly decreased RHs for some ADIs were observed as early as 1996 (i.e., esophageal candidiasis, Pneumocystis carinii pneumonia, brain toxoplasmosis, HIV-wasting syndrome, and pulmonary tuberculosis). In the last period (1997-1998), the decrease was marked and significant for almost all the ADIs, ranging from 55% to 80% compared with the RHs of the reference year (1995). Conversely, primary lymphoma of the brain and Burkitt's lymphoma showed a low and not statistically significant decrease; these were the ADIs with the worst outcome. After 1995, there was a rather uniform increase in the survival of PWAs diagnosed with most specific ADIs but not for patients affected by primary brain lymphoma and Burkitt's lymphoma. The determinants of this differential effect need to be investigated.


Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas.
E-Cadherin, a cell adhesion molecule, which plays a key role in maintaining the epithelial phenotype, is regarded as an invasion-suppressor gene in light of accumulating evidence from in vitro experiments and clinical observations. In an attempt to clarify the mechanism responsible for inactivation of this gene in carcinomas, we investigated the methylation state around the promoter region by digestion of DNA with the methylation-sensitive restriction enzyme Hpa II, as CpG methylation of the promoter has been postulated to be a mechanism of transcriptional inactivation of some genes. We found that E-cadherin expression-negative carcinoma cell lines were accompanied by the hypermethylation state, whereas E-cadherin-positive cell lines were not. Furthermore, treatment of E-cadherin-negative carcinoma cells with the demethylating agent 5-azacytidine resulted in reexpression of the gene and reversion of scattered spindle-shaped cells to cells with epithelial morphology. These results suggest that hypermethylation around the promoter may be a mechanism of E-cadherin inactivation in human carcinomas and that treatment of E-cadherin-inactivated cells with a demethylating agent may cause gene expression reversion leading to epithelial morphogenesis with acquisition of the homophilic cell-cell adhesive property.


Transformation by a nucleotide-activated P2Y receptor is mediated by activation of Galphai, Galphaq and Rho-dependent signaling pathways.
Nucleotide-actived P2Y receptors play critical roles in the growth of tumor cells by regulating cellular proliferation, differentiation and survival. Here we demonstrate that an avian P2Y purinoceptor (tP2YR) with unique pharmacological and signal transduction properties induces morphologic and growth transformation of rodent fibroblasts. tP2YR induced a transformed phenotype similar to the mas oncogene, a G protein-coupled receptor which causes transformation by activation of Rac-dependent pathways. tP2YR-transformed cells exhibited increased steady-state activation of Rac1 and RhoA. Like activated Rho GTPases, tP2YR cooperated with activated Raf and caused synergistic transformation of NIH3T3 cells. Our data indicate that the ability of tP2YR to cause transformation is due to its unique ability among purinergic receptors to simultaneously activate Galphaq and Galphai. Co-expression of constitutively activated mutants of these two Galpha subunits caused the same transformed phenotype as tP2YR and Mas. Furthermore, transformation by both tP2YR and Mas was blocked by pharmacological inhibition of GalphaI by pertussis toxin (PTX) indicating an essential role for Galphai in transformation by these G-protein coupled receptors. Our data suggest that coordinated activation of Galphaq and Galphai may link the tP2YR and possibility the Mas oncogene with signaling pathways resulting in activation of Rho family proteins to promote cellular transformation.


Twelfth International Foamy Virus Conference-Meeting Report.
The 12th International Foamy Virus Conference took place on August 30⁻31, 2018 at the Technische Universität Dresden, Dresden, Germany. The meeting included presentations on current research on non-human primate and non-primate foamy viruses (FVs; also called spumaretroviruses) as well as keynote talks on related research areas in retroviruses. The taxonomy of foamy viruses was updated earlier this year to create five new genera in the subfamily, Spumaretrovirinae, based on their animal hosts. Research on viruses from different genera was presented on topics of potential relevance to human health, such as natural infections and cross-species transmission, replication, and viral-host interactions in particular with the immune system, dual retrovirus infections, virus structure and biology, and viral vectors for gene therapy. This article provides an overview of the current state-of-the-field, summarizes the meeting highlights, and presents some important questions that need to be addressed in the future.


Ultrasonic hearing in humans: applications for tinnitus treatment.
Masking of tinnitus is possible using high audio frequencies and low-frequency ultrasound. The mechanisms involved in reception and perception of both audio frequencies and ultrasound are identical, with the exception that ultrasound interacts with an intermediary site, the brain. We proposed brain ultrasonic demodulation as the means of place-mapping ultrasound on the first few millimeters of the basilar membrane. We present modeling and psychoacoustic data in support of this theory.


Autonomy of differentiation in avian branchial somites and the influence of adjacent tissues.
This study investigates the differentiative abilities of avian brachial somites at stages of development before, during and after the migration of somitic cells into the wing primordium. These somites are the source of cells that migrate into the forelimbs and there give rise exclusively, and totally, to the skeletal muscle lineage of the wing and yet show no morphological evidence of commitment to that fate when they leave the somites. The aim of the study was to see if the brachial somitic cells are committed to particular developmental pathways at these stages. The brachial somites were isolated from HH stage-12, -15 and -18 chick embryos, either by microdissection or enzymatic dissociation, and grown in organ culture, in explant culture on different substrata or on the chorioallantoic membrane (CAM) of host chicks, either alone or in combination with adjacent tissues. Myogenesis and chondrogenesis occurred in all stage-18 enzymatically separated somites, regardless of the growth environment. Myogenesis was reduced in stage-15 somites and unobservable in stage-12 somites; however, recombination of stage-12 somites with epithelium or neural tube increased the incidence of myogenesis at this stage. The incidence of chondrogenesis was also less in the younger explants. Unlike its effect on myogenic expression, recombination with epithelium resulted in a dramatic decrease in chondrogenesis in both stage-12 and -15 somites. The recombination experiments suggest that conditions that maintain the normal spatial relationships within isolated somites permit expression of a preexisting specification to a particular fate. They also show that the overlying epithelium can inhibit chondrogenesis in these somites. Overall, the results suggest that by the time migration of somitic cells into wing regions is finishing, brachial somitic cells have become stabilized in their ability to undergo both myogenesis and chondrogenesis for they will do so under a variety of growth conditions and independently of adjacent tissues. However, immediately before (stage 12) and shortly after (stage 15) the onset of migration, both myogenic and chondrogenic expression by brachial somitic cells are still under the influence of interactions with adjacent tissues.


TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis.
Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.


Three-year outcomes of vaginal mesh for prolapse: a randomized controlled trial.
To present the 3-year outcomes of a double-blind, multicenter, randomized trial comparing vaginal prolapse repair with and without mesh. This was a planned final analysis of women with Pelvic Organ Prolapse Quantification (POP-Q) stage 2-4 prolapse randomized to traditional vaginal prolapse surgery without mesh and vaginal colpopexy repair with mesh. We evaluated anatomic, symptomatic, and combined cure rates for those with at least 3-year validated quality-of-life questionnaires and 2- or 3-year postoperative blinded POP-Q examination. Participants undergoing reoperation for recurrent prolapse were removed for anatomic and subjective outcomes analysis and considered failures for combined outcomes analysis. Sixty-five women were enrolled (33 mesh, 32 no mesh) before the study was prematurely halted as a result of a 15.6% mesh exposure rate. At 3 years, 51 of 65 (78%) had quality-of-life questionnaires (25 mesh, 26 no mesh) and 41 (63%) had examinations. Three participants died, three required reoperation for recurrent prolapse (all in mesh group), and eight were lost to follow-up. No differences were observed between groups at 3 years for prolapse stage or individual prolapse points. Stage improved for each group (90% and 86%) from baseline to 3 years (P<.01). Symptomatic improvement was observed with no differences in scores between groups. Cure rates did not differ between groups using a variety of definitions, and anatomic cure was lowest for the anterior compartment. There was no difference in 3-year cure rates when comparing patients undergoing traditional vaginal prolapse surgery without mesh with those undergoing vaginal colpopexy repair with mesh. Clinicaltrials.gov, www.clinicaltrials.gov, NCT00475540. : I.


AR2, a novel automatic muscle artifact reduction software method for ictal EEG interpretation: Validation and comparison of performance with commercially available software.
Objective: To develop a novel software method (AR2) for reducing muscle contamination of ictal scalp electroencephalogram (EEG), and validate this method on the basis of its performance in comparison to a commercially available software method (AR1) to accurately depict seizure-onset location. Methods: A blinded investigation used 23 EEG recordings of seizures from 8 patients. Each recording was uninterpretable with digital filtering because of muscle artifact and processed using AR1 and AR2 and reviewed by 26 EEG specialists. EEG readers assessed seizure-onset time, lateralization, and region, and specified confidence for each determination. The two methods were validated on the basis of the number of readers able to render assignments, confidence, the intra-class correlation (ICC), and agreement with other clinical findings. Results: Among the 23 seizures, two-thirds of the readers were able to delineate seizure-onset time in 10 of 23 using AR1, and 15 of 23 using AR2 (p<0.01). Fewer readers could lateralize seizure-onset (p<0.05). The confidence measures of the assignments were low (probable-unlikely), but increased using AR2 (p<0.05). The ICC for identifying the time of seizure-onset was 0.15 (95% confidence interval (CI), 0.11-0.18) using AR1 and 0.26 (95% CI 0.21-0.30) using AR2. The EEG interpretations were often consistent with behavioral, neurophysiological, and neuro-radiological findings, with left sided assignments correct in 95.9% (CI 85.7-98.9%, n=4) of cases using AR2, and 91.9% (77.0-97.5%) (n=4) of cases using AR1. Conclusions: EEG artifact reduction methods for localizing seizure-onset does not result in high rates of interpretability, reader confidence, and inter-reader agreement. However, the assignments by groups of readers are often congruent with other clinical data. Utilization of the AR2 software method may improve the validity of ictal EEG artifact reduction.


Johne's disease in the eyes of Irish cattle farmers: A qualitative narrative research approach to understanding implications for disease management.
Bovine Johne's Disease (JD) is a disease characterised by chronic granulomatous enteritis which manifests clinically as a protein-losing enteropathy causing diarrhoea, hypoproteinaemia, emaciation and, eventually death. Some research exists to suggest that the aetiologic pathogen Mycobacterium avium subspecies paratuberculosis may pose a zoonotic risk. Nationally coordinated control programmes have been introduced in many of the major milk producing countries across the world. However, JD is challenging to control in infected herds owing to limitations of diagnostic tests and the long incubation period of the disease. Internationally, research increasingly recognises that improved understanding of farmers' subjective views and behaviours may inform and enhance disease management strategies and support the identification and implementation of best practice at farm level. The aim of this study was to use qualitative research methods to explore the values and knowledges of farmers relative to the control of JD at farm level. The Biographical Narrative Interpretive Method (BNIM) was used to generate data from both infected and presumed uninfected farms in Ireland. Qualitative analysis revealed that cultural and social capital informed farmers' decisions on whether to introduce control and preventive measures. Cultural capital refers to the pride and esteem farmers associate with particular objects and actions whereas social capital is the value that farmers associate with social relationships with others. On-farm controls were often evaluated by farmers as impractical and were frequently at odds with farmers' knowledge of calf management. Knowledge from farmers of infected herds did not disseminate among peer farmers. Owners of herds believed to be uninfected expressed a view that controls and preventive measures were not worthy of adoption until there was clear evidence of JD in the herd. These findings highlight important barriers and potential aids to prevention and control in both infected and uninfected herds.


Association of Optimal Combination Drug Treatment with Obesity Status among Recent Ischemic Stroke Patients: Results of the Vitamin Intervention for Stroke Prevention (VISP) Trial.
One explanation for the 'obesity paradox', where obese patients seem to have better cardiovascular outcomes than lean patients, is that obese patients display an identifiable high cardiovascular risk phenotype that may lead to receiving or seeking earlier/more aggressive treatment. We analyzed a clinical trial dataset comprising 3643 recent (<120 days) ischemic stroke patients followed up for 2 years. Subjects were categorized as lean (body mass index [BMI], <25 kg/m2, n=1,006), overweight (25-29.9 kg/m2, n=1,493), or obese (≥30 kg/m2, n=1,144). Subjects were classified as level 0 to III depending on the number of secondary prevention prescriptions divided by the number of potentially indicated drugs (0=none of the indicated medications and III=all indicated medications as optimal combination drug treatment [OCT]). Independent associations between each BMI category and stroke/myocardial infarction/vascular death (major vascular events [MVEs]) and all-cause death were assessed. MVEs occurred in 17.4% of lean, 16.1% of overweight, and 17.1% of obese patients; death occurred in 7.3%, 5.5%, and 5.1%, respectively. Individuals with a higher BMI status received more OCT (45.8%, 51.7%, and 55.3%, respectively; P<0.001). In the lean patient group, multivariable adjusted Cox analyses, showed that compared with levels 0-I, level II and level III were linked to lower risk of MVEs (hazard ratio [HR] 0.55; 95% confidence interval [CI]: 0.32-0.95 and HR 0.48; 95% CI: 0.28-0.83, respectively) and death (0.44; 0.21-0.96 and 0.23; 0.10-0.54, respectively). OCT for secondary prevention after an ischemic stroke is less frequent in lean (vs. obese) subjects, but when implemented is related to significantly better clinical outcomes.


Kapalabhati--yogic cleansing exercise. I. Cardiovascular and respiratory changes.
We studied cardiovascular and respiratory changes during yogic breathing exercise kapalabhati (KB) in 17 advanced yoga practitioners. The exercise consisted in fast shallow abdominal respiratory movements at about 2 Hz frequency. Blood pressure, ECG and respiration were recorded continuously during three 5 min periods of KB and during pre- and post-KB resting periods. The beat-to-beat series of systolic blood pressure (SBP) and diastolic blood pressure (DBP), R-R intervals and respiration were analysed by spectral analysis of time series. The mean absolute power was calculated in three frequency bands--band of spontaneous respiration, band of 0.1 Hz rhythm and the low-frequency band greater than 15 s in all spectra. The mean modulus calculated between SBP and R-R intervals was used as a parameter of baroreceptor-cardiac reflex sensitivity (BRS). Heart rate increased by 9 beats per min during KB. SBP and DBP increased during KB by 15 and 6 mmHg respectively. All frequency bands of R-R interval variability were reduced in KB. Also the BRS parameter was reduced in KB. The amplitude of the high-frequency oscillations in SBP and DBP increased during KB. The low-frequency blood pressure oscillations were increased after KB. The results point to decreased cardiac vagal tone during KB which was due to changes in respiratory pattern and due to decreased sensitivity of arterial baroreflex. Decreased respiratory rate and increased SBP and low-frequency blood pressure oscillations after KB suggest a differentiated pattern of vegetative activation and inhibition associated with KB exercise.


Birthweight, vitamin D receptor genotype and the programming of osteoporosis.
Studies of the association between polymorphisms of the gene for the vitamin D receptor (VDR) and adult bone mass have been inconsistent, pointing to the possibility that gene--environment interactions may vary in different populations. We have demonstrated previously an association between weight in infancy (a marker of the intrauterine and early post-natal environment) and each of adult bone mass and VDR genotype. We therefore sought to extend these observations in an elderly UK cohort and to investigate the possibility of an interaction between these genetic and early environmental markers of later osteoporosis risk. One hundred and sixty-five men and 126 women aged 61--73 years for whom birth records were available underwent bone mass measurements at baseline and follow-up 4 years later. Whole-blood samples were obtained, DNA extracted using standard techniques and polymorphisms in the VDR and collagen type I alpha 1 (Col IA1) genes identified. In the cohort as a whole, there were no significant associations between either birthweight or VDR genotype and bone mineral density (BMD) or bone loss rate at either site. However, the relationship between lumbar spine BMD and VDR genotype varied according to birthweight. Among individuals in the lowest third of birthweight, spine BMD was higher (P = 0.01) in individuals of genotype 'BB' after adjustment for age, sex and weight at baseline. In contrast, spine BMD was reduced (P = 0.04) in individuals of the same genotype who were in the highest third of the birthweight distribution. A significant (P = 0.02) statistical interaction was also found between VDR genotype and birthweight as determinants of BMD. Similar but slightly weaker associations were seen between lumbar spine bone mineral content (BMC) and VDR genotype in the lowest birthweight tertile. When examining the relationship between Col1A1 genotype and bone mass, lumbar spine BMC was higher in individuals of genotype 'Ss' or 'ss' in the lowest birthweight tertile (P = 0.02) after adjustment for age, sex and weight at baseline. These results suggest that genetic influences on adult bone size and mineral density may be modified by undernutrition in utero.


Program- and service-level costs of seven screening, brief intervention, and referral to treatment programs.
This paper examines the costs of delivering screening, brief intervention, and referral to treatment (SBIRT) services within the first seven demonstration programs funded by the US Substance Abuse and Mental Health Services Administration. Service-level costs were estimated and compared across implementation model (contracted specialist, inhouse specialist, inhouse generalist) and service delivery setting (emergency department, hospital inpatient, outpatient). Program-level costs were estimated and compared across grantee recipient programs. Service-level data were collected through timed observations of SBIRT service delivery. Program-level data were collected during key informant interviews using structured cost interview guides. At the service level, support activities that occur before or after engaging the patient comprise a considerable portion of the cost of delivering SBIRT services, especially short duration services. At the program level, average costs decreased as more patients were screened. Comparing across program and service levels, the average annual operating costs calculated at the program level often exceeded the cost of actual service delivery. Provider time spent in support of service provision may comprise a large share of the costs in some cases because of potentially substantial fixed and quasifixed costs associated with program operation. The cost structure of screening, brief intervention, and referral to treatment is complex and discontinuous of patient flow, causing annual operating costs to exceed the costs of actual service provision for some settings and implementation models.


The effects of Ca(2+) binding on the conformation of calbindin D(28K): a nuclear magnetic resonance and microelectrospray mass spectrometry study.
Calbindin D(28K) is a six-EF-hand calcium-binding protein found in the brain, peripheral nervous system, kidney, and intestine. There is a paucity of information on the effects of calcium binding on calbindin D(28K) structure. To further examine the mechanism and structural consequences of calcium binding to calbindin D(28K) we performed detailed complementary heteronuclear NMR and microelectrospray mass spectrometry investigations of the calcium-induced conformational changes of calbindin D(28K). The combined use of these two powerful analytical techniques clearly and very rapidly demonstrates the following: (i). apo-calbindin D(28K) has an ordered structure which changes to a notably different ordered conformation upon Ca(2+) loading, (ii). calcium binding is a sequential process and not a simultaneous event, and (iii). EF-hands 1, 3, 4, and 5 take up Ca(2+), whereas EF-hands 2 and 6 do not. Our results support the opinion that calbindin D(28K) has characteristics of both a calcium sensor and a buffer.


Experimental study of three-wave interactions among capillary-gravity surface waves.
In propagating wave systems, three- or four-wave resonant interactions constitute a classical nonlinear mechanism exchanging energy between the different scales. Here we investigate three-wave interactions for gravity-capillary surface waves in a closed laboratory tank. We generate two crossing wave trains and we study their interaction. Using two optical methods, a local one (laser doppler vibrometry) and a spatiotemporal one (diffusive light photography), a third wave of smaller amplitude is detected, verifying the three-wave resonance conditions in frequency and in wave number. Furthermore, by focusing on the stationary regime and by taking into account viscous dissipation, we directly estimate the growth rate of the resonant mode. The latter is then compared to the predictions of the weakly nonlinear triadic resonance interaction theory. The obtained results confirm qualitatively and extend previous experimental results obtained only for collinear wave trains. Finally, we discuss the relevance of three-wave interaction mechanisms in recent experiments studying gravity-capillary turbulence.


Comparison of myocardial performance index and right ventricular myocardial acceleration during isovolumic contraction in detection of right ventricular dysfunction in obese patients.
Although obesity is a risk factor for heart failure, studies analyzing the effect of obesity on heart functions have primarily examined the left side of the heart. This study is an analysis of the effect of the severity of obesity on right heart functions and a comparison of the sensitivity and specificity of different echocardiographic modalities in the detection of right heart dysfunction. A total of 116 subjects were included and divided into 4 age- and sex-matched groups according to body mass index (BMI) values. Right heart functions were evaluated with transthoracic echocardiography. The right atrium (RA) diameter was significantly larger in the obese group (OBG) and the morbidly obese group (MOG); the right ventricle (RV) diameter was significantly larger only in the MOG. In the overweight group, the OBG, and the MOG, the RV isovolumic acceleration (R-IVA) was significantly lower (p=0.020; p<0.001; p<0.001, respectively) and the myocardial performance index (MPI) value was significantly higher (p=0.015; p<0.001; p<0.001, respectively). There was a strong positive correlation between the MPI and the BMI (r=0.833, p<0.001), and a moderate negative correlation between the R-IVA and the BMI (r=-0.547, p<0.001). A cut-off value of 30.45 kg/m2 was associated with 93.3% sensitivity and 94.3% specificity in the prediction of RV systolic dysfunction defined by the MPI. A cut-off value of 30.50 kg/m2 was associated with 76.7% sensitivity and 72.3% specificity in the prediction of RV systolic dysfunction defined by the R-IVA. Obesity significantly affected right heart function and there was a significant correlation between the degree of obesity and right heart functional deterioration. The BMI could be used to predict RV systolic dysfunction.


Characterization of sorbent properties of soil organic matter and carbonaceous geosorbents using n-alkanes and cycloalkanes as molecular probes.
Nonspecific interactions and modes (i.e., adsorption vs absorption) of sorption by noncondensed, amorphous organic phases (here termed organic matter; OM) in soils and by rigid, aromatic, and condensed phases (termed carbonaceous geosorbents; CGs) were investigated using n-alkanes and cycloalkanes as molecular probes. Sorption isotherms of n- and cyclooctane from water for seven CGs (charcoal, lignite coke, activated carbon, graphite, partially oxidized graphite, diesel soot, bituminous coal), four sorbents with a predominance of OM (lignite, peat, two sapric soils), and two soils containing OM and high amounts of CGs were measured in batch systems. The peat and the sapric soils showed extensively linear sorption, while the CGs exhibited highly nonlinear (Freundlich exponents 0.2-0.7) and strong (Koc values being up to 10(5) times those for the OM-rich materials at low concentrations) sorption for the alkanes studied, showing that enhanced sorption by CGs can occur to completely apolar sorbates that do not undergo any specific interaction. Sorption by CGs was generally stronger and more nonlinear for n-octane than for cyclooctane, which suggests a strong dependence of sorption on the 3-D structure of sorbate molecules. The n-octane-to-cyclooctane sorption coefficient ratios (Kn/Kc) for adsorption to CGs were > or = 1, being distinctly different from those for absorption to the OM-rich materials (Kn/Kc < 1). The measured sorption isotherms and the CG compositions in the soils determined by quantitative petrography analysis suggest, however, that CGs occurring in soils may be far less effective sorbents than the reference CGs used in the sorption experiments at least for nonspecifically interacting sorbates, probably because of competitive sorption and/or pore blocking by natural OM. The presented approaches and results offer a basis for interpreting sorption data for other organic compounds, as nonspecific interactions and sorption modes are relevant for any compound.


THE IMPACT OF WARM-UP ON YOUTH GOLFER CLUBHEAD SPEED AND SELF-REPORTED SHOT QUALITY.
Physical preparation in golf is now considered a key component of the game. With players becoming more athletic, warm-up has become an important area in a player's preparation for practice and competition. Much of the research to date has focused on the adult golfer, showing potential for improvements in clubhead speed, driving distance and shot quality, as well as reductions in injury risk. However, there is currently no work specifically investigating the impacts of warm-up in youth golf. The aim of this study was to examine the impact of a club only warm-up and a dynamic exercise routine followed by a club warm-up on club head speed and self-reported shot quality. Using a counterbalanced repeated measures design, eight male and 13 female youth golfers completed a control (no warm-up), club only warm-up and an exercise based dynamic warm-up followed by club warm-up on three non-consecutive days. In each session, players were required to hit 10 maximal effort shots with a driver and clubhead speed (CHS) was recorded using a launch monitor alongside self-reported shot quality scores. Statistically significant improvements in clubhead speed and self-reported shot quality were seen in the dynamic warm-up combined with club warm-up. No significant differences were seen in the club-warm up only or control groups for either clubhead speed or self-reported shot quality. A combined dynamic physical warm-up and club warm-up improves clubhead speed and self-reported shot quality in youth golfers. However, a club warm-up alone does not seem to be sufficient in eliciting these same improvements. 3.


The influence of interspecific interactions on species range expansion rates.
Ongoing and predicted global change makes understanding and predicting species' range shifts an urgent scientific priority. Here, we provide a synthetic perspective on the so far poorly understood effects of interspecific interactions on range expansion rates. We present theoretical foundations for how interspecific interactions may modulate range expansion rates, consider examples from empirical studies of biological invasions and natural range expansions as well as process-based simulations, and discuss how interspecific interactions can be more broadly represented in process-based, spatiotemporally explicit range forecasts. Theory tells us that interspecific interactions affect expansion rates via alteration of local population growth rates and spatial displacement rates, but also via effects on other demographic parameters. The best empirical evidence for interspecific effects on expansion rates comes from studies of biological invasions. Notably, invasion studies indicate that competitive dominance and release from specialized enemies can enhance expansion rates. Studies of natural range expansions especially point to the potential for competition from resident species to reduce expansion rates. Overall, it is clear that interspecific interactions may have important consequences for range dynamics, but also that their effects have received too little attention to robustly generalize on their importance. We then discuss how interspecific interactions effects can be more widely incorporated in dynamic modeling of range expansions. Importantly, models must describe spatiotemporal variation in both local population dynamics and dispersal. Finally, we derive the following guidelines for when it is particularly important to explicitly represent interspecific interactions in dynamic range expansion forecasts: if most interacting species show correlated spatial or temporal trends in their effects on the target species, if the number of interacting species is low, and if the abundance of one or more strongly interacting species is not closely linked to the abundance of the target species.


Contribution of Neurotrophins to the Immune System Regulation and Possible Connection to Alcohol Addiction.
The first references to neurotrophic factors date back to the middle of the 20th century when the nerve growth factor (NGF) was first discovered. Later studies delivered a large amount of data on neurotrophic factors. However, many questions regarding neurotrophin signaling still remain unanswered. One of the principal topics in neurotrophin research is their role in the immune system regulation. Another important research question is the possible involvement of neurotrophin signaling in the pathological processes associated with alcoholism. Among known neurotrophins, NT-4 remains the least studied and appears to be involved in alcoholism and chronic stress pathogenesis. In this review we discuss known neurotrophin signaling cascades mediated by different neurotrophin receptors, as well as provide a generalization of the data regarding the influence of neurotrophins NGF, BDNF, and NT-4 on the immune system and their potential contribution to the pathogenesis of alcoholism.


Impact of receiving recorded mental health recovery narratives on quality of life in people experiencing psychosis, people experiencing other mental health problems and for informal carers: Narrative Experiences Online (NEON) study protocol for three randomised controlled trials.
Mental health recovery narratives have been defined as first-person lived experience accounts of recovery from mental health problems which refer to events or actions over a period of time and which include elements of adversity or struggle, and also self-defined strengths, successes or survival. They are readily available in invariant recorded form, including text, audio or video. Previous studies have provided evidence that receiving recorded recovery narratives can provide benefits to recipients. This protocol describes three pragmatic trials that will be conducted by the Narrative Experiences Online (NEON) study using the NEON Intervention, a web application that delivers recorded recovery narratives to its users. The aim of the NEON Trial is to understand whether receiving online recorded recovery narratives through the NEON Intervention benefits people with experience of psychosis. The aim of the NEON-O and NEON-C trials is to evaluate the feasibility of conducting a definitive trial on the use of the NEON Intervention with people experiencing non-psychosis mental health problems and those who care for others experiencing mental health problems respectively. The NEON Trial will recruit 683 participants with experience of psychosis. The NEON-O Trial will recruit at least 100 participants with experience of non-psychosis mental health problems. The NEON-C Trial will recruit at least 100 participants with experience of caring for others who have experienced mental health problems. In all three trials, participants will be randomly allocated into one of two arms. Intervention arm participants will receive treatment as usual plus immediate access to the NEON Intervention for 1 year. Control arm participants will receive treatment as usual plus access to the NEON Intervention after 1 year. All participants will complete demographics and outcome measures at baseline, 1 week, 12 weeks and 52 weeks. For the NEON Trial, the primary outcome measure is the Manchester Short Assessment of Quality of Life at 52 weeks, and secondary outcome measures are the CORE-10, Herth Hope Index, Mental Health Confidence Scale and Meaning in Life Questionnaire. A cost-effectiveness analysis will be conducted using data collected through the EQ-5D-5 L and the Client Service Receipt Inventory. NEON Trial analyses will establish both effectiveness and cost-effectiveness of the NEON Intervention for people with experience of psychosis, and hence inform future clinical recommendations for this population. All trials were prospectively registered with ISRCTN. NEON Trial: ISRCTN11152837 . Registered on 13 August 2018. NEON-C Trial: ISRCTN76355273 . Registered on 9 January 2020. NEON-O Trial: ISRCTN63197153 . Registered on 9 January 2020.


Low income, race, and the use of mammography.
To describe national trends in mammography use by race and income and to test whether higher use of mammography among low-income African American women than low-income white women can be explained by health insurance coverage, usual place of health care, or place of residence. Data from five years of the National Health Interview Survey spanning the period 1987-1994. Trends in the percentage of women 50-64 years of age with a mammogram within the past two years were analyzed by race and income. Data for 1993-1994 were pooled, and with logistic regression analysis, variation in use of recent mammography for low-income women was investigated. Independent variables are age, race, family income, education, health insurance coverage, place of usual source of health care, metropolitan residence, and geographic region. The National Health Interview Survey is a cross-sectional national survey conducted by the National Center for Health Statistics. Data are collected through household interviews. [Editor's note: in keeping with HSR policy, the term black is used to conform to its use in the surveys studied. In other references to race, the term African American is used.] Among women 50-64 years of age use of recent mammograms increased rapidly between 1987 and 1991 for all groups of women, and between 1991 and 1994 the increases slowed. However, increases between 1991 and 1994 have been more rapid among low-income black women than among low-income white women. In 1993-1994, low-income black women were about one-third more likely than low-income white women to report mammography within the past two years. This difference could not be explained by health insurance coverage, usual source of health care, metropolitan status, or region of residence. These results, which provide some evidence of success for screening programs targeted to the poor, raise the question of why low-income black women appear to be to more likely than low-income white women to have benefited from recent efforts to promote mammography. Continued evaluation of mammography programs focused on women who are underserved as well as the monitoring of trends and variations in service use by race and income are needed.


Snoring management with nasal surgery and upper airway radiofrequency ablation.
To review techniques and outcomes of nasal surgery with upper airway radiofrequency ablation (RFA) when used for socially disruptive snoring, including the rate of infection with reused RFA applicator tips. Case series with chart review. Community-based sleep-disordered breathing clinic. A prospectively acquired sleep quality assurance database was reviewed to determine demographics, complications, snoring outcomes, level of daytime sleepiness, and sleep-related quality of life in patients with socially disruptive snoring treated with nasal surgery and upper airway RFA. One hundred thirty patients (48 women; 82 men) with a mean age of 50 years (range, 24-83 years) underwent nasal surgery and upper airway RFA for the treatment of chronic nasal blockage with socially disruptive snoring. All patients underwent septoplasty with or without inferior turbinate reduction and RFA to the soft palate and/or base of tongue. Patients received a mean of 2.2 (range, 1-4) applications of upper airway RFA during the course of treatment. No infections occurred with reuse of applicator tips. Fifty-four bed partners (42%) reported complete snoring resolution, whereas 68 (52%) reported residual snoring that was improved. Snoring resolution was more common in patients who underwent repeated applications of upper airway RFA (odds ratio 2.39; 95% confidence interval, 1.09-5.26). Nasal surgery combined with upper airway RFA improved snoring with few complications in this series of patients with anatomic nasal obstruction with socially disruptive snoring. Reuse of RFA applicator tips at palatal sites reduces cost without an observed increase in the risk of upper airway infection.


Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man.
The present study was undertaken to define the source of endogenous triiodothyronine (T3) production responsible for maintaining serum T3 levels in euthyroid subjects with depressed serum thyroxine (T4) values. After withdrawal from 4 wk of exogenous T3 administration, a 22% decline in serum T3 values (from 129 +/- 6 to 99 +/- 4 ng/dl) was observed in six euthyroid subjects, despite a twofold reduction in serum T4 concentrations (from 7.5 +/- 0.5 to 3.2 +/- 0.5 micrograms/dl). This was accompanied by a nearly twofold increase in serum T3/T4 ratio values (17 +/- 1 to 29 +/- 6) but no significant alteration in reverse T3/T4 ratio values. This phenomenon did not appear to be thyroid stimulating hormone (TSH) dependent, since base-line serum TSH values were subnormal. Nor was it dependent on changes in thyroid gland function, since a blunted T3 response to exogenous bovine TSH occurred and pharmacologic doses of iodide did not influence the phenomenon. The finding in three athyreotic subjects that serum T3/T4 ratio values increased from 14 +/- 1 on T4 therapy (mean serum T4, 9.6 +/- 0.8 micrograms/dl and T3, 132 +/- 8 ng/dl) to 40 +/- 2 after withdrawal from 2 wk of T3 administration (serum T4 1.2 +/- 0.1 micrograms/dl and T3 46 +/- 3 ng/dl) provided direct evidence that an alteration in peripheral thyroid hormone metabolism was probably responsible for these findings previously observed in euthyroid subjects. The results of this study support the possible existence in euthyroid man of a peripheral tissue autoregulatory mechanism for maintaining serum T3 values in states of T4 deficiency. Whether this process involves an alteration in the efficiency of T4 to T3 conversion or the rate of T3 clearance is presently unknown.


Neuropeptide Y and agouti-related peptide mediate complementary functions of hyperphagia and reduced energy expenditure in leptin receptor deficiency.
Neuropeptide Y (NPY) and agouti-related peptide (AGRP) can produce hyperphagia, reduce energy expenditure, and promote triglyceride deposition in adipose depots. As these two neuropeptides are coexpressed within the hypothalamic arcuate nucleus and mediate a major portion of the obesity caused by leptin signaling deficiency, we sought to determine whether the two neuropeptides mediated identical or complementary actions. Because of separate neuropeptide receptors and signal transduction mechanisms, there is a possibility of distinct encoding systems for the feeding and energy expenditure aspects of leptin-regulated metabolism. We have genetically added NPY deficiency and/or AGRP deficiency to LEPR deficiency isolated to AGRP cells. Our results indicate that the obesity of LEPR deficiency in AGRP/NPY neurons can produce obesity with either AGRP or NPY alone with AGRP producing hyperphagia while NPY promotes reduced energy expenditure. The absence of both NPY and AGRP prevents the development of obesity attributable to isolated LEPR deficiency in AGRP/NPY neurons. Operant behavioral testing indicated that there were no alterations in the reward for a food pellet from the AGRP-specific LEPR deficiency.


Neoadjuvant Atezolizumab With Gemcitabine and Cisplatin in Patients With Muscle-Invasive Bladder Cancer: A Multicenter, Single-Arm, Phase II Trial.
Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC. Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non-muscle-invasive downstaging to < pT2N0. Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)-positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 (P = .3 for association between PD-L1 and < pT2N0). Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker.


Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells.
The anaplastic lymphoma kinase (ALK) gene is overexpressed, mutated or amplified in most neuroblastoma (NB), a pediatric neural crest-derived embryonal tumor. The two most frequent mutations, ALK-F1174L and ALK-R1275Q, contribute to NB tumorigenesis in mouse models, and cooperate with MYCN in the oncogenic process. However, the precise role of activating ALK mutations or ALK-wt overexpression in NB tumor initiation needs further clarification. Human ALK-wt, ALK-F1174L, or ALK-R1275Q were stably expressed in murine neural crest progenitor cells (NCPC), MONC-1 or JoMa1, immortalized with v-Myc or Tamoxifen-inducible Myc-ERT, respectively. While orthotopic implantations of MONC- 1 parental cells in nude mice generated various tumor types, such as NB, osteo/ chondrosarcoma, and undifferentiated tumors, due to v-Myc oncogenic activity, MONC-1-ALK-F1174L cells only produced undifferentiated tumors. Furthermore, our data represent the first demonstration of ALK-wt transforming capacity, as ALK-wt expression in JoMa1 cells, likewise ALK-F1174L, or ALK-R1275Q, in absence of exogenous Myc-ERT activity, was sufficient to induce the formation of aggressive and undifferentiated neural crest cell-derived tumors, but not to drive NB development. Interestingly, JoMa1-ALK tumors and their derived cell lines upregulated Myc endogenous expression, resulting from ALK activation, and both ALK and Myc activities were necessary to confer tumorigenic properties on tumor-derived JoMa1 cells in vitro.


Efficient Nd:YAG laser end pumped by a high-power multistripe laser-diode bar with multiprism array coupling.
A 10-W laser-diode bar, a multistripe monolithic laser-diode array, has been used to end pump Nd:YAG. Twelve beams emitted from 12 stripes, spaced 800 µm apart, of a 1-cm linear diode array were collimated with a multiprism array consisting of 14 prismlets with 800-µm width to pump the Nd:YAG facet. The maximum Nd:YAG cw output power at 1064 nm of 3 W was obtained at 10-W laser-diode-bar power with a slope efficiency of 35%, and a TEM(00) spatial mode with values of beam-quality factor M(2) of 1.29 and 1.76 in the planes perpendicular and parallel to the junction, respectively. A pulse width of 25.2 ns (1-kHz repetition) was obtained in acousto-optic Q-switched operation.


Effect of partial recording protocols on severity estimates of periodontal disease.
The study aim was to assess bias magnitudes of periodontal disease severity estimates for specific partial recording protocols (PRPs) in epidemiological studies. Estimates of mean clinical attachment loss (MCAL) and mean probing pocket depth (MPPD) were derived for 20 different PRPs using full-mouth periodontal data from 1437 dentate Brazilian subjects 14-103 years old having at least four teeth. Biases, relative biases and intra-class correlations for all PRPs were evaluated. Graphical methods were used to assess how well the PRP-based estimates agreed with full-mouth scores across levels of disease. Slightly higher levels of disease were evidenced on lingual than on buccal sites. Seven multi-site PRPs and the Ramfjörd PRP produced small biases in MPPD (-0.17 to 0.04 mm) and MCAL with relative biases under 8% and 4% in absolute value for MPPD and MCAL, respectively. Biases for full- and random half-mouth-based PRPs were similar. The three-site random half-mouth MB-B-DL and the Ramfjörd PRPs produced the smallest biases, with relative biases <3% in absolute value for MPPD and MCAL. Bias for MPPD or MCAL estimates varies by site type, number of sites per tooth and number of quadrants included in the PRP.


[In vitro activity of ceftaroline to MRSA isolates: a multicenter study].
Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging pathogen that cause severe community- and hospital-acquired infections. Studies continue on searching alternatives due to the limited number of therapeutic options in MRSA infections. Ceftaroline is a wide-spectrum new generation cephalosporin which has been begun to be used in treatment of skin and respiratory tract infections caused by MRSA. The aim of this study was to investigate the in vitro activity of ceftaroline against MRSA strains isolated from various clinical specimens in microbiology laboratories of seven hospitals located at different provinces (Bolu, Samsun, Rize, Tekirdag, Sakarya, Amasya, Osmaniye) of Turkey. A total of 192 MRSA isolates (89 skin/wound/abscess, 38 blood, 36 respiratory tract, 29 urine/sterile body fluids/catheter) were included in the study, and ceftaroline susceptibilities of the strains were detected by broth microdilution method. MIC values of 181 (94.3%) isolates were determined as ≤ 1 µg/ml meaning of susceptible according to the criteria of CLSI, and MIC values of 11 (5.7%) isolates were found as 2 µg/mL indicating intermediate susceptibility. The range of MIC values of the isolates was found between 0.25-2 µg/ml. The rates of intermediate isolates have varied between 0-12.5% from the participating centers. MIC50 and MIC90 values of all the isolates were determined as 0.5 µg/ml and 1 µg/ml, respectively. No significant differences were found between the centers in terms of mean MIC values (p> 0.05). MIC50 and MIC90 values in Samsun and Bolu isolates were found to be the same with the whole group, however, MIC50 and MIC90 were 0.5 µg/ml and 0.5 µg/ml in Amasya isolates and 1 µg/ml and 1 µg/ml in Rize, Tekirdag, Osmaniye and Sakarya isolates, respectively. When evaluating MIC50 and MIC90 values and isolation rates of intermediate strains according to the specimen types, there were no significant differences (p> 0.05). Susceptibility rates to ceftaroline and the distribution profiles of MIC values of the isolates obtained from seven centers of Turkey have been detected similar with the previous American and European reports. With this study, initial data on the activity of ceftaroline against MRSA were obtained from Turkey. These preliminary findings indicate that ceftaroline is effective even on Turkish isolates and can be a suitable treatment in cases requiring wide-spectrum antimicrobiotic use, however further large-scaled studies are needed.


Neuraesthenia revisited: ICD-10 and DSM-III-R psychiatric syndromes in chronic fatigue patients and comparison subjects.
Different definitions of chronic fatigue syndrome (CFS) have different psychiatric exclusion criteria and this affects the type and frequency of associated psychiatric morbidity found. The operational criteria for neuraesthenia in ICD-10 vary in this and other respects from the Centers for Disease Control and Prevention (CDC) criteria for CFS. Neuraesthenia and associated psychiatric morbidity in CDC-defined CFS are evaluated. CFS subjects and controls were interviewed with the Schedule for the Clinical Assessment of Neuropsychiatry (SCAN). The computerised scoring program for SCAN (CATEGO5) facilitates the assignment of operational definitions according to DSM-III-R and ICD-10. Subjects were re-interviewed with SCAN an average of 11 months later. No specific treatments or interventions were given during this period. The majority of subjects fulfilled ICD-10 operational criteria for neuraesthenia and had two and a half times the rate of psychiatric morbidity as the healthy comparison group according to the CATEGO5 Index of Definition (ID). Approximately 80% of subjects fulfilled both DSM-III-R and ICD-10 criteria for sleep disorders. There was a significant fall in the number of subjects fulfilling criteria for depression and anxiety disorders and a significant increase in the number of subjects with no diagnosis for DSM-III-R criteria over time. There were no significant changes over time for any diagnosis according to ICD-10 criteria or for overall levels of psychopathology as reflected in CATEGO5 ID levels. The ICD-10 'neuraesthenia' definition identifies almost all subjects with CDC-defined CFS. Fifty percent of CFS subjects also had depressive or anxiety disorders, some categories of which remit spontaneously over time.


Transgenic tobacco plants constitutively expressing Arabidopsis NPR1 show enhanced resistance to root-knot nematode, Meloidogyne incognita.
In Arabidopsis, non-expressor of pathogenesis related genes-1, NPR1 has been shown to be a positive regulator of the salicylic acid controlled systemic acquired resistance pathway and modulates the cross talk between SA and JA signaling. Transgenic plants expressing AtNPR1 constitutively exhibited resistance against pathogens as well as herbivory. In the present study, tobacco transgenic plants expressing AtNPR1 were studied further for their response to infection by the sedentary endoparasitic root knot nematode, Meloidogyne incognita. Transgenic plants showed enhanced resistance against the root-knot nematode infection. Prominent differences in the shoot and root weights of wild type and transgenic plants were observed post-inoculation with M. incognita. This was associated with a decrease in the number of root galls and egg masses in transgenic plants compared to WT. The transgenic plants also showed constitutive and induced expression of some PR protein genes, when challenged with M. incognita.


Health Care Costs 1 Year After Pediatric Traumatic Brain Injury.
This study sought to estimate total health care costs for mild, moderate, and severe pediatric traumatic brain injury (TBI) and to compare individual- and population-level costs across levels of TBI severity. Using 2007 to 2010 MarketScan Commercial Claims and Encounters data, we estimated total quarterly health care costs 1 year after TBI among enrollees (aged < 18 years). We compared costs across levels of TBI severity using generalized linear models. Mild TBI accounted for 96.6% of the 319 103 enrollees with TBI; moderate and severe TBI accounted for 1.7% and 1.6%, respectively. Adjusted individual health care costs for moderate and severe TBI were significantly higher than mild TBI in the year after injury (P < .01). At the population level, moderate and severe TBI costs were 88% and 75% less than mild TBI, respectively. Individually, moderate and severe TBI initially generated costs that were markedly higher than those of mild TBI. At the population level, costs following mild TBI far exceeded those of more severe cases, a result of the extremely high population burden of mild TBI.


Rosiglitazone decreases postprandial production of acylation stimulating protein in type 2 diabetics.
We evaluated plasma ASP and its precursor C3 in type 2 diabetic men with/without rosiglitazone (ROSI) treatment compared to healthy non-obese men. We tested (1) whether plasma ASP or C3 are altered postprandially in subcutaneous adipose tissue or forearm muscle effluent assessed by arteriovenous (A-V) differences in healthy lean men and older obese diabetic men and (2) whether treatment with ROSI changes the arteriovenous gradient of ASP and/or C3. In this ongoing placebo-controlled, crossover, double-blinded study, AV differences following a mixed meal were measured in diabetic men (n = 6) as compared to healthy men (n = 9). Postprandial arterial and adipose venous TG and venous NEFA were increased in diabetics vs. controls (p < 0.05-0.0001). ROSI treatment decreased postprandial arterial TG (p < 0.001), adipose venous NEFA (p < 0.005), reduced postprandial glucose (p < 0.0001) and insulin concentrations (p < 0.006). In healthy men, there was no change in postprandial C3, but an increase in adipose venous ASP vs. arterial ASP (p < 0.02), suggesting ASP production, with no change in forearm muscle. In older, obese diabetic subjects, arterial C3 was greater than in controls (p < 0.001). Arterial C3 was greater than venous C3 (p < 0.05), an effect that was lost with ROSI treatment. In diabetics, postprandial venous ASP was greater than arterial (p < 0.05), indicating ASP production, an effect that was lost with ROSI treatment (p < 0.01). Increased postprandial venous production of ASP is specific for adipose tissue (absent in forearm muscle). Increased postprandial C3 and ASP in diabetic subjects is consistent with an ASP resistant state, this state is partially normalized by treatment with ROSI.


An outbreak of Mayaro virus disease in Belterra, Brazil. I. Clinical and virological findings.
An outbreak of human illness caused by Mayaro (MAY) virus occurred in Belterra, Pará, Brazil in the first half of 1978. A total of 55 cases were confirmed, 43 by virus isolation and serology, and 12 by serology alone. The disease in Belterra presented as a distinct clinical syndrome characterized by fever, arthralgia and exanthema. No fatalities could be attributed to MAY virus infection. Arthralgia, accompanied by joint edema in 20% of cases, was a very prominent sign which caused temporary incapacity in many patients. Arthralgia was present in virtually all confirmed cases and persisted in some for at least 2 months, although with decreasing severity. Rash was present in two-thirds of the cases, and was either maculopapular or micropapular. The incidence of rash was higher in children than in adults. Contrary to arthralgia, which started with the onset of clinical illness, rash usually appeared on the 5th day and faded within 3-4 days. Fever, chills, headache, myalgia, lymph-adenopathy and other minor clinical manifestations were also recorded, and generally persisted for from 2-5 days. Leucopenia was a constant finding in all cases. Mild albuminuria was seen in four of 25 patients, and slight thrombocytopenia was seen in 10 of 20 cases. The fact that viremia levels higher tha 5.0 log10/1.0 ml of blood were recorded in 10 patients rises the possibility that man may have be an amplifying host in the MAY virus cycle. The MAY virus illness, as seen in Belterra, has clinical features similar to those observed in persons infected with chikungunya virus.


Communicative and strategic action in interpreted consultations in primary health care: a Habermasian perspective.
We report a qualitative study of accounts of interpreted consultations in UK primary care. The study sought to explore how three Habermasian tensions between (a) system and lifeworld, (b) communicative and strategic action, and (c) interpersonal and macropolitical spheres played out in the triadic consultation between clinician, interpreter and patient. In a total of 69 individual interviews and two focus groups, we collected narratives from service users (through interpreters or bilingual researchers), interpreters and doctors and other staff in general practice. We recorded, transcribed and analysed these, taking the story as the main unit of analysis. Our data suggest that the preconditions for communicative action are rarely met in the interpreted consultation. The interpreter's presence makes a dyadic interaction into a triad, adding considerable complexity to the social situation and generating operational and technical challenges. Lack of trust, intense pressure of time, mismatch of agendas (biomedical versus lifeworld), firm expectations of a specific outcome (e.g. referral, prescription) and profound power imbalances all promote strategic action (i.e. speech that seeks consciously or unconsciously to manipulate an outcome) rather than communicative action (i.e. sincere efforts to achieve understanding, and reach consensus) by all parties. In consultations interpreted by family members (an option traditionally seen as 'second best' by policy makers), the social situation is very different. Family members are generally trusted, share the lifeworld agenda, and shift the power balance in the patient's favour. The interpreter occupies multiple social roles, including translator, interpersonal mediator, system mediator, educator, advocate, and link worker. The essence of professionalism in interpreting is shifting judiciously between these potentially conflicting roles. We discuss the implications of our findings for communication with limited English speakers in healthcare consultations and for realizing contemporary policy goals such as concordance, shared decision-making, empowerment, and choice.


Effects of environmental methylmercury on the health of wild birds, mammals, and fish.
Wild piscivorous fish, mammals, and birds may be at risk for elevated dietary methylmercury intake and toxicity. In controlled feeding studies, the consumption of diets that contained Hg (as methylmercury) at environmentally realistic concentrations resulted in a range of toxic effects in fish, birds, and mammals, including behavioral, neurochemical, hormonal, and reproductive changes. Limited field-based studies, especially with certain wild piscivorous bird species, e.g., the common loon, corroborated laboratory-based results, demonstrating significant relations between methylmercury exposure and various indicators of methylmercury toxicity, including reproductive impairment. Potential population effects in fish and wildlife resulting from dietary methylmercury exposure are expected to vary as a function of species life history, as well as regional differences in fish-Hg concentrations, which, in turn, are influenced by differences in Hg deposition and environmental methylation rates. However, population modeling suggests that reductions in Hg emissions could have substantial benefits for some common loon populations that are currently experiencing elevated methylmercury exposure. Predicted benefits would be mediated primarily through improved hatching success and development of hatchlings to maturity as Hg concentrations in prey fish decline. Other piscivorous species may also benefit from decreased Hg exposure but have not been as extensively studied as the common loon.


Kawasaki disease in England: ethnicity, deprivation, and respiratory pathogens.
Kawasaki disease is now the commonest cause of acquired heart disease in children in the United Kingdom. Its incidence has increased in recent years. Epidemiologic analyses have provided insights into the possible etiology, but European data are scarce. We analyzed linked English-wide hospital admission data for Kawasaki disease in people younger than 18 years of age, during a 5-year period (1998-2003), relating incidence to geographic location, urbanization, deprivation, ethnicity, and to laboratory reports of respiratory infection. There were 2432 admissions with Kawasaki disease in the study period for 1704 individuals. One thousand twenty-eight (60%) of the 1704 were male and 1228 (72%) were younger than 5 years of age. The annual age-specific incidence rate in those younger than 5 years was 8.39/100,000. Incidence rates in different areas of residence were significantly and independently related to both the degree of deprivation of the area and the proportion of the population in each area who were Chinese. After adjusting for the winter peaks in both the incidence of Kawasaki disease and respiratory virus infections, there was no correlation between Kawasaki disease and specific viruses. The previously reported increase in Kawasaki disease incidence in England has reached a plateau. These data support the concept of an infectious trigger in a genetically susceptible population, but known respiratory viral pathogens are unlikely to be the specific etiologic agents