HLA-B*57 versus HLA-B*81 in HIV-1 infection: slow and steady wins the race?
Two human leukocyte antigen (HLA) variants, HLA-B*57 and -B*81, are consistently known as favorable host factors in human immunodeficiency virus type 1 (HIV-1)-infected Africans and African-Americans. In our analyses of prospective data from 538 recent HIV-1 seroconverters and cross-sectional data from 292 subjects with unknown duration of infection, HLA-B*57 (mostly B*57:03) and -B*81 (exclusively B*81:01) had mostly discordant associations with virologic and immunologic manifestations before antiretroviral therapy. Specifically, relatively low viral load (VL) in HLA-B*57-positive subjects (P ≤ 0.03 in various models) did not translate to early advantage in CD4(+) T-cell (CD4) counts (P ≥ 0.37). In contrast, individuals with HLA-B*81 showed little deviation from the normal set point VL (P > 0.18) while maintaining high CD4 count during early and chronic infection (P = 0.01). These observations suggest that discordance between VL and CD4 count can occur in the presence of certain HLA alleles and that effective control of HIV-1 viremia is not always a prerequisite for favorable prognosis (delayed immunodeficiency). Of note, steady CD4 count associated with HLA-B*81 in HIV-1-infected Africans may depend on the country of origin, as observations differed slightly between subgroups enrolled in southern Africa (Zambia) and eastern Africa (Kenya, Rwanda, and Uganda).


The impact of research governance in healthcare and higher education organizations.
This paper reports a study exploring the impact and implementation of research governance in the North West region of England. In 2001, the UK Government launched a framework to ensure the governance of research within the National Health Service. Whilst this framework was undoubtedly geared towards improving the standards and practice of research, concerns have been raised in the academic literature about the potentially negative impact on future research. A mixed method approach, using questionnaires (n = 350), semi-structured interviews and focus groups with a volunteer sample, was used to explore research staff perspectives about research governance. Survey data were analysed using Microsoft Excel, and a thematic analysis was used to elicit themes from the semi-structured interviews. The study lasted for 12 months and used a range of study sites, giving insight into potentially different experiences or approaches to implementing the research governance framework. Questionnaire data revealed a good level of awareness about the Research Governance Framework. However, a range of concerns was also raised, such as the increased workload associated with the research governance application process and lack of transparency about the process. Five themes emerged from the focus groups: control, epistemology, organizational issues, impact on teaching and learning, and ambiguity in the definitions of research and audit. Recommendations emerging from the study include the promotion of transparent research governance guidelines for practitioners, and the need for staff education about governance processes and greater parity between organizations in research governance processes.


What to eat now? Shifts in polar bear diet during the ice-free season in western Hudson Bay.
Under current climate trends, spring ice breakup in Hudson Bay is advancing rapidly, leaving polar bears (Ursus maritimus) less time to hunt seals during the spring when they accumulate the majority of their annual fat reserves. For this reason, foods that polar bears consume during the ice-free season may become increasingly important in alleviating nutritional stress from lost seal hunting opportunities. Defining how the terrestrial diet might have changed since the onset of rapid climate change is an important step in understanding how polar bears may be reacting to climate change. We characterized the current terrestrial diet of polar bears in western Hudson Bay by evaluating the contents of passively sampled scat and comparing it to a similar study conducted 40 years ago. While the two terrestrial diets broadly overlap, polar bears currently appear to be exploiting increasingly abundant resources such as caribou (Rangifer tarandus) and snow geese (Chen caerulescens caerulescens) and newly available resources such as eggs. This opportunistic shift is similar to the diet mixing strategy common among other Arctic predators and bear species. We discuss whether the observed diet shift is solely a response to a nutritional stress or is an expression of plastic foraging behavior.


Viral assembly of oriented quantum dot nanowires.
The highly organized structure of M13 bacteriophage was used as an evolved biological template for the nucleation and orientation of semiconductor nanowires. To create this organized template, peptides were selected by using a pIII phage display library for their ability to nucleate ZnS or CdS nanocrystals. The successful peptides were expressed as pVIII fusion proteins into the crystalline capsid of the virus. The engineered viruses were exposed to semiconductor precursor solutions, and the resultant nanocrystals that were templated along the viruses to form nanowires were extensively characterized by using high-resolution analytical electron microscopy and photoluminescence. ZnS nanocrystals were well crystallized on the viral capsid in a hexagonal wurtzite or a cubic zinc blende structure, depending on the peptide expressed on the viral capsid. Electron diffraction patterns showed single-crystal type behavior from a polynanocrystalline area of the nanowire formed, suggesting that the nanocrystals on the virus were preferentially oriented with their [001] perpendicular to the viral surface. Peptides that specifically directed CdS nanocrystal growth were also engineered into the viral capsid to create wurtzite CdS virus-based nanowires. Lastly, heterostructured nucleation was achieved with a dual-peptide virus engineered to express two distinct peptides within the same viral capsid. This work represents a genetically controlled biological synthesis route to a semiconductor nanoscale heterostructure.


The Flynn Effect revisited.
The Flynn Effect postulates that intelligence is increasing over time. However, as an environment becomes optimal, a plateau occurs when general growth becomes largely determined by genetics. There is evidence that such a plateau is occurring for intelligence in countries with optimal social environments. In the United States, examination of adult Wechsler test scores between normings indicates a reduction of the FSIQ increase such that average FSIQ would plateau about 2024. However, the WAIS-III norming process eliminates many types of subjects with possible brain impairment. This probably raises the average FSIQ level. With an increase of only 1 FSIQ point in 16 years, a plateau in the Flynn Effect would have been reached in 2004.


Why does power output decrease at high pedaling rates during sprint cycling?
The objective of this study was to partly explain, from electromyographical (EMG) activity, the decrease in power output beyond optimal pedaling rate (PRopt) during sprint cycling. Eleven cyclists performed four 8-s nonisokinetic sprints on a cycle ergometer against four randomized friction loads (0.5, twice 0.75, and 0.9 N x kg(-1) of body mass). Power output and EMG activity of both right and left gluteus maximus, rectus femoris, biceps femoris, and vastus lateralis were measured continuously. Individual crank cycles were analyzed. Crank angles corresponding to the beginning and the peak of each downstroke and EMG burst onset and offset crank angles were computed. Moreover, crank angles corresponding to the beginning and the end of muscle force response were determined assuming a 100-ms lag time between the EMG activity and the relevant force response (or electromechanical delay). Muscle coordination (EMG onset and offset) was altered at high pedaling rates. Thus, crank angles corresponding to muscle force response increased significantly with pedaling rate. Consequently, at pedaling rates higher than the optimal pedaling rate, force production of lower-limb extensor muscles was shifted later in the crank cycle. Mechanical data confirmed that downstrokes occurred later in the crank cycle when pedaling rate increased. Hence, force was produced on the pedals during less effective crank cycle sectors of the downstroke and during the beginning of the upstroke. During nonisokinetic sprint cycling, the decrease in power output when pedaling rates increased beyond PRopt may be partly explained by suboptimal muscle coordination.


A composite indicator approach to assess the sustainability and resilience of wastewater management alternatives.
Evaluating the sustainability of wastewater management alternatives is a challenging task. This paper proposes an innovative methodology to assess and compare the sustainability of four wastewater management alternatives: a) centralised water resource recovery facility (WRRF) based on activated sludge (AS); b) centralised WRRF with membrane bioreactors (MBR); c) decentralised WRRFs with upflow anaerobic sludge blanket reactors and trickling filters; d) centralised-decentralised hybrid system. In doing so, a composite indicator embracing total annual equivalent costs, carbon emission intensity, eutrophication and resilience (based on robustness and rapidity metrics) was developed using the analytic hierarchy process (AHP) method. The results show that decentralised and hybrid systems contribute less to carbon emission and eutrophication because of energy and fertilizer harvest and with a trade-off of higher costs of 7-17% than the ones of AS and MBR. In addition, decentralised and hybrid systems are more resilient, contributing to lower environmental impacts facing natural disasters. Based on the weights obtained by AHP, the decentralised alternative appears to be the most sustainable option due to its best performance in terms of carbon emission intensity and resilience. By contrast, the MBR alternative appeared the least sustainable evaluated wastewater management alternative. However, this alternative is sustainable option when the eutrophication criterion is heavily prioritized. The proposed approach contributes to the selection of the most sustainable wastewater management alternative from a holistic perspective.


Histopathology of experimental scuticociliatosis in turbot Scophthalmus maximus.
A scuticociliate strain (B-2), originally isolated from an outbreak in a turbot Scophthalmus maximus (= Psetta maxima) farm in Galicia (northwestern Spain) and maintained in axenic culture, was injected intracoelomically (lethal dose 80 equivalent, LD80) in healthy turbot (50 g). Ciliate-injected fish were kept under controlled conditions in a recirculating seawater system and sampled on Days 1 through 8, 10, 12 and 14 postinfection (PI). Necropsies were conducted and included blood collection from the caudal vein and samples of liver, spleen, heart, digestive tract, kidney, gills, abdominal wall and neurocranium taken for routine histology. Mortality occurred from Day 6 until Day 12 PI and reached 66.7% by the end of the experiment. Presence of ciliates in the coelomic fluid was scarce until Day 4 PI. Parasitaemia was only observed from Day 5 until Day 10 PI and its incidence was always low. Presence of scuticociliates in tissue sections followed a progressive pattern of diffusion, with ciliates showing preference for loose connective tissue and also a clear haematophagous activity. The most severely affected organs were the pancreas and digestive tract. No special tropism for nervous tissues was observed in this study. The inflammatory reaction was variable depending on the tissue. After 3 wk, survivors had apparently managed to extinguish the infection.


Use of the distomedial-proximolateral oblique radiographic view of the elbow joint for examination of the medial coronoid process in dogs.
To describe and evaluate a new radiographic view of the elbow joint in dogs that would potentially enhance observation of the medial coronoid process (MCP). 20 cadaver limbs from 10 dogs and clinical examination of 100 elbow joints of 53 dogs. Twenty elbow joints from 10 cadavers were imaged by use of mediolateral, flexed mediolateral, craniocaudal, craniolateral-caudomedial oblique (Cr15L-CdMO), and distomedial-proximolateral oblique (Di35M-PrLO) radiographic views before and after placement of 3 lead pellets placed on the cranial, medial, and craniodistal aspect of the MCP. Three examiners independently reviewed these radiographs. One hundred elbow joints of 53 dogs with forelimb lameness and signs of pain elicited on palpation of the elbow joint were examined. These joints were radiographed and treated by use of arthroscopy. Three examiners independently graded the radiographs. The MCP was identified on all Di35M-PrLO views made during the anatomic study. The Di35M-PrLO view had the largest area under the receiving operating characteristic (ROC) curve for detection of abnormalities of the MCP. Fractured and nonfractured MCP could only be significantly differentiated on Di35M-PrLO and mediolateral views. The Di35M-PrLO view had a higher agreement between examiners than other radiographic views for detection of fractures of the MCP. The Di35M-PrLO view enhances the identification of anomalies and fragmentation of the MCP in dogs, compared with other radiographic views. The Di35M-PrLO view may be of benefit for early screening of dogs potentially affected with elbow dysplasia.


Clinical presentation of hypothyroidism: a case control analysis.
Hypothyroidism is a common endocrinological disorder. Its clinical presentation is variable but well established. However, clinical features vary significantly among different populations owing to their climate, education status and awareness about the disease. This study is designed to evaluate the difference in clinical presentation of our population from already available literature. In this study we have compared the symptoms and signs of hypothyroid and euthyroid patients coming to a diagnostic centre (PINUM, Faisalabad) from January to July 1999. Of the 1594 patients coming to the centre, 394 were included in the study and were examined. After the laboratory investigations, 109 were identified as the cases of hypothyroidism, the rest were declared as euthyroid and selected as controls. We compared the 21 common signs and symptoms of hypothyroidism in our patients. Lethargy was the commonest symptom and facial oedema was the most prevalent sign in our population. Old age is reported to be a risk factor for hypothyroidism but in this study we could not find a rising trend with increasing age (odds ratio 1.15, p-value 0.71). We also compared the clinical presentation of our patients with the available literature. It was also proved that the signs elicited by the physicians were more reliable and specific for the identification of hypothyroidism. Thus, the presentation of hypothyroidism is non-specific and high degree of suspicion is required for its early diagnosis.


Weighted Burden Analysis of Exome-Sequenced Case-Control Sample Implicates Synaptic Genes in Schizophrenia Aetiology.
A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive variants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish contribution to ancestry. We have reanalysed the same dataset after removal of these subjects and we have also included non-singleton variants of all types using a weighted burden test which assigns higher weights to variants predicted to have a greater effect on protein function. We investigated the same 31 gene sets as previously and also 1454 GO gene sets. The reduced dataset consisted of 4225 cases and 5834 controls. No individual variants or genes were significantly enriched in cases but 13 out of the 31 gene sets were significant after Bonferroni correction and the "FMRP targets" set produced a signed log p value (SLP) of 7.1. The gene within this set with the highest SLP, equal to 3.4, was FYN, which codes for a tyrosine kinase which phosphorylates glutamate metabotropic receptors and ionotropic NMDA receptors, thus modulating their trafficking, subcellular distribution and function. In the most recent GWAS of schizophrenia it was identified as a "prioritized candidate gene". Two of the subunits of the NMDA receptor which are substrates of FYN are coded for by GRIN1 (SLP = 1.7) and GRIN2B (SLP = 2.1). Of note, for some sets there was a substantial enrichment of non-singleton variants. Of 1454 GO gene sets, three were significant after Bonferroni correction. Identifying specific genes and variants will depend on genotyping them in larger samples and/or demonstrating that they cosegregate with illness within pedigrees.


A mutant form of JAB/SOCS1 augments the cytokine-induced JAK/STAT pathway by accelerating degradation of wild-type JAB/CIS family proteins through the SOCS-box.
Cytokines exert biological functions by activating Janus tyrosine kinases (JAKs), and JAK inhibitors JAB (also referred to as SOCS1 and SSI1) and CIS3 (SOCS3) play an essential role in the negative regulation of cytokine signaling. We have found that transgenic (Tg) mice expressing a mutant JAB (F59D-JAB) exhibited a more potent STAT3 activation and a more severe colitis than did wild-type littermates after treatment with dextran sulfate sodium. We now find that there is a prolonged activation of JAKs and STATs in response to a number of cytokines in T cells from Tg mice with lck promoter-driven F59D-JAB. Overexpression of F59D-JAB also sustained activation of JAK2 in Ba/F3 cells. These data suggested that F59D-JAB up-regulated STAT activity by sustaining JAK activation. To elucidate molecular mechanisms related to F59D-JAB, we analyzed the effects of F59D-JAB on the JAK/STAT pathway using the 293 cell transient expression system. We found that the C-terminal SOCS-box played an essential role in augmenting cytokine signaling by F59D-JAB. The SOCS-box interacted with the Elongin BC complex, and this interaction stabilized JAB. F59D-JAB induced destabilization of wild-type JAB, whereas overexpression of Elongin BC canceled this effect. Levels of endogenous JAB and CIS3 in T cells from F59D-JAB Tg-mouse were lower than in wild-type mice. We propose that F59D-JAB destabilizes wild-type, endogenous JAB and CIS3 by chelating the Elongin BC complex, thereby sustaining JAK activation.


Thermomonas haemolytica gen. nov., sp. nov., a gamma-proteobacterium from kaolin slurry.
Four aerobic, gram-negative bacterial strains isolated from kaolin slurry used in the production of paper were subjected to a polyphasic analysis and characterization to determine their taxonomic position. Analysis of the 16S rDNA sequences of the four strains revealed that they represent a new lineage within the gamma-Proteobacteria, related to the genera Xanthomonas, Pseudoxanthomonas, Stenotrophomonas, Luteimonas, Xylella and Rhodanobacter. Analysis of the quinone system, the polyamines, the fatty acids and the polar lipids revealed a combination of characteristics that is unique and not described for the phylogenetic relatives. The four strains contain a ubiquinone Q-8, spermidine as the major polyamine, diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine as the predominant polar lipids, and a fatty acid profile with predominantly iso-branched fatty acids. The G+C content of the genomic DNA was determined to be within the narrow range 67.1-68.7 mol%. Determination of DNA relatedness, as well as riboprint band patterns and amplified fragment length polymorphism profiles, clearly demonstrated that the four strains are members of a single species. Antibiotic-susceptibility patterns were identical for the four strains. Although showing a high degree of similarites in physiological and biochemical patterns, each of the four strains could be distinguished from the others on the basis of a few biochemical characteristics. On the basis of the estimates of phylogenetic relationships derived from the 16S rDNA sequence analyses, the observed chemotaxonomic characteristics and other phenotypic traits, a new genus, Thermomonas gen. nov., and species, Thermomonas haemolytica sp. nov., are proposed for the strains A50-7-3T (= DSM 13605T = LMG 19653T), B 50-7-1 (= DSM 13598 = LMG 19655), D50-7-1 (= DSM 13610 = LMG 19656) and B50-8-1 (= DSM 13599 = LMG 19654), with strain A50-7-3T as the type strain.


Ambulatory Medication Reconciliation and Frequency of Hospitalizations and Emergency Department Visits in Patients With Diabetes.
To investigate the association between ambulatory medication reconciliation and health care utilization in patients with diabetes. In this retrospective cohort analysis, we studied adults taking at least one diabetes medication treated in primary care practices affiliated with two academic medical centers between 2000 and 2014. We assessed the relationship between the fraction of outpatient diabetes medications reconciled over a 6-month period and the composite primary outcome of combined frequency of emergency department (ED) visits and hospitalizations over the subsequent 6 months. Among 261,765 reconciliation assessment periods contributed by 31,689 patients, 176,274 (67.3%), 27,775 (10.6%), and 57,716 (22.1%) had all, some, or none of the diabetes medications reconciled, respectively. Patients with all, some, or no diabetes medications reconciled had 0.354, 0.377, and 0.384 primary outcome events per 6 months, respectively (P < 0.0001). In a multivariable analysis adjusted for demographics and comorbidities, having some or all versus no diabetes medications reconciled was associated with a lower risk of the primary outcome (rate ratio 0.94 [95% CI 0.90-0.98; P = 0.0046] vs. 0.92 [0.89-0.95; P < 0.0001], respectively). Introduction of feedback to individual providers was associated with a significant increase in the odds of all diabetes medications being reconciled (2.634 [2.524-2.749]; P < 0.0001). A higher fraction of reconciled outpatient diabetes medications was associated with a lower frequency of ED visits and hospitalizations. Individual performance feedback could help to achieve more comprehensive medication reconciliation.


The effect of cisatracurium and rocuronium on lung function in anesthetized children.
Neuromuscular blocking drugs have been implicated in intraoperative bronchoconstrictive episodes. We examined the effects of clinically relevant doses of cisatracurium and rocuronium on the lung mechanics of pediatric subjects. We hypothesized that cisatracurium and rocuronium would have bronchoconstrictive effects. We studied ASA physical status I and II pediatric subjects having elective dental or urological procedures, requiring general anesthesia with endotracheal intubations with either cisatracurium or rocuronium. Pulmonary function tests were performed before and after neuromuscular blocking drug dosing and again after albuterol administration. Using forced deflation and passive deflation techniques, forced vital capacity (FVC) and maximum expiratory flow rate at 10% (MEF10) of FVC were obtained. Fractional changes from the baseline were used to compare subjects. Changes in MEF10 of >30% were considered clinically significant. A Shapiro-Wilk test, paired t test, and Wilcoxon rank sum test were used to analyze the data. Twenty-five subjects (median age = 5.25 years; range = 9 months-9.9 years) were studied; 12 subjects received cisatracurium and 13 subjects received rocuronium. Data are shown as mean proportional change ± SD or, in the case of not normally distributed, median proportional change (first, third quartile) with P values. In the cisatracurium group, there were no differences between baseline and postneuromuscular blocker administration in the fractional change from the baselines of FVC (1.00 ± 0.04, P = 0.5), but there was a significant decrease in MEF10 (0.80 ± 0.18, P = 0.002). In the rocuronium group, there were small yet significant decreases of FVC (0.99 [first quartile 0.97, third quartile 1], P = 0.02) and significant decreases in MEF10 (0.78 ± 0.26, P = 0.008). After administration of albuterol in the cisatracurium group, FVC increased slightly but significantly from baseline values (1.02 ± 0.02, P = 0.005). MEF10 increased significantly beyond baseline values (1.24 ± 0.43, P =0.04). In the rocuronium group, there were also significant differences between baseline and postalbuterol administration from the baseline value of FVC (1.02 ± 0.02, P = 0.004) and MEF10 (1.23 ± 0.29, P = 0.01). At clinically relevant doses, both cisatracurium and rocuronium caused changes in lung function, indicating constriction of smaller airways. In general, these changes were mild and not clinically detectable. However, in the rocuronium group, 3 of 13 patients showed more noticeable decreases in MEF10 (≤50%), demonstrating the potential for significant broncho-bronchiolar constriction in susceptible patients.


Effects of Creatine Supplementation on Lower-Limb Muscle Endurance Following an Acute Bout of Aerobic Exercise in Young Men.
We aimed to determine whether creatine supplementation influences lower-limb muscle endurance following an acute bout of aerobic exercise (AE) in young healthy men. Using a randomized, double-blind, placebo-controlled crossover design, 11 men (26.5 ± 6.2 years, body mass index 26.6 ± 2.1 kg/m2),with 12 months of experience in strength training (three times/week) and AE (two times/week) were randomized to receive creatine (20 g/day plus 20 g/day maltodextrin) and placebo (40 g/day maltodextrin) for 7 days, separated by a washout period of 14 days, before performing an acute bout of AE (30 min on treadmill at 80% baseline maximum velocity) which was followed by four sets of bilateral leg extension endurance exercise using a 10-repetition maximum protocol (10 RM)). There was a significant decrease in the number of repetitions performed in the third (Placebo: -20% vs. Creatine: -22%) and fourth set (Placebo: -22% vs. Creatine: -28%) compared with the first set (p < 0.05), with no differences between creatine and placebo. Additionally, no differences were observed between creatine and placebo for the total number of repetitions performed across all four sets (Placebo: 33.9 ± 7.0 vs. Creatine: 34.0 ± 6.9 repetitions, p = 0.97), nor for total work volume (Placebo: 3030.5 ± 1068.2 vs. Creatine: 3039.8 ± 1087.7 kg, p = 0.98). Short-term creatine supplementation has no effect on lower-limb muscle endurance following an acute bout of aerobic exercise in trained young men.


Individual Differences and State-Dependent Responses in Transcranial Direct Current Stimulation.
Transcranial direct current stimulation (tDCS) has been extensively used to examine whether neural activities can be selectively increased or decreased with manipulations of current polarity. Recently, the field has reevaluated the traditional anodal-increase and cathodal-decrease assumption due to the growing number of mixed findings that report the effects of the opposite directions. Therefore, the directionality of tDCS polarities and how it affects each individual still remain unclear. In this study, we used a visual working memory (VWM) paradigm and systematically manipulated tDCS polarities, types of different independent baseline measures, and task difficulty to investigate how these factors interact to determine the outcome effect of tDCS. We observed that only low-performers, as defined by their no-tDCS corsi block tapping (CBT) performance, persistently showed a decrement in VWM performance after anodal stimulation, whereas no tDCS effect was found when participants were divided by their performance in digit span. In addition, only the optimal level of task difficulty revealed any significant tDCS effect. All these findings were consistent across different blocks, suggesting that the tDCS effect was stable across a short period of time. Lastly, there was a high degree of intra-individual consistency in one's responsiveness to tDCS, namely that participants who showed positive or negative effect to anodal stimulation are also more likely to show the same direction of effects for cathodal stimulation. Together, these findings imply that tDCS effect is interactive and state dependent: task difficulty and consistent individual differences modulate one's responsiveness to tDCS, while researchers' choices of independent behavioral baseline measures can also critically affect how the effect of tDCS is evaluated. These factors together are likely the key contributors to the wide range of "noises" in tDCS effects between individuals, between stimulation protocols, and between different studies in the literature. Future studies using tDCS, and possibly tACS, should take such state-dependent condition in tDCS responsiveness into account.


Biological macromolecules based targeted nanodrug delivery systems for the treatment of intracellular infections.
Intracellular infections are tricky to treat, the reason being the poor penetration of antibiotics/antimycotics into the microbial niche (host cell). Macrophages are primary targets of facultative and obligate intracellular bacteria/fungi to be abused as host cells. The need for drugs with better intracellular penetration led to the development of endocytosable drug carriers, which can cross the cell membrane of the host cells (macrophages) by imitating the entry path of the pathogens. Therefore, the drugs can be targeted to macrophages ensuring enhanced therapeutic effect. This review discusses the exploitation of various nanocarriers for targeted delivery of drugs to the macrophages in the last two decades.


Effects of Yoga and Aerobic Exercise on Actigraphic Sleep Parameters in Menopausal Women with Hot Flashes.
To determine effects of yoga and aerobic exercise compared with usual activity on objective assessments of sleep in midlife women. Secondary analyses of a randomized controlled trial in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) network conducted among 186 late transition and postmenopausal women aged 40-62 y with hot flashes. Women were randomized to 12 w of yoga, supervised aerobic exercise, or usual activity. The mean and coefficient of variation (CV) of change in actigraph sleep measures from each intervention group were compared to the usual activity group using linear regression models. Baseline values of the primary sleep measures for the entire sample were mean total sleep time (TST) = 407.5 ± 56.7 min; mean wake after sleep onset (WASO) = 54.6 ± 21.8 min; mean CV for WASO = 37.7 ± 18.7 and mean CV for number of long awakenings > 5 min = 81.5 ± 46.9. Changes in the actigraphic sleep outcomes from baseline to weeks 11-12 were small, and none differed between groups. In an exploratory analysis, women with baseline Pittsburgh Sleep Quality Index higher than 8 had significantly reduced TST-CV following yoga compared with usual activity. This study adds to the currently scant literature on objective sleep outcomes from yoga and aerobic exercise interventions for this population. Although small effects on self-reported sleep quality were previously reported, the interventions had no statistically significant effects on actigraph measures, except for potentially improved sleep stability with yoga in women with poor self-reported sleep quality.


18F-FDG PET and MR imaging associations across a spectrum of pediatric brain tumors: a report from the pediatric brain tumor consortium.
The purpose of this study was to describe (18)F-FDG uptake across a spectrum of pediatric brain tumors and correlate (18)F-FDG PET with MR imaging variables, progression-free survival (PFS), and overall survival (OS). A retrospective analysis was conducted of children enrolled in phase I/II clinical trials through the Pediatric Brain Tumor Consortium from August 2000 to June 2010. PET variables were summarized within diagnostic categories using descriptive statistics. Associations of PET with MR imaging variables and PFS and OS by tumor types were evaluated. Baseline (18)F-FDG PET was available in 203 children; 66 had newly diagnosed brain tumors, and 137 had recurrent/refractory brain tumors before enrolling in a Pediatric Brain Tumor Consortium trial. MR imaging was performed within 2 wk of PET and before therapy in all cases. The (18)F-FDG uptake pattern and MR imaging contrast enhancement (CE) varied by tumor type. On average, glioblastoma multiforme and medulloblastoma had uniform, intense uptake throughout the tumor, whereas brain stem gliomas (BSGs) had low uptake in less than 50% of the tumor and ependymoma had low uptake throughout the tumor. For newly diagnosed BSG, correlation of (18)F-FDG uptake with CE portended reduced OS (P = 0.032); in refractory/recurrent BSG, lack of correlation between (18)F-FDG uptake and CE suggested decreased PFS (P = 0.023). In newly diagnosed BSG for which more than 50% of the tumor had (18)F-FDG uptake, there was a suggestion of lower apparent diffusion coefficient (P = 0.061) and decreased PFS (P = 0.065). (18)F-FDG PET and MR imaging showed a spectrum of patterns depending on tumor type. In newly diagnosed BSG, the correlation of (18)F-FDG uptake and CE suggested decreased OS, likely related to more aggressive disease. When more than 50% of the tumor had (18)F-FDG uptake, the apparent diffusion coefficient was lower, consistent with increased cellularity. In refractory/recurrent BSG, poor correlation between (18)F-FDG uptake and CE was associated with decreased PFS, which may reflect concurrent tissue breakdown at sites of treated disease and development of new sites of (18)F-FDG-avid malignancy.


Asparagine stimulates piglet intestinal Cl- secretion by a mechanism requiring a submucosal glutamate receptor and nitric oxide.
Amino acids are potential components of oral rehydration solutions for infants, which could combine with glucose to further stimulate intestinal Na+ and water absorption. L-Glutamine, the principal fuel of the intestine, stimulates neutral NaCl absorption and enhances enterocyte DNA synthesis, but is unstable in solution. L-Asparagine (ASN), a more stable amino acid with similar structure to L-glutamine, also stimulates enterocyte proliferation. We determined the effects of ASN on electrolyte transport across piglet jejunum in Ussing chambers. Mucosal but not serosal ASN produced electrogenic Cl- secretion (delta JClnet = -1.8 +/- 0.3 microEq/cm2.hr-1). ASN, when added at 0.1 to 30 mM, increased short-circuit current in a dose-dependent manner with a K1/2 of approximately 5 mM and maximal effect at approximately 10 mM. The stimulation of Cl- secretion by ASN was blocked by pretreatment with serosal tetrodotoxin and bumetanide and was inhibited by preincubation with capsaicin (8-methyl-N-vanillyl-6-nonenamide) or substance P. Inhibition of nitric oxide synthesis with the structural analog of L-arginine, NG-monomethyl-L-arginine, reduced ASN-stimulated secretion by > 70%. Additionally, serosal 6-cyanonitro-quinoxaline 2-3-dione, which is a nonspecific blocker of neural non-N-methyl D-aspartate (NMDA) glutamate receptors, fully inhibited the ASN response (IC50 = 10(-6) M). Inhibition was specific for neurally mediated secretion. We found no inhibition of ASN-stimulated secretion by atropine, ketanserin, indomethacin or L-2-amino-5-phosphonovalerate (specific for NMDA receptors). When compared to ASN, L-glutamate was a weaker stimulator of jejunal Cl- secretion.(ABSTRACT TRUNCATED AT 250 WORDS)


The role of electrospinning in the emerging field of nanomedicine.
The fact that in vivo the extracellular matrix (ECM) or substratum with which cells interact often includes topography at the nanoscale underscores the importance of investigating cell-substrate interactions and performing cell culture at the submicron scale. An important and exciting direction of research in nanomedicine would be to gain an understanding and exploit the cellular response to nanostructures. Electrospinning is a simple and versatile technique that can produce a macroporous scaffold comprising randomly oriented or aligned nanofibers. It can also accommodate the incorporation of drug delivery function into the fibrous scaffold. Endowed with both topographical and biochemical signals such electrospun nanofibrous scaffolds may provide an optimal microenvironment for the seeded cells. This review covers the analysis and control of the electrospinning process, and describes the types of electrospun fibers fabricated for biomedical applications such as drug delivery and tissue engineering.


Proper application of antibodies for immunohistochemical detection: antibody crimes and how to prevent them.
For several decades antibodies raised against specific proteins, peptides, or peptide epitopes have proven to be versatile and very powerful tools to demonstrate molecular identity in cells and tissues. New techniques of immunohistochemistry and immunofluorescence have improved both the optical resolution of such protein identification as well as its sensitivity, particularly through the use of amplification methodology. However, this improved sensitivity has also increased the risks of false-positive and false-negative staining and thereby raised the necessity for proper and adequate controls. In this review, the authors draw on many years of experience to illuminate many of the more common errors and problematic issues in immunohistochemistry, and how these may be avoided. A key factor in all of this is that techniques need to be properly documented and especially antibodies and procedures must be adequately described. Antibodies are a valuable and shared resource within the scientific community; it is essential therefore that mistakes involving antibodies and their controls are not perpetuated through inadequate reporting in the literature.


Brain stem blood flow, pupillary response, and outcome in patients with severe head injuries.
Acute pupillary dilation in a head-injured patient is a neurological emergency. Pupil dilation is thought to be the result of uncal herniation causing mechanical compression of the IIIrd cranial nerve and subsequent brain stem compromise. However, not all patients with herniation have fixed and dilated pupils, and not all patients with nonreactive, enlarged pupils have uncal herniation. Therefore, we have tested an alternative hypothesis that a decrease in brain stem blood flow (BBF) is a more frequent cause of mydriasis and brain stem symptomatology after severe head injury. We determined the relation of BBF to outcome and pupillary response in patients with severe head injuries. One hundred sixty-two patients with a Glasgow Coma Scale score of 8 or less underwent stable xenon computed tomographic blood flow determination at the level of the superior colliculus, and this blood flow was correlated with pupillary features, intracranial pressure, computed tomographic scan pathology, and outcome. A BBF of less than 40 ml/100 g/min was significantly associated with poor outcome (P < 0.009). In patients with bilaterally nonreactive pupils, the BBF was 30.5+/-16.8 ml/100 g/min, and in those with normally reactive pupils, the BBF was 43.8+/-18.7 ml/100 g/min (P < 0.001). Intracranial pressure and the presence of a brain stem lesion observed on the computed tomographic scan did not correlate with BBF, pupillary size, or reactivity. Unfavorable outcome at 12 months was directly related to age (P = 0.062) and inversely related to pupillary responsiveness (P = 0.0006), pupil size (P = 0.005), and BBF of less than 40 ml/100 g/min (P = 0.009). These findings suggest that pupillary dilation is associated with decreased BBF and that ischemia, rather than mechanical compression of the IIIrd cranial nerve, is an important causal factor. More important, pupil dilation may be an indicator of ischemia of the brain stem. If cerebral blood flow and cerebral perfusion pressure can be rapidly restored in the patient with severe head injury who has dilated pupils, the prognosis may be good.


Manipulating the Perceived Shape and Color of a Virtual Limb Can Modulate Pain Responses.
Changes in body representation may affect pain perception. The effect of a distorted body image, such as the telescoping effect in amputee patients, on pain perception, is unclear. This study aimed to investigate whether distorting an embodied virtual arm in virtual reality (simulating the telescoping effect in amputees) modulated pain perception and anticipatory responses to pain in healthy participants. Twenty-seven right-handed participants were immersed in virtual reality and the virtual arm was shown with three different levels of distortion with a virtual threatening stimulus either approaching or contacting the virtual hand. We evaluated pain/discomfort ratings, ownership, and skin conductance responses (SCRs) after each condition. Viewing a distorted virtual arm enhances the SCR to a threatening event with respect to viewing a normal control arm, but when viewing a reddened-distorted virtual arm, SCR was comparatively reduced in response to the threat. There was a positive relationship between the level of ownership over the distorted and reddened-distorted virtual arms with the level of pain/discomfort, but not in the normal control arm. Contact with the threatening stimulus significantly enhances SCR and pain/discomfort, while reduced SCR and pain/discomfort were seen in the simulated-contact condition. These results provide further evidence of a bi-directional link between body image and pain perception.


BRCA1 cooperates with NUFIP and P-TEFb to activate transcription by RNA polymerase II.
The tumor suppressor gene product BRCA1 is a component of the RNA polymerase II (pol II) holoenzyme that is involved, through binding to various regulatory proteins, in either activation or repression of transcription. Using a yeast two-hybrid screen, we have identified a human zinc-finger-containing protein NUFIP that interacts with BRCA1. The ubiquitous, stably expressed, nuclear protein NUFIP specifically stimulates activator-independent pol II transcription in vitro and in vivo. Immunodepletion of the endogenous NUFIP causes a marked decrease of pol II transcription, which is then shown to be restored by stable complex of ectopically produced NUFIP and associated factors. NUFIP not only interacts with BRCA1 but also associates with the positive elongation factor P-TEFb through interaction with the regulatory Cyclin T1 subunit. Cyclin T1 is required for BRCA1- and NUFIP-dependent synergistic activation of pol II transcription in 293 cells. Mutation of the zinc-finger domain abolishes the NUFIP-mediated transcriptional activation. We show that NUFIP is associated with preinitiation complexes, open transcription complexes, and elongation complexes. In addition, NUFIP facilitates ATP-dependent dissociation of hyperphosphorylated pol II from open transcription complexes in vitro.


Branching pattern of airways and air spaces of a single human terminal bronchiole.
A polyurethane-foam enlarged reconstruction was made from serial sections of a portion of young adult human lung parenchyman. Study of the progeny of a terminal bronchiole disclosed three generations of respiratory bronchioles and an irregular branching pattern of eight generations of alveolar ducts. Sacs and alveoli arose from the lateral and distal aspects of all generations of ducts. There were an average of 3.5 alveoli per sac. Considering the terminal bronchiole as the first generation branch of the acinus, over 60 per cent of the alveoli counted and predicted were members of the 10-12th generations. The acinus contained one terminal bronchiole and approximately 14 respiratory bronchioles, 1,200-1,500 ducts, 2,500-4,500 sacs, and 14,000-20,000 alveoli.


Medicaid reform: programming solutions to the equity problem.
This paper demonstrates the application of a mathematical programming model to a longstanding policy issue in the Medicaid reform debate: the redistribution of program funds necessary to achieve equity in eligibility and benefit coverage across states. The model is used to estimate the potential degree of equity achievable in the current Medicaid system given various budgetary and political constraints. Two model simulations, based on a 1979 data set for aged recipients of Supplementary Security Income, are presented. The results indicate that half or more of the interstate differences in spending for this population group are due to actuarial and efficiency factors rather than deviations from equity potential. The implications of eliminating the remaining differences are discussed.


The transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis.
We have identified the Drosophila transmembrane molecule kekkon 1 (kek1) as an inhibitor of the epidermal growth factor receptor (EGFR) and demonstrate that it acts in a negative feedback loop to modulate the activity of the EGFR tyrosine kinase. During oogenesis, kek1 is expressed in response to the Gurken/EGFR signaling pathway, and loss of kek1 activity is associated with an increase in EGFR signaling. Consistent with our loss-of-function studies, we demonstrate that ectopic overexpression of kek1 mimics a loss of EGFR activity. We show that the extracellular and transmembrane domains of Kek1 can inhibit and physically associate with the EGFR, suggesting potential models for this inhibitory mechanism.


Missed opportunities for tuberculosis screening in primary care.
To assess how frequently pediatric practitioners perform latent tuberculosis infection (LTBI) screening according to guidelines. We hypothesized that screening occurs less frequently among children whose parents do not speak English as the primary language. We conducted a retrospective cohort study of patients attending well-child visits in an urban academic pediatric primary care clinic between April 1, 2012, and March 31, 2013. We assessed documentation of 3 LTBI screening components and tested the association between parent primary language and tuberculin skin test (TST) placement and documentation of results. During the study period, 387 of 9143 children (4%) had no documentation of screening question responses. Among the other 8756 children, 831 (10%) were identified as at high risk for LTBI. Of these, 514 (62%) did not have documented TST placement in the appropriate time frame. Thirty-nine of 213 children (18%) who had a TST placed did not have documented results. Multivariable regression showed that parent language was not associated with TST placement or documentation of results, but non-Hispanic Black children were more likely to not have a documented test result (aOR, 2.12; 95% CI, 1.07-4.19; P=.03) when adjusting for age, sex, parent primary language, insurance status, day of the week, and study year of TST placement. Parent primary language was not associated with LTBI testing. However, we found substantial gaps in TST placement and documentation of TST results among high-risk children, the latter of which was associated with race/ethnicity. Targeted quality improvement efforts should focus on developing processes to ensure complete screening in high-risk children.


An evolutionary algorithm for interval solid transportation problems.
The Solid Transportation Problem arises when bounds are given on three item properties. Usually, these properties are source, destination and mode of transport (conveyance), and may be given in an interval way. This paper deals with solid transportation problems in which the data in the constraint set are expressed in an interval form, i.e. when sources, destinations and conveyances have interval values instead of point values. An arbitrary linear or nonlinear objective function is also considered. To solve the problem, an Evolutionary Algorithm which extends and generalizes other approaches considering only point values, is proposed.


Critically Elevated Potassium in a 55-Year-Old Female With Chronic Lymphocytic Leukemia.
Hyperkalemia in specimens from patients with chronic lymphocytic leukemia (CLL) may be due to tumor lysis syndrome (TLS) or specimen processing. This report describes a 55-year-old Caucasian woman with CLL who presented to an outside hospital with hyperkalemia and was transferred to a second hospital. Initial evaluation on the core laboratory chemistry analyzer (the VITROS 5600) and the ABL90 FLEX blood gas analyzer showed markedly elevated levels of potassium (K+). TLS was subsequently diagnosed, and dialysis was initiated. However, follow-up K+ measurements in whole blood (WB) yielded low levels that were unexpected after a single dialysis treatment. We then discovered that the initially elevated K+ level was from centrifuged plasma specimens and concluded that it indicated pseudohyperkalemia, likely from centrifugation. This case demonstrates that medical teams need be alert to potentially false K+ results in patients with elevated white blood cell counts. WB specimens are preferable, and steps to minimize trauma to the specimen and immediate analysis using blood gas instruments are recommended.


Infliximab for the treatment of fistulas in patients with Crohn's disease.
Enterocutaneous fistulas are a serious complication of Crohn's disease and are difficult to treat. Infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, has recently been developed as a treatment for Crohn's disease. We conducted a randomized, multicenter, double-blind, placebo-controlled trial of infliximab for the treatment of fistulas in patients with Crohn's disease. The study included 94 adult patients who had draining abdominal or perianal fistulas of at least three months' duration as a complication of Crohn's disease. Patients were randomly assigned to receive one of three treatments: placebo (31 patients), 5 mg of infliximab per kilogram of body weight (31 patients), or 10 mg of infliximab per kilogram (32 patients); all three were to be administered intravenously at weeks 0, 2, and 6. The primary end point was a reduction of 50 percent or more from base line in the number of draining fistulas observed at two or more consecutive study visits. A secondary end point was the closure of all fistulas. Sixty-eight percent of the patients who received 5 mg of infliximab per kilogram and 56 percent of those who received 10 mg per kilogram achieved the primary end point, as compared with 26 percent of the patients in the placebo group (P=0.002 and P=0.02, respectively). In addition, 55 percent of the patients assigned to receive 5 mg of infliximab per kilogram and 38 percent of those assigned to 10 mg per kilogram had closure of all fistulas, as compared with 13 percent of the patients assigned to placebo (P=0.001 and P=0.04, respectively). The median length of time during which the fistulas remained closed was three months. More than 60 percent of patients in all the groups had adverse events. For patients treated with infliximab, the most common were headache, abscess, upper respiratory tract infection, and fatigue. Infliximab is an efficacious treatment for fistulas in patients with Crohn's disease.


Inframolecular acid-base and coordination properties towards Na(+) and Mg(2+) of myo-inositol 1,3,4,5,6-pentakisphosphate: a structural approach to biologically relevant species.
The myo-inositol phosphates (InsPs) are specific signalling metabolites ubiquitous in eukaryotic cells. Although Ins(1,3,4,5,6)P(5) is the second most abundant member of the InsPs family, its certain biological roles are far from being elucidated, in part due to the large number of species formed by Ins(1,3,4,5,6)P(5) in the presence of metal ions. In light of this, we have strived in the past to make a complete and at the same time "biological-user-friendly" description of the Ins(1,3,4,5,6)P(5) chemistry with mono and multivalent cations. In this work we expand these studies focusing on the inframolecular aspects of its protonation equilibria and the microscopic details of its coordination behaviour towards biologically relevant metal ions. We present here a systematic study of the Ins(1,3,4,5,6)P(5) intrinsic acid-base processes, in a non-interacting medium, and over a wide pH range, analyzing the (31)P NMR curves by means of a model based on the Cluster Expansion Method. In addition, we have used a computational approach to analyse the energetic and structural features of the protonation and conformational changes of Ins(1,3,4,5,6)P(5), and how they are influenced by the presence of two physiologically relevant cations, Na(+) and Mg(2+).


Complete complementary DNA sequence of the third component of complement of lamprey. Implication for the evolution of thioester containing proteins.
Lamprey liver mRNA sequences were amplified by reverse transcriptase-polymerase chain reaction using primers synthesized according to the amino acid sequences at the thioester region common to the mammalian C3, C4, and alpha 2-macroglobulin (alpha 2M). Two different cDNA species were identified that showed a close similarity to the mammalian C3 or alpha 2M sequences, respectively. Using the C3-like sequence as a probe, two overlapping cDNA clones were isolated from the lambda ZAP library, which together covered the entire region encoding the putative lamprey pro-C3. The deduced amino acid sequence of the putative lamprey pro-C3 contained 1660 amino acids and showed 31%, 22%, 23%, and 16% amino acid sequence identity with mouse C3, C4, C5, and human alpha 2M, respectively. The distributions of cysteine residues were completely identical between the mouse C3 and the putative lamprey C3 except that the lamprey sequence had two additional cysteine residues in the alpha-chain. The possible beta-alpha and alpha-gamma processing sites were found at exactly the same positions as in mammalian C4. These results suggest that the putative lamprey C3 retains a close similarity to the common ancestor of the mammalian C3 and C4, which appeared to have had a three-subunit chain structure.


A randomized controlled pilot study of the effectiveness of occupational therapy for children with sensory modulation disorder.
A pilot randomized controlled trial (RCT) of the effectiveness of occupational therapy using a sensory integration approach (OT-SI) was conducted with children who had sensory modulation disorders (SMDs). This study evaluated the effectiveness of three treatment groups. In addition, sample size estimates for a large scale, multisite RCT were calculated. Twenty-four children with SMD were randomly assigned to one of three treatment conditions; OT-SI, Activity Protocol, and No Treatment. Pretest and posttest measures of behavior, sensory and adaptive functioning, and physiology were administered. The OT-SI group, compared to the other two groups, made significant gains on goal attainment scaling and on the Attention subtest and the Cognitive/Social composite of the Leiter International Performance Scale-Revised. Compared to the control groups, OT-SI improvement trends on the Short Sensory Profile, Child Behavior Checklist, and electrodermal reactivity were in the hypothesized direction. Findings suggest that OT-SI may be effective in ameliorating difficulties of children with SMD.


Abnormal perfusion in patellofemoral subchondral bone marrow in the rat anterior cruciate ligament transection model of post-traumatic osteoarthritis: a dynamic contrast-enhanced magnetic resonance imaging study.
Although anterior cruciate ligament (ACL) injury is a well-recognized risk factor for developing knee post-traumatic osteoarthritis (PTOA), the process in the patellofemoral (PF) joint after ACL injury is still under-researched. Our aim was to investigate the perfusion changes in PF subchondral bone marrow in the rat ACL transection (ACLX) model of PTOA using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Eighteen male Sprague Dawley rats were randomly separated into three groups (n = 6 each group): a normal control group and groups receiving ACLX and sham-surgery, respectively, in the right knee. Perfusion parameters in the patellar and femoral subchondral bone marrows of all rats were measured on DCE-MRI at 0, 4, 8, and 16 weeks after respective treatment. After the last MRI at week 16, the rats were sacrificed and their right knees were harvested for histologic examination. In addition, to observe the long-term histologic change in PF joints, 9 additional rats (n = 3 in each group) were included and sacrificed at week 32 for histologic examination. In the ACLX group vs the sham and control groups, the perfusion parameters were significantly changed in both patellar and femoral subchondral bone marrows at week 16. Histologic examination revealed cartilage defects in ACLX rats at 32 weeks after surgery. These data point to a possible functional relationship between subchondral bone marrow perfusion abnormalities and cartilage breakdown in PTOA. Moreover, the perfusion parameters derived from DCE-MRI can potentially serve as biomarkers of early OA.


Molecular rotary motors: Unidirectional motion around double bonds.
The field of synthetic molecular machines has quickly evolved in recent years, growing from a fundamental curiosity to a highly active field of chemistry. Many different applications are being explored in areas such as catalysis, self-assembled and nanostructured materials, and molecular electronics. Rotary molecular motors hold great promise for achieving dynamic control of molecular functions as well as for powering nanoscale devices. However, for these motors to reach their full potential, many challenges still need to be addressed. In this paper we focus on the design principles of rotary motors featuring a double-bond axle and discuss the major challenges that are ahead of us. Although great progress has been made, further design improvements, for example in terms of efficiency, energy input, and environmental adaptability, will be crucial to fully exploit the opportunities that these rotary motors offer.


Effects of exposure measurement error on particle matter epidemiology: a simulation using data from a panel study in Baltimore, MD.
Ascertaining the true risk associated with exposure to particulate matter (PM) is difficult, given the fact that pollutant components are frequently correlated with each other and with other gaseous pollutants; relationships between ambient concentrations and personal exposures are often not well understood; and PM, unlike its gaseous co-pollutants, does not represent a single chemical. In order to examine differences between observed versus true health risk estimate from epidemiologic studies, we conducted a simulation using data from a recent multi-pollutant exposure assessment study in Baltimore, MD. The objectives of the simulation were twofold: (a) to estimate the distribution of personal air pollutant exposures one might expect to observe within a population, given the corresponding ambient concentrations found in that location and; (b) using an assumed true health risk with exposure to one pollutant, to estimate the distribution of health risk estimates likely to be observed in an epidemiologic study using ambient pollutant concentrations as a surrogate of exposure as compared with actual personal pollutant exposures. Results from the simulations showed that PM2.5 was the only pollutant where a true association with its total personal exposures resulted in a significant observed association with its ambient concentrations. The simulated results also showed that true health risks associated with personal exposure to O3 and NO2 would result in no significant observed associations with any of their respective ambient concentrations. Conversely, a true association with PM2.5 would result in a significant, observed association with NO2 (beta=0.0115, 95% confidence interval (CI): 0.0056, 0.0185) and a true association with exposure to SO4(2-) would result in an observed significant association with O3 (beta=0.0035, 95% CI: 0.0021, 0.0051) given the covariance of the ambient pollutant concentrations. The results provide an indication that, in Baltimore during this study period, ambient gaseous concentrations may not have been adequate surrogates for corresponding personal gaseous exposures to allow the question to be investigated using central site monitors. Alternatively, the findings may suggest that in some locations, observed associations with the gaseous pollutants should be interpreted with caution, as they may be reflecting associations with PM or one of its chemical components.


Health comorbidities and cognitive abilities across the lifespan in Down syndrome.
Down syndrome (DS) is associated with variable intellectual disability and multiple health and psychiatric comorbidities. The impact of such comorbidities on cognitive outcomes is unknown. We aimed to describe patterns of physical health and psychiatric comorbidity prevalence, and receptive language ability, in DS across the lifespan, and determine relationships with cognitive outcomes. Detailed medical histories were collected and cognitive abilities measured using standardised tests for 602 individuals with DS from England and Wales (age range 3 months to 73 years). Differences in prevalence rates between age groups and between males and females were determined using chi-squared or Fisher's exact tests. In adults, rates for psychiatric comorbidities were compared to expected population rates using standardised morbidity ratios (SMRs). Adapted ANCOVA functions were constructed to explore age and sex associations with receptive language ability across the lifespan, and regression analyses were performed to determine whether the presence of health comorbidities or physical phenotypes predicted cognitive abilities. Multiple comorbidities showed prevalence differences across the lifespan, though there were few sex differences. In adults, SMRs were increased in males and decreased in females with DS for schizophrenia, bipolar disorder, and anxiety. Further, SMRs were increased in both males and females with DS for dementia, autism, ADHD, and depression, with differences more pronounced in females for dementia and autism, and in males for depression. Across the lifespan, receptive language abilities increasingly deviated from age-typical levels, and males scored poorer than females. Only autism and epilepsy were associated with poorer cognitive ability in those aged 16-35 years, with no relationships for physical health comorbidities, including congenital heart defects. Our results indicate the prevalence of multiple comorbidities varies across the lifespan in DS, and in adults, rates for psychiatric comorbidities show different patterns for males and females relative to expected population rates. Further, most health comorbidities are not associated with poorer cognitive outcomes in DS, apart from autism and epilepsy. It is essential for clinicians to consider such differences to provide appropriate care and treatment for those with DS and to provide prognostic information relating to cognitive outcomes in those with comorbidities.


Source attribution of black and Brown carbon near-UV light absorption in Beijing, China and the impact of regional air-mass transport.
Black and Brown Carbon (BC, BrC) are key parameters of climate forcing, yet significant challenges exist assigning emission source contributions to light-absorption by carbonaceous aerosols. Additionally, BC and BrC emissions add to extreme air pollution events in Chinese mega-cities, which harm human health and detract from the natural and built environment. To address these concerns, the ability to estimate atmospheric light absorption related to emission sources and global inventories is a highly valuable tool for climate modelers and policy makers. Three months of BC and BrC data was collected using an Aethalometer in parallel to PM2.5 filter sampling during a stringent emission controls period and post controls period, including during the regional heating season. In this study reconstructed 370 nm wavelength absorption was calculated by applying source specific Mass Absorption Cross-Sections to PMF apportioned EC and OC results. Reconstructed absorption showed good agreement with the ambient measured absorption for both BC and BrC. In Beijing, the major contributor to near-UV absorption was mobile sources, which accounted for 45-54% of absorption by BC and 14-18% by BrC. BrC absorption from secondary aerosols, biomass burning, and soil dust was also estimated, with these sources contributing from 1 to 9% individually. Meteorological cluster analysis showed that air mass origin did not impact the absorption reconstruction and that the highest regional contribution to near-UV light absorption originated primarily in areas south and east of Beijing. The study shows ambient near-UV light absorption can be predicted using BC and BrC MAC values from sources. However, the current number of multi-wavelength and source specific BrC MAC values reported in the literature is limited. The reconstruction approach allows for a more robust method of assigning light absorption to source categories, allowing the expansion of aethalometer derived BrC apportionment to multiple sources, including biomass burning.


The economic burden of obesity worldwide: a systematic review of the direct costs of obesity.
In the last decade, the prevalence of obesity has increased significantly in populations worldwide. A less dramatic, but equally important increase has been seen in our knowledge of its effects on health and the burden it places on healthcare systems. This systematic review aims to assess the current published literature on the direct costs associated with obesity. A computerized search of English language articles published between 1990 and June 2009 yielded 32 articles suitable for review. Based on these articles, obesity was estimated to account for between 0.7% and 2.8% of a country's total healthcare expenditures. Furthermore, obese individuals were found to have medical costs that were approximately 30% greater than their normal weight peers. Although variations in inclusion/exclusion criteria, reporting methods and included costs varied widely between the studies, a lack of examination of how and why the excess costs were being accrued appeared to be a commonality between most studies. Accordingly, future studies must better explore how costs accrue among obese populations, in order to best facilitate health and social policy interventions.


Level of environmental threat posed by horticultural trade in Cactaceae.
Ornamental horticulture has been identified as an important threat to plant biodiversity and is a major pathway for plant invasions worldwide. In this context, the family Cactaceae is particularly challenging because it is considered the fifth most threatened large taxonomic group in the world; several species are among the most widespread and damaging invasive species; and Cactaceae is one of the most popular horticultural plant groups. Based on the Convention on International Trade in Endangered Species of Wild Flora and Fauna and the 11 largest online auction sites selling cacti, we documented the international cactus trade. To provide an in-depth look at the dynamics of the industry, we surveyed the businesses involved in the cactus trade in South Africa (a hotspot of cactus trade and invasions). We purchased seeds of every available species and used DNA barcoding to identify species to the genus level. Although <20% of this trade involved threatened species and <3% involved known invasive species, many species were identified by a common name. However, only 0.02% of the globally traded cacti were collected from wild populations. Despite a large commercial network, all South African imports (of which 15% and 1.5% were of species listed as threatened and invasive, respectively) came from the same source. With DNA barcoding, we identified 24% of the species to genus level. Based on our results, we believe that if trade restrictions are placed on the small proportion of cacti that are invasive and there is no major increase in harvesting of native populations, then the commercial trade in cactus poses a negligible environmental threat. However, there are currently no effective methods for easily identifying which cacti are traded, and both the illicit harvesting of cacti from the wild and the informal trade in invasive taxa pose on-going conservation challenges.


Coexposure to mercury increases immunotoxicity of trichloroethylene.
We have shown previously that chronic (32 weeks) exposure to occupationally relevant concentrations of the environmental pollutant trichloroethylene (TCE) induced autoimmune hepatitis (AIH) in autoimmune-prone MRL+/+ mice. In real-life, individuals are never exposed to only one chemical such as TCE. However, very little is known about the effects of chemical mixtures on the immune system. The current study examined whether coexposure to another known immunotoxicant, mercuric chloride (HgCl(2)), altered TCE-induced AIH. Female MRL+/+ mice were treated for only 8 weeks with TCE (9.9 or 186.9 mg/kg/day in drinking water) and/or HgCl(2) (260 μg/kg/day, sc). Unlike mice exposed to either TCE or HgCl(2) alone, mice exposed to both toxicants for 8 weeks developed significant liver pathology commensurate with early stages of AIH. Disease development in the coexposed mice was accompanied by a unique pattern of anti-liver and anti-brain antibodies that recognized, among others, a protein of approximately 90 kDa. Subsequent immunoblotting showed that sera from the coexposed mice contained antibodies specific for heat shock proteins, a chaperone protein targeted by antibodies in patients with AIH. Thus, although TCE can promote autoimmune disease following chronic exposure, a shorter exposure to a binary mixture of TCE and HgCl(2) accelerated disease development. Coexposure to TCE and HgCl(2) also generated a unique liver-specific antibody response not found in mice exposed to a single toxicant. This finding stresses the importance of including mixtures in assessments of chemical immunotoxicity.


The importance of ion-pairing in peptide purification by reversed-phase liquid chromatography.
The adsorption mechanism for three peptides was studied under overloaded conditions through adsorption isotherm measurements in the presence of an ion-pairing reagent, trifluoroacetic acid (TFA), on an end-capped C18-bonded stationary phase. The overall aim of the study was to obtain a better understanding of how the acetonitrile and the TFA fractions in the eluent affected the overloaded elution profiles and the selectivity between peptides using mechanistic modelling and multivariate design of experiments. When studying the effect of TFA, direct evidence for ion pair formation between a peptide and TFA in acetonitrile-water solutions was provided by fluorine-proton nuclear Overhauser NMR enhancement experiments and the adsorption of TFA on the stationary phase was measured by frontal analysis. The adsorption isotherms for each peptide were then determined by the inverse method at eight TFA concentrations ranging from 2.6mM to 37.3mM (0.02-0.29vol-%) in isocratic elution. The equilibrium between the peptide ion and the peptide-TFA complex was modelled by coupling the mass-balance to reaction kinetics and determining separate adsorption isotherms for the two species. We found that a Langmuir isotherm described the elution profile of peptide-TFA complex well while the peptide ion was described by a bi-Langmuir adsorption isotherm since it exhibited strong secondary interactions. The elution profiles had an unfavorable shape at low TFA concentrations consisting of a spike in their front and a long tailing rear due to the secondary interactions for the peptide ion having very low saturation capacity. The acetonitrile dependence on the adsorption isotherms was studied by determination of adsorption isotherms directly from elution profiles obtained in gradient elution which enabled a broad acetonitrile interval to be studied. Here, it was found that the column saturation capacity was quickly reached at very low acetonitrile fractions and that there were significant variations in adsorption with the molecular weight. Finally, practical implications for method development are discussed based on an experimental design where gradient slope and TFA concentrations are used as factors.


Multi-population genomic analysis of malaria parasites indicates local selection and differentiation at the gdv1 locus regulating sexual development.
Parasites infect hosts in widely varying environments, encountering diverse challenges for adaptation. To identify malaria parasite genes under locally divergent selection across a large endemic region with a wide spectrum of transmission intensity, genome sequences were obtained from 284 clinical Plasmodium falciparum infections from four newly sampled locations in Senegal, The Gambia, Mali and Guinea. Combining these with previous data from seven other sites in West Africa enabled a multi-population analysis to identify discrete loci under varying local selection. A genome-wide scan showed the most exceptional geographical divergence to be at the early gametocyte gene locus gdv1 which is essential for parasite sexual development and transmission. We identified a major structural dimorphism with alternative 1.5 kb and 1.0 kb sequence deletions at different positions of the 3'-intergenic region, in tight linkage disequilibrium with the most highly differentiated single nucleotide polymorphism, one of the alleles being very frequent in Senegal and The Gambia but rare in the other locations. Long non-coding RNA transcripts were previously shown to include the entire antisense of the gdv1 coding sequence and the portion of the intergenic region with allelic deletions, suggesting adaptive regulation of parasite sexual development and transmission in response to local conditions.


The health information system security threat lifecycle: an informatics theory.
This manuscript describes the health information system security threat lifecycle (HISSTL) theory. The theory is grounded in case study data analyzing clinicians' health information system (HIS) privacy and security (P&S) experiences in the practice context. The 'questerview' technique was applied to this study of 26 clinicians situated in 3 large Australian (across Victoria) teaching hospitals. Questerviews rely on data collection that apply standardized questions and questionnaires during recorded interviews. Analysis (using Nvivo) involved the iterative scrutiny of interview transcripts to identify emergent themes. Issues including poor training, ambiguous legal frameworks containing punitive threats, productivity challenges, usability errors and the limitations of the natural hospital environment emerged from empirical data about the clinicians' HIS P&S practices. The natural hospital environment is defined by the permanence of electronic HISs (e-HISs), shared workspaces, outdated HIT infrastructure, constant interruption, a P&S regulatory environment that is not conducive to optimal training outcomes and budgetary constraints. The evidence also indicated the obtrusiveness, timeliness, and reliability of P&S implementations for clinical work affected participant attitudes to, and use of, e-HISs. The HISSTL emerged from the analysis of study evidence. The theory embodies elements such as the fiscal, regulatory and natural hospital environments which impede P&S implementations in practice settings. These elements conflict with improved patient care outcomes. Efforts by clinicians to avoid conflict and emphasize patient care above P&S tended to manifest as security breaches. These breaches entrench factors beyond clinician control and perpetuate those within clinician control. Security breaches of health information can progress through the HISSTL. Some preliminary suggestions for addressing these issues are proposed. Legislative frameworks that are not related to direct patient care were excluded from this study. Other limitations included an exclusive focus on patient care tasks post-admission and pre-discharge from public hospital wards. Finally, the number of cases was limited by the number of participants who volunteered to participate in the study. It is reasonable to assume these participants were more interested in the P&S of patient care work than their counterparts, though the study was not intended to provide quantitative or statistical data. Nonetheless, additional case studies would strengthen the HISSTL theory if confirmatory, practice-based evidence were found.


Corrosion and biocompatibility testing of palladium alloy castings.
The biocompatibility of palladium-copper alloys has been questioned in the literature. The intention of the present work was to study: (a) the release of ions in an immersion test from a copper-containing alloy, Option((R)) (79% Pd, 10% Cu, 9% Ga, 2% Au), compared with an alloy without Cu, IS85 (82% Pd, 6% Ga, 3.5% Sn, 3.5% In, 2.5% Ag, 2.5% Au); (b) the effect of oxide films produced by preoxidation on corrosion resistance; and (c) the possibility of biologically synergetic effects of ions released. Specimens of both alloys were cast, rubbed and ultrasonically cleaned. Metallographic specimens were prepared after (a) casting and (b) preoxidizing treatment at approximately 1000 degrees C and studied by SEM and EDS. Immersion tests were carried out in a solution of 0.1mol/l of NaCl and 0.1mol/l of lactic acid at 37 degrees C for 7 days. The alloy specimens were tested in the following three steps: (1) as preoxidized; (2) after subsequent removal of a 0.1mm thick layer by grinding; and (3) after an additional removal of approximately 0.1mm by grinding. The test solutions were analyzed by means of ICP to record the amounts of ions that had leached out from the alloy specimens. The biocompatibility was studied by cell culture tests and the HET-CAM method. Test solutions were prepared by dissolving PdCl(2) and CuCl(2) to appropriate concentrations. The metallographic investigations revealed moderate segregations in interdendritic regions and grain boundaries. After preoxidation in air a zone of oxidation from 25 up to 200 microm thickness for Option and from 5 to 10 microm for IS85 was found. Oxidation was observed along a rim for both alloys and for Option also along interdendritic positions. The oxides were seen as small, dark spots <1 microm in a metallic matrix. These results indicate that: (1) the oxidation of the copper-containing palladium alloy is far more severe than that of the alloy with no copper; and (2) the elemental release from these oxides is substantially larger than that from the corrosion of the metallic structure. The results of the cell culture testing showed that Cu was most toxic, followed by Cu(2+)+Pd(2+) (1:2), based on the determination of the concentration that caused 50% cytotoxicity. The HET-CAM testing showed Cu(2+)+Pd(2+) (1:2) to have the highest irritation score. The copper-containing Pd alloy developed a 0.1mm thick rim with small oxide particles in a metallic matrix during preoxidation. If this rim is not completely removed, significantly more Cu, Ga and Pd ions have been shown to leach into the test solution than from the alloy structure. No synergetic effect of Cu and Pd ions was observed in cultured cells, while the mixture Pd(2+)+Cu(2+) (1:2) was most irritating to mucous membrane as evaluated by the HET-CAM method.


Factors associated with attrition of African Americans during the recruitment phase of a clinical trial examining adherence among individuals with rheumatoid arthritis.
To examine factors contributing to the loss of potential minority participants in a study of medication adherence among rheumatoid arthritis patients. Chi-square statistics were used to test for differences in refusal/ineligibility by race and site at 4 screening points (initial eligibility review, initial patient contact, adherence screening, and informed consent). Differences in criteria-specific risks for exclusion at initial eligibility review were examined across 4 sites by race. Odds ratios (95% confidence intervals) were estimated if differences were significant. Multivariate logistic regression was used to examine sociodemographic factors associated with the probability for ineligibility at the initial eligibility review. Stated reasons for refusal were qualitatively quantified. A greater percentage of African Americans were lost at every screening point when compared with whites, but only the difference at the initial eligibility review was statistically significant. Factors associated with attrition included selection of area medical sites, research design issues, comorbid conditions, alcohol abuse, and being younger, unmarried, African American, and male.


The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of stathmin/Op18.
The polarization of a neuron generally results in the formation of one axon and multiple dendrites, allowing for the establishment of neuronal circuitry. The molecular mechanisms involved in priming one neurite to become the axon, particularly those regulating the microtubule network, remain elusive. Here we report the identification of DOCK7, a member of the DOCK180-related protein superfamily, as a Rac GTPase activator that is asymmetrically distributed in unpolarized hippocampal neurons and selectively expressed in the axon. Knockdown of DOCK7 expression prevents axon formation, whereas overexpression induces formation of multiple axons. We further demonstrate that DOCK7 and Rac activation lead to phosphorylation and inactivation of the microtubule destabilizing protein stathmin/Op18 in the nascent axon and that this event is important for axon development. Our findings unveil a pathway linking the Rac activator DOCK7 to a microtubule regulatory protein and highlight the contribution of microtubule network regulation to axon development.


A genotype of exceptional longevity is associated with preservation of cognitive function.
To test whether cholesterol ester transfer protein (CETP) genotype (VV homozygosity for I405V) is associated with preservation of cognitive function in addition to its association with exceptional longevity. We studied Ashkenazi Jews with exceptional longevity (n = 158; age 99.2 +/- 0.3 years) for the associations of CETP VV genotype and lipoprotein phenotype, using the Mini-Mental State Examination (MMSE). To confirm the role of CETP in a younger cohort, we studied subjects from the Einstein Aging Study (EAS) for associations between CETP VV and cognitive impairment. Subjects with MMSE > 25 were twice as likely to have the CETP VV genotype (29% vs 14%, p = 0.02), and those with the VV genotype were more likely (61% vs 30%, p = 0.02) to have MMSE > 25. Subjects with the VV genotype had lower levels of CETP (1.73 +/- 0.11 vs 2.12 +/- 0.10 mug/mL, p = 0.01), higher high-density lipoprotein (HDL) levels (p = 0.02), and larger lipoprotein particles (p = 0.03). In the EAS cohort, an approximately fivefold increase in the VV genotype (21% vs 4%, p = 0.02), higher HDL levels, and larger lipoprotein particle sizes were associated with less dementia and improved memory. Using two independent cohorts, we implicate the longevity CETP gene as a modulator of age-related cognitive function. A specific CETP genotype is associated with lower CETP levels and a favorable lipoprotein profile. It has not been determined whether modulation of this gene prevents age-related decline or AD.


Synthesis and room temperature photo-induced electron transfer in biologically active bis(terpyridine)ruthenium(II)-cytochrome c bioconjugates and the effect of solvents on the bioconjugation of cytochrome c.
Photo-active bis(terpyridine)ruthenium(ii) chromophores were synthesised and attached to the redox enzyme iso-1 cytochrome c in a mixed solvent system to form photo-induced bioconjugates in greater than 40% yield after purification. The effects of up to 20% (v/v) of acetonitrile, tetrahydrofuran, dimethylformamide, or dimethyl sulfoxide at 4, 25 and 35 degrees C on the stability and biological activity of cytochrome c and its reactivity towards the model compound 4,4'-dithiodipyridine (DTDP) was measured. The second-order rate constant for the DTDP reaction was found to range between k = 2.5-4.3 M(-1) s(-1) for reactions with 5% organic solvent added compared to k = 5.6 M(-1) s(-1) in pure water at 25 degrees C. Use of 20% solvent generally results in significant protein oxidation, and 20% acetonitrile and tetrahydrofuran in particular result in significant protein dimerization, which competes with the bioconjugation reaction. Cyclic voltammetry studies indicated that the rate of electron transfer to the heme in solution was reduced in the bis(terpyridine)ruthenium(ii) cytochrome c bioconjugates compared to unmodified cytochrome c. Steady-state fluorescence studies on these bioconjugates showed that energy or electron transfer is taking place between the bis(terpyridine)ruthenium(ii) chromophores and cytochrome c. The bis(terpyridine)ruthenium(ii) cytochrome c bioconjugates demonstrate room temperature photo-activated electron transfer from the bis(terpyridine)ruthenium(ii) donor to the protein acceptor. Two sacrificial donors were used; in 50% glycerol, the bioconjugates were reduced in about 15 min while in 20 mM EDTA the bioconjugates were fully reduced in less than 5 min upon irradiation with a xenon lamp source. Under these conditions, the reduction of the non-covalent mixture of cytochrome c and bis(terpyridine)ruthenium(ii) mixtures took over 30 min. Control experiments showed that the photo-induced reduction of cytochrome c only occurs in the absence of oxygen and presence of a sacrificial donor. These results are encouraging for future incorporation of these bioconjugates in light-responsive bioelectronic circuits, including photo-activated biosensors and biofuel cells.


Crystal structure of the DNA-binding domain of Mbp1, a transcription factor important in cell-cycle control of DNA synthesis.
During the cell cycle, cells progress through four distinct phases, G1, S, G2 and M; transcriptional controls play an important role at the transition between these phases. MCB-binding factor (MBF), a transcription factor from budding yeast, binds to the so-called MCB (MluI cell-cycle box) elements found in the promoters of many DNA synthesis genes, and activates the transcription of those at the G1-->S phase transition. MBF is comprised of two proteins, Mbp1 and Swi6. The three-dimensional structure of the N-terminal DNA-binding domain of Mbp1 has been determined by multiwavelength anomalous diffraction from crystals of the selenomethionyl variant of the protein. The structure is composed of a six-stranded beta sheet interspersed with two pairs of alpha helices. The most conserved core region among Mbp1-related transcription factors folds into a central helix-turn-helix motif with a short N-terminal beta strand and a C-terminal beta hairpin. Despite little sequence similarity, the structure within the core region of the Mbp1 N-terminal domain exhibits a similar fold to that of the DNA-binding domains of other proteins, such as hepatocyte nuclear factor-3gamma and histone H5 from eukaryotes, and the prokaryotic catabolite gene activator. However, the structure outside the core region defines Mbp1 as a larger entity with substructures that stabilize and display the helix-turn-helix motif.


Global health post-2015: the case for universal health equity.
Set in 2000, with a completion date of 2015, the deadline for the Millennium Development Goals is approaching, at which time a new global development infrastructure will become operational. Unsurprisingly, the discussions on goals, topics, priorities and monitoring and evaluation are gaining momentum. But this is a critical juncture. Over a decade of development programming offers a unique opportunity to reflect on its structure, function and purpose in a contemporary global context. This article examines the topic from an analytical health perspective and identifies universal health equity as an operational and analytical priority to encourage attention to the root causes of unnecessary and unfair illness and disease from the perspectives of those for whom the issues have most direct relevance.


Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function.
Tregs require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Tregs persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator ubiquitin-like with plant homeodomain and RING finger domains 1 (Uhrf1) is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3+ cells resulted in global yet nonuniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg lineage, and spontaneous inflammation. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg genome for both lineage establishment and stability of identity and suppressive function.


Functional characterization of DNase X, a novel endonuclease expressed in muscle cells.
The activation of endonucleases resulting in the degradation of genomic DNA is one of the most characteristic changes in apoptosis. Here, we report the characterization of a novel endonuclease, termed DNase X due to its X-chromosomal localization. The active nuclease is a 35 kDa protein with 39% identity to DNase I. When incubated with isolated nuclei, recombinant DNase X was capable of triggering DNA degradation at internucleosomal sites. Similarly to DNase I, the nuclease activity of DNase X was dependent on Ca(2+) and Mg(2+) and inhibited by Zn(2+) ions or chelators of bivalent cations. Overexpression of DNase X caused internucleosomal DNA degradation and induction of cell death associated with increased caspase activation. Despite the presence of two potential caspase cleavage sites, DNase X was processed neither in vitro nor in vivo by different caspases. Interestingly, after initiation of apoptosis DNase X was translocated from the cytoplasm to the nuclear compartment and aggregated as a detergent-insoluble complex. Abundant expression of DNase X mRNA was detected in heart and skeletal muscle cells, suggesting that DNase X may be involved in apoptotic or other biological events in muscle tissues.


Sea Buckthorn (Hippophaë rhamnoides L.) Oil Improves Atopic Dermatitis-Like Skin Lesions via Inhibition of NF-κB and STAT1 Activation.
The objective of this study was to evaluate the topical effects of sea buckthorn (SBT) oil on atopic dermatitis (AD)-like lesions in a mouse model generated by repeated topical administration of DNCB in BALB/c mice. DNCB was applied repeatedly on the dorsal skin of mice to induce AD-like lesions. Following AD induction, SBT oil was applied daily on the dorsal skin for 4 weeks. The severity of skin lesions was examined macroscopically and histologically. We further measured the production of MDC/CCL22 and TARC/CCL17 in IFN-γ/TNF-α activated HaCaT cells. Topically applied SBT oil in DNCB-treated mice ameliorated the severity score of dermatitis, decreased epidermal thickness, reduced spleen and lymph node weights, and prevented mast cell infiltration. In addition, SBT oil suppressed the Th2 chemokines TARC and MDC via dose-dependent inhibition of NF-κB, JAK2/STAT1, and p38-MAPK signaling pathways in IFN-γ/TNF-α-activated HaCaT cells. These results suggest that SBT oil had a beneficial effect on AD-like skin lesions, partially via inhibition of the Th2 chemokines TARC and MDC in inflamed skin.


Autoantibodies and pain.
Over the last 20 years, several neurological conditions have been identified which appear to be caused directly by autoantibodies targeting receptors, ion channels and related proteins on neuronal or glial cells. Neuroimmune interactions are now accepted contributors to chronic pain conditions. Autoantibodies might be one such cause and here we highlight their potential role in pathological pain. Recent studies have given more weight to the idea that autoantibodies can be directly related to pain; this is suggested by the success of immunotherapy in patients and preclinical studies in animal models. For example, in complex regional pain syndrome, plasma exchange or intravenous immunoglobulins have been successful in reducing pain scores. Similarly, immunotherapies reduce autoantibody levels and pain in neuromyelitis optica and voltage-gated potassium channel complex antibody positive patients. Furthermore, animal studies show that IgG autoantibodies from patients with rheumatoid arthritis or complex regional pain syndrome can recapitulate pain phenotypes in mice. There is growing evidence that some pain syndromes may be caused by autoantibodies to proteins that modify or exacerbate pain sensation. This has potentially direct therapeutic advantages for these patients and possible wider implications for sufferers of chronic pain more generally.


Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation.
TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR Vβ sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3-based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post-allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post-allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses.


Effect of High Fiber Cereal Intake on Satiety and Gastrointestinal Symptoms during Ramadan.
(1) Background: Fasting during Ramadan involves large changes in daily eating patterns which strongly impacts the daily biorhythm and challenges the regular function of the digestive tract. The aim of this study was to assess satiety, bowel habits, body composition, blood glycaemia, and blood lipidemia after the consumption of high fiber cereal at dawn (Sohor) during the month of Ramadan; (2) Methods: A two-arm randomized, controlled, single-blinded, parallel-design study was conducted in Ramadan month. Participants were randomized to consume either 90 g of high fiber cereal (11 g fiber/90 g) at Sohor for 20 consecutive days (intervention group, n = 45) or to maintain their habitual diet intake (control group; n = 36); (3) Results: The intervention group reported higher satiety rating scores, improved bowel habits and reduced bloating frequency after the 20-day intervention. Significantly higher intake of carbohydrates and dietary fiber were observed in the intervention group. Total cholesterol and low density lipoprotein (LDL) cholesterol were significantly lower among the intervention group compared to the control group (p-value = 0.043, and p-value = 0.033, respectively) at the end of the intervention. No significant differences in body weight, body fat percentage, waist circumference, body mass index, blood glucose, high density lipoprotein (HDL) cholesterol, and triglycerides were observed between the two groups; (4) Conclusions: Consuming high fiber cereal had a positive effect on health and well-being during the month of Ramadan with better satiety, improved bowel functions, and improved blood lipids.


Offline replay supports planning in human reinforcement learning.
Making decisions in sequentially structured tasks requires integrating distally acquired information. The extensive computational cost of such integration challenges planning methods that integrate online, at decision time. Furthermore, it remains unclear whether 'offline' integration during replay supports planning, and if so which memories should be replayed. Inspired by machine learning, we propose that (a) offline replay of trajectories facilitates integrating representations that guide decisions, and (b) unsigned prediction errors (uncertainty) trigger such integrative replay. We designed a 2-step revaluation task for fMRI, whereby participants needed to integrate changes in rewards with past knowledge to optimally replan decisions. As predicted, we found that (a) multi-voxel pattern evidence for off-task replay predicts subsequent replanning; (b) neural sensitivity to uncertainty predicts subsequent replay and replanning; (c) off-task hippocampus and anterior cingulate activity increase when revaluation is required. These findings elucidate how the brain leverages offline mechanisms in planning and goal-directed behavior under uncertainty.