Life Cycle Assessment of Completely Recyclable Concrete.
Since the construction sector uses 50% of the Earth's raw materials and produces 50% of its waste, the development of more durable and sustainable building materials is crucial. Today, Construction and Demolition Waste (CDW) is mainly used in low level applications, namely as unbound material for foundations, e.g., in road construction. Mineral demolition waste can be recycled as crushed aggregates for concrete, but these reduce the compressive strength and affect the workability due to higher values of water absorption. To advance the use of concrete rubble, Completely Recyclable Concrete (CRC) is designed for reincarnation within the cement production, following the Cradle-to-Cradle (C2C) principle. By the design, CRC becomes a resource for cement production because the chemical composition of CRC will be similar to that of cement raw materials. If CRC is used on a regular basis, a closed concrete-cement-concrete material cycle will arise, which is completely different from the current life cycle of traditional concrete. Within the research towards this CRC it is important to quantify the benefit for the environment and Life Cycle Assessment (LCA) needs to be performed, of which the results are presented in a this paper. It was observed that CRC could significantly reduce the global warming potential of concrete.


Inactivation of bacterial DD-peptidase by beta-sultams.
N-Acyl-beta-sultams are time-dependent, irreversible active site-directed inhibitors of Streptomyces R61 DD-peptidase. The rate of inactivation is first order with respect to beta-sultam concentration, and the second-order rate constants show a dependence on pH similar to that for the hydrolysis of a substrate. Inactivation is due to the formation of a stable 1:1 enzyme-inhibitor complex as a result of the active site serine being sulfonylated by the beta-sultam as shown by ESI-MS analysis and by X-ray crystallography. A striking feature of the sulfonyl enzyme is that the inhibitor is not bound to the oxyanion hole but interacts extensively with the "roof" of the active site where the Arg 285 is located.


Connectivity-based neurofeedback: dynamic causal modeling for real-time fMRI.
Neurofeedback based on real-time fMRI is an emerging technique that can be used to train voluntary control of brain activity. Such brain training has been shown to lead to behavioral effects that are specific to the functional role of the targeted brain area. However, real-time fMRI-based neurofeedback so far was limited to mainly training localized brain activity within a region of interest. Here, we overcome this limitation by presenting near real-time dynamic causal modeling in order to provide feedback information based on connectivity between brain areas rather than activity within a single brain area. Using a visual-spatial attention paradigm, we show that participants can voluntarily control a feedback signal that is based on the Bayesian model comparison between two predefined model alternatives, i.e. the connectivity between left visual cortex and left parietal cortex vs. the connectivity between right visual cortex and right parietal cortex. Our new approach thus allows for training voluntary control over specific functional brain networks. Because most mental functions and most neurological disorders are associated with network activity rather than with activity in a single brain region, this novel approach is an important methodological innovation in order to more directly target functionally relevant brain networks.


Chamomile Methanolic Extract Mitigates Small Bowel Inflammation and ROS Overload Related to the Intestinal Nematodes Infection in Mice.
Chamomile (Matricaria recutita L.) is a plant which has been reported to be effective in treating several parasitic and digestive diseases. The present study was conducted to evaluate the anthelmintic activity of chamomile methanolic extract (CME). In vitro, the anthelmintic activities of CME were investigated on the L3 larvae of Heligmosomoides polygyrus in comparison to albendazole. In vivo, Swiss albino mice were infected with infective third (L3) larval stage of H. polygyrus by intragastric administration. Moreover, the effect of CME and albendazole on worm eggs, adult worms, serum cytokine production, and oxidative stress was studied. All used doses of CME showed a potent anthelmintic activity both in vitro and in vivo and the effect being similar to treatment with albendazole. Moreover, H. polygyrus infestation was accompanied by an intestinal oxidative stress status characterized by an increased lipoperoxidation, a depletion of antioxidant enzyme activity, as well as an overload of hydrogen peroxide. We have also recorded an increase of pro-inflammatory mediator (TNF-α, IL-6, and IL-1β) levels after treatment with CME (14 ± 0.8; 41 ± 2; 58 ± 4 pg/mg protein, respectively, with the concentration 800 mg/kg, body weight) when compared with infected control mice (20 ± 1; 59 ± 2, and 83 ± 4 pg/mg protein, respectively). However, extract treatment alleviated all the deleterious effects associated with H. polygyrus infection. These findings suggest that CME can be used in the control of gastrointestinal helminthiasis and associated oxidative stress.


Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women.
The role of dietary antioxidant vitamins in preventing coronary heart disease has aroused considerable interest because of the knowledge that oxidative modification of low-density lipoprotein may promote atherosclerosis. We studied 34,486 postmenopausal women with no cardiovascular disease who in early 1986 completed a questionnaire that assessed, among other factors, their intake of vitamins A, E, and C from food sources and supplements. During approximately seven years of follow-up (ending December 31, 1992), 242 of the women died of coronary heart disease. In analyses adjusted for age and dietary energy intake, vitamin E consumption appeared to be inversely associated with the risk of death from coronary heart disease. This association was particularly striking in the subgroup of 21,809 women who did not consume vitamin supplements (relative risks from lowest to highest quintile of vitamin E intake, 1.0, 0.68, 0.71, 0.42, and 0.42; P for trend 0.008). After adjustment for possible confounding variables, this inverse association remained (relative risks from lowest to highest quintile, 1.0, 0.70, 0.76, 0.32, and 0.38; P for trend, 0.004). There was little evidence that the intake of vitamin E from supplements was associated with a decreased risk of death from coronary heart disease, but the effects of high-dose supplementation and the duration of supplement use could not be definitely addressed. Intake of vitamins A and C did not appear to be associated with the risk of death form coronary heart disease. These results suggest that in postmenopausal women the intake of vitamin E from food is inversely associated with the risk of death from coronary heart disease and that such women can lower their risk without using vitamin supplements. By contrast, the intake of vitamins A and C was not associated with lower risks of dying from coronary disease.


Metabolite changes during natural and lactic acid bacteria fermentations in pastes of soybeans and soybean-maize blends.
The effect of natural and lactic acid bacteria (LAB) fermentation processes on metabolite changes in pastes of soybeans and soybean-maize blends was studied. Pastes composed of 100% soybeans, 90% soybeans and 10% maize, and 75% soybeans and 25% maize were naturally fermented (NFP), and were fermented by lactic acid bacteria (LFP). LAB fermentation processes were facilitated through back-slopping using a traditional fermented gruel, thobwa as an inoculum. Naturally fermented pastes were designated 100S, 90S, and 75S, while LFP were designated 100SBS, 90SBS, and 75SBS. All samples, except 75SBS, showed highest increase in soluble protein content at 48 h and this was highest in 100S (49%) followed by 90SBS (15%), while increases in 100SBS, 90S, and 75S were about 12%. Significant (P < 0.05) increases in total amino acids throughout fermentation were attributed to cysteine in 100S and 90S; and methionine in 100S and 90SBS. A 3.2% increase in sum of total amino acids was observed in 75SBS at 72 h, while decreases up to 7.4% in 100SBS at 48 and 72 h, 6.8% in 100S at 48 h and 4.7% in 75S at 72 h were observed. Increases in free amino acids throughout fermentation were observed in glutamate (NFP and 75SBS), GABA and alanine (LFP). Lactic acid was 2.5- to 3.5-fold higher in LFP than in NFP, and other organic acids detected were acetate and succinate. Maltose levels were the highest among the reducing sugars and were two to four times higher in LFP than in NFP at the beginning of the fermentation, but at 72 h, only fructose levels were significantly (P < 0.05) higher in LFP than in NFP. Enzyme activities were higher in LFP at 0 h, but at 72 h, the enzyme activities were higher in NFP. Both fermentation processes improved nutritional quality through increased protein and amino acid solubility and degradation of phytic acid (85% in NFP and 49% in LFP by 72 h).


Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway.
The Drosophila insulin receptor (dInR) regulates cell growth and proliferation through the dPI3K/dAkt pathway, which is conserved in metazoan organisms. Here we report the identification and functional characterization of the Drosophila forkhead-related transcription factor dFOXO, a key component of the insulin signaling cascade. dFOXO is phosphorylated by dAkt upon insulin treatment, leading to cytoplasmic retention and inhibition of its transcriptional activity. Mutant dFOXO lacking dAkt phosphorylation sites no longer responds to insulin inhibition, remains in the nucleus, and is constitutively active. dFOXO activation in S2 cells induces growth arrest and activates two key players of the dInR/dPI3K/dAkt pathway: the translational regulator d4EBP and the dInR itself. Induction of d4EBP likely leads to growth inhibition by dFOXO, whereas activation of dInR provides a novel transcriptionally induced feedback control mechanism. Targeted expression of dFOXO in fly tissues regulates organ size by specifying cell number with no effect on cell size. Our results establish dFOXO as a key transcriptional regulator of the insulin pathway that modulates growth and proliferation.


Large acoustic transients induced by nonthermal melting of InSb.
We have observed large-amplitude strain waves following a rapid change in density of InSb due to nonthermal melting. The strain has been measured in real time via time-resolved x-ray diffraction, with a temporal resolution better than 2 ps. The change from the solid to liquid density of the surface layer launches a high-amplitude strain wave into the crystalline material below. This induces an effective plane rotation in the asymmetrically cut crystal leading to deflection of the diffracted beam. The uniform strain in the layer below the molten layer is 2.0(+/-0.2)%. A strain of this magnitude develops within 5 ps of the incident pulse showing that the liquid has reached the equilibrium density within this time frame. Both the strain amplitude and the depth of the strained material in the solid can be explained by assuming a reduction in the speed of sound in the nonequilibrium liquid compared to measured equilibrium values.


The effect of anxiety on anticipation, allocation of attentional resources, and visual search behaviours.
Successful sports performance requires athletes to be able to mediate any detrimental effects of anxiety whilst being able to complete tasks simultaneously. In this study, we examine how skill level influences the ability to mediate the effects of anxiety on anticipation performance and the capacity to allocate attentional resources to concurrent tasks. We use a counterbalanced, repeated measures design that required expert and novice badminton players to complete a film-based anticipation test in which they predicted serve direction under high- and low-anxiety conditions. On selected trials, participants completed an auditory secondary task. Visual search data were recorded and the Mental Readiness Form v-3 was used to measure cognitive anxiety, somatic anxiety and self-confidence. The Rating Scale of Mental Effort was used to measure mental effort. The expert players outperformed their novice counterparts on the anticipation task across both anxiety conditions, with both groups anticipation performance deteriorating under high- compared to low-anxiety. This decrease across anxiety conditions was significantly greater in the novice compared to the expert group. High-anxiety resulted in a shorter final visual fixation duration for both groups when compared to low-anxiety. Anxiety had a negative impact on secondary task performance for the novice, but not the expert group. Our findings suggest that expert athletes more effectively allocated attentional resources during performance under high-anxiety conditions. In contrast, novice athletes used more attentional resources when completing the primary task and, therefore, were unable to maintain secondary task performance under high-anxiety.


In-Hospital Complication Rates and Associated Factors After Simultaneous Bilateral Versus Unilateral Total Knee Arthroplasty.
Data comparing complication rates following simultaneous bilateral total knee arthroplasty with those of unilateral total knee arthroplasty are conflicting. The purpose of this study was to compare in-hospital complication rates following simultaneous bilateral versus unilateral total knee arthroplasty and to determine factors associated with in-hospital complication rates in a large cohort of patients identified from the Nationwide Inpatient Sample (NIS). The 2004 to 2007 NIS data set was used to identify 407,070 total knee arthroplasties: 24,574 simultaneous bilateral and 382,496 unilateral total knee arthroplasties. Complications, based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, were categorized as none, minor, major, or mortality. Covariates included comorbidities, demographic information, payer type, and hospital total knee arthroplasty volume. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Simultaneous bilateral total knee arthroplasty was associated with significantly higher odds of an in-hospital complication compared with unilateral total knee arthroplasty: OR, 1.51 (95% CI, 1.42 to 1.62) for minor complication; OR, 1.30 (95% CI, 1.14 to 1.47) for major complication; and OR, 2.51 (95% CI, 1.66 to 3.80) for mortality. Patients with greater numbers of medical comorbidities were more likely to have an in-hospital complication. Compared with whites, African-American and Asian/Pacific Islander groups had significantly higher odds of a minor complication. Female patients were less likely than male patients to have an in-hospital complication. Patients who were less than sixty-five years old at the time of surgery had significantly reduced odds of a minor complication and mortality compared with patients who were seventy-five years of age or older. Compared with hospitals with a very-high volume of total knee arthroplasty procedures performed (≥850), lower-volume hospitals had significantly increased odds of minor complications and mortality. While complication rates following either unilateral or simultaneous bilateral total knee arthroplasty are low, simultaneous bilateral total knee arthroplasty was associated with higher odds of in-hospital complications, including mortality, compared with unilateral total knee arthroplasty. Patient demographic information, preoperative health status, payer type, and hospital total knee arthroplasty volume were all significant factors in complication rates following bilateral total knee arthroplasty. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Factors associated with change in sexual transmission risk behavior over 3 years among HIV-infected patients in Tanzania.
The reduction of HIV transmission risk behaviors among those infected with HIV remains a major global health priority. Psychosocial characteristics have proven to be important correlates of sexual transmission risk behaviors in high-income countries, but little attention has focused on the influence of psychosocial and psychological factors on sexual transmission risk behaviors in African cohorts. The CHAT Study enrolled a representative sample of 499 HIV-infected patients in established HIV care and 267 newly diagnosed HIV-infected individuals from the Kilimanjaro Region of Tanzania. Participants completed in-person interviews every 6 months for 3 years. Using logistic random effects models to account for repeated observations, we assessed sociodemographic, physical health, and psychosocial predictors of self-reported unprotected sexual intercourse. Among established patients, the proportion reporting any recent unprotected sex was stable, ranging between 6-13% over 3 years. Among newly diagnosed patients, the proportion reporting any unprotected sex dropped from 43% at baseline to 11-21% at 6-36 months. In multivariable models, higher odds of reported unprotected sex was associated with female gender, younger age, being married, better physical health, and greater post-traumatic stress symptoms. In addition, within-individual changes in post-traumatic stress over time coincided with increases in unprotected sex. Changes in post-traumatic stress symptomatology were associated with changes in sexual transmission risk behaviors in this sample of HIV-infected adults in Tanzania, suggesting the importance of investing in appropriate mental health screening and intervention services for HIV-infected patients, both to improve mental health and to support secondary prevention efforts.


Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery.
One barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. We measured fentanyl concentrations in plasma from leftover clinically-obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness-of-fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model-driven weight-adjusted per kg vs. fixed per kg fentanyl dosing. Fentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h(-1) (2.2-9.2 l h(-1) ), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter-individual variability remained. In simulation studies, model-driven weight-adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. We show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens.


Pontine haemorrhage mimicked by an olanzapine overdose.
Olanzapine, an atypical antipsychotic of the thienobenzodiazepine class, has been on the market since 1996. Its popularity has increased over recent years because of excellent clinical results as well as a favourable side effect profile. Mirroring this increased olanzapine use has been a rise in the number of non-accidental overdoses. The clinical picture of olanzapine overdose can be surprisingly variable. In the case presented, the patient's low Glasgow Coma Score prevented an accurate history being taken. Examination revealed bilateral upgoing plantars, pinpoint pupils, increased tone, and brisk reflexes; however initial investigations, including an urgent CT head, were normal. The patient required 24 hours of intensive care before he regained consciousness and admitted to the overdose. Although there are several reports of olanzapine mimicking opiate intoxication in overdose, this is one of the first cases where overdose has mimicked an intracerebral event. The authors highlight some of the literature regarding clinical presentation and treatment options, and discuss the relation between olanzapine therapy and diabetes.


Fermented carrot juice attenuates type 2 diabetes by mediating gut microbiota in rats.
In the present study, we aimed to investigate the therapeutic mechanisms of carrot juice fermented with Lactobacillus rhamnosus GG (LGG) on type 2 diabetic mellitus (T2DM) based on the regulation of gut microbiota. Carrot juice fermented with LGG was enriched with free phenols, organic acids and short-chain fatty acids (SCFAs). Supplementation of carrot juice fermented with LGG (DFCL) could favorably regulate blood glucose, insulin, antioxidant capacity and morphology of the pancreas and kidney in the diabetic rats, accompanied by an increase of SCFAs in the cecum. Furthermore, high-throughput sequencing (HTS) analysis revealed that DFCL supplementation altered the composition of gut microbiota, showing increased relative abundances of functionally relevant enterotypes, such as Christensenellaceae_R-7_group, Oscillibacter, Ruminococcaceae_UCG-013, Lachnospiraceae_NK4A136_group and Akkermansia. In addition, Spearman's correlation analysis revealed that Desulfovibrio, Ruminococcaceae and Alloprevotella were closely correlated with biochemical biomarkers. Meanwhile, DFCL treatment regulated the expressions of genes involved in glucose metabolism at the mRNA and protein levels.


Intermixed medullary and papillary thyroid cancer in a patient with renal cell carcinoma.
We report a rare case of concurrent medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC) with intermixed disease in several of the lymph node (LN) metastases in a patient who was subsequently diagnosed with clear cell renal cell carcinoma (RCC). A 56 year old female presented with dysphagia and was found to have a left thyroid nodule and left superior cervical LN with suspicious sonographic features. Fine needle aspiration biopsy (FNAB) demonstrated PTC in the left thyroid nodule and MTC in the left cervical LN. Histopathology demonstrated multifocal PTC with 3/21 LNs positive for metastatic PTC. One LN in the left lateral neck dissection exhibited features of both MTC and PTC within the same node. In the right lobe, a 0.3 cm focus of MTC with extra-thyroidal extension was noted. Given persistent calcitonin elevation, a follow-up ultrasound displayed an abnormal left level 4 LN. FNAB showed features of both PTC and MTC on the cytopathology itself. The patient underwent repeat central and left radical neck dissection with 3/6 LNs positive for PTC in the central neck and 2/6 LNs positive for intermixed PTC and MTC in the left neck. There was no evidence of distant metastases on computed tomography and whole body scintigraphy, however a 1.9 x 2.5 cm enhancing mass within the right inter-polar kidney was discovered. This lesion was highly suspicious for RCC. Surgical pathology revealed a 2.5 cm clear cell RCC, Fuhrman grade 2/4, with negative surgical margins. She continues to be observed with stable imaging of her triple malignancies. Mixed medullary-papillary thyroid neoplasm is characterized by the presence of morphological and immunohistochemical features of both medullary and papillary thyroid cancers within the same lesion. Simultaneous occurrence of these carcinomas has been previously reported, but a mixed disease within the same lymph node is an infrequent phenomenon. Prognosis of mixed medullary-papillary thyroid carcinomas is determined by the medullary component. Therefore, when PTC and MTC occur concurrently, the priority should be given to the management of MTC, which involves total thyroidectomy and central lymph node dissection. Patients with thyroid cancer, predominantly PTC, have shown higher than expected rates of RCC. To our knowledge, this is the first report describing the combination of MTC, PTC, and RCC in a single patient.


Genome mining of astaxanthin biosynthetic genes from Sphingomonas sp. ATCC 55669 for heterologous overproduction in Escherichia coli.
As a highly valued keto-carotenoid, astaxanthin is widely used in nutritional supplements and pharmaceuticals. Therefore, the demand for biosynthetic astaxanthin and improved efficiency of astaxanthin biosynthesis has driven the investigation of metabolic engineering of native astaxanthin producers and heterologous hosts. However, microbial resources for astaxanthin are limited. In this study, we found that the α-Proteobacterium Sphingomonas sp. ATCC 55669 could produce astaxanthin naturally. We used whole-genome sequencing to identify the astaxanthin biosynthetic pathway using a combined PacBio-Illumina approach. The putative astaxanthin biosynthetic pathway in Sphingomonas sp. ATCC 55669 was predicted. For further confirmation, a high-efficiency targeted engineering carotenoid synthesis platform was constructed in E. coli for identifying the functional roles of candidate genes. All genes involved in astaxanthin biosynthesis showed discrete distributions on the chromosome. Moreover, the overexpression of exogenous E. coli idi in Sphingomonas sp. ATCC 55669 increased astaxanthin production by 5.4-fold. This study described a new astaxanthin producer and provided more biosynthesis components for bioengineering of astaxanthin in the future.


International palliative care research priorities: A systematic review.
There has been increasing evidence and debate on palliative care research priorities and the international research agenda. To date, however, there is a lack of synthesis of this evidence, examining commonalities, differences, and gaps. To identify and synthesize literature on international palliative care research priorities originating from Western countries mapped to a quality assessment framework. A systematic review of several academic and grey databases were searched from January 2008-June 2019 for studies eliciting research priorities in palliative care in English. Two researchers independently reviewed, critically appraised, and conducted data extraction and synthesis. The search yielded 10,235 articles (academic databases, n = 4108; grey literature, n = 6127), of which ten were included for appraisal and review. Priority areas were identified: service models; continuity of care; training and education; inequality; communication; living well and independently; and recognising family/carer needs and the importance of families. Methodological approaches and process of reporting varied. There was little representation of patient and caregiver driven agendas. The priorities were mapped to the Donabedian framework for assessing quality reflecting structure, process and outcomes and key priority areas. Limited evidence exists pertaining to research priorities across palliative care. Whilst a broad range of topics were elicited, approaches and samples varied questioning the credibility of findings. The voice of the care provider dominated, calling for more inclusive means to capture the patient and family voice. The findings of this study may serve as a template to understand the commonalities of research, identify gaps, and extend the palliative care research agenda.


Dissociation in the excretion of different aldosterone metabolites and unmetabolized ('free') aldosterone in hypertension.
1. The determination of aldosterone-18-glucuronide (pH 1-labile aldosterone) was complemented by concomitant measurements of free urinary aldosterone and tetrahydroaldosterone in 307 patients, most of whom were hypertensive. In 38 cases (12.3%) the normal, aldosterone-18-glucuronide concentration was clinically misleading, but increased free aldosterone and/or tetrahydroaldosterone values suggested the presence of hyperaldosteronism, which in many of these cases was confirmed by elevated excretion of the possible major aldosterone precursor 18-hydroxycorticosterone (18-OH-B). 2. Of 224 patients with essential hypertension and normal or low plasma renin activity 18 had an elevated free aldosterone and/or tetrahydroaldosterone excretion without increased aldosterone-18-glucuronide. These cases may represent early or pre-symptomatic forms of primary hyperaldosteronism. In other cases, particularly when tetrahydroaldosterone was increased alone, abnormalities of aldosterone metabolism were suspected. 3. In two out of 15 patients with primary hyperaldosteronism, aldosterone-18-glucuronide values were frequently found to be normal, although elevations were noted in other variables. However, no relation to the morphological abnormality (adenoma versus hyperplasia) was seen.


Improvement in hand grip strength in normal volunteers and rheumatoid arthritis patients following yoga training.
The present study aimed at assessing the effects of a set of yoga practices on normal adults (n = 37), children (n = 86), and patients with rheumatoid arthritis (n = 20). An equal number of normal adults, children, and patients with rheumatoid arthritis who did not practice yoga were studied under each category, forming respective control groups. Yoga and control group subjects were assessed at baseline and after varying intervals, as follows, adults after 30 days, children after 10 days and patients after 15 days, based on the duration of the yoga program, which they attended, which was already fixed. Hand grip strength of both hands, measured with a grip dynamometer, increased in normal adults and children, and in rheumatoid arthritis patients, following yoga, but not in the corresponding control groups, showing no re-test effect. Adult female volunteers and patients showed a greater percentage improvement than corresponding adult males. This gender-based difference was not observed in children. Hence yoga practice improves hand grip strength in normal persons and in patients with rheumatoid arthritis, though the magnitude of improvement varies with factors such as gender and age.


Prevalence and determinants of metabolic syndrome: a cross-sectional survey of general medical outpatient clinics using National Cholesterol Education Program-Adult Treatment Panel III criteria in Botswana.
Low- and middle-income countries, including Botswana, are facing rising prevalence of obesity and obesity-related cardiometabolic complications. Very little information is known about clustering of cardiovascular risk factors in the outpatient setting during routine visits. We aimed to assess the prevalence and identify the determinants of metabolic syndrome among the general outpatients' attendances in Botswana. A cross-sectional study was conducted from August to October 2014 involving outpatients aged ≥20 years without diagnosis of diabetes mellitus. A precoded questionnaire was used to collect data on participants' sociodemographics, risk factors, and anthropometric indices. Fasting blood samples were drawn and analyzed for glucose and lipid profile. Metabolic syndrome was assessed using National Cholesterol Education Program-Adult Treatment Panel III criteria. In total, 291 participants were analyzed, of whom 216 (74.2%) were females. The mean age of the total population was 50.1 (±11) years. The overall prevalence of metabolic syndrome was 27.1% (n=79), with no significant difference between the sexes (female =29.6%, males =20%, P=0.11). A triad of central obesity, low high-density lipoprotein-cholesterol, and elevated blood pressure constituted the largest proportion (38 [13.1%]) of cases of metabolic syndrome, followed by a combination of low high-density lipoprotein, elevated triglycerides, central obesity, and elevated blood pressure, with 17 (5.8%) cases. Independent determinants of metabolic syndrome were antihypertensive use and increased waist circumference. Metabolic syndrome is highly prevalent in the general medical outpatients clinics. Proactive approaches are needed to screen and manage cases targeting its most important predictors.


Life History Consequences of the Facultative Expression of a Dispersal Life Stage in the Phoretic Bulb Mite (Rhizoglyphus robini).
Life history traits play an important role in population dynamics and correlate, both positively and negatively, with dispersal in a wide range of taxa. Most invertebrate studies on trade-offs between life history traits and dispersal have focused on dispersal via flight, yet much less is known about how life history trade-offs influence species that disperse by other means. In this study, we identify effects of investing in dispersal morphology (dispersal expression) on life history traits in the male dimorphic bulb mite (Rhizoglyphus robini). This species has a facultative juvenile life stage (deutonymph) during which individuals can disperse by phoresy. Further, adult males are either fighters (which kill other mites) or benign scramblers. Here, in an experiment, we investigate the effects of investing in dispersal on size at maturity, sex and male morph ratio, and female lifetime reproductive success. We show that life history traits correlate negatively with the expression of the dispersal stage. Remarkably, all males that expressed the dispersal life stage developed into competitive fighters and none into scramblers. This suggests that alternative, male reproductive strategies and dispersal should not be viewed in isolation but considered concurrently.


International, multicentre, observational study of fluid bolus therapy in neonates.
To assess the prevalence, types and indications for fluid bolus therapy in neonates with haemodynamic compromise. This was a pragmatic, international, multicentre observational study in neonatal units across Australasia, Europe and North America with a predefined study period of 10-15 study days per participating neonatal unit between December 2015 and March 2017. Infants ≤28 days of age who received a fluid bolus for the management of haemodynamic compromise (≥10 mL/kg given at ≤6 h) were included. A total of 163 neonates received a bolus over 8479 eligible patient days in 41 neonatal units. Prevalence of fluid bolus therapy varied between centres from 0 to 28.6% of admitted neonates per day, with a pooled prevalence rate of 1.5% (95% confidence interval 1.1-1.9%). The most common fluid used was 0.9% sodium chloride (129/163; 79%), and the volume of fluid administered was most commonly 10 mL/kg (115/163; 71%) over a median of 30 min (interquartile range 20-60). The most frequent indications were hypotension (n = 56; 34%), poor perfusion (n = 20; 12%) and metabolic acidosis (n = 20; 12%). Minimal or no clinical improvement was reported by clinicians in 66 of 163 cases (40%). Wide international variations in types, indications and effects of fluid bolus administration in haemodynamically compromised neonates suggest uncertainty in the risk-benefit profile. This is likely to reflect the lack of robust evidence to support the efficacy of different fluid types, doses and appropriate indications. Together, these highlight a need for further clinically relevant studies.


Deciphering the plasma membrane hallmarks of apoptotic cells: phosphatidylserine transverse redistribution and calcium entry.
During apoptosis, Ca2+-dependent events participate in the regulation of intracellular and morphological changes including phosphatidylserine exposure in the exoplasmic leaflet of the cell plasma membrane. The occurrence of phosphatidylserine at the surface of specialized cells, such as platelets, is also essential for the assembly of the enzyme complexes of the blood coagulation cascade, as demonstrated by hemorrhages in Scott syndrome, an extremely rare genetic deficiency of phosphatidylserine externalization, without other apparent pathophysiologic consequences. We have recently reported a reduced capacitative Ca2+ entry in Scott cells which may be part of the Scott phenotype. Taking advantage of these mutant lymphoblastoid B cells, we have studied the relationship between this mode of Ca2+ entry and phosphatidylserine redistribution during apoptosis. Ca2+ ionophore induced apoptosis in Scott but not in control cells. However, inhibition of store-operated Ca2+ channels led to caspase-independent DNA fragmentation and decrease of mitochondrial membrane potential in both control and Scott cells. Inhibition of cytochrome P450 also reduced capacitative Ca2+ entry and induced apoptosis at comparable extents in control and Scott cells. During the apoptotic process, both control and more markedly Scott cells externalized phosphatidylserine, but in the latter, this membrane feature was however dissociated from several other intracellular changes. The present results suggest that different mechanisms account for phosphatidylserine transmembrane migration in cells undergoing stimulation and programmed death. These observations testify to the plasticity of the plasma membrane remodeling process, allowing normal apoptosis even when less fundamental functions are defective.


Unlocking the bottleneck in forward genetics using whole-genome sequencing and identity by descent to isolate causative mutations.
Forward genetics screens with N-ethyl-N-nitrosourea (ENU) provide a powerful way to illuminate gene function and generate mouse models of human disease; however, the identification of causative mutations remains a limiting step. Current strategies depend on conventional mapping, so the propagation of affected mice requires non-lethal screens; accurate tracking of phenotypes through pedigrees is complex and uncertain; out-crossing can introduce unexpected modifiers; and Sanger sequencing of candidate genes is inefficient. Here we show how these problems can be efficiently overcome using whole-genome sequencing (WGS) to detect the ENU mutations and then identify regions that are identical by descent (IBD) in multiple affected mice. In this strategy, we use a modification of the Lander-Green algorithm to isolate causative recessive and dominant mutations, even at low coverage, on a pure strain background. Analysis of the IBD regions also allows us to calculate the ENU mutation rate (1.54 mutations per Mb) and to model future strategies for genetic screens in mice. The introduction of this approach will accelerate the discovery of causal variants, permit broader and more informative lethal screens to be used, reduce animal costs, and herald a new era for ENU mutagenesis.


Palliative terminal cancer care in community hospitals and a hospice: a comparative study.
Despite palliative care being an accepted role of community hospitals, there is little quantitative evidence of the type of care provided. To obtain quantitative data comparing palliative cancer care provided in 12 community hospitals in 10 towns (approximately 350 medical beds) and in a consultant-led purpose-built hospice (12 beds). Retrospective medical and nursing case note analysis over one year of cancer deaths in the former Exeter Health District. A total of 171 community hospital and 116 hospice casenotes were analysed. Hospice patients had significantly different reasons for admission compared with community hospital patients (P < 0.001), with pain and symptom control being more frequent and terminal nursing care less frequent reasons for admission to the hospice. Community hospital length of stay was significantly longer than hospice length of stay (P = 0.002; mean community hospital stay 16 days, mean hospice stay eight days). Symptoms on admission differed significantly. Drug prescribing on admission and at death and indications of active treatment of symptoms were broadly similar. Community hospital patients received more investigations than hospice patients, linked to the observation that around one in ten community hospital patients were admitted for investigation and active treatment. Community hospital medical notes were significantly less likely to meet minimum quality standards than were hospice notes (81/171 vs. 18/116; P < 0.001), with major deficiencies in the areas of examination, progress reporting, and absence of confirmation of death. This study confirms the role of community hospitals in palliative terminal cancer care. Differences in care between community hospitals and a hospice have been demonstrated that may reflect either different admission populations to each setting or differences in the way care was delivered.


Invasive dental treatment and risk for vascular events: a self-controlled case series.
Treatment of periodontal disease may reduce cardiovascular risk in the longer term, but studies have suggested a link among dental procedures, acute inflammation, and endothelial dysfunction. However, whether such acute inflammatory effects translate into a short-lived increased risk for vascular events is not known. To investigate whether invasive dental treatment transiently increases the risk for vascular events. Self-controlled case series. Data came from the U.S. Medicaid claims database. All persons exposed to invasive dental treatment with a primary hospital discharge diagnosis of ischemic stroke (n = 650) or myocardial infarction (n = 525) from 2002 to 2006. The incidence of ischemic stroke and myocardial infarction in periods immediately after invasive dental treatment was compared with the incidence in all other observed time periods. Incidence ratios and 95% CIs were calculated. The rate of vascular events significantly increased in the first 4 weeks after invasive dental treatment (incidence ratio, 1.50 [95% CI, 1.09 to 2.06]) and gradually returned to the baseline rate within 6 months. The positive association remained after exclusion of persons with diabetes, hypertension, or coronary artery disease or persons with prescriptions for antiplatelet or salicylate drugs before treatment. Power to examine the effects of invasive dental treatment on stroke and myocardial infarction separately was limited because of the low frequency of invasive dental procedures. Lack of information about use of over-the-counter drugs limited the ability to assess confounding by possible withholding of antiplatelet or salicylate drugs before invasive dental treatment or by the use of nonsteroidal anti-inflammatory drugs after treatment. Invasive dental treatment may be associated with a transient increase in the risk for vascular events. However, the absolute risks are minimal, and the long-term benefits on vascular health will probably outweigh the short-lived adverse effects.


Kinesiological and kinematical analysis for stroke subjects with asymmetrical cycling movement patterns.
This aim of this study is to provide quantitative analyses of asymmetrical movements between affected and unaffected limbs for hemiparetic subjects in a cycling ergometer. To acquire kinesiological and kinematical data, electromyography (EMG) of quadriceps muscles in the both legs as well as crank positions under three cycling workloads were recorded. The symmetry index (SI) was designed to measure the similarity between muscle activities recorded from affected and unaffected limbs. Using kinematical information of the crank position, the cycling unsmoothness (denoted as roughness index, RI) can be derived from the curvature of the instantaneous cycling speed. Thirteen hemiparetic subjects following a cerebrovascular accident (CVA) and eight able-bodied subjects participated in this study. With total symmetry at SI=1, the average SIs of hemiparetic subjects (0.66+/-0.18) were significantly lower (p<0.01) than those of normal subjects (0.91+/-0.08) but no significant difference found among three workloads. From the average RI, subjects with hemiparesis exhibited less smooth cycling movements compared to normal group (p<0.01). Non-parametric Friedman and Wilcoxon tests of RIs further indicated that the workload factors are significantly different only for hemiparetic group (p<0.01). No significant difference between lower workloads in RIs showed that the CVA subjects' sound side alone can execute most of the cycling load with minimal involvement of the affected side under lower workload condition. When cycling at a heavier load, however, it is essential to force the affected limb to assist in the pedaling, thus accomplishing an effective cycling exercise. By combining these two quantitative indices, we can observe the kinesiological measurement of the symmetry of EMG phasic activities from SI and the kinematical cycling smoothness in a coordinated movement from RI, which could provide a clinical guideline for cycling exercises for hemiparetic subjects.


Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke.
Recombinant tissue-type plasminogen activator (rt-PA) improves outcomes for patients with acute ischemic stroke, but current approved use is limited to within 3 hours of symptom onset. This restricts the number of patients who can be treated, since most stroke patients present more than 3 hours after symptom onset. To test the efficacy and safety of rt-PA in patients with acute ischemic stroke when administered between 3 and 5 hours after symptom onset. The Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study is a phase 3, placebo-controlled, double-blind randomized study conducted between December 1993 and July 1998, with up to 90 days of follow-up. One hundred forty university and community hospitals in North America. An intent-to-treat population of 613 acute ischemic stroke patients was enrolled, with 547 of these treated as assigned within 3 to 5 hours of symptom onset. A total of 39 others were treated within 3 hours of symptom onset, 24 were treated more than 5 hours after symptom onset, and 3 never received any study drug. Administration of 0.9 mg/kg of rt-PA (n = 272) or placebo (n = 275) intravenously over 1 hour. Primary efficacy was an excellent neurologic recovery at day 90 (National Institutes of Health Stroke Scale [NIHSS] score of < or =1); secondary end points included excellent recovery on functional outcome measures (Barthel index, modified Rankin scale, and Glasgow Outcome Scale) at days 30 and 90. Serious adverse events were also assessed. In the target population, 32% of the placebo and 34% of rt-PA patients had an excellent recovery at 90 days (P = .65). There were no differences on any of the secondary functional outcome measures. In the first 10 days treatment with rt-PA significantly increased the rate of symptomatic intracerebral hemorrhage (ICH) (1.1% vs 7.0% [P<.001]), a symptomatic ICH (4.7% vs 11.4% [P = .004]), and fatal ICH (0.3% vs 3.0% [P<.001]). Mortality at 90 days was 6.9% with placebo and 11.0% with rt-PA (P = .09). Results in the intent-to-treat population were similar. This study found no significant rt-PA benefit on the 90-day efficacy end points in patients treated between 3 and 5 hours. The risk of symptomatic ICH increased with rt-PA treatment. These results do not support the use of intravenous rt-PA for stroke treatment beyond 3 hours.


An international comparison of retinopathy of prematurity grading performance within the Benefits of Oxygen Saturation Targeting II trials.
PurposeTo investigate whether the observed international differences in retinopathy of prematurity (ROP) treatment rates within the Benefits of Oxygen Saturation Targeting (BOOST) II trials might have been caused by international variation in ROP disease grading.MethodsGroups of BOOST II trial ophthalmologists in UK, Australia, and New Zealand (ANZ), and an international reference group (INT) used a web based system to grade a selection of RetCam images of ROP acquired during the BOOST II UK trial. Rates of decisions to treat, plus disease grading, ROP stage grading, ROP zone grading, inter-observer variation within groups and intra-observer variation within groups were measured.ResultsForty-two eye examinations were graded. UK ophthalmologists diagnosed treat-requiring ROP more frequently than ANZ ophthalmologists, 13.9 (3.49) compared to 9.4 (4.46) eye examinations, P=0.038. UK ophthalmologists diagnosed plus disease more frequently than ANZ ophthalmologists, 14.1 (6.23) compared to 8.5 (3.24) eye examinations, P=0.021. ANZ ophthalmologists diagnosed stage 2 ROP more frequently than UK ophthalmologists, 20.2 (5.8) compared to 12.7 (7.1) eye examinations, P=0.026. There were no other significant differences in the grading of ROP stage or zone. Inter-observer variation was higher within the UK group than within the ANZ group. Intra-observer variation was low in both groups.ConclusionsWe have found evidence of international variation in the diagnosis of treatment-requiring ROP. Improved standardisation of the diagnosis of treatment-requiring ROP is required. Measures might include improved training in the grading of ROP, using an international approach, and further development of ROP image analysis software.


N-acetylaspartate catabolism determines cytosolic acetyl-CoA levels and histone acetylation in brown adipocytes.
Histone acetylation depends on the abundance of nucleo-cytoplasmic acetyl-CoA. Here, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. N-acetylaspartate (NAA) is a highly abundant brain metabolite catabolized by aspartoacylase yielding aspartate and acetate. The latter can be further used for acetyl-CoA production. Prior to this work, the presence of NAA has not been described in adipocytes. Here, we show that accumulation of NAA decreases the brown adipocyte phenotype. We increased intracellular NAA concentrations in brown adipocytes via media supplementation or knock-down of aspartoacylase and measured reduced lipolysis, thermogenic gene expression, and oxygen consumption. Combinations of approaches to increase intracellular NAA levels showed additive effects on lipolysis and gene repression, nearly abolishing the expression of Ucp1, Cidea, Prdm16, and Ppara. Transcriptome analyses of aspartoacylase knock-down cells indicate deficiencies in acetyl-CoA and lipid metabolism. Concordantly, cytoplasmic acetyl-CoA levels and global histone H3 acetylation were decreased. Further, activating histone marks (H3K27ac and H3K9ac) in promoters/enhancers of brown marker genes showed reduced acetylation status. Taken together, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. Thereby, we mechanistically connect the NAA pathway to the epigenomic regulation of gene expression, modulating the phenotype of brown adipocytes.


Immunological properties of the primer-independent glucosyltransferase of Streptococcus mutans serotypes d and g.
Streptococcus mutans serotype g secretes at least three kinds of glucosyltransferase with different enzymological and immunological properties. One of them is a primer-independent enzyme and seems to be the source of primer for the others, both of which are primer-dependent enzymes. Recently, we purified the primer-independent enzyme, the third glucosyltransferase in this group from S. mutans strain AHT-k serotype g. In the present study, we examined the specificity of the antiserum against the primer-independent glucosyltransferase using extracellular culture-conditioned fluids of many strains of the various serotypes of S. mutans. The antiserum cross-reacted with the extracellular culture fluids from strains of serotypes d and a, in addition to serotype g, but not with those of other serotypes, indicating that the primer-independent glucosyltransferase is secreted by the S. sobrinus and S. cricetus, but not by S. mutans and S. rattus. The antiserum did not completely inhibit the activity of the enzyme, even at more than twofold antibody excess, determined by indirect precipitation with immobilized staphylococcal protein A.


Functional aspects of apoptosis in hematopoiesis and consequences of failure.
Apoptosis is an internally directed, physiological method of cell destruction. Cellular components are dismantled within the confines of an intact cell membrane, and rapid ingestion by phagocytic cells prevents local inflammation. A variety of genes have now been identified as positive or negative regulators of apoptosis. Transfection experiments and studies of gene cooperation in viral transformation suggest that full cellular transformation requires not only the deregulation of proliferation, but also the inhibition of concomitant apoptosis programs. The regulation of apoptosis is fundamental to hematopoietic homeostasis. Stem cell renewal is continuously counterbalanced by apoptosis in functionally inactive or terminally differentiated cells. Extensive cell death in developing lymphocyte populations ensures that only cells recognizing non-self antigens are released into the periphery, and the finite lifespan of terminally differentiated cells enables the extensive cell turnover demanded by functional aspects of the hematopoietic system. The requirement of each hematopoietic sub-population for a specific sub-set of survival factors, provides a flexible mechanism for dictating the cellular composition of the mature population and for controlling population size. Surplus cell production and apoptosis are therefore normal features of hematopoiesis. The consequences of deregulated apoptosis are severe. Excessive apoptosis in lymphocyte populations plays a major role in the pathogenesis of acquired immunodeficiency syndrome (AIDS), whereas ineffective apoptosis has been associated with the development of inflammation, autoimmunity and hematological malignancies. The identification of various genetic abnormalities which influence apoptosis in leukaemic cells (e.g., mutant p53, Bcr-Abl and over-expression of Bcl-2), suggests that the acquisition of an anti-apoptotic lesions is an important event in the multi-step evolution of hematological malignancies. In addition, the nature of some leukaemias particularly the chronic leukemias, in which the leukemic cells are nonproliferative and long lived, suggests that anti-apoptotic lesions are early events in the pathogenesis of these diseases. It is likely that the utilization of mechanisms to evade apoptosis would facilitate disease progression in all leukemias and contribute to the development of multi-drug resistance. A better understanding of apoptosis mechanisms in hematopoietic cells, and their exploitation by leukemic cells should be useful in the development of improved cytotoxic regimes.


Thyroid hormone transporter genes and grey matter changes in patients with major depressive disorder and healthy controls.
Several studies have established links between thyroid gland dysfunction and mood disorders, in particular major depressive disorder (MDD). Preliminary evidence also suggests that thyroid hormone gene variants influence grey matter (GM) volume, which is reportedly altered in patients with MDD. This study tested for associations of single nucleotide polymorphisms (SNPs) in two thyroid hormone transporter genes with regional GM volume differences in a large sample population of patients with recurrent MDD and healthy volunteers. High-resolution T1-weighted magnetic resonance images were acquired at the Max Planck Institute, Munich, Germany. After quality control procedures were applied to images and genotypes, data for 134 patients and 144 well-matched controls were included in a stringent voxel-based morphometry analysis using non-stationary cluster-based inference. We first tested for associations between 10 candidate SNPs and regional GM volume differences across the combined sample population. We then tested for group-by-genotype interactions (i.e., differential associations determined by group status). No significant associations were found between SNPs and regional GM volume when testing across the combined sample population. However, group-by-genotype interactions for two highly correlated SNPs (rs496549 and rs479640) revealed co-localised association clusters in the left occipital cortex (P-values 0.002 and 0.004, respectively, after full correction for whole brain and multiple SNP testing). The effect magnitudes within the average modulated GM clusters were greater in the control group relative to the MDD group. This study provides supporting evidence to the existing literature that thyroid-related gene variants influence regional GM volume. We propose that future studies should consider neuroimaging phenotypes when investigating the effects of thyroid hormones on brain structure and function.


Associations of eHealth Literacy With Health Behavior Among Adult Internet Users.
In the rapidly developing use of the Internet in society, eHealth literacy-having the skills to utilize health information on the Internet-has become an important prerequisite for promoting healthy behavior. However, little is known about whether eHealth literacy is associated with health behavior in a representative sample of adult Internet users. The aim of this study was to examine the association between eHealth literacy and general health behavior (cigarette smoking, physical exercise, alcohol consumption, sleeping hours, eating breakfast, eating between meals, and balanced nutrition) among adult Internet users in Japan. The participants were recruited among registrants of a Japanese Internet research service company and asked to answer a cross-sectional Internet-based survey in 2012. The potential respondents (N=10,178) were randomly and blindly invited via email from the registrants in accordance with the set sample size and other attributes. eHealth literacy was assessed using the Japanese version of the eHealth Literacy Scale. The self-reported health behaviors investigated included never smoking cigarettes, physical exercise, alcohol consumption, sleeping hours, eating breakfast, not eating between meals, and balanced nutrition. We obtained details of sociodemographic attributes (sex, age, marital status, educational attainment, and household income level) and frequency of conducting Internet searches. To determine the association of each health behavior with eHealth literacy, we performed a logistic regression analysis; we adjusted for sociodemographic attributes and frequency of Internet searching as well as for other health behaviors that were statistically significant with respect to eHealth literacy in univariate analyses. We analyzed the data of 2115 adults (response rate: 24.04%, 2142/10,178; male: 49.74%, 1052/2115; age: mean 39.7, SD 10.9 years) who responded to the survey. Logistic regression analysis showed that individuals with high eHealth literacy were significantly more likely to exhibit the good health behaviors of physical exercise (adjusted odds ratio [AOR] 1.377, 95% CI 1.131-1.678) and eating a balanced diet (AOR 1.572, 95% CI 1.274-1.940) than individuals with low eHealth literacy. We found that some health behaviors, including exercise and balanced nutrition, were independently associated with eHealth literacy among Japanese adult Internet users.


Identification of hepatitis B virus-specific CTL epitopes presented by HLA-A*33:03 in peripheral blood mononuclear cells from patients and transgenic mice.
Cytotoxic T lymphocyte (CTL) epitopes in the HBV protein of hepatitis B virus (HBV) may play a key role in viral control and liver damage. The aim of this study was to identify and study the function of HLA-A(∗)33:03-restricted CTL epitopes in HBV protein of the HBV genotypes B and C, which are epidemic in China. Sixteen HBV peptides were predicated by computational analysis, and synthesized peptides were examined for their affinity to HLA-A(∗)33:03 using a stable cell line. After being analyzed by enzyme-linked immunospot and cytolytic activity assays, as well as the tetramers staining method using peripheral blood mononuclear cells isolated from HBV-infected patients, five peptides (Hbs245-253, HBs335-343, HBc119-127, HBc104-112, and HBp391-399) were chosen to further confirm their HLA_A(∗)33:03 restriction in transgenic mice.


Presence of brain pathology in deceased subjects with and without chronic obstructive pulmonary disease.
Patients with chronic obstructive pulmonary disease (COPD) have extrapulmonary co-morbidities, such as cardiovascular disease, musculoskeletal wasting and neuropsychological conditions. To date, it remains unknown whether and to what extent COPD is associated with a higher prevalence of brain pathology. Therefore, the aim of this retrospective study was to compare the prevalence of neuropathological brain changes between deceased donors with and without COPD. Brain autopsy reports of age-matched donors with (n = 89) and without COPD (n = 89) from the Netherlands Brain Bank were assessed for demographics, cause of death, co-morbidities and brain pathology. The prevalence of degenerative brain changes was comparable for donors with and without COPD (50.6% vs. 61.8%, p > 0.05). Neoplastic brain changes were reported in a minority of the donors (5.6% vs. 10.1%, p > 0.05). After correction for cerebrovascular accident or cardiac cause of death and Charlson co-morbidity index score, the prevalence of vascular brain changes was higher among control versus COPD donors (27.0% vs. 11.2%, adjusted p = 0.013, odds ratio = 2.98). Brain autopsy reports of donors with and without COPD did not reveal differences in the presence of degenerative or neoplastic brain changes. Vascular brain changes were described more often in controls. Prospective studies including spirometry and structural and functional brain imaging should corroborate our findings.


The maintenance gap: a new theoretical perspective on the evolution of aging.
One of the prevailing theories of aging, the disposable soma theory, views aging as the result of the accumulation of damage through imperfect maintenance. Aging, then, is explained from an evolutionary perspective by asserting that this lack of maintenance exists because the required resources are better invested in reproduction. However, the amount of maintenance necessary to prevent aging, 'maintenance requirement' has so far been largely neglected and has certainly not been considered from an evolutionary perspective. To our knowledge we are the first to do so, and arrive at the conclusion that all maintenance requirement needs an evolutionary explanation. Increases in maintenance requirement can only be selected for if these are linked with either higher fecundity or better capabilities to cope with environmental challenges to the integrity of the organism. Several observations are suggestive of the latter kind of trade-off, the existence of which leads to the inevitable conclusion that the level of maintenance requirement is in principle unbound. Even the allocation of all available resources to maintenance could be unable to stop aging in some organisms. This has major implications for our understanding of the aging process on both the evolutionary and the mechanistic level. It means that the expected effect of measures to reallocate resources to maintenance from reproduction may be small in some species. We need to have an idea of how much maintenance is necessary in the first place. Our explorations of how natural selection is expected to act on the maintenance requirement provides the first step in understanding this.


[Fast tests in bacteriology].
Advances in biotechnologies and miniaturization over the past few decades have led to an explosion in the number of rapid tests in in vitro diagnosis and explain their ever-growing presence in international markets. Although based on classic immunological and biochemical methods, these tests deliver many more benefits for laboratories. They are rapid and simple to perform, provide results rapidly and can be performed in remote laboratories, making them invaluable for both routine and emergency analyses. As beneficial as they may be, however, they still have a long way to go before they find widespread use in infectious disease control. Currently, rapid testing methods are used only to screen for urinary tract infections, monitor certain infectious parameters and make more accurate diagnosis of a still small number of species of bacteria. This narrow catalogue of available tests is yet another disadvantage in a list of drawbacks typically associated with rapid tests. A good portion of complaints centers on the fact that they are still too recent to have sufficient information on their levels of sensitivity and reliability. Furthermore, regulations, in particularly concerning accountability, remain to be established. Nevertheless, constant innovation coupled with the experience of laboratory professionals in the field should open the way for rapid testing to earn its place in the line-up of medical laboratory tests.


A framework for developing research protocols for evaluation of microbial hazards and controls during production that pertain to the application of untreated soil amendments of animal origin on land used to grow produce that may be consumed raw.
Application of manure or soil amendments of animal origin (untreated soil amendments; UTSAs) to agricultural land has been a long-standing practice to maintain or improve soil quality through addition of organic matter, nitrogen, and phosphorus. Much smaller quantities of these types of UTSAs are applied to land used for food crops than to land used for animal grain and forage. UTSAs can harbor zoonotic enteric pathogens that may survive for extended periods after application. Additional studies are needed to enhance our understanding of preharvest microbial food safety hazards and control measures pertaining to the application of UTSAs especially for land used to grow produce that may be consumed raw. This document is intended to provide an approach to study design and a framework for defining the scope and type of data required. This document also provides a tool for evaluating the strength of existing data and thus can aid the produce industry and regulatory authorities in identifying additional research needs. Ultimately, this framework provides a means by which researchers can increase consistency among and between studies and facilitates direct comparison of hazards and efficacy of controls applied to different regions, conditions, and practices.


Effects of combined genes of CTLA4Ig and IDO in post-liver transplantation immune tolerance of rats.
Background and rationale for the study. Previous studies showed that CTLA4Ig and indoleamine 2,3-dioxygenase (IDO) genes played regulatory role in organ transplantation but failed to reach satisfactory effects. In this study, we constructed an adenovirus- mediated gene expressing CTLA4Ig-IDO and established rat liver transplantation models. Recipients were randomly divided into four groups of 10 rats each. During the operation, CTLA4Ig, IDO, and CTLA4Ig-IDO genes, as well as a blank plasmid, were infused into different rat groups via portal vein to determine their effects on inducing immune tolerance. Survival rate of recipients, histological changes of graft liver, post-transplantation liver function, and cytokine levels were observed at day 14 after operation. Serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and total bilirubin level (TBIL) in the CTLA4Ig-IDO group were lower than those in the other three groups at 14 days post-transplantation (P < 0.05); mRNA and protein expressions of IL-2 and IFN-γ were higher in the control group, but lower in the CTLA4Ig-IDO group (P < 0.05). By contrast, expressions of IL-4, TGF-b, IL-10, and T lymphocyte apoptosis were higher in the CTLA4Ig-IDO group than those in the other three groups (P < 0.05). The CTLA4Ig-IDO group exhibited mild acute rejection and higher survival rate compared with the other groups (P < 0.05). Compared with using CTLA4Ig or IDO alone, combined transfection of CTLA4Ig-IDO was more effective in inducing immune tolerance after liver transplantation.


Applying dimension reduction to EEG data by Principal Component Analysis reduces the quality of its subsequent Independent Component decomposition.
Independent Component Analysis (ICA) has proven to be an effective data driven method for analyzing EEG data, separating signals from temporally and functionally independent brain and non-brain source processes and thereby increasing their definition. Dimension reduction by Principal Component Analysis (PCA) has often been recommended before ICA decomposition of EEG data, both to minimize the amount of required data and computation time. Here we compared ICA decompositions of fourteen 72-channel single subject EEG data sets obtained (i) after applying preliminary dimension reduction by PCA, (ii) after applying no such dimension reduction, or else (iii) applying PCA only. Reducing the data rank by PCA (even to remove only 1% of data variance) adversely affected both the numbers of dipolar independent components (ICs) and their stability under repeated decomposition. For example, decomposing a principal subspace retaining 95% of original data variance reduced the mean number of recovered 'dipolar' ICs from 30 to 10 per data set and reduced median IC stability from 90% to 76%. PCA rank reduction also decreased the numbers of near-equivalent ICs across subjects. For instance, decomposing a principal subspace retaining 95% of data variance reduced the number of subjects represented in an IC cluster accounting for frontal midline theta activity from 11 to 5. PCA rank reduction also increased uncertainty in the equivalent dipole positions and spectra of the IC brain effective sources. These results suggest that when applying ICA decomposition to EEG data, PCA rank reduction should best be avoided.


Surface structure, model and mechanism of an insect integument adapted to be damaged easily.
BACKGROUND: Several sawfly larvae of the Tenthredinidae (Hymenoptera) are called easy bleeders because their whole body integument, except the head capsule, disrupts very easily at a given spot, under a slight mechanical stress at this spot. The exuding haemolymph droplet acts as a feeding deterrent towards invertebrate predators. The present study aimed to describe the cuticle surface, to consider it from a mechanistic point of view, and to discuss potential consequences of the integument surface in the predator-prey relationships. RESULTS: The integument surface of sawfly larvae was investigated by light microscopy (LM) and scanning electron microscopy (SEM) which revealed that the cuticle of easy bleeders was densely covered by what we call "spider-like" microstructures. Such microstructures were not detected in non-easy bleeders. A model by finite elements of the cuticle layer was developed to get an insight into the potential function of the microstructures during easy bleeding. Cuticle parameters (i.e., size of the microstructures and thickness of the epi-versus procuticle) were measured on integument sections and used in the model. A shear force applied on the modelled cuticle surface led to higher stress values when microstructures were present, as compared to a plan surface. Furthermore, by measuring the diameter of a water droplet deposited on sawfly larvae, the integument of several sawfly species was determined as hydrophobic (e.g., more than Teflon(R)), which was related to the sawfly larvae's ability to bleed easily. CONCLUSION: Easy bleeders show spider-like microstructures on their cuticle surface. It is suggested that these microstructures may facilitate integument disruption as well as render the integument hydrophobic. This latter property would allow the exuding haemolymph to be maintained as a droplet at the integument surface.


Early warning of EUSIG-defined hypotensive events using a Bayesian Artificial Neural Network.
Hypotension is recognized as a potentially damaging secondary insult after traumatic brain injury. Systems to give clinical teams some early warning of likely hypotensive instability could be added to the range of existing techniques used in the management of this group of patients. By using the Edinburgh University Secondary Insult Grades (EUSIG) definitions for -hypotension (systolic arterial pressure <90 mmHg OR mean arterial -pressure <70 mmHg) we collected a group of ∼2,000 events by analyzing the Brain-IT database. We then constructed a Bayesian Artificial Neural Network (an advanced statistical modeling technique) that is able to provide some early warning when trained on this previously collected demographic and physiological data. Using EUSIG defined event data from the Brain-IT database, we identified a Bayesian artificial neural network (BANN) topology and constructed a series of datasets using a group of clinically guided input variables. This allowed us to train a BANN, which was then tested on an unseen set of patients from the Brain-IT database. The initial tests used a particularly harsh assessment criterion whereby a true positive prediction was only allowed if the BANN predicted an upcoming event to the exact minute. We have now developed the system to the point where it is about to be used in a two-stage Phase II clinical trial and we are also researching a more realistic assessment technique. We have constructed a BANN that is able to provide early warning to the clinicians based on a model that uses information from the physiological inputs; systolic and mean arterial pressure and heart rate; and demographic variables age and gender. We use 15-min SubWindows starting at 15 and 30 min before an event and process mean, slope and standard deviations. Based on 10 simulation runs, our current sensitivity is 36.25% (SE 1.31) with a specificity of 90.82% (SE 0.85). Initial results from a Phase I clinical study shows a model sensitivity of 40.95% (SE 6%) and specificity of 86.46% (SE 3%) Although this figure is low it is considered clinically useful for this dangerous condition, provided the false positive rate can be kept sufficiently low as to be practical in an intensive care environment. We have shown that using advanced statistical modeling techniques can provide clinical teams with useful information that will assist clinical care.


Characterising the smoking status and quit smoking behaviour of aboriginal health workers in South Australia.
The study objectives were to characterise the smoking status and quit smoking behaviour of Aboriginal Health Workers (AHWs) in South Australia (SA), Australia; and identify the psychosocial, socio-demographic, and household smoking characteristics that distinguish smokers from quitters and never smokers. A self-reported cross-sectional survey was completed by AHWs in SA. Non-parametric statistics were used for inferential analyses. Eighty-five AHWs completed surveys representing a response rate of 63.0%. The prevalence of current smokers was 50.6%. Non-smokers (49.5%) included quitters (22.4%) and never smokers (27.1%). Smoking status did not differ by gender or geographic location. Of current smokers, 69.0% demonstrated a readiness to quit and 50.0% had made at least one quit attempt in the last 12 months. Compared to quitters and never smokers, current smokers expressed lower emotional wellbeing, and three times as many resided with another smoker. Quitters had the highest levels of perceived social support and part-time employment. A high proportion of AHWs who smoke desire, and are ready to quit. Individual, social and household factors differentiated smokers from non-smokers and quitters. Social support, and relationships and structures that favour social support, are implicated as necessary to enable AHWs who smoke to act on their desire to quit smoking.


Comment on "Erosion of lizard diversity by climate change and altered thermal niches".
Using a regionally calibrated model, Sinervo et al. (Reports, 14 May 2010, p. 894) predicted potential climate change impacts on lizard populations and estimated that many extinctions are under way. We argue that this model is not sufficient for predicting global losses in lizard species in response to anthropogenic climate change.


Lunar sample 14425: characterization and resemblance to high-magnesium microtektites.
Measurements by energy-dispersive x-ray analysis of the surface of lunar sample 14425, a large glass bead, yield a noritic composition enriched in aluminum and magnesium and, as compared with other norites, depleted in iron and especially calcium. The sample is close in composition to the most basic microtektites. Spherical inclusions of nickel-iron, flattened where they protrude, are found to be enriched in sulfur and phosphorus, at least at the surface. The inclusions form approximately 1 percent of the volume.


Treatment Outcome in Male Gambling Disorder Patients Associated with Alcohol Use.
The primary objective of this study was to analyze the association between alcohol consumption and short-term response to treatment (post intervention) in male patients with gambling disorder enrolled in a group cognitive behavioral therapy (CBT) program. The sample consisted of 111 male individuals with a diagnosis of Gambling Disorder, with a mean age of 45 years (SD = 12.2). All participants were evaluated by a comprehensive assessment battery and assigned to CBT groups of 10-14 patients attending 16 weekly outpatient sessions lasting 90 min each. The highest mean pre- and post-therapy differences were recorded for the alcohol risk/dependence group on the obsessive/compulsive and anxiety dimensions of the SCL-90-R. As regards the presence of relapses and dropouts over the course of the CBT sessions, the results show a significant association with moderate effect size: patients with risk consumption or alcohol dependence were more likely to present poor treatment outcomes. Alcohol abuse was frequent in GD, especially in patients with low family income and high accumulated debts. High levels of somatization and high overall psychopathology (measured by the SCL-90-R) were associated with increased risk of alcohol abuse. Alcohol abuse was also associated with poor response to treatment.


Sensory Polyneuropathies.
This article describes the methods of diagnosis and management of the sensory-predominant polyneuropathies. To simplify the approach to this category of patients, sensory-predominant polyneuropathies are divided broadly into either small fiber (or pain-predominant) neuropathies and large fiber (or ataxia-predominant) neuropathies, of which the sensory neuronopathies (dorsal root ganglionopathies) are highlighted. Physicians can now easily perform skin biopsies in their offices, allowing access to the gold standard pathologic diagnostic tool for small fiber neuropathies. Additional diagnostic techniques, such as corneal confocal microscopy, are emerging. Recently, small fiber neuropathies have been associated with a broader spectrum of diseases, including fibromyalgia, sodium channel mutations, and voltage-gated potassium channel antibody autoimmune disease. Despite advances in diagnosing small fiber neuropathies and sensory neuronopathies, many of these neuropathies remain refractory to treatment. In select cases, early identification and treatment may result in better outcomes. "Idiopathic" should be a diagnosis of exclusion and a thorough investigation for treatable causes pursued.


JTP-4819: a novel prolyl endopeptidase inhibitor with potential as a cognitive enhancer.
JTP-4819 ((S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N- phenylmethyl)-1-pyrrolidinecarboxamide) is a potent (IC50: 0.83 +/- 0.09 nM in rat brain supernatant; 5.43 +/- 0.81 nM in Flavobacterium meningosepticum) and specific inhibitor of prolyl endopeptidase (PEP). JTP-4819 (3 mg/kg p.o.) exhibited a strong and durable ex vivo inhibitory effect on PEP in various regions of the rat brain. In addition, JTP-4819 inhibited the degradation of substance P, arginine-vasopressin, thyrotropin-releasing hormone, neurotensin, oxytocin, bradykinin, and angiotensin II by purified PEP with IC50 values of 9.6, 13.9, 10.7, 14.0, 4.5, 7.6 and 10.6 nM, respectively. In the one-trial passive avoidance test in rats with scopolamine-induced amnesia, JTP-4819 significantly prolonged the retention time when administered orally at doses of 1 and 3 mg/kg 1 hr before acquisition or at 3 and 10 mg/kg 1 hr before retention. In addition, coadministration of JTP-4819 and substance P, arginine-vasopressin or thyrotropin-releasing hormone (at doses at which each drug alone did not prolong the retention time) improved the retention time of rats with scopolamine-induced amnesia. Microdialysis studies demonstrated that JTP-4819 caused a significant increase in ACh release in the frontal cortex and hippocampus of young rats at oral doses of 1 and 3 mg/kg, as well as in both brain regions of aged rats at a dose of 3 mg/kg. These results indicate that JTP-4819 potentiates neuropeptide functions inhibiting PEP, that it activates cholinergic transmission and that it enhances learning and memory.


D-limonene suppresses doxorubicin-induced oxidative stress and inflammation via repression of COX-2, iNOS, and NFκB in kidneys of Wistar rats.
D-limonene is a naturally occurring monoterpene and has been found to posses numerous therapeutic properties. In this study, we used D-limonene as a protective agent against the nephrotoxic effects of anticancer drug doxorubicin (Dox). Rats were given D-limonene at doses of 5% and 10% mixed with diet for 20 consecutive days. Dox was give at the dose of 20 mg/kg body weight intraperitoneally. The protective effects of D-limonene on Dox-induced oxidative stress and inflammation were investigated by assaying oxidative stress biomarkers, lipid peroxidation, serum toxicity markers, proinflammatory cytokines, and expression of nuclear factor kappa B (NFκB), cyclo-oxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and Nitrite levels. Administration of Dox (20 mg/kg body weight) in rats enhanced renal lipid peroxidation; depleted glutathione content and anti-oxidant enzymes; elevated levels of kidney toxicity markers viz. kidney injury molecule-1 (KIM-1), blood urea nitrogen (BUN), and creatinine; enhanced expression of NFκB, COX-2, and iNOS and nitric oxide. Treatment with D-limonene prevented oxidative stress by restoring the levels of antioxidant enzymes, further both doses of 5% and 10% showed significant decrease in inflammatory response. Both the doses of D-limonene significantly decreased the levels of kidney toxicity markers KIM-1, BUN, and creatinine. D-limonene also effectively decreased the Dox induced overexpression of NF-κB, COX-2, and iNOS and nitric oxide. Data from the present study indicate the protective role of D-limonene against Dox-induced renal damage.


Relationship between early life respiratory illness, family size over time, and the development of asthma and hay fever: a seven year follow up study.
The timing and mechanism of the inverse association between increasing sibling number and atopic disease are not yet understood. A study was undertaken to examine how family size at birth predicts early respiratory illness, to report the association between infant respiratory illness and childhood atopic disease, and to determine whether the protective effect of large family size operates during infancy or later childhood. A prospective follow up study was carried out on 863 children (78%) of 1111 participants in the Tasmanian Infant Health Survey performed in 1988. In 1988 household size and history of respiratory illness were obtained by parental interview at home (median age 35 days) and later by telephone (median age 85 days). In 1995 asthma, hay fever, and household size were assessed by parental questionnaire in a large cross sectional survey. In 1988 increasing resident number (per resident) (adjusted odds ratio (AOR) 1.17 (95% CI 1.05 to 1.31)) and resident density (AOR 1.77 (95% CI 1.07 to 2.94)) were related to parental report of an upper respiratory tract infection (URTI) by one month of age. Children with a reported URTI by home interview were more likely to have subsequent asthma (adjusted relative risk (ARR) 1.27 (95% CI 1.05 to 1.53)). The association between lower respiratory tract infection (LRTI) at telephone interview (relative risk (RR) 1.34 (95% CI 1.02 to 1.75) and asthma was reduced after adjustment for family history of asthma (ARR 1.27 (95% CI 0.98 to 1.66)). Antibiotic use by home interview was not associated with subsequent asthma or hay fever. Indicators of family size in 1988 were associated with hay fever but not asthma but, in contrast, resident number in 1995 was inversely associated with asthma (AOR 0.82 (95% CI 0.72 to 0.92) per resident) and hay fever (AOR 0.82 (95% CI 0.71 to 0.96) per resident). Children with no siblings were at risk for current asthma, particularly if symptoms began after the age of four (RR 2.81 (95% CI 1.36 to 5.84)). The apparent protective effect of large household size and asthma could not be explained by an increase in reported early respiratory illness. The first year of life may not be the most critical time for the protective effect of large household size to be mediated in relation to asthma, but this effect occurred by the seventh year of life.


Carbohydrate binding activities of Bradyrhizobium japonicum. I. Saccharide-specific inhibition of homotypic and heterotypic adhesion.
Bradyrhizobium japonicum (R110d) exhibited four saccharide-specific binding activities: (a) adsorption to Sepharose beads containing covalently coupled lactose; (b) homotypic agglutination through one pole of the cell (star formation); (c) heterotypic adhesion to the cultured soybean cell line, SB-1; and (d) attachment to roots of soybean plants. Each of these binding activities can be inhibited by the addition of galactose or lactose, but not by derivatives such as N-acetyl-D-galactosamine or melibiose. Treatment of wild-type bacteria with N-methyl-N'-nitro-N-nitrosoguanidine followed by selection on the basis of reduced binding to SB-1 cells, resulted in two specific mutants, designated N4 and N6. Compared to wild type, these two mutants also exhibited decreased binding activity in: (a) adsorption to lactose-Sepharose beads; (b) homotypic star formation; and (c) heterotypic attachment to roots of soybeans plants. These results suggest that all four of the saccharide-inhibitable binding activities of Bradyrhizobium japonicum may be mediated by the same mechanism(s) or molecular component(s).


Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer.
Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ2 tests determined the differences in variable distribution. The rate of subtype conversion was 0% in basal-like tumors, 23.1% in HER2-enriched (HER2-E) tumors, 30.0% in luminal B tumors, and 55.3% in luminal A tumors. In 40.2% of cases, luminal A tumors converted to luminal B tumors, whereas in 14.3% of cases luminal A and B tumors converted to HER2-E tumors. We identified 47 genes that were expressed differentially in metastatic versus primary disease. Metastatic tumors were enriched for proliferation-related and migration-related genes and diminished for luminal-related genes. Expression of proliferation-related genes were better at predicting overall survival in metastatic disease (OSmet) when analyzed in metastatic tissue rather than primary tissue. In contrast, a basal-like gene expression signature was better at predicting OSmet in primary disease compared with metastatic tissue. We observed correlations between time to tumor relapse and the magnitude of changes of proliferation, luminal B, or HER2-E signatures in metastatic versus primary disease. Although the intrinsic subtype was largely maintained during metastatic progression, luminal/HER2-negative tumors acquired a luminal B or HER2-E profile during metastatic progression, likely reflecting tumor evolution or acquisition of estrogen independence. Overall, our analysis revealed the value of stratifying gene expression by both cancer subtype and tissue type, providing clinicians more refined tools to evaluate prognosis and treatment. Cancer Res; 77(9); 2213-21. ©2017 AACR.


Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer.
Metastatic pancreatic cancer (PDAC) has a poor clinical outcome with a 5-year survival rate below 3%. Recent transcriptome profiling of PDAC biopsies has identified 2 clinically distinct subtypes - the "basal-like" (BL) subtype with poor prognosis and therapy resistance compared with the less aggressive and drug-susceptible "classical" (CLA) subtype. However, the mechanistic events and environmental factors that promote the BL subtype identity are not very clear. Using preclinical models, patient-derived xenografts, and FACS-sorted PDAC patient biopsies, we report here that the axon guidance receptor, roundabout guidance receptor 3 (ROBO3), promotes the BL metastatic program via a potentially unique AXL/IL-6/phosphorylated STAT3 (p-STAT3) regulatory axis. RNA-Seq identified a ROBO3-mediated BL-specific gene program, while tyrosine kinase profiling revealed AXL as the key mediator of the p-STAT3 activation. CRISPR/dCas9-based ROBO3 silencing disrupted the AXL/p-STAT3 signaling axis, thereby halting metastasis and enhancing therapy sensitivity. Transcriptome analysis of resected patient tumors revealed that AXLhi neoplastic cells associated with the inflammatory stromal program. Combining AXL inhibitor and chemotherapy substantially restored a CLA phenotypic state and reduced disease aggressiveness. Thus, we conclude that a ROBO3-driven hierarchical network determines the inflammatory and prometastatic programs in a specific PDAC subtype.


Evidence for association between endothelial nitric oxide synthase gene polymorphism (G894T) and inflammatory markers: the ATTICA study.
We evaluated the effect of the point mutation of guanine to thymine at nucleotide position 894 (G894T) of the endothelial nitric oxide synthase (eNOS) gene on inflammatory and oxidative stress markers. We studied genetic information from 270 men (18-87 years old) and 325 women (18-89 years old). Participants without any clinical evidence of cardiovascular or other atherosclerotic disease were randomly selected from the general population according to the age-sex distribution of Athens greater area. Genomic DNA was extracted from 2 to 5 mL of fresh or frozen whole blood using standard methods. The DNA analysis showed that 10.6% of the participants were Asp-homozygotes (Asp/Asp), 40% heterozygotes (Asp/Glu) and 49.4% Glu-homozygotes (Glu/Glu). Compared to Asp/Glu and Glu/Glu, Asp/Asp had higher levels of fibrinogen (332 +/- 46 or 329 +/- 33 vs 319 +/- 29 mg/dL, P =.029), white blood cells (6.9 +/- 0.6 or 6.5 +/- 0.3 vs 6.1 +/- 0.9 x 10(3) counts, P =.044), and oxidized low-density lipoprotein cholesterol (68 +/- 21 or 61 +/- 22 vs 59 +/- 20 mg/dL, P =.039), after controlling for several potential confounders. An insignificant association was found between homocysteine (P =.08), C-reactive protein (P =.096), and the distribution of G894T polymorphism (P <.1). No association between the distribution of the polymorphism and hypertension status of the participants was observed. Our results imply that G894T polymorphism of the endothelial nitric oxide synthase gene is associated with elevated levels of inflammatory and oxidative stress markers, which may partially explain the increased prevalence of G894T polymorphism among patients with cardiovascular disease.


JOINT AND INDIVIDUAL VARIATION EXPLAINED (JIVE) FOR INTEGRATED ANALYSIS OF MULTIPLE DATA TYPES.
Research in several fields now requires the analysis of datasets in which multiple high-dimensional types of data are available for a common set of objects. In particular, The Cancer Genome Atlas (TCGA) includes data from several diverse genomic technologies on the same cancerous tumor samples. In this paper we introduce Joint and Individual Variation Explained (JIVE), a general decomposition of variation for the integrated analysis of such datasets. The decomposition consists of three terms: a low-rank approximation capturing joint variation across data types, low-rank approximations for structured variation individual to each data type, and residual noise. JIVE quantifies the amount of joint variation between data types, reduces the dimensionality of the data, and provides new directions for the visual exploration of joint and individual structure. The proposed method represents an extension of Principal Component Analysis and has clear advantages over popular two-block methods such as Canonical Correlation Analysis and Partial Least Squares. A JIVE analysis of gene expression and miRNA data on Glioblastoma Multiforme tumor samples reveals gene-miRNA associations and provides better characterization of tumor types.


The fine structure of Streptomyces coelicolor. I. The cytoplasmic membrane system.
Colonies and spore suspensions of Streptomyces coelicolor were fixed by the method of Kellenberger, Ryter, and Séchaud (1958) and embedded in methacrylate or araldite. Thin sections were cut with an A. F. Huxley microtome and examined in a Siemens' Elmiskop I. At all stages of development the hyphae of Streptomyces coelicolor have an extensive membranous component in the cytoplasm. The membranes are continuous with the plasma membrane and have a variety of configurations at different places in the hyphae. Tubular structures, vesicles, and parallel stacks of membranes are seen. In some areas concentric layers of membranes form whorled structures which are particularly frequent in the region of developing cross-walls and within maturing spores. In the spores membranous structures often lie embedded in the nuclear material. In disintegrating hyphae the intracytoplasmic membranes round off into small vesicles and remain when the rest of the cytoplasmic structure has gone. In the absence of typical mitochondria and other cytoplasmic membranous structures it is possible that the membranous component of the cytoplasm of Streptomyces coelicolor may perform the functions of the endoplasmic reticulum and/or the mitochondria of higher cells.


Mindfulness Mechanisms in Sports: Mediating Effects of Rumination and Emotion Regulation on Sport-Specific Coping.
The main objective of the project was to examine a proposed theoretical model of mindfulness mechanisms in sports. We conducted two studies (the first study using a cross-sectional design and the second a longitudinal design) to investigate if rumination and emotion regulation mediate the relation between dispositional mindfulness and sport-specific coping. Two hundred and forty-two young elite athletes, drawn from various sports, were recruited for the cross-sectional study. For the longitudinal study, 65 elite athletes were recruited. All analyses were performed using Bayesian statistics. The path analyses showed credible indirect effects of dispositional mindfulness on coping via rumination and emotion regulation in both the cross-sectional study and the longitudinal study. Additionally, the results in both studies showed credible direct effects of dispositional mindfulness on rumination and emotion regulation. Further, credible direct effects of emotion regulation as well as rumination on coping were also found in both studies. Our findings support the theoretical model, indicating that rumination and emotion regulation function as essential mechanisms in the relation between dispositional mindfulness and sport-specific coping skills. Increased dispositional mindfulness in competitive athletes (i.e. by practicing mindfulness) may lead to reductions in rumination, as well as an improved capacity to regulate negative emotions. By doing so, athletes may improve their sport-related coping skills, and thereby enhance athletic performance.


Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A five-year retrospective study in the Children's Hospital of Damascus, Syria.
Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders. 21-hydroxylase deficiency is responsible for the majority of cases (90-95%) and considered the most common cause of genital ambiguity. There are no statistics concerning the prevalence of this disorder in Syria, although the high rate of consanguineous marriages indicates a possible high prevalence. This study aims to collect baseline information about CAH in Syria to evaluate the potential need of a screening program. All medical records of inpatients who had CAH as a final or presumptive diagnosis at the Children's Hospital of Damascus between 2008-2012, or were diagnosed elsewhere and then admitted at the hospital for the first time within the same period, were retrospectively reviewed and divided into two groups: confirmed and suspected cases. Eighty-nine cases were confirmed, 25 were still suspected. Of the 89 confirmed cases: 20 (22.5%) were males, 66 (74.1%) were females, and 3 were ambiguous. Sixty-one patients (68.5%) were of the salt wasting type and 28 (31.5%) were of the simple virilizing type. The mortality rate was 6.7%. Thirty-two females were assigned as males at birth. Seventeen cases (19.1%) underwent previous hospitalization. 69.7% of patients were not diagnosed during the first month of life. Of the 25 suspected cases: 12 were males, 8 were females and 5 were ambiguous. Confirmatory tests had not been performed because of death in 7 patients (28%) and early discharge upon parental request in another 7 patients (28%). A mandatory screening program for CAH in Syria seems necessary due to the obvious lack of awareness, delayed diagnosis and high expected prevalence. However, further efforts are needed to confirm the effectiveness of such a program in the Syrian society.