Computational models of large-scale genome architecture.
The spatial architecture and dynamics of the genomic material in the limited volume of the nucleus plays an important role in biological processes ranging from gene expression to DNA repair. Yet, detailed descriptions of dynamic genome architecture are still lacking and its governing principles and functional implications remain largely unknown. Powerful experimental methods have been developed to address this gap, including single-cell imaging and chromosome conformation capture methods, leading to rapidly growing quantitative data sets. Despite their importance, however, these data are insufficient to provide a full understanding of genome architecture and function. Computational models are becoming an increasingly indispensable complement in order to make sense of the experimental data and to allow a quantitative understanding of how chromosomes fold, move and interact. Here, we review efforts, developed over the last ~25 years, to model the large-scale 3D organization and dynamics of chromosomes or genomes quantitatively. We discuss models based on theories and simulations of polymer physics or computational reconstruction methods, highlighting similarities and differences between models, as well as limitations and possible improvements.


Incorporating evolutionary adaptation in species distribution modelling reduces projected vulnerability to climate change.
Based on the sensitivity of species to ongoing climate change, and numerous challenges they face tracking suitable conditions, there is growing interest in species' capacity to adapt to climatic stress. Here, we develop and apply a new generic modelling approach (AdaptR) that incorporates adaptive capacity through physiological limits, phenotypic plasticity, evolutionary adaptation and dispersal into a species distribution modelling framework. Using AdaptR to predict change in the distribution of 17 species of Australian fruit flies (Drosophilidae), we show that accounting for adaptive capacity reduces projected range losses by up to 33% by 2105. We identify where local adaptation is likely to occur and apply sensitivity analyses to identify the critical factors of interest when parameters are uncertain. Our study suggests some species could be less vulnerable than previously thought, and indicates that spatiotemporal adaptive models could help improve management interventions that support increased species' resilience to climate change.


Time for children: trends in the employment patterns of parents, 1967-2009.
Using data from the 1967-2009 years of the March Current Population Surveys (CPS), we examine two important resources for children's well-being: time and money. We document trends in parental employment, from the perspective of children, and show what underlies these trends. We find that increases in family work hours mainly reflect movements into jobs by parents-particularly mothers, who in prior decades would have remained at home. This increase in market work has raised incomes for children in the typical two-parent family but not for those in lone-parent households. Time use data from 1975 and 2003-2008 reveal that working parents spend less time engaged in primary childcare than their counterparts without jobs but more than employed peers in previous cohorts. Analysis of 2004 work schedule data suggests that non-daytime work provides an alternative method of coordinating employment schedules for some dual-earner families.


Characterization of TREM-3, an activating receptor on mouse macrophages: definition of a family of single Ig domain receptors on mouse chromosome 17.
We recently reported the cloning of two triggering receptors expressed by myeloid cells (TREM), TREM-2a and TREM-2b, which are highly homologous to each other. These receptors associate with DAP12, and ligation of TREM-2 on the surface of macrophages leads to the release of nitric oxide. Using the immunoglobulin (Ig) domain of TREM-2 to screen a mouse EST database we have isolated a novel receptor, derived from a WEHI-3 macrophage library, which shows homology to TREM-2 (20%). The DNA sequence of this receptor has been submitted to Genbank with the name TREM-3. The predicted amino acid sequence contains a single Ig domain and a transmembrane lysine residue. We found transcripts for TREM-3 in two macrophage cell lines (RAW264.7 and MT2) but not in P388D1 macrophage cells. TREM-3 transcripts could also be detected at low levels in T cell lines, but were not detectable in NK, B cell, or mast cell lines. Furthermore, in macrophage cells, transcripts for TREM-3 were up-regulated by LPS, but were down-regulated by IFN-gamma. Like TREM-1 and TREM-2, TREM-3 signals through DAP12, and when TREM-3 is transfected into an NK cell line it mediates redirected lysis. Thus, TREM-3 functions as an activating receptor. Analysis of the mouse genome reveals that the gene for TREM-3 lies adjacent to the gene for TREM-1 and in close proximity to a number of other single Ig domain receptors, including TREM-2. Thus, TREM-3 is a novel member of a family of immunoglobulin receptors that form an innate immune gene complex on chromosome 17.


The impact of the 'open' workspace on human collaboration.
Organizations' pursuit of increased workplace collaboration has led managers to transform traditional office spaces into 'open', transparency-enhancing architectures with fewer walls, doors and other spatial boundaries, yet there is scant direct empirical research on how human interaction patterns change as a result of these architectural changes. In two intervention-based field studies of corporate headquarters transitioning to more open office spaces, we empirically examined-using digital data from advanced wearable devices and from electronic communication servers-the effect of open office architectures on employees' face-to-face, email and instant messaging (IM) interaction patterns. Contrary to common belief, the volume of face-to-face interaction decreased significantly (approx. 70%) in both cases, with an associated increase in electronic interaction. In short, rather than prompting increasingly vibrant face-to-face collaboration, open architecture appeared to trigger a natural human response to socially withdraw from officemates and interact instead over email and IM. This is the first study to empirically measure both face-to-face and electronic interaction before and after the adoption of open office architecture. The results inform our understanding of the impact on human behaviour of workspaces that trend towards fewer spatial boundaries.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'.


Survey of the UK veterinary profession 2: sources of information used by veterinarians.
Access to the most up-to-date evidence is an important cornerstone for veterinarians attempting to practice in an evidence-based manner; therefore, an understanding of what and how information is accessed is vital. The aim of this study was to identify what resources the UK veterinary profession access and regard as most useful. Based on questionnaires received from veterinarians, the Veterinary Times was nominated as most often read journal or magazine by respondents (n=3572, 79 per cent). In Practice (n=3224, 82 per cent) and the Veterinary Record (n=165, 34 per cent) were seen as most useful by clinicians, and non-clinicians, respectively. Google was the most often nominated electronic resource by all respondents (n=3076, 71 per cent), with Google (n=459, 23 per cent) and PubMed (n=60, 17 per cent) seen as most useful by clinicians and non-clinicians, respectively. The abstract and conclusion sections were the most read parts of scientific manuscripts nominated by all respondents. When looking for assistance with difficult cases, colleagues were the common information choice for clinicians. Different sections of the veterinary profession access information, and deem resources useful, in different ways. Access to good quality evidence is important for the practice of evidence-based veterinary medicine, and therefore, researchers should think about disseminating their findings in a targeted way for optimal use by the profession.


The proximal chromosome 14q microdeletion syndrome: delineation of the phenotype using high resolution SNP oligonucleotide microarray analysis (SOMA) and review of the literature.
We report on two patients with overlapping small interstitial deletions involving regions 14q12 to 14q13.1. Both children had severe developmental delay, failure to thrive, microcephaly, and distinctive facial features, including abnormal spacing of the eyes, epicanthal folds, sloping forehead, low-set ears, rounded eyebrows with triangular media aspect and outer tapering, depressed and broad nasal bridge, small mouth, a long philtrum, and a prominent Cupid's bow. Brain MRI of both children showed partial agenesis of the corpus callosum. Our first patient had bilateral hypoplastic optic nerves causing blindness, mild hearing impairment, sinus arrhythmia, abnormal temperature regulation, frequent apneic episodes, myoclonic jerks, and opisthotonus. Our second patient had a seizure disorder confirmed by EEG, sleep apnea, chronic interstitial lung disease, and several episodes of pneumonia and gastroenteritis. Cytogenetic analysis showed a normal karyotype in Patient 1 and a unique apparently balanced three-way translocation in Patient 2 involving chromosomes 4, 14, and 11. High resolution SNP Oligonucleotide Microarray Analysis (SOMA) revealed a deletion in the proximal region of chromosome 14q overlapping with the deletion of our first patient, and no copy number changes in chromosomes 4 and 11. Here, we review and compare published cases with a deletion involving the 14q12-22.1 chromosomal region in an effort to correlate phenotype and genotype. We also examine the underlying genomic architecture to identify the possible mechanism of the chromosomal abnormality. Our review found a patient with a mirror duplication of our first patient's deletion, confirming the existence of an underlying genomic structural instability in the region. © 2011 Wiley-Liss, Inc.


Systemic treatment in advanced biliary cancers: A multicenter Australian analysis and review.
While first-line palliative chemotherapy (CT1) improves survival and quality of life in advanced biliary cancer (ABC), there is no randomized evidence to support second-line chemotherapy (CT2) in ABC. We aim to explore to role of CT2 in ABC. We performed a retrospective review of all patients who received one or more lines of chemotherapy for ABC at four Australian cancer centers between 2008 and 2011. A Cox proportional hazard model was developed to determine the impact of clinicopathologic variables on overall survival (OS) from time of progression on CT1. We identified 73 patients who received palliative chemotherapy for ABC. Twenty-five patients (34%) received two or more lines of chemotherapy. Patients with a preserved performance status on progression on first-line chemotherapy (CT1) were more likely to receive second-line chemotherapy (CT2) (P < 0.001). Disease control rate with CT2 was 36%, and mean progression-free survival was 3.2 months (95% confidence interval 1.5-4.9 months). The following variables were significant in the univariate analysis of OS from time of progression on CT1: lines of chemotherapy (P = 0.0001), Eastern Cooperative Oncology Group performance status at progression on CT1 (P < 0.0001) and disease control with CT1 (P = 0.027). Lines of chemotherapy received and performance status remained significant in the multivariate analysis for OS from progression on CT1. Second-line chemotherapy is feasible in a subset of patients with ABC. Even after accounting for confounding variables, CT2 appears to increase OS in ABC, although we are unable to exclude other unmeasured factors such as tumor biology. These findings warrant further evaluation with prospective trials.


The role of the commensal microbiota in the regulation of tolerance to dietary allergens.
We review the evidence that environmental stimuli that perturb naturally selected host-microbe interactions are driving the increasing prevalence of food allergy and examine the mechanisms by which commensal bacteria regulate tolerance to dietary allergens. Antibiotic use and the consumption of a high-fat/low-fiber diet have a major and rapid impact on gut bacterial populations, with long-term consequences for both overall microbial community structure and the regulation of host immunity. Recent work emphasizes the role of mucosa-associated commensal bacteria in eliciting a barrier-protective response critical to preventing allergic sensitization to food. Murine model studies are informing the development of novel live biotherapeutic approaches as an adjunctive therapy to enhance antigen-specific oral desensitization and to promote lasting tolerance in patients with food allergy. Strategies based on modulating the composition and/or functionality of the gut microbiome hold promise for the treatment of food allergy.


Catecholamine turnover in normotensive and hypertensive man: effects of antiadrenergic drugs.
Intravenous administration of tritium-labeled 3,4-dihydroxyphenylalanine (dopa) to human subjects resulted in the labeling of endogenous catecholamines and vanillylmandelic acid (VMA). Determination of the changes in specific activity of these compounds with time in fractional collections of urine and in cardiac biopsies from patients undergoing corrective cardiac surgery permitted estimation of apparent turnover rates. The average half-time of the exponential decline in specific activity of labeled urinary norepinephrine was about 8 hr and that of VMA was 11-16 hr in five normal subjects. No significant differences from normal were observed in eight patients with essential hypertension. The average half-life of norepinephrine was only 5 hr in cardiac patients undergoing surgery, and the levels and rate of decline of cardiac norepinephrine specific activity correlated well with the exponential phase of the urinary disappearance curve. There were significant effects of treatment with alpha-methyltyrosine, reserpine, and pargyline hydrochloride on the labeling and apparent turnover rates of norepinephrine and VMA; the effects noted were consistent with known actions of these three drugs. It is suggested that the technique used is a suitable means of assessing "over-all" catecholamine metabolism in man, particulary if combined with quantitative assay of urinary catecholamine metabolites.


Adaptive centroid-finding algorithm for freeform surface measurements.
Wavefront sensing systems measure the slope or curvature of a surface by calculating the centroid displacement of two focal spot images. Accurately finding the centroid of each focal spot determines the measurement results. This paper studied several widely used centroid-finding techniques and observed that thresholding is the most critical factor affecting the centroid-finding accuracy. Since the focal spot image of a freeform surface usually suffers from various types of image degradation, it is difficult and sometimes impossible to set a best threshold value for the whole image. We propose an adaptive centroid-finding algorithm to tackle this problem and have experimentally proven its effectiveness in measuring freeform surfaces.


Serum γ-glutamyltransferase and uric acid levels are associated with impaired fasting glucose in adults from Inner Mongolia, China.
Serum γ-glutamyltransferase (GGT) and uric acid (UA) levels are elevated in patients with diabetes or cardiovascular disease. Prediabetes, characterized by impaired glucose tolerance, is an important risk factor for overt diabetes as well as cardiovascular disease. Therefore, the aim of this study was to explore the relationship between GGT, UA and prediabetes in a Chinese population, and provide a scientific basis for the early prevention and treatment of diabetes. We performed a cross-sectional population-based study in a cohort of 2694 subjects (1211 men and 1483 women, aged 35-86 years). Questionnaires and physical examinations were performed using standardized procedures. Fasting blood was collected to measure glucose and other biochemical parameters. The subjects were divided into two groups with either normal fasting glucose (NFG) or impaired fasting glucose (IFG), according to international diagnostic criteria. Logistic regression analysis was performed to estimate odds ratios (OR) and 95% confidence intervals. Compared with the NFG group, the IFG group had significantly higher blood pressure but lower high-density lipoprotein-cholesterol in women. Body mass index, waist circumference, triglyceride, glucose, GGT, and UA levels were significantly higher in males and females in the IFG group than those in the NFG group. Logistic regression analysis revealed that the OR for prediabetes increased with increasing serum GGT quartiles and UA quartiles. GGT and UA were positively associated with prediabetes in men and women, independent of age, ethnicity, smoking, alcohol consumption, blood pressure, physical labor, and other confounders. We found that serum GGT and UA levels were positively associated with prediabetes in men and women living in areas inhabited by Chinese ethnic minorities. As elevated GGT and UA levels were associated with significantly increased risk of prediabetes, they may be used as sensitive biological markers of prediabetes.


Single- and two-photon imaging of human micrometastases and disseminated tumour cells with conjugates of nanobodies and quantum dots.
Early detection of malignant tumours and, especially, micrometastases and disseminated tumour cells is still a challenge. In order to implement highly sensitive diagnostic tools we demonstrate the use of nanoprobes engineered from nanobodies (single-domain antibodies, sdAbs) and fluorescent quantum dots (QDs) for single- and two-photon detection and imaging of human micrometastases and disseminated tumour cells in ex vivo biological samples of breast and pancreatic metastatic tumour mouse models expressing human epidermal growth factor receptor 2 (HER2) or carcinoembryonic antigen (CEA). By staining thin (5-10 µm) paraffin and thick (50 µm) agarose tissue sections, we detected HER2- and CEA-positive human tumour cells infiltrating the surrounding tissues or metastasizing to different organs, including the brain, testis, lung, liver, and lymph nodes. Compared to conventional fluorescently labelled antibodies the sdAb-HER2-QD and sdAb-CEA-QD nanoprobes are superior in detecting micrometastases in tissue sections by lower photobleaching and higher brightness of fluorescence signals ensuring much better discrimination of positive signals versus background. Very high two-photon absorption cross-sections of QDs and small size of the nanoprobes ensure efficient imaging of thick tissue sections unattainable with conventional fluorescent probes. The nanobody-QD probes will help to improve early cancer diagnosis and prognosis of progression by assessing metastasis.


Simulation-based optimisation to quantify heterogeneity of specific ventilation and perfusion in the lung by the Inspired Sinewave Test.
The degree of specific ventilatory heterogeneity (spatial unevenness of ventilation) of the lung is a useful marker of early structural lung changes which has the potential to detect early-onset disease. The Inspired Sinewave Test (IST) is an established noninvasive 'gas-distribution' type of respiratory test capable of measuring the cardiopulmonary parameters. We developed a simulation-based optimisation for the IST, with a simulation of a realistic heterogeneous lung, namely a lognormal distribution of spatial ventilation and perfusion. We tested this method in datasets from 13 anaesthetised pigs (pre and post-lung injury) and 104 human subjects (32 healthy and 72 COPD subjects). The 72 COPD subjects were classified into four COPD phenotypes based on 'GOLD' classification. This method allowed IST to identify and quantify heterogeneity of both ventilation and perfusion, permitting diagnostic distinction between health and disease states. In healthy volunteers, we show a linear relationship between the ventilatory heterogeneity versus age ([Formula: see text]). In a mechanically ventilated pig, IST ventilatory heterogeneity in noninjured and injured lungs was significantly different (p < 0.0001). Additionally, measured indices could accurately identify patients with COPD (area under the receiver operating characteristic curve is 0.76, p < 0.0001). The IST also could distinguish different phenotypes of COPD with 73% agreement with spirometry.


Starting the conversation: community perspectives on preterm birth and kangaroo mother care in southern Malawi.
Despite introduction of Kangaroo Mother Care (KMC) in Malawi over a decade ago, preterm birth remains the leading cause of neonatal mortality. Although KMC is initiated in the health care facility, robust community follow-up is critical for survival and optimal development of preterm and low birth weight infants post-discharge. The objective of this qualitative study was to gain insight into community and health worker understanding, attitudes, beliefs and practices around preterm and low birth weight babies and KMC in Malawi. A total of 152 participants were interviewed in two districts in southern Malawi, Machinga and Thyolo, in April 2015. Focus group discussions (groups = 11, n = 132) were conducted with pregnant women, community members and women who have practiced KMC. In-depth interviews (n = 20) were conducted with fathers who have practiced KMC, community and religious leaders, and health workers. Purposive and snowball sampling were employed to identify participants. Thematic content analysis was conducted. KMC mothers and fathers only learned about KMC and care for preterm newborns after delivery of a child in need of this care. Men typically were not included in KMC counseling due to societal gender roles. Health facilities were the main source of information on KMC, however informal networks among women provided some degree of knowledge exchange. Community leaders were regarded as major facilitators of health information, conveners, key influencers, and policy-makers. Religious leaders were regarded as advocates and emotional support for families with preterm infants. Finally, while many participants initially had negative feelings towards preterm births and KMC, the large majority saw a shift in their perceptions through health counseling, peer modeling, and personal success with KMC. The findings offer several opportunities to improve KMC implementation including 1) earlier introduction of KMC to pregnant women and their families that are at-risk for preterm birth, 2) greater involvement of men in KMC counselling, practice and care for preterm infants, and 3) strengthening and defining partnerships with community and religious leaders. Finally, as parental perceptions of preterm infants and KMC improved with successful KMC practice, it is hopeful that KMC itself can positively affect social norms surrounding preterm infants, leading to a virtuous cycle of improved perceptions of preterm infants and increased uptake of KMC.


Study of the non-covalent interaction between amyloid-beta-peptide and melatonin using electrospray ionization mass spectrometry.
Oxidative stress and unregulated immune response are believed to play a key role in the processes inherent to Alzheimer's disease (AD). The fact that free radicals can result in neurodegeneration suggests that actions against reactive oxygen species may be beneficial in treating and preventing AD. In the light of the suggested link between oxidative stress and AD, it is proposed that antioxidants and, even more, endogenous antioxidants may offer a therapeutic regime for protection against the risk of this disease. For this reason, the formation of non-covalent complexes between amyloid-beta-peptide (A beta) or its oxidized forms and melatonin was studied by quadrupole and Fourier transform ion cyclotron resonance electrospray ionization mass spectrometry. The stability of the non-covalent complex was examined under several experimental conditions, such as orifice voltage, pH, presence of organic modifier, concentration and time. Two different digestion protocols combined with mass spectrometric analysis of the resulting peptide fragments were employed in order to locate the binding site of melatonin in A beta.


The association between mode of birth delivery and attention-deficit/hyperactivity disorder: a systematic review protocol of epidemiological evidence.
Caesarean section is currently the most frequently performed intervention after episiotomy in obstetrics and one of the most common abdominal operations overall. Rates of caesarean section have been rising globally. Given the increasing rate worldwide it is therefore necessary and important to understand how caesarean section affects child development. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioural disorder in children. ADHD is characterized by a combination of symptoms including inattention, impulsivity and hyperactivity. Caesarean section may affect psychological development through changes in microbiota or stress response, and birth by caesarean section can be associated with a small increased risk of ADHD. In the current literature, there is no systematic review or protocol of the systematic review answering the question of whether the mode of delivery has influence on the risk of ADHD development.The objective of this review is to synthesize the best available evidence regarding the epidemiological association between the mode of delivery (caesarean section versus vaginal delivery) as exposure and ADHD as the outcome.A three-step strategy will be utilized in this review, aiming to find both published and unpublished studies. The initial search will be conducted using the MEDLINE, CINAHL and EMBASE. The second search will involve 21 databases and sources. Following the Preferred Reporting Items for Systematic Review and Meta-analysis statement analysis of title, abstracts and full texts, critical appraisal and data extraction will be carried out on selected studies using standardized instruments developed by Joanna Briggs Institute. All steps will be performed by two independent reviewers. If possible, statistical meta-analysis using Joanna Briggs Institute within the System for the Unified Management, Assessment and Review of Information will be pooled. Statistical heterogeneity will be assessed.The results will be disseminated by publishing in a peer-reviewed journal. Ethical assessment is not needed - we will search/evaluate the existing sources of literature.


Fluorescence lifetime imaging of alterations to cellular metabolism by domain 2 of the hepatitis C virus core protein.
Hepatitis C virus (HCV) co-opts hepatic lipid pathways to facilitate its pathogenesis. The virus alters cellular lipid biosynthesis and trafficking, and causes an accumulation of lipid droplets (LDs) that gives rise to hepatic steatosis. Little is known about how these changes are controlled at the molecular level, and how they are related to the underlying metabolic states of the infected cell. The HCV core protein has previously been shown to independently induce alterations in hepatic lipid homeostasis. Herein, we demonstrate, using coherent anti-Stokes Raman scattering (CARS) microscopy, that expression of domain 2 of the HCV core protein (D2) fused to GFP is sufficient to induce an accumulation of larger lipid droplets (LDs) in the perinuclear region. Additionally, we performed fluorescence lifetime imaging of endogenous reduced nicotinamide adenine dinucleotides [NAD(P)H], a key coenzyme in cellular metabolic processes, to monitor changes in the cofactor's abundance and conformational state in D2-GFP transfected cells. When expressed in Huh-7 human hepatoma cells, we observed that the D2-GFP induced accumulation of LDs correlated with an increase in total NAD(P)H fluorescence and an increase in the ratio of free to bound NAD(P)H. This is consistent with an approximate 10 fold increase in cellular NAD(P)H levels. Furthermore, the lifetimes of bound and free NAD(P)H were both significantly reduced--indicating viral protein-induced alterations in the cofactors' binding and microenvironment. Interestingly, the D2-expressing cells showed a more diffuse localization of NAD(P)H fluorescence signal, consistent with an accumulation of the co-factor outside the mitochondria. These observations suggest that HCV causes a shift of metabolic control away from the use of the coenzyme in mitochondrial electron transport and towards glycolysis, lipid biosynthesis, and building of new biomass. Overall, our findings demonstrate that HCV induced alterations in hepatic metabolism is tightly linked to alterations in NAD(P)H functional states.


Cell-free multi-layered collagen-based scaffolds demonstrate layer specific regeneration of functional osteochondral tissue in caprine joints.
Developing repair strategies for osteochondral tissue presents complex challenges due to its interfacial nature and complex zonal structure, consisting of subchondral bone, intermediate calcified cartilage and the superficial cartilage regions. In this study, the long term ability of a multi-layered biomimetic collagen-based scaffold to repair osteochondral defects is investigated in a large animal model: namely critical sized lateral trochlear ridge (TR) and medial femoral condyle (MC) defects in the caprine stifle joint. The study thus presents the first data in a clinically applicable large animal model. Scaffold fixation and early integration was demonstrated at 2 weeks post implantation. Macroscopic analysis demonstrated improved healing in the multi-layered scaffold group compared to empty defects and a market approved synthetic polymer osteochondral scaffold groups at 6 and 12 months post implantation. Radiological analysis demonstrated superior subchondral bone formation in both defect sites in the multi-layered scaffold group as early as 3 months, with complete regeneration of subchondral bone by 12 months. Histological analysis confirmed the formation of well-structured subchondral trabecular bone and hyaline-like cartilage tissue in the multi-layered scaffold group by 12 months with restoration of the anatomical tidemark. Demonstration of improved healing following treatment with this natural polymer scaffold, through the recruitment of host cells with no requirement for pre-culture, shows the potential of this device for the treatment of patients presenting with osteochondal lesions.


Instanton approach to large N Harish-Chandra-Itzykson-Zuber integrals.
We reconsider the large N asymptotics of Harish-Chandra-Itzykson-Zuber integrals. We provide, using Dyson's Brownian motion and the method of instantons, an alternative, transparent derivation of the Matytsin formalism for the unitary case. Our method is easily generalized to the orthogonal and symplectic ensembles. We obtain an explicit solution of Matytsin's equations in the case of Wigner matrices, as well as a general expansion method in the dilute limit, when the spectrum of eigenvalues spreads over very wide regions.


The accuracy of diagnostic ultrasound imaging for musculoskeletal soft tissue pathology of the extremities: a comprehensive review of the literature.
Musculoskeletal diagnostic ultrasound imaging (MSK-DUSI) has been growing outside the traditional radiology speciality. Increased use of this technology has been reported in several healthcare settings, however an apparent gap in the knowledge of the accuracy of this diagnostic technology indicated a review was warranted. We undertook a structured review of the literature to assess the accuracy of MSK-DUSI for the diagnosis of musculoskeletal soft tissue pathology of the extremities. An electronic search of the National Library of Medicine's PubMed database (1972 to mid-2014) was conducted. All relevant systematic reviews of diagnostic studies, all diagnostic studies published after the date of the latest systematic reviews and relevant diagnostic studies outside the scope the systematic reviews that directly compared the accuracy of MSK-DUSI (the index test) to an appropriate reference standard for the target condition were included. A fundamental appraisal of the methodological quality of studies was completed. The individual sensitivity, specificity and likelihood ratio data were extracted and entered into diagnostic accuracy tables. A total of 207 individual studies were included. The results show that MSK-DUSI has acceptable diagnostic accuracy for a wide spectrum of musculoskeletal conditions of the extremities. However, there is a lack of high quality prospective experimental studies in this area and as such clinicians should interpret the results with some caution due to the potential for overestimation of diagnostic accuracy.


Tooth eruption: theories and facts.
The mechanisms of tooth eruption (i.e., the answer to the question of how and why teeth erupt) has been a matter of long historical debate. This review focuses on human and other mammalian teeth with a time- and spacewise limited period of eruption and analyzes recent observations and experimental data on dogs, rats, primates, and humans in a framework of basic biological parameters to formulate a guiding theory of tooth eruption. Acknowledging basic parameters (i.e., that teeth move in three-dimensional space, erupt with varying speed, and arrive at a functional position that in inheritable) eliminates a number of previously held theories and favors those that accommodate basic parameters, such as alveolar bone remodeling in association with root elongation, with possible correction factors in the form of cementum apposition and periodontal ligament formation. We have critically analyzed, summarized, and integrated recent findings associated with preeruptive movements of developing teeth, the intraosseous stage of premolar eruption in dogs, molar eruption in rodents, and premolar and molar eruption in primates. The variable speeds of eruption are particularly important. We conclude with basic principles of tooth eruption--that is, the type of signals generated by the dental follicle proper, the conditions under which teeth are moved and the clinical understanding to be derived from this knowledge.


Precancerous lesions in the kidney.
Renal cell carcinoma (RCC), although occurring less frequently than prostate and bladder cancer, is actually the most malignant urologic disease, killing >35% of affected patients. Therefore, investigation of the nature of premalignant lesions of the kidney is a relevant issue. Following the most recent histological classification RCC can be subdivided into four categories: conventional RCC; papillary RCC; chromophobe RCC; and collecting duct carcinoma. In contrast to many genitourinary malignancies, premalignant alterations in the kidney are scarcely described. Intratubular epithelial dysplasia has been recognized as the most common precursor of RCC. In analogy to prostatic intraepithelial neoplasia (PIN), the premalignant lesions of the kidney are described as high or low-grade renal intratubular neoplasia. In contrast, precancerous lesions have been described as part of the von Hippel-Lindau syndrome (VHL) where the evolution from a simple cyst to an atypical cyst with epithelial hyperplasia to cystic or solid conventional-type RCC is well documented. Finally, in the genesis of papillary RCC an adenoma-carcinoma sequence has been recognized with specific genetic changes. There are no data on the epidemiology of premalignant lesions of the kidney, but research into the etiology of RCC has been extended substantially. Familial and genetic factors are well documented in VHL disease, in hereditary papillary RCC, in the tuberous sclerosis complex and in familial RCC. Cigarette smoking and obesity are established risk factors for RCC. Hypertension or its medication has also been associated with an increased risk. Among dietary factors an inverse relation between risk and consumption of vegetables and fruit has been found. Occupational exposure to substances such as asbestos and solvents has been linked to an increased risk of RCC. Specific RCC variants have distinctive chromosome alterations and several genes have been implicated in the development of RCC. Loss of material from the 3p chromosome characterizes conventional RCC and the deletion of the VHL suppressor gene plays an important role in the genesis of this RCC variant. In contrast, numerical changes with trisomy of chromosomes 7 and 17 and loss of the sex chromosome are typical changes in papillary tumors, whereas papillary RCC have additional trisomies. Chromophobe RCC is characterized by loss of chromosomes with a combination of monosomies. Less consistent genetic alterations are associated with collecting duct carcinoma. The traditional treatment of RCC is surgery by radical or partial nephrectomy. The latter approach carries a risk of tumor recurrence as a result of unrecognized satellite lesions or premalignant lesions that might have been present at the time of surgery. However, the reported recurrence rates after partial nephrectomy are <1% and therefore the possible presence of premalignant disease does not alter the actual treatment strategy advocated. Although multifocality and bilateral occurrence of RCC are much more likely in cases of papillary RCC, biopsy of the renal remnant or contralateral kidney is not justified even in patients with this tumor type. Conversely, patients with RIN in a partial or radical nephrectomy specimen or in a renal biopsy taken for whatever reason should be subjected to closer follow-up with regularly repeated ultrasound. When an effective chemopreventive regimen becomes available it might be useful for patients with an inherited risk of RCC as well as in those who are at risk of tumor recurrence after intervention. Mass screening with the purpose of detecting RCC at its earliest stage is not recommended at the present time, but screening focused on certain risk groups can be advocated. Further research is needed to identify avoidable risks, develop effective chemoprevention and recognize patients at risk.


Clinical intervals and diagnostic characteristics in a cohort of prostate cancer patients in Spain: a multicentre observational study.
Little is known about the healthcare process for patients with prostate cancer, mainly because hospital-based data are not routinely published. The main objective of this study was to determine the clinical characteristics of prostate cancer patients, the, diagnostic process and the factors that might influence intervals from consultation to diagnosis and from diagnosis to treatment. We conducted a multicentre, cohort study in seven hospitals in Spain. Patients' characteristics and diagnostic and therapeutic variables were obtained from hospital records and patients' structured interviews from October 2010 to September 2011. We used a multilevel logistic regression model to examine the association between patient care intervals and various variables influencing these intervals (age, BMI, educational level, ECOG, first specialist consultation, tumour stage, PSA, Gleason score, and presence of symptoms) and calculated the odds ratio (OR) and the interquartile range (IQR). To estimate the random inter-hospital variability, we used the median odds ratio (MOR). 470 patients with prostate cancer were included. Mean age was 67.8 (SD: 7.6) years and 75.4% were physically active. Tumour size was classified as T1 in 41.0% and as T2 in 40% of patients, their median Gleason score was 6.0 (IQR:1.0), and 36.1% had low risk cancer according to the D'Amico classification. The median interval between first consultation and diagnosis was 89 days (IQR:123.5) with no statistically significant variability between centres. Presence of symptoms was associated with a significantly longer interval between first consultation and diagnosis than no symptoms (OR:1.93, 95%CI 1.29-2.89). The median time between diagnosis and first treatment (therapeutic interval) was 75.0 days (IQR:78.0) and significant variability between centres was found (MOR:2.16, 95%CI 1.45-4.87). This interval was shorter in patients with a high PSA value (p = 0.012) and a high Gleason score (p = 0.026). Most incident prostate cancer patients in Spain are diagnosed at an early stage of an adenocarcinoma. The period to complete the diagnostic process is approximately three months whereas the therapeutic intervals vary among centres and are shorter for patients with a worse prognosis. The presence of prostatic symptoms, PSA level, and Gleason score influence all the clinical intervals differently.


Vascular clamping in liver surgery: physiology, indications and techniques.
This article reviews the historical evolution of hepatic vascular clamping and their indications. The anatomic basis for partial and complete vascular clamping will be discussed, as will the rationales of continuous and intermittent vascular clamping.Specific techniques discussed and described include inflow clamping (Pringle maneuver, extra-hepatic selective clamping and intraglissonian clamping) and outflow clamping (total vascular exclusion, hepatic vascular exclusion with preservation of caval flow). The fundamental role of a low Central Venous Pressure during open and laparoscopic hepatectomy is described, as is the difference in their intra-operative measurements. The biological basis for ischemic preconditioning will be elucidated. Although the potential dangers of vascular clamping and the development of modern coagulation devices question the need for systemic clamping; the pre-operative factors and unforseen intra-operative events that mandate the use of hepatic vascular clamping will be highlighted.


Lessons learned reconstructing complex scalp defects using free flaps and a cranioplasty in one stage.
The purpose of this study was to review our experience in single-stage reconstruction of skull and scalp defects, aiming to highlight pitfalls in our management. We performed a retrospective chart review of all patients who had a single-stage cranioplasty and free-tissue transfer at our institution over the last 10 years. Thirteen patients (9 men and 4 women) with an average age of 66.5 years (range, 34-83 years) were identified. Etiology of the defects included malignancy (n = 7), osteoradionecrosis (n = 3), and infection (n = 3). The size of the bony defect averaged 103.1 cm(2) (range, 12-300 cm(2)). Cranioplasty procedures included reconstruction by methylmethacrylate and titanium mesh (n = 10), methylmethacrylate only (n = 1), or mesh only (n = 2). Free flaps used were anterolateral thigh (n = 10), latissimus dorsi (n = 2), or a rectus flap (n = 1). Five patients (38%) developed at least 1 complication. These included 2 anastomotic problems that were successfully salvaged, 5 cases of wound dehiscence, and 1 mortality due to a respiratory event. Four patients developed a recurrence, and 2 patients required flap contouring at a second stage. Two patients had further reconstruction using 1 (1 patient) or 2 (1 patient) additional free flaps. Given the complexity of these procedures, the high recurrence rate, and the likelihood of complications, methylmethacrylate is contraindicated in 1-stage cranioplasty and soft-tissue reconstruction in high-risk patients. For unfavorable local conditions (eg previous infection, radiotherapy), the surgeon can either postpone the cranioplasty until the soft-tissue reconstruction has healed, or use a nonanatomical titanium mesh alone. The soft-tissue flap should be harvested of larger dimensions than anticipated.


A simple route to 1,4-addition reactions by Co-catalyzed reductive coupling of organic tosylates and triflates with activated alkenes.
An efficient Co-catalyzed 1,4-addition reaction of alkyl/aryl triflates and tosylates with activated alkenes is described. In this reaction, an air-stable cobalt(ii) complex, a mild reducing agent Zn and a simple proton source (H2O) are used. A radical mechanism for the addition of alkyl tosylates to activated alkenes is likely involved.


Mid-infrared transmitter and receiver modules for free-space optical communication.
We report on the experimental implementation of single-frequency fiber-laser pumped mid-infrared (mid-IR) transmitter and receiver modules for free-space communications. These modules enable frequency upconversion and downconversion between the 1550-nm telecom wavelength and the mid-IR, thus providing essential free-space transmission links with mid-IR single-frequency lasers in the 3.6 μm region. Specifically, based on difference frequency generation (DFG) in MgO-doped periodically poled LiNbO3 (MgO:PPLN), the mid-IR transmitter produces 9.3-mW power at 3594 nm with 5-W pump power at 1083 nm (<10 kHz linewidth) and 3-W signal power at 1550 nm (<10 kHz linewidth), and the mid-IR receiver reproduces 12-μW power at 1550 nm with 4.7-W pump power at 1083 nm and 5-mW laser at 3594 nm. The whole modules are integrated into portable and compact devices by incorporating single-frequency fiber lasers, fiber amplifiers, DFG units, and related electronic circuits. In addition, the uses of all polarization-maintaining fiber configuration and well-controlled heat dissipation make the mid-IR transmitter and receiver exhibit a long-term stability.


Ensure preparation and capsule endoscopy: a two-center prospective study.
To compare small bowel (SB) cleanliness and capsule endoscopy (CE) image quality following Ensure(®), polyethylene glycol (PEG) and standard preparations. A preparation protocol for CE that is both efficacious and acceptable to patients remains elusive. Considering the physiological function of the SB as a site for the digestion and absorption of food and not as a stool reservoir, preparation consisting of a liquid, fiber-free formula ingested one day before a CE study might have an advantage over other kinds of preparations. We conducted a prospective, blind-to-preparation, two-center study that compared four types of preparations. The participants' demographic and clinical data were collected. Gastric and SB transit times were calculated. The presence of bile in the duodenum was scored by a single, blinded-to-preparation gastroenterologist expert in CE, as was cleanliness within the proximal, middle and distal part of the SB. A four-point scale was used (grade 1 = no bile or residue, grade 4 ≥ 90% of lumen full of bile or residual material). The 198 consecutive patients who were referred to CE studies due to routine medical reasons were divided into four groups. They all observed a 12-h overnight fast before undergoing CE. Throughout the 24 h preceding the fast, control group 1 (n = 45 patients) ate light unrestricted meals, control group 2 (n = 81) also ate light meals but free of fruits and vegetables, the PEG group (n = 50) ate unrestricted light meals and ingested the PEG preparation, and the Ensure group (n = 22) ingested only the Ensure formula. Preparation with Ensure improved the visualization of duodenal mucosa (a score of 1.76) by decreasing the bile content compared to preparation with PEG (a score of 2.9) (P = 0.053). Overall, as expected, there was less residue and stool in the proximal part of the SB than in the middle and distal parts in all groups. The total score of cleanliness throughout the length of the SB showed some benefit for Ensure (a score of 1.8) over control group 2 (a score of 2) (P = 0.06). The cleanliness grading of the proximal and distal parts of the SB was similar in all four groups (P = 0.6 for both). The cleanliness in the middle part of the SB in the PEG (a score of 1.8) and Ensure groups (a score of 1.7) was equally better than that of control group 2 (a score of 2.1) (P = 0.057 and P = 0.07, respectively). All 50 PEG patients had diarrhea as an anticipated side effect, compared with only one patient in the Ensure group. Preparation with Ensure, a liquid, fiber-free formula has advantages over standard and PEG preparations, with significantly fewer side effects than PEG.


Health service use among children with and without eczema, asthma, and hay fever.
Atopic diseases, for example, eczema, asthma, and hay fever, are among the most common chronic diseases of childhood. Knowledge on health service use among children with atopic disease is limited. This study aimed to investigate the total use and costs of health services for children with and without eczema, asthma, and hay fever in a Danish general population. We conducted a health survey with four complete birth cohorts from the City of Copenhagen. Individual questionnaire data on eczema, asthma, and hay fever for children aged 3, 6, 11, and 15 years were linked to register information on use and costs of health services and prescribed medication and parental education. In total 9,720 children participated (50.5%). We found increased health service use (number of additional consultations per year [95% confidence interval]) among children with current eczema symptoms (1.77 [1.29-2.26]), current asthma symptoms (2.53 [2.08-2.98]), and current hay fever symptoms (1.21 [0.74-1.67]), compared with children without these symptoms. We also found increased use of prescribed medication and most subtypes of health services. Current asthma symptoms and current eczema symptoms, but not current hay fever symptoms, increased the health service costs with at least €300 per year per child. Children with eczema, asthma, and hay fever used health services and prescribed medication more than children without these diseases.


Effects of 10 cleaning instruments on four different implant surfaces.
The aim of this study was to evaluate the effects of a variety of implant cleaning instruments on different implant surfaces, specifically surface roughness and cleaning efficacy. Biofilm layers of Streptococcus mutans were cultivated on titanium disks with four different surface structures (polished, grit-blasted, acid-etched, and acid-etched/grit-blasted). Five disks each were cleaned using nine mechanical implant cleaning instruments or an erbium:yttrium-aluminum-garnet laser. Surface roughness (average, Ra; maximum, Rz) and waviness (Lr) were evaluated by two-dimensional laser profilometry. Surface structure damage and cleaning scores were assessed by scanning electron microscopy. Statistical analyses of the results were performed with one- and two-way analyses of variance and Bonferroni-Dunn multiple-comparison post hoc analysis (α = .05). Ra and Rz values for the acid-etched surfaces and Ra, Rz, and Lr values for the polished and the grit-blasted surfaces showed no significant differences between the different cleaning methods or cleaning instruments compared to the control (not cultured, not cleaned) groups. Significantly lower Ra and Rz values on grit-blasted/acid-etched implant surfaces were found following use of the Sonic-Flex clean with prophylaxis brush and the plastic curette compared to Satelec ProphyMax with Periosoft curette. Ra and Rz values of the different implant structure surfaces before cleaning were significantly different between all implant surfaces except for the polished compared to the acid-etched surfaces. Cleaning effect and alterations of the implant surfaces were strongly dependent on the implant cleaning method used.


Fractional Fourier domain optical image hiding using phase retrieval algorithm based on iterative nonlinear double random phase encoding.
We present a novel image hiding method based on phase retrieval algorithm under the framework of nonlinear double random phase encoding in fractional Fourier domain. Two phase-only masks (POMs) are efficiently determined by using the phase retrieval algorithm, in which two cascaded phase-truncated fractional Fourier transforms (FrFTs) are involved. No undesired information disclosure, post-processing of the POMs or digital inverse computation appears in our proposed method. In order to achieve the reduction in key transmission, a modified image hiding method based on the modified phase retrieval algorithm and logistic map is further proposed in this paper, in which the fractional orders and the parameters with respect to the logistic map are regarded as encryption keys. Numerical results have demonstrated the feasibility and effectiveness of the proposed algorithms.


HCF-1 is cleaved in the active site of O-GlcNAc transferase.
Host cell factor-1 (HCF-1), a transcriptional co-regulator of human cell-cycle progression, undergoes proteolytic maturation in which any of six repeated sequences is cleaved by the nutrient-responsive glycosyltransferase, O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). We report that the tetratricopeptide-repeat domain of O-GlcNAc transferase binds the carboxyl-terminal portion of an HCF-1 proteolytic repeat such that the cleavage region lies in the glycosyltransferase active site above uridine diphosphate-GlcNAc. The conformation is similar to that of a glycosylation-competent peptide substrate. Cleavage occurs between cysteine and glutamate residues and results in a pyroglutamate product. Conversion of the cleavage site glutamate into serine converts an HCF-1 proteolytic repeat into a glycosylation substrate. Thus, protein glycosylation and HCF-1 cleavage occur in the same active site.


Tuberculosis challenges: Resistance, co-infection, diagnosis, and treatment.
Early diagnosis of tuberculosis (TB), followed by effective treatment, is the cornerstone of global TB control efforts. An estimated 3 million cases of TB remain undetected each year. Early detection and effective management of TB can prevent severe disease and reduce mortality and transmission. Intrinsic and acquired drug resistance of Mycobacterium tuberculosis (MTB) severely restricted the anti-TB therapeutic options, and public health policies are required to preserve the new medications to treat TB. In addition, TB and HIV frequently accelerate the progression of each other, and one disease can enhance the other effect. Overall, TB-HIV co-infections show an adverse bidirectional interaction. For HIV-infected patients, the risk of developing TB disease is approximately 22 times higher than for persons with a protective immune response. Analysis of the current TB challenges is critical to meet the goals of the end TB strategy and can go a long way in eradicating the disease. It provides opportunities for global TB control and demonstrates the efforts required to accelerate eliminating TB. This review will discuss the main challenges of the TB era, including resistance, co-infection, diagnosis, and treatment.


Scaling of maximal oxygen uptake by lower leg muscle volume in boys and men.
The aim of this study was to critically examine the influence of body size on maximal oxygen uptake (VO2 max) in boys and men using body mass (BM), estimated fat-free mass (FFM), and estimated lower leg muscle volume (Vol) as the separate scaling variables. VO2 max and an in vivo measurement of Vol were assessed in 15 boys and 14 men. The FFM was estimated after percentage body fat had been predicted from population-specific skinfold measurements. By using nonlinear allometric modeling, common body size exponents for BM, FFM, and Vol were calculated. The point estimates for the size exponent (95% confidence interval) from the separate allometric models were: BM 0.79 (0.53-1.06), FFM 1.00 (0.78-1.22), and Vol 0.64 (0.40-0.88). For the boys, substantial residual size correlations were observed for VO2 max/BM0.79 and VO2 max/FFM1.00, indicating that these variables did not correctly partition out the influence of body size. In contrast, scaling by Vol0.64 led to no residual size correlation in boys or men. Scaling by BM is confounded by heterogeneity of body composition and potentially substantial differences in the mass exponent between boys and men. The FFM is precluded as an index of involved musculature because Vol did not represent a constant proportion of FFM [Vol proportional, variantFFM1.45 (95% confidence interval, 1.13-1.77)] in the boys (unlike the men). We conclude that Vol, as an indicator of the involved muscle mass, is the most valid allometric denominator for the scaling of VO2 max in a sample of boys and men heterogeneous for body size and composition.


The magnitude and trend of artemether-lumefantrine stock-outs at public health facilities in Kenya.
Health facility stock-outs of artemether-lumefantrine (AL), the common first-line therapy for uncomplicated malaria across Africa, adversely affect effective malaria case-management. They have been previously reported on various scales in time and space, however the magnitude of the problem and trends over time are less clear. Here, 2010-2011 data are reported from public facilities in Kenya where alarming stock-outs were revealed in 2008. Data were collected between January 2010 and June 2011 as part of 18 monthly cross-sectional surveys undertaken at nationally representative samples of public health facilities. The primary monitoring indicator was total stock-out of all four weight-specific AL packs. The secondary indicators were stock-outs of at least one AL pack and individual stock-outs for each AL pack. Monthly proportions and summary means of the proportions over the monitoring period were measured for each indicator. Stock-out trends were assessed using linear regression. The number of surveyed facilities across 18 time points ranged between 162 and 176 facilities. The stock-out means of the proportion of health facilities were 11.6% for total AL stock-out, 40.6% for stock-out of at least one AL pack, and between 20.5% and 27.4% for stock-outs of individual AL packs. Monthly decrease of the total AL stock-out was 0.005% (95% CI: -0.5 to +0.5; p = 0.983). Monthly decrease in the stock-out of at least one AL pack was 0.7% (95% CI: -1.5 to +0.3; p = 0.058) while stock-outs of individual AL packs decreased monthly between 0.2% for AL 24-pack and 0.7% for AL six-pack without statistical significance for any of the weight-specific packs. Despite lower levels of AL stock-outs compared to the reports in 2008, the stock-outs at Kenyan facilities during 2010-2011 are still substantial and of particular worry for the most detrimental:- simultaneous absence of any AL pack. Only minor decrease was observed in the stock-outs of individual AL packs. Recently launched interventions to eliminate AL stock-outs in Kenya are fully justified.


Recommendations on breast cancer screening and prevention in the context of implementing risk stratification: impending changes to current policies.
In recent years, risk stratification has sparked interest as an innovative approach to disease screening and prevention. The approach effectively personalizes individual risk, opening the way to screening and prevention interventions that are adapted to subpopulations. The international perspective project, which is developing risk stratification for breast cancer, aims to support the integration of its screening approach into clinical practice through comprehensive tool-building. Policies and guidelines for risk stratification-unlike those for population screening programs, which are currently well regulated-are still under development. Indeed, the development of guidelines for risk stratification reflects the translational aspects of perspective. Here, we describe the risk stratification process that was devised in the context of perspective, and we then explain the consensus-based method used to develop recommendations for breast cancer screening and prevention in a risk-stratification approach. Lastly, we discuss how the recommendations might affect current screening policies.


A phylogenetic model for understanding the effect of gene duplication on cancer progression.
As biotechnology advances rapidly, a tremendous amount of cancer genetic data has become available, providing an unprecedented opportunity for understanding the genetic mechanisms of cancer. To understand the effects of duplications and deletions on cancer progression, two genomes (normal and tumor) were sequenced from each of five stomach cancer patients in different stages (I, II, III and IV). We developed a phylogenetic model for analyzing stomach cancer data. The model assumes that duplication and deletion occur in accordance with a continuous time Markov Chain along the branches of a phylogenetic tree attached with five extended branches leading to the tumor genomes. Moreover, coalescence times of the phylogenetic tree follow a coalescence process. The simulation study suggests that the maximum likelihood approach can accurately estimate parameters in the phylogenetic model. The phylogenetic model was applied to the stomach cancer data. We found that the expected number of changes (duplication and deletion) per gene for the tumor genomes is significantly higher than that for the normal genomes. The goodness-of-fit test suggests that the phylogenetic model with constant duplication and deletion rates can adequately fit the duplication data for the normal genomes. The analysis found nine duplicated genes that are significantly associated with stomach cancer.


Neighbourhood unemployment and other socio-demographic predictors of emergency hospitalisation for infectious intestinal disease in England: A longitudinal ecological study.
Previous studies have observed that infectious intestinal disease (IID) related hospital admissions are higher in more deprived neighbourhoods. These studies have mainly focused on paediatric populations and are cross-sectional in nature. This study examines recent trends in emergency IID admission rates, and uses longitudinal methods to investigate the effects of unemployment (as a time varying measure of neighbourhood deprivation) and other socio-demographic characteristics on IID admissions for adults and children in England. A longitudinal ecological analysis was performed using Hospital Episode Statistics on emergency hospitalisations for IID, collected over the time period 2012-17 across England. Analysis was conducted at the neighbourhood (Lower-layer Super Output Area) level for three age groups (0-14; 15-64; 65+ years). Mixed-effect Poisson regression models were used to assess the relationship between trends in neighbourhood unemployment and emergency IID admission rates, whilst controlling for measures of primary and secondary care access, underlying morbidity and the ethnic composition of each neighbourhood. From 2012-17, declining trends in emergency IID admission rates were observed for children and older adults overall, while rates increased for some sub-groups in the population. Each 1 percentage point increase in unemployment was associated with a 6.3, 2.4 and 4% increase in the rate of IID admissions per year for children [IRR=1.06, 95%CI 1.06-1.07], adults [IRR=1.02, 95%CI 1.02-1.03] and older adults [IRR=1.04, 95%CI 1.036-1.043], respectively. Increases in poor primary care access, the percentage of people from a Pakistani ethnic background, and the prevalence of long-term health problems, in a neighbourhood, were also associated with increases in IID admission rates. Increasing trends in neighbourhood deprivation, as measured by unemployment, were associated with increases in emergency IID admission rates for children and adults in England, despite controlling for measures of healthcare access, underlying morbidity and ethnicity. Research is needed to improve understanding of the mechanisms that explain these inequalities, so that effective policies can be developed to reduce the higher emergency IID admission rates experienced by more disadvantaged communities.


[Acute intestinal infections: current and upcoming vaccines].
Currently, only a few licensed vaccines against intestinal infections are available. Existing vaccines have shown good efficacy when used by travelers in industrialized countries. However, these vaccines have lower efficacy in endemic areas with high prevalence of enteric pathogens. Current vaccines are too expensive to be efficiently distributed in endemic countries. Immune correlates of protection are not well defined for current licensed vaccines. A better understanding of protection mechanisms at the intestinal mucosal surfaces should allow the development of more efficient vaccines. Gut physiology and microbial composition play an important role in both physical integrity and immunological status of the gastro-intestinal tract. These parameters can partially explain the disparities observed in current vaccines efficiency. Several next-generation vaccines combined or not with adjuvant able to promote a strong mucosal response in the intestine, are under preclinical and clinical investigations.


Hormonal, morphological, and physiological responses of yellow perch (Perca flavescens) to chronic environmental metal exposures.
The effects of a chronic environmental exposure to metals on the hormonal, physiological, and reproductive status were assessed in yellow perch (Perca flavescens) sampled in six lakes situated along a contamination gradient of Cd, Zn, Cu, Pb, and Ni in the mining region of Rouyn-Noranda, Québec. Fish were captured in the summer and fall, and sampled before or after a confinement of one hour. Metal concentrations in the kidneys and the interrenal tissues (homologous to mammalian adrenals) were measured to compare tissue-specific metal accumulation. An exposure-related decrease of condition factor, gonadosomatic index (GSI), branchial Na+/K(+)-ATPase activity, plasma thyroxine (T4), triiodothyronine (T3), and 17 beta-estradiol and an impaired capacity to enhance cortisol levels after confinement were observed. Fish from the metal-contaminated lakes possessed gonads at less mature stages and exhibited structural alterations of their gills, interrenal cells, and thyroid follicle epithelium. A comparison of the morphological, biochemical, and physiological endpoints measured in the present study revealed that plasma concentrations of hormones and parameters of gill function were the most affected by metal contamination. The results of this study indicate that lifelong exposures to sublethal concentrations of metals alter the physiological functions of fish and delay reproduction.


High-water-content mouldable hydrogels by mixing clay and a dendritic molecular binder.
With the world's focus on reducing our dependency on fossil-fuel energy, the scientific community can investigate new plastic materials that are much less dependent on petroleum than are conventional plastics. Given increasing environmental issues, the idea of replacing plastics with water-based gels, so-called hydrogels, seems reasonable. Here we report that water and clay (2-3 per cent by mass), when mixed with a very small proportion (<0.4 per cent by mass) of organic components, quickly form a transparent hydrogel. This material can be moulded into shape-persistent, free-standing objects owing to its exceptionally great mechanical strength, and rapidly and completely self-heals when damaged. Furthermore, it preserves biologically active proteins for catalysis. So far no other hydrogels, including conventional ones formed by mixing polymeric cations and anions or polysaccharides and borax, have been reported to possess all these features. Notably, this material is formed only by non-covalent forces resulting from the specific design of a telechelic dendritic macromolecule with multiple adhesive termini for binding to clay.


Suppression of the HPA axis stress-response: implications for relapse.
This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. This symposium explored the potential role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation upon relapse. HPA axis stimulation induces the release of the glucocorticoid cortisol, a compound with profound effects upon behavior and emotion. Altered stress-responses of the HPA axis in abstinent alcohol-dependent subjects, therefore, may influence their affective and behavioral regulation, thus impacting their potential for relapse. Bryon Adinoff began the symposium with a review of HPA axis dysfunction in alcohol-dependent subjects, including recent studies from his lab demonstrating an attenuated glucocorticoid response to both endogenous and exogenous stimulation in one-month abstinent men. Klaus Junghanns presented his work demonstrating that a blunted ACTH or cortisol response to subjective stressors (social stressor or alcohol exposure) is predictive of a return to early drinking. The final two presenters examined the interaction between naltrexone and HPA responsiveness in alcohol-dependent or at-risk subjects, as naltrexone induces an increase in ACTH and cortisol. Falk Kiefer discussed the relationship between basal HPA axis responsivity and clinical outcome following treatment with naltrexone or acamprosate. Plasma ACTH significantly decreased over the course of the study in the placebo group, but not the medication groups [corrected] Lower basal concentrations of ACTH and cortisol were associated with quicker relapse in the placebo group only. Suchitra Krishnan-Sarin described her preliminary work, in which family-history positive (FH+) and family history negative (FH-) subjects were administered naltrexone, followed by an assessment of alcohol-induced craving. The cortisol response to alcohol was significantly and inversely related to craving in the FH+, but not the FH-, subjects. Alterations in HPA axis responsivity may therefore have a negative impact upon clinical outcome in alcohol-dependent subjects, and disinhibition of the axis with medication may have therapeutic potential.


Incidence rates and management of urinary tract infections among children in Dutch general practice: results from a nation-wide registration study.
We aimed to investigate incidence rates of urinary tract infections in Dutch general practice and their association with gender, season and urbanisation level, and to analyse prescription and referral in case of urinary tract infections. During one calendar year, 195 general practitioners in 104 practices in the Netherlands registered all their patient contacts. This study was performed by the Netherlands Institute for Health Services Research (NIVEL) in 2001. Of 82,053 children aged 0 to 18 years, the following variables were collected: number of episodes per patient, number of contacts per episode, month of the year in which the diagnosis of urinary tract infection was made, age, gender, urbanisation level, drug prescription and referral. The overall incidence rate was 19 episodes per 1000 person years. The incidence rate in girls was 8 times as high as in boys. The incidence rate in smaller cities and rural areas was 2 times as high as in the three largest cities. Throughout the year, incidence rates varied with a decrease in summertime for children at the age of 0 to 12 years. Of the prescriptions, 66% were in accordance with current guidelines, but only 18% of the children who had an indication were actually referred. This study shows that incidence rates of urinary tract infections are not only related to gender and season, but also to urbanisation. General practitioners in the Netherlands frequently do not follow the clinical guidelines for urinary tract infections, especially with respect to referral.


Endocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea.
Obstructive sleep apnoea (OSA) is a relatively common condition producing disabling somnolence and profound physiological responses to hypoxaemic episodes during sleep, including significant oscillations in blood pressure. This study aimed to provide controlled data on the interaction between OSA and endocrine axes to establish whether overrepresentation of pathology such as hypertension and hypogonadism in OSA subjects might have an endocrine basis. Parallel randomized sham placebo controlled 1-month trial of nasal continuous positive airway pressure (nCPAP) in 101 male subjects with OSA presenting to a respiratory sleep clinic. Analysis of gonadotrophins, testosterone, sex hormone binding protein (SHBG), prolactin, cortisol, thyroid stimulating hormone (TSH), free thyroxine (free T4), insulin-like growth factor-1 (IGF-1), renin and aldosterone were performed at baseline and after 1 month's active or placebo nCPAP intervention. Quality of life questionnaire scoring was also recorded over the same time period. Testosterone and SHBG showed significant negative correlations with baseline OSA severity. Active treatment of OSA produced SHBG elevation and TSH reduction (P< or =0.03). Both groups showed an increase in aldosterone (P<0.001) and IGF-1 (P< or =0.03), associated with a large improvement in subjective quality of life scoring. These findings demonstrate significant changes in endocrine axes not previously reported in a placebo-controlled trial. OSA is a recognized reversible cause of testosterone reduction; SHBG suppression correlating to baseline OSA severity supports a diagnosis of secondary hypogonadism. Significant rises in aldosterone and IGF-1 on treatment coincide with increased physical activity and an improved quality of life score.


(Z)-3-Hy-droxy-4-(4-meth-oxy-phen-yl)but-3-en-2-one.
The title compound, C11H12O3, is potentially a butane-2,3-dione derivative but exists in the enol form in the solid state. In the mol-ecule, the 3-hy-droxy-but-3-en-2-one, benzene and methoxyl fragments are almost co-planar. The 3-hy-droxy-but-3-en-2-one fragment is almost planar with an r.m.s. deviation of 0.040 Å. The dihedral angle between this plane and that of the benzene ring is 5.88 (4)°. The 4-meth-oxy group also lies close to the benzene ring plane, with deviations of 0.0206 (11) Å for the O and 0.087 (2) Å for methyl C atoms. Hence, the whole mol-ecule is almost planar with an r.m.s. deviation of 0.0617 Å from a plane through all 14 non-H atoms. In the crystal, the molecules are linked by O-H⋯O hydrogen bonds, generating [010] chains.


Impact of sevelamer hydrochloride on serum magnesium concentrations in hemodialysis patients.
Serum Mg levels are elevated in patients with renal insufficiency: harmful effects of hypomagnesemia have been reported in patients receiving hemodialysis (HD). In this cross-sectional study, which included 86 HD patients (male : female = 56:30, age 68 ± 12 years), we examined the clinical factors associated with serum Mg levels, with a focus on sevelamer, a phosphate binder widely used to control the hyperphosphatemia of HD patients. The mean serum Mg concentration among our patients was 2.48 ± 0.37 mg/dL (1.02 ± 0.15 mmol/L). Sevelamer was administered to 67 patients (77.9%) at a mean dose of 1.98 ± 1.64 g/day. Sex, diabetes mellitus, cardiovascular disease, anuria, and drugs other than sevelamer were not associated with serum Mg levels. HD duration, serum calcium, albumin, high-density lipoprotein cholesterol, normalized protein catabolic rate (nPCR), creatinine generation rate, and sevelamer dose correlated positively with serum Mg levels, whereas a negative correlation was observed for age and high-sensitivity C-reactive protein. A stepwise multiple regression analysis revealed that age, nPCR, and the dose of sevelamer were independently associated with serum Mg levels. Sevelamer and Mg have been reported to exhibit similar effects, such as an anti-inflammatory effect, inhibition of cardiovascular calcification, and decreased mortality. Therefore, the pleiotropic effects of sevelamer may be partly attributable to the increase in serum Mg levels caused by the drug itself.


Anomalous photovoltaic effect based on molecular chirality: influence of enantiomeric purity on the photocurrent response in π-conjugated ferroelectric liquid crystals.
(S)- and (R)-forms of chiral π-conjugated ferroelectric liquid crystals were synthesized. The dielectric properties in the ferroelectric liquid-crystalline (FLC) phases were evaluated using the Sawyer-Tower method. Spontaneous polarization of (S)-1 reached 68 nC cm-2 at 127 °C. Hole mobilities in the FLC phases estimated using the time-of-flight (TOF) method were on the order of 10-4 cm2 V-1 s-1. Each chiral π-conjugated compound exhibited a photovoltaic effect based on spontaneous polarization without p-n or Schottky junctions. This phenomenon could be attributed to an anomalous photovoltaic (APV) effect that has been observed in ferroelectric ceramics. In addition, liquid-crystalline enantiomeric mixtures of (S)-1 and (R)-1 were prepared and the APV response under UV illumination was studied. The APV response was enhanced with an increase in enantiomeric purity and was minimized in the racemic mixture. From this result, it was concluded that the APV effect in this FLC compound originated from the molecular chirality.


A cross-sectional study of basal platelet intracellular free calcium concentration in normotensive and hypertensive primigravid pregnancies.
1. The intracellular free calcium concentration ([Ca2+]i) in washed human platelets was measured using the fluorescent indicator, fura-2, in a cross-sectional study of 36 normotensive, primigravid volunteers, 12 in each trimester of pregnancy and a further 12 at 6 weeks post partum. The results were compared with those obtained from 30 normal female volunteers not using oral contraception. 2. The mean basal [Ca2+]i in the platelets of the pregnant women in the first two trimesters (115.6 +/- 6.7 and 120.1 +/- 5.7 nmol/l, respectively) was not shown to differ significantly from that of normal non-pregnant volunteers (112.3 +/- 2.9 nmol/l). However, during the third trimester a significant increase in [Ca2+]i was noted (134.0 +/- 4.9 nmol/l; P less than 0.05), with a return to normal values in the post-partum period (108.2 +/- 6.1 nmol/l). 3. [Ca2+]i was also measured in the platelets of a group of 12 primigravid pregnant women in the third trimester whose pregnancies were complicated by gestational hypertension (pregnancy-induced hypertension and pre-eclampsia). A significant rise in basal [Ca2+]i was noted in the platelets of primigravidae whose pregnancies were complicated by pre-eclampsia (163.6 +/- 8.8 nmol/l) as compared with normotensive, third-trimester primigravidae (P less than 0.02). However, no correlation could be demonstrated between [Ca2+]i and systemic blood pressure.


Cytotoxic effect of natural trans-resveratrol obtained from elicited Vitis vinifera cell cultures on three cancer cell lines.
trans-Resveratrol (trans-R) has been reported to be a potential cancer chemopreventive agent. Although its cytotoxic activity against different cancer cell lines has been tested, its effect on human acute leukemia cell lines has scarcely been investigated, and only a few in vitro studies were performed using human breast epithelial cell lines. Due to its potential value for human health, demand for trans-R has rapidly increased, and new biotechnological strategies to obtain it from natural edible sources have been developed. Thus, grapevine cell cultures represent a reliable system of trans-R production since they biosynthesize trans-R constitutively or in response to elicitation. In addition, there are no studies deepen on the inhibitory effect of trans-R, produced by elicited grapevine cell cultures, on growth of human tumor cell lines. In this work, the effect of trans-R extracted from the culture medium, after elicitation of grapevine cell cultures, was tested on two human acute lymphocytic and monocytic leukemia cell lines, and one human breast cancer cell line. The effect of trans-R on cell proliferation was not only dose- and time-dependent but also cell type-dependent, as seen from the different degrees of susceptibility of cancer cell lines tested. As regards the effect of trans-R on cell cycle distribution, low trans-R concentrations increased cells in the S phase whereas a high trans-R concentration increased G₀/G₁ phase in all cell lines. Perturbation of the cell cycle at low trans-R concentrations did not correlate with the induction of cell death, whereas a high trans-R concentration, cell proliferation decreased as a result of increasing apoptosis in the three cell lines. In leukemia cells, trans-R up-regulated the expression of caspase-3 while trans-R-induced apoptosis in breast cells occur through a caspase-3-independent mechanism mediated by a down-regulation of Bcl-2.


MO-A-213AB-10: Scattering System Optimization for Proton Therapy.
To describe a method for optimization and production of a dual scattering system for proton beam delivery. Dual-foil passive scattering is currently the prevalent modality for proton therapy delivery. Large uniform proton fields are created using a 2-stage scattering system comprising an upstream uniform lead foil (stage 1) followed by a contoured lead/Lexan foil to provide beam and range uniformity (stage 2). Optimizing the parameters of these foils, including thickness, contour and placement, provides not only a flat and symmetrical radiation field with a uniform range, but also affects the overall efficiency of the beam line. An analytical method for optimizing the scattering system design was applied and validated with GEANT4 simulations. This method has been used to create passively scattered therapeutic and research proton fields at our proton therapy facility. A novel Cerrobend casting method is described that allows for cost-effective and accurate production of this important beam-line component. A number of dual scattering foil combinations for research and therapeutic purposes have been created and were evaluated with GEANT4 simulations. We demonstrated that the use of this system can generate passively scattered proton fields up to 60cm diameter with improved efficiency and beam flatness over existing dual-scattering systems. Scattering system performance was verified using physical measurements including Gafchromic film and ion chamber data. This analytical method allows the user to optimize the proton dual scattering system with respect to specific input parameters, while the casting method provides a cost-effective way to create a unique scattering system for a given application.


A missense mutation in the murine Opa3 gene models human Costeff syndrome.
Opa3 mRNA is expressed in all tissues examined to date, but currently the function of the OPA3 protein is unknown. Intriguingly, various mutations in the OPA3 gene lead to two similar diseases in humans: autosomal dominant inherited optic atrophy and cataract (ADOAC) and a metabolic condition; type 3-methylglutaconic aciduria (MGA). Early onset bilateral optic atrophy is a common characteristic of both disorders; retinal ganglion cells are lost and visual acuity is impaired from an early age. In order to investigate the function of the OPA3 protein, we have generated a novel ENU-induced mutant mouse carrying a missense mutation in the OPA3 gene. The heterozygous mutation in exon 2, causes an amino acid change p.L122P (c.365T>C), which is predicted to alter tertiary protein structure. In the heterozygous state, the mice appear uncompromised however; in the homozygous state mice display some of the features of MGA. Visual function is severely reduced, consistent with significant loss of retinal ganglion cells and degeneration of axons in the optic nerve. In the homozygous optic nerve, there was evidence of increased mitochondrial activity, as demonstrated by the increased presence of mitochondrial marker Cytochrome C Oxidase (COX) histochemistry. Mice homozygous for the opa3(L122P) mutation also display a severe multi-systemic disease characterized by reduced lifespan (majority dying before 4 months), decreased weight, dilated cardiomyopathy, extrapyramidal dysfunction and gross neuro-muscular defects. All of these defects are synonymous with the phenotypic characteristics of Type III MGA found in humans. This model will be of major importance for future studies of the specific function of the OPA3 gene.


Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin.
Pathological processes involved in the initiation of rheumatoid synovitis remain unclear. We undertook the present study to identify immune and stromal processes that are present soon after the clinical onset of rheumatoid arthritis (RA) by assessing a panel of T cell, macrophage, and stromal cell related cytokines and chemokines in the synovial fluid of patients with early synovitis. Synovial fluid was aspirated from inflamed joints of patients with inflammatory arthritis of duration 3 months or less, whose outcomes were subsequently determined by follow up. For comparison, synovial fluid was aspirated from patients with acute crystal arthritis, established RA and osteoarthritis. Rheumatoid factor activity was blocked in the synovial fluid samples, and a panel of 23 cytokines and chemokines measured using a multiplex based system. Patients with early inflammatory arthritis who subsequently developed RA had a distinct but transient synovial fluid cytokine profile. The levels of a range of T cell, macrophage and stromal cell related cytokines (e.g. IL-2, IL-4, IL-13, IL-17, IL-15, basic fibroblast growth factor and epidermal growth factor) were significantly elevated in these patients within 3 months after symptom onset, as compared with early arthritis patients who did not develop RA. In addition, this profile was no longer present in established RA. In contrast, patients with non-rheumatoid persistent synovitis exhibited elevated levels of interferon-gamma at initiation. Early synovitis destined to develop into RA is thus characterized by a distinct and transient synovial fluid cytokine profile. The cytokines present in the early rheumatoid lesion suggest that this response is likely to influence the microenvironment required for persistent RA.


Biogenic amine transporters: regulation in flux.
Following vesicular release, the biogenic amine neurotransmitters dopamine, norepinephrine and serotonin are actively cleared from extracellular spaces by presynaptic transporters. These transporters interact with multiple psychoactive agents including cocaine, amphetamines and antidepressants. Recent findings indicate that amine reuptake is likely to be a tightly regulated component of synaptic plasticity rather than a constitutive determinant of transmitter clearance. Protein kinase C activation and transporter phosphorylation have been linked to regulatory protein trafficking, and both phosphorylation and trafficking may be influenced by transporter ligands. Recognition that transmitters, antagonists and second messengers can modify the intrinsic activity, surface expression or protein levels of amine transporters raises new questions about the fundamental nature of drug actions in vivo. The theory that dysregulation of transporters may contribute to disease states is supported by the recent discovery that a coding mutation in the human norepinephrine transporter contributes to orthostatic intolerance.


Surgical treatment of acquired ventricular septal defects in the elderly.
As the population continues to age, older patients are being referred for repair of acquired ventricular septal defect (VSD) following myocardial infarction (MI). The purpose of this study was to assess the effect of age (> or = 70 years) on operative risk and long term survival following repair of an acquired VSD. Between January 1972 and December 1995, 179 patients have undergone repair of acquired VSDs following MI in our unit. There were 118 males and 61 females (age range 43-80 years) of whom 60 were aged 70 years or above. The overall early mortality was 27%. On univariate analysis risk factors for early death included shorter time from both MI and detection of murmur to operation (P < 0.01, P = 0.04), site of MI (P < 0.01), higher NYHA class (P < 0.01), lower preoperative blood pressure (P < 0.01) and longer cardiopulmonary bypass and cross clamp times (P < 0.01, P = 0.03). Non significant variables included age, sex, concomitant CABG and preoperative renal function. Early mortality was 28.6% (34/119) in patients under 70 and 25.0% (15/60) in those over 70. This difference was not significant. The only significant differences between the age groups were sex distribution (females > males, P < 0.01), in the older group, and shorter time from both MI and detection of murmur to operation (P = 0.04, P = 0.02). Cardiopulmonary bypass was the only statistically significant variable on multivariate analysis (P = 0.01). There was no significant difference in early mortality between the two age groups. As shorter times from both MI and detection of murmur to operation adversely affect early mortality, age over 70 years should not be used to determine suitability for surgery.


Pediatric vancomycin use in 421 hospitals in the United States, 2008.
Recommendations to prevent the spread of vancomycin resistance have been in place since 1995 and include guidelines for inpatient pediatric use of vancomycin. The emergence of large databases allows us to describe variation in pediatric vancomycin across hospitals. We analyzed a database with hospitalizations for children under 18 at 421 hospitals in 2008. The Premier hospital 2008 database, consisting of records for 877,201 pediatric hospitalizations in 421 hospitals, was analyzed. Stratified analyses and logistic mixed effects models were used to calculate the probability of vancomycin use while considering random effects of hospital variation, hospital fixed effects and patient effects, and the hierarchical structure of the data. Most hospitals (221) had fewer than 10 hospitalizations with vancomycin use in the study period, and 47 hospitals reported no vancomycin use in 17,271 pediatric hospitalizations. At the other end of the continuum, 21 hospitals (5.6% of hospitals) each had over 200 hospitalizations with vancomycin use, and together, accounted for more than 50% of the pediatric hospitalizations with vancomycin use. The mixed effects modeling showed hospital variation in the probability of vancomycin use that was statistically significant after controlling for teaching status, urban or rural location, size, region of the country, patient ethnic group, payor status, and APR-mortality and severity codes. The number and percentage of pediatric hospitalizations with vancomycin use varied greatly across hospitals and was not explained by hospital or patient characteristics in our logistic models. Public health efforts to reduce vancomycin use should be intensified at hospitals with highest use.


Alterations of epigenetic signatures in hepatocyte nuclear factor 4α deficient mouse liver determined by improved ChIP-qPCR and (h)MeDIP-qPCR assays.
Hepatocyte nuclear factor 4α (HNF4α) is a liver-enriched transcription factor essential for liver development and function. In hepatocytes, HNF4α regulates a large number of genes important for nutrient/xenobiotic metabolism and cell differentiation and proliferation. Currently, little is known about the epigenetic mechanism of gene regulation by HNF4α. In this study, the global and specific alterations at the selected gene loci of representative histone modifications and DNA methylations were investigated in Hnf4a-deficient female mouse livers using the improved MeDIP-, hMeDIP- and ChIP-qPCR assay. Hnf4a deficiency significantly increased hepatic total IPed DNA fragments for histone H3 lysine-4 dimethylation (H3K4me2), H3K4me3, H3K9me2, H3K27me3 and H3K4 acetylation, but not for H3K9me3, 5-methylcytosine,or 5-hydroxymethylcytosine. At specific gene loci, the relative enrichments of histone and DNA modifications were changed to different degree in Hnf4a-deficient mouse liver. Among the epigenetic signatures investigated, changes in H3K4me3 correlated the best with mRNA expression. Additionally, Hnf4a-deficient livers had increased mRNA expression of histone H1.2 and H3.3 as well as epigenetic modifiers Dnmt1, Tet3, Setd7, Kmt2c, Ehmt2, and Ezh2. In conclusion, the present study provides convenient improved (h)MeDIP- and ChIP-qPCR assays for epigenetic study. Hnf4a deficiency in young-adult mouse liver markedly alters histone methylation and acetylation, with fewer effects on DNA methylation and 5-hydroxymethylation. The underlying mechanism may be the induction of epigenetic enzymes responsible for the addition/removal of the epigenetic signatures, and/or the loss of HNF4α per se as a key coordinator for epigenetic modifiers.


Eruca sativa seeds possess antioxidant activity and exert a protective effect on mercuric chloride induced renal toxicity.
Mercuric chloride (HgCl(2)) is a well-known nephrotoxic agent. Increasing number of evidences suggest the role of oxidative stress in HgCl(2) induced nephrotoxicity. Eruca sativa is widely used in folklore medicines and has a good reputation as a remedy of renal ailments. In the present study, the antioxidant potential of ethanolic extract of E. sativa seeds was determined and its protective effect on HgCl(2) induced renal toxicity was investigated. The extract was found to possess a potent antioxidant effect, with a large amount of polyphenols and a high reducing ability. HPLC analysis of the extract revealed glucoerucin and flavonoids to be the major antioxidants present in it. E. sativa extract significantly scavenged several reactive oxygen species (ROS) and reactive nitrogen species (RNS). Feeding of the extract to rats afforded a significant protection against HgCl(2) induced renal toxicity. Subcutaneous administration of 4 mg/kg body weight HgCl(2) induced renal injury evident as a marked elevation in serum creatinine and blood urea nitrogen levels, and histopathological changes such as necrosis, oedema and congestion of stroma and glomeruli. Oxidative modulation of renal tissues following HgCl(2) exposure was evident from a significant elevation in lipid peroxidation and attenuation in glutathione (GSH) contents and activities of antioxidant enzymes viz., catalase (CAT), glutathione peroxidase (GPX), superoxide dismutase (SOD) and glutathione reductase (GR). Oral administration of E. sativa extract to rats at a dose regimen: 50-200 mg/kg body weight for 7 days prior to HgCl(2) treatment significantly and dose dependently protected against alterations in all these diagnostic parameters. The data obtained in the present study suggests E. sativa seeds to possess a potent antioxidant and renal protective activity and preclude oxidative damage inflicted to the kidney.


Keeping our heads above water: A systematic review of fatal drowning in South Africa.
Drowning is defined as the process of experiencing respiratory impairment from submersion/immersion in liquid, and can have one of three outcomes - no morbidity, morbidity or mortality. The World Health Organization African region accounts for approximately 20% of global drowning, with a drowning mortality rate of 13.1 per 100 000 population. The strategic implementation of intervention programmes driven by evidence-based decisions is of prime importance in resource-limited settings such as South Africa (SA). To review the available epidemiological data on fatal drowning in SA in order to identify gaps in the current knowledge base and priority intervention areas. A systematic review of published literature was conducted to review the available epidemiological data describing fatal drowning in SA. In addition, an internet search for grey literature, including technical reports, describing SA fatal drowning epidemiology was conducted. A total of 13 published research articles and 27 reports obtained through a grey literature search met the inclusion and exclusion criteria. These 40 articles and reports covered data collection periods between 1995 and 2016, and were largely focused on urban settings. The fatal drowning burden in SA is stable at approximately 3.0 per 100 000 population, but is increasing as a proportion of all non-natural deaths. Drowning mortality rates are high in children aged <15 years, particularly in those aged <5. This review suggests that SA drowning prevention initiatives are currently confined to the early stages of an effective injury prevention strategy. The distribution of mortality across age groups and drowning location differs substantially between urban centres and provinces. There is therefore a need for detailed drowning surveillance to monitor national trends and identify risk factors in all SA communities.


Efficacy of low level laser therapy on painful diabetic peripheral neuropathy.
Diabetic peripheral neuropathy (DPN) accounts for most common complications of T2DM. Painful DPN is associated with functional limitation & poor quality of life. Therefore, objective of the study is to find the effect of low level laser therapy on painful diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) Materials & methods: The study design is pre-post observational design. After obtaining ethical clearance and informed consent, 19 T2DM subjects were screened and confirmed for peripheral neuropathy in an outpatient setting with biochemical parameter, pain scale and Michigan Neuropathy Screening Instrument (MNSI). Low Level Laser therapy was irradiated through scanning mode with dosage of 3.1J/cm(2) on the plantar and dorsum of the foot and 3.4j/cm(2) with contact method for 10days and all subjects were reassessed at the end of the 10 day. Descriptive statistics and paired' test was used to analyze the pre-post finding within the group. Level of significance was set at p<0.05 RESULTS: The result analysis showed significant reduction in Pain using VAS scale (6.47 ± 0.84 to 1.21 ± 0.78 (p<0.001), MNSI (5.52 ± 1.26 to 2.71 ± 0.97 (reduction in Vibration perception threshold (32.68 ± 6.08 to 24.84 ± 4.29 (<0.001) and a significant increase in the temperature from baseline to post intervention (30.01 ± 2.11 to 31.75 ± 1.03 (p<0. 001). In the present study, Low level laser therapy was found to be effective in type 2 DM with peripheral neuropathy.