An overview of the first 5 years of the ENIGMA obsessive-compulsive disorder working group: The power of worldwide collaboration.
Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive-compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.


PBS140: new competition in the organ preservation market?
PBS140 offers good cold preservation in renal transplantation and now, crucially, has been shown to promote immediate function following warm ischemia. For a new cold preservation solution to compete with UW solution, improved efficacy and lower price may not be enough. Reducing rates of delayed graft function in organs from non-heart-beating and marginal donors might be the key.


A survey of patients' experience of pain and other symptoms while receiving care from palliative care services.
In Australia, patients at the end of life with complex symptoms and needs are often referred to palliative care services (PCSs), but little is known about the symptoms of patients receiving palliative care in different settings. To explore patients' levels of pain and other symptoms while receiving care from PCSs. PCSs registered through Australia's national Palliative Care Outcomes Collaboration (PCOC) were invited to participate in a survey between 2008 and 2011. Patients (or if unable, a proxy) were invited to complete the Palliative Care Outcome Scale. Questionnaires were completed for 1800 patients. One-quarter of participants reported severe pain, 20% reported severe 'other symptoms', 20% reported severe patient anxiety, 45% reported severe family anxiety, 66% experienced depressed feelings and 19% reported severe problems with self-worth. Participants receiving care in major cities reported higher levels of depressed feelings than participants in inner regional areas. Participants receiving care in community and combined service settings reported higher levels of need for information, more concerns about wasted time, and lower levels of family anxiety and depressed feelings when compared to inpatients. Participants in community settings had lower levels of concern about practical matters than inpatients. Patients receiving care from Australian PCSs have physical and psychosocial concerns that are often complex and rated as 'severe'. Our findings highlight the importance of routine, comprehensive assessment of patients' concerns and the need for Specialist Palliative Care clinicians to be vigilant in addressing pain and other symptoms in a timely, systematic and holistic manner, whatever the care setting.


Why we recommend analytic treatment for some patients and not for others.
One hundred consecutive patients applying for analysis completed a comprehensive battery of structured interviews and self-report questionnaires assessing dimensions of psychopathology and psychological functions that analysts consider important when evaluating patients for analysis. Patients were evaluated for analysis by a candidate supervised by a training analyst. Fifty patients were accepted for analysis and fifty rejected. In both groups, psychiatric morbidity and psychosocial impairment were high, with a 50% current and 74% lifetime diagnosis of mood disorder, 56% current and 61% lifetime history of anxiety disorder. The mean Beck Depression Inventory score fell in the moderate range, 19.1 (SD = 11.0), mean Hamilton Depression score in the mild range, 14.1 (SD = 7.8), and the mean Hamilton Anxiety score in the moderate range, 14.6 ( SD = 8.1), with 57% meeting criteria for an Axis II diagnosis, and mean social adjustment in the moderate to high pathology range. Patients accepted and rejected for analysis did not differ with regard to any of these dimensions. Accepted patients scored lower on measures of impulsivity, aggression, and sociopathy, and on scores of personality rigidity, primitive defenses, and outward aggression. The major finding was the striking similarity between patients accepted and rejected for psychoanalytic treatment.


Textile-Based Capacitive Sensor for Physical Rehabilitation via Surface Topological Modification.
Wearable sensor technologies, especially continuous monitoring of various human health conditions, are attracting increased attention. However, current rigid sensors present obvious drawbacks, like lower durability and poor comfort. Here, a strategy is proposed to efficiently yield wearable sensors using cotton fabric as an essential component, and conductive materials conformally coat onto the cotton fibers, leading to a highly electrically conductive interconnecting network. To improve the conductivity and durability of conductive coatings, a topographical modification approach is developed with genus-3 and genus-5 structures, and topological genus structures enable cage metallic seeds on the surface of substrates. A textile-based capacitive sensor with flexible, comfortable, and durable properties has been demonstrated. High sensitivity and convenience of signal collection have been achieved by the excellent electrical conductivity of this sensor. Based on results of deep investigation on capacitance, effects of distance and angles between two conductive fabrics contribute to the capacitive sensitivity. In addition, the textile-based capacitive sensor has successfully been used for real-time monitoring human breathing, speaking, blinking, and joint motions during physical rehabilitation exercises.


Dietary selenium intake and risk of hospitalization for type 2 diabetes in the Moli-sani study cohort.
Experimental and non-experimental human studies have consistently shown a positive association between exposure to the trace element selenium, which occurs primarily through diet, and risk of type 2 diabetes mellitus. Plausible biological mechanisms include adverse effects of selenium and selenium-containing proteins on glucose metabolism. However, the levels of exposure above which risk increases are uncertain. We examined the association between selenium intake and first hospitalization for type 2 diabetes during a median follow-up period of 8.2 years among 21,335 diabetes-free participants in the Moli-sani cohort, Italy. Selenium intake was ascertained at baseline using a food frequency questionnaire, showing a median value of 59 μg/day. During follow-up, we identified 135 incident cases of hospitalization for diabetes, based on population-based hospital discharge data. We used a Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for hospitalization for diabetes, adjusting for potential confounders. HRs (95% CIs) were 1.01 (0.60-1.70), 1.13 (0.66-1.96) and 1.75 (0.99-3.10) comparing the second, third, and fourth sex-specific quartiles with the first quartile, respectively. Risk was 64% greater in the fourth quartile as compared with the previous three. Spline regression analysis also indicated a steeper increase in risk occurring among men compared with women. In a large population of Italian adults free of type 2 diabetes at cohort entry, high dietary selenium intake was associated with increased risk of hospitalization for diabetes.


Failing finals is often a surprise for the student but not the teacher: identifying difficulties and supporting students with academic difficulties.
Weak students often continue with little guidance and feedback, and often have ongoing difficulties. Early support may stop students experiencing a cycle of failure. Key to supporting struggling students is to identify reasons for poor performance. We explored the reasons for poor performance in a cohort of fifth year students who failed their final clinical examinations. Qualitative methods (interviews and a focus group) identified several themes. Many of the students had experienced personal problems or issues. They regarded themselves as competent students although they had significantly greater problems with earlier exams than the year mean, and significantly lower scores in formative assessments during the year leading up to these exams than their peers. Factors relating to the exam itself were seen as relevant to failure. More specific support and feedback throughout the MBcHB was seen as desirable. They tended to take little personal responsibility for their performance and were reluctant to seek help. We conclude that while the onus is on Faculty to identify and support failing students, the results indicate that students would benefit from support in developing self-reflection skills in such a way to support life-long learning.


Changes in EEG and autonomic nervous activity during meditation and their association with personality traits.
Meditation is the attainment of a restful yet fully alert physical and mental state practiced by many as a self-regulatory approach to emotion management, but the psychophysiological properties and personality traits that characterize this meditative state have not been adequately studied. We quantitatively analyzed changes in psychophysiological parameters during Zen meditation in 20 normal adults, and evaluated the results in association with personality traits assessed by Cloninger's Temperament and Character Inventory (TCI). During meditation, increases were observed in fast theta power and slow alpha power on EEG predominantly in the frontal area, whereas an increase in the normalized unit of high-frequency (nuHF) power (as a parasympathetic index) and decreases in the normalized unit of low-frequency (nuLF) power and LF/HF (as sympathetic indices) were observed through analyses of heart rate variability. We analyzed the possible correlations among these changes in terms of the percent change during meditation using the control condition as the baseline. The percent change in slow alpha EEG power in the frontal area, reflecting enhanced internalized attention, was negatively correlated with that in nuLF as well as in LF/HF and was positively correlated with the novelty seeking score (which has been suggested to be associated with dopaminergic activity). The percent change in fast theta power in the frontal area, reflecting enhanced mindfulness, was positively correlated with that in nuHF and also with the harm avoidance score (which has been suggested to be associated with serotonergic activity). These results suggest that internalized attention and mindfulness as two major core factors of behaviors of mind during meditation are characterized by different combinations of psychophysiological properties and personality traits.


Informing patients about the negative effect of nephrectomy on sexual function.
The quality-of-life concept has increasingly gained attention, but an important aspect has been neglected, which is the sexual function of patients with kidney cancer after surgery. The aim of this study was to explore the impact of nephrectomy on sexual function in patients with kidney cancer and the information patients received with this regard. We conducted a retrospective study of patients who underwent nephrectomy or nephro-ureterectomy within a 5-year period at the Department of Urology, Odense University Hospital, Denmark. Among 310 patients having undergone surgery, 226 were still alive and eligible for participation. Their records were reviewed, and a validated questionnaire concerning their sex life was mailed to them. All participants were invited to take part in a semi-structured interview in person or by phone. Of 154 former patients who replied, 95 were men (mean age, 66 years, range 37-89), 59 were women (mean age 63 years, range 26-87). A significant difference was observed regarding problems with sexual relationships prior to operation compared after (P<0.0001). Seven patients (5%) had been informed about potential effects and changes in their sex life following operation. Both male and female participants were worried about their sex life (61.4%). Among sexually active male responders, 54.7% reported having some degree of erectile dysfunction. Patients experience significantly more problems in their sexual relationships after surgery. Very few were informed about this, showing the need to offer sex counselling before surgery. More research is required to fully comprehend the magnitude of the problem.


Mitochondrial DNA (mtDNA) haplotypes reveal maternal population genetic affinities of Sea Island Gullah-speaking African Americans.
To better understand the population substructure of African Americans living in coastal South Carolina, we used restriction site polymorphisms and an insertion/deletion in mitochondrial DNA (mtDNA) to construct seven-position haplotypes across 1,395 individuals from Sierra Leone, Africa, from U.S. European Americans, and from the New World African-derived populations of Jamaica, Gullah-speaking African Americans of the South Carolina Sea Islands (Gullahs), African Americans living in Charleston, South Carolina, and West Coast African Americans. Analyses showed a high degree of similarity within the New World African-derived populations, where haplotype frequencies and diversities were similar. Phi-statistics indicated that very little genetic differentiation has occurred within New World African-derived populations, but that there has been significant differentiation of these populations from Sierra Leoneans. Genetic distance estimates indicated a close relationship of Gullahs and Jamaicans with Sierra Leoneans, while African Americans living in Charleston and the West Coast were progressively more distantly related to the Sierra Leoneans. We observed low maternal European American admixture in the Jamaican and Gullah samples (m = 0.020 and 0.064, respectively) that increased sharply in a clinal pattern from Charleston African Americans to West Coast African Americans (m = 0.099 and 0.205, respectively). The appreciably reduced maternal European American admixture noted in the Gullah indicates that the Gullah may be uniquely situated to allow genetic epidemiology studies of complex diseases in African Americans with low European American admixture.


Imagery-Focused Cognitive Therapy (ImCT) for Mood Instability and Anxiety in a Small Sample of Patients with Bipolar Disorder: a Pilot Clinical Audit.
Despite the global impact of bipolar disorder (BD), treatment success is limited. Challenges include syndromal and subsyndromal mood instability, comorbid anxiety, and uncertainty around mechanisms to target. The Oxford Mood Action Psychology Programme (OxMAPP) offered a novel approach within a cognitive behavioural framework, via mental imagery-focused cognitive therapy (ImCT). This clinical audit evaluated referral rates, clinical outcomes and patient satisfaction with the OxMAPP service. Eleven outpatients with BD received ImCT in addition to standard psychiatric care. Mood data were collected weekly from 6 months pre-treatment to 6 months post-treatment via routine mood monitoring. Anxiety was measured weekly from start of treatment until 1 month post-treatment. Patient feedback was provided via questionnaire. Referral and treatment uptake rates indicated acceptability to referrers and patients. From pre- to post-treatment, there was (i) a significant reduction in the duration of depressive episode relapses, and (ii) a non-significant trend towards a reduction in the number of episodes, with small to medium effect size. There was a large effect size for the reduction in weekly anxiety symptoms from assessment to 1 month follow-up. Patient feedback indicated high levels of satisfaction with ImCT, and underscored the importance of the mental imagery focus. This clinical audit provides preliminary evidence that ImCT can help improve depressive and anxiety symptoms in BD as part of integrated clinical care, with high patient satisfaction and acceptability. Formal assessment designs are needed to further test the feasibility and efficacy of the new ImCT treatment on anxiety and mood instability.


Is APOC3 the driver of cardiovascular disease in people with type I diabetes mellitus?
In this issue of the JCI, Kanter et al. make a strong case for implicating apolipoprotein C3 (APOC3) as a central player in atherosclerotic cardiovascular disease that is commonly seen in individuals with type 1 diabetes mellitus (T1DM). Kanter and colleagues suggest that insulin deficiency elevates plasma APOC3 as well as atherogenic triglyceride-rich (TG-rich) lipoproteins (TRLs). Using two mouse models of T1DM, the authors investigated APOC3-mediated inhibition of both TG hydrolysis by lipoprotein lipase and hepatic uptake of remnant lipoproteins. They suggest that poorly catabolized lipoproteins, enriched in both APOC3 and APOE content, are particularly atherogenic. Notably, treating both mouse models with an APOC3 antisense oligonucleotide lowered both plasma APOC3 and TRLs, and prevented atherosclerosis. These impactful mouse studies were supported by the initial finding that APOC3 predicted coronary artery disease events in participants of the prospective Coronary Artery Calcification in Type 1 Diabetes study with normal TG levels.


Trichiasis surgery in The Gambia: a 4-year prospective study.
Trachoma is the leading infectious cause of blindness. Conjunctival Chlamydia trachomatis infection causes scarring, entropion, trichiasis, and blinding corneal opacification. Worldwide, there are 8 million people with trichiasis. Although trichiasis surgery can reduce the risk of blindness, retrospective data suggest that long-term recurrence rates may be high. A 4-year prospective investigation of recurrent trichiasis was conducted in The Gambia. Patients with trichiasis were examined at baseline, 6 months, 1 year, and 4 years after posterior lamellar tarsal rotation surgery. Conjunctival swabs for bacteriology and PCR for C. trachomatis were collected at baseline, 6 months, and 1 year. Three hundred fifty-six Gambian patients were enrolled at baseline and 266 were reassessed at 4 years (94% of surviving patients). The recurrence rates were 32%, 40%, and 41% at 6 months, 1 year, and 4 years, respectively. At 4 years, 30% of patients had bilateral trichiasis and 21% had bilateral corneal opacity. Recurrence was associated with severe conjunctival inflammation and severe trichiasis (>10 lashes) at baseline. Trichiasis recurrence rates were high, and most cases recurred within 6 months of surgery. The results suggest that there are important aspects of surgical technique and quality that should to be addressed. Persistent inflammation is strongly associated with recurrence at 4 years.


Development of a Standardized Kalamazoo Communication Skills Assessment Tool for Radiologists: Validation, Multisource Reliability, and Lessons Learned.
The purpose of this study was to develop and test a standardized communication skills assessment instrument for radiology. The Delphi method was used to validate the Kalamazoo Communication Skills Assessment instrument for radiology by revising and achieving consensus on the 43 items of the preexisting instrument among an interdisciplinary team of experts consisting of five radiologists and four nonradiologists (two men, seven women). Reviewers assessed the applicability of the instrument to evaluation of conversations between radiology trainees and trained actors portraying concerned parents in enactments about bad news, radiation risks, and diagnostic errors that were video recorded during a communication workshop. Interrater reliability was assessed by use of the revised instrument to rate a series of enactments between trainees and actors video recorded in a hospital-based simulator center. Eight raters evaluated each of seven different video-recorded interactions between physicians and parent-actors. The final instrument contained 43 items. After three review rounds, 42 of 43 (98%) items had an average rating of relevant or very relevant for bad news conversations. All items were rated as relevant or very relevant for conversations about error disclosure and radiation risk. Reliability and rater agreement measures were moderate. The intraclass correlation coefficient range was 0.07-0.58; mean, 0.30; SD, 0.13; and median, 0.30. The range of weighted kappa values was 0.03-0.47; mean, 0.23; SD, 0.12; and median, 0.22. Ratings varied significantly among conversations (χ26 = 1186; p < 0.0001) and varied significantly by viewing order, rater type, and rater sex. The adapted communication skills assessment instrument is highly relevant for radiology, having moderate interrater reliability. These findings have important implications for assessing the relational competencies of radiology trainees.


Nanostructured thermoelectrics: big efficiency gains from small features.
The field of thermoelectrics has progressed enormously and is now growing steadily because of recently demonstrated advances and strong global demand for cost-effective, pollution-free forms of energy conversion. Rapid growth and exciting innovative breakthroughs in the field over the last 10-15 years have occurred in large part due to a new fundamental focus on nanostructured materials. As a result of the greatly increased research activity in this field, a substantial amount of new data--especially related to materials--have been generated. Although this has led to stronger insight and understanding of thermoelectric principles, it has also resulted in misconceptions and misunderstanding about some fundamental issues. This article sets out to summarize and clarify the current understanding in this field; explain the underpinnings of breakthroughs reported in the past decade; and provide a critical review of various concepts and experimental results related to nanostructured thermoelectrics. We believe recent achievements in the field augur great possibilities for thermoelectric power generation and cooling, and discuss future paths forward that build on these exciting nanostructuring concepts.


Automatic determination of diltiazem and desacetyldiltiazem in human plasma using liquid-solid extraction on disposable cartridges coupled to HPLC--Part I: Optimization of the HPLC system and method validation.
A sensitive and automated method for the analysis of diltiazem and desacetyldiltiazem in plasma has been developed using liquid-solid extraction (LSE) on disposable extraction cartridges (DECs) in combination with HPLC. After isolation from plasma, the analytes are separated on a highly deactivated octyl silica column with a mobile phase of methanol-0.05 M phosphate buffer (pH 7.4) (62:38, v/v). The analytes are monitored photometrically at 238 nm. The complete preparation of the plasma sample as well as the injection of the final extract on to the analytical column are performed automatically by means of a sample processor equipped with a robotic arm to which is attached a needle dispensing the different liquids. The internal standard solution is first added to the plasma sample. The DEC is then conditioned successively with methanol and phosphate buffer (pH 7.4). A 1.0-ml volume of sample containing the internal standard solution is applied on an extraction cartridge filled with cyanopropyl silica (50 mg). After the DEC has been washed with the same buffer, the analytes are eluted with 0.16 ml of methanol. A 0.14-ml volume of buffer is then passed through the DEC and 0.25 ml of the final extract is injected onto the HPLC column. The absolute recoveries of the drugs are about 90% and the limit of detection for diltiazem is 0.8 ng ml-1. Relative standard deviations of 2.6% (within-day) and 3.7% (between-day) have been obtained for this compound at a plasma concentration of 50 ng ml-1.


Remote ischemic conditioning in percutaneous coronary intervention and coronary artery bypass grafting.
Although remote ischemic conditioning (RIC) by transient limb ischemia in percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) has shown favorable effects on myocardial (ischemia-reperfusion) injury, recent trials provide inconsistent results. The aim of the present study was to assess the effect of RIC in PCI or CABG. Medline/Embase/conference reports were searched for randomized RIC trials and were included if they reported on biomarkers of myocardial injury (CK-MB/troponin T/I), after which, standardized mean differences (SMDs) were calculated (Hedges g statistic). Meta-analysis of 4 studies on PCI, involving 557 patients, indicated reduced biomarkers for myocardial injury with RIC compared to control (random effects model: SMD, -0.21; 95% confidence interval [CI]: -0.66 to 0.24). Analysis of primary PCI studies, involving 314 patients, indicated a highly significant positive effect of RIC on myocardial injury (SMD, -0.55; 95% CI: -0.77 to -0.32). The 13 CABG studies taken together, involving 891 patients, indicated a significant effect of RIC on myocardial injury (SMD, -0.34; 95% CI: -0.59 to -0.08). The statistical tests indicated moderate to high heterogeneity across the studies (Q-statistic: PCI, P=0.0006, I(2)=83%; CABG, P<0.0001, I(2)=69%). In patients undergoing PCI or CABG, RIC with transient episodes of limb ischemia is associated with lower biomarkers of myocardial injury compared to control, but this effect failed to reach statistical significance in the overall PCI analysis.


Revised Knox Preschool Play Scale: interrater agreement and construct validity.
Interrater agreement and construct validity of the Revised Knox Preschool Play Scale (RKPPS) were examined. Two separately trained raters evaluated 38 typically developing children, ages 36 to 72 months. For each child, the raters observed two 15-min free-play sessions. For the overall play age, the scores of the two raters were within 8 months of each other 86.8% of the time; for the 4 dimension scores, they were within 12 months of each other 91.7% to 100% of the time; and for the 12 category scores, they were within one age level of each other 81.8% to 100% of the time. Construct validity results showed a general match between the children's chronological ages and their overall play age scores. Findings suggest that two raters can score the RKPPS with some consistency and that scores on this measure progress developmentally, thus supporting its construct validity.


Prevalence of rotator cuff tear in paraplegic patients compared with controls.
Musculoskeletal injuries of the shoulder in paraplegic patients with long-term survival can result from overuse and/or inappropriate use of wheelchairs. The purpose of the present study was to evaluate the prevalence and risk of pathological changes in the weight-bearing shoulder girdle of paraplegic patients who have been wheelchair-dependent for more than thirty years in comparison with able-bodied volunteers. One hundred paraplegic patients were matched for sex and age with a group of 100 able-bodied volunteers. Two hundred shoulders from each group were evaluated with use of magnetic resonance imaging. Collected outcome measures included a standardized clinical examination protocol, the Constant score, and a visual analog score for pain intensity. Shoulder function according to the Constant score was significantly worse in the paraplegic patients than in the able-bodied volunteers. Similarly, the visual analog scale pain scores were significantly worse for the paraplegic patients. Magnetic resonance imaging showed that the prevalence of rotator cuff tears in either shoulder was significantly higher in the paraplegic patients than in the able-bodied volunteers (63% compared with 15%), resulting in a tenfold higher risk of rotator cuff rupture among paraplegic patients. The present study demonstrates that the structural and functional changes of the shoulder joint are more severe and the risk of development of shoulder girdle damage is significantly higher in individuals with long-term paraplegia than in age-matched controls.


Effects of two lipid-lowering, carotenoid-controlled diets on the oxidative modification of low-density lipoproteins in free-living humans.
This study compares the effects of two lipid-lowering diets [a diet enriched in MUFAs (monounsaturated fatty acids) and a HCLF (high-carbohydrate/low-fat) diet] with a controlled carotenoid content on risk factors for coronary heart disease, including in vitro copper-induced LDL (low-density lipoprotein) oxidation and serum lipid levels. A randomized crossover dietary intervention study, with two diets each consumed for 14-16 days, was conducted in 18 women and 13 men aged 20-70 years, recruited via personal contacts and advertisements in newspapers. Both diets (MUFA-enriched diet and HCLF diet) contained the same basic foods and had a controlled carotenoid content, high in lycopene. The in vitro copper-induced oxidation of isolated LDL showed a longer lag phase (mean difference 7.4 min in women and 7.34 min in men) after the MUFA-enriched diet compared with the HCLF diet. Serum total cholesterol, LDL cholesterol and carotenoid levels were similar after the two diets. Serum triacylglycerol levels were significantly lower and those of HDL (high-density lipoprotein) cholesterol were significantly higher at the end of the MUFA-enriched diet compared with the HCLF diet. It is concluded that the significantly longer lag phase for oxidation of LDL, the higher HDL cholesterol level and the lower triacylglycerol level in subjects following a carotenoid-controlled, MUFA-enriched diet may decrease the risk of coronary heart disease.


Modification of osteoarthritis by pulsed electromagnetic field--a morphological study.
Hartley guinea pigs spontaneously develop arthritis that bears morphological, biochemical, and immunohistochemical similarities to human osteoarthritis. It is characterized by the appearance of superficial fibrillation by 12 months of age and severe cartilage lesions and eburnation by 18 months of age. This study examines the effect of treatment with a pulsed electromagnetic field (PEMF) upon the morphological progression of osteoarthritis in this animal model. Hartley guinea pigs were exposed to a specific PEMF for 1h/day for 6 months, beginning at 12 months of age. Control animals were treated identically, but without PEMF exposure. Tibial articular cartilage was examined with histological/histochemical grading of the severity of arthritis, by immunohistochemistry for cartilage neoepitopes, 3B3(-) and BC-13, reflecting enzymatic cleavage of aggrecan, and by immunoreactivity to collagenase (MMP-13) and stromelysin (MMP-3). Immunoreactivity to TGFbeta, interleukin (IL)-1beta, and IL receptor antagonist protein (IRAP) antibodies was examined to suggest possible mechanisms of PEMF activity. PEMF treatment preserves the morphology of articular cartilage and retards the development of osteoarthritic lesions. This observation is supported by a reduction in the cartilage neoepitopes, 3B3(-) and BC-13, and suppression of the matrix-degrading enzymes, collagenase and stromelysin. Cells immunopositive to IL-1 are decreased in number, while IRAP-positive cells are increased in response to treatment. PEMF treatment markedly increases the number of cells immunopositive to TGFbeta. Treatment with PEMF appears to be disease-modifying in this model of osteoarthritis. Since TGFbeta is believed to upregulate gene expression for aggrecan, downregulate matrix metalloprotease and IL-1 activity, and upregulate inhibitors of matrix metalloprotease, the stimulation of TGFbeta may be a mechanism through which PEMF favorably affects cartilage homeostasis.


Polychlorinated biphenyl (PCB) contamination of subsistence species on Unalaska Island in the Aleutian Archipelago.
Polychlorinated biphenyls (PCBs) are a group of synthetic, lipophilic organochlorines that were banned due to their impacts on human and wildlife health and environmental persistence. Although banned, the continued release from pre-banned products allows them to persist at toxic levels in the environment. This is especially the case in lipid rich food webs of the Arctic, where PCBs accumulate due to both long-range atmospheric transport and locally contaminated sites such as formerly used defense (FUD) sites. At the request of the leadership of the Qawalangin Tribe of Unalaska Island in the Aleutian Archipelago, we analyzed PCB concentrations in samples of threespine stickleback (Gasterosteus aculeatus) and subsistence foods (i.e., salmonid species and blue mussels [Mytilus edulis]) collected at both FUD and non-FUD sites. PCBs were extracted from samples using a QuEChERS method. The mean PCB concentrations across all mussel samples was 6.1 ppb; mussels from FUD sites had nearly double the PCB concentrations (7.6 ppb) compared to non-military sites (3.9 ppb), and at two FUD sites the PCB concentrations exceeded safe consumption guidelines. The mean total PCB concentration for fish was 2.8 ppb; fish PCB concentrations were higher at FUD sites (3.2 ppb) compared to non-military sites (1.2 ppb). These results support the need to remediate the FUD sites of "Building 551/T Dock to Airport" and "Delta Western". More generally, these results provide further evidence of the continued problem of PCB contamination at FUD sites in the Arctic, many of which are co-located with indigenous communities.


Genome-wide colocalization of RNA-DNA interactions and fusion RNA pairs.
Fusion transcripts are used as biomarkers in companion diagnoses. Although more than 15,000 fusion RNAs have been identified from diverse cancer types, few common features have been reported. Here, we compared 16,410 fusion transcripts detected in cancer (from a published cohort of 9,966 tumor samples of 33 cancer types) with genome-wide RNA-DNA interactions mapped in two normal, noncancerous cell types [using iMARGI, an enhanced version of the mapping of RNA-genome interactions (MARGI) assay]. Among the top 10 most significant RNA-DNA interactions in normal cells, 5 colocalized with the gene pairs that formed fusion RNAs in cancer. Furthermore, throughout the genome, the frequency of a gene pair to exhibit RNA-DNA interactions is positively correlated with the probability of this gene pair to present documented fusion transcripts in cancer. To test whether RNA-DNA interactions in normal cells are predictive of fusion RNAs, we analyzed these in a validation cohort of 96 lung cancer samples using RNA sequencing (RNA-seq). Thirty-seven of 42 fusion transcripts in the validation cohort were found to exhibit RNA-DNA interactions in normal cells. Finally, by combining RNA-seq, single-molecule RNA FISH, and DNA FISH, we detected a cancer sample with EML4-ALK fusion RNA without forming the EML4-ALK fusion gene. Collectively, these data suggest an RNA-poise model, where spatial proximity of RNA and DNA could poise for the creation of fusion transcripts.


Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program.
To date, few large studies have been reported of patients with peritoneal mesothelioma, and treatment of this disease has been largely extrapolated from the treatment of pleural disease. Hence, it was considered important to study and report on this specific patient population. Before the regulatory approval of pemetrexed, an expanded access program (EAP) provided access to eligible patients with malignant pleural or peritoneal mesothelioma. Patients received pemetrexed 500 mg/m2 alone or in combination with cisplatin 75 mg/m2 once every 21 days for > or = 6 cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. Serious adverse events (SAEs) were compiled in a pharmacovigilance database, which included all patients in the EAP with pleural or peritoneal mesothelioma. From June 12, 2002 to February 18, 2004, 1056 patients with malignant mesothelioma were enrolled and received > or = 1 dose of treatment at 462 sites in the United States. Of these patients, 98 (9.3%) had peritoneal mesothelioma (57 previously treated, 38 chemotherapy-naive, and 3 with missing data). Response data were available for 73 patients (43 previously treated, 28 chemotherapy-naive, and 2 not classified), indicating response rates of 23.3% for previously treated patients (0 complete responses [CRs], 10 partial responses [PRs], 21 cases of stable disease [SDs], 12 cases of progressive disease [PDs]) and 25% for chemotherapy-naive patients (3 CRs, 4 PRs, 12 SDs, and 9 PDs). Median survival was 13.1 months for previously treated patients and has not been reached for chemotherapy-naive patients. The most commonly reported SAEs for the total EAP were dehydration (7.2%), nausea (5.2%), and vomiting (4.9%). Pemetrexed with or without cisplatin had a favorable safety profile, and the disease control rate (CR + PR + SD) of 71.2% in the subset of patients with peritoneal mesothelioma indicated activity in this patient population.


Genomic insights into the mitochondria of 11 eastern North American species of Cladonia.
Cladonia is among the most species-rich genera of lichens globally. Species in this lineage, commonly referred to as reindeer lichens, are ecologically important in numerous regions worldwide. In some locations, species of Cladonia can comprise the dominant groundcover, and are a major food source for caribou and other mammals. Additionally, many species are known to produce substances with antimicrobial properties or other characteristics with potentially important medical applications. This exceptional morphological and ecological variation contrasts sharply with the limited molecular divergence often observed among species. As a new resource to facilitate ongoing and future studies of these important species, we analyse here the sequences of 11 Cladonia mitochondrial genomes, including new mitochondrial genome assemblies and annotations representing nine species: C. apodocarpa, C. caroliniana, C. furcata, C. leporina, C. petrophila, C. peziziformis, C. robbinsii, C. stipitata, and C. subtenuis. These 11 genomes varied in size, intron content, and complement of tRNAs. Genes annotated within these mitochondrial genomes include 15 protein-coding genes, the large and small ribosomal subunits (mtLSU and mtSSU), and 23-26 tRNAs. All Cladonia mitochondrial genomes contained atp9, an important energy transport gene that has been lost evolutionarily in some lichen mycobiont mitochondria. Using a concatenated alignment of five mitochondrial genes (nad2, nad4, cox1, cox2, and cox3), a Bayesian phylogeny of relationships among species was inferred and was consistent with previously published phylogenetic relationships, highlighting the utility of these regions in reconstructing phylogenetic history.


Protein diffusion and long-term adsorption states at charged solid surfaces.
The diffusion pathways of lysozyme adsorbed to a model charged ionic surface are studied using fully atomistic steered molecular dynamics simulation. The simulations start from existing protein adsorption trajectories, where it has been found that one particular residue, Arg128 at the N,C-terminal face, plays a crucial role in anchoring the lysozyme to the surface [Langmuir 2010 , 26 , 15954 - 15965]. We first investigate the desorption pathway for the protein by pulling the Arg128 side chain away from the surface in the normal direction, and its subsequent readsorption, before studying diffusion pathways by pulling the Arg128 side chain parallel to the surface. We find that the orientation of this side chain plays a decisive role in the diffusion process. Initially, it is oriented normal to the surface, aligning in the electrostatic field of the surface during the adsorption process, but after resorption it lies parallel to the surface, being unable to return to its original orientation due to geometric constraints arising from structured water layers at the surface. Diffusion from this alternative adsorption state has a lower energy barrier of ∼0.9 eV, associated with breaking hydrogen bonds along the pathway, in reasonable agreement with the barrier inferred from previous experimental observation of lysozyme surface clustering. These results show the importance of studying protein diffusion alongside adsorption to gain full insight into the formation of protein clusters and films, essential steps in the future development of functionalized surfaces.


Antimicrobial Effect of Orthodontic Materials on Cariogenic Bacteria Streptococcus mutans and Lactobacillus acidophilus.
BACKGROUND White spot lesions (WSLs) are a common complication after orthodontic treatment. The aim of this study was to characterize and compare the antimicrobial properties of selenium-containing vs. fluoride-containing orthodontic materials. MATERIAL AND METHODS Antibacterial efficacy of orthodontic materials (SeLECT Defense bonding agent, Adhesive agent, Band Cement, Transbond Plus SEP bonding agent, Transbond Plus Adhesive agent, Fuji I Band cement, Fuji Ortho LC Adhesive agent, Ortho Solo Bonding agent, Transbond XT bonding agent, and Transbond XT primer) was tested with the inhibition of 2 bacterial strains: S. mutans (ATCC 10449) and L. acidophilus (ATCC 4356). The antimicrobial efficacy of the materials was measured by agar diffusion test. The diameters of inhibition zones around each disk were measured in millimeters (mm). RESULTS Materials containing selenium and fluoride showed significant differences from the negative control (both p<0.001). Orthodontic materials containing fluoride as a potential antimicrobial agent showed larger zones of inhibition in total (9.1±2.6 mm), the selenium group was the second-most effective (4.7±4.9 mm), and the group without any potential antimicrobial agent showed the least antimicrobial effect (0.9±1.0 mm). Materials from the group with no antibacterial agent were not significantly different from the negative control group (p>0.05). CONCLUSIONS Materials containing selenium carried the most significance when comparing microorganisms with the agent, since they were the only ones showing difference between the 2 microorganisms. They showed statistically significant difference in efficacy against S. mutans, and poor antimicrobial effect against L. acidophilus. These data suggest that orthodontic materials containing selenium might have the potential to prevent WSLs due to their antimicrobial properties.


Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and GEICO--the MIMOSA study.
To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission. Patients with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer in complete clinical remission after primary surgery and platinum- and taxane-based chemotherapy were randomly assigned at a ratio of 2:1 in a phase III, double-blind, placebo-controlled, multicenter study. Abagovomab 2 mg or placebo was administered as 1-mL suspension once every 2 weeks for 6 weeks (induction phase) and then once every 4 weeks (maintenance phase) until recurrence or up to 21 months after random assignment of the last patient. The primary end point was RFS; secondary end points were OS and immunologic response. Characteristics of the 888 patients included: mean age, 56.3 years; Eastern Cooperative Oncology Group performance status, ≤ 1 in > 99% of patients; serous papillary subtype, 81.5%; stage III, 85.9%; and cancer antigen 125 ≤ 35 U/mL after third cycle, 80.9%. Mean exposure to study treatment (± standard deviation) was 449.7 ± 333.08 days. Hazard ratio (HR) of RFS for the treatment group using tumor size categorization (≤ 1 cm, > 1 cm) was 1.099 (95% CI, 0.919 to 1.315; P = .301). HR of OS using tumor size categorization (≤ 1 cm, > 1 cm) was 1.150 (95% CI, 0.872 to 1.518; P = .322). The most frequently reported type of adverse event was an injection site reaction in 445 patients (50.2%), followed by injection site erythema and fatigue in 227 (25.6%) and 212 patients (23.9%), respectively. By the final visit, median anti-anti-idiotypic antibody level was 493,000.0 ng/mL, indicating a robust response. Abagovomab administered as repeated monthly injections is safe and induces a measurable immune response. Administration as maintenance therapy for patients with ovarian cancer in first remission does not prolong RFS or OS.


Ambulatory blood pressure is associated with polymorphic variation in P2X receptor genes.
The P2X receptor gene family encodes a series of proteins that function as ATP-gated nonselective ion channels. P2X receptor channels are involved in transducing aldosterone-mediated signaling in the distal renal tubule and are potential candidate genes for blood pressure regulation. We performed a family based quantitative genetic association study in 248 families ascertained through a proband with hypertension to investigate the relationship between common genetic variation in the P2X4, P2X6, and P2X7 genes and ambulatory blood pressure. We genotyped 28 single nucleotide polymorphisms, which together captured the common genetic variability in the 3 genes. We corrected our results for multiple comparisons specifying a false discovery rate of 5%. We found significant evidence of association between the single nucleotide polymorphism rs591874 in the first intron of the P2X7 gene and blood pressure. The strongest association was found for nighttime diastolic blood pressure (P=0.0032), although association was present for both systolic and diastolic blood pressures measured by an observer during the day and at night. Genotypes were associated with a 0.2 SD ( approximately 2.5 mm Hg) difference in night diastolic blood pressure per allele and accounted for approximately 1% of the total variability in this measurement. Other suggestive associations were found, but these were nonsignificant after correction for multiple testing. These genetic data suggest that drugs affecting P2X receptor signaling may have promise as clinical antihypertensive agents.


The Risk of Hospitalization for Motor Vehicle Accident Injury in Narcolepsy and the Benefits of Stimulant Use: A Nationwide Cohort Study in Taiwan.
To examine the risk of hospitalization for motor vehicle accident injury (MVAI) in patients with narcolepsy and the effects of stimulant use on MVAI occurrence in patients with narcolepsy. This is a population-based, retrospective cohort study using Taiwan's National Health Insurance Research Database between 2000 and 2013. We included patients with narcolepsy based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, 347. The case and matched control participants were selected in a ratio of 1:3, and the traffic accident (ICD-9-CM codes: E810-E819) plus injury codes (ICD-9-CM codes: 800.xx-999.xx) due to MVAI following hospitalization were used for the study outcome. The type of injury, causes, intentionality, and the effects of stimulant use on patients with narcolepsy were also assessed. A total of 1,316 participants were enrolled, including 329 participants with narcolepsy and 987 participants without narcolepsy. During a 14-year follow-up period, a total of 104 participants had MVAI, of whom 47 (1,559.54 per 100,000 person-years) belonged to the narcolepsy cohort and 57 (556.21 per 100,000 person-years) to the non-narcolepsy cohort. After adjusting for covariates, the risk of hospitalization for MVAI among participants with narcolepsy was still significantly higher than those without narcolepsy (adjusted hazard ratio = 6.725; 95% confidence interval = 4.421-10.231; P < .001). The use of modafinil or methylphenidate, as monotherapy or combined treatment, was associated with a lower risk of MVAI in the narcolepsy cohort. Patients with narcolepsy may have a higher risk of hospitalization for MVAI and stimulant use could mitigate such risk.


Decline of childhood cancer mortality in Italy, 1955-1980.
The decline in childhood cancer mortality in Italy from 1955 to 1980 has been evaluated through (1) comparison of age-specific and age-standardized (0-14 years) rates for the periods 1955-1960 and 1979-1980 and (2) computation of expected numbers of deaths by application of the age-specific rates for the period 1955-1960 to the population structure of subsequent periods. Certified mortality fell by 35% for leukaemias, 90% for Hodgkin's disease, 30% for non-Hodgkin's lymphomas, 40% for bone sarcomas, 30% for kidney (Wilms') tumours, 65% for retinoblastoma. No clear trend was reported for other neoplasms, including neuroblastoma. About 300 cancer deaths per year were avoided in the period 1979-1980 compared with the expected number based on the 1955-1960 rates (170 for leukaemias alone). Although clearly encouraging, these trends are substantially less favourable than those from several other developed countries. It is therefore likely that several dozen other deaths from childhood cancer could be avoided each year through earlier (or more accurate) application of effective therapies, particularly for neoplasms requiring radiotherapy or surgical treatment.


Safety of dipyridamole testing in 73,806 patients: the Multicenter Dipyridamole Safety Study.
Dipyridamole imaging is widely used as an alternative to exercise testing to identify and risk stratify patients with coronary artery disease. Safety data on intravenous dipyridamole stress testing has been derived largely from individual institutional data. Data were collected retrospectively by 85 coinvestigators from 73,806 patients who underwent intravenous dipyridamole stress imaging in 59 hospitals and 19 countries to determine the incidence of major adverse reactions during testing. The dose of dipyridamole infused was 0.56 mg/kg in 64,740 patients, 0.74 mg/kg in 6551 patients, and 0.84 mg/kg in 2515 patients. Combined major adverse events among the entire 73,806 patients included seven cardiac deaths (0.95 per 10,000), 13 nonfatal myocardial infarctions (1.76 per 10,000), six nonfatal sustained ventricular arrhythmias (0.81 per 10,000) (ventricular tachycardia in two and ventricular fibrillation in four), nine transient cerebral ischemic attacks (1.22 per 10,000), (with speech or motor deficit), one stroke, and nine severe bronchospasms (1.22 per 10,000) (one intubation and eight near intubations). In addition to the safety data, detailed demographic, peripheral hemodynamic, side effect, and concomitant drug data were examined in a subgroup of 3751 patients. End points from subsets of patients were compared with those of the group as a whole. Multivariate analysis revealed that dipyridamole-induced chest pain was more common in patients less than 70 years old (p = 0.0017), those with a history of coronary revascularization (p = 0.002), or patients taking aspirin (p = 0.0001). Minor noncardiac side effects were less frequent among the elderly (p = 0.0053) and more frequent in women (p = 0.0001) and patients taking maintenance aspirin (p = 0.0034). When a patient was judged on the basis of the adequacy of hemodynamic response to be a dipyridamole "nonresponder" (< 10 mm Hg drop in systolic blood pressure and 10 beats/min increase in heart rate), the only significant predictor was angiotensin-converting enzyme inhibitor intake (p = 0.0025). Inferoposterior hypoperfusion was significantly more frequent in patients with dipyridamole-induced hypotension: 57% (44/77) (p < 0.0001) of those who had hypotension and 89% (8/9) (p = 0.0076) who had severe symptomatic bradyarrhythmias displayed inferoposterior defects on thallium scanning. Caffeine levels were determined in 391 consecutive patients: levels greater than 5 mg/L were observed in only eight patients (2%), suggesting that methylxanthine levels sufficient to alter the hemodynamic response to dipyridamole resulting in suboptimal hyperemic stress are unlikely when patients take nothing by mouth after midnight. The risk of serious dipyridamole-induced side effects is very low and is comparable to that reported for exercise testing in a similar patient population.


Persistent Hyperactivation of Endothelial Cells in Patients with Alcoholic Hepatitis.
Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. AH patients have intense hepatic infiltration of leukocytes. Up-regulation of cell adhesion molecules (CAMs) upon endothelial cell (EC) activation plays an important role in leukocyte transendothelial migration. CAMs can shed from EC surface and accumulate in the blood, serving as soluble markers for EC activation. In this study, we examined the impact of heavy drinking on expression of soluble forms of EC activation markers (CD146, ICAM-1, VCAM-1, and VEGF-A) and the effect of alcohol abstinence on the reversal of these abnormalities in heavy drinkers with and without AH. ELISA and multiplex immunoassays were used to measure soluble EC activation markers in plasma samples from 79 AH patients, 66 heavy drinkers without overt liver disease (HDC), and 44 healthy controls (HC) at baseline, 31 AH patients and 30 HDC at 6-month follow-up, and 18 AH patients and 25 HDC at 12-month follow-up. At baseline, the 4 soluble markers were significantly up-regulated in AH patients compared with HDC and HC, whereas only sVCAM-1 was elevated in HDC relative to HC. At follow-ups, plasma levels of CD146, VCAM-1, and VEGF-A remained higher in AH patients, even for those who stopped drinking. These dysregulated markers correlated with AH disease severity, clinical parameters, and several soluble inflammatory factors. The levels of soluble CD146, ICAM-1, VCAM-1, and VEGF-A were highly elevated in AH patients, and alcohol abstinence did not completely reverse these abnormalities.


Ability of Hand Hygiene Interventions Using Alcohol-Based Hand Sanitizers and Soap To Reduce Microbial Load on Farmworker Hands Soiled during Harvest.
Effective hand hygiene is essential to prevent the spread of pathogens on produce farms and reduce foodborne illness. The U.S. Food and Drug Administration Food Safety Modernization Act Proposed Rule for Produce Safety recommends the use of soap and running water for hand hygiene of produce handlers. The use of alcohol-based hand sanitizer (ABHS) may be an effective alternative hygiene intervention where access to water is limited. There are no published data on the efficacy of either soap or ABHS-based interventions to reduce microbial contamination in agricultural settings. The goal of this study was to assess the ability of two soap-based (traditional or pumice) and two ABHS-based (label-use or two-step) hygiene interventions to reduce microbes (coliforms, Escherichia coli, and Enterococcus spp.) and soil (absorbance of hand rinsate at 600 nm [A600]) on farmworker hands after harvesting produce, compared with the results for a no-hand-hygiene control. With no hand hygiene, farmworker hands were soiled (median A600, 0.48) and had high concentrations of coliforms (geometric mean, 3.4 log CFU per hand) and Enterococcus spp. (geometric mean, 5.3 log CFU per hand) after 1 to 2 h of harvesting tomatoes. Differences in microbial loads in comparison to the loads in the control group varied by indicator organism and hygiene intervention (0 to 2.3 log CFU per hand). All interventions yielded lower concentrations of Enterococcus spp. and E. coli (P < 0.05), but not of coliforms, than were found in the control group. The two-step ABHS intervention led to significantly lower concentrations of coliforms and Enterococcus spp. than the pumice soap and label-use ABHS interventions (P < 0.05) and was the only intervention to yield significantly fewer samples with E. coli than were found in the control group (P < 0.05). All interventions removed soil from hands (P < 0.05), soap-based interventions more so than ABHS-based interventions (P < 0.05). ABHS-based interventions were equally as effective as hand washing with soap at reducing indicator organisms on farmworker hands. Based on these results, ABHS is an efficacious hand hygiene solution for produce handlers, even on soiled hands.


The contributions of lesion laterality and lesion volume to decision-making impairment following frontal lobe damage.
Lesions to prefrontal cortex (PFC) in humans can severely disrupt everyday decision-making, with concomitant effects on social and occupational functioning. Forty-six patients with unilateral lesions to prefrontal cortex and 21 healthy control subjects were administered three neuropsychological measures of decision-making: the Iowa Gambling Task, the Cambridge Gamble Task, and the Risk Task. Magnetic resonance imaging (MRI) scans were acquired from 40 patients, with region of interest (ROI) mapping of prefrontal subregions. The frontal patients showed only limited damage in medial and orbital prefrontal cortex, but greater damage in lateral prefrontal regions of interest. Patients with right frontal lesions preferred the risky decks on the Iowa Gambling Task, and differed significantly from left frontal and control subjects. Within the right frontal group, the preference for the risky decks was correlated with the total lesion volume and the volume of damage outside of the ventromedial prefrontal region. Right and left frontal groups did not differ significantly on the Cambridge Gamble Task or the Risk Task, and performance was not associated with lesion volume. The results indicate a laterality effect on the Iowa Gambling Task, and the contribution of prefrontal regions outside the ventromedial region to task performance. The Cambridge Gamble Task and Risk Task were less sensitive to the effects of unilateral frontal lobe lesions, and may be more selectively associated with ventral prefrontal damage.


Annotation of cis-regulatory elements by identification, subclassification, and functional assessment of multispecies conserved sequences.
An important step toward improving the annotation of the human genome is to identify cis-acting regulatory elements from primary DNA sequence. One approach is to compare sequences from multiple, divergent species. This approach distinguishes multispecies conserved sequences (MCS) in noncoding regions from more rapidly evolving neutral DNA. Here, we have analyzed a region of approximately 238kb containing the human alpha globin cluster that was sequenced and/or annotated across the syntenic region in 22 species spanning 500 million years of evolution. Using a variety of bioinformatic approaches and correlating the results with many aspects of chromosome structure and function in this region, we were able to identify and evaluate the importance of 24 individual MCSs. This approach sensitively and accurately identified previously characterized regulatory elements but also discovered unidentified promoters, exons, splicing, and transcriptional regulatory elements. Together, these studies demonstrate an integrated approach by which to identify, subclassify, and predict the potential importance of MCSs.


Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study.
To evaluate mildly abnormal liver function test (LFT) results in general practice among patients who do not have known liver disease. Prospective cohort study of people with abnormal LFT results identified in primary care. Participants were intensively investigated using a common protocol and followed up for 2 years. Substudies investigated the psychological sequelae of abnormal test results, clinicians' reasons for testing, decision options when LFT results were abnormal and early detection of liver fibrosis. Eleven primary-care practices: eight in Birmingham and three in Lambeth. Adults with abnormal LFT results who did not have pre-existing or obvious liver disease. Eight analytes were included in the panel of LFTs. Statistical tests were used to identify the interactions between clinical features, the initial pattern of abnormal LFT results and (1) specific viral, genetic and autoimmune diseases, such as viral hepatitis, haemochromatosis and primary biliary cirrhosis; (2) a range of other serious diseases, such as metastatic cancer and hypothyroidism; (3) 'fatty liver' not associated with the above; and (4) the absence of detectable disease. Fewer than 5% of people with abnormal LFT results had a specific disease of the liver, and many of these were unlikely to need treatment. The diagnostic potential of the LFT panel is largely subsumed into just two analytes: alanine aminotransferase (ALT) and alkaline phosphatase (ALP). Gamma-glutamyltransferase (GGT) offers a small increase in sensitivity at the margin at the cost of a large loss of specificity. Eighty-four per cent of abnormal LFT results remain abnormal on retesting 1 month later. In many cases, carrying out a definitive or specific test will be more efficient than repeating LFTs, with a view to specific testing only if the test remains abnormal. An ultrasound diagnosis of 'fatty liver' was present in nearly 40% of patients with abnormal LFTs and a small amount of weight loss over 2 years was associated with a reduced incidence of liver fat. There was a J-shaped relationship between alcohol intake and fatty liver in men. An abnormal LFT result causes temporary anxiety, which does not appear to promote sustained behaviour change. Liver disease is rare among people with abnormal LFT results in primary care. Only two analytes (ALT and ALP) are helpful in identifying the majority of liver disease. GGT adds little information in return for a high false-positive rate but it is sensitive to alcohol intake. LFT results seldom revert from abnormal to normal over a 1-month period, and modelling shows that repeating an abnormal LFT panel, as recommended in the current guidelines, is inefficient. LFTs are often undertaken to meet perceived patient need for a blood test, but as they are neither specific nor indicative of any particular disease they are among the least suitable tests for this purpose. Obesity and raised ALT provide strong evidence for a presumptive diagnosis of 'fatty' liver. Abnormal LFTs and 'fatty' liver provoke only short-term anxiety and neither is associated with sustained weight loss. Even a small amount of weight loss reduces liver fat. (1) the cases of 'fatty liver' and controls should be followed up in the long term to identify features that predict development of hepatosteatosis and then cirrhosis; (2) the acceptability of replacing the traditional six- to eight-analyte LFT panel with a drop down menu including the ALT/ALP combination should be evaluated. The National Institute for Health Research Health Technology Assessment programme.


A regulatory calcium-binding site at the subunit interface of CLC-K kidney chloride channels.
The two human CLC Cl(-) channels, ClC-Ka and ClC-Kb, are almost exclusively expressed in kidney and inner ear epithelia. Mutations in the genes coding for ClC-Kb and barttin, an essential CLC-K channel beta subunit, lead to Bartter syndrome. We performed a biophysical analysis of the modulatory effect of extracellular Ca(2+) and H(+) on ClC-Ka and ClC-Kb in Xenopus oocytes. Currents increased with increasing [Ca(2+)](ext) without full saturation up to 50 mM. However, in the absence of Ca(2+), ClC-Ka currents were still 20% of currents in 10 mM [Ca(2+)](ext), demonstrating that Ca(2+) is not strictly essential for opening. Vice versa, ClC-Ka and ClC-Kb were blocked by increasing [H(+)](ext) with a practically complete block at pH 6. Ca(2+) and H(+) act as gating modifiers without changing the single-channel conductance. Dose-response analysis suggested that two protons are necessary to induce block with an apparent pK of approximately 7.1. A simple four-state allosteric model described the modulation by Ca(2+) assuming a 13-fold higher Ca(2+) affinity of the open state compared with the closed state. The quantitative analysis suggested separate binding sites for Ca(2+) and H(+). A mutagenic screen of a large number of extracellularly accessible amino acids identified a pair of acidic residues (E261 and D278 on the loop connecting helices I and J), which are close to each other but positioned on different subunits of the channel, as a likely candidate for forming an intersubunit Ca(2+)-binding site. Single mutants E261Q and D278N greatly diminished and the double mutant E261Q/D278N completely abolished modulation by Ca(2+). Several mutations of a histidine residue (H497) that is homologous to a histidine that is responsible for H(+) block in ClC-2 did not yield functional channels. However, the triple mutant E261Q/D278N/H497M completely eliminated H(+) -induced current block. We have thus identified a protein region that is involved in binding these physiologically important ligands and that is likely undergoing conformational changes underlying the complex gating of CLC-K channels.


Comparison between biodentine and formocresol for pulpotomy of primary teeth: A randomized clinical trial.
To assess and compare the clinical and radiographic success rates of biodentine and formocresol for pulpotomy in human primary teeth. A randomized, split-mouth, double-blind, controlled clinical trial was carried out in 37 healthy 4- to 8-year-old children with 56 pairs (112 teeth) of contralateral primary molars indicated for pulpotomy. Matched teeth in each pair were randomized to undergo either biodentine (n = 56 teeth) or formocresol (n = 56 teeth) pulpotomy. In both groups, the teeth were restored with stainless steel crowns. The teeth were evaluated clinically and radiographically at 3 and 6 months by two blinded, standardized, and calibrated examiners. The data were analyzed using chi-square and McNemar tests with a P value of < .05 considered significant. At both the 3- and 6-month follow-ups, all the 37 children with 112 treated teeth were evaluated. Clinical and radiographic success was similar for biodentine (100%) and formocresol (100%), without any statistically significant difference (P = 1). Pulp canal obliteration was radiographically observed in 10/56 (17.9%) and 7/56 (12.5%) cases in the biodentine and formocresol groups, respectively. Both pulpotomy techniques showed favorable clinical and radiographic outcomes at 3 and 6 months posttreatment without any significant difference. Hence, biodentine has the potential to become a substitute for formocresol in primary molar pulpotomies.


Exercise hemodynamics and oxygen delivery in human hypertension. Response to verapamil.
To characterize the hemodynamic response to exercise and the effects of calcium channel antagonism in hypertensive subjects, invasive exercise hemodynamics were performed in the baseline state after intravenous infusion of verapamil and after 5 to 7 days of oral verapamil in 10 subjects with moderate to severe hypertension. We also assessed oxygen delivery and use and the response of the sympathetic nervous system by measuring plasma norepinephrine levels at rest and during exercise. Both routes of administration were associated with significant reductions of mean arterial pressure and systemic vascular resistance at rest and peak exercise (p less than 0.05). Changes in heart rate were not statistically significant. Following oral administration of verapamil, stroke volume increased significantly in both the resting and exercise states. Pulmonary wedge pressure did not increase; in fact, the Frank-Starling relationship of cardiac performance actually was improved. Oxygen delivery and use were unchanged with both routes of administration. There was no significant difference in rest and exercise plasma norepinephrine levels following verapamil therapy. Thus, verapamil resulted in a significant reduction of mean arterial pressure, mediated by a significant reduction of systemic vascular resistance, following both intravenous and short-term oral administration. This reduction occurred without expression of left ventricular dysfunction and was not at the expense of increased oxygen use or enhanced sympathetic nervous systemic activity.


The Keller Plan in Science Teaching: An individually paced, student-tutored, and mastery-oriented instructional method is evaluated.
A review of evaluative research on the Keller plan establishes the following points: 1) The Keller plan is an attractive teaching method to most students. In every published report, students rate the Keller plan much more favorably than teaching by lecture. 2) Self-pacing and interaction with tutors seem to be the features of the Keller courses most favored by students. 3) Several investigators report higher-than-average withdrawal rates for their Keller sections. The conditions that influence withdrawal and procrastination in Keller courses have been studied, and it seems possible to control procrastination and withdrawal through course design. 4) Content learning (as measured by final examinations) is adequate in Keller courses. In the published studies, final examination performance in Keller sections always equals, and usually exceeds, performance in lecture sessions. 5) Students almost invariably report that they learn more in PSI than in lecture courses, and also nearly always report putting more time and effort into the Keller courses.


Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice.
Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance. In this in vivo study, eight-week-old C57BL/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group (n = 6) (2) HF diet; group (n = 6) (3) HF diet treated with PSO (40 mL/kg food) (n = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome. The PSO group displayed an increase in oxygen consumption, as well as a decrease in fasting glucose and blood pressure (p < 0.05) when compared to the HFD-fed mice group. PSO increased both the activity and expression of hepatic HO-1, downregulated inflammatory adipokines, and decreased hepatic fibrosis. PSO increased the levels of thermogenic genes, mitochondrial signaling, and lipid metabolism through increases in Mfn2, OPA-1, PRDM 16, and PGC1α. Furthermore, PSO upregulated obesity-mediated hepatic insulin receptor phosphorylation Tyr-972, p-IRB tyr1146, and pAMPK, thereby decreasing insulin resistance. These results indicated that PSO decreased obesity-mediated insulin resistance and the progression of hepatic fibrosis through an improved liver signaling, as manifested by increased insulin receptor phosphorylation and thermogenic genes. Furthermore, our findings indicate a potential therapeutic role for PSO in the prevention of obesity-associated NAFLD, NASH, and other metabolic disorders.


The neural mechanisms for minimizing cross-modal distraction.
The neural circuitry that increases attention to goal-relevant stimuli when we are in danger of becoming distracted is a matter of active debate. To address several long-standing controversies, we asked participants to identify a letter presented either visually or auditorily while we varied the amount of cross-modal distraction from an irrelevant letter in the opposite modality. Functional magnetic resonance imaging revealed three novel results. First, activity in sensory cortices that processed the relevant letter increased as the irrelevant letter became more distracting, consistent with a selective increase of attention to the relevant letter. In line with this view, an across-subjects correlation indicated that the larger the increase of activity in sensory cortices that processed the relevant letter, the less behavioral interference there was from the irrelevant letter. Second, regions of the dorsolateral prefrontal cortex (DLPFC) involved in orienting attention to the relevant letter also participated in increasing attention to the relevant letter when conflicting stimuli were present. Third, we observed a novel pattern of regional specialization within the cognitive division of the anterior cingulate cortex (ACC) for focusing attention on the relevant letter (dorsal ACC) versus detecting conflict from the irrelevant letter (rostral ACC). These findings indicate novel roles for sensory cortices, the DLPFC, and the ACC in increasing attention to goal-relevant stimulus representations when distracting stimuli conflict with behavioral objectives. Furthermore, they potentially resolve a long-standing controversy regarding the key contribution of the ACC to cognitive control.


Mechanical knowledge does matter to tool use even when assessed with a non-production task: Evidence from left brain-damaged patients.
In the literature on apraxia of tool use, it is now accepted that using familiar tools requires semantic and mechanical knowledge. However, mechanical knowledge is nearly always assessed with production tasks, so one may assume that mechanical knowledge and familiar tool use are associated only because of their common motor mechanisms. This notion may be challenged by demonstrating that familiar tool use depends on an alternative tool selection task assessing mechanical knowledge, where alternative uses of tools are assumed according to their physical properties but where actual use of tools is not needed. We tested 21 left brain-damaged patients and 21 matched controls with familiar tool use tasks (pantomime and single tool use), semantic tasks and an alternative tool selection task. The alternative tool selection task accounted for a large amount of variance in the single tool use task and was the best predictor among all the semantic tasks. Concerning the pantomime of tool use task, group and individual results suggested that the integrity of the semantic system and preserved mechanical knowledge are neither necessary nor sufficient to produce pantomimes. These results corroborate the idea that mechanical knowledge is essential when we use tools, even when tasks assessing mechanical knowledge do not require the production of any motor action. Our results also confirm the value of pantomime of tool use, which can be considered as a complex activity involving several cognitive abilities (e.g., communicative skills) rather than the activation of gesture engrams.


SDF-1 Bound Heparin Nanoparticles Recruit Progenitor Cells for Their Differentiation and Promotion of Angiogenesis After Stroke.
Angiogenesis after stroke is correlated with enhanced tissue repair and functional outcomes. The existing body of research in biomaterials for stroke focuses on hydrogels for the delivery of stem cells, growth factors, or small molecules or drugs. Despite the ability of hydrogels to enhance all these delivery methods, no material has significantly regrown vasculature within the translatable timeline of days to weeks after stroke. Here we developed 2 novel biomaterials for tissue regeneration after stroke, a highly porous granular hydrogel termed Cryo microgels, and heparin-norbornene nanoparticles with covalently bound SDF-1α. The combination of these materials resulted in fully revascularized vessels throughout the stroke core in only 10 days, as well as increased neural progenitor cell migration and maintenance and increased neurons.


The Longitudinal Associations Between Paternal Incarceration and Family Well-Being: Implications for Ethnic/Racial Disparities in Health.
Ethnic/racial minority children in the United States are more likely to experience father loss to incarceration than White children, and limited research has examined the health implications of these ethnic/racial disparities. Telomere length is a biomarker of chronic stress that is predictive of adverse health outcomes. This study examined whether paternal incarceration predicted telomere length shortening among offspring from childhood to adolescence, whether maternal depression mediated the link, and whether ethnicity/race moderated results. Research participants included 2,395 families in the Fragile Families and Child Wellbeing study, a national and longitudinal cohort study of primarily low-income families from 20 large cities in the United States. Key constructs were measured when children were on average ages 9 (2007-2010) and 15 (2014-2017). Children who experienced paternal incarceration exhibited shorter telomere lengths between ages 9 and 15, and changes in maternal depression mediated this finding. Specifically, mothers who experienced a partner's incarceration were more likely to have depression between children's ages 9 and 15. In turn, increases in maternal depression between children's ages 9 and 15 predicted more accelerated telomere length shortening among children during this period. Paternal incarceration was more prevalent and frequent for ethnic/racial minority youth than for White youth. Paternal incarceration is associated with a biomarker of chronic stress among children in low-income families. Rates of paternal incarceration were more prevalent and frequent among Black American and multiethnic/multiracial families than among White Americans. As a result, the mass incarceration crisis of the criminal justice system is likely shaping intergenerational ethnic/racial health disparities.


Epigallocatechin gallate inhibits the HIV reverse transcription step.
Epigallocatechin gallate (EGCG), the most abundant catechin in green tea, has been reported to inhibit HIV-1 replication prior to its integration into host DNA via various proposed mechanisms; however, the specific main target(s) of EGCG remain unclear. In this study, we investigated a number of these proposed detailed mechanism(s) using a cell-based model. Multinuclear activation of galactosidase indicator assays were used for all experiments, including examination of the time of addition and the synergisms with a nucleoside reverse transcriptase inhibitor, 3'-azido-3'-deoxythymidine (AZT). The experiments revealed that EGCG suppressed both HIV-1(IIIB) and HIV-2(EHO) infection in HeLa-CD4-LTR-β-gal cells, with relatively low 50% effective concentrations of 1.6 and 2.0 μM, respectively. The inhibitory profile of EGCG generated using a time-of-addition assay was identical to that of a non-nucleoside reverse transcriptase inhibitor (NNRTI), MKC-442. Furthermore, synergistic inhibition was observed in EGCG with AZT. Based on our findings, EGCG appears to act mainly as an allosteric reverse transcriptase inhibitor with mechanisms different from those of currently approved NNRTIs that directly interact with the NNRTI binding pocket. Thus, EGCG is a good candidate for use as an additional or supportive anti-HIV agent derived from natural plants.


Occupational Exposure and Carriage of Antimicrobial Resistance Genes (tetW, ermB) in Pig Slaughterhouse Workers.
Slaughterhouse staff is occupationally exposed to antimicrobial resistant bacteria. Studies reported high antimicrobial resistance gene (ARG) abundances in slaughter pigs. This cross-sectional study investigated occupational exposure to tetracycline (tetW) and macrolide (ermB) resistance genes and assessed determinants for faecal tetW and ermB carriage among pig slaughterhouse workers. During 2015-2016, 483 faecal samples and personal questionnaires were collected from workers in a Dutch pig abattoir, together with 60 pig faecal samples. Human dermal and respiratory exposure was assessed by examining 198 carcass, 326 gloves, and 33 air samples along the line, next to 198 packed pork chops to indicate potential consumer exposure. Samples were analyzed by qPCR (tetW, ermB). A job exposure matrix was created by calculating the percentage of tetW and ermB positive carcasses or gloves for each job position. Multiple linear regression models were used to link exposure to tetW and ermB carriage. Workers are exposed to tetracycline and macrolide resistance genes along the slaughter line. Tetw and ermB gradients were found for carcasses, gloves, and air filters. One packed pork chop contained tetW, ermB was non-detectable. Human faecal tetW and ermB concentrations were lower than in pig faeces. Associations were found between occupational tetW exposure and human faecal tetW carriage, yet, not after model adjustments. Sampling round, nationality, and smoking were determinants for ARG carriage. We demonstrated clear environmental tetracycline and macrolide resistance gene exposure gradients along the slaughter line. No robust link was found between ARG exposure and human faecal ARG carriage.


Denervation of the ear and the 'folding flower' illusion.
Following acute denervation of the ear, I experienced altered cutaneous sensory perception analogous to that reported by patients after limb amputation. This suggests that any sudden, complete loss of somaesthetic sensation can result in cortical reorganisation reflecting lost peripheral input. Although the short time course of the phenomenon suggests an initial functional reorganisation, it does not preclude longer time course structural alterations at multiple levels of the nervous system.


The impact of diabetes in patients with necrotizing soft tissue infections.
Given the association of diabetes with necrotizing soft tissue infections (NSTIs) and hyperglycemia with mortality in critically ill patients, this study investigates the impact of diabetes and hyperglycemia in NSTI patients. This is a retrospective review of NSTI patients at LBJ General Hospital between January 1995 and December 2002, assessing infectious morbidity, mortality, and length of hospital stay. There was a trend towards increased infectious complications, defined as a hospital-acquired (not present within 48 h of presentation) infection at a secondary site, amongst diabetic patients (RR 2.1, 95% CI 0.7-6.8) and patients with admission hyperglycemia greater than 200 mg/dL (OR 1.9, 95% CI 0.7-5.7) but not with admission hyperglycemia greater than 120 mg/dL (OR 1.6, 95% CI 0.3-8.7). Patients with an infectious complication had a longer hospital stay (median, interquartile range [IQR]; 36, 30-44 days vs. 10, 7-20 days, p < 0.001), increased mortality (29% vs. 7%, p = 0.05), and poorer outcome defined as death, amputation, or hospital stay exceeding the 75th percentile for length of stay (79% vs. 20%, p < 0.001). Diabetes mellitus and admission hyperglycemia may increase infectious complications in NSTI patients, predicting a longer and more complicated hospital course. Further study is required to define the optimal metabolic target in this patient population.


The formation of tri-iodothyronine and reverse tri-iodothyronine from thyroxine in isolated rat renal tubules.
1. Conversion of thyroxine into tri-iodothyronine and reverse tri-iodothyronine in intact cells was studied with isolated renal tubules prepared by collagenase digestion. 2. Conversion of thyroxine into tri-iodothyronine and reverse tri-iodothyronine increased progressively for at least 90 min. 3. Studies of tri-iodothyronine production from increasing amounts of thyroxine revealed that the thyroxine to tri-iodothyronine conversion is saturable. 4. Iodine and carbimazole had no effect on the thyroxine to tri-iodothyronine conversion. 5. 6-Propyl-2-thiouracil had a direct non-competitive inhibitory effect on the conversion of thyroxine into tri-iodothyronine with a 75% inhibition of the conversion at a propylthiouracil concentration within the therapeutic range in vivo. Propylthiouracil also inhibited the net formation of reverse tri-iodothyronine from thyroxine at a similar propylthiouracil concentration, as well as inhibiting the subsequent degradation of reverse tri-iodothyronine.


Use of NHANES data to link chemical exposures to chronic diseases: a cautionary tale.
The National Health and Nutrition Examination Survey (NHANES) is one example of cross-sectional datasets that have been used to draw causal inferences regarding environmental chemical exposures and adverse health outcomes. Our objectives were to analyze four NHANES datasets using consistent a priori selected methods to address the following questions: Is there a consistent association between urinary bisphenol A (BPA) measures and diabetes, coronary heart disease (CHD), and/or heart attack across surveys? Is NHANES an appropriate dataset for investigating associations between chemicals with short physiologic half-lives such as BPA and chronic diseases with multi-factorial etiologies? Data on urinary BPA and health outcomes from 2003-2004, 2005-2006, 2007-2008, and 2009-2010 were available. Regression models were adjusted for creatinine, age, gender, race/ethnicity, education, income, smoking, heavy drinking, BMI, waist circumference, calorie intake, family history of heart attack, hypertension, sedentary time, and total cholesterol. Urinary BPA was not significantly associated with adverse health outcomes for any of the NHANES surveys, with ORs (95% CIs) ranging from 0.996 (0.951-1.04) to 1.03 (0.978-1.09) for CHD, 0.987 (0.941-1.04) to 1.04 (0.996-1.09) for heart attack, and 0.957 (0.899-1.02) to 1.01 (0.980-1.05) for diabetes. Using scientifically and clinically supportable exclusion criteria and outcome definitions, we consistently found no associations between urinary BPA and heart disease or diabetes. These results do not support associations and causal inferences reported in previous studies that used different criteria and definitions. We are not drawing conclusions regarding whether BPA is a risk factor for these diseases. We are stating the opposite--that using cross-sectional datasets like NHANES to draw such conclusions about short-lived environmental chemicals and chronic complex diseases is inappropriate. We need to expend resources on appropriately designed epidemiologic studies and toxicological explorations to understand whether these types of chemicals play a causal role in chronic diseases.


Frequency-dependent synaptic potentiation, depression and spike timing induced by Hebbian pairing in cortical pyramidal neurons.
Experiments by Markram and Tsodyks (Nature, 382 (1996) 807-810) have suggested that Hebbian pairing in cortical pyramidal neurons potentiates or depresses the transmission of a subsequent pre-synaptic spike train at steady-state depending on whether the spike train is of low frequency or high frequency, respectively. The frequency above which pairing induced a significant decrease in steady-state synaptic efficacy was as low as about 20 Hz and this value depends on such synaptic properties as probability of release and time constant of recovery from short-term synaptic depression. These characteristics of cortical synapses have not yet been fully explained by neural models, notably the decreased steady-state synaptic efficacy at high pre-synaptic firing rates. This article suggests that this decrease in synaptic efficacy in cortical synapses was not observed at steady-state, but rather during a transition period preceding it whose duration is frequency-dependent. It is shown that the time taken to reach steady-state may be frequency-dependent, and may take considerably longer to occur at high than low frequencies. As a result, the pairing-induced decrease in synaptic efficacy at high pre-synaptic firing rates helps to localize the firing of the post-synaptic neuron to a short time interval following the onset of high-frequency pre-synaptic spike trains. This effect may "speed up the time scale" in response to high-frequency bursts of spikes, and may contribute to rapid synchronization of spike firing across cortical cells that are bound together by associatively learned connections.


Ligand endocytosis drives receptor dissociation and activation in the Notch pathway.
Endocytosis of the ligand delta; is required for activation of the receptor Notch during Drosophila development. The Notch extracellular domain (NotchECD) dissociates from the Notch intracellular domain (NotchICD) and is trans-endocytosed into delta;-expressing cells in wild-type imaginal discs. Reduction of dynamin-mediated endocytosis in developing eye and wing imaginal discs reduces Notch dissociation and Notch signalling. Furthermore, dynamin-mediated delta endocytosis is required for Notch trans-endocytosis in Drosophila cultured cell lines. Endocytosis-defective delta proteins fail to mediate trans-endocytosis of Notch in cultured cells, and exhibit aberrant subcellular trafficking and reduced signalling capacity in Drosophila. We suggest that endocytosis into delta-expressing cells of NotchECD bound to delta plays a critical role during activation of the Notch receptor and is required to achieve processing and dissociation of the Notch protein.


Health service providers' perceptions of barriers to tuberculosis care in Russia.
The Russian Federation has witnessed a marked rise in rates of tuberculosis (TB) over the past decade. Public health TB control institutions remain broadly modelled along pre-1990 lines despite substantial programmes of investment and advocacy in implementing the World Health Organization's 'Directly Observed Treatment--short course' (DOTS) strategy. In 2002, we undertook a qualitative study to explore health care providers' perceptions of existing barriers to access to TB services in Samara Oblast in Russia. Six focus group discussions were conducted with physicians and nurses from facilities in urban and rural areas. Data were analyzed using a framework approach for applied policy research. Barriers to access to care were identified in interconnected areas: barriers associated with the health care system, care process barriers, barriers related to wider contextual issues, and barriers associated with patients' personal characteristics and behaviour. In the health care system, insufficient funding was identified as an underlying problem resulting in a decrease in screening coverage, low salaries, staff shortages, irregularities in drug supplies and outdated infrastructure. Suboptimal collaboration with general health services and social services limits opportunities for care and social support to patients. Worsening socioeconomic conditions were seen both as a cause of TB and a major obstacle to access to care. Behavioural characteristics were identified as an important barrier to effective care and treatment, and health staff favoured compulsory treatment for 'noncompliant' patients and involvement of the police in defaulter tracing. TB was profoundly associated with stigma and this resulted in delays in accessing care and barriers to ensuring treatment success.


A Nationwide Assessment of the Emergency Department Management of Acute Urinary Retention Due to Urethral Stricture.
To evaluate the nationwide practice patterns of the management of acute urinary retention (AUR) secondary to urethral stricture (US) in an emergency department (ED) setting. We used the 2006-2010 Nationwide Emergency Department Sample to identify men with US who received treatment for AUR. We excluded patients with benign prostatic hyperplasia, vesicourethral anastomotic stenosis, neurogenic bladder, and bladder cancer. Primary outcome was urethral dilation or suprapubic tube (SPT) placement as initial AUR management. Patient demographics and hospital factors were also examined. Multivariate logistic regression was performed to examine factors associated with initial AUR management. We identified 4794 weighted ED encounters of men with US who underwent urethral dilation or SPT placement for AUR. Mean age was 58.6 ± 0.8 years. A total of 4084 (85%) men received urethral dilation, whereas 710 had SPT (15%) placement. In bivariate analysis, patients who received SPT were likely to be younger (P <.001), treated in recent years (P = .002), and in hospitals in the West region (P = .003). In multivariate analysis, SPT placement was significantly associated with younger age (P = .004), public insurance (P = .03), recent treatment years (P = .02), and hospitals in the West region (P = .02). Income and hospital teaching status did not have significant association with initial treatment choice. Urethral dilation remains the most common urologic intervention in the ED for AUR due to US; however, there is an increasing trend toward SPT placement. Patients who are younger, publicly insured, or who receive care in the West region are more likely to receive a SPT for initial treatment of AUR due to US.


Internet pathways in suicidality: a review of the evidence.
The general aim of this study was to review the scientific literature concerning the Internet and suicidality and to examine the different pathways by which suicidal risks and prevention efforts are facilitated through the Internet. An online literature search was conducted using the MEDLINE and Google Scholar databases. The main themes that were investigated included pathological Internet use and suicidality, pro-suicide websites, suicide pacts on the Internet, and suicide prevention via the Internet. Articles were screened based on the titles and abstracts reporting on the themes of interest. Thereafter, articles were selected based on scientific relevance of the study, and included for full text assessment. The results illustrated that specific Internet pathways increased the risk for suicidal behaviours, particularly in adolescents and young people. Several studies found significant correlations between pathological Internet use and suicidal ideation and non-suicidal self-injury. Pro-suicide websites and online suicide pacts were observed as high-risk factors for facilitating suicidal behaviours, particularly among isolated and susceptible individuals. Conversely, the evidence also showed that the Internet could be an effective tool for suicide prevention, especially for socially-isolated and vulnerable individuals, who might otherwise be unreachable. It is this paradox that accentuates the need for further research in this field.


Role of nitric oxide and adenosine in control of coronary blood flow in exercising dogs.
Inhibition of nitric oxide (NO) synthesis results in very little change in coronary blood flow, but this is thought to be because cardiac adenosine concentration increases to compensate for the loss of NO vasodilation. Accordingly, in the present study, adenosine measurements were made before and during NO synthesis inhibition during exercise. Experiments were performed in chronically instrumented dogs at rest and during graded treadmill exercise before and during inhibition of NO synthesis with N(omega)-nitro-L-arginine (L-NNA, 35 mg/kg IV). Before inhibition of NO synthesis, myocardial oxygen consumption increased approximately 3.7-fold, and coronary blood flow increased approximately 3.2-fold from rest to the highest level of exercise, and this was not changed by NO synthesis inhibition. Coronary venous oxygen tension was modestly reduced by L-NNA at all levels of myocardial oxygen consumption. However, the slope of the relationship between myocardial oxygen consumption and coronary venous oxygen tension was not altered by L-NNA. Inhibition of NO synthesis did not increase coronary venous plasma or estimated interstitial adenosine concentration. During exercise, estimated interstitial adenosine remained well below the threshold concentration necessary for coronary vasodilation before or after L-NNA. NO causes a modest coronary vasodilation at rest and during exercise but does not act as a local metabolic vasodilator. Adenosine does not mediate a compensatory local metabolic coronary vasodilation when NO synthesis is inhibited.


Improvement of endothelial nitric oxide synthase activity retards the progression of diabetic nephropathy in db/db mice.
Impaired endothelial nitric oxide synthase (eNOS) activity may be involved in the pathogenesis of diabetic nephropathy. To test this, we used the type 2 diabetic db/db mouse (BKS background) model and found impaired eNOS dimerization and phosphorylation along with moderate glomerular mesangial expansion and increased glomerular basement membrane (GBM) thickness at 34 weeks of age. Cultured murine glomerular endothelial cells exposed to high glucose had similar alterations in eNOS dimerization and phosphorylation. Treatment with sepiapterin, a stable precursor of the eNOS cofactor tetrahydrobiopterin, or the nitric oxide precursor L-arginine corrected changes in eNOS dimerization and phosphorylation, corrected permeability defects, and reduced apoptosis. Sepiapterin or L-arginine, administered to db/db mice from weeks 26 to 34, did not significantly alter hyperfiltration or affect mesangial expansion, but reduced albuminuria and GBM thickness, and decreased urinary isoprostane and nitrotyrosine excretion (markers of oxidative stress). Although there was no change in glomerular eNOS monomer expression, both sepiapterin and L-arginine partially reversed the defect in eNOS dimerization and phosphorylation. Hence, our results support an important role for eNOS dysfunction in diabetes and suggest that sepiapterin supplementation might have therapeutic potential in diabetic nephropathy.