Strong sensitivity of Pine Island ice-shelf melting to climatic variability.
Pine Island Glacier has thinned and accelerated over recent decades, significantly contributing to global sea-level rise. Increased oceanic melting of its ice shelf is thought to have triggered those changes. Observations and numerical modeling reveal large fluctuations in the ocean heat available in the adjacent bay and enhanced sensitivity of ice-shelf melting to water temperatures at intermediate depth, as a seabed ridge blocks the deepest and warmest waters from reaching the thickest ice. Oceanic melting decreased by 50% between January 2010 and 2012, with ocean conditions in 2012 partly attributable to atmospheric forcing associated with a strong La Niña event. Both atmospheric variability and local ice shelf and seabed geometry play fundamental roles in determining the response of the Antarctic Ice Sheet to climate.


Psychiatry and politics in Pelotas, Brazil: the equivocal quality of conduct disorder and related diagnoses.
The world-wide emergence of categories for diagnosing mental health problems in children and youth such as conduct disorder is often attributed to the globalization of a highly biomedical form of psychiatry. In Brazil, a small group of therapists are resisting biomedicalization by keeping psychodynamic traditions alive and aiming to transform psychotherapy into a resource for politicized youth empowerment. Nevertheless, clinical practices demonstrate an increased use of biomedical diagnoses and therapeutic routines. On the basis of fieldwork with therapists and teachers, and a nine-year-long ethnography of young people, this article explores the localized effects of these potentially contradictory developments. Results show that the growth of biomedical practices alongside politicized therapeutic approaches is not indicative of underlying ambiguities but has, rather, emerged from the purposefully equivocal nature of Brazilian social, medical, and professional life. The article uses this Brazilian case study to critically debate theories of medicalization in the anthropology of psychiatry.


Successful controlled ovarian stimulation and vitrification of oocytes in an adolescent diagnosed with myelodysplastic/pre-malignant clone with monosomy 7.
An improvement in long-term outcomes for malignancies and non-malignant conditions, together with a review of the NICE Guideline, has led to a need to provide clinical services to deal with the sequelae of disease, its treatment, and subsequent survival of young people diagnosed with cancer. In this article, we describe fertility preservation in an adolescent female diagnosed with Myelodysplastic/pre-malignant Clone with Monosomy 7 with pathophysiology like that of chronic myeloid leukaemia (CML) with known genetic markers in the tumour cells. We used random start controlled ovarian stimulation (COS) leading to oocyte collection and vitrification of metaphase II oocytes. Despite successful COS and vitrification, there remain numerous ethical considerations that merit more focussed discussion. Not least, in determining best practice for informed consent, but consideration of individualised protocols for ovarian stimulation, monitoring follicular development, together with prevention of ovarian hyperstimulation syndrome (OHSS) when considering most appropriate trigger for oocyte maturation. Random-start controlled ovarian stimulation and oocyte vitrification for adolescent girls diagnosed with cancer can be safely achieved through a collaborative, multidisciplinary and expert team approach. This case study offers a promising approach to fertility preservation, and would minimise the risk of introducing malignant cells after recovery.


Improved machine learning models for predicting selective compounds.
The identification of small potent compounds that selectively bind to the target under consideration with high affinities is a critical step toward successful drug discovery. However, there is still a lack of efficient and accurate computational methods to predict compound selectivity properties. In this paper, we propose a set of machine learning methods to do compound selectivity prediction. In particular, we propose a novel cascaded learning method and a multitask learning method. The cascaded method decomposes the selectivity prediction into two steps, one model for each step, so as to effectively filter out nonselective compounds. The multitask method incorporates both activity and selectivity models into one multitask model so as to better differentiate compound selectivity properties. We conducted a comprehensive set of experiments and compared the results with those of other conventional selectivity prediction methods, and our results demonstrated that the cascaded and multitask methods significantly improve the selectivity prediction performance.


What promotes sustainability in Safe Community programmes?
The theory and practice of safety promotion has traditionally focused on the safety of individuals. This study also includes systems, environments, and organizations. Safety promotion programmes are designed to support community health initiatives taking a bottom-up approach. This is a long-term and complex process. The aim of this study was to try to empirically identify factors that promote sustainability in the structures of programmes that are managed and coordinated by the local government. Four focus group sessions with local government politicians and administrators in designated Safe Communities were conducted and analyzed using qualitative content analysis. Collaboration was found to be the basis for sustainability. Networks, enabling municipalities to exchange ideas, were reported to positively influence the programmes. Personal contacts rather than organizations themselves, determine whether collaboration is sustained. Participants reported an increase in cross-disciplinary collaboration among staff categories. Administrators and politicians were reported to collaborate well, which was perceived to speed up decision-making and thus to facilitate the programme work. Support from the politicians and the county council was seen as a prerequisite. Participants reported an increased willingness to share information between units, which, in their view, supports sustainability. A structure in which all local authorities' offices were located in close proximity to one another was considered to support collaboration. Appointing a public health coordinator responsible for the programme was seen as a way to strengthen the relational resources of the programme. With a public health coordinator, the 'external' negotiating power was concentrated in one person. Also, the 'internal' programme strength increased when the coordination was based on a bureaucratic function rather than on one individual. Increased relational resources facilitated the transfer of information. A regular flow of information to policy-makers, residents, and staff was needed in order to integrate safety programmes into routines. Adopting a bottom-up approach requires that informal and ad hoc activities in information management be replaced by formalized, organizationally sanctioned routines. In contrast to injury prevention, which focuses on technical solutions, safety promotion tries to influence attitudes. Collaboration with the media was an area that could be improved.


Development of tolerance to the prolongation of hexobarbitone sleeping time caused by cannabidiol.
1 The effects of acute and subacute cannabidiol (CBD) administration on hexobarbitone sleeping time and on some constituents of the hepatic microsomal drug-metabolizing system were assessed in the mouse.2 Acutely administered CBD prolonged sleeping time; but with subacute treatment, tolerance to the effect rapidly developed.3 Brain hexobarbitone concentration upon awakening was unchanged by either acute or subacute CBD treatment, which suggests that neither the prolongation of sleeping time nor the tolerance is the result of a change in sensitivity of the central nervous system to the barbiturate.4 Acute CBD treatment increased the half-time of hexobarbitone in the brain, which returned toward normal with the development of tolerance.5 Acutely, CBD caused a 30% decrease in hepatic cytochrome P-450 level; with tolerance, the cytochrome concentration returned to normal.6 The evidence suggests that the CBD-induced prolongation of barbiturate sleeping time and the tolerance to this effect are the result of changes in the rate of drug metabolism, which are related to changes in the amount of cytochrome P-450.7 The effects of CBD on the hepatic microsomal drug-metabolizing enzyme system are different from those attributed to SKF 525-A and piperonyl butoxide because the cannabinoid does not decrease cytochrome P-450 quantitatively by complex formation, it does not produce a recovery overshoot in the cytochrome concentration and, finally, it does not cause an induction of the hexobarbitone-metabolizing enzymes.


Multivariate ratio analysis and DNA markers reveal a new Australian species and three synonymies in eucalypt-gall-associated Megastigmus (Hymenoptera: Megastigmidae).
The genus Megastigmus Dalman, 1820 (Hymenoptera: Megastigmidae) contains potential biocontrol agents of the invasive eucalypt galling chalcid Leptocybe spp. (Hymenoptera: Eulophidae), with several species reported in various parts of the world. Species discrimination is challenging due to intraspecific morphological variation, difficulty in measuring sizes of body parts, and the lack of information regarding the global distribution of parasitic Megastigmus. We used two species commonly associated with Leptocybe in its native range to review taxonomic methods and determine the most reliable morphological characters in species delimitation. We examined size variation of body characters, and conducted species discrimination using multivariate ratio analysis, mitochondrial Cytochrome c oxidase subunit 1 (COI) and nuclear 28S rDNA (28S) sequences. Morphological traits were effective in species delimitation yet revealed high variation in several characters employed in current keys. Knowledge generated on morphology and DNA justified the description of a new species, M. manonae, sp. n., the first record of M. pretorianensis in Australia, and revised diagnostic characters for M. zvimendeli. Based on these diagnostic characters and molecular data, we synonymize three species (M. judikingae, syn. n., from Australia, M. sichuanensis, syn. n., from China and M. icipeensis, syn. n., from Kenya) with M. zvimendeli. Our findings highlight the importance of molecular markers in assisting taxonomic decision-making and the need for coordinated work in identifying Megastigmus associated with Leptocybe spp.


Sensorimotor network rewiring in mild cognitive impairment and Alzheimer's disease.
This study aimed at elucidating whether (a) brain areas associated with motor function show a change in functional magnetic resonance imaging (fMRI) signal in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD), (b) such change is linear over the course of the disease, and (c) fMRI changes in aMCI and AD are driven by hippocampal atrophy, or, conversely, reflect a nonspecific neuronal network rewiring generically associated to brain tissue damage. FMRI during the performance of a simple motor task with the dominant right-hand, and structural MRI (i.e., dual-echo, 3D T1-weighted, and diffusion tensor [DT] MRI sequences) were acquired from 10 AD patients, 15 aMCI patients, and 11 healthy controls. During the simple-motor task, aMCI patients had decreased recruitment of the left (L) inferior frontal gyrus compared to controls, while they showed increased recruitment of L postcentral gyrus and head of L caudate nucleus, and decreased activation of the cingulum compared with AD patients. Effective connectivity was altered between primary sensorimotor cortices (SMC) in aMCI patients vs. controls, and between L SMC, head of L caudate nucleus, and cingulum in AD vs. aMCI patients. Altered fMRI activations and connections were correlated with the hippocampal atrophy in aMCI and with the overall GM microstructural damage in AD. Motor-associated functional cortical changes in aMCI and AD mirror fMRI changes of the cognitive network, suggesting the occurrence of a widespread brain rewiring with increasing structural damage rather than a specific response of cognitive network.


Antibiotics alone for uncomplicated acute appendicitis in high operative risk adult patients: Analytical review of RCTs and proposal of evidence based treatment decision.
Clinical trials have so far shown controversial results as regards the standard of care for treating uncomplicated acute appendicitis (uC-AA). High operational risk adult patients (HORAP) could represent selected patients where primary antibiotic conservative therapy (pACT or A) could be indicated. We carried a comprehensive search of the PubMed searching engine in the English language scientific literature from 1995 to 2015, using medical subject headings "antibiotics", "uncomplicated appendicitis", "appendicectomy", "conservative treatment", "surgery" and "randomized clinical trial". All RCTs comparing the outcomes of pACT versus primary surgical open or laparoscopic appendectomy (pSOLA or S) as primary treatment options for uC-AA were identified. Inclusion criteria for our analytical review were RCTs evaluating outcomes in terms of or related to all of the following four parameters: treatment efficacy, post therapeutic/operative complications, in hospital length of stay (LOS) and recurrence. The conclusion of all five RCTs considered antibiotics alone in the treatment of AA as an efficient and non inferior therapeutic option respect to surgery. Primary ACT was characterised by a higher LOS, a higher rate of recurrence and a lower rate of postoperative complication than pSOLA. Based on the current body of evidence, an appropriate pACT could be a rational tailored primary treatment option for CT proven uC-AA in HORAP. Accurate diagnoses and surgical risk stratification in patients with uC-AA could aid decision making for target therapy. However, results of large sample prospective multicenter RCTs are required to routinely recommend pACT for uC-AA in the clinical practice.


Affordability, cost-effectiveness and efficiency of primary health care: the Bamako Initiative experience in Benin and Guinea.
Since 1986 two West African countries, Benin and Guinea, have been actively reorganizing their peripheral health systems according to strategies subsequently called the "Bamako Initiative". Two preceding articles described the strategies implemented and the increased effectiveness of primary health care (PHC) witnessed over a period of six years. This article presents an analysis of cost and coverage data from biannual monitoring sessions between 1988 and 1993 in approximately 200 health centres in Benin and 214 in Guinea. In order to assess affordability, the total and per capita recurrent costs for operational health centres are analysed and then compared. The cost analysis reveals a mean total cost per health centre per year of slightly over US+11,000 in Benin and nearly US+9,000 in Guinea. The median cost per capita per year is approximately US+1.0 in Benin and between US+0.60 and US+0.80 in Guinea. Comparisons of these costs between regions, health centres and over time (as coverage levels evolved) show very little variation in either country. Cost-effectiveness is estimated by allocating these costs to immunization, antenatal and curative care and comparing them to the coverage achieved with these interventions. First, the cost-effectiveness of the Bamako Initiative (BI) system as a whole is analysed. The cost per fully vaccinated child is calculated at US+10.9 in Benin and US+8.8 in Guinea. The cost per woman receiving at least three antenatal visits is US+7 in Benin and US+4.7 in Guinea. For curative care, cost per full treatment is US+1.6 in Benin and half this amount in Guinea. Cost-effectiveness is variable between regions, health centres reveals that these differences in cost-effectiveness are mainly caused by the coverage levels achieved, since total costs are relatively stable. Finally the efficiency of drug management and prescriptions as well as of outreach for the expanded programme of immunizations (EPI) is estimated by relating specific drug and outreach activities costs to the number of beneficiaries. The average cost of drugs per treatment is around US+0.5 in Benin and around US+0.3 in Guinea. Cost analysis of outreach activities undertaken for EPI in Guinea revealed a similar average cost per child completely vaccinated for health centres with different intensities of outreach (approximately US+10) and an additional cost per child vaccinated attributable to outreach of US+1-2.


Minimal effects of two aldose reductase inhibitors, AL-1576 and AL-4114, after subacute topical-ocular dosing on xenobiotic biotransformation in rabbits.
Aldose reductase is believed to be involved in teh etiology of diabetic complications, including cataractogenesis, nephropathy, and neuropathy. AL-1576 and AL-4114, two spirohydantoin aldose reductase inhibitors, were specifically developed for prevention of diabetic cataractogenesis. This study has determined whether AL-1576 and AL-4114 are inducers of biotransformation by assaying the activities of some phase I and phase II enzymes in the liver, kidney, intestine, and five ocular tissues (cornea, lens, iris-ciliary body, retina, and choroid). The aldose reductase inhibitors were administered topically (the intended route for use in preventing cataractogenesis) in two concentrations (0.5 and 5.0%) each 3 times/day to both eyes of New Zealand white rabbits for 14 days. Lenticular aldose reductase activity was decreased by 30-75% by the aldose reductase inhibitors. Monooxygenase activity toward benzo(a)pyrene, ethoxyresorufin, and methoxycoumarin was not increased by AL-1576 or AL-4114 treatment in any tissue. Activities of 1-chloro-2,4-dinitrobenzene glutathione S-transferase, 2-naphthol sulfotransferase, and 1-naphthol UDP-glucuronosyltransferase were not significantly induced in the eight tissues. Clearly, ocular dosing with AL-4114 and AL-1576 for 14 days had little effect on hepatic, intestinal, and ocular biotransformation.


Increase in frailty of older workers and retirees predicted by negative psychosocial working conditions on the job.
Well-established evidence has shown that negative psychosocial working conditions adversely affect the health and well-being of prime-age workers, yet little is known about the consequences on the health of older workers. Our article examines the associations between declines in health in later life, measured as frailty, and negative psychosocial working conditions, and considers the role of retirement. We use longitudinal cross-national data collected by SHARE I and SHARE IV and focus on the respondents who were working at baseline. We find that low reward, high effort, effort to reward ratio, and effort to control ratio were all predictors of increasing frailty. The association between low reward and change in frailty was modified by retirement status at follow-up, with nonretired respondents in low-reward jobs experiencing the largest increases in frailty at follow-up. These results suggest that the effect of psychosocial working conditions on physical health may extend well past the prime working age, and retirement may have a protective effect on the health of older workers in low reward jobs.


Key stages in mammary gland development: the mammary end bud as a motile organ.
In the rodent, epithelial end buds define the tips of elongating mammary ducts. These highly motile structures undergo repeated dichotomous branching as they aggressively advance through fatty stroma and, turning to avoid other ducts, they finally cease growth leaving behind the open, tree-like framework on which secretory alveoli develop during pregnancy. This review identifies the motility of end buds as a unique developmental marker that represents the successful integration of systemic and local mammotrophic influences, and covers relevant advances in ductal growth regulation, extracellular matrix (ECM) remodeling, and cell adhesion in the inner end bud. An unexpected growth-promoting synergy between insulin-like growth factor-1 and progesterone, in which ducts elongate without forming new end buds, is described as well as evidence strongly supporting self-inhibition of ductal elongation by end-bud-secreted transforming growth factor-beta acting on stromal targets. The influence of the matrix metalloproteinase ECM-remodeling enzymes, notably matrix metalloproteinase-2, on end bud growth is discussed in the broader context of enzymes that regulate the polysaccharide-rich glycosaminoglycan elements of the ECM. Finally, a critical, motility-enabling role for the cellular architecture of the end bud is identified and the contribution of cadherins, the netrin/neogenin system, and ErbB2 to the structure and motility of end buds is discussed.


Nutrient removal and microbial communities' development in a young unplanted constructed wetland using Bauxsol™ pellets to treat wastewater.
Municipal wastewater was treated over a six month period in an unplanted constructed wetland with a lower soil layer and an upper Bauxsol™ pellet layer. The interactions between Bauxsol™ pellets, soil, effluent and microbial communities demonstrated a positive influence on contaminant removal. Bauxsol™ treated effluent showed >95% phosphate removal and ~26% nitrogen removal during the trial. Substantial quantities of nitrate, trace-metals and Colwell P were bound to the pellets, whereas only ammonium was bound to the soil. The structure of microbial communities analysed by denaturing gradient gel electrophoresis (DGGE) showed distinct bacterial communities attached to Bauxsol™ pellets and soil owing to differences in geochemistry and micro-environmental conditions. Polymerase chain reaction (PCR) amplification of specific marker genes (i.e. bacterial and archaeal amoA genes, nosZ gene, and hzo gene) was used to evaluate the presence of microbial communities associated with nitrogen transformation. Data revealed the co-existence of aerobic ammonia-oxidising bacteria, anaerobic ammonia-oxidising bacteria (anammox) and denitrifiers attached to Bauxsol™ pellets and ammonia-oxidising bacteria and archaea attached to soil. This study successfully demonstrates that Bauxsol™ pellets are a suited alternative media for constructed wetland to treat wastewater effectively removing phosphate and serving as biomass support particles for bacterial communities associated with nitrogen-cycling.


C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis.
The C9orf72 repeat expansion has been reported as a negative prognostic factor in amyotrophic lateral sclerosis (ALS). We have examined the prognostic impact of the C9orf72 repeat expansion in European subgroups based on gender and site of onset. C9orf72 status and demographic/clinical data from 4925 patients with ALS drawn from 3 prospective ALS registers (Ireland, Italy and the Netherlands), and clinical data sets in the UK and Belgium. Flexible parametric survival models were built including known prognostic factors (age, diagnostic delay and site of onset), gender and the presence of an expanded repeat in C9orf72. These were used to explore the effects of C9orf72 on survival by gender and site of onset. Individual patient data (IPD) meta-analysis was used to estimate HRs for results of particular importance. 457 (8.95%) of 4925 ALS cases carried the C9orf72 repeat expansion. A meta-analysis of C9orf72 estimated a survival HR of 1.36 (1.18 to 1.57) for those carrying the expansion. Models evaluating interaction between gender and C9orf72 repeat expansions demonstrated that the reduced survival due to C9orf72 expansion was being driven by spinal onset males (HR 1.56 (95% CI 1.25 to 1.96). This study represents the largest combined analysis of the prognostic characteristics of the C9orf72 expansion. We have shown for the first time that the negative prognostic implication of this variant is driven by males with spinal onset disease, indicating a hitherto unrecognised gender-mediated effect of the variant that requires further exploration.


Multiple genes for essential-hypertension susceptibility on chromosome 1q.
Essential hypertension, defined as elevated levels of blood pressure (BP) without any obvious cause, is a major risk factor for coronary heart disease, stroke, and renal disease. BP levels and susceptibility to development of essential hypertension are partially determined by genetic factors that are poorly understood. Similar to other efforts to understand complex, non-Mendelian phenotypes, genetic dissection of hypertension-related traits employs genomewide linkage analyses of families and association studies of patient cohorts, to uncover rare and common disease alleles, respectively. Family-based mapping studies of elevated BP cover the large intermediate ground for identification of genes with common variants of significant effect. Our genomewide linkage and candidate-gene-based association studies demonstrate that a replicated linkage peak for BP regulation on human chromosome 1q, homologous to mouse and rat quantitative trait loci for BP, contains at least three genes associated with BP levels in multiple samples: ATP1B1, RGS5, and SELE. Individual variants in these three genes account for 2-5-mm Hg differences in mean systolic BP levels, and the cumulative effect reaches 8-10 mm Hg. Because the associated alleles in these genes are relatively common (frequency >5%), these three genes are important contributors to elevated BP in the population at large.


Impact of valve surgery on 6-month mortality in adults with complicated, left-sided native valve endocarditis: a propensity analysis.
Complicated, left-sided native valve endocarditis causes significant morbidity and mortality in adults. The presumed benefits of valve surgery remain unproven due to lack of randomized controlled trials. To determine whether valve surgery is associated with reduced mortality in adults with complicated, left-sided native valve endocarditis. Retrospective, observational cohort study conducted from January 1990 to January 2000 at 7 Connecticut hospitals. Propensity analyses were used to control for bias in treatment assignment and prognostic imbalances. Of the 513 adults with complicated, left-sided native valve endocarditis, 230 (45%) underwent valve surgery and 283 (55%) received medical therapy alone. All-cause mortality at 6 months after baseline. In the 6-month period after baseline, 131 patients (26%) died. In unadjusted analyses, valve surgery was associated with reduced mortality (16% vs 33%; hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.29-0.63; P<.001). After adjustment for baseline variables associated with mortality (including hospital site, comorbidity, congestive heart failure, microbial etiology, immunocompromised state, abnormal mental status, and refractory infection), valve surgery remained associated with reduced mortality (adjusted HR, 0.35; 95% CI, 0.23-0.54; P<.02). In further analyses of 218 patients matched by propensity scores, valve surgery remained associated with reduced mortality (15% vs 28%; HR, 0.45; 95% CI, 0.23-0.86; P =.01). After additional adjustment for variables that contribute to heterogeneity and confounding within the propensity-matched group, surgical therapy remained significantly associated with a lower mortality (HR, 0.40; 95% CI, 0.18-0.91; P =.03). In this propensity-matched group, patients with moderate to severe congestive heart failure showed the greatest reduction in mortality with valve surgery (14% vs 51%; HR, 0.22; 95% CI, 0.09-0.53; P =.001). Valve surgery for patients with complicated, left-sided native valve endocarditis was independently associated with reduced 6-month mortality after adjustment for both baseline variables associated with the propensity to undergo valve surgery and baseline variables associated with mortality. The reduced mortality was particularly evident among patients with moderate to severe congestive heart failure.


Effectiveness of vegetative filter strips in reducing pesticide loading: quantifying pesticide trapping efficiency.
Pesticide trapping efficiency of vegetated filter strips (VFS) is commonly predicted with low success using empirical equations based solely on physical characteristics such as width and slope. The objective of this research was to develop and evaluate an empirical model with a foundation of VFS hydrological, sedimentological, and chemical specific parameters. The literature was reviewed to pool data from five studies with hypothesized significant parameters: pesticide and soil properties, percent reduction in runoff volume (i.e., infiltration) and sedimentation, and filter strip width. The empirical model was constructed using a phase distribution parameter, defined as the ratio of pesticide mass in dissolved form to pesticide mass sorbed to sediment, along with the percent infiltration, percent sedimentation, and the percent clay content (R(2) = 0.86 and standard deviation of differences [STDD] of 7.8%). Filter strip width was not a statistically significant parameter in the empirical model. For low to moderately sorbing pesticides, the phase distribution factor became statistically insignificant; for highly sorbing pesticides, the phase distribution factor became the most statistically significant parameter. For independent model evaluation datasets, the empirical model based on infiltration and sediment reduction, the phase distribution factor, and the percent clay content (STDD of 14.5%) outperformed existing filter strip width equations (STDD of 38.7%). This research proposed a procedure linking a VFS hydrologic simulation model with the proposed empirical trapping efficiency equation. For datasets with sufficient information for the VFS modeling, the linked numerical and empirical models significantly (R(2) = 0.74) improved predictions of pesticide trapping over empirical equations based solely on physical VFS characteristics.


In vivo effects of mebendazole and levamisole in the treatment of trichuriasis and ascariasis.
The anthelmintic drugs mebendazole (Vermox) and levamisole were tested in patients for their possible ovicidal effects on the eggs of Trichuris trichiura and Ascaris lumbricoides. The patients studied were 20 Africans of Sierra Leone, and 11 children of Nassau, Bahamas. Egg counts were made before treatment, and for 5 consecutive days following treatment. Eggs were incubated in 2.5% aqueous potassium dichromate and percentages of larval development were determined. Mebendazole completely inhibited the development of the eggs of T. trichiura by day 3 of the follow-up period. The ovicidal action of mebendazole on the eggs of A. lumbricoides was determined to be 64.8% by day 5 of the follow-up study. Levamisole had little (11.6%) ovicidal action on the eggs of T. trichiura and no ovicidal activity for A. lumbricoides.


Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons, associated with frontotemporal dementia (FTD) in about 14% of incident cases. We assessed the frequency of the recently identified C9orf72 repeat expansion in familial and apparently sporadic cases of ALS and characterised the cognitive and clinical phenotype of patients with this expansion. A population-based register of patients with ALS has been in operation in Ireland since 1995, and an associated DNA bank has been in place since 1999. 435 representative DNA samples from the bank were screened using repeat-primed PCR for the presence of a GGGGCC repeat expansion in C9orf72. We assessed clinical, cognitive, behavioural, MRI, and survival data from 191 (44%) of these patients, who comprised a population-based incident group and had previously participated in a longitudinal study of cognitive and behavioural changes in ALS. Samples from the DNA bank included 49 cases of known familial ALS and 386 apparently sporadic cases. Of these samples, 20 (41%) cases of familial ALS and 19 (5%) cases of apparently sporadic ALS had the C9orf72 repeat expansion. Of the 191 patients for whom phenotype data were available, 21 (11%) had the repeat expansion. Age at disease onset was lower in patients with the repeat expansion (mean 56·3 [SD 8·3] years) than in those without (61·3 [10·6] years; p=0·043). A family history of ALS or FTD was present in 18 (86%) of those with the repeat expansion. Patients with the repeat expansion had significantly more co-morbid FTD than patients without the repeat (50%vs 12%), and a distinct pattern of non-motor cortex changes on high-resolution 3 T magnetic resonance structural neuroimaging. Age-matched univariate analysis showed shorter survival (20 months vs 26 months) in patients with the repeat expansion. Multivariable analysis showed an increased hazard rate of 1·9 (95% 1·1-3·7; p=0·035) in those patients with the repeat expansion compared with patients without the expansion Patients with ALS and the C9orf72 repeat expansion seem to present a recognisable phenotype characterised by earlier disease onset, the presence of cognitive and behavioural impairment, specific neuroimaging changes, a family history of neurodegeneration with autosomal dominant inheritance, and reduced survival. Recognition of patients with ALS who carry an expanded repeat is likely to be important in the context of appropriate disease management, stratification in clinical trials, and in recognition of other related phenotypes in family members. Health Seventh Framework Programme, Health Research Board, Research Motor Neuron, Irish Motor Neuron Disease Association, The Motor Neurone Disease Association of Great Britain and Northern Ireland, ALS Association.


Disease modifying genes in cystic fibrosis: therapeutic option or one-way road?
Cystic fibrosis (CF) is the most common genetic disease among Caucasians and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF affects multiple organs but lung disease is the major determinant for morbidity and mortality. Many studies have focussed on the correlation between CFTR genotype and severity of disease. Since patients with identical CFTR mutations often show considerable variability in disease progression, genes other than CFTR are thought to have the potential to modify the course of lung disease in CF patients. Therefore, identification of CF-modifying genes has become the goal of several studies over the last 15 years. Pharmaceutical approaches for CF lung disease have been developed regardless of the underlying genetic defect and in general target symptoms such as airway obstruction and treatment of bacterial infection. Analysing the pathophysiological processes of modifiers may lead to the discovery of pathways involved in CF pathophysiology and possibly to the design of new therapeutics. The purpose of this review is not only to list potential CFTR modifier genes, but also to discuss new therapeutic strategies that could be derived from knowledge of these CF modifiers.


Development of Immunoassays for Burkholderia pseudomallei Typical and Atypical Lipopolysaccharide Strain Typing.
Burkholderia pseudomallei is the causative agent of melioidosis, a severe infection endemic to many tropical regions. Lipopolysaccharide (LPS) is recognized as an important virulence factor used by B. pseudomallei Isolates of B. pseudomallei have been shown to express one of four different types of LPS (typical LPS, atypical LPS types B and B2, and rough LPS) and in vitro studies have demonstrated that LPS types may impact disease severity. The association between LPS types and clinical manifestations, however, is still unknown, in part because an effective method for LPS type identification is not available. Thus, we developed antigen capture immunoassays capable of distinguishing between the LPS types. Mice were injected with B or B2 LPS for atypical LPS-specific monoclonal antibody (mAb) isolation; only two mAbs (3A2 and 5B4) were isolated from mice immunized with B2 LPS. Immunoblot analysis and surface plasmon resonance demonstrated that 3A2 and 5B4 are reactive with both B2 and B LPS where 3A2 was shown to possess higher affinity. Assays were then developed using capsular polysaccharide-specific mAb 4C4 for bacterial capture and 4C7 (previously shown to bind typical LPS) or 3A2 mAbs for typical or atypical LPS strain detection, respectively. The evaluations performed with 197 strains of Burkholderia and non-Burkholderia species showed that the assays are reactive to B. pseudomallei and Burkholderia mallei strains and have an accuracy of 98.8% (zero false positives and two false negatives) for LPS typing. The results suggest that the assays are effective and applicable for B. pseudomallei LPS typing.


CD200 in growing rat lungs: developmental expression and control by dexamethasone.
CD200 belongs to cell adhesion molecules of the immunoglobulin superfamily. It lacks intracellular signaling motifs and exerts immunosuppressive effect in various tissues. We have reported previously that CD200 is predominantly associated with the capillary network in the alveolar septum of adult rats. The alveolar endothelial cells express CD200, which is confined to their luminal cell membrane facing the blood-air barrier. Our present results show that lung CD200 protein increases gradually with advancing age, being maximally expressed in the early postnatal (P) period. CD200 protein expression, however, declines at P5 but increases again after P7, reaching the adult level at P21. In developing lungs in fetal and neonatal stages, double-immunofluorescence staining has confirmed intense CD200 immunoreactivity delineating the vascular profiles in the double layers of the alveolar capillaries; this staining becomes diffuse and patchy with time. Unlike in adult lungs, immunoelectron microscopy has revealed that CD200 expression in fetal and early postnatal lungs is localized over the entire luminal cell membrane and in the cytoplasm of the endothelia. CD200 expression is progressively redistributed to a specific luminal domain of alveolar endothelia during pulmonary microvascular maturation. In neonatal rats treated with dexamethasone, the amount of lung CD200 significantly increases and is also elevated with time. Upregulation of endothelial CD200 has further been confirmed in isolated pulmonary microvascular endothelial cells treated with dexamethasone. Thus, lung CD200 is developmentally regulated, possibly under hormonal influence.


Evolution of antibody immunity to SARS-CoV-2.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.


The patient-centered medical home in the Veterans Health Administration.
The Veterans Health Administration (VHA) is the largest integrated US health system to implement the patient-centered medical home. The Patient Aligned Care Team (PACT) initiative (implemented 2010-2014) aims to achieve team based care, improved access, and care management for more than 5 million primary care patients nationwide. To describe PACT and evaluate interim changes in PACT-related care processes. Data from the VHA Corporate Data Warehouse were obtained from April 2009 (pre- PACT) to September 2012. All patients assigned to a primary care provider (PCP) at all VHA facilities were included. Nonparametric tests of trend across time points. VHA increased primary care staff levels from April 2010 to December 2011 (2.3 to 3.0 staff per PCP full-time equivalent). In-person PCP visit rates slightly decreased from April 2009 to April 2012 (53 to 43 per 100 patients per calendar quarter; P < .01), while in-person nurse encounter rates remained steady. Large increases were seen in phone encounters (2.7 to 28.8 per 100 patients per quarter; P < .01), enhanced personal health record use (3% to 13% of patients enrolled), and electronic messaging to providers (0.01% to 2.3% of patients per quarter). Post hospitalization follow-up improved (6.6% to 61% of VA hospital discharges), but home telemonitoring (0.8% to 1.4% of patients) and group visits (0.2 to 0.65 per 100 patients per quarter; P < .01) grew slowly. Thirty months into PACT, primary care staff levels and phone and electronic encounters have greatly increased; other changes have been positive but slower.


Organization of prefrontal network activity by respiration-related oscillations.
The medial prefrontal cortex (mPFC) integrates information from cortical and sub-cortical areas and contributes to the planning and initiation of behaviour. A potential mechanism for signal integration in the mPFC lies in the synchronization of neuronal discharges by theta (6-12 Hz) activity patterns. Here we show, using in vivo local field potential (LFP) and single-unit recordings from awake mice, that prominent oscillations in the sub-theta frequency band (1-5 Hz) emerge during awake immobility in the mPFC. These oscillation patterns are distinct from but phase-locked to hippocampal theta activity and occur synchronized with nasal respiration (hence termed prefrontal respiration rhythm [PRR]). PRR activity modulates the amplitude of prefrontal gamma rhythms with greater efficacy than theta oscillations. Furthermore, single-unit discharges of putative pyramidal cells and GABAergic interneurons are entrained by prefrontal PRR and nasal respiration. Our data thus suggest that PRR activity contributes to information processing in the prefrontal neuronal network.


Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men.
Shift workers are at increased risk of metabolic morbidities. Clock genes are known to regulate metabolic processes in peripheral tissues, eg, glucose oxidation. This study aimed to investigate how clock genes are affected at the epigenetic and transcriptional level in peripheral human tissues following acute total sleep deprivation (TSD), mimicking shift work with extended wakefulness. In a randomized, two-period, two-condition, crossover clinical study, 15 healthy men underwent two experimental sessions: x sleep (2230-0700 h) and overnight wakefulness. On the subsequent morning, serum cortisol was measured, followed by skeletal muscle and subcutaneous adipose tissue biopsies for DNA methylation and gene expression analyses of core clock genes (BMAL1, CLOCK, CRY1, PER1). Finally, baseline and 2-h post-oral glucose load plasma glucose concentrations were determined. In adipose tissue, acute sleep deprivation vs sleep increased methylation in the promoter of CRY1 (+4%; P = .026) and in two promoter-interacting enhancer regions of PER1 (+15%; P = .036; +9%; P = .026). In skeletal muscle, TSD vs sleep decreased gene expression of BMAL1 (-18%; P = .033) and CRY1 (-22%; P = .047). Concentrations of serum cortisol, which can reset peripheral tissue clocks, were decreased (2449 ± 932 vs 3178 ± 723 nmol/L; P = .039), whereas postprandial plasma glucose concentrations were elevated after TSD (7.77 ± 1.63 vs 6.59 ± 1.32 mmol/L; P = .011). Our findings demonstrate that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues. Tissue-specific clock alterations could explain why shift work may disrupt metabolic integrity as observed herein.


Correlation between antimicrobial consumption and incidence of health-care-associated infections due to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci at a university hospital in Taiwan from 2000 to 2010.
This study was conducted to investigate the correlation between antibiotic consumption and the incidence of health-care-associated infections (HCAIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) (HCAI-MRSA) and vancomycin-resistant enterococci (VREs) (HCAI-VREs) at a university hospital in Taiwan during the period from 2000 to 2010. Data on annual patient-days and annual consumption (defined daily dose/1000 patient-days) of glycopeptides (vancomycin and teicoplanin), linezolid, fusidic acid, tigecycline, and daptomycin were analyzed. Yearly aggregated data on the number of nonduplicate clinical MRSA and VRE isolates causing HCAI were collected. Overall, the consumption of teicoplanin and linezolid significantly increased during the study period. A significant decrease in the incidence of HCAI-MRSA and a significant increase in the incidence of HCAI-VRE were found during the study period. A significant correlation was found between the increased use of teicoplanin and linezolid and the decreased incidence of HCAI-MRSA. By contrast, positive correlations were found between the consumption of teicoplanin and tigecycline and the incidence of HCAI-VRE. This study identified various correlations between the consumption of antibiotics and the incidence of HCAI-MRSA and HCAI-VRE. Strict implementation of infection-control guidelines and reinforcement of administering appropriate antibiotic agents would be helpful in decreasing the incidence of MRSA and VRE in hospitals.


Antidepressants versus placebo for panic disorder in adults.
Panic disorder is characterised by repeated, unexpected panic attacks, which represent a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes, and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. It is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, the National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology consider antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Several classes of antidepressants have been studied and compared, but it is still unclear which antidepressants have a more or less favourable profile in terms of effectiveness and acceptability in the treatment of this condition. To assess the effects of antidepressants for panic disorder in adults, specifically:1. to determine the efficacy of antidepressants in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison to placebo;2. to review the acceptability of antidepressants in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate the adverse effects of antidepressants in panic disorder, with or without agoraphobia, including the general prevalence of adverse effects, compared to placebo. We searched the Cochrane Common Mental Disorders' (CCMD) Specialised Register, and CENTRAL, MEDLINE, EMBASE and PsycINFO up to May 2017. We handsearched reference lists of relevant papers and previous systematic reviews. All double-blind, randomised, controlled trials (RCTs) allocating adults with panic disorder to antidepressants or placebo. Two review authors independently checked eligibility and extracted data using a standard form. We entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details and settings. Primary outcomes included failure to respond, measured by a range of response scales, and treatment acceptability, measured by total number of dropouts for any reason. Secondary outcomes included failure to remit, panic symptom scales, frequency of panic attacks, agoraphobia, general anxiety, depression, social functioning, quality of life and patient satisfaction, measured by various scales as defined in individual studies. We used GRADE to assess the quality of the evidence for each outcome MAIN RESULTS: Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias.We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo.Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference.When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference. The identified studies comprehensively address the objectives of the present review.Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants.The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review.Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes.Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.


In vitro cellular models of human hepatic fatty acid metabolism: differences between Huh7 and HepG2 cell lines in human and fetal bovine culturing serum.
Human primary hepatocytes are the gold standard for investigating lipid metabolism in nonalcoholic fatty liver disease (NAFLD); however, due to limitations including availability and donor variability, the hepatoma cell lines Huh7 and HepG2 are commonly used. Culturing these cell lines in human serum (HS) has been reported to improve functionality; however, direct comparison of fatty acid (FA) metabolism in response to culturing in HS is lacking. The aim of this study was to compare FA metabolism between HepG2 and Huh7 cells in response to culturing in different sera. Both HepG2 and Huh7 cells were grown in media containing 11 mmol/L glucose and either 2% HS or 10% fetal bovine serum. After 3 days, insulin and insulin-like growth factor-1 signaling were measured. At 7 days, intracellular triacylglycerol (TAG) and media 3-hydroxybutyrate, TAG and apolipoprotein B were measured, as was the FA composition of intracellular TAG and phospholipids. Both cell lines demonstrated higher levels of polyunsaturated fatty acid content, increased insulin sensitivity, higher media TAG levels and increased FA oxidation when cultured in HS Notably, independent of serum type, Huh7 cells had higher intracellular TAG compared to HepG2 cells, which was in part attributable to a higher de novo lipogenesis. Our data demonstrate that intrahepatocellular FA metabolism is different between cell lines and influenced by culturing sera. As a result, when developing a physiologically-relevant model of FA metabolism that could be developed for the study of NAFLD, consideration of both parameters is required.


Experiences of community and parental violence among HIV-positive young racial/ethnic minority men who have sex with men.
Adolescents and young adults (ages 13-24) in the USA are frequently exposed to violence in their community and home. While studies have examined the prevalence and impact of violence exposure among adolescents, there is a lack of data focusing specifically on adolescent men of color who have sex with men. Eight demonstration sites funded through a Special Projects of National Significance (SPNS) Initiative recruited 363 HIV-positive racial/ethnic minority young men who have sex with men (YMSM) for a longitudinal study between 2006 and 2009. Over two-thirds of participants (83.8%) had witnessed community violence, 55.1% in the prior three months. Witnessing violence committed with a deadly weapon was significantly associated with being African-American, having ever used drugs, and drinking alcohol in the prior two weeks. Fear of violence in the community was significantly associated with depressive symptomatology, having less than a high school degree, not possessing health insurance, and site of enrollment. Having been emotionally or physically abused by a parent or caretaker was significantly associated with depressive symptomatology, attempting suicide, site of enrollment, and increased age. Witnessing violence with a deadly weapon was significantly associated with alcohol and drug use but not with high-risk sexual behaviors. As this was one of the first studies on the prevalence and correlates of violence exposure among racial/ethnic minority YMSM living with HIV, the findings can be used to inform the development of culturally appropriate resilience-focused interventions to address the aftereffects of violence exposures and help develop social support systems outside of the family.


Safety and outcomes of cryoablation for ventricular tachyarrhythmias: results from a multicenter experience.
Catheter ablation of ventricular arrhythmias (VAs) with cryoenergy has not been widely reported. The purpose of this study was to assess the feasibility and safety of cryoablation for VA. Cases where cryoablation of VA was attempted as the initial strategy or was considered to prevent potential damage to other structures such as the coronary arteries, phrenic nerve, and His bundle were collected. Thirty-three patients with either normal heart or structural heart disease undergoing VA ablation using cryoenergy at six different institutions were enrolled in the study. Epicardial access was obtained when appropriate. Fifteen patients (7 men) underwent endocardial ablation, 13 (9 men) epicardial ablation (from the coronary sinus in 7), and 5 (2 men) aortic cusp ablation. Mean age was 54 ± 8 years, and ejection fraction was 45% ± 5%. In 15 (45%) patients, VAs were successfully ablated, whereas cryoablation was unsuccessful in the remaining 18 (55%) patients. Cryoablation was successful in all parahisian cases (100%). In three patients, epicardial cryoablation was successful after several failed attempts with open irrigated catheter. An aortic dissection occurred during catheter placement in the aortic cusp. At follow-up of 24 ± 5 months, all patients with acute success were free from clinical VA. Use of cryoenergy for ablation of VA has excellent success for arrhythmias near the His bundle; however, success rates at other sites appear less favorable. Cryoablation may be considered as an alternative approach for reducing complications during ablation of VAs originating from sites close to other relevant cardiac structures (conduction system, coronary arteries, phrenic nerve) and, in rare cases, could be used epicardially when radiofrequency energy applications have failed.


A link between mitotic entry and membrane growth suggests a novel model for cell size control.
Addition of new membrane to the cell surface by membrane trafficking is necessary for cell growth. In this paper, we report that blocking membrane traffic causes a mitotic checkpoint arrest via Wee1-dependent inhibitory phosphorylation of Cdk1. Checkpoint signals are relayed by the Rho1 GTPase, protein kinase C (Pkc1), and a specific form of protein phosphatase 2A (PP2A(Cdc55)). Signaling via this pathway is dependent on membrane traffic and appears to increase gradually during polar bud growth. We hypothesize that delivery of vesicles to the site of bud growth generates a signal that is proportional to the extent of polarized membrane growth and that the strength of the signal is read by downstream components to determine when sufficient growth has occurred for initiation of mitosis. Growth-dependent signaling could explain how membrane growth is integrated with cell cycle progression. It could also control both cell size and morphogenesis, thereby reconciling divergent models for mitotic checkpoint function.


3D-structured illumination microscopy provides novel insight into architecture of human centrosomes.
Centrioles are essential for the formation of cilia and flagella. They also form the core of the centrosome, which organizes microtubule arrays important for cell shape, polarity, motility and division. Here, we have used super-resolution 3D-structured illumination microscopy to analyse the spatial relationship of 18 centriole and pericentriolar matrix (PCM) components of human centrosomes at different cell cycle stages. During mitosis, PCM proteins formed extended networks with interspersed γ-Tubulin. During interphase, most proteins were arranged at specific distances from the walls of centrioles, resulting in ring staining, often with discernible density masses. Through use of site-specific antibodies, we found the C-terminus of Cep152 to be closer to centrioles than the N-terminus, illustrating the power of 3D-SIM to study protein disposition. Appendage proteins showed rings with multiple density masses, and the number of these masses was strongly reduced during mitosis. At the proximal end of centrioles, Sas-6 formed a dot at the site of daughter centriole assembly, consistent with its role in cartwheel formation. Plk4 and STIL co-localized with Sas-6, but Cep135 was associated mostly with mother centrioles. Remarkably, Plk4 formed a dot on the surface of the mother centriole before Sas-6 staining became detectable, indicating that Plk4 constitutes an early marker for the site of nascent centriole formation. Our study provides novel insights into the architecture of human centrosomes and illustrates the power of super-resolution microscopy in revealing the relative localization of centriole and PCM proteins in unprecedented detail.


Nitrogen-regulated transcription and enzyme activities in continuous cultures of Saccharomyces cerevisiae.
Variations in the transcription of nitrogen-regulated genes and in the activities of nitrogen-regulated enzymes of the yeast Saccharomyces cerevisiae were studied by changing the carbon and nitrogen fluxes. S. cerevisiae was grown in continuous culture at various dilution rates (D) under nitrogen limitation with NH4Cl as sole nitrogen source. With an increase in D from 0.05 to 0.29 h-1, both the glucose and the ammonia flux increased sixfold. The activities of the two ammonia-incorporating enzymes, NADPH-dependent glutamate dehydrogenase (NADPH-GDH) and glutamine synthetase (GS), encoded by GDH1 and GLN1, respectively, increased with increasing D, while the activity of the glutamate-degrading enzyme, NAD-dependent glutamate dehydrogenase (NAD-GDH), decreased. Surprisingly, no changes were observed in the transcription of GDH1 and GLN1; however increased D was accompanied by an increase in GAP1 transcription. At the metabolite level, the increase in the glucose and nitrogen flux did not result in changes in the intracellular 2-oxoglutarate, glutamate or glutamine concentrations. It is shown that growth on ammonia alone is not sufficient to cause repression of GAP1 and GLN1 transcription and that the regulation of GAP1 transcription and both NADPH-GDH and GS activity is not an on/off switch, but is gradually modulated in correlation with the ammonia concentration.


The Rapid and Progressive Degeneration of the Cervical Multifidus in Whiplash: An MRI Study of Fatty Infiltration.
Single-center prospective longitudinal study. To study the (1) temporal development of muscle fatty infiltrates (MFI) in the cervical multifidi after whiplash, (2) differences in multifidi MFI between those who recover or report milder pain-related disability and those who report moderate/severe symptoms at 3 months, and (3) predictive value of multifidi MFI outcomes. The temporal development of MFI on conventional magnetic resonance image has been shown to be associated with specific aspects of pain and psychological factors. The replication of such findings has yet to be explored longitudinally. Thirty-six subjects with whiplash injury were enrolled at less than 1 week postinjury and classified at 3 months using percentage scores on the Neck Disability Index as recovered/mild (0%-28%) or severe (≥30%). A fat/water magnetic resonance imaging measure, patient self-report of pain-related disability, and post-traumatic stress disorder were collected at less than 1 week, 2 weeks, and 3 months postinjury. The effects of time and group (per Neck Disability Index) and the interaction of time by group on MFI were determined. Receiver operating characteristic curve analysis was used to determine a cut-point for MFI at 2 weeks to predict outcome at 3 months. There was no difference in MFI across groups at enrolment. MFI values were significantly higher in the severe group than those in the recovered/mild group at 2 weeks and 3 months. The receiver operating characteristic curve analysis indicated that MFI levels of 20.5% or above resulted in a sensitivity of 87.5% and a specificity of 92.9% for predicting outcome at 3 months. Consistent with previous evidence, muscle degeneration occurs soon after injury but only in those patients with poor functional recovery. This study provides further evidence that (1) multifidi MFI occur in tandem with known predictive risk factors (older age, pain-related disability, and post-traumatic stress disorder) and (2) routine imaging protocols may need to be reconsidered in the vast majority of patients after whiplash. 3.


Chromium contributes to human bronchial epithelial cell carcinogenesis by activating Gli2 and inhibiting autophagy.
Occupational and environmental inhalation exposure to hexavalent chromium [Cr(vi)] compounds has been confirmed to cause respiratory system injury and cancer. The molecular mechanisms of chromium carcinogenesis still require further study. We established Cr(vi)-transformed cells (BEAS-2B-Cr) after chronic exposure of immortalized normal human bronchial epithelial BEAS-2B cells to low doses of Cr(vi), which obtained the ability of anchorage-independent growth. BEAS-2B-Cr cells not only exhibited stronger proliferation, migration, invasion and tumorigenesis capabilities but also acquired an altered and distinct Gli2 gene expression pattern compared with untreated parental BEAS-2B cells (P-NC) and the control BEAS-2B cells (NC). Interestingly, we found that activation of Gli2 by Cr(vi) treatment prevented the induction of autophagy. Using a gene silencing approach, we showed that Gli2 plays an important role in the malignant properties of BEAS-2B-Cr cells. Downregulation of Gli2 induced autophagy and inhibited cell proliferation and colony forming abilities, which are both upregulated in BEAS-2B-Cr cells compared to NC cells. In addition, inhibition of autophagy by 3-methyladenine (3-MA) partially suppressed the cytotoxicity induced by GANT61-induced inhibition of Gli2. These results demonstrate that hexavalent chromium Cr(vi) activates Gli2 to promote the proliferation of BEAS-2B-Cr cells by inhibition of autophagy, which contributes to human bronchial epithelial cell carcinogenesis. Gli2 may not only play an important role in lung cancer pathogenesis, but also be a promising early indicator in monitoring exposure to chromium.


Mucosal expression and luminal release of epidermal and transforming growth factors in patients with duodenal ulcer before and after eradication of Helicobacter pylori.
Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF alpha) are potent gastric acid inhibitors and stimuli of mucosal growth and protection but their involvement in Helicobacter pylori associated duodenal ulcer has been little examined. To assess gastric acid secretion, plasma gastrin concentrations, mucosal content of EGF and TGF alpha, and mucosal expression of these peptides and their receptor (EGFr) as well as salivary and gastric luminal release of EGF under basal conditions and after pentagastrin stimulation in 10 healthy subjects and in 25 H pylori positive patients with duodenal ulcer before and after two weeks of triple anti-H pylori therapy and four weeks after the termination of this therapy. Pentagastrin stimulation caused a significant increase in salivary and gastric release of EGF both in healthy controls and patients with duodenal ulcers but in the patients, the eradication of H pylori resulted in several fold higher gastric luminal (but not salivary) EGF release than before the anti-H pylori therapy. Mucosal contents of immunoreactive EGF and TGF alpha and mucosal expression of EGF, TGF alpha, and EGFr in H pylori positive patients with duodenal ulcer were significantly higher than those in healthy H pylori negative controls and this increase persisted after eradication of H pylori. Basal plasma gastrin was significantly reduced after two weeks of triple therapy and four weeks after the H pylori eradication all ulcers were completely healed. (1) H pylori infection in patients with duodenal ulcer was accompanied by enhanced plasma gastrin and increased mucosal content and expression of TGF alpha, EGF, and EGFr; (2) H pylori eradication resulted in ulcer healing, reduction in plasma gastrin, and enhancement of gastric (but not salivary) luminal release of EGF, particularly after pentagastrin stimulation; and (3) enhanced mucosal content and expression of TGF alpha, EGF, and EGFr and increased luminal release of EGF may contribute to ulcer healing after eradication of H pylori.


Parthenolide inhibits osteoclast differentiation and bone resorbing activity by down-regulation of NFATc1 induction and c-Fos stability, during RANKL-mediated osteoclastogenesis.
Parthenolide, a natural product derived from Feverfew, prevents septic shock and inflammation. We aimed to identify the effects of parthenolide on the RANKL (receptor activator of NF-κB ligand)-induced differentiation and bone resorbing activity of osteoclasts. In this study, parthenolide dose-dependently inhibited RANKL-mediated osteoclast differentiation in BMMs, without any evidence of cytotoxicity and the phosphorylation of p38, ERK, and IκB, as well as IκB degradation by RANKL treatment. Parthenolide suppressed the expression of NFATc1, OSCAR, TRAP, DC-STAMP, and cathepsin K in RANKL-treated BMMs. Furthermore, parthenolide down-regulated the stability of c-Fos protein, but could not suppress the expression of c-Fos. Overexpression of NFATc1 and c-Fos in BMMs reversed the inhibitory effect of parthenolide on RANKL-mediated osteoclast differentiation. Parthenolide also inhibited the bone resorbing activity of mature osteoclasts. Parthenolide inhibits the differentiation and bone-resolving activity of osteoclast by RANKL, suggesting its potential therapeutic value for bone destructive disorders associated with osteoclast-mediated bone resorption.


Transient neurological symptoms (TNS) following spinal anaesthesia with lidocaine versus other local anaesthetics in adult surgical patients: a network meta-analysis.
Spinal anaesthesia has been implicated as one of the possible causes of neurological complications following surgical procedures. This painful condition, occurring during the immediate postoperative period, is termed transient neurological symptoms (TNS) and is typically observed after the use of spinal lidocaine. Alternatives to lidocaine that can provide high-quality anaesthesia without TNS development are needed. This review was originally published in 2005, and last updated in 2009. To determine the frequency of TNS after spinal anaesthesia with lidocaine and compare it with other types of local anaesthetics by performing a meta-analysis for all pair-wise comparisons, and conducting network meta-analysis (NMA) to rank interventions. We searched CENTRAL, MEDLINE, Elsevier Embase, and LILACS on 25 November 2018. We searched clinical trial registries and handsearched the reference lists of trials and review articles. We included randomized and quasi-randomized controlled trials comparing the frequency of TNS after spinal anaesthesia with lidocaine to other local anaesthetics. Studies had to have two or more arms that used distinct local anaesthetics (irrespective of the concentration and baricity of the solution) for spinal anaesthesia in preparation for surgery. We included adults who received spinal anaesthesia and considered all pregnant participants as a subgroup. The follow-up period for TNS was at least 24 hours. Four review authors independently assessed studies for inclusion. Three review authors independently evaluated the quality of the relevant studies and extracted the data from the included studies. We performed meta-analysis for all pair-wise comparisons of local anaesthetics, as well as NMA. We used an inverse variance weighting for summary statistics and a random-effects model as we expected methodological and clinical heterogeneity across the included studies resulting in varying effect sizes between studies of pair-wise comparisons. The NMA used all included studies based on a graph theoretical approach within a frequentist framework. Finally, we ranked the competing treatments by P scores. The analysis included 24 trials reporting on 2226 participants of whom 239 developed TNS. Two studies are awaiting classification and one is ongoing. Included studies mostly had unclear to high risk of bias. The NMA included 24 studies and eight different local anaesthetics; the number of pair-wise comparisons was 32 and the number of different pair-wise comparisons was 11. This analysis showed that, compared to lidocaine, the risk ratio (RR) of TNS was lower for bupivacaine, levobupivacaine, prilocaine, procaine, and ropivacaine with RRs in the range of 0.10 to 0.23 while 2-chloroprocaine and mepivacaine did not differ in terms of RR of TNS development compared to lidocaine. Pair-wise meta-analysis showed that compared with lidocaine, most local anaesthetics were associated with a reduced risk of TNS development (except 2-chloroprocaine and mepivacaine) (bupivacaine: RR 0.16, 95% confidence interval (CI) 0.09 to 0.28; 12 studies; moderate-quality evidence; 2-chloroprocaine: RR 0.09, 95% CI 0.01 to 1.51; 2 studies; low-quality evidence; levobupivacaine: RR 0.13, 95% CI 0.02 to 0.69; 2 studies; low-quality evidence; mepivacaine: RR 1.01, 95% CI 0.18 to 5.82; 4 studies; very low-quality evidence; prilocaine: RR 0.18, 95% CI 0.07 to 0.49; 4 studies; moderate-quality evidence; procaine: RR 0.14, 95% CI 0.04 to 0.52; 2 studies; moderate-quality evidence; ropivacaine: RR 0.10, 95% CI 0.01 to 0.78; 2 studies; low-quality evidence). We were unable to perform any of our planned subgroup analyses due to the low number of TNS events. Results from both NMA and pair-wise meta-analysis indicate that the risk of developing TNS after spinal anaesthesia is lower when bupivacaine, levobupivacaine, prilocaine, procaine, and ropivacaine are used compared to lidocaine. The use of 2-chloroprocaine and mepivacaine had a similar risk to lidocaine in terms of TNS development after spinal anaesthesia. Patients should be informed of TNS as a possible adverse effect of local anaesthesia with lidocaine and the choice of anaesthetic agent should be based on the specific clinical context and parameters such as the expected duration of the procedure and the quality of anaesthesia. Due to the very low- to moderate-quality evidence (GRADE), future research efforts in this field are required to assess alternatives to lidocaine that would be able to provide high-quality anaesthesia without TNS development. The two studies awaiting classification and one ongoing study may alter the conclusions of the review once assessed.


Clinico-hormonal correlation of oligospermic patients in the below sea level environment (Jordan Valley).
A correlation between serum levels of luteinizing hormone (LH), total testosterone (T), free T and sex-hormone binding globulin (SHBG) in normospermic and in oligospermic male people was done. This study was designed to measure serum levels of these hormones and of SHBG in people living at different altitude environments relative to sea level: at 209-408 meters below (the Jordan Valley, JV) and at 620 meters above (Irbid city, IC). In addition, a clinical awareness study of oligospermia was done in the North of Jordan (IC). Seminal analysis in 287 male people (age range, 18 to 40 years old) during the period between 12/6/1999 and 12/2/2002 showed an oligospermia of 31.4%. Serum levels of LH, total T, free T and SHBG in normospermic subjects in IC were similar to those in normospermic of the JV (3.4 +/- 1.2 vs. 4.0 +/- 1.7 MIU/ml, 19.9 +/- 4.0 vs. 20.4 +/- 5.6 ng/ml, 53.9 +/- 15.6 vs. 47.9 +/- 10.7 pg/ml, 19.5 +/- 3.2 vs. 18.6 +/- 2.16 nmol/l, respectively). Oligospermia was associated with increase in total T at both IC (27.5 +/- 4.6 vs. 19.9 +/- 4.0 ng/ml) and the JV (30.7 +/- 3.4 vs. 20.5 +/- 5.6). The higher serum level of total T in oligospermic people in both IC and the JV was associated with higher levels of SHBG compared to those levels in normospermic subjects. On the other hand, oligospermic subjects have lower serum level of free T than in normospermic males (41.5 +/- 10.0 vs. 53.9 +/- 15.6) only in IC, while in the JV, serum free T level was similar (46.5 +/- 6.1 vs. 47.9 +/- 10.7). Taken together data for both locations, IC and the JV, suggest a clear correlation between total T and SHBG levels in both groups' normospermic and oligospermic subjects.


Diagnostic performance of real-time tissue elastography in chronic hepatitis C patients with sustained virological response.
Real-time tissue elastography is a non-invasive method for measuring liver elasticity. However, there are no reports evaluating the value of real-time tissue elastography for liver fibrosis in hepatitis C virus-infected patients with sustained virological response. The aim of this study is to clarify the diagnostic performance of real-time tissue elastography in patients with sustained virological response. In this prospective study, we enrolled 425 chronic hepatitis C patients who underwent liver biopsy: 118 patients with sustained virological response (45.8% women) and 307 patients with hepatitis C virus (51.1% women). The post-sustained virological response biopsy was performed 5.9 ± 1.8 years after the therapy. Liver fibrosis index measurements as assessed using real-time tissue elastography were performed on the same day of biopsy. The respective mean liver fibrosis index values for fibrosis stages F0, F1, F2, F3, and F4 were 2.82 ± 0.33, 2.90 ± 0.51, 3.06 ± 0.58, 3.65 ± 0.24, and 3.83 ± 0.65, respectively, in patients with sustained virological response. The diagnostic accuracies expressed as areas under the receiver operating characteristic curves in patients with sustained virological response were 0.776 for the diagnosis of significant fibrosis (≥F2), 0.885 for severe fibrosis (≥F3), and 0.860 for cirrhosis (F4), respectively. The optimum cut-off values liver fibrosis index were 3.14 for ≥F2, 3.24 for ≥F3, and 3.30 for F4 in patients with sustained virological response. Real-time tissue elastography is an acceptable method for predicting the severity of fibrosis in hepatitis C virus patients with sustained virological response.


Recent progress in van der Waals heterojunctions.
Following the development of many novel two-dimensional (2D) materials, investigations of van der Waals heterojunctions (vdWHs) have attracted significant attention due to their excellent properties such as smooth heterointerface, highly gate-tunable bandgap, and ultrafast carrier transport. Benefits from the atom-scale thickness, physical and chemical properties and ease of manipulation of the heterojunctions formulated by weak vdW forces were demonstrated to indicate their outstanding potential in electronic and optoelectronic applications, including photodetection and energy harvesting, and the possibility of integrating them with the existing semiconductor technology for the next-generation electronic and sensing devices. In this review, we summarized the recent developments of vdWHs and emphasized their applications. Basically, we introduced the physical properties and some newly discovered phenomena in vdWHs. Then, we emphatically presented four classical vdWHs and some novel heterostructures formed by vdW forces. Based on their unique physical properties and structures, we highlighted the applications of vdWHs including in photodiodes, phototransistors, tunneling devices, and memory devices. Finally, we provided a conclusion on the recent advances in vdWHs and outlined our perspectives. We aim for this review to serve as a solid foundation in this field and to pave the way for future research on vdW-based materials and their heterostructures.


Longitudinal Follow-up of Impedance Drift in Deep Brain Stimulation Cases.
Impedance is an integral property of neuromodulation devices that determines the current delivered to brain tissue. Long-term variability in therapeutic impedance following deep brain stimulation (DBS) has not been extensively investigated across different brain targets. The aim was to evaluate DBS impedance drift and variability over an extended postoperative period across common DBS targets. Retrospective data from 1,764 electrode leads were included and drawn from 866 DBS patients enrolled in the University of Florida Institutional Review Board-approved INFORM database and analyzed up to 84 months post implantation. An exploratory analysis was conducted to identify trends in impedances using a Mann-Kendall test of trend. There were 866 patients and 1,764 leads available for analysis. The majority of subjects had Parkinson's disease (60.7%). The mean age at implantation was 58.7 years old and the mean follow-up time was 36.8 months. There were significant fluctuations in the mean impedance of all electrodes analyzed that largely stabilized by 6 months except for the subthalamic nucleus (STN) target, in which fluctuations persisted throughout the duration of follow-up with a continued downward trend (p < 0.001). The drift in impedance observed primarily within the first 6 months is in keeping with prior studies and is likely due to surgical micro-lesioning effects and brain parenchyma remodeling at the electrode-tissue interface, typically at values approximating 1,000 Ω. The differences in impedance trends over time in the various DBS targets may be due to underlying differences in structure and tissue composition.


Analysis of the effects of food and of digestive secretions on the small intestine of the rat. 1. Mucosal morphology and epithelial replacement.
A modified Roux-en-Y repositioning of rat small intestine was performed so that the proximal segment of bowel (A) received only bile and pancreastic secretions, the second (B) received food direct from the stomach, and these two segments drained into a third (C). Four to five weeks after operation, cell production was assessed by injection of vincristine into operated, sham-operated and unoperated rats, and counts of blocked metaphases were made on isolated microdissected crypts. Villus height, crypt depth, and the number of crypts per villus (crypt/villus ratio) were also measured. Most of segment A showed no significant differences from sham-operated intestine, although the normal proximo-distal gradient of villus height was abolished. At the distal end (near the anastomosis with segments B and C), crypt depth and cell production were increased. The villus height gradient in segment B was also abolished, although crypt depth and cell production were significantly increased, especially at the proximal end. Crypt/villus ratio was also increased. Segment C showed all the characteristics of small bowel promoted to a more proximal position: increased villus height, crypt depth and cell production. Increased crypt/villus ratio was also observed. These results are discussed in terms of the role of food and of digestive secretions in the control of mucosal morphology and epithelial replacement.


Image reconstruction from coded data: II. Code design.
A strategy is given for the design of coded apertures with respect to a given class of objects that are to be imaged. Previous knowledge of the first- and second-order statistics for the object class is assumed. The object class is characterized by its Karhunen-Loève eigenvectors and eigenvalues, whereas the imaging system is characterized by its singular-value decomposition. We introduce the concept of alignment in which the aperture parameters are adjusted until the system is tuned to measure the given object class well. A mean-square-error figure of merit that indicates degree of alignment is given, and alignment is performed by standard optimization techniques. We illustrate this technique with a simple proof-of-principle experiment. These concepts are general and may be applied to any linear imaging system.


Melanoma immunotherapy using mature DCs expressing the constitutive proteasome.
Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen-loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo. Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5). Vaccination stimulated antigen-specific T cell responses in all subjects, which peaked after 3-4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2⁺ subjects, CD8⁺ T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response. These results suggest that the efficacy of melanoma DC-based immunotherapy is enhanced when tumor antigen-loaded DCs used for vaccination express cPs. Clinicaltrials.gov NCT00672542. Duke Clinical Research Institute/Duke Translational Medicine Institute, Duke Melanoma Consortium, and Duke University Department of Surgery.


Small conductance Ca2+-activated K+ channels and calmodulin: cell surface expression and gating.
Small conductance Ca2+-activated K+ channels (SK channels) are heteromeric complexes of pore-forming alpha subunits and constitutively bound calmodulin (CaM). The binding of CaM is mediated in part by the electrostatic interaction between residues Arg-464 and Lys-467 of SK2 and Glu-84 and Glu-87 of CaM. Heterologous expression of the double charge reversal in SK2, SK2 R464E/K467E (SK2:64/67), did not yield detectable surface expression or channel activity in whole cell or inside-out patch recordings. Coexpression of SK2:64/67 with wild type CaM or CaM1,2,3,4, a mutant lacking the ability to bind Ca2+, rescued surface expression. In patches from cells coexpressing SK2:64/67 and wild type CaM, currents were recorded immediately following excision into Ca2+-containing solution but disappeared within minutes after excision or immediately upon exposure to Ca2+-free solution and were not reactivated upon reapplication of Ca2+-containing solution. Channel activity was restored by application of purified recombinant Ca2+-CaM or exposure to Ca2+-free CaM followed by application of Ca2+-containing solution. Coexpression of the double charge reversal E84R/E87K in CaM (CaM:84/87) with SK2:64/67 reconstituted stable Ca2+-dependent channel activity that was not lost with exposure to Ca2+-free solution. Therefore, Ca2+-independent interactions with CaM are required for surface expression of SK channels, whereas the constitutive association between the two channel subunits is not an essential requirement for gating.


A multicenter comparative trial of tobramycin and ticarcillin vs moxalactam and ticarcillin in febrile neutropenic patients.
During a multicenter prospective randomized trial in febrile neutropenic patients (neutrophil count, less than 1,000/cu mm), 103 episodes were treated with tobramycin sulfate plus ticarcillin disodium (TT) while 117 were treated with moxalactam plus ticarcillin disodium (MT). The majority of patients had an underlying diagnosis of leukemia (60%) and most (62.8%) had granulocyte counts of less than 100/cu mm at the start of therapy. The response rates for clinically or microbiologically documented episodes were 38 of 60 (55.1%) for TT and 38 of 64 (59.4%) for MT. The MT regimen appeared to be more effective for gram-positive infections (56% vs 33%) while TT appeared more effective for gram-negative infections (64% vs 40%). Nephrotoxicity attributable to study drugs occurred in only 2.3% of cases (one on each treatment arm). Prolongation of the prothrombin time was observed in only six of 78 (7.7%) in the TT arm as compared with 39 of 103 (38%) in the MT arm. Neither regimen was adequate for the unusually high frequency of gram-positive pathogens seen during this study.


Total small vessel disease score and risk of recurrent stroke: Validation in 2 large cohorts.
In patients with TIA and ischemic stroke, we validated the total small vessel disease (SVD) score by determining its prognostic value for recurrent stroke. Two independent prospective studies were conducted, one comprising predominantly Caucasian patients with TIA/ischemic stroke (Oxford Vascular Study [OXVASC]) and one predominantly Chinese patients with ischemic stroke (University of Hong Kong [HKU]). Cerebral MRI was performed and assessed for lacunes, microbleeds, white matter hyperintensities (WMH), and perivascular spaces (PVS). Predictive value of total SVD score for risk of recurrent stroke was determined and potential refinements considered. In 2,002 patients with TIA/ischemic stroke (OXVASC n = 1,028, HKU n = 974, 6,924 patient-years follow-up), a higher score was associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio [HR] per unit increase: 1.32, 1.16-1.51, p < 0.0001; c statistic 0.61, 0.56-0.65, p < 0.0001) and intracerebral hemorrhage (ICH) (HR 1.54, 1.11-2.13, p = 0.009; c statistic 0.65, 0.54-0.76, p = 0.006). A higher score predicted recurrent stroke in SVD and non-SVD TIA/ischemic stroke subtypes (c statistic 0.67, 0.59-0.74, p < 0.0001 and 0.60, 0.55-0.65, p < 0.0001). Including burden of microbleeds and WMH and adjusting the cutoff of basal ganglia PVS potentially improved predictive power for ICH (c statistic 0.71, 0.60-0.81, phet = 0.45), but not for recurrent ischemic stroke (c statistic 0.60, 0.56-0.65, phet = 0.76) on internal validation. The total SVD score has predictive value for recurrent stroke after TIA/ischemic stroke. Prediction of recurrence in patients with nonlacunar events highlights the potential role of SVD in wider stroke etiology.


Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength.
In the mature nervous system, changes in synaptic strength correlate with changes in neuronal structure. Members of the Nogo-66 receptor family have been implicated in regulating neuronal morphology. Nogo-66 receptor 1 (NgR1) supports binding of the myelin inhibitors Nogo-A, MAG (myelin-associated glycoprotein), and OMgp (oligodendrocyte myelin glycoprotein), and is important for growth cone collapse in response to acutely presented inhibitors in vitro. After injury to the corticospinal tract, NgR1 limits axon collateral sprouting but is not important for blocking long-distance regenerative growth in vivo. Here, we report on a novel interaction between NgR1 and select members of the fibroblast growth factor (FGF) family. FGF1 and FGF2 bind directly and with high affinity to NgR1 but not to NgR2 or NgR3. In primary cortical neurons, ectopic NgR1 inhibits FGF2-elicited axonal branching. Loss of NgR1 results in altered spine morphologies along apical dendrites of hippocampal CA1 neurons in vivo. Analysis of synaptosomal fractions revealed that NgR1 is enriched synaptically in the hippocampus. Physiological studies at Schaffer collateral-CA1 synapses uncovered a synaptic function for NgR1. Loss of NgR1 leads to FGF2-dependent enhancement of long-term potentiation (LTP) without altering basal synaptic transmission or short-term plasticity. NgR1 and FGF receptor 1 (FGFR1) are colocalized to synapses, and mechanistic studies revealed that FGFR kinase activity is necessary for FGF2-elicited enhancement of hippocampal LTP in NgR1 mutants. In addition, loss of NgR1 attenuates long-term depression of synaptic transmission at Schaffer collateral-CA1 synapses. Together, our findings establish that physiological NgR1 signaling regulates activity-dependent synaptic strength and uncover neuronal NgR1 as a regulator of synaptic plasticity.


Consequence-based communication about adolescent romantic experience between parents and adolescents: A qualitative study underpinned by social constructionism.
Chinese adolescents are increasingly engaging in romantic experiences and high-risk sexual behaviors within a rapidly-changing cultural and socio-economic context. Parental communication about sexuality has been recognized as protective for adolescents to make informed decisions about sexual practice. In this study, we explored what was discussed about adolescent romantic experience between parents and adolescents in China. Twenty-seven parents and 38 adolescents from a northern-eastern city of China were interviewed. Interviews were transcribed verbatim and thematically analyzed using a social constructionism framework. Four themes were identified: (i) detriments of romantic experience to education and future prospect; (ii) health and sociocultural risks of romantic and sexual engagement; (iii) ways of handling romantic experience; and (iv) marriage and family building. The messages were mainly prohibitive and consequence oriented in nature, and lacked specific romantic and sexual information. These messages reflected sociocultural beliefs in education, sexuality, marriage, and family in China, but did not meet the needs of current adolescents. External support from health professionals, such as nurses, is important for parents and adolescents to improve their sexual knowledge and communication skills.


Light pollution inequities in the continental United States: A distributive environmental justice analysis.
Excessive exposure to ambient light at night is a well-documented hazard to human health, yet analysts have not examined it from an environmental justice (EJ) perspective. We conducted the first EJ study of exposure to light pollution by testing for socially disparate patterns across the continental United States (US). We first calculated population-weighted mean exposures to examine whether ambient light pollution in the US differed between racial/ethnic groups. We then used multivariable generalized estimating equations (GEEs) that adjust for geographic clustering to examine whether light pollution was distributed inequitably based on racial/ethnic composition and socioeconomic status across US neighborhoods (census tracts). Finally, we conducted a stratified analysis of metropolitan core, suburban, and small city-rural tracts to determine whether patterns of inequity varied based on urban-rural context. We found evidence of disparities in exposures to light pollution based on racial/ethnic minority and low-to-mid socioeconomic statuses. Americans of Asian, Hispanic or Black race/ethnicity had population-weighted mean exposures to light pollution in their neighborhoods that were approximately two times that of White Americans. GEEs indicated that neighborhoods composed of higher proportions of Blacks, Hispanics, Asians, or renter-occupants experienced greater exposures to ambient light at night. Stratified analyses indicated that those patterns of inequity did not substantially vary based on urban-rural context. Findings have implications for understanding environmental influences on health disparities, raise concerns about the potential for a multiple environmental jeopardy situation, and highlight the need for policy actions to address light pollution.


Expression of galectin-3 modulates T-cell growth and apoptosis.
Galectin-3 is a member (if a large family of beta-galactoside-binding animal lectins. It has been shown that the expression of galectin-3 is upregulated in proliferating cells, suggesting a possible role for this lectin in regulation of cell growth. Previously, we have shown that T cells infected with human T-cell leukemia virus type I express high levels of galectin-3, in contrast to uninfected cells, which do not express detectable amounts of this protein. In this study, we examined growth properties of human leukemia T cells transfected with galectin-3 cDNA, and thus constitutively overexpressing this lectin. Transfectants expressing galectin-3 displayed higher growth rates than control transfectants, which do not express this lectin. Furthermore, galectin-3 expression in these cells confers resistance to apoptosis induced by anti-Fas antibody and staurosporine. Galectin-3 was found to have significant sequence similarity with Bcl-2, a well-characterized suppressor of apoptosis. In particular, the lectin contains the NWGR motif that is highly conserved among members of the Bcl-2 family and shown to be critical for the apoptosis-suppressing activity. We further demonstrated that galectin-3 interacts with Bc1-2 in a lactose-inhibitable manner. We conclude that galectin-3 is a regulator of cell growth and apoptosis and it may function through a cell death inhibition pathway that involves Bcl-2.


Observation of Long-Range Elliptic Azimuthal Anisotropies in sqrt[s]=13 and 2.76 TeV pp Collisions with the ATLAS Detector.
ATLAS has measured two-particle correlations as a function of the relative azimuthal angle, Δϕ, and pseudorapidity, Δη, in sqrt[s]=13 and 2.76 TeV pp collisions at the LHC using charged particles measured in the pseudorapidity interval |η|<2.5. The correlation functions evaluated in different intervals of measured charged-particle multiplicity show a multiplicity-dependent enhancement at Δϕ∼0 that extends over a wide range of Δη, which has been referred to as the "ridge." Per-trigger-particle yields, Y(Δϕ), are measured over 2<|Δη|<5. For both collision energies, the Y(Δϕ) distribution in all multiplicity intervals is found to be consistent with a linear combination of the per-trigger-particle yields measured in collisions with less than 20 reconstructed tracks, and a constant combinatoric contribution modulated by cos(2Δϕ). The fitted Fourier coefficient, v_{2,2}, exhibits factorization, suggesting that the ridge results from per-event cos(2ϕ) modulation of the single-particle distribution with Fourier coefficients v_{2}. The v_{2} values are presented as a function of multiplicity and transverse momentum. They are found to be approximately constant as a function of multiplicity and to have a p_{T} dependence similar to that measured in p+Pb and Pb+Pb collisions. The v_{2} values in the 13 and 2.76 TeV data are consistent within uncertainties. These results suggest that the ridge in pp collisions arises from the same or similar underlying physics as observed in p+Pb collisions, and that the dynamics responsible for the ridge has no strong sqrt[s] dependence.