Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity.
Memory CD8 T cells can provide long-term protection against tumors, which depends on their enhanced proliferative capacity, self-renewal and unique metabolic rewiring to sustain cellular fitness. Specifically, memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic demands. In contrast, tumor-infiltrating lymphocytes (TILs) display severe metabolic defects, which may underlie their functional decline. Here, we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1α expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1α maintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free host. Altogether, our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation, metabolic fitness, and antitumor immunity in vivo.


Hepatic toxicity during chemotherapy for severe tuberculosis meningitis.
The possible development of hepatotoxic effects as a result of high dosages of isoniazid, rifampin, pyrazinamide, and ethionamide was assessed in 56 young children (median age, 22 months) treated for severe tuberculous meningitis (TBM). Only one of the 56 children became jaundiced, probably as result of hepatitis A infection. Of 33 children observed for at least eight weeks, only five (15%) had normal serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase levels throughout, but in only three patients were AST or ALT values greater than 200 U/L, and enzyme levels tended to normalize toward the end of the period. In this group of 33 children, those at stage III TBM had higher enzyme levels than did those at stage II. The remaining 23 children were observed for a mean period of only four weeks, and 18 (75%) had at least one abnormal liver function test result.


Autophagy and hypoxia in colonic adenomas related to aggressive features.
The study investigated whether autophagic activity and hypoxia parallel the adenoma-carcinoma sequence. The study comprised 120 tubular adenomas with high-grade dysplasia, including 22 with questionable evidence of invasion, 37 with definite stromal invasion and 29 with severely dysplastic adenoma, 10 traditional serrated adenomas and 22 classical tubular adenomas lacking aggressive features. The samples were stained immunohistochemically for autophagy (LC3A and Beclin-1) and hypoxia-inducible factor1-alpha (HIF1α) markers. LC3A was detected as diffuse cytoplasmic staining and as dense "stone-like" structures (SLS) within cytoplasmic vacuoles. Beclin-1 reactivity was purely cytoplasmic, whereas that of HIF1α was both cytoplasmic and nuclear. SLS counts in noninvasive, nontransformed areas of tubular adenomas were consistently low (median SLS = 0.5; 200× magnification), whereas a progressive increase was noted from areas of equivocal invasion (median SLS = 1.3; 200× magnification) and intramucosal carcinoma (median SLS = 1.4; 200× magnification) to unequivocal invasive foci (median SLS = 2.1; 200× magnification) (P < 0.0001). A similar association was shown for Beclin-1 and HIF1α expression (P < 0.05). Traditional serrated adenomas yielded low SLS counts and weak HIF1α reactivity, but high cytoplasmic LC3A and Beclin-1 expression (P < 0.01). A hypoxia-driven autophagy in adenomatous polyps, when particularly intense and localized, is commonly associated with early invasion or severely dysplastic adenoma.


A study on indoor environment contaminants related to dust mite in dwellings of allergic asthma patients and of healthy subjects.
This study investigated the pollution of dust mite allergens in the houses of 30 families and their infection to young allergic asthma patients in Shanghai. Medical records, family information, and dust samples were collected from the dwellings of 15 young allergic asthma patients and 15 healthy subjects. Der 1 allergen, which is a common allergen causing allergic asthma, was measured in collected dust samples using the Pharmacia Uni-CAP System. A significant correlation was found between the number of Der 1 allergens collected from floor surfaces and the number of Der 1 allergens collected from bed surfaces. Some factors influencing Der 1 allergen levels were found in this study. Relative humidity in dwellings was found to be most influential to the allergen levels. The findings suggested that traditional reduction methods for coarse particles, such as opening windows and periodic cleaning of beddings, may be effective in removing dust mite allergens.


SOGS and CGPI: parallel comparison on a diverse population.
The Northern Territory of Australia, one of the most demographically and socially diverse jurisdictions in the country, conducted its first population-based gambling and problem gambling prevalence survey in 2005. Both the South Oaks Gambling Screen (SOGS) and the Canadian Problem Gambling Index (CPGI) were administered to the same sample of respondents. Using data from this survey, the current paper presents a parallel comparison of the respective screens with particular reference to gender, region, and the socio-demographic characteristics of respondents. The respective screens produced significantly different groups of problem gamblers as measured by their association with a range of socio-demographic variables. Specifically, the large number of SOGS items related to money issues may cause selective overrepresentation among low socioeconomic groups, including Indigenous people, who exist in relatively high proportions in the Northern Territory. In addition, there existed substantial gender-based differences within screens. Identified female problem gamblers were associated with household level variables (i.e. employment status, household type and marital status), while males were associated with socio-economic variables including language, education, and income. Further research is required to validate the use of problem gambling screens within the Indigenous population and to understand the role of gender in the experience and categorisation of problem gambling.


Direct Pathway Cloning (DiPaC) to unlock natural product biosynthetic potential.
Specialized metabolites from bacteria are an important source of inspiration for drug development. The genes required for the biosynthesis of such metabolites in bacteria are usually organized in so-called biosynthetic gene clusters (BGCs). Using modern bioinformatic tools, the wealth of genomic data can be scanned for such BGCs and the expected products can often structurally be predicted in silico. This facilitates the directed discovery of putatively novel bacterial metabolites. However, the production of these molecules often requires genetic manipulation of the BGC for activation or the expression of the pathway in a heterologous host. The latter necessitates the transplantation of the BGC into a suitable expression system. To achieve this goal, powerful cloning strategies based on in vivo homologous recombination have recently been developed. This includes LCHR and LLHR in E. coli as well as TAR cloning in yeast. Here, we present Direct Pathway Cloning (DiPaC) as an efficient complementary BGC capturing strategy that relies on long-amplicon PCR and in vitro DNA assembly. This straightforward approach facilitates full pathway assembly, BGC refactoring and direct transfer into any vector backbone in vitro. The broad applicability and efficiency of DiPaC is demonstrated by the discovery of a new phenazine from Serratia fonticola, the first heterologous production of anabaenopeptins from Nostoc punctiforme and the transfer of the native erythromycin BGC from Saccharopolyspora erythraea into Streptomyces. Due to its simplicity, we envisage DiPaC to become an essential method for BGC cloning and metabolic pathways construction with significant applications in metabolic engineering, synthetic biology and biotechnology.


Dynamics of a binary mixture of non-spherical molecules: Test of hydrodynamic predictions.
We consider a new class of model systems to study systematically the role of molecular shape in the transport properties of dense liquids. Our model is a liquid binary mixture where both the molecules are non-spherical and characterized by a collection of parameters. Although in the real world most of the molecules are non-spherical, only a limited number of theoretical studies exist on the effects of molecular shapes and hardly any have addressed the validity of the hydrodynamic predictions of rotational and translational diffusion of these shapes in liquids. In this work, we study a model liquid consisting of a mixture of prolate and oblate (80:20 mixture) ellipsoids with interactions governed by a modified Gay-Berne potential for a particular aspect ratio (ratio of the length and diameter of the ellipsoids), at various temperature and pressure conditions. We report calculations of transport properties of this binary mixture by varying temperature over a wide range at a fixed pressure. We find that for the pressure-density conditions studied, there is no signature of any phase separation, except transitions to the crystalline phase at low temperatures and relatively low pressure (the reason we largely confined our studies to high pressure). We find that for our model binary mixture, both stick and slip hydrodynamic predictions break down in a major fashion, for both prolates and oblates and particularly so for rotation. Moreover, prolates and oblates themselves display different dynamical features in the mean square displacement and in orientational time correlation functions.


General hospital-treated self-poisoning in England and Australia: comparison of presentation rates, clinical characteristics and aftercare based on sentinel unit data.
Hospital-treated deliberate self-poisoning (DSP) is common and the existing national monitoring systems are often deficient. Clinical Practice Guidelines (UK and Australia) recommend universal psychosocial assessment within the general hospital as standard care. We compared presentation rates, patient characteristics, psychosocial assessment and aftercare in UK and Australia. We used a cross sectional design, for a ten year study of all DSP presentations identified through sentinel units in Oxford, UK (n=3042) and Newcastle, Australia (n=3492). Oxford had higher presentation rates for females (standardised rate ratio 2.4: CI 99% 1.9, 3.2) and males (SRR 2.5: CI 99% 1.7, 3.5). Female to male ratio was 1.6:1, 70% presented after-hours, 95% were admitted to a general hospital and co-ingestion of alcohol occurred in a substantial minority (Oxford 24%, Newcastle 32%). Paracetamol, minor tranquilisers and antidepressants were the commonest drug groups ingested, although the overall pattern differed. Psychosocial assessment rates were high (Oxford 80%, Newcastle 93%). Discharge referral for psychiatric inpatient admission (Oxford 8%, Newcastle 28%), discharge to home (Oxford 80%, Newcastle 70%) and absconding (Oxford 11%, Newcastle 2%) differed between the two units. Oxford has higher age-standardised rates of DSP than Newcastle, although many other characteristics of patients are similar. Services can provide a high level of assessment as recommended in clinical guidelines. There is some variation in after-care. Sentinel service monitoring routine care of DSP patients can provide valuable comparisons between countries.


Demographic and risk factors associated with chronic dieting in adolescents.
A comprehensive, school-based survey was administered to 36,320 Minnesota public school students in grades 7 through 12 during the 1987-1988 school year. Self-reported chronic dieting was much higher in girls than in boys (12.1% of all girls vs 2.1% of boys). For girls, the percentage of chronic dieters was significantly less in grades 7 and 8 (7.8%) than in grades 9 and 10 (13.5%) or grades 11 and 12 (14.3%). There were no differences among urban, suburban, or rural youth. Black girls were less likely to diet compared with white girls. Chronic dieters were more likely than other students to report maladaptive weight-loss techniques, such as self-induced vomiting (relative risk, 9.92 for girls and 9.40 for boys), laxative use (relative risk, 7.18 for girls and 11.00 for boys), ipecac use (relative risk, 8.33 for girls and 11.00 for boys), and diuretic use (relative risk, 7.30 for girls and 13.5 for boys). It is suggested that chronic dieting may serve as a screening marker for more severe eating and weight-loss behaviors.


Skin Regeneration with Self-Assembled Peptide Hydrogels Conjugated with Substance P in a Diabetic Rat Model.
The wound healing process requires enough blood to supply nutrients and various growth factors to the wound area. However, chronic wounds such as diabetic skin ulcers have limited regeneration due to a lack of cellular and molecular signals because of a deficient blood flow. Mesenchymal stem cells (MSCs) are known to provide various factors, including growth factors, cytokines, and angiogenic mediators. Although MSCs have great therapeutic potential, their transplantation has many obstacles, including the time required to culture the cells, the invasiveness of the procedure, and limited stem cell sources. In this study, we induced a diabetic 1 model in rats aged 7 weeks by injecting streptozotocin and citrate buffer solution. After confirming that diabetes was induced in the rats, we created critical sized wounds on the dorsal area of the rats and then injected hydrogels. We performed the experiments with four groups (defect model for the control, self-assembled peptides (SAPs), SAP with soluble substance P, and SAP conjugated with substance P) to treat the wound defect. Tissues were harvested at 1, 2, and 3 weeks after injection and examined for the wound closure, histological analysis, quantitative real-time polymerase chain reaction analysis, and quantification of collagen deposits to investigate stem cell recruitment and full recovery of wounds at an accelerated time period. As our results show, the wounds treated with SAP and substance P exhibited significantly accelerated wound closure, enhanced collagen deposition, and increased angiogenesis. Furthermore, we confirmed the ability of SAP with substance P to promote the recruitment and homing of cells by immunofluorescence staining of a MSC marker. In addition, it was observed that substance P remained in the wound area up to 3 weeks after the injection of SAP with substance P. It is believed that the endogenous MSCs mobilized by substance P had therapeutic effects through their proper differentiation and release of paracrine factors into the wound sites. In conclusion, this study shows that SAP with substance P can promote wound healing to enhance skin regeneration without cell transplantation in a diabetic model.


Effect of Lactocare® Synbiotic on Disease Severity in Ulcerative Colitis: A Randomized Placebo-Controlled Double-Blind Clinical Trial.
BACKGROUND Inflammatory bowel diseases are managed by different methods, which may not be well tolerated because of their side effects. Recently, pro-prebiotics are considered as a supplementary treatment in gastrointestinal diseases. In this study, the effect of Lactocare® (ZistTakhmir Company) was investigated on the disease severity in mild to moderate ulcerative colitis. METHODS In this randomized, double-blind clinical trial (Iranian Registry of Clinical Trials number: IRCT201407271264N5), 60 patients with mild to moderate ulcerative colitis were included. An 8-week trial was carried out comparing Lactocare® as a supplement with standard therapy against placebo. Simple Clinical Colitis Activity Index (SCCAI) was measured at baseline and after 8 weeks. Statistical analysis was performed using paired ttest to assess the temporal changes (before and after the treatment) in the mean of SCCAI in each group. Chi-square test was used to compare the response rates. Odds ratios (OR) and the 95% confidence intervals (95%CI) were also calculated. p values of less than 0.05 were considered significant. RESULTS A significant decreased mean SCCAI was seen in the intervention group (4.56 ± 2.56) vs. placebo group (6.54 ± 2.47) (p < 0.05). Response to treatment was seen in 64.3% of the treatment group vs. 47% in the placebo group (p = 0.18). Response to treatment was observed in 90.9% of patients with ulcerative colitis for more than 5 years compared with 44.4% of the control group (p = 0.01). CONCLUSION Regarding the effectiveness of pre-probiotics in mitigating symptoms in patients with ulcerative colitis, it could be suggested to try pre-probiotics in the standard treatment particularly in those with more than five years ofthe disease.


Central-stimulating and analgesic activity of the ethanolic extract of Alternanthera sessilis in mice.
Alternanthera sessilis is a popular vegetable and used in traditional medicinal practice of Bangladesh and other parts of Asia to relive tiredness, laziness, and sleeps as well as pain and inflammation. However, no report was found on the neuropharmacological and analgesic activity of this plant to-date. Present study was undertaken to evaluate the neuropharmacological and analgesic activity of the ethanol extract of A. sessilis whole plant (ETAS) in mice models. Central stimulating activity was investigated by pentobarbitone induced sleeping time, open field, and hole cross tests. Analgesic activity was evaluated by acetic acid induced writhing and hot-plate methods. The tests were performed at 250 and 500 mg/kg body weight dose levels. In sleeping time test, ETAS significantly (p < 0.001) increased the onset of sleep, and decreased the duration of sleep. In open field and hole cross tests, ETAS significantly (p < 0.001) increased the movements of mice which persisted throughout the study period. In writhing test, ETAS showed, significant (p < 0.001) inhibition of writhing reflex. In hot plate test, ETAS significantly (p < 0.001) raised the pain threshold. In HPLC analysis for polyphenols, (+)-catechin, rutin, ellagic acid, and quercetin were detected in ETAS (117.72, 490.74, 3007.26, and 13.85 mg/100 g of dry extract, respectively). Present study supported the traditional uses of A. sessilis and indicated that the plant can be a potential source of bioactive molecules.


Effect of GSTM1 and GSTT1 Polymorphisms on Genetic Damage in Humans Populations Exposed to Radiation From Mobile Towers.
All over the world, people have been debating about associated health risks due to radiation from mobile phones and mobile towers. The carcinogenicity of this nonionizing radiation has been the greatest health concern associated with mobile towers exposure until recently. The objective of our study was to evaluate the genetic damage caused by radiation from mobile towers and to find an association between genetic polymorphism of GSTM1 and GSTT1 genes and DNA damage. In our study, 116 persons exposed to radiation from mobile towers and 106 control subjects were genotyped for polymorphisms in the GSTM1 and GSTT1 genes by multiplex polymerase chain reaction method. DNA damage in peripheral blood lymphocytes was determined using alkaline comet assay in terms of tail moment (TM) value and micronucleus assay in buccal cells (BMN). There was a significant increase in BMN frequency and TM value in exposed subjects (3.65 ± 2.44 and 6.63 ± 2.32) compared with control subjects (1.23 ± 0.97 and 0.26 ± 0.27). However, there was no association of GSTM1 and GSTT1 polymorphisms with the level of DNA damage in both exposed and control groups.


Mechanism of hsp70i gene bookmarking.
In contrast to most genomic DNA in mitotic cells, the promoter regions of some genes, such as the stress-inducible hsp70i gene that codes for a heat shock protein, remain uncompacted, a phenomenon called bookmarking. Here we show that hsp70i bookmarking is mediated by a transcription factor called HSF2, which binds this promoter in mitotic cells, recruits protein phosphatase 2A, and interacts with the CAP-G subunit of the condensin enzyme to promote efficient dephosphorylation and inactivation of condensin complexes in the vicinity, thereby preventing compaction at this site. Blocking HSF2-mediated bookmarking by HSF2 RNA interference decreases hsp70i induction and survival of stressed cells in the G1 phase, which demonstrates the biological importance of gene bookmarking.


Anti-tumor effects of Ganoderma lucidum (reishi) in inflammatory breast cancer in in vivo and in vitro models.
The medicinal mushroom Ganoderma lucidum (Reishi) was tested as a potential therapeutic for Inflammatory Breast Cancer (IBC) using in vivo and in vitro IBC models. IBC is a lethal and aggressive form of breast cancer that manifests itself without a typical tumor mass. Studies show that IBC tissue biopsies overexpress E-cadherin and the eukaryotic initiation factor 4GI (eIF4GI), two proteins that are partially responsible for the unique pathological properties of this disease. IBC is treated with a multimodal approach that includes non-targeted systemic chemotherapy, surgery, and radiation. Because of its non-toxic and selective anti-cancer activity, medicinal mushroom extracts have received attention for their use in cancer therapy. Our previous studies demonstrate these selective anti-cancer effects of Reishi, where IBC cell viability and invasion, as well as the expression of key IBC molecules, including eIF4G is compromised. Thus, herein we define the mechanistic effects of Reishi focusing on the phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, a regulator of cell survival and growth. The present study demonstrates that Reishi treated IBC SUM-149 cells have reduced expression of mTOR downstream effectors at early treatment times, as we observe reduced eIF4G levels coupled with increased levels of eIF4E bound to 4E-BP, with consequential protein synthesis reduction. Severe combined immunodeficient mice injected with IBC cells treated with Reishi for 13 weeks show reduced tumor growth and weight by ∼50%, and Reishi treated tumors showed reduced expression of E-cadherin, mTOR, eIF4G, and p70S6K, and activity of extracellular regulated kinase (ERK1/2). Our results provide evidence that Reishi suppresses protein synthesis and tumor growth by affecting survival and proliferative signaling pathways that act on translation, suggesting that Reishi is a potential natural therapeutic for breast and other cancers.


Systems-level overview of host protein phosphorylation during Shigella flexneri infection revealed by phosphoproteomics.
The enteroinvasive bacterium Shigella flexneri invades the intestinal epithelium of humans. During infection, several injected effector proteins promote bacterial internalization, and interfere with multiple host cell responses. To obtain a systems-level overview of host signaling during infection, we analyzed the global dynamics of protein phosphorylation by liquid chromatography-tandem MS and identified several hundred of proteins undergoing a phosphorylation change during the first hours of infection. Functional bioinformatic analysis revealed that they were mostly related to the cytoskeleton, transcription, signal transduction, and cell cycle. Fuzzy c-means clustering identified six temporal profiles of phosphorylation and a functional module composed of ATM-phosphorylated proteins related to genotoxic stress. Pathway enrichment analysis defined mTOR as the most overrepresented pathway. We showed that mTOR complex 1 and 2 were required for S6 kinase and AKT activation, respectively. Comparison with a published phosphoproteome of Salmonella typhimurium-infected cells revealed a large subset of coregulated phosphoproteins. Finally, we showed that S. flexneri effector OspF affected the phosphorylation of several hundred proteins, thereby demonstrating the wide-reaching impact of a single bacterial effector on the host signaling network.


Recombinant Production of Mussel Byssus Inspired Proteins.
Mussel byssus, the holdfast of mussels, has attracted much attention due to the mechanical gradient properties of its threads and the robust and flexible adhesion to various substrates, features that originate mainly from mussel byssus proteins and could be used in potential applications in biomedicine. However, the applications have been impeded owing to the difficulties concerning the extraction of the natural materials, that is, proteins. Recent advances in recombinant production provide a novel approach to generate mussel byssus inspired proteins, even with the opportunities for scale-up production. Here, we review the recently investigated mussel byssus inspired proteins produced by biotechnological approaches and applications thereof with particular emphasis on adhesion and coatings.


Characteristics of Korean Patients with Primary Adrenal Insufficiency: A Registry-Based Nationwide Survey in Korea.
Primary adrenal insufficiency (PAI) is a rare, potentially life-threatening condition. There are few Korean studies on PAI, and most have had small sample sizes. We aimed to examine the etiology, clinical characteristics, treatment, and mortality of PAI in Korean patients. A nationwide, multicenter, registry-based survey was conducted to identify adults diagnosed with or treated for PAI at 30 secondary or tertiary care institutions in Korea between 2000 and 2014. A total of 269 patients with PAI were identified. The prevalence of PAI was 4.17 per million. The estimated incidence was 0.45 per million per year. The mean age at diagnosis was 49.0 years, and PAI was more prevalent in men. Adrenal tuberculosis was the most common cause of PAI in patients diagnosed before 2000; for those diagnosed thereafter, adrenal metastasis and tuberculosis were comparable leading causes. The etiology of PAI was not identified in 34.9% of cases. Of the patients receiving glucocorticoid replacement therapy, prednisolone was more frequently administered than hydrocortisone (69.4% vs. 26.5%, respectively), and only 27.1% of all patients received fludrocortisone. We observed an increased prevalence of metabolic disease and osteoporosis during the follow-up period (median, 60.2 months). The observed overall mortality and disease-specific mortality rates were 11.9% and 3.1%, respectively. The prevalence of PAI is significantly lower in Koreans than in reports from Western countries. The high frequency undetermined etiology in patients with PAI suggests the need to reveal accurate etiology of PAI in Korea.


Changes in neurocognitive functioning during transition to manifest disease: comparison of individuals at risk for schizophrenic and bipolar affective psychoses.
Neurocognitive deficits are important aspects of schizophrenic disorder because they have a strong impact on social and vocational outcomes. Previously it was assumed that cognitive abilities progressively deteriorate with illness onset. However, recent research results have contradicted this with observations of continuous or even improved performance in individuals at risk for psychosis or manifest schizophrenia. The objective of our longitudinal study was to examine neurocognitive functioning in help-seeking individuals meeting basic symptoms or ultra-high-risk criteria for schizophrenic psychosis (HRSchiz) or risk criteria for affective psychosis (HRBip). The progression of cognitive functioning in individuals converting to psychosis was compared with that of at-risk individuals who did not convert during the follow-up period. Data were available from 86 study participants who completed neurocognitive and clinical assessments at baseline and, on average, 12.8 (s.d. = 1.5) months later. Neurocognitive measures were grouped according to their load in factor analysis to five cognitive domains: speed, attention, fluency, learning and memory, and working memory. Neurocognitive functioning in HRSchiz and HRBip individuals generally improved over time. Subjects converting to manifest psychosis displayed a stable neurocognitive profile from baseline to follow-up. Compared with non-converters, they had already demonstrated a significantly lower level of performance during their baseline examinations. Our data provide no evidence for a progressive cognitive decline in individuals at risk of psychosis. In line with the neurodevelopmental model, our findings suggest that cognitive deficits are already present very early, before or during the prodromal stage of the illness.


Interventions to Reduce Future Cancer Incidence from Diesel Engine Exhaust: What Might Work?
Exposure to diesel engine exhaust (DEE) contributes appreciably to the burden of occupational cancer. This study aims to estimate the potential impact of a range of interventions on the future burden of cancer from occupational exposure to DEE in Australia. The future excess fraction method, a novel method based on the lifetime risk approach, was used to model changes in the future burden of cancer among the Australian working age population exposed to DEE at work in 2012 under various intervention strategies. The interventions modeled were based on the widely accepted hierarchy of control model. At baseline, 600 (0.4%) future bladder and 4,450 (0.6%) future lung cancer cases over the lifetime of the cohort were estimated to be attributable to occupational exposure to DEE in those exposed in 2012. Up to 2,000 of these cases were estimated to be avoidable through the use of various interventions. Exhaust hoses (engineering controls) were estimated to be particularly effective. This study provides an indication of which intervention strategies may be most useful in reducing the future burden of cancer associated with occupational DEE exposure. These results show the potential effect of changing current exposure, rather than focusing on past exposures, and thus provide relevant information for policy planning.


Dexamethasone decreases the transmesothelial electrical resistance of the parietal and visceral pleura.
The effect of dexamethasone on the transmesothelial electrical resistance (R(TM)) of sheep pleura was investigated by Ussing chamber experiments. Our results show that dexamethasone decreases the R(TM) of sheep pleurae, in part by stimulation of glucocorticoid receptors. This finding may be of importance in regard to the faster resolution of corticosteroid-treated pleural effusions.


The opinion of Turkish cardiologists on current malpractice system and an alternative patient compensation system proposal: PCS study group.
Cardiologists participate in the diagnosis and interventional treatment of numerous high-risk patients. The goal of this study was to investigate how the current malpractice system in Turkey influences cardiologists' diagnostic and interventional behavior and to obtain their opinions about an alternative patient compensation system. The present cross-sectional study assessed the practice of defensive medicine among cardiologists who are actively working in various types of workplace within the Turkish healthcare system. A 24-item questionnaire was distributed to cardiology residents, specialists, and academics in Turkey in print format, by electronic mail, or via cell phone message. A total of 253 cardiologists responded to the survey. Among them, 29 (11.6%) had been sued for malpractice claims in the past. Of the cardiologists who had been sued, 2 (6.9%) had been ordered to pay financial compensation, and 1 (3.4%) was given a sentence of imprisonment due to negligence. In all, 132 (52.8%) of the surveyed cardiologists reported that they had changed their practices due to fear of litigation, and 232 (92.8%) reported that they would prefer the new proposed patient compensation system to the current malpractice system. Among the cardiologists surveyed, 78.8% indicated that malpractice fear had affected their decision-making with regard to requesting computed tomography angiography or thallium scintigraphy, 71.6% for coronary angiography, 20% for stent implantation, and 83.2% for avoiding treating high-risk patients. The results of this survey demonstrated that cardiologists may request unnecessary tests and perform unneeded interventions due to the fear of malpractice litigation fear. Many also avoid high-risk patients and interventions. The majority indicated that they would prefer the proposed alternative patient compensation system to the current malpractice system.


Development of a metabolic pathway transfer and genomic integration system for the syngas-fermenting bacterium Clostridium ljungdahlii.
Clostridium spp. can synthesize valuable chemicals and fuels by utilizing diverse waste-stream substrates, including starchy biomass, lignocellulose, and industrial waste gases. However, metabolic engineering in Clostridium spp. is challenging due to the low efficiency of gene transfer and genomic integration of entire biosynthetic pathways. We have developed a reliable gene transfer and genomic integration system for the syngas-fermenting bacterium Clostridium ljungdahlii based on the conjugal transfer of donor plasmids containing large transgene cassettes (> 5 kb) followed by the inducible activation of Himar1 transposase to promote integration. We established a conjugation protocol for the efficient generation of transconjugants using the Gram-positive origins of replication repL and repH. We also investigated the impact of DNA methylation on conjugation efficiency by testing donor constructs with all possible combinations of Dam and Dcm methylation patterns, and used bisulfite conversion and PacBio sequencing to determine the DNA methylation profile of the C. ljungdahlii genome, resulting in the detection of four sequence motifs with N6-methyladenosine. As proof of concept, we demonstrated the transfer and genomic integration of a heterologous acetone biosynthesis pathway using a Himar1 transposase system regulated by a xylose-inducible promoter. The functionality of the integrated pathway was confirmed by detecting enzyme proteotypic peptides and the formation of acetone and isopropanol by C. ljungdahlii cultures utilizing syngas as a carbon and energy source. The developed multi-gene delivery system offers a versatile tool to integrate and stably express large biosynthetic pathways in the industrial promising syngas-fermenting microorganism C. ljungdahlii. The simple transfer and stable integration of large gene clusters (like entire biosynthetic pathways) is expanding the range of possible fermentation products of heterologously expressing recombinant strains. We also believe that the developed gene delivery system can be adapted to other clostridial strains as well.


Cerebro-retinal microangiopathy with calcifications and cysts due to recessive mutations in the CTC1 gene.
Cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) or Coats plus syndrome is a pleiotropic disorder affecting the eyes, brain, bone and gastrointestinal tract. Its primary pathogenesis involves small vessel obliterative microangiopathy. Recently, autosomal recessively inherited mutations in CTC1 have been reported in CRMCC patients. We herein report an adolescent referred to our hospital following new seizures in a context of an undefined multisystem disorder. Cerebral imaging disclosed asymmetrical leukopathy, intracranial calcifications and cysts. In addition, he presented other typical CRMCC features i.e. a history of intrauterine growth retardation, skeletal demineralization and osteopenia, bilateral exudative vitreo-retinopathy reminiscent of Coats disease, recurrent gastrointestinal hemorrhages secondary to watermelon stomach and variceal bleeding of the esophagus due to idiopathic portal hypertension and telangiectatic and angiodysplasic changes in the small intestine and colon, and anemia due to recurrent bleeding and bone marrow abnormalities. The patient was diagnosed with Coats plus syndrome. CTC1 gene screening confirmed the diagnosis with the identification of heterozygous deleterious mutations. CRMCC due to CTC1 mutations has a broad clinical expressivity. Our case report illustrates the main possible associated phenotypes and their complications, demonstrating the need for a careful etiological search in order to initiate appropriate therapeutic and preventive measures.


Use of two-part regression calibration model to correct for measurement error in episodically consumed foods in a single-replicate study design: EPIC case study.
In epidemiologic studies, measurement error in dietary variables often attenuates association between dietary intake and disease occurrence. To adjust for the attenuation caused by error in dietary intake, regression calibration is commonly used. To apply regression calibration, unbiased reference measurements are required. Short-term reference measurements for foods that are not consumed daily contain excess zeroes that pose challenges in the calibration model. We adapted two-part regression calibration model, initially developed for multiple replicates of reference measurements per individual to a single-replicate setting. We showed how to handle excess zero reference measurements by two-step modeling approach, how to explore heteroscedasticity in the consumed amount with variance-mean graph, how to explore nonlinearity with the generalized additive modeling (GAM) and the empirical logit approaches, and how to select covariates in the calibration model. The performance of two-part calibration model was compared with the one-part counterpart. We used vegetable intake and mortality data from European Prospective Investigation on Cancer and Nutrition (EPIC) study. In the EPIC, reference measurements were taken with 24-hour recalls. For each of the three vegetable subgroups assessed separately, correcting for error with an appropriately specified two-part calibration model resulted in about three fold increase in the strength of association with all-cause mortality, as measured by the log hazard ratio. Further found is that the standard way of including covariates in the calibration model can lead to over fitting the two-part calibration model. Moreover, the extent of adjusting for error is influenced by the number and forms of covariates in the calibration model. For episodically consumed foods, we advise researchers to pay special attention to response distribution, nonlinearity, and covariate inclusion in specifying the calibration model.


Affective meanings of life review through activities and discussion.
Life review is often incorporated into therapy with the elderly in the form of verbal or activity groups. This study compares the affective meanings of life review through activities with life review through discussion. Twenty-two women between 60 and 85 years of age participated in one of two activity groups or in one of two discussion groups. Individuals in the activity groups expressed a positive event or accomplishment of their past by drawing and making collages. Then they discussed their finished products. In the discussion groups, subjects took turns describing a positive life event to other group members. Afterward, all subjects rated how they felt about themselves during the group using Osgood's semantic differential scale. Analyses of variance for nested designs were completed on the scale's evaluation, power, and action factors of affective meaning. They revealed significant differences between the groups within the activity and discussion conditions. However, differences between the activity and discussion conditions were not significant. In terms of clinical practice, life review was perceived as good, powerful, and active by this sample, and practitioners are urged to consider the importance of group-to-group differences in responses to activities.


Continuous, noninvasive monitoring of total hemoglobin concentration by an optoacoustic technique.
Measurement of total hemoglobin concentration [Hgb] is a blood test that is widely used to evaluate outpatients, hospital inpatients, and surgical patients, especially those undergoing surgery associated with extensive blood loss, rapid fluid administration, and transfusion of packed red blood cells. Current techniques for measurement of [Hgb] are invasive (requiring blood sampling) and cannot provide real-time, continuous monitoring. We propose to use an optoacoustic technique for noninvasive and continuous monitoring of [Hgb]. The high resolution of the optoacoustic technique may provide accurate measurement of [Hgb] by detection and analysis of optoacoustic signals induced by short optical pulses in blood circulating in arteries or veins. We designed, built, and tested in vitro (in both tissue phantoms and in preliminary in vivo experiments) a portable optoacoustic system for the monitoring of [Hgb] in the radial artery. The system includes a nanosecond laser operating in the near-infrared spectral range and a sensitive optoacoustic probe designed to irradiate the radial artery through the skin and detect optoacoustic signals induced in blood. Results of our studies demonstrated that (1) the slope of optoacoustic waves induced in blood in the transmission mode is linearly dependent on [Hgb] in the range from 6.2 to 12.4 g/dl, (2) optoacoustic signals can be detected despite optical attenuation in turbid tissue phantoms with a thickness of 1 cm, and (3) the optoacoustic system detects signals induced in blood circulating in the radial artery. These data suggest that the optoacoustic system can be used for accurate, noninvasive, real-time, and continuous monitoring of [Hgb].


Multimodal Optimization by Covariance Matrix Self-Adaptation Evolution Strategy with Repelling Subpopulations.
During the recent decades, many niching methods have been proposed and empirically verified on some available test problems. They often rely on some particular assumptions associated with the distribution, shape, and size of the basins, which can seldom be made in practical optimization problems. This study utilizes several existing concepts and techniques, such as taboo points, normalized Mahalanobis distance, and the Ursem's hill-valley function in order to develop a new tool for multimodal optimization, which does not make any of these assumptions. In the proposed method, several subpopulations explore the search space in parallel. Offspring of a subpopulation are forced to maintain a sufficient distance to the center of fitter subpopulations and the previously identified basins, which are marked as taboo points. The taboo points repel the subpopulation to prevent convergence to the same basin. A strategy to update the repelling power of the taboo points is proposed to address the challenge of basins of dissimilar size. The local shape of a basin is also approximated by the distribution of the subpopulation members converging to that basin. The proposed niching strategy is incorporated into the covariance matrix self-adaptation evolution strategy (CMSA-ES), a potent global optimization method. The resultant method, called the covariance matrix self-adaptation with repelling subpopulations (RS-CMSA), is assessed and compared to several state-of-the-art niching methods on a standard test suite for multimodal optimization. An organized procedure for parameter setting is followed which assumes a rough estimation of the desired/expected number of minima available. Performance sensitivity to the accuracy of this estimation is also studied by introducing the concept of robust mean peak ratio. Based on the numerical results using the available and the introduced performance measures, RS-CMSA emerges as the most successful method when robustness and efficiency are considered at the same time.


Amygdalar and hippocampal volumetry in control participants: differences regarding handedness.
Amygdalar and hippocampal volume measurements indicate a right-greater-than-left asymmetry for right-handed normal participants in most studies. The purpose of this study was to compare amygdalar and hippocampal volume ratios between right- and left-handed participants. Amygdalar and hippocampal volume measurements were performed in 34 (20 right-handed and 14 left-handed) normal participants. All participants completed a 10-item handedness questionnaire. The MR imaging sequence was a 3D T1-weighted gradient-echo acquisition of the whole brain (24/6 [TR/TE]; flip angle, 25 degrees). MR images were spatially normalized, and volumes were painted with a 1.0-mm(3) resolution cursor on an SGI workstation. In right-handed participants, the amygdala and hippocampus (P <.001 for both) were significantly larger on the right side than on the left. The left-handed group did not show a significant difference between right- and left-sided structures. Right-to-left volume ratios differed significantly between right- and left-handed participants for both amygdalar (P <.02) and hippocampal (P <.01) structures. Gender did not affect right-to-left amygdalar and hippocampal volume ratios in right- or left-handed participants. Handedness, but not gender, seems to affect right-to-left amygdalar and hippocampal volume ratios.


An evaluation of the Constant-Murley shoulder assessment.
We have analysed the Constant-Murley (1987) assessment for 25 patients with shoulder pathology. We found the score easy to use, with low inter- and intraobserver errors, but sufficiently imprecise in repeated measurements to give concern in its use for clinical follow-up of patients. We have calculated 95% confidence limits for a single assessment to be within 16 to 20 points in most cases. In addition, we found that all our subjects with instability as their main problem scored within five points of the maximum; this suggests that the scoring method may need to be revised for use on these patients.


Construction of Novel Bacillus thuringiensis Strains with Different Insecticidal Activities by Transduction and Transformation.
The shuttle vector pHT3101 and its derivative pHT408, bearing a copy of a cryIA(a) delta-endotoxin gene, were transferred into several Bacillus thuringiensis subspecies through phage CP-54Ber-mediated transduction, with frequencies ranging from 5 x 10 to 2 x 10 transductant per CFU, depending on the strain and on the plasmid. In Cry and Cry native recipients, the introduction of the cryIA(a) gene resulted in the formation of large bipyramidal crystals that were active against the insect Plutella xylostella (order Lepidoptera). In both cases, high levels of gene expression were observed. Transductants displaying a dual specificity were constructed by using as recipients the new isolates LM63 and LM79, which have larvicidal activity against insects of the order Coleoptera. It was not possible, however, to introduce pHT7911 into B. thuringiensis subsp. entomocidus, aizawai, or israelensis by transduction. However, electrotransformation was successful, and transformants expressing the toxin gene cryIIIA, carried by pHT7911, were obtained. Again, high levels of expression of the cloned gene were observed. The results indicate that CP-54Ber-mediated transduction is a useful procedure for introducing cloned crystal protein genes into various B. thuringiensis recipients and thereby creating strains with new combinations of genes. Finally it was also shown that pHT3101 is a very good expression vector for the cloned delta-endotoxin genes in the different recipients.


Thoracoscopic-assisted pulmonary surgery for partial and complete lung lobectomy in dogs and cats: 11 cases (2008-2013).
To describe the use of thoracoscopic-assisted pulmonary surgery (TAPS) for partial and complete lung lobectomy in small animal patients and to evaluate short-term outcome. Retrospective case series. 11 client-owned dogs and cats. Procedures-Medical records of dogs and cats that underwent a partial or complete TAPS lung lobectomy were reviewed. All patients underwent general anesthesia and were positioned in lateral recumbency with the affected hemithorax uppermost. One-lung ventilation was not implemented in any patient. For initial exploration, a 5- to 10-mm incision was made for insertion of a 30° telescope approximately 5 to 7 rib spaces away from the site of the pulmonary lesion in the dorsal third of the thorax. All subsequent incision placements were case dependent and determined by the location of the lesion to be resected. Following lesion localization, a 2- to 7-cm minithoracotomy incision was made with direct thoracoscopic visualization without the use of rigid rib retractors. In 10 of 11 patients, a 360° wound retraction device was placed at the minithoracotomy site prior to exteriorization and resection of the affected lung. Lymph nodes were inspected intraoperatively, but biopsies were not performed; incisions were closed routinely, and a thoracostomy tube was placed in all patients. 3 cats and 8 dogs underwent successful partial (5) or complete (6) TAPS lung lobectomy over a 5-year period (2008 through 2013). Median surgery time was 92.7 minutes (range, 77 to 150 minutes). Thoracostomy tubes were removed a median of 22.3 hours after surgery (range, 18 to 36 hours). The median time to discharge was 3.1 days (range, 1 to 6 days). No intraoperative complications were encountered. All patients were discharged from the hospital, with 9 of 11 patients alive 6 months after surgery. Results of this study suggested that lung lobectomy by means of TAPS can be successfully performed in dogs and cats. When compared with total thoracoscopic surgery, TAPS may offer a more technically feasible approach from both a surgical and anesthetic standpoint, because it provides the benefits of minimally invasive thoracic surgery without the necessity of 1-lung ventilation.


Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program.
In a randomized phase III trial, pemetrexed plus cisplatin was associated with improved survival compared with cisplatin alone for patients with malignant pleural mesothelioma (MPM). However, there are limited data available on the efficacy of these and other chemotherapy regimens in patients who have received previous systemic chemotherapy. To gather additional efficacy and safety data of pemetrexed/cisplatin and pemetrexed alone in previously treated patients, we examined patients treated on the Eli Lilly and Company expanded access program (EAP). Patients with malignant mesothelioma were enrolled in this trial. Of 1056 patients receiving at least one dose of the study drug, 187 (17.7%) were previously treated patients with MPM. Patients were treated every 21 days with pemetrexed 500 mg/m alone (n = 91) or in combination with cisplatin 75 mg/m (n = 96) for a maximum of six cycles. All patients received folic acid and vitamin B12 supplementation and steroid prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmaco-vigilance database for all patients enrolled in the EAP. Median age of the previously treated pleural mesothelioma subset was 66 years (range, 27-87 years). Based on 153 evaluable patients (a subset of the larger intent-to-treat population of 187), the overall response rate was 32.5% for pemetrexed and cisplatin and 5.5% for pemetrexed alone. The disease control rate (response rate + stable disease) was 68.7% for pemetrexed and cisplatin and 46.6% for pemetrexed alone. Median survival was 7.6 months for pemetrexed plus cisplatin (67% censored) and 4.1 months for pemetrexed alone (55% censored). The most commonly reported serious adverse events in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). The data from this EAP study suggest that patients with previously treated MPM can benefit from treatment with pemetrexed alone or in combination with cisplatin. The treatment is associated with acceptable toxicity.


Upregulation of immunoregulatory Src homology 2 molecule containing inositol phosphatase and mononuclear cell hyporesponsiveness in oral mucosa during chronic periodontitis.
Our group and others have shown in vitro that repeated exposure of human mononuclear cells (MNC) to lipopolysaccharide can induce endotoxin tolerance, evidenced by downregulation of TLR2 and TLR4 mRNA and surface protein; moreover, the ability of the MNC to secrete inflammatory cytokines is reduced. In situ studies performed on diseased and healthy gingiva suggest that a similar pattern of endotoxin tolerance occurs in human oral mucosa with chronic periodontitis (CP). We hypothesized that this represents a fundamental immunoregulatory mechanism to restore immune homeostasis and protect the host from further tissue damage. In the current study, we extend these published studies by providing evidence that Src homology 2 containing inositol phosphatase, an inhibitor of NF-kappaB activation and a negative regulator of the immune response, is upregulated in the oral mucosa during CP compared to its level during gingival health. We have also isolated MNC from patients with CP and those with healthy gingiva and show that MNC from CP subjects have a reduced capacity to upregulate TLR2, TLR4, and interleukin-1beta in response to endotoxin. Thus, we provide more definitive evidence for a basic mechanism of immunoregulation in the oral mucosa.


IMPAIRED DARK ADAPTATION ASSOCIATED WITH A DISEASED BRUCH MEMBRANE IN PSEUDOXANTHOMA ELASTICUM.
To characterize dark adaptation in patients with pseudoxanthoma elasticum, a systemic disease leading to calcification of elastic tissue including the Bruch membrane. In this prospective case-control study, dark adaptation thresholds were measured using a Goldmann-Weekers dark adaptometer. Additional assessments included best-corrected visual acuity testing, contrast sensitivity, low luminance deficit, and vision-related quality of life. Dark adaptation thresholds were significantly higher, and adaptation periods were prolonged in patients with pseudoxanthoma elasticum (n = 35; 33 with 2 ABCC6 mutations) compared with controls (n = 35). The time to adapt 4 log units (20.6 ± 8.6 vs. 8.0 ± 1.3 minutes) and the mean dark adaptation threshold after 15 minutes (3.5 ± 1.1 vs. 1.8 ± 0.2 log units) were significantly different between patients and controls (both P < 0.001). Low luminance deficits (12.3 ± 6.4 vs. 6.1 ± 4.3 ETDRS letters), contrast sensitivity (1.4 ± 0.3 vs. 1.9 ± 0.1), and low luminance-related quality of life (LLQ score: 1,286 ± 355 vs. 2,167 ± 68) were also significantly worse in patients with pseudoxanthoma elasticum (all, P < 0.001). Two patients were treated with high-dose vitamin A which partially reversed impaired dark adaptation. Patients with pseudoxanthoma elasticum often have impaired dark adaptation. Positive effects of vitamin A supplementation may indicate restricted retinal access of vitamin A through the Bruch membrane as one possible underlying pathogenic factor.


Lessons Learned From Hurricane Maria in Puerto Rico: Practical Measures to Mitigate the Impact of a Catastrophic Natural Disaster on Radiation Oncology Patients.
Although the wind, rain, and flooding of Hurricane Maria in Puerto Rico abated shortly after its landfall on September 20, 2017, the disruption of the electrical, communications, transportation, and medical infrastructure of the island was unprecedented in scope and caused lasting harm for many months afterward. A compilation of recommendations from radiation oncologists who were in Puerto Rico during the disaster, and from a panel of American Society for Radiation Oncology (ASTRO) cancer experts was created. Radiation oncologists throughout Puerto Rico collaborated and improvised to continue treating patients in the immediate aftermath of the storm and as routine clinical operations were restored gradually. Empirical lessons from the experience of radiation therapy administration in this profoundly altered context of limited resources, impaired communication, and inadequate transportation were organized into a recommended template, applicable to any radiation oncology practice. ASTRO disease-site experts provided evidence-guidelines for mitigating the impact of a 2- to 3-week interruption in radiation therapy. Practical measures to mitigate the medical impact of a disaster are summarized within the framework of "Prepare, Communicate, Operate, Compensate." Specific measures include the development of an emergency operations plan tailored to specific circumstances, prospective coordination with other radiation oncology clinics before a disaster, ongoing communications with emergency management organizations, and routine practice of alternate methods to disseminate information among providers and patients. These recommendations serve as a starting point to assist any radiation oncology practice in becoming more resiliently prepared for a local or regional disruption from any cause. Disease-site experts provide evidence-based guidelines on how to mitigate the impact of a 2- to 3-week interruption in radiation therapy for lung, head and neck, uterine cervix, breast, and prostate cancers through altered fractionation or dose escalation.


Mindfulness based cognitive therapy versus treatment as usual in adults with attention deficit hyperactivity disorder (ADHD).
Adults with attention deficit hyperactivity disorder (ADHD) often present with a lifelong pattern of core symptoms that is associated with impairments of functioning in daily life. This has a substantial personal and economic impact. In clinical practice there is a high need for additional or alternative interventions for existing treatments, usually consisting of pharmacotherapy and/or psycho-education. Although previous studies show preliminary evidence for the effectiveness of mindfulness-based interventions in reducing ADHD symptoms and improving executive functioning, these studies have methodological limitations. This study will take account of these limitations and will examine the effectiveness of Mindfulness Based Cognitive Therapy (MBCT) in further detail. A multi-centre, parallel-group, randomised controlled trial will be conducted in N = 120 adults with ADHD. Patients will be randomised to MBCT in addition to treatment as usual (TAU) or TAU alone. Assessments will take place at baseline and at three, six and nine months after baseline. Primary outcome measure will be severity of ADHD symptoms rated by a blinded clinician. Secondary outcome measures will be self-reported ADHD symptoms, executive functioning, mindfulness skills, self-compassion, positive mental health and general functioning. In addition, a cost-effectiveness analysis will be conducted. This trial will offer valuable information about the clinical and cost-effectiveness of MBCT in addition to TAU compared to TAU alone in adults swith ADHD. ClinicalTrials.gov NCT02463396. Registered 8 June 2015.


The requirement for molecular chaperones during endoplasmic reticulum-associated protein degradation demonstrates that protein export and import are mechanistically distinct.
Polypeptide import into the yeast endoplasmic reticulum (ER) requires two hsp70s, Ssa1p in the cytosol and BiP (Kar2p) in the ER lumen. After import, aberrant polypeptides may be exported to the cytoplasm for degradation by the proteasome, and defects in the ER chaperone calnexin (Cne1p) compromise their degradation. Both import and export require BiP and the Sec61p translocation complex, suggesting that import and export may be mechanistically related. We now show that the cne1Delta and two kar2 mutant alleles exhibit a synthetic interaction and that the export and degradation of pro-alpha factor is defective in kar2 mutant microsomes. Pulse-chase analysis indicates that A1PiZ, another substrate for degradation, is stabilized in the kar2 strains at the restrictive temperature. Because two of the kar2 mutants examined are proficient for polypeptide import, the roles of BiP during ER protein export and import differ, indicating that these processes must be mechanistically distinct. To examine whether Ssa1p drives polypeptides from the ER and is also required for degradation, we assembled reactions using strains either containing a mutation in SSA1 or in which the level of Ssa1p could be regulated. We found that pro-alpha factor and A1PiZ were degraded normally, indicating further that import and export are distinct and that other cytosolic factors may pull polypeptides from the ER.


Genetics of cognitive control: Implications for Nimh's research domain criteria initiative.
Cognitive control refers to a set of mental processes that modulate other cognitive and emotional systems in service of goal-directed adaptive behavior. There is growing support for the notion that cognitive control abnormalities are a central component of many of the neuropsychological deficits observed in individuals with mental illnesses, particularly those with psychotic disorders. NIMH's research domain criteria (RDoC) initiative, which is designed to develop biologically informed constructs to better understand psychopathology, designated cognitive control a construct within the cognitive systems domain. Identification of genes that influence cognitive control or its supportive brain systems will improve our understating of the RDoC construct and provide candidate genes for psychotic disorders. We examine evidence for cognitive control deficits in psychosis, determine if these measures could be useful endophenotypes, and explore work linking genetic variation to cognitive control performance. While there is a wealth of evidence to support the notion the cognitive control is a valid endophenotype for psychosis, its genetic underpinning remains ill characterized. However, existing work provides a promising foundation on which future endeavors might build. Confirming existing individual gene associations will go some way to expanding our understanding of the genetics of cognitive control, and by extension, psychotic disorders. Yet, to truly understand the molecular underpinnings of such complex traits, it may be necessary to evaluate genes in tandem, focusing not on single genes but rather on empirically derived gene sets or on functionally defined networks of genes.


Australian association for exercise and sports science position statement on exercise and hypertension.
Hypertension (high blood pressure; BP) is a leading contributor to premature death and disability from cardiovascular disease. Lifestyle modification that includes regular physical activity is often recommended to patients with hypertension as one of the first line treatments for lowering BP, as well as improving overall risk for cardiovascular events. It is recognised that allied health care professionals play an important role in helping patients to achieve BP control by influencing and reinforcing appropriate lifestyle behavior. The minimum amount of exercise that is recommended in patients with hypertension comprises a mix of moderate to vigorous aerobic (endurance) activity (up to 5 days/week) in addition to resistance (strength) training (on 2 or more non-consecutive days/week). However, due to the dose-response relationship between physical activity and health, exercise levels performed beyond the minimum recommendations are expected to confer additional health benefits. Vigorous exercise training is generally safe and well tolerated by most people, including those with hypertension, although some special considerations are required and these are discussed in this review.


Perinatal outcomes in women with multiple sclerosis exposed to disease-modifying drugs.
The incidence of disease-modifying drug (DMD) exposure during pregnancy in multiple sclerosis (MS) is unknown and limited data exists regarding the potential harm of DMD exposure during pregnancy. To investigate the incidence and effect of in utero DMD exposure on perinatal outcomes. We conducted a retrospective analysis by linking two provincial, population-based databases, the British Columbia (BC) MS database with the BC Perinatal Database Registry. Delivery (duration of the second stage of labor, assisted vaginal delivery and Cesarean section) and neonatal (birth weight, gestational age, 5-minute Apgar score and congenital anomalies) outcomes were compared between women exposed and unexposed to a DMD within 1 month prior to conception and/or during pregnancy. Findings were reported as odds ratios (ORs) with 95% confidence intervals (CIs). In all, 311 women with relapsing-remitting MS delivered 418 singleton babies between April 1998 and March 2009. 21/101 (21%) of births to MS women treated with DMD prior to pregnancy were exposed to a DMD. In all cases, exposure was documented as unintentional and DMD treatment was stopped within 2 months of gestation. The overall incidence of exposure was 21/418 (5%). DMD exposure was associated with a trend towards a greater risk of assisted vaginal delivery compared to the DMD naïve groups (OR = 3.0; 95% CI: 1.0-9.2). All other comparisons of perinatal outcomes were unremarkable. The incidence of DMD exposure was relatively low and no cases were intentional. Further studies are needed to ascertain the safety of DMD exposure during pregnancy in MS.


Communication during counseling sessions about inhaled corticosteroids at the community pharmacy.
Pharmaceutical care is one of the major tasks of pharmacists, which aims to improve patient outcomes. Counseling patients with asthma or chronic obstructive pulmonary disease about their use of inhaled corticosteroids (ICS) might enhance medication adherence and symptom control. Therefore, effective pharmacist-patient communication is very important. In this regard, both affective communication, for handling emotions, and instrumental communication, for exchanging biomedical and lifestyle information, are relevant. Until now, only few studies have explored pharmacist-patient communication, and further insight is needed in this regard. The aim of this study is to investigate how pharmacists and pharmacy technicians communicate about ICS with patients with asthma and/or chronic obstructive pulmonary disease, what topics are discussed by them, and whether pharmacists and pharmacy technicians differ in their communication during counseling sessions. Patients aged ≥18 years who had used ICS for at least 1 year and filled at least two ICS prescriptions in the preceding year were recruited through 12 pharmacies. Participants had one counseling session with a pharmacist or a pharmacy technician, which was video-recorded. The process and content of the provider-patient communication were analyzed using the Roter interaction analysis system, adapted to the pharmaceutical setting. A total of 169 sessions were recorded and analyzed. The communication appeared largely instrumental. Lifestyle, psychosocial issues, and ICS adherence were not discussed in detail. The pharmacists had longer conversations and more affective talk than the pharmacy technicians. Pharmacists and pharmacy technicians may need to pay more attention to ICS adherence, lifestyle, and psychosocial topics. They differed in their communication; the pharmacists exhibited more affective behavior and discussed medical and therapeutic issues more extensively compared to the pharmacy technicians. Educational courses for pharmacists and pharmacy technicians could focus more on the discussion of adherence, lifestyle, and psychosocial topics with patients.


Optical Scully vortex and its spatial evolution.
The structure of an optical vortex formed in a partially coherent Laguerre-Gauss laser beam was considered. The main object of study was the recorded vector field of wavefront tilts that consisted of the vortical and potential components. It was found that the vortical motion weakened as the coherence decreased. Main regularities in the behavior of the vortical component can be described by the Scully vortex model of vortical liquid flow. In the spatial evolution, the potential component of tilts may alternate the sign, thus determining the direction of energy flow to the center or to the periphery of the vortex. Energy flow lines in the beam demonstrate the pattern of decay of an optical vortex similar to the pattern of decaying vortical motion in viscous liquid.


Rising incidence of gastric malignancies in Karachi, 1995- 2002.
South Asia is an enigma for gastric cancer, a low risk region with a contradictory high prevalence for Helicobacter pylori. To examine the demographics, pathology and trends of gastric cancer in Pakistan, epidemiological data of 335 gastric malignancies, registered at Karachi Cancer Registry (KCR) for Karachi South (KS), during 1st January 1995 to 31st December 2002 were reviewed. Trends were studied by categorizing the cases into two time periods '1995-7' and '1998-2002'. Ninety six cases of gastric cancers were registered in the 1995-7 period, 61 in males and 35 in females. In males, the ASR (world), and crude incidence rate (CIR) per 100,000 were 3.9 and 2.3 respectively. In females, the values were 3.0 and 1.5. In the 1998-02 period 239 cases of gastric cancer were registered, 156 cases in males and 83 in females. The ASR and CIR per 100,000 were 6.0 and 3.4 in males and 3.6 and 2.1 in females. An 18% increase was observed in males and 14% in females during the seven year study period. The male to female ratio was 2:1.The mean age of male patients was 51.9 years (95% CI 45.8; 58.1; SD -/+17.9) in 1995-7 and 53.7 years (95% CI 51.6; 55.9; SD -/+14.0) in 1998-02. In females the mean age for the two periods was 48.8 years (95% CI 42.5; 55.0; SD -/+ 18.2) and 48.4 years (95% CI 45.4; 51.5; SD -/+13.9) respectively. Age-specific curves showed a gradual increase in risk from the second until the seventh decade. The majority of the cases presented as poorly or moderately differentiated distal (non-cardia) cancers with a regional spread. Gastric cancers in Karachi fall into the prototype of a low risk developing country pattern. The incidence is increasing, most marked in males above 40 years of age. Larger pathology-based studies are required to comment on the precise morphological sub-types of gastric adenocarcinoma. Etiological studies focused on different strains of H. pylori are required to address the gastric cancer enigma, whilst examining possible protective environmental or genetic factors.


A history of frequent dental care reduces the risk of tooth loss but not periodontitis in older subjects.
Information on the significance of dental care in older adults is limited. We hypothesized that regular dental visits has an effect on the number of remaining teeth and periodontal conditions in older subjects. 1020 randomly selected individuals age 60 - 96 from the Swedish National Study on Aging and Care Blekinge received a comprehensive oral health examination. Dentate women and men had, on average 18.4 teeth (SD +7.6,) and 18.9 teeth (SD + 7.5) respectively (NS). In the youngest group (60 and 66 years old) with less than one dental visit per year, 37% had >20 teeth, compared with 73% among those with at least annual visits. Among the old-old, comparable figures were 1.8 % and 37% respectively. Across age groups, bleeding on probing was 23 %.When adjusting for age, and number of teeth GLM univariate analysis failed to demonstrate an effect of dental visit frequency on alveolar bone loss (p = 0.18), the number of periapical lesions (p = 0.65), or the number of endodontically treated teeth ( p = 0.41). Frequent dental visitors had more teeth than infrequent visitors (p = 0.001). Tooth loss and alveolar bone loss severity increase with age. Individuals with regular dental visits retained more teeth but the frequency of dental visits had no impact on plaque deposits, gingival inflammation, or alveolar bone levels.


Detection of Actinomyces spp. in cervical exudates from women with cervical intraepithelial neoplasia or cervical cancer.
Under certain circumstances, Actinomyces behaves as an opportunistic microorganism and can cause actinomycosis, a chronic and inflammatory granulomatous infection. The purpose of this project was to detect the presence of Actinomyces in cervical exudates from women with cervical intraepithelial neoplasia (CIN) and women with cervical cancer. Cervical samples from 92 women were divided into three groups: CIN, cervical cancer and healthy women. Metagenomic DNA extraction was performed following the Qiagen QIAamp Mini Kit protocol. A specific fragment (675 bp) was amplified by PCR in order to detect the presence of Actinomycetales. Samples in which Actinomycetales was detected were subjected to separate amplification reactions with primer pairs for A. israelii, A. viscosus, A. meyeri and A. odontolyticus. Amplified products were observed by 2 % agarose gel electrophoresis. Actinomyces were found in 10 % of women with CIN, 36.6 % of women with cervical cancer and 9 % of healthy women. The species identified in this study were A. meyeri in 14/92 samples (15.2 %), A. viscosus in 10/92 samples (10.8 %), A. odontolyticus in 4/92 samples (4.3 %) and A. israelii in 6/92 samples (6.5 %). Patients with cervical cancer had a higher prevalence of the presence of Actinomyces compared to the CIN and control groups. This is the first study in which a deliberate search of this genus has been performed in women with cervical pathologies. The use of specific primers for each species facilitated their detection in comparison with traditional isolation methods. More information is necessary to understand the molecular mechanisms involved in the complex role that bacterial communities may play in the development of cancer (and vice versa).


Male gender results in more severe lupus nephritis.
Gender may produce different characteristics in the manifestation of systemic lupus erythematosus (SLE). The present study investigated the influence of gender on clinical, laboratory, autoantibodies and histopathological classes of lupus nephritis (LN). As much as 81 patients diagnosed with SLE (ACR criteria) and active nephritis, who underwent renal biopsy between 1999 and 2004, and who had frozen serum samples and clinical data available from the time of biopsy, were selected for this study. The presence of anti-P and antichromatin antibodies was measured using ELISA, and anti-dsDNA was measured using indirect immunofluorescence. All of the renal biopsies were reviewed in a blinded manner by the same expert renal pathologist. The charts were extensively reviewed for demographic and renal features obtained at the time of the biopsy. Of the 81 patients (13.6%), 11 were male SLE patients. Both male and female lupus patients were of similar age and race, and had similar durations of lupus and renal disease. The female patients had more cutaneous (95.7 vs. 45.5%, P = 0.0001) and haematological (52.9 vs. 18.2%, P = 0.04) involvements than the male SLE patients. In addition, the articular data, central nervous system analyses, serositis findings and SLEDAI scores were similar in both experimental groups. Positivity for anti-dsDNA, anti-ribosomal P and antichromatin did not differ between the two groups, and both groups showed similarly low C3 or C4 serum levels. Our analysis indicated that no histopathological class of LN was predominant in both males and females. Interestingly, the serum creatinine levels were higher in the male SLE patients compared to the female SLE group (3.16 +/- 2.49 vs. 1.99 +/- 1.54 mg/dL, P = 0.03), with an increased frequency of high creatinine (81.8 vs. 47.1%, P = 0.04) as well as renal activity index (7.6 +/- 3.5 vs. 4.8 +/- 3.5, P = 0.02). In addition, whilst the mean levels of proteinuria, cylindruria and serum albumin were markedly altered, they were comparable between both lupus men and women. Moreover, the frequencies of dialysis, renal transplantation and death were similar between the two groups. These data suggest that male patients had a more severe LN compared to women diagnosed with this renal abnormality.


Challenging risk factors for right and left laparoscopic adrenalectomy: A single centre experience with 272 cases.
This study aimed to compare perioperative and postoperative results of right and left laparoscopic adrenalectomy (LA), and to evaluate the impact of challenging factors on these outcomes. A total of 272 patient's medical records that underwent single side LA between October 2006 and September 2017 were retrospectively reviewed. The patients were divided into 2 groups according to operation side. Moreover, pheochromocytoma, metastatic masses and adrenal lesions >5cm in size were considered to be difficult adrenalectomy cases and the outcomes of these cases were compared between two groups. 135 patients (49.6%) underwent right LA and 137 patients (50.4%) underwent left LA. Operation time, estimated blood loss (EBL) and hospitalization time were similar between the groups (p=0.415, p=0.242, p=0.741, respectively). Although EBL was higher on the right side than the left (p=0.038) in the fi rst 20 cases, after this learning period has been completed, there was no significant difference between the groups. In patients with pheochromocytoma, metastatic mass and a mass >5cm in size, despite bleeding complications were clinically higher on the right side, this difference was not statistically significant. During the learning period of LA, EBL is higher on the right side. Due to the greater risk of bleeding complications on the right side even on the hands of experienced surgeons, extra care and preoperative planning are required in patients with pheochromocytoma, metastatic masses and masses >5cm in size.


The energy trade-off between growth and longevity.
Understanding the trade-offs between organisms' life history traits has been a major goal of physiology, ecology and evolution. In the last few decades, two types of intra-specific studies have highlighted the trade-off between growth and longevity. First, diet restriction (DR), as an environmental intervention, has been shown to suppress growth and extend the lifespan of a broad range of animals. Second, genetic studies have also shown that mice, whose growth hormone function is genetically modified (GM), grow slower and live longer than their wild-type siblings. Despite a wealth of empirical data, still largely missing is a theoretical framework that specifies and makes quantitative predictions on this trade-off. Here, I present a mechanistic model based on the principles of energy conservation. The model quantifies explicitly how DR and GM alter the animal's energy budget, and channel metabolic energy to somatic maintenance by suppressing growth, thereby extending lifespan. Data from a diverse set of empirical studies on small rodents supports the predictions of the model. More importantly, the model reveals that although DR and GM are two different methods to extend lifespan, i.e., environmental vs. genetic, the underlying mechanisms of them are the same from the energetic viewpoint.


Harmonic distortion in microwave photonic filters.
We present a theoretical and experimental analysis of nonlinear microwave photonic filters. Far from the conventional condition of low modulation index commonly used to neglect high-order terms, we have analyzed the harmonic distortion involved in microwave photonic structures with periodic and non-periodic frequency responses. We show that it is possible to design microwave photonic filters with reduced harmonic distortion and high linearity even under large signal operation.


1q24 deletion syndrome. Two cases and new insights into genotype-phenotype correlations.
1q24q25 deletions cause a distinctive phenotype including proportionate short stature, microcephaly, brachydactyly, dysmorphic facial features and intellectual disability. We present a mother and son who have a 672 kb microdeletion at 1q24q25. They have the typical skeletal features previously described but do not have any associated intellectual disability. We compare the genes within our patients' deletion to those in the deletions of previously reported cases. This indicates two genes that may be implicated in the intellectual disability usually associated with this deletion syndrome; PIGC and C1orf105. In addition, our cases provide supporting evidence to recent published work suggesting that the skeletal features may be linked to the microRNAs miR199 and miR214, encoded within intron 14 of the Dynamin-3 gene.


Distinct autoimmune syndromes in morphea: a review of 245 adult and pediatric cases.
To determine the prevalence of extracutaneous manifestations and autoimmunity in adult and pediatric patients with morphea. A retrospective review of 245 patients with morphea. University of Texas Southwestern Medical Center-affiliated institutions. Patients Patients with clinical findings consistent with morphea. Prevalence of concomitant autoimmune diseases, prevalence of familial autoimmune disease, prevalence of extracutaneous manifestations, and laboratory evidence of autoimmunity (antinuclear antibody positivity). Secondary outcome measures included demographic features. In this group, adults and children were affected nearly equally, and African Americans were affected less frequently than expected. The prevalence of concomitant autoimmunity in the generalized subtype of morphea was statistically significantly greater than that found in all other subtypes combined (P = .01). Frequency of a family history of autoimmune disease showed a trend in favor of generalized and mixed subgroups. The linear subtype showed a significant association with neurologic manifestations, while general systemic manifestations were most common in the generalized subtype. Antinuclear antibody positivity was most frequent in mixed and generalized subtypes. High prevalences of concomitant and familial autoimmune disease, systemic manifestations, and antinuclear antibody positivity in the generalized and possibly mixed subtypes suggest that these are systemic autoimmune syndromes and not skin-only phenomena. This has implications for the management and treatment of patients with morphea.


DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223.
Irradiation with high linear energy transfer α-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the decay, ranging from 0 to 142 mGy. γ-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values, being in agreement with a negligible β-contribution (3.7%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223-treated patients and early after incorporation of α-emitters.


Does short term placebo treatment of chronic schizophrenia produce long term harm?
A randomised double blind placebo controlled trial is the most reliable method of assessing putative new developments in medical treatment. In schizophrenia, however, some clinicians believe that relapse contributes to long term deterioration and therefore that patients exposed to either placebo or an inactive new treatment may be put at a disadvantage in the long run if the trial leads to an additional relapse. A seven year follow up of patients included in a randomised placebo controlled trial of fluphenazine decanoate, in which 66% of the group given placebo relapsed compared with 8% of those who received the active drug, permitted examination of any long term adverse consequences in those patients who had received placebo. Seventy six (94%) of the 81 patients in the original trial were followed up. At the end of the follow up period there were no consistent or important differences in any measure of clinical or social outcome between the patients who had received placebo and those who had received the active drug. This negative finding has implications for the debate on the risk of placebo controlled trials of maintenance treatment in chronic schizophrenia.


Association between cognitive performance and functional outcome following traumatic brain injury: a longitudinal multilevel examination.
Individuals' cognitive abilities predict functional outcomes following traumatic brain injury (TBI). However, it is not known to what extent concurrent cognitive abilities affect the magnitude or the rate of functional recovery. The current study modeled the progression of functional outcome as it related to background, injury severity, and cognitive variables over the first year postinjury. This study comprised 111 individuals with moderate-to-severe TBI assessed on average at 3, 6, and 13 months postinjury. In addition, 79 healthy controls were assessed at a single time point. Each assessment consisted of an administration of a neuropsychological battery--comprising measures of memory, information processing speed, and executive functions--as well as an administration of the Mayo-Portland Adaptability Inventory to examine functional outcomes. Older age, lower levels of education, and greater days of posttraumatic amnesia were associated with poorer functional outcomes. The addition of cognitive variables resulted in better models than simply considering background and injury severity variables. However, the results showed that the model comprising executive functions best characterized the progression of functional outcomes. The findings indicate that consideration of cognitive ability, rather than reliance on demographic and injury severity variables, provide a more accurate representation of functional outcome over the first year postinjury. In addition, the results suggest that specific cognitive domains, particularly executive functions, are likely to have the strongest effect on functional outcomes.


Further delineation of Nevo syndrome.
Nevo syndrome is an autosomal recessive syndrome characterised by prenatal overgrowth, joint laxity, kyphosis, wrist drop, spindle shaped fingers, and volar oedema. Four children from two families have been reported previously. We report two further children from two unrelated Arab families from two different tribes. Both presented at birth with hypotonia, joint laxity, kyphosis, wrist drop, spindle shaped fingers, and volar oedema. Both have delayed motor development at the ages of 2 years 10 months and 3 months respectively. Cognitive development is normal in one, and the other case appears to be developing normally at 3 months of age. One has, in addition, a wide spinal canal on MRI of the spine indicating some degree of dural ectasia. This report brings the total number of children reported with this syndrome to six from four families; three of these families are Arab. This indicates that the gene for this syndrome is probably commoner in Arabs than in other populations.


Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy.
We analyzed current prescribing patterns for antiepileptic drugs (AEDs) in pregnant women with epilepsy (PWWE) at 20 USA tertiary epilepsy centers. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women from December 2012 to January 2016. Inclusion criteria for PWWE included ages 14-45 years and up to 20 weeks gestational age. Exclusion criteria included history of psychogenic nonepileptic spells, expected intelligence quotient (IQ) <70, other major medical illness, progressive cerebral disease, and switching AEDs in pregnancy prior to enrollment. Three hundred fifty-one PWWE were enrolled in the MONEAD study, which included 259 (73.8%) on monotherapy, 77 (21.9%) on polytherapy, and 15 (4.3%) on no AEDs. The most common AED monotherapy regimens were lamotrigine (42.1% of monotherapies), levetiracetam (37.5%), carbamazepine (5.4%), zonisamide (5.0%), oxcarbazepine (4.6%), and topiramate (3.1%). All other individual monotherapies were each <1%. The most common AED polytherapy combination was lamotrigine + levetiracetam (42.9% of polytherapies), followed by lacosamide + levetiracetam (6.5%), lamotrigine + zonisamide (5.2%), and all other remaining combinations (each <4%); only 5.2% of polytherapy subjects were on ≥3 AEDs (1.1% of total PWWE). Only four subjects (1.1%) were on valproate (1 monotherapy, 3 polytherapy). The distribution of AED use likely reflects current prescribing patterns for PWWE cared for in USA tertiary epilepsy centers. This distribution has changed markedly since the turn of the century, but changes in the general population remain uncertain.


Management of constipation in children and adolescents with autism spectrum disorders.
To develop a practical, readily applied algorithm for primary health care providers to identify, evaluate, and manage constipation in children with autism spectrum disorders (ASDs). The Gastroenterology Committee of the Autism Speaks Autism Treatment Network (ATN), a multisite consortium of centers dedicated to improving standards of medical care for children with ASDs, guided the development of the constipation algorithm through expert opinion and literature review. The algorithm was finalized based on results of field testing by nongastrointestinal, ATN autism medical specialists at 4 ATN sites. A systematic review and grading of the literature pertaining to constipation and children with ASDs was also performed. Consensus among the ATN Gastroenterology Committee identified that in children with ASDs, (1) subtle or atypical symptoms might indicate the presence of constipation; (2) screening, identification, and treatment through a deliberate approach for underlying causes of constipation is appropriate; (3) diagnostic-therapeutic intervention can be provided when constipation is documented; and (4) careful follow-up after any intervention be performed to evaluate effectiveness and tolerance of the therapy. Literature review revealed limited evidence for the clinical evaluation or treatment strategies of children with ASD and constipation. Constipation and its underlying etiology have the potential to be effectively identified and managed using a systematic approach. Lack of evidence on this topic in the literature emphasizes the need for research.


An Outbreak of Chikungunya in Rural Bangladesh, 2011.
The first identified Chikungunya outbreak occurred in Bangladesh in 2008. In late October 2011, a local health official from Dohar Sub-district, Dhaka District, reported an outbreak of undiagnosed fever and joint pain. We investigated the outbreak to confirm the etiology, describe the clinical presentation, and identify associated vectors. During November 2-21, 2011, we conducted house-to-house surveys to identify suspected cases, defined as any inhabitant of Char Kushai village with fever followed by joint pain in the extremities with onset since August 15, 2011. We collected blood specimens and clinical histories from self-selected suspected cases using a structured questionnaire. Blood samples were tested for IgM antibodies against Chikungunya virus. The village was divided into nine segments and we collected mosquito larvae from water containers in seven randomly selected houses in each segment. We calculated the Breteau index for the village and identified the mosquito species. The attack rate was 29% (1105/3840) and 29% of households surveyed had at least one suspected case: 15% had ≥3. The attack rate was 38% (606/1589) in adult women and 25% in adult men (320/1287). Among the 1105 suspected case-patients, 245 self-selected for testing and 80% of those (196/245) had IgM antibodies. In addition to fever and joint pain, 76% (148/196) of confirmed cases had rash and 38%(75/196) had long-lasting joint pain. The village Breteau index was 35 per 100 and 89%(449/504) of hatched mosquitoes were Aedes albopictus. The evidence suggests that this outbreak was due to Chikungunya. The high attack rate suggests that the infection was new to this area, and the increased risk among adult women suggests that risk of transmission may have been higher around households. Chikungunya is an emerging infection in Bangladesh and current surveillance and prevention strategies are insufficient to mount an effective public health response.


Spirituality in nursing: a systematic review of the literature from 2006-10.
Spirituality in nursing care has been discussed for many years in the nursing press. There has been no literature review that explores only UK literature, and this article updates a literature review carried out in 2006 (Ross, 2006). aIM: The review was designed to investigate the current nursing evidence underpinning the concept of spirituality and its application. A systematic review of the literature was undertaken and a thematic analysis performed following a search for literature using defined dates, databases and search terms. Four major themes emerged from the literature: concept clarification; spiritual care-giving; religion and spirituality; and nurse education. Definitions of spiritual care vary, and the concept of spirituality in nursing is still under development. However, until a common language of spirituality is developed, models of spiritual care developed through research involving mainly nursing staff will be difficult for nurses to apply.


Increased Trichotillomania Symptoms in a Child With Fluoxetine Treatment.
Trichotillomania (TTM) is a mental disorder characterized by uncontrolled and impulsive hair pulling leading to hair loss, distress, and disordered functioning. Treatment choices include behavioral therapy (especially habit reversal training) and selective serotonin reuptake inhibitors. However, randomized controlled trials conducted with selective serotonin reuptake inhibitors have led to controversial results of effectiveness for TTM. Here, we report a female patient whose TTM symptoms increased after fluoxetine use.


Gaussian beam spread in biological tissues.
Flux density distributions were measured in large tissue sections illuminated with 633- and 1064-nm laser radiation delivered by an optical fiber. The results were modeled by solving the 2-D diffusion approximation for an incident Gaussian beam and fitting the data with nonlinear regression. It is shown that the radial average flux density is exponentially attenuated for an arbitrary incident irradiance profile.


Equivalent Long-term Transplantation Outcomes for Kidneys Donated After Brain Death and Cardiac Death: Conclusions From a Nationwide Evaluation.
Despite growing waiting lists for renal transplants, hesitations persist with regard to the use of deceased after cardiac death (DCD) renal grafts. We evaluated the outcomes of DCD donations in The Netherlands, the country with the highest proportion of DCD procedures (42.9%) to test whether these hesitations are justified. This study included all procedures with grafts donated after brain death (DBD) (n = 3611) and cardiac death (n = 2711) performed between 2000 and 2017. Transplant outcomes were compared by Kaplan Meier and Cox regression analysis, and factors associated with short (within 90 days of transplantation) and long-term graft loss evaluated in multi-variable analyses. Despite higher incidences of early graft loss (+ 50%) and delayed graft function (+ 250%) in DCD grafts, 10-year graft and recipient survival were similar for the two graft types (Combined 10-year graft survival: 73.9% (95% CI: 72.5-75.2), combined recipient survival: 64.5% (95 CI: 63.0-66.0%)). Long-term outcome equivalence was explained by a reduced impact of delayed graft function on DCD graft survival (RR: 0.69 (95% CI: 0.55-0.87), p < 0.001). Mid and long-term graft function (eGFR), and the impact of incident delayed graft function on eGFR were similar for DBD and DCD grafts. Mid and long term outcomes for DCD grafts are equivalent to DBD kidneys. Poorer short term outcomes are offset by a lesser impact of delayed graft function on DCD graft survival. This nation-wide evaluation does not justify the reluctance to use of DCD renal grafts. A strong focus on short-term outcome neglects the superior recovery potential of DCD grafts.


Temporally correlated fluctuations drive epileptiform dynamics.
Macroscopic models of brain networks typically incorporate assumptions regarding the characteristics of afferent noise, which is used to represent input from distal brain regions or ongoing fluctuations in non-modelled parts of the brain. Such inputs are often modelled by Gaussian white noise which has a flat power spectrum. In contrast, macroscopic fluctuations in the brain typically follow a 1/fb spectrum. It is therefore important to understand the effect on brain dynamics of deviations from the assumption of white noise. In particular, we wish to understand the role that noise might play in eliciting aberrant rhythms in the epileptic brain. To address this question we study the response of a neural mass model to driving by stochastic, temporally correlated input. We characterise the model in terms of whether it generates "healthy" or "epileptiform" dynamics and observe which of these dynamics predominate under different choices of temporal correlation and amplitude of an Ornstein-Uhlenbeck process. We find that certain temporal correlations are prone to eliciting epileptiform dynamics, and that these correlations produce noise with maximal power in the δ and θ bands. Crucially, these are rhythms that are found to be enhanced prior to seizures in humans and animal models of epilepsy. In order to understand why these rhythms can generate epileptiform dynamics, we analyse the response of the model to sinusoidal driving and explain how the bifurcation structure of the model gives rise to these findings. Our results provide insight into how ongoing fluctuations in brain dynamics can facilitate the onset and propagation of epileptiform rhythms in brain networks. Furthermore, we highlight the need to combine large-scale models with noise of a variety of different types in order to understand brain (dys-)function.