Antimicrobial usage among hospitalized children in Latvia: a neonatal and pediatric antimicrobial point prevalence survey.
The point prevalence survey was conducted as part of the Antibiotic Resistance and Prescribing in European Children (ARPEC) Project. The study aimed at analyzing pediatric and neonatal antimicrobial prescribing patterns in Latvian hospitals, to identify targets for quality improvement. A one day cross-sectional point prevalence survey on antibiotic use in hospitalized children was conducted in November 2012 in 10 Latvian hospitals, using a previously validated and standardized method. The survey included all inpatient pediatric and neonatal beds and identified all children receiving an antimicrobial treatment on the day of survey. Overall 549 patients were included in the study; 167 (39%) patients admitted to pediatric wards and 25 (21%) patients admitted to neonatal wards received at least one antimicrobial. Pediatric top three antibiotic groups were third-generation cephalosporins (55 prescriptions, 28%), extended spectrum penicillins (n=32, 16%) and first-generation cephalosporins (n=26, 13%). Eleven pediatric patients (85%) received surgical prophylaxis more than 1 day; 143 pediatric patients (86%) received antibiotics intravenously. Lower respiratory tract infections were the most common indications for antibiotic use both in pediatric (n=60, 35.9%) and neonatal patients (n=9, 36%). The most used antibiotics for neonatal patients were benzylpenicillin (n=12, 32%), and gentamicin (n=9, 24%). We identified a few problematic areas, which need improvement: the high use of third-generation cephalosporins for pediatric patients, prolonged surgical prophylaxis, predominant use of parenteral antibiotics and an urgent need for local antibiotic guidelines.


An infant with chronic severe neutropenia.
Neutropenia in infancy and childhood poses a diagnostic challenge as the aetiology ranges from acute life-threatening conditions to chronic benign diseases. Chronic benign neutropenia of infancy is a rare disorder occurring in 1:100,000. The neutrophil count continues to be low for a prolonged period until spontaneous resolution by the age of 3-4 years. Such infants are having higher incidences of minor infections requiring treatment with antibiotics and rare incidences of meningitis and sepsis. The authors describe an infant presenting with fever and cervical lymphadenitis, who was found to have isolated severe neutropenia and its persistence posing a diagnostic challenge. The prolonged course with minor infections and absence of serious underlying conditions finally confirmed chronic benign neutropenia of infancy.


Interventions to improve adherence to antenatal and postnatal care regimens among pregnant women in sub-Saharan Africa: a systematic review.
Pregnant women in sub-Saharan Africa tend to have low adherence to antenatal and postnatal care regimens, contributing to high infant and child mortality rates. Despite low adherence figures and the high returns from attending antenatal and postnatal care visits, research on interventions to improve adherence is in its infancy. Our aim was to determine the effectiveness of existing interventions to improve adherence to antenatal and postnatal care regimens among pregnant women in sub-Saharan Africa. Full text, peer-reviewed articles, published in English and listed in PubMed or PsycINFO through January 2018 were identified in a systematic review. Studies were restricted to randomized controlled trials only and had to assess intervention impact on antenatal and postnatal care adherence, operationalized as the frequency of visits attended. Two reviewers independently screened papers for inclusion and evaluated the risk of systematic error in each study using the Cochrane risk of bias tool. Any discrepancies were reconciled by a third independent reviewer. The initial search generated 186 articles, of which, five met our inclusion criteria. Due to the small sample size and methodological variation across studies, a pooled effect size estimate could not be obtained. Therefore, effects on antenatal and postnatal care adherence were examined and reported at the individual study level. None of the interventions were directly aimed at improving adherence, but two of the five, both behavioral interventions, demonstrated effectiveness in increasing antenatal care (rate ratio 5.86, 95% CI 2.6-13.0, p<0.0001) and postnatal care adherence (31.3%, 95% CI 15.4-47.2, p=0.0009), respectively. Three home visit interventions had no effect on antenatal care adherence. Although the risk of bias was unclear or high in some cases, it remained low in most categories across studies. Results point to a large gap in the literature on interventions to address antenatal and postnatal care adherence in sub-Saharan Africa. Interventions drawing upon the executive function literature and the promising results of the behavioral interventions reviewed here are urgently needed to address these gaps. The review was prospectively registered with PROSPERO, id number https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=88152, on February 7, 2018.


Genome-wide analysis reveals diverged patterns of codon bias, gene expression, and rates of sequence evolution in picea gene families.
The recent sequencing of several gymnosperm genomes has greatly facilitated studying the evolution of their genes and gene families. In this study, we examine the evidence for expression-mediated selection in the first two fully sequenced representatives of the gymnosperm plant clade (Picea abies and Picea glauca). We use genome-wide estimates of gene expression (>50,000 expressed genes) to study the relationship between gene expression, codon bias, rates of sequence divergence, protein length, and gene duplication. We found that gene expression is correlated with rates of sequence divergence and codon bias, suggesting that natural selection is acting on Picea protein-coding genes for translational efficiency. Gene expression, rates of sequence divergence, and codon bias are correlated with the size of gene families, with large multicopy gene families having, on average, a lower expression level and breadth, lower codon bias, and higher rates of sequence divergence than single-copy gene families. Tissue-specific patterns of gene expression were more common in large gene families with large gene expression divergence than in single-copy families. Recent family expansions combined with large gene expression variation in paralogs and increased rates of sequence evolution suggest that some Picea gene families are rapidly evolving to cope with biotic and abiotic stress. Our study highlights the importance of gene expression and natural selection in shaping the evolution of protein-coding genes in Picea species, and sets the ground for further studies investigating the evolution of individual gene families in gymnosperms.


Local enhancement of cannabinoid CB1 receptor signalling in the dorsal hippocampus elicits an antidepressant-like effect.
Systemic administration of direct cannabinoid CB1 receptor agonists and inhibitors of the hydrolytic enzyme fatty acid amide hydrolase have been shown to elicit antidepressant effects. Moreover, the endocannabinoid system in the hippocampus is sensitive to both chronic stress and antidepressant administration, suggesting a potential role of this system in emotional changes associated with these regimens. The aim of this study was to determine if cannabinoid CB1 receptors in the hippocampus modulate emotionality in rats as assessed via the forced swim test. Male Sprague-Dawley rats were bilaterally implanted with cannulae directed at the dentate gyrus of the dorsal hippocampus and subsequently received three infusions of either the cannabinoid CB1 receptor agonist HU-210 (1 and 2.5 microg), the fatty acid amide hydrolase inhibitor URB597 (0.5 and 1 microg), the cannabinoid CB1 receptor antagonist AM251 (1 and 2.5 microg), or vehicle (dimethyl sulfoxide) and were assessed in the forced swim test. Infusion of both doses of HU-210 resulted in a dramatic reduction in immobility and increase in swimming behaviour, indicative of an antidepressant response, which was partially reversed by coadministration of AM251. No effect of URB597 administration or any effect following the administration of AM251 alone was, however, observed. These data indicate that activation of CB1 receptors in the dentate gyrus of the hippocampus results in an antidepressant-like response. Collectively, these data highlight the potential importance of changes in the hippocampal endocannabinoid system following stress or antidepressant treatment with respect to the manifestation and/or treatment of depression.


Stiffness and Strain Properties Derived From Digital Tomosynthesis-Based Digital Volume Correlation Predict Vertebral Strength Independently From Bone Mineral Density.
Vertebral fractures are the most common osteoporotic fractures, but their prediction using standard bone mineral density (BMD) measurements from dual energy X-ray absorptiometry (DXA) is limited in accuracy. Stiffness, displacement, and strain distribution properties derived from digital tomosynthesis-based digital volume correlation (DTS-DVC) have been suggested as clinically measurable metrics of vertebral bone quality. However, the extent to which these properties correlate to vertebral strength is unknown. To establish this relationship, two independent experiments, one examining isolated T11 and the other examining L3 vertebrae within the L2-L4 segments from cadaveric donors were utilized. Following DXA and DTS imaging, the specimens were uniaxially compressed to fracture. BMD, bone mineral content (BMC), and bone area were recorded for the anteroposterior and lateromedial views from DXA, stiffness, endplate to endplate displacement and distribution statistics of intravertebral strains were calculated from DTS-DVC and vertebral strength was measured from mechanical tests. Regression models were used to examine the relationships of strength with the other variables. Correlations of BMD with vertebral strength varied between experimental groups (R2adj = 0.19-0.78). DTS-DVC derived properties contributed to vertebral strength independently from BMD measures (increasing R2adj to 0.64-0.95). DTS-DVC derived stiffness was the best single predictor (R2adj = 0.66, p < 0.0001) and added the most to BMD in models of vertebral strength for pooled T11 and L3 specimens (R2adj = 0.95, p < 0.0001). These findings provide biomechanical relevance to DTS-DVC calculated properties of vertebral bone and encourage further efforts in the development of the DTS-DVC approach as a clinical tool.


The relationship between manual coordination and mental health.
Motor coordination impairments frequently co-occur with other developmental disorders and mental health problems in clinically referred populations. But does this reflect a broader dimensional relationship within the general population? A clearer understanding of this relationship might inform improvements in mental health service provision. However, ascertainment and referral bias means that there is limited value in conducting further research with clinically referred samples. We, therefore, conducted a cross-sectional population-based study investigating children's manual coordination using an objective computerised test. These measures were related to teacher-completed responses on a behavioural screening questionnaire [the Strength and Difficulties Questionnaire (SDQ)]. We sampled 298 children (4-11 years old; 136 males) recruited from the general population. Hierarchical (logistic and linear) regression modelling indicated significant categorical and continuous relationships between manual coordination and overall SDQ score (a dimensional measure of psychopathology). Even after controlling for gender and age, manual coordination explained 15 % of the variance in total SDQ score. This dropped to 9 % after exclusion of participants whose SDQ responses indicated potential mental health problems. These results: (1) indicate that there is a clear relationship between children's motor and mental health development in community-based samples; (2) demonstrate the relationship's dimensional nature; and (3) have implications for service provision.


A common left occipito-temporal dysfunction in developmental dyslexia and acquired letter-by-letter reading?
We used fMRI to examine functional brain abnormalities of German-speaking dyslexics who suffer from slow effortful reading but not from a reading accuracy problem. Similar to acquired cases of letter-by-letter reading, the developmental cases exhibited an abnormal strong effect of length (i.e., number of letters) on response time for words and pseudowords. Corresponding to lesions of left occipito-temporal (OT) regions in acquired cases, we found a dysfunction of this region in our developmental cases who failed to exhibit responsiveness of left OT regions to the length of words and pseudowords. This abnormality in the left OT cortex was accompanied by absent responsiveness to increased sublexical reading demands in phonological inferior frontal gyrus (IFG) regions. Interestingly, there was no abnormality in the left superior temporal cortex which--corresponding to the onological deficit explanation--is considered to be the prime locus of the reading difficulties of developmental dyslexia cases. The present functional imaging results suggest that developmental dyslexia similar to acquired letter-by-letter reading is due to a primary dysfunction of left OT regions.


Analyzing small data sets using Bayesian estimation: the case of posttraumatic stress symptoms following mechanical ventilation in burn survivors.
Background : The analysis of small data sets in longitudinal studies can lead to power issues and often suffers from biased parameter values. These issues can be solved by using Bayesian estimation in conjunction with informative prior distributions. By means of a simulation study and an empirical example concerning posttraumatic stress symptoms (PTSS) following mechanical ventilation in burn survivors, we demonstrate the advantages and potential pitfalls of using Bayesian estimation. Methods : First, we show how to specify prior distributions and by means of a sensitivity analysis we demonstrate how to check the exact influence of the prior (mis-) specification. Thereafter, we show by means of a simulation the situations in which the Bayesian approach outperforms the default, maximum likelihood and approach. Finally, we re-analyze empirical data on burn survivors which provided preliminary evidence of an aversive influence of a period of mechanical ventilation on the course of PTSS following burns. Results : Not suprisingly, maximum likelihood estimation showed insufficient coverage as well as power with very small samples. Only when Bayesian analysis, in conjunction with informative priors, was used power increased to acceptable levels. As expected, we showed that the smaller the sample size the more the results rely on the prior specification. Conclusion : We show that two issues often encountered during analysis of small samples, power and biased parameters, can be solved by including prior information into Bayesian analysis. We argue that the use of informative priors should always be reported together with a sensitivity analysis.


Oral Health Disparities and Unmet Dental Needs among Preschool Children in Chelsea, MA: Exploring Mechanisms, Defining Solutions.
Significant disparities exist in children's receipt of preventive dental care (PDC) in the United States. Many of the children at greatest risk of dental disease do not receive timely PDC; when they do receive dental care, it is often more for relief of dental pain. Chelsea is a low-income, diverse Massachusetts community with high rates of untreated childhood caries. There are various dental resources available in Chelsea, yet many children do not access dental care at levels equivalent to their needs. Using Chelsea as a case-study, to explore factors contributing to forgone PDC (including the age 1 dental visit) in an in-depth way. We used a qualitative study design that included semi-structured interviews with parents of preschool children residing in Chelsea, and Chelsea-based providers including pediatricians, dentists, a dental hygienist and early childhood care providers. We examined: a) parents' dental attitudes and oral health cultural beliefs; b) parents' and providers' perspectives on facilitators and barriers to PDC, reasons for unmet needs, and proposed solutions to address the problem. We recorded, transcribed and independently coded all interviews. Using rigorous, iterative qualitative data analyses procedures, we identified emergent themes. Factors perceived to facilitate receipt of PDC included Head-Start oral health policies, strong pediatric primary care/dental linkages, community outreach and advertising, and parents' own oral health experiences. Most parents and providers perceived there to be an adequate number of accessible dental services and resources in Chelsea, including for Medicaid enrollees. However, several barriers impeded children from receiving timely PDC, the most frequently cited being insurance related problems for children and adults. Other barriers included limited dental services for children <2 years, perceived poor quality of some dental practices, lack of emphasis on prevention-based dental care, poor care-coordination, and insufficient culturally-appropriate care. Important family-level barriers included parental oral health literacy, cultural factors, limited English proficiency and competing priorities. Several solutions were proposed to address identified barriers. Even in a community with a considerable number of dental resources, various factors may preclude access to these services by preschool-aged children. Opportunities exist to address modifiable factors through strategic oral health policies, community outreach and improved care coordination between physicians, dentists and early childhood care providers.


Closure of a large palatal fistula with maxillary segmental distraction osteogenesis in a cleft palate patient.
Various techniques have been proposed for the repair of palatal clefts. The first surgical closure technique that should be kept in mind is the use of adjacent mucosal flaps. When the palatal cleft is too large to close with adjacent mucosal flaps, distant flaps such as from the tongue or nasolabial region may be considered. This report presents a cleft patient who had previously undergone an unsuccessful palatal cleft repair with a tongue flap. The size of the large palatal fistula was reduced by approximating the segments to each other with maxillary anterior segmental distraction osteogenesis to make it more manageable using conventional mucosal flaps.


A magnitude code common to numerosities and number symbols in human intraparietal cortex.
Activation of the horizontal segment of the intraparietal sulcus (hIPS) has been observed in various number-processing tasks, whether numbers were conveyed by symbolic numerals (digits, number words) or by nonsymbolic displays (dot patterns). This suggests an abstract coding of numerical magnitude. Here, we critically tested this hypothesis using fMRI adaptation to demonstrate notation-independent coding of numerical quantity in the hIPS. Once subjects were adapted either to dot patterns or to Arabic digits, activation in the hIPS and in frontal regions recovered in a distance-dependent fashion whenever a new number was presented, irrespective of notation changes. This remained unchanged when analyzing the hIPS peaks from an independent localizer scan of mental calculation. These results suggest an abstract coding of approximate number common to dots, digits, and number words. They support the idea that symbols acquire meaning by linking neural populations coding symbol shapes to those holding nonsymbolic representations of quantities.


Prevalence of HIV, syphilis, hepatitis B, and hepatitis C among entrants to Maryland correctional facilities.
Although high prevalence of hepatitis C virus (HCV) in correctional institutions has been established, data are sparse regarding the comorbidities of hepatitis B virus (HBV), HCV, and human immunodeficiency virus (HIV), all of which may complicate the management of HCV. This study sought to estimate the prevalence and correlates associated with HCV prevalence among entrants into the Maryland Division of Correction and the Baltimore City Detention Center. Participants included all newly incarcerated entrants between January 28 and March 28, 2002. Excess sera with identifiers removed from samples drawn for routine syphilis testing were assayed for antibodies to HIV and HCV and for HBV surface antigen and surface and total core antibodies. Separately, all HIV-positive specimens were tested using the serological testing algorithm for recent HIV seroconversion. Of the 1,081 inmates and 2,833 detainees, reactive syphilis serology was noted in 0.6% of the combined population; HIV seroprevalence was 6.6%; HCV prevalence was 29.7%; and 25.2% of detainees and prisoners had antigen or core or surface antibodies to HBV. A multivariate analysis of predictors of HCV positivity indicated that detainees, women, whites, older age groups, those who were HIV seropositive, and individuals with past or present infection with HBV were significantly more likely to be positive for HCV. These data indicate that hepatitis C remains an important public health concern among entrants to jail and prison and is complicated with coinfections that need to be addressed for effective treatment.


A review of pterostilbene antioxidant activity and disease modification.
Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a natural dietary compound and the primary antioxidant component of blueberries. It has increased bioavailability in comparison to other stilbene compounds, which may enhance its dietary benefit and possibly contribute to a valuable clinical effect. Multiple studies have demonstrated the antioxidant activity of pterostilbene in both in vitro and in vivo models illustrating both preventative and therapeutic benefits. The antioxidant activity of pterostilbene has been implicated in anticarcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes. In this review, we explore the antioxidant properties of pterostilbene and its relationship to common disease pathways and give a summary of the clinical potential of pterostilbene in the prevention and treatment of various medical conditions.


Critiquing the logic of the domain section of the Occupational therapy practice framework: domain and process.
The Occupational Therapy Practice Framework: Domain and Process (also known as the Framework), an official document of the American Occupational Therapy Association, advocates terminology and a classification system for concepts that are central to the profession of occupational therapy. Its use has been advocated in practice, research, education, and communications with those who wish to know more about occupational therapy. Given its importance to the profession and to society, the Framework deserves intense scrutiny and sustained scholarly inquiry. This article investigates the logic of Occupational Therapy Practice Framework: Domain and Process, with a focus on domain. Are definitions and classifications within the domain logically coherent? The Framework repeatedly violates two rules of logical definitions: (a) a unique term must be applicable to certain particulars and must not be applicable to others (the rule of precision); and (b) the particulars assigned to one term must not be assignable to another term unless there is a logical explanation (the rule of parsimony). The Framework also repeatedly violates two rules of logical classification: (a) a lower-level category must be classifiable only within its assigned higher-level category (the rule of exclusivity); and (b) all relevant particulars must be classifiable (the rule of exhaustiveness). The profession of occupational therapy needs one or more logically coherent conceptual frameworks, but the Framework is not recommended as a logical basis for practice, education, research, and external communications. Specific recommendations are made in support of the development of a logical framework and the refinement of existing frameworks.


Regulation of serum amyloid A3 (SAA3) in mouse colonic epithelium and adipose tissue by the intestinal microbiota.
The gut microbiota has been proposed as an environmental factor that affects the development of metabolic and inflammatory diseases in mammals. Recent reports indicate that gut bacteria-derived lipopolysaccharide (LPS) can initiate obesity and insulin resistance in mice; however, the molecular interactions responsible for microbial regulation of host metabolism and mediators of inflammation have not been studied in detail. Hepatic serum amyloid A (SAA) proteins are markers and proposed mediators of inflammation that exhibit increased levels in serum of insulin-resistant mice. Adipose tissue-derived SAA3 displays monocyte chemotactic activity and may play a role in metabolic inflammation associated with obesity and insulin resistance. To investigate a potential mechanistic link between the intestinal microbiota and induction of proinflammatory host factors, we performed molecular analyses of germ-free, conventionally raised and genetically modified Myd88-/- mouse models. SAA3 expression was determined to be significantly augmented in adipose (9.9+/-1.9-fold; P<0.001) and colonic tissue (7.0+/-2.3-fold; P<0.05) by the presence of intestinal microbes. In the colon, we provided evidence that SAA3 is partially regulated through the Toll-like receptor (TLR)/MyD88/NF-kappaB signaling axis. We identified epithelial cells and macrophages as cellular sources of SAA3 in the colon and found that colonic epithelial expression of SAA3 may be part of an NF-kappaB-dependent response to LPS from gut bacteria. In vitro experiments showed that LPS treatments of both epithelial cells and macrophages induced SAA3 expression (27.1+/-2.5-fold vs. 1.6+/-0.1-fold, respectively). Our data suggest that LPS, and potentially other products of the indigenous gut microbiota, might elevate cytokine expression in tissues and thus exacerbate chronic low-grade inflammation observed in obesity.


GPS-aided method for platform attitude determination based on target images.
Attitude measurement error is one of the main factors that deteriorates the imaging accuracy of laser scanning. In view of the fact that the inertial navigation system (INS) with high accuracy is very costly, a low-cost but effective GPS-aided method based on the target images is proposed to measure the platform attitude angles in this paper. Based on the relationship between the attitude change of the platform and the displacement of two adjacent images, the attitude change can be derived by the proposed method. To quantitatively evaluate the accuracy of the platform attitude angles measured by the proposed method, an outdoor experiment was carried out in comparison with the GPS/INS method. The preliminary results demonstrated that the measurement accuracy using the proposed method was better than 0.05° (RMSE).


Evaluation of susceptibility status of Culex quinquefasciatus larvae to few organophosphorus insecticides based on logistic regression analysis.
A laboratory trial was carried out at Pune to evaluate the effectiveness of five types of larvicides viz. Malathion, Temephos, Fenthion, Dichlorvos and Fenitrothion against Culex quinquesfasciatus larvae. The expected number of mortality at various dose levels for the five types of insecticides were estimated separately using logistic regression model. Based on the fitted model, the estimated dose level corresponding to the 90 percent mortality (LC90) was obtained for each insecticide. Approximate 95 percent confidence intervals for the LC90 dose, in each case, has been provided. The analysis revealed that out of all the five types of insecticides included in the study, fenthion was the most effective. The estimated value of LC90 in this case was the lowest and is equal to 0.007 mg/L. The effectiveness of temephos, dichlorvos and fenitrothion was found to be approximately same and malathion was the least effective. The results were found to be comparable with that obtained under probit method.


Novel Graphical Analyses of Runs of Homozygosity among Species and Livestock Breeds.
Runs of homozygosity (ROH), uninterrupted stretches of homozygous genotypes resulting from parents transmitting identical haplotypes to their offspring, have emerged as informative genome-wide estimates of autozygosity (inbreeding). We used genomic profiles based on 698 K single nucleotide polymorphisms (SNPs) from nine breeds of domestic cattle (Bos taurus) and the European bison (Bison bonasus) to investigate how ROH distributions can be compared within and among species. We focused on two length classes: 0.5-15 Mb to investigate ancient events and >15 Mb to address recent events (approximately three generations). For each length class, we chose a few chromosomes with a high number of ROH, calculated the percentage of times a SNP appeared in a ROH, and plotted the results. We selected areas with distinct patterns including regions where (1) all groups revealed an increase or decrease of ROH, (2) bison differed from cattle, (3) one cattle breed or groups of breeds differed (e.g., dairy versus meat cattle). Examination of these regions in the cattle genome showed genes potentially important for natural and human-induced selection, concerning, for example, meat and milk quality, metabolism, growth, and immune function. The comparative methodology presented here permits visual identification of regions of interest for selection, breeding programs, and conservation.


A case-control analysis of oral contraceptive use and breast cancer subtypes in the African American Breast Cancer Epidemiology and Risk Consortium.
Recent oral contraceptive (OC) use has been consistently associated with increased risk of breast cancer, but evidence on specific breast cancer subtypes is sparse. We investigated recency and duration of OC use in relation to molecular subtypes of breast cancer in a pooled analysis of data from the African American Breast Cancer Epidemiology and Risk Consortium. The study included 1,848 women with estrogen receptor-positive (ER+) breast cancer, 1,043 with ER-negative (ER-) breast cancer (including 494 triple negative (TN) tumors, which do not have receptors for estrogen, progesterone, and human epidermal growth factor 2), and 10,044 controls. Multivariable polytomous logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for exposure categories relative to never use, controlling for potential confounding variables. OC use within the previous 5 years was associated with increased risk of ER+ (OR 1.46, 95% CI 1.18 to 1.81), ER- (OR 1.57, 95% CI 1.22 to 1.43), and TN (OR 1.78, 95% CI 1.25 to 2.53) breast cancer. The risk declined after cessation of use but was apparent for ER+ cancer for 15 to 19 years after cessation and for ER- breast cancer for an even longer interval after cessation. Long duration of use was also associated with increased risk of each subtype, particularly ER-. Our results suggest that OC use, particularly recent use of long duration, is associated with an increased risk of ER+, ER-, and TN breast cancer in African American women. Research into mechanisms that explain these findings, especially the association with ER- breast cancer, is needed.


Phylogenomics of phrynosomatid lizards: conflicting signals from sequence capture versus restriction site associated DNA sequencing.
Sequence capture and restriction site associated DNA sequencing (RADseq) are popular methods for obtaining large numbers of loci for phylogenetic analysis. These methods are typically used to collect data at different evolutionary timescales; sequence capture is primarily used for obtaining conserved loci, whereas RADseq is designed for discovering single nucleotide polymorphisms (SNPs) suitable for population genetic or phylogeographic analyses. Phylogenetic questions that span both "recent" and "deep" timescales could benefit from either type of data, but studies that directly compare the two approaches are lacking. We compared phylogenies estimated from sequence capture and double digest RADseq (ddRADseq) data for North American phrynosomatid lizards, a species-rich and diverse group containing nine genera that began diversifying approximately 55 Ma. Sequence capture resulted in 584 loci that provided a consistent and strong phylogeny using concatenation and species tree inference. However, the phylogeny estimated from the ddRADseq data was sensitive to the bioinformatics steps used for determining homology, detecting paralogs, and filtering missing data. The topological conflicts among the SNP trees were not restricted to any particular timescale, but instead were associated with short internal branches. Species tree analysis of the largest SNP assembly, which also included the most missing data, supported a topology that matched the sequence capture tree. This preferred phylogeny provides strong support for the paraphyly of the earless lizard genera Holbrookia and Cophosaurus, suggesting that the earless morphology either evolved twice or evolved once and was subsequently lost in Callisaurus.


Idiom comprehension in French-speaking children and adolescents with Williams' syndrome.
This study looks at idiom comprehension by French-speaking people with Williams' syndrome (WS) and metapragmatic knowledge is examined. Idiomatic expressions are a nonliteral form of language where there is a considerable difference between what is said (literal interpretation) and what is meant (idiomatic interpretation). WS is characterized by a relatively preserved formal language, social interest and poor conversational skills. Using this framework, the present study aims to explore the comprehension of idiomatic expressions by 20 participants with WS. Participants performed a story completion task (comprehension task), and a task of metapragmatic knowledge to justify their chosen answers. WS performances were compared to typically developing children with the same verbal mental age. The main results can be summarized as follows: (1) people with WS have difficulties to understand idioms; (2) WS group seems to perform partly as typically developing children for the acquisition of metapragmatic knowledge of linguistic convention: there is a progressive increase in metapragmatic knowledge of linguistic convention as age increased. Our results indicate a delay of acquisition in idiom comprehension in Williams' syndrome.


Field Deployable Chemical Redox Probe for Quantitative Characterization of Carboxymethylcellulose Modified Nano Zerovalent Iron.
Nano zerovalent iron synthesized with carboxymethylcelluose (CMC-nZVI) is among the leading formulations of nZVI currently used for in situ groundwater remediation. The main advantage of CMC-nZVI is that it forms stable suspensions, which are relatively mobile in porous media. Rapid contaminant reduction by CMC-nZVI is well documented, but the fate of the CMC-nZVI (including "aging" and "reductant demand") is not well characterized. Improved understanding of CMC-nZVI fate requires methods with greater specificity for Fe(0), less vulnerability to sampling/recovery artifacts, and more practical application in the field. These criteria can be met with a simple and specific colorimetric approach using indigo-5,5'-disulfonate (I2S) as a chemical redox probe (CRP). The measured stoichiometric ratio for reaction between I2S and nZVI is 1.45 ± 0.03, suggesting complete oxidation of nZVI to Fe(III) species. However, near pH 7, reduction of I2S is diagnostic for Fe(0), because aqueous Fe(II) reduces I2S much more slowly than Fe(0). At that pH, adding Fe(II) increased I2S reduction rates by Fe(0), consistent with depassivation of nZVI, but did not affect the stoichiometry. Using the I2S assay to quantify changes in the Fe(0) content of CMC-nZVI, the rate of Fe(0) oxidation by water was found to be orders of magnitude faster than previously reported values for other types of nZVI.


Modeling and simulation methodology for digital optical computing systems.
A modeling and simulation methodology for digital optical computing systems is introduced in this paper. The methodology predicts maximum performance of a given optical computing architecture and evaluates its feasibility. As an application example, we apply this methodology to evaluate the feasibility and performance of the optical content-addressable parallel processor proposed in Appl. Opt. 31, 3241 (1992). The approach consists of two major phases. The first phase involves analytical studies of the effects of design parameters such as cross talk, diffraction-limited beam spot diameter, and pitch on system performance parameters such as signal packing density and skew time. In the second phase, a simulation model and a simulator are introduced by the use of GLAD (General Laser Analysis and Design, an optical software package developed by Applied Optics Research) to evaluate the combined effects of bit-error rate, bit rate, optical power efficiency, available source power, and signal contrast on the perfor ance parameters such as signal packing density, misalignment tolerance, and distance between devices. The methodology presented here investigates the model, not on a component-by-component basis, but as a whole, which produces a more realistic representation of the actual laborator prototype. The proposed methodology is intended to reduce the optical computing system design time as well as the design risk associated with building a prototype system.


Testing "efficient supply chain propositions" using topological characterization of the global supply chain network.
In this paper, we study the topological properties of the global supply chain network in terms of its degree distribution, clustering coefficient, degree-degree correlation, bow-tie structure, and community structure to test the efficient supply chain propositions proposed by E. J.S. Hearnshaw et al. The global supply chain data in the year 2017 are constructed by collecting various company data from the web site of Standard & Poor's Capital IQ platform. The in- and out-degree distributions are characterized by a power law of the form of γin = 2.42 and γout = 2.11. The clustering coefficient decays [Formula: see text] with an exponent βk = 0.46. The nodal degree-degree correlations 〈knn(k)〉 indicates the absence of assortativity. The bow-tie structure of giant weakly connected component (GWCC) reveals that the OUT component is the largest and consists 41.1% of all firms. The giant strong connected component (GSCC) is comprised of 16.4% of all firms. We observe that upstream or downstream firms are located a few steps away from the GSCC. Furthermore, we uncover the community structures of the network and characterize them according to their location and industry classification. We observe that the largest community consists of the consumer discretionary sector based mainly in the United States (US). These firms belong to the OUT component in the bow-tie structure of the global supply chain network. Finally, we confirm the validity of Hearnshaw et al.'s efficient supply chain propositions, namely Proposition S1 (short path length), Proposition S2 (power-law degree distribution), Proposition S3 (high clustering coefficient), Proposition S4 ("fit-gets-richer" growth mechanism), Proposition S5 (truncation of power-law degree distribution), and Proposition S7 (community structure with overlapping boundaries) regarding the global supply chain network. While the original propositions S1 just mentioned a short path length, we found the short path from the GSCC to IN and OUT by analyzing the bow-tie structure. Therefore, the short path length in the bow-tie structure is a conceptual addition to the original propositions of Hearnshaw.


Communication and the primate brain: insights from neuroimaging studies in humans, chimpanzees and macaques.
Considerable knowledge is available on the neural substrates for speech and language from brain-imaging studies in humans, but until recently there was a lack of data for comparison from other animal species on the evolutionarily conserved brain regions that process species-specific communication signals. To obtain new insights into the relationship of the substrates for communication in primates, we compared the results from several neuroimaging studies in humans with those that have recently been obtained from macaque monkeys and chimpanzees. The recent work in humans challenges the longstanding notion of highly localized speech areas. As a result, the brain regions that have been identified in humans for speech and nonlinguistic voice processing show a striking general correspondence to how the brains of other primates analyze species-specific vocalizations or information in the voice, such as voice identity. The comparative neuroimaging work has begun to clarify evolutionary relationships in brain function, supporting the notion that the brain regions that process communication signals in the human brain arose from a precursor network of regions that is present in nonhuman primates and is used for processing species-specific vocalizations. We conclude by considering how the stage now seems to be set for comparative neurobiology to characterize the ancestral state of the network that evolved in humans to support language.


Efficacy of the classic ketogenic and the modified Atkins diets in refractory childhood epilepsy.
We aimed to compare the efficacy, safety, and tolerability of a modified Atkins diet (MAD) with the classic ketogenic diet (KD) for the treatment of intractable childhood epilepsy. From March 2011 to March 2014, 104 patients aged 1-18 years who had refractory epilepsy were randomly assigned to each diet group (ClinicalTrials.gov, number NCT2100501). A seizure diary record was used to compare seizure frequencies with the baseline prediet seizure frequency at the third and sixth months after diet therapy initiation. Fifty-one patients were assigned to the KD and 53 patients to the MAD. The KD group had a lower mean percentage of baseline seizures compared with the MAD group at 3 months (38.6% for KD, 47.9% for MAD) and 6 months (33.8% for KD, 44.6% for MAD), but the differences were not statistically significant (95% confidence interval [CI] 24.1-50.8, p = 0.291 for 3 months; 95% CI 17.8-46.1, p = 0.255 for 6 months). Instead, for patients aged 1-2 years, seizure outcomes were consistently much more favorable in patients consuming the KD compared with those consuming the MAD. The rate of seizure freedom at 3 months after diet therapy initiation was significantly higher (53% for KD, 20% for MAD, p = 0.047) in these patients. The MAD had advantages with respect to better tolerability and fewer serious side effects. The MAD might be considered as the primary choice for the treatment of intractable epilepsy in children, but the classic KD is more suitable as the first line of diet therapy in patients <2 years of age.


Surfactant shedding and gas diffusion during pulsed ultrasound through a microbubble contrast agent suspension.
Interest in coated microbubbles as agents for therapeutic and quantitative imaging applications in biomedical ultrasound has increased the need for their accurate theoretical characterization. Effects such as gas diffusion, variation in the properties of the coating and the resulting changes in bubble behavior under repeated exposure to ultrasound pulses are, however, still not well understood. In this study, a revised equation for microbubble motion is proposed that includes the effects of gas diffusion, as well as adsorption, desorption and shedding of a surfactant from the bubble surface. This is incorporated into a nonlinear wave propagation model to account for these additional time dependent effects in the response of microbubble populations. The results from the model indicate there can be significant changes in both bubble behavior and the propagated pulse over time. This is in agreement with existing experimental data but is not predicted by existing propagation models. The analysis indicates that changes in bubble dynamics are dominated by surfactant shedding on the timescale of a diagnostic ultrasound pulse and gas diffusion over the timescale of the pulse repetition frequency. The implications of these results for the development of more accurate algorithms for quantitative imaging and for therapeutic applications are discussed.


Characterization of indoor air quality and resident health in an Arizona senior housing apartment building.
A survey of key indoor air quality (IAQ) parameters and resident health was carried out in 72 apartments within a single low-income senior housing building in Phoenix, Arizona. Air sampling was carried out simultaneously with a questionnaire on personal habits and general health of residents. Mean PM10 concentrations are 66 +/- 16, 58 +/- 13, and 24 +/- 3 microg/m3 and mean PM2.5 concentrations are 62 +/- 16, 53 +/- 13, and 20 +/- 2 microg/m3 for the living room, kitchen, and outdoor balcony, respectively. Median PM10 concentrations are 17, 18 and 17 microg/m3 and median PM25 concentrations are 13, 14, and 13 microg/m3, respectively. The initial results indicate that increased indoor particle concentrations coincide with residents who report smoking cigarettes. Indoor formaldehyde concentrations revealed median levels of 36.9, 38.8, and 4.3 ppb in the living room, kitchen, and balcony, respectively. Results show that 36% of living room samples and 44% of kitchen samples exceeded the Health Canada REL for chronic exposure to formaldehyde (40 ppb). Associations between occupants' behavior self-reported health conditions, and IAQ are evaluated.


Naive idiotope-specific B and T cells collaborate efficiently in the absence of dendritic cells.
Anti-idiotope (anti-Id) Abs have a role in therapy against B cell lymphomas, as inhibitors of pathogenic autoantibodies, and as surrogate Ags for immunization. Despite these observations, the mechanism by which Id(+) Ig generates anti-Id Abs is essentially unknown. To address this issue, we generated a double knock-in mouse that expresses V regions of a somatically mutated anti-Id mAb with intermediate affinity (affinity constant [Ka] = 0.77 × 10(7) M(-1)) for the myeloma protein M315. The anti-Id mice have normal peripheral B cell populations, and allelic exclusion is efficient. Anti-Id B cells from BCR knock-in mice, together with Id-specific CD4(+) T cells from previously established TCR-transgenic mice, enabled us to study Id-specific T cell-B cell collaboration by dilution of transferred cells into syngeneic BALB/c recipients. We show that previously unstimulated (naive) Id-specific B and T cells collaborate efficiently in vivo, even at low frequencies and in the presence of low amounts of Id(+) Ig, resulting in germinal center formation, plasma cell development, and secretion of isotype-switched anti-Id Abs. We further demonstrate that Id-specific T cell-B cell collaboration occurs readily in the absence of adjuvant and is not dependent on Id-presentation by dendritic cells. The results underscore the potency of anti-Id B cells in MHC class II-restricted presentation of Id(+) Ig and suggest that Id-specific T cell-B cell collaboration is of physiological relevance.


Efficacy and tolerability of a generic and a branded formulation of atorvastatin 20 mg/d in hypercholesterolemic Korean adults at high risk for cardiovascular disease: a multicenter, prospective, randomized, double-blind, double-dummy clinical trial.
The reduction in plasma LDL-C concentrations with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has been reported to reduce cardiovascular risk and mortality in individuals with or without preexisting coronary artery disease and elevated LDL-C concentrations. Atorvastatin is a statin used for lowering LDL-C concentrations. A generic formulation of atorvastatin is being developed in Korea. This study was undertaken for the purposes of marketing the generic formulation. This study was designed to compare the efficacy and tolerability of a generic formulation of atorvastatin 20 mg/d versus a branded formulation at the same dosage in hypercholesterolemic Korean adults at high risk for cardiovascular events. This 8-week, multicenter, randomized, double-blind, double-dummy study was conducted at 10 clinical centers in Korea between September 2008 and May 2009. Male and female patients aged 20 to 85 years at high risk for cardiovascular events (defined as an elevated LDL-C concentration [≥100 mg/dL]) were enrolled. Eligible patients were randomly assigned to receive generic or branded atorvastatin 20 mg once daily for 8 weeks. The primary end point was the percentage change from baseline to 8 weeks in LDL-C concentration. Secondary end points were the percentage changes from baseline in total cholesterol (TC), triglycerides (TG), HDL-C, apolipoprotein (apo) A1 and B, and high-sensitivity C-reactive protein concentrations; small, dense LDL (sdLDL) fraction; and tolerability. Tolerability was assessed using physical examination, laboratory testing, and by recording adverse events (AEs) at each visit. An additional secondary end point was the proportion of patients who achieved an LDL-C goal of <100 mg/dL. A total of 244 patients were randomized to treatment, and 33 patients were withdrawn from the study (9 patients did not receive the study medication, 11 patients due to AEs, and 13 patients due to withdrawal of consent). A total of 211 patients completed the study (50.7% male; 100% Asian; mean [SD] age, 61.7 [9.2] years) (106 patients in the group that received Accepted for publication October 5, 2010. the generic formulation and 105 patients in the group that received the branded formulation). LDL-C concentrations were reduced from the baseline by 44% and 46% after 8 weeks of treatment with the generic and branded formulations, respectively (P = NS). The percentage changes from baseline to study end in HDL-C, TC, TG, apo A1, apo B, and hsCRP concentrations and sdLDL fraction the proportions of patients who achieved the LDL-C goal between the 2 groups did not reach statistical significance. The most commonly reported events were hepatobiliary laboratory abnormality (1.7%), general somatic discomfort (1.7%), and epigastric pain (0.8%) in the group that received the generic formulation, and myalgia (1.7%), epigastric pain (0.9%), and elevation of creatinine phosphokinase (0.9%) in the group that received the branded formulation. No serious AEs were reported in either group. After 8 weeks of treatment, the differences in the LDL-C-lowering effects between the generic and branded formulations of atorvastatin 20 mg/d did not reach statistical significance in these Korean patients at high risk for cardiovascular events. Both formulations were generally well tolerated.


SIRTUIN 1 ACTIVATOR SRT1720 PROTECTS AGAINST ORGAN INJURY INDUCED BY INTESTINAL ISCHEMIA-REPERFUSION.
Intestinal ischemia-reperfusion (I/R) occurs in various clinical situations and causes local and remote organ injury, especially in the lungs, leading to significant morbidity and mortality. The maintenance of mitochondrial biogenesis is essential for cell survival and is regulated in part by sirtuin 1 (SIRT1), an energy-sensing enzyme. We hypothesized that SIRT1 activation with SRT1720 would reduce local and remote organ injury after intestinal I/R. Intestinal I/R was induced by the occlusion of the superior mesenteric artery of adult male C57BL/6 mice for 45 min, followed by reperfusion for 4 h. SRT1720 or vehicle was injected intravenously at the time of reperfusion. Blood, small intestine, and lung tissues were collected for analysis. The SRT1720 treatment of I/R mice resulted in a 57% increase in protein levels of succinate dehydrogenase, an index of mitochondrial mass, and a 120% increase in messenger RNA levels of mitochondrial transcription factor A, a marker for mitochondrial biogenesis. The microscopic architecture and apoptosis of the gut tissue was improved in the SRT1720-treated I/R mice. SRT1720 decreased intestinal messenger RNA levels of tumor necrosis factor-α by 60% and inducible nitric oxide synthase to baseline after I/R. Systemic inflammation, as determined by serum interleukin-6, was reduced in treated mice. Lung injury, as measured by histological architecture and myeloperoxidase activity, and lung apoptosis were also improved after the SRT1720 treatment. SRT1720 preserved mitochondrial biogenesis and mass, leading to inhibition of inflammation and oxidative stress, thereby protecting against intestinal I/R-induced injury. Thus, the SIRT1-mediated pathway is a promising target for the treatment of intestinal I/R injury.


Treatment of partial lacerations in flexor tendons by trimming. A biomechanical in vitro study.
Treatment of a partial laceration in zone 2 of a flexor tendon is controversial. The intact part of the tendon can usually sustain forces of normal unresisted motion, and repaired partially lacerated tendons can actually be weaker than unrepaired ones. However, complications such as triggering or entrapment have been reported in association with unrepaired tendons. The purpose of this study was to measure the biomechanical behavior following trimming of the tendon as an alternative to repair. Thirty-six flexor digitorum profundus tendons were harvested from sixteen unpaired fresh-frozen cadaveric human hands and were randomly assigned to be subjected to either 50% or 75% partial laceration, which was either lateral or volar, and were then assigned to no repair, repair with a running suture, or trimming. Mean and maximum gliding resistances were measured as the flexor digitorum profundus glided through the bone-A2 pulley complex and the flexor digitorum superficialis. Values were normalized to those measured in the intact tendon. The tendons were then distracted to failure, and maximum load and stiffness were recorded. There was triggering or entrapment of eight unrepaired tendons; two cases were severe, and six were minor. When no severe trigger was obvious, the unrepaired tendons had the lowest tendency for gliding resistance, followed by the tendons treated with trimming and then by those treated with the running suture. Overall, the tendons with a volar laceration had higher mean and maximum gliding resistance than those with a lateral laceration (p < 0.05), those with a 75% partial laceration had higher mean gliding resistance than those with a 50% laceration (p < 0.05), and the tendons that were repaired with running suture had higher mean gliding resistance than those treated with trimming (p < 0.05). Tendon strength was not significantly different among the three types of treatment. From the perspective of gliding resistance after partial tendon laceration, no repair appears necessary unless triggering is a problem. If triggering occurs, then trimming of a partially lacerated tendon may be a reliable alternative to repair, at least in terms of gliding resistance and strength.


PGH1, the precursor for the anti-inflammatory prostaglandins of the 1-series, is a potent activator of the pro-inflammatory receptor CRTH2/DP2.
Prostaglandin H(1) (PGH(1)) is the cyclo-oxygenase metabolite of dihomo-γ-linolenic acid (DGLA) and the precursor for the 1-series of prostaglandins which are often viewed as "anti-inflammatory". Herein we present evidence that PGH(1) is a potent activator of the pro-inflammatory PGD(2) receptor CRTH2, an attractive therapeutic target to treat allergic diseases such as asthma and atopic dermatitis. Non-invasive, real time dynamic mass redistribution analysis of living human CRTH2 transfectants and Ca(2+) flux studies reveal that PGH(1) activates CRTH2 as PGH(2), PGD(2) or PGD(1) do. The PGH(1) precursor DGLA and the other PGH(1) metabolites did not display such effect. PGH(1) specifically internalizes CRTH2 in stable CRTH2 transfectants as assessed by antibody feeding assays. Physiological relevance of CRTH2 ligation by PGH(1) is demonstrated in several primary human hematopoietic lineages, which endogenously express CRTH2: PGH(1) mediates migration of and Ca(2+) flux in Th2 lymphocytes, shape change of eosinophils, and their adhesion to human pulmonary microvascular endothelial cells under physiological flow conditions. All these effects are abrogated in the presence of the CRTH2 specific antagonist TM30089. Together, our results identify PGH(1) as an important lipid intermediate and novel CRTH2 agonist which may trigger CRTH2 activation in vivo in the absence of functional prostaglandin D synthase.


A shift of thermokarst lakes from carbon sources to sinks during the Holocene epoch.
Thermokarst lakes formed across vast regions of Siberia and Alaska during the last deglaciation and are thought to be a net source of atmospheric methane and carbon dioxide during the Holocene epoch. However, the same thermokarst lakes can also sequester carbon, and it remains uncertain whether carbon uptake by thermokarst lakes can offset their greenhouse gas emissions. Here we use field observations of Siberian permafrost exposures, radiocarbon dating and spatial analyses to quantify Holocene carbon stocks and fluxes in lake sediments overlying thawed Pleistocene-aged permafrost. We find that carbon accumulation in deep thermokarst-lake sediments since the last deglaciation is about 1.6 times larger than the mass of Pleistocene-aged permafrost carbon released as greenhouse gases when the lakes first formed. Although methane and carbon dioxide emissions following thaw lead to immediate radiative warming, carbon uptake in peat-rich sediments occurs over millennial timescales. We assess thermokarst-lake carbon feedbacks to climate with an atmospheric perturbation model and find that thermokarst basins switched from a net radiative warming to a net cooling climate effect about 5,000 years ago. High rates of Holocene carbon accumulation in 20 lake sediments (47 ± 10 grams of carbon per square metre per year; mean ± standard error) were driven by thermokarst erosion and deposition of terrestrial organic matter, by nutrient release from thawing permafrost that stimulated lake productivity and by slow decomposition in cold, anoxic lake bottoms. When lakes eventually drained, permafrost formation rapidly sequestered sediment carbon. Our estimate of about 160 petagrams of Holocene organic carbon in deep lake basins of Siberia and Alaska increases the circumpolar peat carbon pool estimate for permafrost regions by over 50 per cent (ref. 6). The carbon in perennially frozen drained lake sediments may become vulnerable to mineralization as permafrost disappears, potentially negating the climate stabilization provided by thermokarst lakes during the late Holocene.


Obesity impairs skeletal muscle AMPK signaling during exercise: role of AMPKα2 in the regulation of exercise capacity in vivo.
Skeletal muscle AMP-activated protein kinase (AMPK)α2 activity is impaired in obese, insulin-resistant individuals during exercise. We determined whether this defect contributes to the metabolic dysregulation and reduced exercise capacity observed in the obese state. C57BL/6J wild-type (WT) mice and/or mice expressing a kinase dead AMPKα2 subunit in skeletal muscle (α2-KD) were fed chow or high-fat (HF) diets from 3 to 16 weeks of age. At 15 weeks, mice performed an exercise stress test to determine exercise capacity. In WT mice, muscle glucose uptake and skeletal muscle AMPKα2 activity was assessed in chronically catheterized mice (carotid artery/jugular vein) at 16 weeks. In a separate study, HF-fed WT and α2-KD mice performed 5 weeks of exercise training (from 15 to 20 weeks of age) to test whether AMPKα2 is necessary to restore work tolerance. HF-fed WT mice had reduced exercise tolerance during an exercise stress test, and an attenuation in muscle glucose uptake and AMPKα2 activity during a single bout of exercise (P<0.05 versus chow). In chow-fed α2-KD mice, running speed and time were impaired ∼45 and ∼55%, respectively (P<0.05 versus WT chow); HF feeding further reduced running time ∼25% (P<0.05 versus α2-KD chow). In response to 5 weeks of exercise training, HF-fed WT and α2-KD mice increased maximum running speed ∼35% (P<0.05 versus pre-training) and maintained body weight at pre-training levels, whereas body weight increased in untrained HF WT and α2-KD mice. Exercise training restored running speed to levels seen in healthy, chow-fed mice. HF feeding impairs AMPKα2 activity in skeletal muscle during exercise in vivo. Although this defect directly contributes to reduced exercise capacity, findings in HF-fed α2-KD mice show that AMPKα2-independent mechanisms are also involved. Importantly, α2-KD mice on a HF-fed diet adapt to regular exercise by increasing exercise tolerance, demonstrating that this adaptation is independent of skeletal muscle AMPKα2 activity.


Assessment of Lekhana Basti in the management of hyperlipidemia.
Hyperlipidemia is highly prevalent and is closely related to coronary heart disease which is the most common cause of death. Raised cholesterol is estimated to be responsible for 18% of cerebrovascular disease and 56% of ischemic heart disease. Overall, these diseases account for about 4.4 million deaths (7.9% of the total). Based upon the etiological factors and symptom complexes, hyperlipidemia can be considered as a part of Medoroga. Being a Tikshna formulation, the treatment modality of Lekhana Basti is aimed basically for Apatarpana (emaciation) of the body, as Basti is the fastest Apatarpana. In the present clinical trial, a total of 22 patients were registered of whom 19 patients completed the course of the therapy. Under randomization, the registered patients were divided into two groups of which group A was treated with Lekhana Basti and group B was administered standard control drug, i.e., Triphala Guggulu, for 21 days. The results of the study revealed that in patients treated with Lekhana Basti, there was a decrease of about 4.99% in S. cholesterol, 9.13% in S. low density lipoprotein (LDL), and 0.36% in S. apolipoprotein B. Lekhana Basti was found to have significant effect in reducing the symptoms of Medodushti and in reduction of objective parameters like weight, body mass index (BMI), body fat percentage, body circumferences such as chest, abdomen, hip, pelvis, mid-thigh circumference, etc., and skin fold thickness as biceps, triceps, mid-arm, and abdominal skinfold thickness.


Changing patterns of suicide in Hong Kong.
This paper aims to examine the changes in frequency, distribution and methods of suicide in the past 30 years in Hong Kong, and to explore the sociocultural factors behind such changes. Official data on suicides, undetermined deaths and seven social variables were used to estimate the age-, sex- and method-specific suicide rates and monthly occurrence of suicides, and to measure social changes. A low "anomie" status has been maintained for the past 30 years in Hong Kong. After accounting for undetermined deaths, suicide rates in adult males and young females (aged 15-24 years) decreased, while the rates in adult females remained stable. The phenomenon may be due to a protective effect of employment in males and by the changing status of women in Hong Kong. Suicide by jumping from heights became increasingly common, but appears to have substituted other means of suicide rather than increasing the overall suicide rate. Winter months had lower suicide rates, and the same circannual rhythm across diverse cultures speaks for a shared socio-biological process underlying suicide.


Aesthetic Surgical Approach for Bone Dehiscence Treatment by Means of Single Implant and Interdental Tissue Regeneration: A Case Report with Five Years of Follow-Up.
The replacement of single anterior teeth by means of endosseous implants implies the achievement of success in restoring both aesthetic and function. However, the presence of wide endoperiodontal lesions can lead to horizontal hard and soft tissues defects after tooth extraction, making it impossible to correctly place an implant in the compromised alveolar socket. Vertical augmentation procedures have been proposed to solve these clinical situations, but the amount of new regenerated bone is still not predictable. Furthermore, bone augmentation can be complicated by the presence of adjacent teeth, especially if they bring with them periodontal defects. Therefore, it is used to restore periodontal health of adjacent teeth before making any augmentation procedures and to wait a certain healing period before placing an implant in vertically augmented sites, otherwise risking to obtain a nonsatisfactory aesthetic result. All of these procedures, however, lead to an expansion of treatment time which should affect patient compliance. For this reason, this case report suggests a surgical technique to perform vertical bone augmentation at a single gap left by a central upper incisor while placing an implant and simultaneously to regenerate the periodontal attachment of an adjacent lateral incisor, without compromising the aesthetic result.


Thermal physiological traits and plasticity of metabolism are sensitive to biogeographic breaks in a rock-pool marine shrimp.
Populations of broadly distributed species commonly exhibit latitudinal variation in thermal tolerance and physiological plasticity. This variation can be interrupted when biogeographic breaks occur across the range of a species, which are known to affect patterns of community structure, abundance and recruitment dynamics. Coastal biogeographic breaks often impose abrupt changes in environmental characteristics driven by oceanographic processes and can affect the physiological responses of populations inhabiting these areas. Here, we examined thermal limits, performances for heart rate and plasticity in metabolic rate of the intertidal shrimp Betaeus emarginatus from seven populations along its latitudinal range (∼3000 km). The distribution of this species encompass two breaks along the southeastern Pacific coast of Chile: the northern break is characterized by sharp discontinuities in upwelling regimes, and the southern break constitutes a major discontinuity in water conditions (temperature, pH, dissolved oxygen and nutrients), coastline topography and divergence of main oceanographic currents. For B. emarginatus, we found higher plasticity in metabolism at the sites sampled at the biogeographic breaks, and at the site subjected to seasonal upwelling. The variation in metabolic rate was not consistent with increasing latitude and it was not affected by breaks. The lower and upper thermal limits were lower in populations around breaks, although the optimum temperature decreased towards higher latitudes. Overall, whereas thermal limits and plasticity of metabolism are related to biogeographic breaks, metabolic rate is not related to increasing latitude or the presence of breaks in the sampled range.


A cross-sectional study of US rural adults' consumption of fruits and vegetables: do they consume at least five servings daily?
Rural residents are increasingly identified as being at greater risk for health disparities. These inequities may be related to health behaviors such as adequate fruits and vegetable consumption. There is little national-level population-based research about the prevalence of fruit and vegetable consumption by US rural population adults. The objective of this study was to examine the prevalence differences between US rural and non-rural adults in consuming at least five daily servings of combined fruits and vegetables. Cross-sectional analysis of weighted 2009 Behavioral Risk Factor Surveillance Survey (BRFSS) data using bivariate and multivariate techniques. 52,259,789 US adults were identified as consuming at least five daily servings of fruits and vegetables of which 8,983,840 were identified as living in rural locales. Bivariate analysis revealed that in comparison to non-rural US adults, rural adults were less likely to consume five or more daily servings of fruits and vegetables (OR=1.161, 95% CI 1.160-1.162). Logistic regression analysis revealed that US rural adults consuming at least five daily servings of fruits and vegetables were more likely to be female, non-Caucasian, married or living with a partner, living in a household without children, living in a household whose annual income was > $35,000, and getting at least moderate physical activity. They were also more likely to have a BMI of <30, have a personal physician, have had a routine medical exam in the past 12 months, self-defined their health as good to excellent and to have deferred medical care because of cost. When comparing the prevalence differences between rural and non-rural US adults within a state, 37 States had a lower prevalence of rural adults consuming at least five daily servings of fruits and vegetables and 11 States a higher prevalence of the same. This enhanced understanding of fruit and vegetable consumption should prove useful to those seeking to lessen the disparity or inequity between rural and non-rural adults. Additionally, those responsible for health-related planning could benefit from the knowledge of how their state ranks in comparison to others vis-à-vis the consumption of fruits and vegetables by rural adults---a population increasingly being identified as one at risk for health disparities.


Regulatory cells in allergen-specific immunotherapy.
Allergen-specific immunotherapy (SIT) is currently the best available curative treatment in allergies and has been used for the treatment of patients for the past 100 years. The formation of a Th2 cell predominant inflammation in addition to production of allergen-specific IgE, the attraction of proinflammatory cells and the degranulation of effector cells, such as mast cells, are essential mechanisms in allergy development. Tregs aim to diminish these effects by IL-10- and TGF-β-mediated anti-inflammatory reactions and therefore are one of the main targets in SIT. The induction of allergen tolerance is the key to successful SIT. With a special focus on Tregs, this review aims to clarify what is currently known about allergy development and the mode of action in allergen-SIT, which helps to develop further therapeutic strategies in the fight against allergic diseases.


The role of radiation quality in the stimulation of intercellular induction of apoptosis in transformed cells at very low doses.
An important stage in tumorigenesis is the ability of precancerous cells to escape natural anticancer signals. Apoptosis can be selectively induced in transformed cells by neighboring normal cells through cytokine and ROS/RNS signaling. The intercellular induction of apoptosis in transformed cells has previously been found to be enhanced after exposure of the normal cells to very low doses of both low- and high-LET ionizing radiation. Low-LET ultrasoft X rays with a range of irradiation masks were used to vary both the dose to the cells and the percentage of normal cells irradiated. The results obtained were compared with those after α-particle irradiation. The intercellular induction of apoptosis in nonirradiated src-transformed 208Fsrc3 cells observed after exposure of normal 208F cells to ultrasoft X rays was similar to that observed for γ rays. Intercellular induction of apoptosis was stimulated by irradiation of greater than 1% of the nontransformed 208F cells and increased with the fraction of cells irradiated. A maximal response was observed when ∼10-12% of the cells were irradiated, which gave a similar response to 100% irradiated cells. Between 1% and 10%, high-LET α particles were more effective than low-LET ultrasoft X rays in stimulating intercellular induction of apoptosis for a given fraction of cells irradiated. Scavenger experiments show that the increase in intercellular induction of apoptosis results from NO(•) and peroxidase signaling mediated by TGF-β. In the absence of radiation, intercellular induction of apoptosis was also stimulated by TGF-β treatment of the nontransformed 208F cells prior to coculture; however, no additional increase in intercellular induction of apoptosis was observed if these cells were also irradiated. These data suggest that the TGF-β-mediated ROS/RNS production reaches a maximum at low doses or fluences of particles, leading to a plateau in radiation-stimulated intercellular induction of apoptosis at higher doses.


Cross-cultural adaptation and validity of the Italian version of the Central Sensitization Inventory.
Central sensitization (CS) is an important feature in patients with chronic pain. The Central Sensitization Inventory (CSI) was developed with the goal of detecting the patients' symptoms related to CS. This study aimed at cross-culturally adapting the CSI into Italian, and at assessing its structural and construct validity in patients with different chronic pain disorders. Clinimetric study. The Italian version of the CSI (CSI-I) was generated following forward and backward translations, expert committee review, and pilot-testing. Patients with pain for ≥3 months were eligible if diagnosed with: low back pain (LBP), temporomandibular disorder (TMD), hand osteoarthritis (HOA), fibromyalgia (FM), or rheumatoid arthritis (RA). Structural validity was assessed with exploratory factor analysis and parallel analysis based on minimum rank factor analysis; construct validity was evaluated by testing ten hypotheses on: 1) expected differences between relevant subgroups, 2) expected correlations with other instruments measuring pain intensity, physical functioning, psychological functioning, headache symptoms, and pain self-efficacy. 220 patients were included: 35% with LBP, 17% with TMD, 19% with HOA, 9% with FM, and 20% with RA. Factor analyses revealed that the CSI-I is a unidimensional instrument. Construct validity was satisfactory since 80% of the hypotheses were met. The CSI-I was successfully developed and exhibited satisfactory validity in patients with chronic pain. Its reliability, responsiveness and content validity should be investigated in future studies. Until robust evidence indicates a strong relationship between CS and the CSI-I, caution should be adopted in claiming that the CSI-I measures CS.


Pore-Size Distribution of Silica Colloidal Crystals from Nitrogen Adsorption Isotherms.
Silica colloidal crystals are face-centered cubic structures comprised of silica spheres with the diameters ranging between tens and hundreds of nanometers. The voids between the spheres form pores, which can be probed by nitrogen adsorption porosimetry. Here, we prepared two mesoporous samples and a macroporous reference sample and then measured nitrogen adsorption and desorption isotherms for further characterization. We proposed a straightforward procedure for calculation of the pore-size distribution of silica colloidal crystals from nitrogen adsorption isotherms. The procedure is based on the adsorption integral equation solution with a kernel of theoretical isotherms, consistent with the procedure used for many other porous materials. The solution is carried out using the non-negative least squares (NNLS) regression with Tikhonov regularization. The kernel of mesoporous isotherms is built on the basis of the macroscopic Derjaguin-Broekhoff-de Boer (DBdB) theory of capillary condensation considering the voids as a network of spheres. Application of our procedure for the analysis of the adsorption branches of experimental isotherms resulted in bimodal distributions, where the modes matched well with the sizes of the voids in the colloidal crystals face centered cubic structure: the main mode corresponds to the octahedral voids and the second mode to the tetrahedral voids. Furthermore, we modified the surface of the samples with organics and repeated the characterization procedure for the modified samples. The resulting pore-size distribution for the samples with the modified surface matched the original one quite closely. It demonstrates the procedure as a simple and efficient technique to estimate the pore-size distribution and justifies the spherical shape approximation for the voids in the silica colloidal crystals.


The availability of smoking-permitted accommodations from Airbnb in 12 Canadian cities.
Airbnb is a web-based peer-to-peer (P2P) service that enables potential hosts and guests to broker accommodations in private homes as an alternative to traditional hotels. The hospitality sector has increasingly gone smoke-free over the last decade. This study identified the availability and cost of smoking-permitted accommodations identified on Airbnb. The study team searched for Airbnb accommodations in 12 Canadian cities across each of Canada's 10 provinces. Searches included availability for a single person for a private room, or double occupancy for an entire home/apartment; searches were for 1-night and 1-week stays. Cities across Canada, including Regina, Fredericton and Charlottetown, had no smoking-permitted accommodations available for the searches conducted. The proportion of private rooms available for one night that permitted smoking ranged from 2% in Calgary, 4% in Winnipeg and St. John's, 10% in Halifax and Victoria, 18% in Toronto, 45% in Vancouver and 69% in Montréal. The average cost for a private room for one night in Vancouver was $128, while the cost for a private room that permits smoking was $62; however, in other markets prices were more similar. Across Canada, there is a wide range of smoking-permitted accommodations available through Airbnb. In some markets, smoking-permitted accommodation may be significantly less expensive than smoke-free options. As hotel chains increasingly go smoke-free, it is possible that the marketplace will respond with offerings to fulfil consumer demand. As policy makers consider how to regulate P2P services like Airbnb, public health considerations should be included.


Genetic diversity of Nile tilapia (Oreochromis niloticus) throughout West Africa.
Nile tilapia (Oreochromis niloticus) is a globally significant aquaculture species rapidly gaining status as a farmed commodity. In West Africa, wild Nile tilapia genetic resources are abundant yet knowledge of fine-scale population structure and patterns of natural genetic variation are limited. Coinciding with this is a burgeoning growth in tilapia aquaculture in Ghana and other countries within the region underpinned by locally available genetic resources. Using 192 single nucleotide polymorphism (SNP) markers this study conducted a genetic survey of Nile tilapia throughout West Africa, sampling 23 wild populations across eight countries (Benin, Burkina Faso, Côte d'Ivoire, Ghana, Togo, Mali, Gambia and Senegal), representing the major catchments of the Volta, Niger, Senegal and Gambia River basins. A pattern of isolation-by-distance and significant spatial genetic structure was identified throughout West Africa (Global FST = 0.144), which largely corresponds to major river basins and, to a lesser extent, sub-basins. Two populations from the Gambia River (Kudang and Walekounda), one from the western Niger River (Lake Sélingué) and one from the upper Red Volta River (Kongoussi) showed markedly lower levels of diversity and high genetic differentiation compared to all other populations, suggesting genetically isolated populations occurring across the region. Genetic structure within the Volta Basin did not always follow the pattern expected for sub-river basins. This study identifies clear genetic structuring and differentiation amongst West African Nile tilapia populations, which concur with broad patterns found in previous studies. In addition, we provide new evidence for fine-scale genetic structuring within the Volta Basin and previously unidentified genetic differences of populations in Gambia. The 192 SNP marker suite used in this study is a useful tool for differentiating tilapia populations and we recommend incorporating this marker suite into future population screening of O. niloticus. Our results form the basis of a solid platform for future research on wild tilapia genetic resources in West Africa, and the identification of potentially valuable germplasm for use in ongoing breeding programs for aquaculture.


A conservative pattern of water use, rather than deep or profuse rooting, is critical for the terminal drought tolerance of chickpea.
Chickpea is mostly grown on stored soil moisture, and deep/profuse rooting has been hypothesized for almost three decades to be critical for improving chickpea tolerance to terminal drought. However, temporal patterns of water use that leave water available for reproduction and grain filling could be equally critical. Therefore, variation in water use pattern and root depth/density were measured, and their relationships to yield tested under fully irrigated and terminal drought stress, using lysimeters that provided soil volumes equivalent to field conditions. Twenty chickpea genotypes having similar plant phenology but contrasting for a field-derived terminal drought-tolerance index based on yield were used. The pattern of water extraction clearly discriminated tolerant and sensitive genotypes. Tolerant genotypes had a lower water uptake and a lower index of stomatal conductance at the vegetative stage than sensitive ones, while tolerant genotypes extracted more water than sensitive genotypes after flowering. The magnitude of the variation in root growth components (depth, length density, RLD, dry weight, RDW) did not distinguish tolerant from sensitive genotypes. The seed yield was not significantly correlated with the root length density (RLD) in any soil layers, whereas seed yield was both negatively related to water uptake between 23-38 DAS, and positively related to water uptake between 48-61 DAS. Under these conditions of terminal drought, the most critical component of tolerance in chickpea was the conservative use of water early in the cropping cycle, explained partly by a lower canopy conductance, which resulted in more water available in the soil profile during reproduction leading to higher reproductive success.


An integrative C. elegans protein-protein interaction network with reliability assessment based on a probabilistic graphical model.
In Caenorhabditis elegans, a large number of protein-protein interactions (PPIs) are identified by different experiments. However, a comprehensive weighted PPI network, which is essential for signaling pathway inference, is not yet available in this model organism. Therefore, we firstly construct an integrative PPI network in C. elegans with 12,951 interactions involving 5039 proteins from seven molecular interaction databases. Then, a reliability score based on a probabilistic graphical model (RSPGM) is proposed to assess PPIs. It assumes that the random number of interactions between two proteins comes from the Bernoulli distribution to avoid multi-links. The main parameter of the RSPGM score contains a few latent variables which can be considered as several common properties between two proteins. Validations on high-confidence yeast datasets show that RSPGM provides more accurate evaluation than other approaches, and the PPIs in the reconstructed PPI network have higher biological relevance than that in the original network in terms of gene ontology, gene expression, essentiality and the prediction of known protein complexes. Furthermore, this weighted integrative PPI network in C. elegans is employed on inferring interaction path of the canonical Wnt/β-catenin pathway as well. Most genes on the inferred interaction path have been validated to be Wnt pathway components. Therefore, RSPGM is essential and effective for evaluating PPIs and inferring interaction path. Finally, the PPI network with RSPGM scores can be queried and visualized on a user interactive website, which is freely available at .


Probing the Quantum Interference between Singly and Doubly Resonant Top-Quark Production in pp Collisions at sqrt[s]=13 TeV with the ATLAS Detector.
This Letter presents a normalized differential cross-section measurement in a fiducial phase-space region where interference effects between top-quark pair production and associated production of a single top quark with a W boson and a b-quark are significant. Events with exactly two leptons (ee, μμ, or eμ) and two b-tagged jets that satisfy a multiparticle invariant mass requirement are selected from 36.1 fb^{-1} of proton-proton collision data taken at sqrt[s]=13 TeV with the ATLAS detector at the LHC in 2015 and 2016. The results are compared with predictions from simulations using various strategies for the interference. The standard prescriptions for interference modeling are significantly different from each other but are within 2σ of the data. State-of-the-art predictions that naturally incorporate interference effects provide the best description of the data in the measured region of phase space most sensitive to these effects. These results provide an important constraint on interference models and will guide future model development and tuning.


Hemodynamic Responses to Crystalloid and Colloid Fluid Boluses during Noncardiac Surgery.
Colloids are thought to sustain blood pressure and cardiac index better than crystalloids. However, the relative effects of intraoperative hydroxyethyl starch and crystalloid administration on the cardiac index and blood pressure remain unclear. This study therefore tested in this subanalysis of a previously published large randomized trial the hypothesis that intraoperative goal-directed colloid administration increases the cardiac index more than goal-directed crystalloid administration. Further, the effects of crystalloid and colloid boluses on blood pressure were evaluated. This planned subanalysis of a previous trial analyzed data from 973 patients, of whom 480 were randomized to colloids and 493 were randomized to crystalloids. Fluid administration was guided by esophageal Doppler. The primary outcome was the time-weighted average cardiac index during surgery between the colloid and crystalloid group. The secondary outcomes were the cardiac index just after bolus administration, time elapsed between boluses, and the average real variability during surgery. The study recorded cardiac index, corrected flow time, and blood pressure at 10-min intervals, as well as before and after each bolus. Time-weighted average of cardiac index over the duration of anesthesia was only slightly greater in patients given colloid than crystalloid, with the difference being just 0.20 l · min-1 · m-2 (95% CI, 0.11 to 0.29; P < 0.001). However, the hazard for needing additional boluses was lower after colloid administration (hazard ratio [95% CI], 0.60 [0.55 to 0.66]; P < 0.001) in a frailty time-to-event model accounting for within-subject correlation. The median [quartiles] number of boluses per patient was 4 [2, 6] for colloids and 6 [3, 8] for crystalloids, with a median difference (95% CI) of -1.5 (-2 to -1; P < 0.001). The average real mean arterial pressure variability did not differ significantly between the groups (difference in means [95% CI] of -0.03 (-0.07 to 0.02) mmHg, P = 0.229). There were not clinically meaningful differences in the cardiac index or mean pressure variability in patients given goal-directed colloid and crystalloids. As might be expected from longer intravascular dwell time, the interval between boluses was longer with colloids. However, on a case basis, the number of boluses differed only slightly. Colloids do not appear to provide substantial hemodynamic benefit.


TNF-alpha/IL-1/NF-kappaB transduction pathway in human cancer prostate.
TNFalpha exerts apoptosis throughout an intracellular transduction pathway that involves the kinase proteins TRAF-2 (integration point of apoptotic and survival signals), ASK1 (pro-apoptotic protein), MEK-4 (p38 activator and metastasis suppressor gene), JNK (stress mitogen activated protein kinase) and the transcription factor AP-1. TNFalpha also exerts proliferation by p38 activation, or when TRAF-2 simultaneously induces the transcription factor NF-kappaB by NIK. NIK and p38 may also be activated by IL-1. P38 activated several transcription factors such as Elk-1, ATF-2 and NF-kappaB. NIK also may activate NF-kappaB. The aim of the present article was to evaluate the different components of this TNFalpha/IL-1 transduction pathway in human prostate carcinoma (PC) in comparison with normal human prostate. In prostate cancer, pro-apoptotic TNFalpha/AP-1 pathway is probably inactivated by different factors such as p21 (at ASK-1 level) and bcl-2 (at JNK level), or diverted towards p38 or NIK activation. IL-1alpha enhances proliferation through IL-1RI that activates either NIK or p38 transduction pathway. P38 and NIK activate different transcription factors related with cell proliferation and survival such as ATF-2, Elk-1 or NF-kappaB. In order to search a possible target to cancer prostate treatment we proposed that inhibition of several proinflamatory cytokines such as IL-1 and TNFalpha might be a possible target for PC treatment, because decrease the activity of all transduction pathway members that activate transcription factors as NF-kappaB, Elk-1 or ATF-2.


Loss of HNF-1alpha function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism.
Mutations in hepatocyte nuclear factor 1alpha (HNF-1alpha) lead to maturity-onset diabetes of the young type 3 as a result of impaired insulin secretory response in pancreatic beta-cells. The expression of 50 genes essential for normal beta-cell function was studied to better define the molecular mechanism underlying the insulin secretion defect in Hnf-1alpha(-/-) mice. We found decreased steady-state mRNA levels of genes encoding glucose transporter 2 (Glut2), neutral and basic amino acid transporter, liver pyruvate kinase (L-Pk), and insulin in Hnf-1alpha(-/-) mice. In addition, we determined that the expression of several islet-enriched transcription factors, including Pdx-1, Hnf-4alpha, and Neuro-D1/Beta-2, was reduced in Hnf-1alpha(-/-) mice. These changes in pancreatic islet mRNA levels were already apparent in newborn animals, suggesting that loss of Hnf-1alpha function rather than chronic hyperglycemia is the primary cause of the altered gene expression. This expression profile was pancreatic islet-specific and distinct from hepatocytes, where we found normal expression of Glut2, L-Pk, and Hnf-4alpha in the liver of Hnf-1alpha(-/-) mice. The expression of small heterodimer partner (Shp-1), an orphan receptor that can heterodimerize with Hnf-4alpha and inhibit its transcriptional activity, was also reduced in Hnf-1alpha(-/-) islets. We characterized a 0.58-kb Shp-1 promoter and determined that the decreased expression of Shp-1 may be indirectly mediated by a downregulation of Hnf-4alpha. We further showed that Shp-1 can repress its own transcriptional activation by inhibiting Hnf-4alpha function, thereby establishing a feedback autoregulatory loop. Our results indicate that loss of Hnf-1alpha function leads to altered expression of genes involved in glucose-stimulated insulin secretion, insulin synthesis, and beta-cell differentiation.


Prevalence, haemolytic and haemagglutination activities and antibiotic susceptibility profiles of Campylobacter spp. isolated from human diarrhoeal stools in Vhembe District, South Africa.
Campylobacter species are increasingly being recognized as agents of gastroenteritis worldwide. However, data on the pathogenic characteristics of the organism isolated in rural communities in South Africa are lacking. In this study, the prevalence of Campylobacter spp. from diarrhoeal stools, haemolytic and haemagglutinating activities of the isolates, and antibiotic susceptibility profiles, including minimum inhibitory concentration (MIC) patterns to different antibiotics, were determined using the standard microbiological techniques. Campylobacter spp. were isolated from individuals of all age-groups; however, the infection rate was higher among individuals aged less than two years (30.4%). Of 115 Campylobacter strains isolated, polymerase chain reaction (PCR) analysis indicated that 98 (85%) were C. jejuni, while 17 (15%) were C. coli. Seventy-one (62%) of the strains showed haemolysis on human blood, and 80% agglutinated human blood, whereas 22.6% were beta-lactamase-positive. Resistance to antimicrobials, such as erythromycin, ciprofloxacin, vancomycin, and fusidic acid, was high. Increased resistance to macrolide and quinolone antibiotics poses major risks for treatment failure. Haemolytic and haemagglutinating activities may be useful in preliminary characterization of pathogenic strains in settings where Campylobacter-associated infections are common.


Trends in heart failure hospitalizations.
Heart failure (HF) requiring hospitalization can be defined as an admission to the hospital resulting in a calendar date change. According to the National Hospital Discharge Survey, the number of HF hospitalizations, either as a primary or secondary diagnosis, tripled between 1979 and 2004, and individuals over the age of 65 make 80 % of the prevalent cases of heart failure in the developed countries. HF is the most expensive Diagnosis Related Groups (DRG) diagnosis for hospitalizations in general, and the most frequent diagnosis for 30-day readmissions, incurring 15 billion in cost. To better understand and capture information, registries and trials have started to examine hospitalization rates and HF mortality, in addition to characterizing the hospitalized population. Registries exist worldwide. The role of emergency departments and HF clinics has become paramount in recognizing the preventable hospitalizations and 30-day readmissions, and cost containment.


An active and water-soluble truncation mutant of the human UDP-glucuronosyltransferase 1A9.
The UDP-glucuronosyltransferases (UGTs) are integral membrane proteins, and previous attempts to generate a water-soluble UGT by removing the single trans-membrane helix yielded inactive and membrane-bound proteins. We have now replaced the 45 C-terminal amino acids of the human UGT1A9, including its trans-membrane helix, with a fusion peptide ending with six His residues. Detergent-free extraction of insect cells expressing this mutant, UGT1A9Sol, released scopoletin glucuronidation activity into the supernatant, and subsequent ultracentrifugation did not sediment that activity. UGT1A9Sol was purified by immobilized metal affinity chromatography (IMAC) in the absence of detergents throughout the entire process. The IMAC purification increased somewhat the apparent K(m) of UGT1A9 toward scopoletin and rendered the enzyme sensitive to freezing. The activity of UGT1A9Sol in the cell extract was partly inhibited by Triton X-100, irrespective of the presence or absence of phospholipids. UGT1A9Sol exhibited a relatively high rate of scopoletin glucuronidation, whereas its activity toward 1-naphthol, entacapone, umbelliferone, and 4-nitrophenol was much lower. The kinetics and substrate specificity of UGT1A9Sol resembled the detergent-suspended full-length UGT1A9 rather than the membrane-bound UGT1A9. The apparent K(m) value of UGT1A9Sol for scopoletin was similar to that of the full-length UGT1A9 in the presence of detergent, but much higher than the respective value in the membrane-bound enzyme. The results suggest that either the detergent binding to the trans-membrane helix within the full-length UGT1A9, or the removal of this helix by gene manipulation, affect the interaction of the enzyme with its aglycone substrate in a similar manner.


From the day they are born: a qualitative study exploring violence against children with disabilities in West Africa.
Despite the building evidence on violence against children globally, almost nothing is known about the violence children with disabilities in low and middle-income countries (LMICs) experience. The prevalence of violence against children with disabilities can be expected to be higher in LMICs where there are greater stigmas associated with having a child with a disability, less resources for families who have children with disabilities, and wider acceptance of the use of corporal punishment to discipline children. This study explores violence experienced by children with disabilities based on data collected from four countries in West Africa- Guinea, Niger, Sierra Leone, and Togo. A qualitative study design guided data generation with a total of 419 children, community members, and disability stakeholders. Participants were selected using purposive sampling. Stakeholders shared their observations of or experiences of violence against children with disabilities in their community in interviews and focus groups. Thematic analysis guided data analysis and identified patterns of meaning among participants' experiences. Results illuminate that children with disabilities experience violence more than non-disabled children, episodes of violence start at birth, and that how children with disabilities participate in their communities contributes to their different experiences of violence. The study recommends policy-oriented actions and prevention programs that include children and their families in strategizing ways to address violence.