Use of beta-blockers and the risk of hip/femur fracture in the United Kingdom and The Netherlands.
Data from in vivo studies have indicated a role for beta-blockers in the prevention of bone loss. Some epidemiological studies have found protective effects of beta-blockers on fracture risk. However, there is limited information on the association with cumulative dose and type of beta-blockers used. We conducted two case-control studies using data from the UK General Practice Research Database (GPRD) and the Dutch PHARMO Record Linkage System (RLS). Cases were patients with a first hip or femur fracture; controls were individually matched on practice/region, gender, year of birth, and calendar time. Current use of beta-blockers was defined as a prescription in 90 days before the index date. We adjusted for medical conditions and drugs associated with falling or bone mineral density. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression analysis. The study population included 22,247 cases and controls in the GPRD and 6,763 cases and 26,341 controls in the PHARMO RLS. Current use of beta-blockers was associated with a reduced risk of hip/femur fracture in both the GPRD (adjusted OR = 0.82, 95% CI 0.74-0.91) and PHARMO RLS (adjusted OR = 0.87, 95% CI 0.80-0.95) study populations. However, this reduction of risk was not associated with cumulative dose, lipophilicity, or receptor selectivity of beta-blockers. The protective effect of beta-blockers was only present among patients with a history of use of other antihypertensive agents (GPRD adjusted OR = 0.72, 95% CI 0.64-0.83; PHARMO RLS adjusted OR = 0.76, 95% CI 0.67-0.86) but not in patients using beta-blockers only (GPRD adjusted OR = 0.97, 95% CI 0.82-1.14; PHARMO RLS adjusted OR = 1.01, 95% CI 0.90-1.14). Also, in patients with a history of use of other antihypertensive agents, no dose-response relationship with beta-blocker use was found. The effect was constant with cumulative dose and the OR was below 1.0 even among patients who just started treatment with beta-blockers. As the mechanism by which beta-blockers could influence bone mineral density is likely to need some time to exert a clinically relevant effect, all these finding suggests that the association between beta-blockers and fracture risk is not causal.


Extensive left ventricular remodeling does not allow viable myocardium to improve in left ventricular ejection fraction after revascularization and is associated with worse long-term prognosis.
Extensive left ventricular (LV) remodeling may not allow functional recovery after revascularization, despite the presence of viable myocardium. Seventy-nine consecutive patients with ischemic cardiomyopathy (left ventricle ejection fraction [LVEF] 29+/-7%) underwent surgical revascularization. Before revascularization, viability was assessed by metabolic imaging with F18-fluorodeoxyglucose and SPECT. LV volumes and LVEF were assessed by resting echocardiography. LVEF was re-assessed by echocardiography 8 to 12 months after revascularization. Three-year clinical follow-up (events: cardiac death, infarction, and hospitalization for heart failure) was also obtained. Forty-nine patients had substantial viability; 5 died before re-assessment of LVEF. Of the remaining 44 patients, 24 improved > or =5% in LVEF after revascularization, whereas 20 did not improve in LVEF. LV end-systolic volume was the only parameter that was significantly different between the groups (109+/-46 mL for the improvers versus 141+/-31 mL for the nonimprovers; P<0.05). The change in LVEF after revascularization was linearly related to the baseline LV end-systolic volume, with a higher LV end-systolic volume associated with a low likelihood of improvement in LVEF after revascularization. During the 3-year follow-up, the highest event-rate (67%) was observed in patients without viable myocardium with a large LV size, whereas the lowest event rate (5%) was observed in patients with viable myocardium and a small LV size. Intermediate event rates were observed in patients with viable myocardium and a large LV size (38%), and in patients without viable myocardium and a small LV size (24%). Extensive LV remodeling prohibits improvement in LVEF after revascularization and affects long-term prognosis negatively, despite the presence of viability.


Identification of genetic loci involved in diabetes using a rat model of depression.
While diabetic patients often present with comorbid depression, the underlying mechanisms linking diabetes and depression are unknown. The Wistar Kyoto (WKY) rat is a well-known animal model of depression and stress hyperreactivity. In addition, the WKY rat is glucose intolerant and likely harbors diabetes susceptibility alleles. We conducted a quantitative trait loci (QTL) analysis in the segregating F(2) population of a WKY x Fischer 344 (F344) intercross. We previously published QTL analyses for depressive behavior and hypothalamic-pituitary-adrenal (HPA) activity in this cross. In this study we report results from the QTL analysis for multiple metabolic phenotypes, including fasting glucose, post-restraint stress glucose, postprandial glucose and insulin, and body weight. We identified multiple QTLs for each trait and many of the QTLs overlap with those previously identified using inbred models of type 2 diabetes (T2D). Significant correlations were found between metabolic traits and HPA axis measures, as well as forced swim test behavior. Several metabolic loci overlap with loci previously identified for HPA activity and forced swim behavior in this F(2) intercross, suggesting that the genetic mechanisms underlying these traits may be similar. These results indicate that WKY rats harbor diabetes susceptibility alleles and suggest that this strain may be useful for dissecting the underlying genetic mechanisms linking diabetes, HPA activity, and depression.


Does the learning of two symbolic sets of numbers affect the automaticity of number processing in children?
We explored the effects of learning two different symbolic sets of numerals (Arabic and Indian) on the development of automatic number processing. Children in the school we examined learn Indian numerals between first and third grades. In third grade, they switch to a new set of numerals (i.e., Arabic numbers). Participants in this study performed a numerical Stroop-like task in which they assessed the numerical value or physical size of stimuli varying along these two dimensions. Each participant saw either Arabic or Indian numerals. The results of the size congruity effect in the physical task, for both Indian and Arabic numerals, suggest that studying two sets of numerals interferes with the acquisition of an automatic association of a numerical symbol and magnitude. This is true both for the first learned set of numerals (i.e., Indian numerals) and for the second one (i.e., Arabic numerals). Furthermore, we found an absence of the distance effect, which further supports this conclusion. This learning program gave us the unique opportunity to examine the connection between symbolic sets and the mental representation of numbers in a novel fashion.


Sexual abstinence only programmes to prevent HIV infection in high income countries: systematic review.
To assess the effects of sexual abstinence only programmes for HIV prevention among participants in high income countries. Systematic review. 30 electronic databases without linguistic or geographical restrictions to February 2007, contacts with experts, hand searching, and cross referencing. Two reviewers independently applied inclusion criteria and extracted data, resolving disagreements by consensus and referral to a third reviewer. Randomised and quasirandomised controlled trials of abstinence only programmes in any high income country were included. Programmes aimed to prevent HIV only or both pregnancy and HIV. Trials evaluated biological outcomes (incidence of HIV, sexually transmitted infection, pregnancy) or behavioural outcomes (incidence or frequency of unprotected vaginal, anal, or oral sex; incidence or frequency of any vaginal, anal, or oral sex; number of partners; condom use; sexual initiation). The search identified 13 trials enrolling about 15,940 US youths. All outcomes were self reported. Compared with various controls, no programme affected incidence of unprotected vaginal sex, number of partners, condom use, or sexual initiation. One trial observed adverse effects at short term follow-up (sexually transmitted infections, frequency of sex) and long term follow-up (sexually transmitted infections, pregnancy) compared with usual care, but findings were offset by trials with non-significant results. Another trial observed a protective effect on incidence of vaginal sex compared with usual care, but this was limited to short term follow-up and countered by trials with non-significant findings. Heterogeneity prevented meta-analysis. Programmes that exclusively encourage abstinence from sex do not seem to affect the risk of HIV infection in high income countries, as measured by self reported biological and behavioural outcomes.


Adiposity as a cause of cardiovascular disease: a Mendelian randomization study.
Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22,193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.


A centromere DNA-binding protein from fission yeast affects chromosome segregation and has homology to human CENP-B.
Genetic and biochemical strategies have been used to identify Schizosaccharomyces pombe proteins with roles in centromere function. One protein, identified by both approaches, shows significant homology to the human centromere DNA-binding protein, CENP-B, and is identical to Abp1p (autonomously replicating sequence-binding protein 1) (Murakami, Y., J.A. Huberman, and J. Hurwitz. 1996. Proc. Natl. Acad. Sci. USA. 93:502-507). Abp1p binds in vitro specifically to at least three sites in centromeric central core DNA of S. pombe chromosome II (cc2). Overexpression of abp1 affects mitotic chromosome stability in S. pombe. Although inactivation of the abp1 gene is not lethal, the abp1 null strain displays marked mitotic chromosome instability and a pronounced meiotic defect. The identification of a CENP-B-related centromere DNA-binding protein in S. pombe strongly supports the hypothesis that fission yeast centromeres are structurally and functionally related to the centromeres of higher eukaryotes.


COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.
Collagen, type IV, alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers and are abundant components of basement membranes, including those of the cerebral vasculature. COL4A1 mutations are an increasingly recognized cause of multisystem disorders, including highly penetrant cerebrovascular disease and intracerebral hemorrhage (ICH). Because COL4A1 and COL4A2 are structurally and functionally associated, we hypothesized that variants in COL4A2 would also cause ICH. We sequence COL4A2 in 96 patients with ICH and identify three rare, nonsynonymous coding variants in four patients that are not present in a cohort of 144 ICH-free individuals. All three variants change evolutionarily conserved amino acids. Using a cellular assay, we show that these putative mutations cause intracellular accumulation of COL4A1 and COL4A2 at the expense of their secretion, which supports their pathogenecity. Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH and that mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER). Importantly, two of the three putative mutations found in patients trigger ER stress and activate the unfolded protein response. The identification of putative COL4A2 mutations that might contribute to ICH in human patients provides insight into the pathogenic mechanisms of this disease. Our data suggest that COL4A2 mutations impair COL4A1 and COL4A2 secretion and can also result in cytotoxicity. Finally, our findings suggest that, collectively, mutations in COL4A1 and COL4A2 contribute to sporadic cases of ICH.


The complete genome sequence of the murine respiratory pathogen Mycoplasma pulmonis.
Mycoplasma pulmonis is a wall-less eubacterium belonging to the Mollicutes (trivial name, mycoplasmas) and responsible for murine respiratory diseases. The genome of strain UAB CTIP is composed of a single circular 963 879 bp chromosome with a G + C content of 26.6 mol%, i.e. the lowest reported among bacteria, Ureaplasma urealyticum apart. This genome contains 782 putative coding sequences (CDSs) covering 91.4% of its length and a function could be assigned to 486 CDSs whilst 92 matched the gene sequences of hypothetical proteins, leaving 204 CDSs without significant database match. The genome contains a single set of rRNA genes and only 29 tRNAs genes. The replication origin oriC was localized by sequence analysis and by using the G + C skew method. Sequence polymorphisms within stretches of repeated nucleotides generate phase-variable protein antigens whilst a recombinase gene is likely to catalyse the site-specific DNA inversions in major M.pulmonis surface antigens. Furthermore, a hemolysin, secreted nucleases and a glyco-protease are predicted virulence factors. Surprisingly, several of the genes previously reported to be essential for a self-replicating minimal cell are missing in the M.pulmonis genome although this one is larger than the other mycoplasma genomes fully sequenced until now.


Computer based quantitative analysis of capillary abnormalities in systemic sclerosis and its relation to plasma concentration of von Willebrand factor.
To evaluate an objective and quantitative method for assessment of capillary abnormalities in systemic sclerosis (SSc). Nailfold capillaries were investigated by capillary microscopy and photographed in 17 consecutive SSc patients (five with diffuse cutaneous systemic sclerosis (dSSc) and 12 with limited cutaneous systemic sclerosis (lSSc)) and in 17 healthy controls. Investigators having no access to clinical data made drawings from magnified projections of coded photographs and analysed them using a computer program. Capillary density (capillary loops/mm in the distal row) and median capillary loop area were calculated. Presence of functional or organic arterial changes was evaluated by measurement of finger pressure with finger cooling. Plasma concentration of von Willebrand factor (VWF) was analysed using an enzyme linked immunosorbent assay (ELISA). In 16 of 17 SSc patients and 13 of 17 controls the technical quality of the photographs was sufficient for computer analysis. Capillary density was decreased in dSSc (median 6.9 loops/mm) and in lSSc (median 3.8 loops/mm) compared with healthy controls (8.9 loops/mm) and median capillary loop area was increased in dSSc (7.3 x 10(-3) mm2) and in lSSc (8.5 x 10(-3) mm2) compared with healthy controls (5.0 x 10(-3) mm2). An inverse relation was found between capillary density and median capillary loop area in SSc patients. Plasma VWF was increased in patients (median 401 IE/l in dSSc and 409 IE/l in lSSc) compared with controls matched for age and sex (median 276 IE/l). Computer based analysis showed capillary density below the control range and median capillary loop area above the control range in 14 of 16 SSc patients. Measurement of finger pressure with finger cooling showed organic vascular changes in nine of 13 SSc patients. Computer based quantitative analysis has low interobserver variability and is a quantitative and sensitive method of assessing capillary abnormalities in SSc.


Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis.
We aimed to evaluate the use of baricitinib, a Janus kinase (JAK) 1-2 inhibitor, for the treatment of patients admitted to hospital with COVID-19. This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was done, which included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936) and is ongoing. Between Feb 2 and Dec 29, 2021, from 10 852 enrolled, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% were receiving tocilizumab (with planned use within the next 24 h recorded for a further 9%). Overall, 514 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77-0·99; p=0·028). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of eight previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths), in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0·57; 95% CI 0·45-0·72). Including the results from RECOVERY in an updated meta-analysis of all nine completed trials (involving 11 888 randomly assigned patients and 1485 deaths) allocation to baricitinib or another JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0·80; 95% CI 0·72-0·89; p<0·0001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no significant excess of thrombosis, or other safety outcomes. In patients hospitalised with COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth. UK Research and Innovation (Medical Research Council) and National Institute of Health Research.


Staffing remote rural areas in middle- and low-income countries: a literature review of attraction and retention.
Many countries in middle- and low-income countries today suffer from severe staff shortages and/or maldistribution of health personnel which has been aggravated more recently by the disintegration of health systems in low-income countries and by the global policy environment. One of the most damaging effects of severely weakened and under-resourced health systems is the difficulty they face in producing, recruiting, and retaining health professionals, particularly in remote areas. Low wages, poor working conditions, lack of supervision, lack of equipment and infrastructure as well as HIV and AIDS, all contribute to the flight of health care personnel from remote areas. In this global context of accelerating inequities health service policy makers and managers are searching for ways to improve the attraction and retention of staff in remote areas. But the development of appropriate strategies first requires an understanding of the factors which influence decisions to accept and/or stay in a remote post, particularly in the context of mid and low income countries (MLICS), and which strategies to improve attraction and retention are therefore likely to be successful. It is the aim of this review article to explore the links between attraction and retention factors and strategies, with a particular focus on the organisational diversity and location of decision-making. This is a narrative literature review which took an iterative approach to finding relevant literature. It focused on English-language material published between 1997 and 2007. The authors conducted Pubmed searches using a range of different search terms relating to attraction and retention of staff in remote areas. Furthermore, a number of relevant journals as well as unpublished literature were systematically searched. While the initial search included articles from high- middle- and low-income countries, the review focuses on middle- and low-income countries. About 600 papers were initially assessed and 55 eventually included in the review. The authors argue that, although factors are multi-facetted and complex, strategies are usually not comprehensive and often limited to addressing a single or limited number of factors. They suggest that because of the complex interaction of factors impacting on attraction and retention, there is a strong argument to be made for bundles of interventions which include attention to living environments, working conditions and environments and development opportunities. They further explore the organisational location of decision-making related to retention issues and suggest that because promising strategies often lie beyond the scope of human resource directorates or ministries of health, planning and decision-making to improve retention requires multi-sectoral collaboration within and beyond government. The paper provides a simple framework for bringing the key decision-makers together to identify factors and develop multi-facetted comprehensive strategies. There are no set answers to the problem of attraction and retention. It is only through learning about what works in terms of fit between problem analysis and strategy and effective navigation through the politics of implementation that any headway will be made against the almost universal challenge of staffing health service in remote rural areas.


How modeling can reconcile apparently discrepant experimental results: the case of pacemaking in dopaminergic neurons.
Midbrain dopaminergic neurons are endowed with endogenous slow pacemaking properties. In recent years, many different groups have studied the basis for this phenomenon, often with conflicting conclusions. In particular, the role of a slowly-inactivating L-type calcium channel in the depolarizing phase between spikes is controversial, and the analysis of slow oscillatory potential (SOP) recordings during the blockade of sodium channels has led to conflicting conclusions. Based on a minimal model of a dopaminergic neuron, our analysis suggests that the same experimental protocol may lead to drastically different observations in almost identical neurons. For example, complete L-type calcium channel blockade eliminates spontaneous firing or has almost no effect in two neurons differing by less than 1% in their maximal sodium conductance. The same prediction can be reproduced in a state of the art detailed model of a dopaminergic neuron. Some of these predictions are confirmed experimentally using single-cell recordings in brain slices. Our minimal model exhibits SOPs when sodium channels are blocked, these SOPs being uncorrelated with the spiking activity, as has been shown experimentally. We also show that block of a specific conductance (in this case, the SK conductance) can have a different effect on these two oscillatory behaviors (pacemaking and SOPs), despite the fact that they have the same initiating mechanism. These results highlight the fact that computational approaches, besides their well known confirmatory and predictive interests in neurophysiology, may also be useful to resolve apparent discrepancies between experimental results.


"There Is No Link Between Resource Allocation and Use of Local Data": A Qualitative Study of District-Based Health Decision-Making in West Bengal, India.
Effective coordination among multiple departments, including data-sharing, is needed for sound decision-making for health services. India has a district planning process involving departments for local resource-allocation based on shared data. This study assesses the decision-making process at the district level, with a focus on the extent of local data-use for resource allocation for maternal and child health. Direct observations of key decision-making meetings and qualitative interviews with key informants were conducted in two districts in the State of West Bengal, India. Content analysis of the data maintained within the district health system was done to understand the types of data available and sharing mechanisms. This information was triangulated thematically based on WHO health system blocks. There was no structured decision-making process and only limited inter-departmental data-sharing. Data on all 21 issues discussed in the district decision-making meetings observed were available within the information systems. Yet indicators for only nine issues-such as institutional delivery and immunisation services were discussed. Discussions about infrastructure and supplies were not supported by data, and planning targets were not linked to health outcomes. Existing local data is highly under-used for decision-making at the district level. There is strong potential for better interaction between departments and better use of data for priority-setting, planning and follow-up.


Cochlear implantation in children with Waardenburg syndrome.
Waardenburg syndrome is an autosomal-dominant trait resulting from mutations occurring in different genes. It is often characterized by varying degrees of: congenital hearing loss; dystopia canthorum; synophrys; broad nasal root; depigmentation of hair (white forelock), skin or both; and heterochromic or hypochromic irides. A retrospective case study was done to assess speech perception, speech production, general intelligence and educational setting in six profoundly hearing-impaired children with Waardenburg syndrome (four with type I, one with type II and one with type III) ranging in age from two years to 14 years, seven months (mean = six years, six months). None of the patients had malformation of the cochlea and were implanted using Nucleus 22/24 and Med-el combi40+. Five out of the six cases were of average intelligence and one had a borderline intelligence quotient. The follow-up period ranged from one year, 10 months to six years, six months (mean = three years, six months) after implantation. The evaluation of auditory perception in patients was accomplished using the Persian Auditory Perception Test for the Hearing-Impaired, a Persian Spondee words test and the Categories of Auditory Performance Index. The Speech Intelligibility Rating test was used to evaluate speech production ability. All the patients' speech perception and speech intelligibility capabilities improved considerably after receiving the implants, and they were able to be placed in regular educational settings. Patients used their cochlear-implant devices whenever awake, implying that they benefitted from the devices. We suggest that any further expansion of cochlear-implantation criteria in children include those with Waardenburg syndrome.


Human opinion dynamics: an inspiration to solve complex optimization problems.
Human interactions give rise to the formation of different kinds of opinions in a society. The study of formations and dynamics of opinions has been one of the most important areas in social physics. The opinion dynamics and associated social structure leads to decision making or so called opinion consensus. Opinion formation is a process of collective intelligence evolving from the integrative tendencies of social influence with the disintegrative effects of individualisation, and therefore could be exploited for developing search strategies. Here, we demonstrate that human opinion dynamics can be utilised to solve complex mathematical optimization problems. The results have been compared with a standard algorithm inspired from bird flocking behaviour and the comparison proves the efficacy of the proposed approach in general. Our investigation may open new avenues towards understanding the collective decision making.


Endothelin-1 is synthesized and inhibits cyclic adenosine monophosphate- dependent anion secretion by an autocrine/paracrine mechanism in gallbladder epithelial cells.
Ion and fluid transport across the biliary epithelium contributes to bile secretion. Since endothelin (ET)-1 affects ion transport activities and is released by human gallbladder- derived biliary epithelial cells in primary culture, we examined the expression of ET peptides and ET receptors and the influence of ET-1 on ion transport in this epithelium ex vivo. In freshly isolated gallbladder epithelial cells, preproET-1, -2, and -3 mRNAs were detected by reverse transcription PCR and ET-1 isopeptide was identified by chromatography. The cells also displayed ET receptor mRNAs and high-affinity binding sites for ET-1, mostly of the ETB type. Electrogenic anion secretion across intact gallbladder mucosa was stimulated by forskolin, secretin, and exogenous ATP, as assessed by short-circuit current (Isc) increases in Ussing-type chambers. ET-1 inhibited forskolin- and secretin-induced changes in Isc, without affecting baseline Isc or ATP-induced changes. Accordingly, ET-1 significantly reduced the accumulation of intracellular cAMP elicited by forskolin and secretin in the epithelial cells, and this effect was abolished by pertussis toxin. This is the first evidence that ET-1 is synthesized and inhibits, via a Gi protein-coupled receptor, cAMP-dependent anion secretion in human gallbladder epithelium, indicating a role in the control of bile secretion by an autocrine/paracrine mechanism.


Genome-Wide Architecture of Disease Resistance Genes in Lettuce.
Genome-wide motif searches identified 1134 genes in the lettuce reference genome of cv. Salinas that are potentially involved in pathogen recognition, of which 385 were predicted to encode nucleotide binding-leucine rich repeat receptor (NLR) proteins. Using a maximum-likelihood approach, we grouped the NLRs into 25 multigene families and 17 singletons. Forty-one percent of these NLR-encoding genes belong to three families, the largest being RGC16 with 62 genes in cv. Salinas. The majority of NLR-encoding genes are located in five major resistance clusters (MRCs) on chromosomes 1, 2, 3, 4, and 8 and cosegregate with multiple disease resistance phenotypes. Most MRCs contain primarily members of a single NLR gene family but a few are more complex. MRC2 spans 73 Mb and contains 61 NLRs of six different gene families that cosegregate with nine disease resistance phenotypes. MRC3, which is 25 Mb, contains 22 RGC21 genes and colocates with Dm13. A library of 33 transgenic RNA interference tester stocks was generated for functional analysis of NLR-encoding genes that cosegregated with disease resistance phenotypes in each of the MRCs. Members of four NLR-encoding families, RGC1, RGC2, RGC21, and RGC12 were shown to be required for 16 disease resistance phenotypes in lettuce. The general composition of MRCs is conserved across different genotypes; however, the specific repertoire of NLR-encoding genes varied particularly of the rapidly evolving Type I genes. These tester stocks are valuable resources for future analyses of additional resistance phenotypes.


Allogeneic Mesenchymal Stem Cells for Treatment of AKI after Cardiac Surgery.
AKI after cardiac surgery remains strongly associated with mortality and lacks effective treatment or prevention. Preclinical studies suggest that cell-based interventions may influence functional recovery. We conducted a phase 2, randomized, double-blind, placebo-controlled trial in 27 centers across North America to determine the safety and efficacy of allogeneic human mesenchymal stem cells (MSCs) in reducing the time to recovery from AKI after cardiac surgery. We randomized 156 adult subjects undergoing cardiac surgery with evidence of early AKI to receive intra-aortic MSCs (AC607; n=67) or placebo (n=68). The primary outcome was the time to recovery of kidney function defined as return of postintervention creatinine level to baseline. The median time to recovery of kidney function was 15 days with AC607 and 12 days with placebo (25th, 75th percentile range, 10-29 versus 6-21, respectively; hazard ratio, 0.81; 95% confidence interval, 0.53 to 1.24; P=0.32). We did not detect a significant difference between groups in 30-day all-cause mortality (16.7% with AC607; 11.8% with placebo) or dialysis (10.6% with AC607; 7.4% with placebo). At follow-up, 12 patients who received AC607 and six patients who received placebo had died. Rates of other adverse events did not differ between groups. In these patients with AKI after cardiac surgery, administration of allogeneic MSCs did not decrease the time to recovery of kidney function. Our results contrast with those in preclinical studies and provide important information regarding the potential effects of MSCs in this setting.


Translating cancer genomes and transcriptomes for precision oncology.
Understanding the molecular landscape of cancer has facilitated the development of diagnostic, prognostic, and predictive biomarkers for clinical oncology. Developments in next-generation DNA sequencing technologies have increased the speed and reduced the cost of sequencing the nucleic acids of cancer cells. This has unlocked opportunities to characterize the genomic and transcriptomic landscapes of cancer for basic science research through projects like The Cancer Genome Atlas. The cancer genome includes DNA-based alterations, such as point mutations or gene duplications. The cancer transcriptome involves RNA-based alterations, including changes in messenger RNAs. Together, the genome and transcriptome can provide a comprehensive view of an individual patient's cancer that is beginning to impact real-time clinical decision-making. The authors discuss several opportunities for translating this basic science knowledge into clinical practice, including a molecular classification of cancer, heritable risk of cancer, eligibility for targeted therapies, and the development of innovative, genomic-based clinical trials. In this review, key applications and new directions are outlined for translating the cancer genome and transcriptome into patient care in the clinic.


Ligation of CD40 induces the expression of vascular endothelial growth factor by endothelial cells and monocytes and promotes angiogenesis in vivo.
This study addresses a mechanism by which lymphocytes may promote vascular endothelial growth factor (VEGF) expression and angiogenesis in immune inflammation. Resting human umbilical endothelial cells (HUVECs) were found to express low levels of VEGF messenger RNA (mRNA) by reverse transcription polymerase chain reaction and ribonuclease protection assay with little or no change in expression following activation by cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1, interferon gamma, or IL-4. In contrast, treatment of HUVECs and monocytes with soluble CD40 ligand (sCD40L) resulted in a marked dose-dependent induction of VEGF mRNA (approximately 4-fold), which peaked between 1 and 5 hours post-stimulation. Transient transfection of HUVECs was performed with a luciferase reporter construct under the control of the human VEGF promoter. Treatment of transfected HUVECs with sCD40L was found to enhance luciferase activity (approximately 4-fold) compared with controls, similar to the relative fold induction in mRNA expression in parallel cultures. Thus, CD40-dependent VEGF expression was a result of transcriptional control mechanisms. Treatment of HUVECs with sCD40L was also found to function in vitro to promote growth and proliferation in a VEGF-dependent manner, and CD40-dependent HUVEC growth was comparable to that found following treatment with recombinant human VEGF. Furthermore, subcutaneous injection of sCD40L in severe combined immunodeficient and nude mice induced VEGF expression and marked angiogenesis in vivo. Taken together, these findings are consistent with a function for CD40L-CD40 interactions in VEGF-induced angiogenesis and define a mechanistic link between the immune response and angiogenesis. (Blood. 2000;96:3801-3808)


Human optic nerve head astrocytes as a target for endothelin-1.
To determine whether human optic nerve head astrocytes (hONAs) are target cells for the actions of endothelin (ET)-1, a potent vasoactive peptide, by causing astrocyte proliferation, as occurs in glaucomatous optic nerve heads. ET-1 levels are elevated in glaucomatous eyes, and administration of ET-1 to the retina causes glial activation and optic nerve damage in animal models in a manner similar to that observed in glaucoma. Well-characterized hONAs were used in this study. Cell proliferation of hONAs was assessed, after ET-1 treatment under serum-free culture conditions, with both a formazan assay and [3H]thymidine uptake. ET receptor involvement for cell proliferation was determined with BQ788 (an ETB antagonist), BQ610 (an ETA antagonist), PD142893 (an ET(A/B) mixed antagonist), and sarafotoxin 6C (S6C; an ET(B) agonist). ET-1-induced intracellular calcium ([Ca2+]i) in hONAs was measured by fura-2 imaging. RT-PCR was used to determine whether hONAs express mRNA for preproET-1, ET(A), and ET(B) receptors. ET-1 (10 and 100 nM) caused a time-dependent proliferation of hONAs, which was completely blocked by PD142893, as detected by two different cell proliferation assays. The effects of ET-1 were blocked by BQ788 and were also mimicked by S6C, indicative of the involvement of ET(B) receptor activation. ET-1-induced elevation in [Ca2+]i, and cell proliferation were both blocked completely by the ET(A) antagonist BQ610, suggesting ET(A) receptor involvement. The hONAs expressed mRNA for ET(A) and ET(B) receptors as well as preproET-1, suggesting that these cells may also be a source for ET-1 in the optic nerve head. ET-1 induces astroglial proliferation in cultured human optic nerve head astrocytes through ET(A/B) receptor activation. This is similar to the proliferation of ET-1 in brain astrocytes. These findings suggest that ET-1, which is elevated in glaucoma, could cause proliferation of ONAs in the optic nerve head.


Zinc supplementation improved length growth only in anemic infants in a multi-country trial of iron and zinc supplementation in South-East Asia.
Data from 4 randomized, placebo-controlled, double-blind trials in Indonesia, Thailand, and Vietnam, the South-East Asian Multicountry Trial on Iron and Zinc supplementation in Infants (SEAMTIZI), were pooled to investigate the effects of iron and zinc supplementation infant growth. Infants (n = 2451) aged 4-6 mo old were supplemented with iron (10 mg/d) and/or zinc (10 mg/d) for 6 mo. Overall, neither iron nor zinc supplementation prevented the progressive growth faltering during infancy, which is common in many developing countries. However, infants who received zinc were less likely to be stunted at the end of the supplementation period (odds ratio 0.80; 95% CI 0.64-1.0). Boys had a 30% higher risk of being stunted at the end of the study than girls (P < 0.01). Baseline factors modified the effect of supplementation, with infants anemic at baseline (hemoglobin < 105 g/L) benefiting from zinc supplementation, with an estimated increase in height-for-age Z-score (HAZ) score of 0.17 (P < 0.01), but with no effect of zinc supplementation on growth in infants not anemic at baseline. Iron supplementation negatively affected linear growth in infants with a birth weight of >3500 g (estimated effect size, -0. 14 HAZ score; P < 0.01), but with no significant effect in infants with a lower birth weight. This study shows that blanket supplementation of infants with iron or zinc will not be beneficial to all recipients and may have adverse effects in some. Hence, interventions such as iron and zinc supplementation for infants should be restricted to subgroups in which there is a clear benefit and baseline factors should be considered and characterized before implementing new policies.


Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies.
Body mass index (BMI), a measure of obesity typically assessed in middle age or later, is known to be positively associated with pancreatic cancer. However, little evidence exists regarding the influence of central adiposity, a high BMI during early adulthood, and weight gain after early adulthood on pancreatic cancer risk. We conducted a pooled analysis of individual-level data from 20 prospective cohort studies in the National Cancer Institute BMI and Mortality Cohort Consortium to examine the association of pancreatic cancer mortality with measures of central adiposity (e.g. waist circumference; n = 647 478; 1947 pancreatic cancer deaths), BMI during early adulthood (ages 18-21 years) and BMI change between early adulthood and cohort enrollment, mostly in middle age or later (n = 1 096 492; 3223 pancreatic cancer deaths). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Higher waist-to-hip ratio (HR = 1.09, 95% CI 1.02-1.17 per 0.1 increment) and waist circumference (HR = 1.07, 95% CI 1.00-1.14 per 10 cm) were associated with increased risk of pancreatic cancer mortality, even when adjusted for BMI at baseline. BMI during early adulthood was associated with increased pancreatic cancer mortality (HR = 1.18, 95% CI 1.11-1.25 per 5 kg/m(2)), with increased risk observed in both overweight and obese individuals (compared with BMI of 21.0 to <23 kg/m(2), HR = 1.36, 95% CI 1.20-1.55 for BMI 25.0 < 27.5 kg/m(2), HR = 1.48, 95% CI 1.20-1.84 for BMI 27.5 to <30 kg/m(2), HR = 1.43, 95% CI 1.11-1.85 for BMI ≥30 kg/m(2)). BMI gain after early adulthood, adjusted for early adult BMI, was less strongly associated with pancreatic cancer mortality (HR = 1.05, 95% CI 1.01-1.10 per 5 kg/m(2)). Our results support an association between pancreatic cancer mortality and central obesity, independent of BMI, and also suggest that being overweight or obese during early adulthood may be important in influencing pancreatic cancer mortality risk later in life.


The Neurodevelopmental Perspective of Surgical Necrotizing Enterocolitis: The Role of the Gut-Brain Axis.
This state-of-the-art review article aims to highlight the most recent evidence about the therapeutic options of surgical necrotizing enterocolitis, focusing on the molecular basis of the gut-brain axis in relevance to the neurodevelopmental outcomes of primary peritoneal drainage and primary laparotomy. Current evidence favors primary laparotomy over primary peritoneal drainage as regards neurodevelopment in the surgical treatment of necrotizing enterocolitis. The added exposure to inhalational anesthesia in infants undergoing primary laparotomy is an additional confounding variable but requires further study. The concept of the gut-brain axis suggests that bowel injury initiates systemic inflammation potentially affecting the developing central nervous system. Signals about microbes in the gut are transduced to the brain and the limbic system via the enteric nervous system, autonomic nervous system, and hypothalamic-pituitary axis. Preterm infants with necrotizing enterocolitis have significant differences in the diversity of the microbiome compared with preterm controls. The gut bacterial flora changes remarkably prior to the onset of necrotizing enterocolitis with a predominance of pathogenic organisms. The type of initial surgical approach correlates with the length of functional gut and microbiome equilibrium influencing brain development and function through the gut-brain axis. Existing data favor patients who were treated with primary laparotomy over those who underwent primary peritoneal drainage in terms of neurodevelopmental outcomes. We propose that this is due to the sustained injurious effect of the remaining diseased and necrotic bowel on the developing newborn brain, in patients treated with primary peritoneal drainage, through the gut-brain axis and probably not due to the procedure itself.


A method for reclassifying cause of death in cases categorized as "event of undetermined intent".
We present a method for reclassifying external causes of death categorized as "event of undetermined intent" (EUIs) into non-transport accidents, suicides, or homicides. In nations like Russia and the UK the absolute number of EUIs is large, the EUI death rate is high, or EUIs comprise a non-trivial proportion of all deaths due to external causes. Overuse of this category may result in (1) substantially underestimating the mortality rate of deaths due to specific external causes and (2) threats to the validity of studies of the patterns and causes of external deaths and of evaluations of the impact of interventions meant to reduce them. We employ available characteristics about the deceased and the event to estimate the most likely cause of death using multinomial logistic regression. We use the set of known non-transport accidents, suicides, and homicides to calculate an mlogit-based linear score and an estimated classification probability (ECP). This ECP is applied to EUIs, with varying levels of minimal classification probability. We also present an optional second step that employs a population-level adjustment to reclassify deaths that remain undetermined (the proportion of which varies based on the minimal classification probability). We illustrate our method by applying it to Russia. Between 2000 and 2011, 521,000 Russian deaths (15 % percent of all deaths from external causes) were categorized as EUIs. We used data from anonymized micro-data on the ~3 million deaths from external causes. Our reclassification model used 10 decedent and event characteristics from the computerized death records. Results show that during this period about 14 % of non-transport accidents, 13 % of suicides, and 33 % of homicides were officially categorized as EUIs. Our findings also suggest that 2011 levels of non-transport accidents and suicides would have been about 24 % higher and of homicide about 82 % higher than that reported by official vital statistics data. Overuse of the external cause of death classification "event of undetermined intent" may indicate questionable quality of mortality data on external causes of death. This can have wide-ranging implications for families, medical professionals, the justice system, researchers, and policymakers. With our classification probability set as equal to or higher than 0.75, we were able to reclassify about two-thirds of EUI deaths in our sample. Our optional additional step allowed us to redistribute the remaining unclassified EUIs. Our method can be applied to data from any nation or sub-national population in which the EUI category is employed.


Shared neural circuits for mentalizing about the self and others.
Although many examples exist for shared neural representations of self and other, it is unknown how such shared representations interact with the rest of the brain. Furthermore, do high-level inference-based shared mentalizing representations interact with lower level embodied/simulation-based shared representations? We used functional neuroimaging (fMRI) and a functional connectivity approach to assess these questions during high-level inference-based mentalizing. Shared mentalizing representations in ventromedial prefrontal cortex, posterior cingulate/precuneus, and temporo-parietal junction (TPJ) all exhibited identical functional connectivity patterns during mentalizing of both self and other. Connectivity patterns were distributed across low-level embodied neural systems such as the frontal operculum/ventral premotor cortex, the anterior insula, the primary sensorimotor cortex, and the presupplementary motor area. These results demonstrate that identical neural circuits are implementing processes involved in mentalizing of both self and other and that the nature of such processes may be the integration of low-level embodied processes within higher level inference-based mentalizing.


The two sides of pain communication: effects of pain expressiveness on vicarious brain responses revealed in chronic back pain patients.
The dominant socioaffective model of empathy has emphasized the overlap between brain mechanisms involved in the encoding and the decoding of internal states. The role of dispositional empathy has been extensively studied in this research, but several other individual factors fundamental to communication processes have been largely ignored. We studied the effects of dispositional expressiveness in chronic back pain patients to determine if the decoding of communicative and noncommunicative information signaling pain in others would be enhanced in individuals displaying a spontaneous propensity to consistently express more pain during a behavioral-observational naturalistic standardized lifting task performed on 2 separate occasions. Blood oxygenation level-dependent signal change was measured in response to pictures showing facial pain expressions and hands/feet in pain-evoking situations in chronic back pain patients and healthy controls. Vicarious brain responses to others' pain were comparable between groups. However, more expressive patients rated others' pain higher and showed stronger vicarious pain responses in the right ventral part of the inferior frontal gyrus, the right insula, and the midbrain. Activity in the right insula correlated positively with both the patients' expressiveness (encoding) and the intensity of the pain perceived in the images (decoding), suggesting that this structure linked the dispositional expressiveness with vicarious pain perception. Importantly, these effects were independent from dispositional empathy and were found with both communicative (facial expression) and noncommunicative (hand and foot) cues. These results suggest that dispositional expressiveness is a self-related factor that facilitates vicarious pain processing and might reflect individual tendencies to rely on social coping strategies. This article shows that pain expressivity in chronic pain patients increased the vicarious brain responses and the sensibility to others' pain. These results may help provide empirical support for better defining models of pain communication in chronic pain patients.


Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice.
The mouse autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), is primarily characterized as dysfunction of the blood-brain barrier (BBB). Resveratrol exhibits anti-inflammatory, antioxidative, and neuroprotective activities. We investigated the beneficial effects of resveratrol in protecting the integrity of the BBB in EAE mice and observed improved clinical outcome in the EAE mice after resveratrol treatment. Evans blue (EB) extravasation was used to detect the disruption of BBB. Western blot were used to detected the tight junction proteins and adhesion molecules zonula occludens-1 (ZO-1), occludin, ICAM-1, and VCAM-1. Inflammatory factors inducible nitric oxide synthase (iNOS), IL-1β, and arginase 1 were evaluated by quantitative RT-PCR (qPCR) and IL-10 by ELISA. NADPH oxidase (NOX) levels were evaluated by qPCR, and its activity was analyzed by lucigenin-derived chemiluminescence. Resveratrol at doses of 25 and 50 mg/kg produced a dose-dependent decrease in EAE paralysis and EB leakage, ameliorated EAE-induced loss of tight junction proteins ZO-1, occludin, and claudin-5, as well as repressed the EAE-induced increase in adhesion proteins ICAM-1 and VCAM-1. In addition, resveratrol suppressed the EAE-induced overexpression of proinflammatory transcripts iNOS and IL-1β and upregulated the expression of anti-inflammatory transcripts arginase 1 and IL-10 cytokine in the brain. Furthermore, resveratrol downregulated the overexpressed NOX2 and NOX4 in the brain and suppressed NADPH activity. Resveratrol ameliorates the clinical severity of MS through maintaining the BBB integrity in EAE mice.


Establishment of Locally Adapted Mutations Under Divergent Selection.
We study the establishment probabilities of locally adapted mutations using a multi-type branching process framework. We find a surprisingly simple and intuitive analytical approximation for the establishment probabilities in a symmetric two-deme model under the assumption of weak (positive) selection. This is the first analytical closed-form approximation for arbitrary migration rate to appear in the literature. We find that the establishment probability lies between the weak and the strong migration limits if we condition the origin of the mutation to the deme where it is advantageous. This is not the case when we condition the mutation to first occur in a deme where it is disadvantageous. In this case we find that an intermediate migration rate maximizes the probability of establishment. We extend our results to the cases of multiple demes, two demes with asymmetric rates of gene flow, and asymmetric carrying capacities. The latter case allows us to illustrate how density regulation can affect establishment probabilities. Finally, we use our results to investigate the role of gene flow on the rate of local adaptation and identify cases in which intermediate amounts of gene flow facilitate the rate of local adaptation as compared to two populations without gene flow.


Systems biology and biotechnology of Streptomyces species for the production of secondary metabolites.
Streptomyces species continue to attract attention as a source of novel medicinal compounds. Despite a long history of studies on these microorganisms, they still have many biochemical mysteries to be elucidated. Investigations of novel secondary metabolites and their biosynthetic gene clusters have been more systematized with high-throughput techniques through inspections of correlations among components of the primary and secondary metabolisms at the genome scale. Moreover, up-to-date information on the genome of Streptomyces species with emphasis on their secondary metabolism has been collected in the form of databases and knowledgebases, providing predictive information and enabling one to explore experimentally unrecognized biological spaces of secondary metabolism. Herein, we review recent trends in the systems biology and biotechnology of Streptomyces species.


Transcriptional and cellular responses to defective mitochondrial proteolysis in fission yeast.
Lon and m-AAA are the principal, regulated proteases required for protein maturation and turnover in the mitochondrial matrix of diverse species. To understand their roles in fission yeast (Schizosaccharomyces pombe) mitochondria, we generated deletion strains lacking Lon and m-AAA, individually (Δlon1 and Δm-AAA) or together, Δlon1Δm-AAA (Δ/Δ). All three strains were viable but incapable of respiratory growth on a non-fermentable carbon source due to mitochondrial dysfunction. Confocal and electron microscopy revealed a decrease in membrane potential and ultrastructural changes in Δlon1, Δm-AAA and Δ/Δ mitochondria, consistent with a respiratory defect and aggregation of proteins in the mitochondrial matrix. To understand the global adaptations required for cell survival in the absence of Lon and m-AAA proteases, we compared genome-wide gene expression signatures of the deletion strains with the isogenic wild-type strain. Deletion of lon1 caused a distinctive transcriptional footprint of just 12 differentially expressed genes, 9 of which were up-regulated genes located on the proximal mitochondrial genome (mitochondrial DNA). In contrast, m-AAA deletion caused a much larger transcriptional response involving 268 almost exclusively nuclear genes. Genes ameliorating stress and iron assimilation were up-regulated, while diverse mitochondrial genes and other metabolic enzymes were down-regulated. The connection with iron dysregulation was further explored using biochemical, chemical and cellular assays. Although Δm-AAA and Δ/Δ contained more cellular iron than the wild-type strain, their transcriptomes strongly resembled a signature normally evoked by iron insufficiency or disrupted assembly of iron-sulfur clusters in mitochondria. Based on these findings, we posit that excess iron accumulation could contribute to the pathology of human neurodegenerative disorders arising from defects in m-AAA function.


DRESS syndrome following ciprofloxacin exposure: An unusual association.
Female, 24 FINAL DIAGNOSIS: DRESS syndrome Symptoms: Fever • rash • facial and body swelling • muscular pain • diarrhea Ciprofloxacin Clinical Procedure: - Specialty: Internal Medicine • Hematology. Unusual or unexpected effect of treatment. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a rare, potentially life-threatening drug reaction with a mean latency period of 3.9 weeks. It has been described in association with many medications; yet, Ciprofloxacin was reported once in literature to be the offending drug. We are presenting a rare case of Ciprofloxacin-induced DRESS syndrome with symptom onset 2 days after exposure. A 24-year-old female presented with symptoms suggestive of UTI and was prescribed Ciprofloxacin. Two days later she started to complain of fever, diffuse rash, swelling of her face, arms and flanks, watery diarrhea and muscular pain. Five days after symptom onset she presented to our institution with WBC count 38,810 cells/μL and absolute Eosinophil count 17,080 cell/μL. Peripheral blood smear showed immature Eosinophilic myelocytes and metamyelocytes. Skin biopsy showed superficial perivascular lymphocytic infiltration with dermal edema. Further workup was negative for parasitic infestations, HIV and viral hepatitis, allergic diseases, hematologic and non-hematologic malignancies, vasculitides and autoimmune processes. Ciprofloxacin was discontinued upon admission and the patient started to improve quickly. PATIENT was followed in clinic after 3 weeks and was completely asymptomatic with WBC count 7,250 cell/μL and absolute Eosinophil count 2,900 cell/μL. DRESS syndrome is a possible complication of Ciprofloxacin treatment that clinicians should consider. Shorter latency period might be a unique feature of Fluoroquinolone-induced DRESS syndrome. According to RegiSCAR scoring system, our case is categorized as (probable) with a score of (4). In fact, the vast majority of reported cases are classified as (probable/definite).


Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex.
SUMOs are small ubiquitin-related polypeptides that are reversibly conjugated to many nuclear proteins. Although the number of identified substrates has grown rapidly, relatively little is still understood about when, where, and why most proteins are modified by SUMO. Here, we demonstrate that enzymes involved in the SUMO modification and demodification of proteins are components of the nuclear pore complex (NPC). We show that SENP2, a SUMO protease that is able to demodify both SUMO-1 and SUMO-2 or SUMO-3 protein conjugates, localizes to the nucleoplasmic face of the NPC. The unique amino-terminal domain of SENP2 interacts with the FG repeat domain of Nup153, indicating that SENP2 associates with the nucleoplasmic basket of the NPC. We also investigated the localization of the SUMO conjugating enzyme, Ubc9. Using immunogold labeling of isolated nuclear envelopes, we found that Ubc9 localizes to both the cytoplasmic and the nucleoplasmic filaments of the NPC. In vitro binding studies revealed that Ubc9 and SUMO-1-modified RanGAP1 bind synergistically to form a trimeric complex with a component of the cytoplasmic filaments of the NPC, Nup358. Our results indicate that both SUMO modification and demodification of proteins may occur at the NPC and suggest a connection between the SUMO modification pathway and nucleocytoplasmic transport.


Leucine-rich repeat receptor kinases are sporadically distributed in eukaryotic genomes.
Plant leucine-rich repeat receptor-like kinases (LRR-RLKs) are receptor kinases that contain LRRs in their extracellular domain. In the last 15 years, many research groups have demonstrated major roles played by LRR-RLKs in plants during almost all developmental processes throughout the life of the plant and in defense/resistance against a large range of pathogens. Recently, a breakthrough has been made in this field that challenges the dogma of the specificity of plant LRR-RLKs. We analyzed ~1000 complete genomes and show that LRR-RK genes have now been identified in 8 non-plant genomes. We performed an exhaustive phylogenetic analysis of all of these receptors, revealing that all of the LRR-containing receptor subfamilies form lineage-specific clades. Our results suggest that the association of LRRs with RKs appeared independently at least four times in eukaryotic evolutionary history. Moreover, the molecular evolutionary history of the LRR-RKs found in oomycetes is reminiscent of the pattern observed in plants: expansion with amplification/deletion and evolution of the domain organization leading to the functional diversification of members of the gene family. Finally, the expression data suggest that oomycete LRR-RKs may play a role in several stages of the oomycete life cycle. In view of the key roles that LRR-RLKs play throughout the entire lifetime of plants and plant-environment interactions, the emergence and expansion of this type of receptor in several phyla along the evolution of eukaryotes, and particularly in oomycete genomes, questions their intrinsic functions in mimicry and/or in the coevolution of receptors between hosts and pathogens.


Hematopoietic cell transplantation in the twitcher mouse. The effects of pretransplant conditioning with graded doses of busulfan.
The effects of congenic hematopoietic cell transplantation (HCT; transplantation of bone marrow and spleen cells) after graded doses of busulfan (BU), a myeloablative but nonimmunosuppressive alkylating agent, were evaluated in the twitcher mouse model of human galactosylceramidase deficiency, a demyelinating sphingolipid storage disease. C57BL/6 twitcher mice (immunophenotype Ly-5.1) were given 10 to 50 mg/kg of BU or total-body irradiation (9.0 Gy) at age nine days and HCT from congenic Ly-5.2 donors 24 hr later. The 30-day post-HCT survival, an indicator of tolerance of the preparative regimen, was at least 83% in twitcher mice given 45 mg/kg or less of BU, was 50% in recipients of 50 mg/kg BU and 75% in TBI-conditioned twitchers. The lifespan of twitcher mice given HCT after 10 or 20 mg/kg of BU was similar to that of untreated twitchers (median survival, 42 days; range, 30-47). In contrast, mice transplanted after 35 to 50 mg/kg of BU had significantly prolonged survival (median, 82 days; range, 56-208) and stabilization of hindlimb paralysis, similar to TBI-conditioned recipients. Post-HCT repopulation by donor Ly-5.2 cells was determined by flow cytometry. Thirty days after HCT, only 11-15% of lymphohematopoietic cells in blood, bone marrow, and spleens were of Ly-5.2 donor origin in twitcher mice transplanted after 10 mg/kg of BU but 60-80% were of Ly-5.2 donor origin in mice transplanted after higher doses of BU. These levels further increased to 70-90% by 90 days after HCT, comparable to that seen after TBI. Levels of galactosylceramidase in livers, spleens, and brains of twitchers transplanted after 35-50 mg/kg of BU or after TBI increased to 30-116% of normal control values by 90 days after HCT. Conditioning for HCT with as little as 35 mg/kg of BU provides minimal peritransplant mortality, rapid and sustained establishment of donor lymphohematopoiesis, replacement of lysosomal hydrolase, and prolonged survival in this murine model of human sphingolipidosis.


Intravenous Iron sucrose and change in hemoglobin, ferritin, and oxidative stress markers among moderately anemic pregnant women attending a secondary care level Hospital in Northern India.
Intravenous iron is associated with oxidative stress, and very few studies have assessed change in oxidative stress markers post infusion. The study aimed to measure the change in levels of hemoglobin (Hb), serum ferritin, and select oxidative stress markers (malondialdehyde [MDA], superoxide dismutase [SOD], and ferric reducing ability of plasma [FRAP]) 4 weeks following the administration of intravenous iron sucrose (IVIS) among moderately anemic pregnant women who were attending a secondary-level health-care facility, Haryana, North India. An observational study was conducted (May 2016 to Jan 2018) among pregnant women receiving intravenous iron sucrose i.e., IVIS (300 mg per dose) diluted in 300 mL of normal saline over 20-45 min and were followed up for a period of 4 weeks after the last dose of IVIS (end line). The study outcomes were measured in the levels of Hb, serum ferritin, MDA, SOD, and FRAP from the baseline to the end line. The mean (95% confidence interval) change in the Hb and serum ferritin level 4 weeks after the last dose of IVIS was an increase of 2.5 (2.1-3.0) g/dL (P < 0.001) and 63.0 (44.7-81.3) ng/mL (P < 0.001), respectively. There were no significant changes (baseline to end line) in mean (standard deviation [SD]) MDA level and mean (SD) FRAP level. The mean (SD) SOD level declined significantly (2.2 [0.4] U/mL to 1.6 [0.5] U/mL [P < 0.001]). No life-threatening adverse events were encountered during the study. IVIS was well tolerated and effective in treating moderate anemia in pregnancy. Body iron store was replenished following IVIS administration. There was no increase in oxidative stress following IVIS therapy.


Recent net alien immigration to the United States: its impact on population growth and native fertility.
Estimates of the size and structure of recent alien immigration to the United States are made. Substituting these revised estimates in the Series II projections of the U.S. Bureau of the Census implies a future U.S. population smaller than that implied by the Census Bureau's estimates of immigration. The analysis of Coale (1972)--which calculates the decline in native-born fertility required to accommodate immigration and, at the same time, maintain a stationary population--is replicated, using both the Census Bureau's estimates and the revised estimates reported here. The revised estimates indicate a smaller reduction in native fertility and a smaller ultimate size of the stationary population than are implied by the Census Bureau's immigration estimates. The importance of age structure in all of these calculations is demonstrated.


Albendazole therapy for single small enhancing CT lesions (SSECTL) in the brain in epilepsy.
Single small enhancing CT lesions (SSECTL) of the brain with or without perifocal oedema are common in patients with symptomatic epilepsy in India. Solitary cysticercus granuloma, a benign form of parenchymal neurocysticercosis, is considered to be the most common aetiology for SSECTL. Definite information is lacking regarding the effectiveness of antiparasitic treatment on resolution of these lesions and on long term seizure recurrence. To evaluate the response to albendazole treatment in patients who had SSECTL and new onset seizures treated with antiepileptic drugs (AED) in a prospective clinical trial. 43 patients who presented with new onset seizures and were documented to have SSECTL were alternatively allocated to receive albendazole 15 mg/kg/day for 2 weeks or no cysticidal therapy. All patients were treated with AED and followed for at least 6 months for seizure recurrence, and serial CT scans were obtained at 4 weeks, 3 months and at study completion. 28 (65%) patients were aged 5-25 years and 31 (72%) presented clinically with partial motor seizures with or without generalisation. Most of the SSECTL were ring lesions (75%) and located in and around the sensory-motor cortex at the gray-white junction (65%). In the albendazole group, 56% of patients compared with 35% in the control group showed resolution of SSECTL (p = 0.154) at 1 month. 22 of 23 patients (95.6%), who received albendazole, compared with 14 of 20 patients (70%) in the control group, demonstrated radiological resolution on study completion (p = 0.03). Punctate residual calcification and seizure recurrence were observed in four patients (9.3%) in the control group and in three (7%) patients in the albendazole group (p = 0.47). In patients presenting with seizures due to single viable parenchymal neurocysticercosis, albendazole hastens the resolution of SSECTL if treatment is given in the early phase of the illness.


The subthalamic nucleus and tremor in Parkinson's disease.
The role of the subthalamic nucleus (STN) in the origin of parkinsonian tremor is discussed. Previous studies in monkeys made parkinsonian by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) administration suggested a direct participation of the STN in the pathophysiology of tremor. We recorded tremor-related activity in the STN in 12 patients with Parkinson's disease (PD) and found that microstimulation of the sensorimotor region of the nucleus, where these neurons are present, stopped the tremor with a very short latency. Long-term treatment by means of bilateral deep-brain stimulation (DBS) in the same 12 patients led to a significant reduction of tremor as well as other cardinal features of PD. This effect was blindly assessed at 3 months after implantation. In another group of seven patients, a unilateral lesion of the STN was performed. Both postural and resting tremor were significantly improved on the limbs contralateral to the lesion side. In three patients, tremor disappeared completely after 12 months of follow up. The electrophysiologic data and therapeutic effect of inactivating the STN strongly indicated that this structure is directly involved in the origin of parkinsonian tremor, as suggested by the MPTP model.


Role of pamidronate disodium in the treatment of metastatic bone disease.
Bone metastases are a common feature of advanced neoplastic disease and are considered to be among the most frequent causes of pain and complications in oncologic patients. The main objective of the treatment of such patients is to control their symptoms and improve their quality of life. Pamidronate disodium is a second-generation bisphosphonate capable of inhibiting bone resorption (particularly osteoclast activity) without affecting bone remineralization. After a brief introduction concerning the pathophysiology of bone metastases and neoplastic bone pain, we herein present data on the clinical pharmacology and toxicity of bisphosphonates in general, and pamidronate in particular. We conclude by reviewing the literature on the use of pamidronate in phase II and III trials involving patients with metastatic bone disease. The paper is based on a review of articles published between 1984 and 1997 selected from the Cancerline and Medline databases. In the considered phase II and III studies involving patients with bone metastases (breast cancer and multiple myeloma in particular), pamidronate proved to be efficacious in reducing the incidence of pain and skeletal complications, decreasing the excretion of metabolic markers of bone resorption and improving the quality of life. Intravenous infusions of 60-90 mg over a period of 2 hr every 3-4 weeks did not cause any significant toxic effects and was easily managed. Pamidronate is a bisphosphonate that is efficacious in the treatment of symptomatic bone metastases and can be considered an important therapeutic option in association with systemic treatments, radiotherapy and normal supportive care, especially in patients with breast cancer and multiple myeloma. Further randomized studies are necessary to confirm the positive preliminary results in other neoplasms, analyze the cost/benefit ratio of the treatment, and verify the possibility that, in addition to being used for palliative purposes, pamidronate may also prevent or delay the appearance of bone metastases.


Managing Multi-center Flow Cytometry Data for Immune Monitoring.
With the recent results of promising cancer vaccines and immunotherapy1-5, immune monitoring has become increasingly relevant for measuring treatment-induced effects on T cells, and an essential tool for shedding light on the mechanisms responsible for a successful treatment. Flow cytometry is the canonical multi-parameter assay for the fine characterization of single cells in solution, and is ubiquitously used in pre-clinical tumor immunology and in cancer immunotherapy trials. Current state-of-the-art polychromatic flow cytometry involves multi-step, multi-reagent assays followed by sample acquisition on sophisticated instruments capable of capturing up to 20 parameters per cell at a rate of tens of thousands of cells per second. Given the complexity of flow cytometry assays, reproducibility is a major concern, especially for multi-center studies. A promising approach for improving reproducibility is the use of automated analysis borrowing from statistics, machine learning and information visualization21-23, as these methods directly address the subjectivity, operator-dependence, labor-intensive and low fidelity of manual analysis. However, it is quite time-consuming to investigate and test new automated analysis techniques on large data sets without some centralized information management system. For large-scale automated analysis to be practical, the presence of consistent and high-quality data linked to the raw FCS files is indispensable. In particular, the use of machine-readable standard vocabularies to characterize channel metadata is essential when constructing analytic pipelines to avoid errors in processing, analysis and interpretation of results. For automation, this high-quality metadata needs to be programmatically accessible, implying the need for a consistent Application Programming Interface (API). In this manuscript, we propose that upfront time spent normalizing flow cytometry data to conform to carefully designed data models enables automated analysis, potentially saving time in the long run. The ReFlow informatics framework was developed to address these data management challenges.


Respiratory Sinus Arrhythmia Activity Predicts Internalizing and Externalizing Behaviors in Non-referred Boys.
Atypical respiratory sinus arrhythmia (RSA), a biomarker of emotion dysregulation, is associated with both externalizing and internalizing behaviors. In addition, social adversity and gender may moderate this association. In this study, we investigated if RSA (both resting RSA and RSA reactivity in an emotion regulation task) predicts externalizing and/or internalizing behaviors and the extent to which social adversity moderates this relationship. Two hundred and fifty-three children (at Time 1, mean age = 9.05, SD = 0.60, 48% boys) and their caregivers from the community participated in this study. Resting RSA and RSA reactivity were assessed, and caregivers reported children's externalizing and internalizing behaviors at both Time 1 and Time 2 (1 year later). We found that lower resting RSA (but not RSA reactivity) at Time 1 was associated with increased externalizing and internalizing behaviors at Time 2 in boys, even after controlling for the effects of Time 1 behavioral problems and Time 2 age. Moreover, there was a significant interaction effect between Time 1 resting RSA and social adversity such that lower resting RSA predicted higher externalizing and internalizing behaviors in boys only under conditions of high social adversity. Follow-up analyses revealed that these predictive effects were stronger for externalizing behavior than for internalizing behavior. No significant effects were found for girls. Our findings provide further evidence that low resting RSA may be a transdiagnostic biomarker of emotion dysregulation and a predisposing risk factor for both types of behavior problems, in particular for boys who grow up in adverse environments. We conclude that biosocial interaction effects and gender differences should be considered when examining the etiological mechanisms of child psychopathology.


Genome-wide RNAi screen identifies novel host proteins required for alphavirus entry.
The enveloped alphaviruses include important and emerging human pathogens such as Chikungunya virus and Eastern equine encephalitis virus. Alphaviruses enter cells by clathrin-mediated endocytosis, and exit by budding from the plasma membrane. While there has been considerable progress in defining the structure and function of the viral proteins, relatively little is known about the host factors involved in alphavirus infection. We used a genome-wide siRNA screen to identify host factors that promote or inhibit alphavirus infection in human cells. Fuzzy homologue (FUZ), a protein with reported roles in planar cell polarity and cilia biogenesis, was required for the clathrin-dependent internalization of both alphaviruses and the classical endocytic ligand transferrin. The tetraspanin membrane protein TSPAN9 was critical for the efficient fusion of low pH-triggered virus with the endosome membrane. FUZ and TSPAN9 were broadly required for infection by the alphaviruses Sindbis virus, Semliki Forest virus, and Chikungunya virus, but were not required by the structurally-related flavivirus Dengue virus. Our results highlight the unanticipated functions of FUZ and TSPAN9 in distinct steps of alphavirus entry and suggest novel host proteins that may serve as targets for antiviral therapy.


Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives.
Along with a general decline in overall health, most chronic degenerative human diseases are inherently associated with increasing age. Age-associated cognitive impairments and neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, are potentially debilitating conditions that lack viable options for treatment, resulting in a tremendous economic and societal cost. Most high-profile clinical trials for neurodegenerative diseases have led to inefficacious results, suggesting that novel approaches to treating these pathologies are needed. Numerous recent studies have demonstrated that senescent cells, which are characterized by sustained cell cycle arrest and production of a distinct senescence-associated secretory phenotype, accumulate with age and at sites of age-related diseases throughout the body, where they actively promote tissue deterioration. Cells with features of senescence have been detected in the context of brain aging and neurodegenerative disease, suggesting that they may also promote dysfunction. Here, we discuss the evidence implicating senescent cells in neurodegenerative diseases, the mechanistic contribution of these cells that may actively drive neurodegeneration, and how these cells or their effects may be targeted therapeutically.


Subtilisin-like proprotein convertase PACE4 (SPC4) is a candidate processing enzyme of bone morphogenetic proteins during tooth formation.
The temporospatial expression of PACE4, a member of the mammalian subtilisin-like proprotein convertase family, in the developing rat molar tooth was determined by in situ hybridization. At the initiation stage of tooth development, PACE4 mRNA was weakly expressed in the dental lamina, whereas the mesenchymal cells intensely expressed the PACE4 transcript. At the bud stage, high-level expression of PACE4 mRNA was found in the dental epithelium and condensed dental mesenchyme. Its expression became more localized in the differentiating ameloblasts during cap and early bell stages. In the newborn rats, PACE4 mRNA was localized in the ameloblasts and odontoblasts, but its expression became weaker with advancing development, showing apparent association with the differentiation and establishment of functional ameloblasts and odontoblasts. These expression patterns of PACE4 were very similar to those of several bone morphogenetic proteins (BMPs) reported previously. Because BMPs, which are primarily involved in the morphogenesis in tooth formation, are synthesized as inactive precursors and activated by limited proteolysis at the consensus Arg-X-X-Arg maturation site, the present observations suggest that PACE4 is possibly a candidate proBMP convertase that acts during tooth formation.


Clonal evolution of a case of treatment refractory maxillary sinus carcinoma.
Maxillary sinus carcinoma (MSC) is a rare cancer of the head and neck region. Patients are treated with surgery, radiation therapy, and chemotherapy and the treatment regimen is based on patient's age, general health condition, disease stage, and its extent of spread. There is very little information available on the genetics of this disease. DNA content based flow sorting of tumor cells followed by array comparative genomic hybridization allows for high definition global assessment of distinct clonal changes within tumor populations. We applied this technique to primary and metastatic samples collected from a patient with radio- and chemotherapy refractory maxillary sinus carcinoma to gauge the progression of this disease. A clonal KIT amplicon was present in aneuploid populations sorted from the primary tumor and in divergent subclones arising in metastatic foci found in the brain, lung, and jejunum. The evolution of these subclones was associated with distinct genetic aberrations and DNA ploidies. The information presented here paves the path to understanding the development and progression of this disease.


Efficacy of aqueous extract of Echium amoenum in treatment of obsessive-compulsive disorder.
Traditionally, the dried flower of Echium amoenum (Boraginaceae) has been used in Iran as an anxiolytic and mood enhancer. This study investigated the efficacy and safety of an aqueous extract of E. amoenum in treatment of obsessive-compulsive disorder. Forty-four patients were randomly assigned to receive either E. amoenum aqueous extract (500 mg/day) or placebo in a 6-week, double blind, parallel-group trial. Patients were assessed before the study and during weeks 1, 2, 4, and 6 by the Yale-Brown Obsessive Compulsive (Y-BOCS), the Hamilton Rating Scale for Anxiety (HAM-A), and a score sheet on adverse effects. In weeks 4 and 6, the extract showed a significant superiority over placebo in reducing obsessive and compulsive and anxiety symptoms. There was no significant difference between the two groups in terms of adverse effects. The results suggest that E. amoenum aqueous extract has some anti obsessive and compulsive effects. However, further studies are needed to confirm these findings.


Early transition to comfort measures only in acute stroke patients: Analysis from the Get With The Guidelines-Stroke registry.
Death after acute stroke often occurs after forgoing life-sustaining interventions. We sought to determine the patient and hospital characteristics associated with an early decision to transition to comfort measures only (CMO) after ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) in the Get With The Guidelines-Stroke registry. We identified patients with IS, ICH, or SAH between November 2009 and September 2013 who met study criteria. Early CMO was defined as the withdrawal of life-sustaining treatments and interventions by hospital day 0 or 1. Using multivariable logistic regression, we identified patient and hospital factors associated with an early (by hospital day 0 or 1) CMO order. Among 963,525 patients from 1,675 hospitals, 54,794 (5.6%) had an early CMO order (IS: 3.0%; ICH: 19.4%; SAH: 13.1%). Early CMO use varied widely by hospital (range 0.6%-37.6% overall) and declined over time (from 6.1% in 2009 to 5.4% in 2013; p < 0.001). In multivariable analysis, older age, female sex, white race, Medicaid and self-pay/no insurance, arrival by ambulance, arrival off-hours, baseline nonambulatory status, and stroke type were independently associated with early CMO use (vs no early CMO). The correlation between hospital-level risk-adjusted mortality and the use of early CMO was stronger for SAH (r = 0.52) and ICH (r = 0.50) than AIS (r = 0.15) patients. Early CMO was utilized in about 5% of stroke patients, being more common in ICH and SAH than IS. Early CMO use varies widely between hospitals and is influenced by patient and hospital characteristics.


The genetics of complex cholestatic disorders.
Cholestatic liver diseases are caused by a range of hepatobiliary insults and involve complex interactions among environmental and genetic factors. Little is known about the pathogenic mechanisms of specific cholestatic diseases, which has limited our ability to manage patients with these disorders. However, recent genome-wide studies have provided insight into the pathogenesis of gallstones, primary biliary cirrhosis, and primary sclerosing cholangitis. A lithogenic variant in the gene that encodes the hepatobiliary transporter ABCG8 has been identified as a risk factor for gallstone disease; this variant has been associated with altered cholesterol excretion and metabolism. Other variants of genes encoding transporters that affect the composition of bile have been associated with cholestasis, namely ABCB11, which encodes the bile salt export pump, and ABCB4, which encodes hepatocanalicular phosphatidylcholine floppase. In contrast, studies have associated primary biliary cirrhosis and primary sclerosing cholangitis with genes encoding major histocompatibility complex proteins and identified loci associated with microbial sensing and immune regulatory pathways outside this region, such as genes encoding IL12, STAT4, IRF5, IL2 and its receptor (IL2R), CD28, and CD80. These discoveries have raised interest in the development of reagents that target these gene products. We review recent findings from genetic studies of patients with cholestatic liver disease. Future characterization of genetic variants in animal models, stratification of risk alleles by clinical course, and identification of interacting environmental factors will increase our understanding of these complex cholestatic diseases.


Nationwide trends of hospitalizations for cystic fibrosis in the United States from 2003 to 2013.
Cystic fibrosis (CF) is a multisystem autosomal recessive genetic disorder with significant advances in early diagnosis and treatment in the last decade. It is important to provide updated information regarding these changing demographics as they also reflect a considerable improvement in survival. We analyzed the National Inpatient Sample Database (NIS) in the United States for all patients in which CF was the primary discharge diagnosis (ICD-9: 277.0-277.09) from 2003 to 2013 to evaluate the rate of hospitalizations and determine the cost and mortality associated with CF along with other epidemiological findings. The statistical significance of the difference in the number of hospital discharges, lengths of stays and associated hospital costs over the study period was calculated. In 2003, there were 8,328 hospital discharges with the principal discharge diagnosis of CF in the United States, which increased to 12,590 discharges in 2013 (p < 0.001). The mean hospital charges increased by 57.64% from US$ 60,051 in 2003 to US$ 94,664 in 2013. The aggregate cost of hospital visits increased by 138.31% from US$ 500,105,727 to US$ 1,191,819,760. In the same time, the mortality decreased by 49.3 %. The number of inpatient discharges related to CF has increased from 2003 to 2013. This is due to increased life expectancy of CF patients, resulting in increased disease prevalence. There has been a significant increase in the mean and aggregate cost associated with CF admissions. Over the last decade, many advances have been made in the diagnosis and treatment of CF, consequentially leading to a significant transformation in the epidemiology and demographics of this chronic disease. Rising hospital costs associated with the care of CF patients necessitates future studies analyzing the diagnostic modalities, algorithms and treatment practices of physician's treating CF patients.


Defining the neuroanatomic basis of motor coordination in children and its relationship with symptoms of attention-deficit/hyperactivity disorder.
When children have marked problems with motor coordination, they often have problems with attention and impulse control. Here, we map the neuroanatomic substrate of motor coordination in childhood and ask whether this substrate differs in the presence of concurrent symptoms of attention-deficit/hyperactivity disorder (ADHD). Participants were 226 children. All completed Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)-based assessment of ADHD symptoms and standardized tests of motor coordination skills assessing aiming/catching, manual dexterity and balance. Symptoms of developmental coordination disorder (DCD) were determined using parental questionnaires. Using 3 Tesla magnetic resonance data, four latent neuroanatomic variables (for the cerebral cortex, cerebellum, basal ganglia and thalamus) were extracted and mapped onto each motor coordination skill using partial least squares pathway modeling. The motor coordination skill of aiming/catching was significantly linked to latent variables for both the cerebral cortex (t = 4.31, p < 0.0001) and the cerebellum (t = 2.31, p = 0.02). This effect was driven by the premotor/motor cortical regions and the superior cerebellar lobules. These links were not moderated by the severity of symptoms of inattention, hyperactivity and impulsivity. In categorical analyses, the DCD group showed atypical reduction in the volumes of these regions. However, the group with DCD alone did not differ significantly from those with DCD and co-morbid ADHD. The superior cerebellar lobules and the premotor/motor cortex emerged as pivotal neural substrates of motor coordination in children. The dimensions of these motor coordination regions did not differ significantly between those who had DCD, with or without co-morbid ADHD.


Reliability and validity of a parent questionnaire on childhood motor skills.
As the consequences of clumsiness in children become better understood, the need for valid measurement tools is apparent. Parent report has the potential for providing historical knowledge of the child's motor skills, as well as perceptions of their children's motor difficulties. The objective was to develop a parent questionnaire to identify motor difficulties in children. A sample of 306 children participated in the development of a 17-item parent questionnaire, called the Developmental Coordination Disorder Questionnaire (DCDQ). Internal consistency, concurrent and construct validity were examined. The DCDQ proved capable of distinguishing children who had motor problems (as measured by standardized tests) from children without motor problems. Correlations with standardized tests were significant. Two other studies confirmed the construct validity of the DCDQ. Factor analysis revealed four distinct factors, useful in defining the nature of the difficulties. The DCDQ is a succinct and useful measure for use by occupational therapists.


Epigenetic Changes Induced by Green Tea Catechins a re Associated with Prostate Cancer.
Prostate cancer is one of the most difficult cancers to treat especially when it becomes hormone resistant such as castrate resistant prostate cancer (CRPC) and subsequent metastatic CRPC. Apart from the genetic alterations in prostate cancer, epigenetic modifications also play an important role in the development and neoplastic progression of this disease. These include DNA methylation, histone modifications, and non-coding microRNAs. miRNAs are a novel class of small endogenous single-stranded non-coding RNAs of 19-25 nucleotides in length that typically silence gene expression. Considering the reversibility of epigenetic alterations in early carcinogenesis process, reversion (correction) of these modifications by green tea catechins could be a promising strategy for cancer chemoprevention and therapy. Recent evidence suggests that green tea catechins such as epigallocatechin gallate (EGCG) not only act as epigenetic modulators but can also modify miRNA expression and their target mRNAs, consistently contributing to the inhibition of prostate carcinogenesis. Various studies also indicate that several green tea polyphenols (GTPs) exert synergistic effects with other cancer chemotherapeutic agents. Therefore, the use of appropriate combinations of green tea catechins with the existing chemotherapeutics will lead to a reduction in side effects without decreasing the chemotherapeutic effects. This review will summarize the key results from recent studies detailing the effects of green tea catechins such as EGCG on epigenetic alterations and miRNA expression in prostate cancer.


Factors associated with success of vaginal birth after one caesarean section (VBAC) at three teaching hospitals in Addis Ababa, Ethiopia: a case control study.
Vaginal delivery after previous one cesarean section for a non recurring indication has been described by several authors as safe and having a success rate of 60-80%. Hence many centers are offering VBAC for candidates leaving the century old dictum of once cesarean always cesarean. But predicting success of VBAC after trial of labor (TOL) is still a difficult task due to the lack of a validated prediction tool. Studies on predictors of success are few and most of them conducted in developed countries and difficult to generalize. Therefore assessing factors associated with successful VBAC is very important to for counseling mothers while offering VBAC. The aim of this study was to assess factors associated with successful VBAC in three teaching Hospitals in Addis Ababa Ethiopia. A case control study was conducted to compare the factors associated with successful VBAC in teaching hospitals in Addis Ababa in one year period. The cases were those successfully delivered vaginally and the controls were those with failed VBAC and delivered by caesarean section. The sample size of the cases was 101vaginal deliveries and the controls were 103 failed VBAC patients which made the case to control ratio of 1:1. In this study independent factors determining successful VBAC were, history of successful VBAC in the past, rupture of membrane at admission, and cervical dilatation of more than 3cm at admission. Presence of meconium, malposition and history of stillbirth were associated with failed VBAC. Factors like maternal age, past caesarean indications, inter delivery interval, and birth weight were not found to be significant determinants of success. The most common reason for repeat cesarean section for after trial of labor was labour dysfunction because of absence of a policy for augmentation on a scarred uterus in these hospitals. It is possible to prepare a decision tool on the success of VBAC by taking important past and present obstetric and reproductive performance history as predictor.


Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease.
Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2) are X-linked developmental defects of myelin formation affecting the central nervous system (CNS). They differ clinically in the onset and severity of the motor disability but both are allelic to the proteolipid protein gene (PLP), which encodes the principal protein components of CNS myelin, PLP and its spliced isoform, DM20. We investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by genomic PCR amplification and sequencing of the PLP gene. We identified 29 and 4 abnormalities respectively. Patients with PLP mutations presented a large range of disease severity, with a continuum between severe forms of PMD, without motor development, to pure forms of SPG. Clinical severity was found to be correlated with the nature of the mutation, suggesting a distinct strategy for detection of PLP point mutations between severe PMD, mild PMD and SPG. Single amino-acid changes in highly conserved regions of the DM20 protein caused the most severe forms of PMD. Substitutions of less conserved amino acids, truncations, absence of the protein and PLP-specific mutations caused the milder forms of PMD and SPG. Therefore, the interactions and stability of the mutated proteins has a major effect on the severity of PLP-related diseases.