Targeting of P-Element Reporters to Heterochromatic Domains by Transposable Element 1360 in Drosophila melanogaster.
Heterochromatin is a common DNA packaging form employed by eukaryotes to constitutively silence transposable elements. Determining which sequences to package as heterochromatin is vital for an organism. Here, we use Drosophila melanogaster to study heterochromatin formation, exploiting position-effect variegation, a process whereby a transgene is silenced stochastically if inserted in proximity to heterochromatin, leading to a variegating phenotype. Previous studies identified the transposable element 1360 as a target for heterochromatin formation. We use transgene reporters with either one or four copies of 1360 to determine if increasing local repeat density can alter the fraction of the genome supporting heterochromatin formation. We find that including 1360 in the reporter increases the frequency with which variegating phenotypes are observed. This increase is due to a greater recovery of insertions at the telomere-associated sequences (∼50% of variegating inserts). In contrast to variegating insertions elsewhere, the phenotype of telomere-associated sequence insertions is largely independent of the presence of 1360 in the reporter. We find that variegating and fully expressed transgenes are located in different types of chromatin and that variegating reporters in the telomere-associated sequences differ from those in pericentric heterochromatin. Indeed, chromatin marks at the transgene insertion site can be used to predict the eye phenotype. Our analysis reveals that increasing the local repeat density (via the transgene reporter) does not enlarge the fraction of the genome supporting heterochromatin formation. Rather, additional copies of 1360 appear to target the reporter to the telomere-associated sequences with greater efficiency, thus leading to an increased recovery of variegating insertions.


Effect of tongue position on masseter and temporalis electromyographic activity during swallowing and maximal voluntary clenching: a cross-sectional study.
The purpose of this study was to measure and compare the tonic electromyographic (EMG) activity of the temporalis and masseter muscles following placement of the tongue either on the palate or in the floor of the mouth during swallowing and maximal voluntary clenching (MVC). Thirty healthy dental students with natural dentition and bilateral molar support, between the ages of 18 and 22, with no prior history of oro-facial injury, or current or past pain in the jaw, mouth or tongue participated in the study. Tonic masseter and temporalis EMG activities were recorded using surface electrodes. Subjects were instructed to passively place the tongue either on the anterior hard palate or in the floor of the mouth during swallowing and MVC. At each tongue position, the resulting EMG was recorded. During swallowing, no significant difference in EMG activity was found either for the masseter (P-value = 0.1592) or the temporalis (P-value = 0.0546) muscles, regardless of the tongue position. During MVC, there was a statistically significant difference for both the masseter (P-value = 0.0016) and the temporalis (P-value = 0.0277) muscles with lower levels recorded with the tongue in the floor of the mouth. This study found that in normal, pain-free subjects, placing the tongue in the floor of the mouth significantly reduces masticatory muscle activity during MVC. Thus, it may be considered as a possible therapeutic option to decrease masticatory muscle activity; however, further research is needed in patients with oro-facial pain.


Etiopathogenesis of primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterized by progressive bile duct destruction eventually leading to cirrhosis and liver failure. The serological hallmark of the disease is the presence of circulating antimitochondrial antibodies (AMA). These reflect the presence of autoreactive T and B cells to the culprit antigens, the E2 subunits of mitochondrial 2-oxo-acid dehydrogenase enzymes, chiefly pyruvate dehydrogenase (PDC-E2). The disease results from a combination of genetic and environmental risk factors. Genetic predisposition is indicated by the higher familial incidence of the disease particularly among siblings and the high concordance rate among monozygotic twins. Environmental triggering events appear crucial to disrupt a pre-existing unstable immune tolerance of genetic origin allowing, after a long latency, the emergence of clinical disease. Initiating mimetopes of the vulnerable epitope of the PDC-E2 autoantigen can be derived from microbes that utilize the PDC enzyme or, alternatively, environmental xenobiotics/chemical compounds that modify the structure of native proteins to make them immunogenic. A further alternative as a source of antigen is PDC-E2 derived from apoptotic cells. In the effector phase the biliary ductular cell, by reason of its proclivity to express the antigen PDC-E2 in the course of apoptosis, undergoes a multilineage immune attack comprised of CD4(+) and CD8(+) T cells and antibody. In this article, we critically review the available evidence on etiopathogenesis of PBC and present interpretations of complex data, new developments and theories, and nominate directions for future research.


Guidelines for the preventive treatment of ischaemic stroke and TIA (II). Recommendations according to aetiological sub-type.
To update the ad hoc Committee of the Cerebrovascular Diseases Study Group of The Spanish Neurological Society guidelines on prevention of ischaemic stroke (IS) and Transient Ischaemic Attack (TIA). We reviewed the available evidence on ischaemic stroke and TIA prevention according to aetiological subtype. Levels of evidence and recommendation levels are based on the classification of the Centre for Evidence-Based Medicine. In atherothrombotic IS, antiplatelet therapy and revascularization procedures in selected cases of ipsilateral carotid stenosis (70%-90%) reduce the risk of recurrences. In cardioembolic IS (atrial fibrillation, valvular diseases, prosthetic valves and myocardial infarction with mural thrombus) prevention is based on the use of oral anticoagulants. Preventive therapies for uncommon causes of IS will depend on the aetiology. In the case of cerebral venous thrombosis oral anticoagulation is effective. We conclude with recommendations for clinical practice in prevention of IS according to the aetiological subtype presented by the patient.


Progressive dysbiosis of human orodigestive microbiota along the sequence of gastroesophageal reflux, Barrett's esophagus and esophageal adenocarcinoma.
The incidence of esophageal adenocarcinoma (EA) has drastically increased in the United States since 1970s for unclear reasons. We hypothesized that the widespread usage of antibiotics has increased the procarcinogenic potential of the orodigestive microbiota along the sequence of gastroesophageal reflux (GR), Barrett's esophagus (BE) and EA phenotypes. This case control study included normal controls (NC) and three disease phenotypes GR, BE and EA. Microbiota in the mouth, esophagus, and stomach, and rectum were analyzed using 16S rRNA gene sequencing. Overall, we discovered 44 significant pairwise differences in abundance of microbial taxa between the four phenotypes, with 12 differences in the mouth, 21 in the esophagus, two in the stomach, and nine in the rectum. Along the GR→BE→EA sequence, oral and esophageal microbiota were more diversified, the dominant genus Streptococcus was progressively depleted while six other genera Atopobium, Actinomyces, Veillonella, Ralstonia, Burkholderia and Lautropia progressively enriched. In NC, Streptococcus appeared to control populations of other genera in the foregut via numerous negative and positive connections, while in disease states, the rich network was markedly simplified. Inferred gene functional content showed a progressive enrichment through the stages of EA development in genes encoding antibiotic resistance, ligands of Toll-like and NOD-like receptors, nitrate-nitrite-nitric oxide pathway and acetaldehyde metabolism. The orodigestive microbiota is in a progressive dysbiotic state along the GR-BE-EA sequence. The increasing dysbiosis and antibiotic and procarcinogenic genes in the disease states warrants further study to define their roles in EA pathogenesis.


Predictors of longterm changes in body mass index in rheumatoid arthritis.
Low body mass index (BMI) is a risk factor for poor longterm outcomes in rheumatoid arthritis (RA). The purpose of this study was to identify factors associated with longterm changes in BMI. Subjects with RA from the Veterans Affairs (VA) Rheumatoid Arthritis (VARA) Registry (n = 1474) were studied. Information on inflammatory markers, presence of erosions, and smoking status were extracted from the VARA database. BMI was extracted from VA electronic medical records within 14 days of each visit date. VA pharmacy records were queried to identify prescriptions for specific RA therapies within 1 month of the visit date. We used robust generalized estimating equations marginal regression models to calculate independent associations between clinical variables and BMI over time. Similar models determined predictors of change in weight and risk of weight loss over the subsequent study observation period. Increasing age, active smoking, and the presence of erosions at baseline were associated with lower BMI. Weight decreased over time among older adults. Factors associated with greater reductions in BMI over time and a greater risk of weight loss were higher inflammatory markers, smoking, older age, higher BMI, and less subsequent improvement in inflammation. Methotrexate use was associated with a lower risk of weight loss. The use of prednisone or anti-tumor necrosis factor therapies was not associated with change in BMI or the risk of weight loss independent of other factors. Greater age, greater inflammatory activity, and active smoking are associated with greater weight loss in RA over time.


Conscientiousness and medication adherence: a meta-analysis.
Approximately a quarter to a half of all people fail to take their medication regimen as prescribed (i.e. non-adherence). Conscientiousness, from the five-factor model of personality, has been positively linked to adherence to medications in several recent studies. This study aimed to systematically estimate the strength and variability of this association across multiple published articles and to identify moderators of this relationship. A literature search identified 16 studies (N = 3,476) that met the study eligibility criteria. Estimates of effect sizes (r) obtained in these studies were meta-analysed. Overall, a higher level of conscientiousness was associated with better medication adherence (r = 0.15; 95 % CI, 0.09, 0.21). Associations were significantly stronger in younger samples (r = 0.26, 95 % CI, 0.17, 0.34; k = 7). The small association between conscientiousness and medication adherence may have clinical significance in contexts where small differences in adherence result in clinically important effects.


Simultaneous Production of Psilocybin and a Cocktail of β-Carboline Monoamine Oxidase Inhibitors in "Magic" Mushrooms.
The psychotropic effects of Psilocybe "magic" mushrooms are caused by the l-tryptophan-derived alkaloid psilocybin. Despite their significance, the secondary metabolome of these fungi is poorly understood in general. Our analysis of four Psilocybe species identified harmane, harmine, and a range of other l-tryptophan-derived β-carbolines as their natural products, which was confirmed by 1D and 2D NMR spectroscopy. Stable-isotope labeling with 13 C11 -l-tryptophan verified the β-carbolines as biosynthetic products of these fungi. In addition, MALDI-MS imaging showed that β-carbolines accumulate toward the hyphal apices. As potent inhibitors of monoamine oxidases, β-carbolines are neuroactive compounds and interfere with psilocybin degradation. Therefore, our findings represent an unprecedented scenario of natural product pathways that diverge from the same building block and produce dissimilar compounds, yet contribute directly or indirectly to the same pharmacological effects.


Leprosy susceptibility: genetic variations regulate innate and adaptive immunity, and disease outcome.
The past few years have been very productive concerning the identification of genes associated with leprosy. Candidate gene strategies using both case-control and family-based designs, as well as large-scale approaches such as linkage and gene-expression genomic scans and, more recently, genome-wide association studies, have refined and enriched the list of genes highlighting the most important innate and adaptive immune pathways associated with leprosy susceptibility or resistance. During the early events of host-pathogen interaction identified genes are involved in pattern recognition receptors, and mycobacterial uptake (TLRs, NOD2 and MRC1), which modulate autophagy. Another gene, LTA4H, which regulates the levels of lipoxin A4 and possibly interacts with lipid droplet-related events, also plays a role in the early immune responses to Mycobacterium leprae. Together, the activation of these pathways regulates cellular metabolism upon infection, activating cytokine production through NF-κB and vitamin D-vitamin D receptor pathways, while PARK2 and LRRK2 participate in the regulation of host-cell apoptosis. Concomitantly, genes triggered to form and maintain granulomas (TNF, LTA and IFNG) and genes involved in activating and differentiating T-helper cells (HLA, IL10, as well as the TNF/LTA axis and the IFNG/IL12 axis) bridge immunological regulation towards adaptive immunity. Subtle variations in these genes, mostly single nucleotide polymorphisms, alter the risk of developing the disease or the severity of leprosy. Knowing these genes and their role will ultimately lead to better strategies for leprosy prevention, treatment and early diagnosis. Finally, the same genes associated with leprosy were also associated with autoimmune (Crohn's disease, rheumathoid arthritis, psoriasis) or neurodegenerative diseases (Parkinson's and Alzheimer's). Thus, information retrieved using leprosy as a model could be valuable to understanding the pathogenesis of other complex diseases.


Microplastic contamination in the San Francisco Bay, California, USA.
Despite widespread detection of microplastic pollution in marine environments, data describing microplastic abundance in urban estuaries and microplastic discharge via treated municipal wastewater are limited. This study presents information on abundance, distribution, and composition of microplastic at nine sites in San Francisco Bay, California, USA. Also presented are characterizations of microplastic in final effluent from eight wastewater treatment plants, employing varying treatment technologies, that discharge to the Bay. With an average microplastic abundance of 700,000particles/km(2), Bay surface water appears to have higher microplastic levels than other urban waterbodies sampled in North America. Moreover, treated wastewater from facilities that discharge into the Bay contains considerable microplastic contamination. Facilities employing tertiary filtration did not show lower levels of contamination than those using secondary treatment. As textile-derived fibers were more abundant in wastewater, higher levels of fragments in surface water suggest additional pathways of microplastic pollution, such as stormwater runoff.


On exploring the basis for slow potential oscillations in the mammalian stomach and intestine.
The basic driving unit of oscillatory electrical activity in stomach and intestine is the slow wave, a propagating depolarization of myogenic origin. The slow wave controls contractile activity in the intestine by triggering action potential bursts, while in the stomach there is both action potential and spike-free slow wave activation. This review attempts to summarize recent characterizations of the slow wave and to explore in detail the evidence, which suggests that the mechanisms which generate the electrical oscillations are quite closely coupled to metabolic processes.


Trends in myopia management attitudes and strategies in clinical practice: Survey of eye care practitioners in Africa.
There remains a lack of information on the perception and adoption of myopia control strategies among African eye care practitioners (ECPs). This study provides an African perspective to similar previous studies conducted in other parts of the world. A self-administered survey in English and French was distributed to ECPs across Africa. The items on the questionnaire assessed their level of concern about the increasing prevalence of paediatric myopia, perceived efficacy, opinions on, and adoption of various myopia management modalities. Responses were obtained from 330 ECPs working in 23 African countries. Respondents were highly concerned about the increasing prevalence of paediatric myopia in their clinic (median 8/10) and perceived approved myopia control soft contact lenses as the most effective at slowing myopia progression (mean perceived reduction in myopia progression ± SD; 53.9 ± 27.1%), followed by single vision spectacles (53.1 ± 30.9%), and orthokeratology (52.8 ± 28.0%). Multifocal soft contact lenses (40.4 ± 25.8%) and pharmaceutical agents such as topical atropine drops (39.5 ± 27.1%) were perceived as least effective in slowing myopia progression. Although ECPs reported being aware of various myopia control strategies, they still mainly prescribed single vision spectacles to a large proportion (64.3 ± 29.9%) of young progressing myopes. Nearly one-third (27%) of ECPs who prescribed single vision lenses stated they were concerned about the cost implications to patients. Other reported concerns included safety of, and inadequate information about myopia control options. African ECPs continue to prescribe single vision lenses for progressing myopes despite being aware of the various myopia control options. Practitioners' perceptions of the efficacy of several modalities to slow myopia progression do not align with the current best evidence. Clear practice guidelines and continuing education on myopia control are warranted to inform and guide the management of myopic patients in Africa.


Immunohistologic evaluation of invasion-associated proteases in breast carcinoma.
Immunostaining of two invasion-associated proteolytic enzymes, cathepsin D (CD) and urokinase-type plasminogen activator (uPA), was assessed in cryostat sections of 86 stage-heterogeneous breast carcinomas using monoclonal antibodies. Most tumors displayed a focal and/or heterogeneous staining pattern. Overall, staining was more frequent in host-derived stromal and inflammatory cells (uPA 54%, CD 89%) than neoplastic epithelium per se (uPA 24%, CD 70%). Intense (i.e., 2+) stromal, but not neoplastic, CD was significantly correlated with nodal or systematic metastases (node negative--10% versus node positive/systemic--33%, p = 0.04). Further, cumulative staining of more than one enzyme (CD + uPA) or more than one tumor component (stroma + epithelium) correlated with metastatic disease (no metastases--35% versus metastatic--72%, p = 0.005). Neither stromal nor epithelial CD alone was significantly correlated with short-term recurrence free survival, however additive CD staining (i.e., stromal + epithelial) was strongly predictive, overall (both + -75% recurred versus both weak/negative--16% recurred, p = 0.0004) and in node positive patients (p = 0.02). We conclude that (a) enzymes putatively mediating extracellular matrix dissolution may be derived from multiple sources and (b) the metastatic capacity and/or clinical aggressiveness of breast carcinomas may reflect overall proteolytic enzyme expression, suggesting that cooperative enzyme interaction may be required for invasive growth and/or metastasis.


Monoclonal antibodies to a human prostate antigen.
Three monoclonal antibodies reactive with a purified extractable Mr 34,000 prostate antigen (PA) have been prepared by fusing splenocytes of BALB/c mice preimmunized with purified PA with the NS1 mouse myeloma cell line. The three antibodies were all of the IgG-1 subclass. The antibodies defined two noncross-blocking unique determinants on PA; each present as one site per molecule. IF3 defined one antigenic site and 2G7 and 1C5 defined another antigenic determinant. All of the antibodies reacted with PA in a solid-phase radioimmunoassay and immunoprecipitated 125I-labeled PA. Absorption and sandwich radioimmunoassays showed PA in prostate tissues but not in tonsil, liver, or kidney. Immunoperoxidase staining of formalin-fixed paraffin-embedded sections of benign prostatic hyperplasia and prostatic carcinoma revealed strong prostate epithelial reactivity. None of the antibodies showed reactivity with prostate membrane preparations. A sandwich radioimmunoassay used 2G7 as a plate coat. 125I-labeled 1F3 was used to detect 5 ng PA per ml in sera of patients with prostate cancer. These results confirm previous observations regarding the specificity of PA and shed new evidence for its intracellular localization.


Securing the demographic and genetic future of tuatara through assisted colonization.
Climate change poses a particular threat to species with fragmented distributions and little or no capacity to migrate. Assisted colonization, moving species into regions where they have not previously occurred, aims to establish populations where they are expected to survive as climatic envelopes shift. However, adaptation to the source environment may affect whether species successfully establish in new regions. Assisted colonization has spurred debate among conservation biologists and ecologists over whether the potential benefits to the threatened species outweigh the potential disruption to recipient communities. In our opinion, the debate has been distracted by controversial examples, rather than cases where assisted colonization may be a viable strategy. We present a strategic plan for the assisted migration of tuatara (Sphenodon punctatus), an endemic New Zealand reptile. The plan includes use of extant populations as reference points for comparisons with assisted-colonization populations with respect to demography, phenotypic plasticity, and phenology; optimization of genetic variation; research to fill knowledge gaps; consideration of host and recipient communities; and inclusion of stakeholders in the planning stage. When strategically planned and monitored, assisted colonization could meet conservation and research goals and ultimately result in the establishment of long-term sustainable populations capable of persisting during rapid changes in climate.


Mediterranean dietary patterns and prospective weight change in participants of the EPIC-PANACEA project.
There is an association between a greater adherence to a Mediterranean diet and a reduced risk of developing chronic diseases. However, it is not clear whether this dietary pattern may be protective also against the development of obesity. We assessed the association between the adherence to the Mediterranean dietary pattern (MDP), prospective weight change, and the incidence of overweight or obesity. We conducted a prospective cohort study [the European Prospective Investigation into Cancer and Nutrition-Physical Activity, Nutrition, Alcohol Consumption, Cessation of Smoking, Eating Out of Home, and Obesity (EPIC-PANACEA) project] in 373,803 individuals (103,455 men and 270,348 women; age range: 25-70 y) from 10 European countries. Anthropometric measurements were obtained at recruitment and after a median follow-up time of 5 y. The relative Mediterranean Diet Score (rMED; score range: 0-18) was used to assess adherence to the MDP according to the consumption of 9 dietary components that are characteristic of the Mediterranean diet. The association between the rMED and 5-y weight change was modeled through multiadjusted mixed-effects linear regression. Individuals with a high adherence to the MDP according to the rMED (11-18 points) showed a 5-y weight change of -0.16 kg (95% CI: -0.24, -0.07 kg) and were 10% (95% CI: 4%, 18%) less likely to develop overweight or obesity than were individuals with a low adherence to the MDP (0-6 points). The low meat content of the Mediterranean diet seemed to account for most of its positive effect against weight gain. This study shows that promoting the MDP as a model of healthy eating may help to prevent weight gain and the development of obesity.


Multi-wavelength dye concentration determination for enzymatic assays: evaluation of chromogenic para-nitrophenol over a wide pH range.
Enzymatic assays need robust, rapid colorimetric methods that can follow ongoing reactions. For this, we developed a highly accurate, multi-wavelength detection method that could be used for several systems. Here, it was applied to the detection of para-nitrophenol (pNP) in basic and acidic solutions. First, we confirmed by factor analysis that pNP has two forms, with unique spectral characteristics in the 240 to 600 nm range: Phenol in acidic conditions absorbs in the lower range, whereas phenolate in basic conditions absorbs in the higher range. Thereafter, the method was used for the determination of species concentration. For this, the intensity measurements were made at only two wavelengths with a microtiter plate reader. This yielded total dye concentration, species relative abundance, and solution pH value. The method was applied to an enzymatic assay. For this, a chromogenic substrate that generates pNP after hydrolysis catalyzed by a lipase from the fungus Yarrowia lipolytica was used. Over the pH range of 3-11, accurate amounts of acidic and basic pNP were determined at 340 and 405 nm, respectively. This method surpasses the commonly used single-wavelength assay at 405 nm, which does not detect pNP acidic species, leading to activity underestimations. Moreover, alleviation of this pH-related problem by neutralization is not necessary. On the whole, the method developed is readily applicable to rapid high-throughput of enzymatic activity measurements over a wide pH range.


Comparative Analysis of the Genetic Basis of Branched Nonylphenol Degradation by Sphingobium amiense DSM 16289T and Sphingobium cloacae JCM 10874T.
Branched nonylphenol (BNP), a degradation product of nonylphenol polyethoxylates, exerts estrogenic effects on various organisms. The genes underlying BNP degradation by Sphingobium amiense DSM 16289T were analyzed by complete genome sequencing and compared with those of the versatile BNP-degrading Sphingobium cloacae JCM 10874T. An opdA homolog (opdADSM16289) encoding BNP degradation activity was identified in DSM 16289T, in contrast with JCM 10874T, possessing both the opdA homolog and nmoA. The degradation profile of different BNP isomers was examined by Escherichia coli transformants harboring opdADSM16289, opdAJCM10874, and nmoAJCM10874 to characterize and compare the expression activities of these genes.


Natural history and risk factors of atherosclerosis in children and youth: the PDAY study.
The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study was organized to document the natural history of athersclerosis and to determine the relation of cardiovascular risk factors to atherosclerosis in young subjects. Pathology laboratories in 15 centers collected coronary arteries, aortas, and other tissues from over 3,000 subjects age 15 to 34 who died of external causes between 1987 and 1994. The extent, prevalence, and topography of arterial lesions were evaluated and risk factors were analyzed in a central laboratory. Postmortem risk factors included serum lipoproteins, serum thiocyanate (smoking), glycohemoglobin (diabetes), thickness of panniculus adiposus and body mass index (obesity), changes in small renal arteries (hypertension), and apoprotein isoforms. The PDAY study confirmed the origin of atherosclerosis in childhood, showed that progression toward clinically significant lesions may occur in young adulthood and demonstrated that the progression of atherosclerosis is strongly influenced by coronary heart disease (CHD) risk factors. Recent PDAY studies have shown that a significant number of advanced coronary artery lesions have microscopic qualities associated with susceptibility to rupture and that CHD risk factors are associated with the development of these characteristic microscopic qualities. The PDAY archive continues to provide an important resource for new investigators throughout the world that contribute to the understanding of atherosclerosis, the underlying cause of most cardiovascular disease and the leading cause of debilitating illness and death in this country. The PDAY findings emphasize the need to modify risk factors in young people to retard the development of atherosclerotic lesions, particularly clinically significant lesions. Thus, true primary prevention of atherosclerosis must being in childhood or early adolescence.


Prognostic value of hyponatremia in heart failure patients: an analysis of the Clinical Characteristics and Outcomes in the Relation with Serum Sodium Level in Asian Patients Hospitalized for Heart Failure (COAST) study.
Hyponatremia is a well-known risk factor for poor outcomes in Western studies of heart failure (HF) patients. We evaluated the predictive value of hyponatremia in hospitalized Asian HF patients. The Clinical Characteristics and Outcomes in the Relation with Serum Sodium Level in Asian Patients Hospitalized for Heart Failure (the COAST) study enrolled hospitalized patients with systolic HF (ejection fraction < 45%) at eight centers in South Korea, Taiwan, and China. The relationship between admission sodium level and clinical outcomes was analyzed in 1,470 patients. The mean admission sodium level was 138 ± 4.7 mmol/L, and 247 patients (16.8%) had hyponatremia defined as Na(+) < 135 mmol/L. The 12-month mortality was higher in hyponatremic patients (27.9% vs. 14.6%, p < 0.001), and hyponatremia was an independent predictor of 12-month mortality (hazard ratio, 1.72; 95% confidence interval, 1.12 to 2.65). During hospital admission, 57% of hyponatremic patients showed improvement without improvement in their clinical outcomes (p = 0.620). The proportion of patients with optimal medical treatment was only 26.5% and 44.2% at admission and discharge, respectively, defined as the combined use of angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker and β-blocker. Underuse of optimal medical treatment was more pronounced in hyponatremic patients. In hospitalized Asian HF patients, hyponatremia at admission is common and is an independent predictor of poor clinical outcome. Furthermore, hyponatremic patients receive less optimal medical treatment than their counterparts.


Laparoscopic versus Open surgery for small bowel Crohn's disease.
Crohn's disease (CD) is a chronic inflammatory bowel disease that most commonly involves the terminal ileum and colon (55 percent). Surgical treatment is required in approximately 70 percent of patients. Multiple procedures and repeat operations are required in 30 - 70 percent of all patients (Duepree 2002) but the disease remains incurable.Laparoscopy has gained wide acceptance in gastrointestinal surgery with potential advantages of faster return to normal activity and diet, reduced hospital stay, reduced postoperative pain, better cosmesis (Duepree 2002, Dunker 1998, Milsom 2001, Reissman 1996), improved social and sexual interaction (Albaz 2000) and its use is accepted in benign and malignant colorectal diseases. Laparoscopic surgery offers additional advantage of smaller abdominal fascial wounds, low incidence of hernias, and decreased rate of adhesive small-bowel obstruction (Albaz 2000) compared with conventional surgery reducing the need for non-disease-related surgical procedures in CD population.There are concerns about missing occult segments of disease and critical proximal strictures due to limited tactile ability, earlier recurrence due to possible reduced immune response induced by laparoscopy, technical difficulty due to fragile inflamed bowel and mesentery and the existence of adhesions, fistulas, and abscesses (Uchikoshi 2004). It is therefore important to evaluate the potential benefits and risks of laparoscopic surgery versus open surgery in patients with small bowel CD (Lowney 2005). To determine if there is a difference in the perioperative outcomes and re-operation rates for disease recurrence following laparoscopic surgery compared to open surgery in small bowel CD. Published and unpublished randomised controlled trials were searched for in the following electronic databases: The Cochrane Central Register of Controlled Trials (CENTRAL) 2010 issue 2 The Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects (DARE) 2010 issue 2 The Cochrane Colorectal Cancer Group Controlled Trials Register Ovid MEDLINE (1990 to 2010) EMBASE (1990 to 2010) Health Technology Assessment (HTA) Database (1990 to 2010) Randomised controlled trials (RCT) comparing laparoscopic and open surgery for small bowel CD were included. Two reviewers independently assessed the studies and extracted data. RevMan 5.0 was used for statistical analysis. Two RCTs comparing laparoscopic and open surgery for small bowel CD were identified. Long term outcomes of the patients in both the trials were published separately and these were included in the review.Laparoscopic surgery appeared to be associated with reduced number of wound infections (1/61 vs 9/59), reoperation rates for non disease related complications (3/57 vs 7/54 ) but the difference was not statistically significant [p values were 0.23 and 0.19 respectively]. There was no statistically significant difference between any of the compared outcomes between laparoscopic and open surgery in the management of small bowel CD. Laparoscopic surgery for small bowel CD may be as safe as the open operation. There was no significant difference in the perioperative outcomes and the long term reoperation rates for disease-related or non-disease related complications of CD.


DNA microarray analysis and functional profile of pituitary transcriptome under core-clock protein BMAL1 control.
Although it is known to contain five cell types that synthesize and release hormones with a circadian pattern, the pituitary gland is poorly characterized as a circadian oscillator. By a differential microarray analysis, 252 genes were found to be differentially expressed in pituitaries from Bmal1(-/-) knockout versus wild-type mice. By integrative analyses of the data set with the Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources annotation analysis system, pituitary genes with altered expression in Bmal1(-/-) mice were dispatched among functional categories. Clusters of genes related to signaling and rhythmic processes as well as transcription regulators, in general, were found enriched in the data set, as were pathways such as circadian rhythm, transforming growth factor β (TGFβ) signaling, valine, leucine, and isoleucine degradation, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Gene Ontology term overrepresentation analyses revealed significant enrichment for genes involved in 10 key biological processes. To determine whether genes with altered expression in Bmal1(-/-) mice were actually circadian genes, we further characterized in the mouse pituitary gland the daily pattern of some of these genes, including core-clock genes. Core-clock genes and genes selected from three identified overrepresented biological processes, namely, hormone metabolic process, regulation of transcription from RNA polymerase II promoter, and cell adhesion, displayed a rhythmic pattern. Given the enrichment in genes dedicated to cell adhesion and their daily changes in the pituitary, it is hypothesized that cell-cell interactions could be involved in the transmission of information between endocrine cells, allowing rhythmic hormone outputs to be controlled in a temporally precise manner.


Persistent blood stream infection in patients supported with a continuous-flow left ventricular assist device is associated with an increased risk of cerebrovascular accidents.
Common adverse events in patients supported with Continuous-flow left ventricular assist devices (CF-LVAD) include infections and cerebrovascular accidents (CVA). Some studies have suggested a possible association between blood stream infection (BSI) and CVA. Medical records of patients who received Heartmate II (HMII) CF-LVADs in 2008-2012 at a single center were reviewed. CVA was categorized as either hemorrhagic (HCVA) or ischemic (ICVA). BSI was divided into persistent (pBSI) and nonpersistent (non-pBSI). pBSI was defined as BSI with the same organism on repeated blood culture >72 hours from initial blood culture despite antibiotics. Univariate and multivariate analyses were performed to determine predictors. A total of 149 patients had HMII implanted; 76% were male, and the overall mean age was 55.4 ± 13 years. There were a total of 19 (13%) patients who had CVA (7 HCVA and 12 ICVA) at a median of 295 days (range 5-1,096 days) after implantation. There were a total of 28 (19%) patients with pBSI and 17 (11%) patients with non-pBSI. Patients with pBSI had a trend toward greater BMI (31 kg/m(2) vs 27 kg/m(2); P = .09), and longer duration of support (1,019 d vs 371 d; P < .001) compared with those with non-pBSI. Persistent BSI was associated with an increased risk of mortality and with all-cause CVA on multivariate analysis (odds ratio [OR] 5.97; P = .003) as well as persistent Pseudomonas aeruginosa infection (OR 4.54; P = .048). Persistent BSI is not uncommon in patients supported by CF-LVAD and is highly associated with all-cause CVA and increased all-cause mortality.


Review of the bioenvironmental methods for malaria control with special reference to the use of larvivorous fishes and composite fish culture in central Gujarat, India.
Mosquito control with the use of insecticides is faced with the challenges of insecticide resistance in disease vectors, community refusal, their high cost, operational difficulties, and environmental concern. In view of this, integrated vector control strategies with the use of larvivorous fishes such as Guppy (Poecilia reticulata) and Gambusia (G. affinis) as biological control agents were used in controlling mosquito breeding in different types of breeding places such as intradomestic containers, various types of wells, rice-fields, pools, ponds and elsewhere in malaria prone rural areas of central Gujarat. Attempts were also made to demonstrate composite fish culture in unused abandoned village ponds by culturing Guppy along with the food fishes such as Rohu (Labeo rohita), Catla (Catla catla) and Mrigal (Cirrhinus mrigala). Income generated from these ponds through sale of fishes was utilized for mosquito control and village development. The technology was later adopted by the villagers themselves and food fish culture was practised in 23 ponds which generated an income of Rs 1,02,50,992 between 1985 and 2008. The number of villages increased from 13 to 23 in 2008 and there was also gradual increase of income from Rs 3,66,245 in 1985-90 to Rs 55,06,127 in 2002-08 block. It is concluded that larvivorous fishes can be useful tool in controlling mosquito breeding in certain situations and their use along with composite fish culture may also generate income to make the programme self-sustainable.


An epigenetic basis for autism spectrum disorder risk and oral contraceptive use.
In the United States 1 in 68 children are diagnosed with autism spectrum disorder (ASD). Although the etiology is unknown, many scientists believe ASD is caused by a combination of genetic and environmental factors and/or epigenetic factors. The widespread use of oral contraceptives is one environmental risk factor that has been greatly overlooked in the biomedical literature. Oral contraceptives, synthetic hormones created to imitate natural human hormones and disrupt endogenous endocrine function to inhibit pregnancy, may be causing the harmful neurodevelopmental effects that result in the increased prevalence of ASD. It is conceivable that the synthetic hormones repeatedly assault the oocyte causing persistent changes in expression of the estrogen receptor beta gene. Ethinylestradiol, a known endocrine disruptor, may trigger DNA methylation of the estrogen receptor beta gene causing decreased mRNA resulting in impaired brain estrogen signaling in progeny. In addition, it is possible the deleterious effects are transgenerational as the estrogen receptor gene and many of its targets may be imprinted and the methylation marks protected from global demethylation and preserved through fertilization and beyond to progeny generations. This article will delineate the hypothesis that ethinylestradiol activates DNA methylation of the estrogen receptor beta gene causing decreased mRNA resulting in diminished brain estrogen signaling in offspring of mothers exposed to oral contraceptives. Considering the detrimental epigenetic and transgenerational effects proposed, it calls for further study.


Honey as a Strategy to Fight Candida tropicalis in Mixed-Biofilms with Pseudomonas aeruginosa.
Fungal contaminations with Candida species are commonly responsible for several infections, especially when associated to bacteria. The therapeutic approach commonly used is being compromised due to microbial resistances of these microorganisms to antimicrobial agents, especially in biofilm. The use of honey as an antimicrobial agent has been emerging as a valuable solution and proving its potential in planktonic and in biofilm cells. This work aims to assess the effect of different honeys on biofilms of Candida tropicalis and Pseudomonas aeruginosa. The effect of Portuguese heather (PH) and manuka honeys on planktonic growth of Candida was initially evaluated by determination of the minimum inhibitory concentrations (MIC). Then, the same effect was evaluated in mixed biofilms, by colony-forming units numeration and fluorescence microscopy. The combinations of honey plus fluconazole and gentamicin were also tested. The results showed that the honeys tested enabled a great reduction of C. tropicalis, both in planktonic (12.5% and 25% of MIC for PH and manuka) and in biofilm. In polymicrobial biofilms, the use of PH and manuka honeys was revealed to be a promising choice and an alternative treatment, since they were able to reduce cells from both species. No synergistic effect was observed in antimicrobial combinations assays against polymicrobial biofilms.


Advanced glycation end products and oxidative stress in type 2 diabetes mellitus.
Type 2 diabetes mellitus (T2DM) is a very complex and multifactorial metabolic disease characterized by insulin resistance and β cell failure leading to elevated blood glucose levels. Hyperglycemia is suggested to be the main cause of diabetic complications, which not only decrease life quality and expectancy, but are also becoming a problem regarding the financial burden for health care systems. Therefore, and to counteract the continually increasing prevalence of diabetes, understanding the pathogenesis, the main risk factors, and the underlying molecular mechanisms may establish a basis for prevention and therapy. In this regard, research was performed revealing further evidence that oxidative stress has an important role in hyperglycemia-induced tissue injury as well as in early events relevant for the development of T2DM. The formation of advanced glycation end products (AGEs), a group of modified proteins and/or lipids with damaging potential, is one contributing factor. On the one hand it has been reported that AGEs increase reactive oxygen species formation and impair antioxidant systems, on the other hand the formation of some AGEs is induced per se under oxidative conditions. Thus, AGEs contribute at least partly to chronic stress conditions in diabetes. As AGEs are not only formed endogenously, but also derive from exogenous sources, i.e., food, they have been assumed as risk factors for T2DM. However, the role of AGEs in the pathogenesis of T2DM and diabetic complications-if they are causal or simply an effect-is only partly understood. This review will highlight the involvement of AGEs in the development and progression of T2DM and their role in diabetic complications.


Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis.
Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis use.


Embodied cognition of aging.
Embodiment is revolutionizing the way we consider cognition by incorporating the influence of our body and of the current context within cognitive processing. A growing number of studies which support this view of cognition in young adults stands in stark contrast with the lack of evidence in favor of this view in the field of normal aging and neurocognitive disorders. Nonetheless, the validation of embodiment assumptions on the whole spectrum of cognition is a mandatory step in order for embodied cognition theories to become theories of human cognition. More pragmatically, aging populations represent a perfect target to test embodied cognition theories due to concomitant changes in sensory, motor and cognitive functioning that occur in aging, since these theories predict direct interactions between them. Finally, the new perspectives on cognition provided by these theories might also open new research avenues and new clinical applications in the field of aging. The present article aims at showing the value and interest to explore embodiment in normal and abnormal aging as well as introducing some potential theoretical and clinical applications.


Availability, affordability, and quality of essential antiepileptic drugs in Lao PDR.
Epilepsy is a chronic condition treatable by cost-effective antiepileptic drugs (AEDs), but limited access to treatment was documented. The availability and affordability of good quality of AEDs play a significant role in access to good health care. This study aimed to assess the availability, affordability, and quality of long-term AEDs in Lao PDR. A cross-sectional study was performed in both public and private drug supply chains in urban and rural areas in Lao PDR. Data on AEDs availability and price were obtained through drug suppliers. Affordability was estimated as the number of day wages the lowest-paid government employee must work to purchase a monthly treatment. Samples of AEDs were collected, and the quality of AEDs was assessed through Medicine Quality Assessment Reporting Guidelines. Out of 237 outlets visited, only 50 outlets (21.1% [95% CI 16.1-26.8]) had at least one AED available. The availability was significantly different between urban (24.9%) and rural areas (10.0%), P = .017. Phenobarbital 100 mg was the most available (14.3%); followed by sodium valproate 200 mg (9.7%), phenytoin 100 mg (9.7%), and carbamazepine 200 mg (8.9%). In provincial/district hospitals and health centers, AEDs were provided free of charge. In other healthcare facilities, phenytoin 100 mg and phenobarbital 100 mg showed the best affordability (1.0 and 1.2 day wages, respectively) compared to carbamazepine 200 mg (2.3 days) and other AEDs. No sample was identified as counterfeit, but 15.0% [95% CI 7.1-26.6] of samples were classified as of poor quality. We quantified and qualified the various factors contributing to the high treatment gap in Lao PDR, adding to diagnostic issues (not assessed here). Availability remains very low and phenobarbital which is the most available and affordable AED was the worst in terms of quality. A drug policy addressing epilepsy treatment gap would reduce these barriers.


Mapping early brain development in autism.
Although the neurobiology of autism has been studied for more than two decades, the majority of these studies have examined brain structure 10, 20, or more years after the onset of clinical symptoms. The pathological biology that causes autism remains unknown, but its signature is likely to be most evident during the first years of life when clinical symptoms are emerging. This review highlights neurobiological findings during the first years of life and emphasizes early brain overgrowth as a key factor in the pathobiology of autism. We speculate that excess neuron numbers may be one possible cause of early brain overgrowth and produce defects in neural patterning and wiring, with exuberant local and short-distance cortical interactions impeding the function of large-scale, long-distance interactions between brain regions. Because large-scale networks underlie socio-emotional and communication functions, such alterations in brain architecture could relate to the early clinical manifestations of autism. As such, autism may additionally provide unique insight into genetic and developmental processes that shape early neural wiring patterns and make possible higher-order social, emotional, and communication functions.


Equilibrium cluster fluids: pair interactions via inverse design.
Inverse methods of statistical mechanics are becoming productive tools in the design of materials with specific microstructures or properties. While initial studies have focused on solid-state design targets (e.g., assembly of colloidal superlattices), one can alternatively design fluid states with desired morphologies. This work addresses the latter and demonstrates how a simple iterative Boltzmann inversion strategy can be used to determine the isotropic pair potential that reproduces the radial distribution function of a fluid of amorphous clusters with prescribed size. The inverse designed pair potential of this "ideal" cluster fluid, with its broad attractive well and narrow repulsive barrier at larger separations, is qualitatively different from the so-called SALR form most commonly associated with equilibrium cluster formation in colloids, which features short-range attractive (SA) and long-range repulsive (LR) contributions. These differences reflect alternative mechanisms for promoting cluster formation with an isotropic pair potential, and they in turn produce structured fluids with qualitatively different static and dynamic properties. Specifically, equilibrium simulations show that the amorphous clusters resulting from the inverse designed potentials display more uniformity in size and shape, and they also show greater spatial and temporal resolution than those resulting from SALR interactions.


Can sensitivity to auditory frequency modulation predict children's phonological and reading skills?
Understanding how letter units represent particular speech sounds is a crucial skill for developing competent reading skills. However it is not known whether such phonological ability is constrained by basic auditory capacities such as those necessary for detecting the frequency modulations characteristic of many phonemes. Here we show that nearly 40% of the variability in normal children's phonological and reading skills can be predicted from their sensitivity to 2 Hz frequency modulated (FM) tones. This relationship does not hold for sensitivity to 240 Hz FM. Because lower but not higher rates of FM provide information important for speech comprehension, dynamic auditory sensitivity is likely to play an important role in children's phonological and reading skill development.


Forward and backward connections in the brain: a DCM study of functional asymmetries.
In this paper, we provide evidence for functional asymmetries in forward and backward connections that define hierarchical architectures in the brain. We exploit the fact that modulatory or nonlinear influences of one neuronal system on another (i.e., effective connectivity) entail coupling between different frequencies. Functional asymmetry in forward and backward connections was addressed by comparing dynamic causal models of MEG responses induced by visual processing of normal and scrambled faces. We compared models with and without nonlinear (between-frequency) coupling in both forward and backward connections. Bayesian model comparison indicated that the best model had nonlinear forward and backward connections. Using the best model we then quantified frequency-specific causal influences mediating observed spectral responses. We found a striking asymmetry between forward and backward connections; in which high (gamma) frequencies in higher cortical areas suppressed low (alpha) frequencies in lower areas. This suppression was significantly greater than the homologous coupling in the forward connections. Furthermore, exactly the asymmetry was observed when we examined face-selective coupling (i.e., coupling under faces minus scrambled faces). These results highlight the importance of nonlinear coupling among brain regions and point to a functional asymmetry between forward and backward connections in the human brain that is consistent with anatomical and physiological evidence from animal studies. This asymmetry is also consistent with functional architectures implied by theories of perceptual inference in the brain, based on hierarchical generative models.


What is appropriate to post on social media? Ratings from students, faculty members and the public.
The purpose of this study was to ascertain what medical students, doctors and the public felt was unprofessional for medical students, as future doctors, to post on a social media site, Facebook(®) . The significance of this is that unprofessional content reflects poorly on a student, which in turn can significantly affect a patient's confidence in that student's clinical abilities. An online survey was designed to investigate the perceptions of University of Michigan medical students, attending physicians and non-health care university-wide employees (that serves as a subset of the public) regarding mock medical students' Facebook(®) profile screenshots. For each screenshot, respondents used a 5-point Likert scale to rate 'appropriateness' and whether they would be 'comfortable' having students posting such content as their future doctors. Compared with medical students, faculty members and public groups rated images as significantly less appropriate (p < 0.001) and indicated that they would be less comfortable (p < 0.001) having posting students as future doctors. All three groups rated screenshots containing derogatory or private information about patients, followed by images suggesting marijuana use, as least appropriate. Images conveying intimate heterosexual couples were rated as most appropriate. Overall, the doctor group, females and older individuals were less permissive when compared with employee and student groups, males and younger individuals, respectively. The most significant conclusion of our study is that faculty members, medical students and the 'public' have different thresholds of what is acceptable on a social networking site. Our findings will prove useful for students to consider the perspectives of patients and faculty members when considering what type of content to post on their social media sites. In this way, we hope that our findings provide insight for discussions, awareness and the development of guidelines related to online professionalism for medical students.


Network-targeted stimulation engages neurobehavioral hallmarks of age-related memory decline.
To test whether targeting hippocampal-cortical brain networks with high-frequency transcranial magnetic stimulation in older adults influences behavioral and neural measures characteristic of age-related memory impairment. Fifteen adults aged 64 to 80 years (mean = 72 years) completed a single-blind, sham-controlled experiment. Stimulation targets in parietal cortex were determined based on fMRI connectivity with the hippocampus. Recollection and recognition memory were assessed after 5 consecutive daily sessions of full-intensity stimulation vs low-intensity sham stimulation using a within-subjects crossover design. Neural correlates of recollection and recognition memory formation were obtained via fMRI, measured within the targeted hippocampal-cortical network vs a control frontal-parietal network. These outcomes were measured approximately 24 hours after the final stimulation session. Recollection was specifically impaired in older adults compared to a young-adult control sample at baseline. Relative to sham, stimulation improved recollection to a greater extent than recognition. Stimulation increased recollection fMRI signals throughout the hippocampal-cortical network, including at the targeted location of the hippocampus. Effects of stimulation on fMRI recollection signals were greater than those for recognition and were greater in the targeted network compared to the control network. Age-related recollection impairments were causally related to hippocampal-cortical network function in older adults. Stimulation selectively modified neural and behavioral hallmarks of age-related memory impairment, indicating effective engagement of memory intervention targets in older adults.


Regulation of masticatory force during cortically induced rhythmic jaw movements in the anesthetized rabbit.
To examine the relationships between masticatory force, electromyogram (EMG) of masticatory muscles, and jaw movement pattern, we quantitatively evaluated the effects of changing hardness of a chewing substance on these three variables. Cortically induced rhythmic jaw movements of a crescent-shaped pattern were induced by electrical stimulation of the cerebral cortical masticatory area in the anesthetized rabbit. The axially directed masticatory force was recorded with a small force-displacement transducer mounted on the ground surface of the lower molars. EMGs were recorded from the masseter and digastric muscles simultaneously with jaw movements. Five test strips of polyurethane foam of different hardness were prepared and inserted between the upper molar and the transducer during the movements. The peak, impulse, and buildup speed of the masticatory force increased with strip hardness, whereas duration of the exerted force did not vary with strip hardness. The integrated activity and duration of the masseteric EMG bursts also increased with strip hardness. The integrated EMG activity of the digastric bursts was weakly related to strip hardness, whereas the duration was not. The minimum gape increased with strip hardness, but the maximum gape did not. The horizontal excursion of the jaw did not vary in a hardness-dependent manner, although it was greater in the cycles with strip application than in the cycles without strip application. Deprivation of periodontal sensation by cutting the nerves to the teeth reduced the buildup speed of the force, maximum gape, net gape, and horizontal jaw movements. The denervation also elongated the force duration and that of masseteric EMG bursts. However, the rate of the hardness-dependent changes in the above parameters did not alter after denervation. The latency of the masseteric EMG response to strip application was evaluated before and after denervation. In both conditions, it was > or = 6 ms in approximately 70% of the cycles and <6 ms in the remaining approximately 30%, which cannot be explained by a simple reflex mechanism. On the basis of the analysis of correlation coefficients, the masseteric integrated EMG seemed to be a good indicator of the peak and impulse of the masticatory force both before and after denervation. We conclude that periodontal afferents would be responsible for a quick buildup of masticatory force and that afferents other than those from periodontal tissue would contribute to the hardness-dependent change of masticatory force during cortically induced rhythmic jaw movements.


Predictors of severe outcome following opioid intoxication in children.
While the opioid crisis has claimed the lives of nearly 500,000 in the U.S. over the past two decades, and pediatric cases of opioid intoxications are increasing, only sparse data exist regarding risk factors for severe outcome in children following an opioid intoxication. We explore predictors of severe outcome (i.e., intensive care unit [ICU] admission or in-hospital death) in children who presented to the Emergency Department with an opioid intoxication. In this prospective cohort study we collected data on all children (0-18 years) who presented with an opioid intoxication to the 50 medical centers in the US and two international centers affiliated with the Toxicology Investigators Consortium (ToxIC) of the American College of Medical Toxicology, from August 2017 through June 2020, and who received a bedside consultation by a medical toxicologist. We collected relevant demographic, clinical, management, disposition, and outcome data, and we conducted a multivariable logistic regression analysis to explore predictors of severe outcome. The primary outcome was a composite severe outcome endpoint, defined as ICU admission or in-hospital death. Covariates included sociodemographic, exposure and clinical characteristics. Of the 165 (87 females, 52.7%) children with an opioid intoxication, 89 (53.9%) were admitted to ICU or died during hospitalization, and 76 did not meet these criteria. Seventy-four (44.8%) children were exposed to opioids prescribed to family members. Fentanyl exposure (adjusted OR [aOR] = 3.6, 95% CI: 1.0-11.6; p = 0.03) and age ≥10 years (aOR = 2.5, 95% CI: 1.2-4.8; p = 0.01) were independent predictors of severe outcome. Children with an opioid toxicity that have been exposed to fentanyl and those aged ≥10 years had 3.6 and 2.5 higher odds of ICU admission or death, respectively, than those without these characteristics. Prevention efforts should target these risk factors to mitigate poor outcomes in children with an opioid intoxication.


Influence of leukotriene pathway polymorphisms on response to montelukast in asthma.
Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes. To determine associations between polymorphisms in leukotriene pathway candidate genes with outcomes in patients with asthma receiving montelukast for 6 mo who participated in a clinical trial. Polymorphisms were typed using Sequenom matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array spectrometry and published methods; haplotypes were imputed using single nucleotide polymorphism-expectation maximization (SNP-EM). Analysis of variance and logistic regression models were used to test for changes in outcomes by genotype. In addition, chi(2) and likelihood ratio tests were used to test for differences between groups. Case-control comparisons were analyzed using the SNP-EM Omnibus likelihood ratio test. Outcomes were asthma exacerbation rate and changes in FEV(1) compared with baseline. DNA was collected from 252 participants: 69% were white, 26% were African American. Twenty-eight SNPs in the ALOX5, LTA4H, LTC4S, MRP1, and cysLT1R genes, and an ALOX5 repeat polymorphism were successfully typed. There were racial disparities in allele frequencies in 17 SNPs and in the repeat polymorphism. Association analyses were performed in 61 whites. Associations were found between genotypes of SNPs in the ALOX5 (rs2115819) and MRP1 (rs119774) genes and changes in FEV(1) (p < 0.05), and between two SNPs in LTC4S (rs730012) and in LTA4H (rs2660845) genes for exacerbation rates. Mutant ALOX5 repeat polymorphism was associated with decreased exacerbation rates. There was strong linkage disequilibrium between ALOX5 SNPs. Associations between ALOX5 haplotypes and risk of exacerbations were found. Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response.


Mastery-Based Virtual Reality Robotic Simulation Curriculum: The First Step Toward Operative Robotic Proficiency.
Hepatobiliary surgery is a highly complex, low-volume specialty with long learning curves necessary to achieve optimal outcomes. This creates significant challenges in both training and measuring surgical proficiency. We hypothesize that a virtual reality curriculum with mastery-based simulation is a valid tool to train fellows toward operative proficiency. This study evaluates the content and predictive validity of robotic simulation curriculum as a first step toward developing a comprehensive, proficiency-based pathway. A mastery-based simulation curriculum was performed in a virtual reality environment. A pretest/posttest experimental design used both virtual reality and inanimate environments to evaluate improvement. Participants self-reported previous robotic experience and assessed the curriculum by rating modules based on difficulty and utility. This study was conducted at the University of Pittsburgh Medical Center (Pittsburgh, PA), a tertiary care academic teaching hospital. A total of 17 surgical oncology fellows enrolled in the curriculum, 16 (94%) completed. Of 16 fellows who completed the curriculum, 4 fellows (25%) achieved mastery on all 24 modules; on average, fellows mastered 86% of the modules. Following curriculum completion, individual test scores improved (p < 0.0001). An average of 2.4 attempts was necessary to master each module (range: 1-17). Median time spent completing the curriculum was 4.2 hours (range: 1.1-6.6). Total 8 (50%) fellows continued practicing modules beyond mastery. Survey results show that "needle driving" and "endowrist 2" modules were perceived as most difficult although "needle driving" modules were most useful. Overall, 15 (94%) fellows perceived improvement in robotic skills after completing the curriculum. In a cohort of board-certified general surgeons who are novices in robotic surgery, a mastery-based simulation curriculum demonstrated internal validity with overall score improvement. Time to complete the curriculum was manageable.


Impact of Gut Bacteria on the Infection and Transmission of Pathogenic Arboviruses by Biting Midges and Mosquitoes.
Tripartite interactions among insect vectors, midgut bacteria, and viruses may determine the ability of insects to transmit pathogenic arboviruses. Here, we investigated the impact of gut bacteria on the susceptibility of Culicoides nubeculosus and Culicoides sonorensis biting midges for Schmallenberg virus, and of Aedes aegypti mosquitoes for Zika and chikungunya viruses. Gut bacteria were manipulated by treating the adult insects with antibiotics. The gut bacterial communities were investigated using Illumina MiSeq sequencing of 16S rRNA, and susceptibility to arbovirus infection was tested by feeding insects with an infectious blood meal. Antibiotic treatment led to changes in gut bacteria for all insects. Interestingly, the gut bacterial composition of untreated Ae. aegypti and C. nubeculosus showed Asaia as the dominant genus, which was drastically reduced after antibiotic treatment. Furthermore, antibiotic treatment resulted in relatively more Delftia bacteria in both biting midge species, but not in mosquitoes. Antibiotic treatment and subsequent changes in gut bacterial communities were associated with a significant, 1.8-fold increased infection rate of C. nubeculosus with Schmallenberg virus, but not for C. sonorensis. We did not find any changes in infection rates for Ae. aegypti mosquitoes with Zika or chikungunya virus. We conclude that resident gut bacteria may dampen arbovirus transmission in biting midges, but not so in mosquitoes. Use of antimicrobial compounds at livestock farms might therefore have an unexpected contradictory effect on the health of animals, by increasing the transmission of viral pathogens by biting midges.


MS lesions are better detected with 3D T1 gradient-echo than with 2D T1 spin-echo gadolinium-enhanced imaging at 3T.
In multiple sclerosis, gadolinium enhancement is used to classify lesions as active. Regarding the need for a standardized and accurate method for detection of multiple sclerosis activity, we compared 2D-spin-echo with 3D-gradient-echo T1WI for the detection of gadolinium-enhancing MS lesions. Fifty-eight patients with MS were prospectively imaged at 3T by using both 2D-spin-echo and 3D-gradient recalled-echo T1WI in random order after the injection of gadolinium. Blinded and independent evaluation was performed by a junior and a senior reader to count gadolinium-enhancing lesions and to characterize their location, size, pattern of enhancement, and the relative contrast between enhancing lesions and the adjacent white matter. Finally, the SNR and relative contrast of gadolinium-enhancing lesions were computed for both sequences by using simulations. Significantly more gadolinium-enhancing lesions were reported on 3D-gradient recalled-echo than on 2D-spin-echo (n = 59 versus n = 30 for the junior reader, P = .021; n = 77 versus n = 61 for the senior reader, P = .017). The difference between the 2 readers was significant on 2D-spin-echo (P = .044), for which images were less reproducible (κ = 0.51) than for 3D-gradient recalled-echo (κ = 0.65). Further comparisons showed that there were statistically more small lesions (<5 mm) on 3D-gradient recalled-echo than on 2D-spin-echo (P = .04), while other features were similar. Theoretic results from simulations predicted SNR and lesion contrast for 3D-gradient recalled-echo to be better than for 2D-spin-echo for visualization of small enhancing lesions and were, therefore, consistent with clinical observations. At 3T, 3D-gradient recalled-echo provides a higher detection rate of gadolinium-enhancing lesions, especially those with smaller size, with a better reproducibility; this finding suggests using 3D-gradient recalled-echo to detect MS activity, with potential impact in initiation, monitoring, and optimization of therapy.


Effect of posture on the diurnal variation in clinically significant diabetic macular edema.
To investigate the role of posture and other systemic factors in the diurnal variation of clinically significant diabetic macular edema (CSDME). Ten eyes of 10 diabetic subjects with CSDME underwent four OCT foveal thickness measurements with StratusOCT at 9 AM and 12, 3, and 6 PM consecutively on two different days, with the subject in an upright position on one and in a recumbent position on the other. For the "recumbent-position" measurements, the patients were admitted the night before and remained in bed during the entire day of testing. Clinical laboratory results at baseline included HbA1c, urinary albumin, and serum creatinine. Refraction and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity were also measured before each OCT measurement was taken. Variations in blood pressure, body temperature, plasma glucose, renin, aldosterone, and cortisol levels were measured and then correlated with macular thickness. Foveal thickening decreased in all cases over the course of the day. The decrease, however, was significantly greater for the upright-position measurements (relative mean +/- SD decrease of 20.6% +/- 6.5% in the upright position and 6.2% +/- 4.6% in the recumbent position). Visual acuity improved by at least 1 ETDRS line in three eyes in the upright position as opposed to only one eye in the recumbent position. There seemed to be no association between any of the systemic factors studied and foveal thickening, with the exception of cortisol. The results support the hypothesis that posture and hydrostatic pressure play a major role in determining time-related shifts in CSDME and suggest that the forces of Starling's law can in part, account for CSDME formation.


Translumbar central venous catheters for long-term haemodialysis.
Vascular access for haemodialysis is achieved by tunnelled central venous catheter (CVC) in at least 23% of prevalent patients in the UK, Canada and the USA. Use of CVCs is associated with an increased incidence of venous stenosis that can progressively limit future vascular access routes. Lack of conventional venous access routes mandates the use of alternative strategies such as the translumbar approach. We retrospectively analysed patients at our centre requiring translumbar inferior vena caval CVCs (TesioCath) for haemodialysis in the period 1999-2008. Written and electronic records capturing dialysis adequacy and complications, hospital admissions and laboratory data were examined. Thirty-nine pairs of translumbar CVCs were inserted in 26 patients with 15 864 catheter days follow-up, mean patient age 61.9 +/- 12.1 years, 31% diabetic, 15% with ischaemic heart disease. All insertions were successful. Insertion of one CVC was associated with a self-limiting retroperitoneal haematoma. No patients died of a catheter-related cause or through lack of vascular access. Cumulative assisted primary catheter site patency was 81% at 6 months and 73% at 1 year (median 18.5 months). Good dialysis adequacy was achieved throughout (mean single-pool Kt/V 1.5 +/- 0.4). The incidence of access-related infection was 2.84/1000 catheter days (exit site infection rate 2.02/1000 catheter days; catheter-related bacteraemia rate 0.82/1000 catheter days). Catheter dysfunction (need for thrombolytic infusion or catheter change) led to 0.88 admissions per 1000 catheter days. Translumbar inferior vena caval CVCs can offer relatively safe and effective long-term haemodialysis access in patients with no other options.


Hierarchical Assembly of Tungsten Spheres and Epoxy Composites in Three-Dimensional Graphene Foam and Its Enhanced Acoustic Performance as a Backing Material.
Backing materials play important role in enhancing the acoustic performance of an ultrasonic transducer. Most backing materials prepared by conventional methods failed to show both high acoustic impedance and attenuation, which however determine the bandwidth and axial resolution of acoustic transducer, respectively. In the present work, taking advantage of the structural feature of 3D graphene foam as a confined space for dense packing of tungsten spheres with the assistance of centrifugal force, the desired structural requirement for high impedance is obtained. Meanwhile, superior thermal conductivity of graphene contributes to the acoustic attenuation via the conversion of acoustic waves to thermal energy. The tight contact between tungstate spheres, epoxy matrix, or graphene makes the acoustic wave depleted easily for the absence of air barrier. The as-prepared 3DG/W80 wt %/epoxy film in 1 mm, prepared using ∼41 μm W spheres in diameter, not only displays acoustic impedance of 13.05 ± 0.11 MRayl but also illustrates acoustic attenuation of 110.15 ± 1.23 dB/cm MHz. Additionally, the composite film exhibits a high acoustic absorption coefficient, which is 94.4% at 1 MHz and 100% at 3 MHz, respectively. Present composite film outperforms most of the reported backing materials consisting of metal fillers/polymer blending in terms of the acoustic impedance and attenuation.


The effect of poverty on child development and educational outcomes.
Poverty affects a child's development and educational outcomes beginning in the earliest years of life, both directly and indirectly through mediated, moderated, and transactional processes. School readiness, or the child's ability to use and profit from school, has been recognized as playing a unique role in escape from poverty in the United States and increasingly in developing countries. It is a critical element but needs to be supported by many other components of a poverty-alleviation strategy, such as improved opportunity structures and empowerment of families. The paper reviews evidence from interventions to improve school readiness of children in poverty, both in the United States and in developing countries, and provides recommendations for future research and action.


Comparison of the sensitivity of the UKCAT and A Levels to sociodemographic characteristics: a national study.
The UK Clinical Aptitude Test (UKCAT) was introduced to facilitate widening participation in medical and dental education in the UK by providing universities with a continuous variable to aid selection; one that might be less sensitive to the sociodemographic background of candidates compared to traditional measures of educational attainment. Initial research suggested that males, candidates from more advantaged socioeconomic backgrounds and those who attended independent or grammar schools performed better on the test. The introduction of the A* grade at A level permits more detailed analysis of the relationship between UKCAT scores, secondary educational attainment and sociodemographic variables. Thus, our aim was to further assess whether the UKCAT is likely to add incremental value over A level (predicted or actual) attainment in the selection process. Data relating to UKCAT and A level performance from 8,180 candidates applying to medicine in 2009 who had complete information relating to six key sociodemographic variables were analysed. A series of regression analyses were conducted in order to evaluate the ability of sociodemographic status to predict performance on two outcome measures: A level 'best of three' tariff score; and the UKCAT scores. In this sample A level attainment was independently and positively predicted by four sociodemographic variables (independent/grammar schooling, White ethnicity, age and professional social class background). These variables also independently and positively predicted UKCAT scores. There was a suggestion that UKCAT scores were less sensitive to educational background compared to A level attainment. In contrast to A level attainment, UKCAT score was independently and positively predicted by having English as a first language and male sex. Our findings are consistent with a previous report; most of the sociodemographic factors that predict A level attainment also predict UKCAT performance. However, compared to A levels, males and those speaking English as a first language perform better on UKCAT. Our findings suggest that UKCAT scores may be more influenced by sex and less sensitive to school type compared to A levels. These factors must be considered by institutions utilising the UKCAT as a component of the medical and dental school selection process.


High Prevalence of Pneumocystis jirovecii Dihydropteroate Synthase Gene Mutations in Patients with a First Episode of Pneumocystis Pneumonia in Santiago, Chile, and Clinical Response to Trimethoprim-Sulfamethoxazole Therapy.
Mutations in the dihydropteroate synthase (DHPS) gene of Pneumocystis jirovecii are associated with the failure of sulfa prophylaxis. They can develop by selection in patients receiving sulfa drugs or be acquired via person-to-person transmission. DHPS mutations raise concern about the decreasing efficacy of sulfa drugs, the main available therapeutic tool for Pneumocystis pneumonia (PCP). The prevalence of Pneumocystis DHPS mutations was examined in Pneumocystis isolates from 56 sulfa-prophylaxis-naive adults with a first episode of PCP from 2002 to 2010 in Santiago, Chile. Their clinical history was reviewed to analyze the effect of these mutations on response to trimethoprim-sulfamethoxazole (TMP-SMX) therapy and outcome. Mutant genotypes occurred in 22 (48%) of 46 HIV-infected patients and in 5 (50%) of 10 HIV-uninfected patients. Compared to patients with a wild-type genotype, those with mutant genotypes were more likely to experience sulfa treatment-limiting adverse reactions and to have a twice-longer duration of mechanical ventilation if mechanically ventilated. Specific genotypes did not associate with death, which occurred in none of the HIV-infected patients and in 50% of the non-HIV-infected patients. Chile has a high prevalence of DHPS mutations, which were presumably acquired through interhuman transmission because patients were not on sulfa prophylaxis. These results contrast with the low prevalence observed in other Latin American countries with similar usage of sulfa drugs, suggesting that additional sources of resistant genotypes may be possible. The twice-longer duration of mechanical ventilation in patients with mutant DHPS genotypes suggests a decreased efficacy of TMP-SMX and warrants collaborative studies to assess the relevance of DHPS mutations and further research to increase therapeutic options for PCP.


Coronary Artery Bypass Grafting in a Patient with Situs Inversus Totalis.
BACKGROUND We report a rare case of total arterial coronary artery bypass grafting (CABG) in a patient with situs inversus totalis (SIT). SIT is a rare variant of biologically normal anatomy, in which the main internal organs are mirrored compared to normal localization. CASE REPORT A 50-year-old patient with SIT and severe coronary stenosis of the left anterior descending artery (LAD) and the ramus circumflexus (RCX) was admitted to our hospital. CABG was performed promptly using 2 conduits. After medial sternotomy, both mammary arteries were isolated by the skeletal method. Next, the cannulation of the aorta and the physiologically right atrium was performed. Custodiol cardioplegia was performed antegrade in a single shot. The left internal mammary artery (LIMA) was anastomosed to the LAD and the right internal mammary artery (RIMA) to the RCX. The aortic clamping time was 29 minutes. The operation was completed without complications. The patient was extubated 6 hours after surgery. On the first postoperative day, the patient was transferred to a regular ward. Postoperative therapy was performed without complications. CONCLUSIONS Surgical correction is indicated for many patients with SIT in combination with coronary heart disease. Performing a CABG operation on these patients requires the operating team to have certain skills. Surgeons face a number of problems and issues: preoperative preparation of the patient, the position of the surgeon to the left or right during the operation, the choice of conduit for anastomosis, and the tactics of the operation.


Effect of metformin and oral contraceptives on polycystic ovary syndrome and IVF cycles.
The aim of this study is to investigate the effect of metformin and/or OC added to the treatment of PCOS patients at our clinic on IVF outcome. This study is a retrospective study that assesses the data of PCOS patients who received IVF between 2005 and 2015 at a private IVF center. The study included 496 PCOS cases aged between 24 and 40. Participants diagnosed with PCOS were divided into 4 groups according to the use of metformin and OC prior to the IVF cycle: 11.1% were in the metformin group, 31.3% in the OC group, 14.9% in the Metformin + OC group, and 42.7% in the control group. No difference was found in the total gonadotropin dose and duration of stimulation between the groups. Clinical pregnancy rates and implantation rates were similar in all groups, although the numbers of oocytes, mature oocytes, fertilized oocytes, and transferred embryos were lower in the treatment groups received metformin compared to the OC group and control group. There was no significant difference in the presence of OHSS and the singleton and multiple pregnancies between the four groups. The present study established no positive role of metformin and OC use in increasing the treatment success in IVF/ICSI cycles in PCOS patients. It would be appropriate to limit the use of these agents with special indications such as decreasing insulin resistance or synchronizing follicular cohort.


The source of fermentable carbohydrates influences the in vitro protein synthesis by colonic bacteria isolated from pigs.
Two in vitro experiments were carried out to quantify the incorporation of nitrogen (N) by pig colonic bacteria during the fermentation of dietary fibre, including non-starch polysaccharides and resistant starch. In the first experiment, five purified carbohydrates were used: starch (S), cellulose (C), inulin (I), pectin (P) and xylan (X). In the second experiment, three pepsin-pancreatin hydrolysed ingredients were investigated: potato, sugar-beet pulp and wheat bran. The substrates were incubated in an inoculum, prepared from fresh faeces of sows and a buffer solution providing 15N-labelled NH4Cl. Gas production was monitored. Bacterial N incorporation (BNI) was estimated by measuring the incorporation of 15N in the solid residue at half-time to asymptotic gas production (T/2). The remaining substrate was analysed for sugar content. Short-chain fatty acids (SCFA) were determined in the liquid phase. In the first experiment, the fermentation kinetics differed between the substrates. P, S and I showed higher rates of degradation (P < 0.001), while X and C showed a longer lag time and T/2. The sugar disappearance reached 0.91, 0.90, 0.81, 0.56 and 0.46, respectively, for P, I, S, C and X. Among them, S and I fixed more N per gram substrate (P < 0.05) than C, X and P (22.9 and 23.2 mg fixed N per gram fermented substrate v. 11.3, 12.3 and 9.8, respectively). Production of SCFA was the highest for the substrates with low N fixation: 562 and 565 mg/g fermented substrate for X and C v. 290 to 451 for P, I and S (P < 0.01). In the second experiment, potato and sugar-beet pulp fermented more rapidly than wheat bran (P < 0.001). Substrate disappearance at T/2 varied from 0.17 to 0.50. BNI were 18.3, 17.0 and 10.2 fixed N per gram fermented substrate, for sugar-beet pulp, potato and wheat bran, respectively, but were not statistically different. SCFA productions were the highest with wheat bran (913 mg/g fermented substrate) followed by sugar-beet pulp (641) and potato (556) (P < 0.05). The differences in N uptake by intestinal bacteria are linked to the partitioning of the substrate energy content between bacterial growth and SCFA production. This partitioning varies according to the rate of fermentation and the chemical composition of the substrate, as shown by the regression equation linking BNI to T/2 and SCFA (r2 = 0.91, P < 0.01) and the correlation between BNI and insoluble dietary fibre (r = -0.77, P < 0.05) when pectin was discarded from the database.


[Quali-quantitative study on healthcare for children below the age of 3 at health establishments in nine underdeveloped regions of Peru].
To assess five elements of healthcare quality (physical space, equipment, personnel, waiting time, and counseling) in growth and development services (GDS) at 18 healthcare establishments in nine regions of Peru with high rates of poverty. A quali-quantitative study was carried out in the Amazonas, Apurímac, Ayacucho, Cajamarca, Cusco, Huánuco, Huancavelica, Puno, and Ucayali regions, that included direct observation (DO) during medical assistance in GDS, focus groups (FG, one user per healthcare establishment), and in-depth interviews (IDI) with healthcare workers (two per healthcare establishment). There were 18 DOs carried out to assess environment and equipment, 23 DOs of complete service shifts, 67 accompaniments to users during medical assistance in GDS, 18 FGs (118 participating mothers), and 36 IDIs. Both mothers and healthcare professionals agreed that there were limitations in infrastructure, equipment, materials, and personnel that impacted quality medical assistance in GDS. Delays in medical assistance, failure to comply with schedules, and lack of friendliness when providing medical care were the aspects that produced the greatest user dissatisfaction. Only 24.3% of the total amount of time spent at the healthcare establishment corresponded to beneficial activities for the user, although the Health Department was meeting the objective to promote improvement of childcare practices. The study was useful in identifying weaknesses and strengths that may help redirect GDS efforts within the framework of policies aimed at strengthening first-class medical assistance.


Children's gender-based reasoning about toys.
The goal of these studies was to investigate how preschool children use gender-based reasoning in making judgments about toy preferences for themselves and for others. In Studies 1 and 2, children (n = 22, n = 71) were shown unfamiliar, non-sex-typed toys and asked to rate how much they, other girls, and other boys would like each toy. As expected, children made gender-based inferences: "What I like, children of my sex will also like, and children of the other sex will not like." Study 3 was designed to assess how children use gender-based reasoning to make decisions about attractive and unattractive toys when they are given gender labels. Children (n = 91) were shown unfamiliar toys varying in attractiveness that were given explicit gender labels (e.g., "this is a toy girls really like") or no label. With a different experimenter (to avoid demand characteristics), children rated their own and others' liking of the toys. Children used gender labels to guide their own preferences and their expectations for others. Even with very attractive toys, children liked toys less if they were labeled as being for the other sex, and expected other girls and boys to do the same. The role of gender-based reasoning in cognitive theories of gender and on children's play preferences is discussed.


Stimulation of mucosal secretion by lubiprostone (SPI-0211) in guinea pig small intestine and colon.
Actions of lubiprostone, a selective type-2 chloride channel activator, on mucosal secretion were investigated in guinea pig small intestine and colon. Flat-sheet preparations were mounted in Ussing flux chambers for recording short-circuit current (Isc) as a marker for electrogenic chloride secretion. Lubiprostone, applied to the small intestinal mucosa in eight concentrations ranging from 1-3000 nM, evoked increases in Isc in a concentration-dependent manner with an EC50 of 42.5 nM. Lubiprostone applied to the mucosa of the colon in eight concentrations ranging from 1-3000 nM evoked increases in Isc in a concentration-dependent manner with an EC50 of 31.7 nM. Blockade of enteric nerves by tetrodotoxin did not influence stimulation of Isc by lubiprostone. Antagonists acting at prostaglandin (PG)E2, EP1-3, or EP4 receptors did not suppress stimulation of Isc by lubiprostone but suppressed or abolished PGE2-evoked responses. Substitution of gluconate for chloride abolished all responses to lubiprostone. The selective CFTR channel blocker, CFTR(inh)-172, did not suppress lubiprostone-evoked Isc. The broadly acting blocker, glibenclamide, suppressed (P<0.001) lubiprostone-evoked Isc. Lubiprostone, in the presence of tetrodotoxin, enhanced carbachol-evoked Isc. The cholinergic component, but not the putative vasoactive intestinal peptide component, of neural responses to electrical field stimulation was enhanced by lubiprostone. Application of any of the prostaglandins, E2, F2, or I2, evoked depolarization of the resting membrane potential in enteric neurons. Unlike the prostaglandins, lubiprostone did not alter the electrical behavior of enteric neurons. Exposure to the histamine H2 receptor agonists increased basal Isc followed by persistent cyclical increases in Isc. Lubiprostone increased the peak amplitude of the dimaprit-evoked cycles.


Metabolite intermediate complexation of microsomal cytochrome P450 2C11 in male rat liver by nortriptyline.
Antidepressant drugs that contain alkylaminoalkyl substituents have been associated with serious pharmacokinetic interactions in humans that may be related to the inhibition of cytochrome P450 (P450) enzymes. In this study, the propensity of the tricyclic antidepressant nortriptyline (NOR) to inhibit individual microsomal P450 enzymes in rat liver was investigated to provide a mechanistic explanation for these pharmacokinetic interactions. Enzyme kinetic studies revealed that NOR inhibited steroid 2 alpha-, 6 beta, 7 alpha-, and 16 alpha-hydroxylation in untreated rat liver with Km/Ki ratios of 0.53, 0.59, 0.25, and 0.29, respectively. When the drug was preincubated with microsomes and NADPH before testosterone hydroxylation was conducted, marked increases in the Km/Ki ratios were observed (to 8.8, 3.9, 0.62, and 13, respectively). Thus, enzymic oxidation of NOR enhanced its inhibition capacity against P450 activities. Indeed, the altered Km/Ki ratios indicate 17-, 6.6-, 2.5-, and 47-fold increases in inhibition of the four pathways of testosterone hydroxylation after the biotransformation of NOR to its metabolites. From these experiments it was apparent that testosterone 2 alpha- and 16 alpha-hydroxylations, catalyzed predominantly by P450 2C11, were subject to the most pronounced increase in inhibition. Under these conditions, the apparent content of microsomal P450 was decreased, thus suggesting the formation of a NOR metabolite intermediate (MI) complex with the cytochrome. Further, optical difference spectroscopy of NADPH-supported metabolism of NOR in microsomes and in a reconstituted system incorporating purified P450 2C11 indicated the appearance of an absorbance peak near 454 nm, similar to those produced by triacetyloleandomycin, SKF 525-A, and orphenadrine. Formation of this absorbance peak in microsomes was inhibited by an antibody raised against the male-specific P450 2C11. Because oxidative metabolism of NOR to inhibitory products would not necessarily involve MI complexation, additional experiments were undertaken in which NOR-related free metabolites produced in microsomal incubations were removed on Sep-Pak mini-C18 columns before estimation of testosterone hydroxylation. The principal finding from this experiment was that P450 3A2-dependent steroid 6 beta-hydroxylase activity was inhibited to a much lesser extent after removal of unbound NOR metabolites on Sep-Pak columns (25% inhibition after Sep-Pak extraction, compared with 82% inhibition observed when all NOR metabolites were present during subsequent testosterone hydroxylation); inhibition of P450 2C11-mediated 2 alpha- and 16 alpha-hydroxylation was not noticeably different after Sep-Pak treatment.(ABSTRACT TRUNCATED AT 400 WORDS)


Preparation of films of a highly aligned lipid cubic phase.
We demonstrate a method by which we can produce an oriented film of an inverse bicontinuous cubic phase (Q(II)(D)) formed by the lipid monoolein (MO). By starting with the lipid as a disordered precursor (the L(3) phase) in the presence of butanediol, we can obtain a film of the Q(II)(D) phase showing a high degree of in-plane orientation by controlled dilution of the sample under shear within a linear flow cell. We demonstrate that the direction of orientation of the film is different from that found in the oriented bulk material that we have reported previously; therefore, we can now reproducibly form Q(II)(D) samples oriented with either the [110] or the [100] axis aligned in the flow direction depending on the method of preparation. The deposition of MO as a film, via a moving fluid-air interface that leaves a coating of MO in the L(3) phase on the capillary wall, leads to a sample in the [110] orientation. This contrasts with the bulk material that we have previously demonstrated to be oriented in the [100] direction, arising from flow producing an oriented bulk slug of material within the capillary tube. The bulk sample contains significant amounts of residual butanediol, which can be estimated from the lattice parameter of the Q(II)(D) phase obtained. The sample orientation and lattice parameters are determined from synchrotron small-angle X-ray scattering patterns and confirmed by simulations. This has potential applications in the production of template materials and the growth of protein crystals for crystallography as well as deepening our understanding of the mechanisms underlying the behavior of lyotropic liquid-crystal phases.


Modified Thomas splint-cast combination for the management of limb fractures in small equids.
To describe the management and outcome of limb fractures in small domestic equids treated with a modified Thomas splint-cast combination (MTSCC). Retrospective case series. Client owned horses and donkeys. Medical records, including radiographs, were reviewed for details of animals diagnosed with a limb fracture and treated by external coaptation using a MTSCC (2001-2012). Follow-up >6 months after discharge was obtained via telephone consultation with owners or veterinarians. Nine horses and 4 donkeys were identified with fractures of the tibial diaphysis (n = 4), ulna (n = 3), distal metatarsus (n = 2), proximal metacarpus (n = 1), radial diaphysis (n = 1), calcaneus (n = 1), and distal femoral physis (n = 1). Follow-up was available for 12 equids, of which 8 (67%) recovered from the fracture and became pasture sound. Six equids developed obvious external deformation of the affected limb. Selected small equids with long bone fractures, and without athletic expectations, can be managed with external coaptation using an MTSCC. The owner should be informed that the treatment is considered a salvage procedure.