Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations.
Epstein-Barr virus (EBV) is detected in the tumor cells of some but not all Hodgkin lymphoma (HL) patients, and evidence indicates that EBV-positive and -negative HL are distinct entities. Racial/ethnic variation in EBV-positive HL in international comparisons suggests etiologic roles for environmental and genetic factors, but these studies used clinical series and evaluated EBV presence by differing protocols. Therefore, we evaluated EBV presence in the tumors of a large (n = 1,032), racially and sociodemographically diverse series of California incident classical HL cases with uniform pathology re-review and EBV detection methods. Tumor EBV-positivity was associated with Hispanic and Asian/Pacific Islander (API) but not black race/ethnicity, irrespective of demographic and clinical factors. Complex race-specific associations were observed between EBV-positive HL and age, sex, histology, stage, neighborhood socioeconomic status (SES), and birth place. In Hispanics, EBV-positive HL was associated not only with young and older age, male sex, and mixed cellularity histology, but also with foreign birth and lower SES in females, suggesting immune function responses to correlates of early childhood experience and later environmental exposures, respectively, as well as of pregnancy. For APIs, a lack of association with birth place may reflect the higher SES of API than Hispanic immigrants. In blacks, EBV-positive HL was associated with later-stage disease, consistent with racial/ethnic variation in certain cytokine polymorphisms. The racial/ethnic variation in our findings suggests that EBV-positive HL results from an intricate interplay of early- and later-life environmental, hormonal, and genetic factors leading to depressed immune function and poorly controlled EBV infection.


Body Fat in Children with Chronic Kidney Disease - A Comparative Study of Bio-impedance Analysis with Dual Energy X-ray Absorptiometry.
Nutritional impairment in patients with chronic kidney disease (CKD) is due to decreased body stores of both protein and fat. We need a tool that can be used in clinics to determine and monitor fat composition with a special focus on normalizing fat measurements to height in these children. Bio-impedance analysis (BIA), a portable and simple tool, has been used to estimate body fat in children with CKD but needs validation against the reference tool dual energy X-ray absorptiometry (DXA). The purpose of the cross-sectional study was to estimate the prevalence of low body fat in children with stages 2-5 CKD (non-dialysis) and CKD 5D (dialysis), and to compare fat measures from two different methods namely BIA and DXA. Children in stages 2-5 CKD (n = 19) and in CKD 5D (n = 14) were recruited for assessment of fat mass (FM, Kg) by BIA and DXA, from which percent body fat (BF %) and fat mass index (FMI, Kg/M2) were obtained. Low body fat was defined as <5th age and gender centile for BF% or FMI by DXA and BF% by BIA. Low body fat was detected equally using BF% and FMI in 18% of children by DXA while only 12% were detected using BF% by BIA. In children with CKD2-5, a good degree of reliability was found with FMI measurements (ICC 0.76 CI [0.48,0.9]) and poor reliability in children with CKD 5D (ICC 0.58 CI [0.1,0.84]). BF% had poor to fair reliability in the children with CKD 2-5 and CKD 5D (ICC 0.64 [0.28,0.84] and 0.53 [0.02,0.82]), respectively. Comparing BF% and FMI obtained by BIA and DEXA, BIA overestimated BF% by 3.5% in comparison to DXA. In children with CKD, body fat is preserved in the majority. Among the two measures of fat, BF% estimated by BIA did not compare well with DXA while FMI measure was comparable with a lower bias. However, due to lack of reference values in Indian children for FMI obtained by BIA, BIA cannot be used to measure fat in this population.


Visualization of odor-induced neuronal activity by immediate early gene expression.
Sensitive detection of sensory-evoked neuronal activation is a key to mechanistic understanding of brain functions. Since immediate early genes (IEGs) are readily induced in the brain by environmental changes, tracing IEG expression provides a convenient tool to identify brain activity. In this study we used in situ hybridization to detect odor-evoked induction of ten IEGs in the mouse olfactory system. We then analyzed IEG induction in the cyclic nucleotide-gated channel subunit A2 (Cnga2)-null mice to visualize residual neuronal activity following odorant exposure since CNGA2 is a key component of the olfactory signal transduction pathway in the main olfactory system. We observed rapid induction of as many as ten IEGs in the mouse olfactory bulb (OB) after olfactory stimulation by a non-biological odorant amyl acetate. A robust increase in expression of several IEGs like c-fos and Egr1 was evident in the glomerular layer, the mitral/tufted cell layer and the granule cell layer. Additionally, the neuronal IEG Npas4 showed steep induction from a very low basal expression level predominantly in the granule cell layer. In Cnga2-null mice, which are usually anosmic and sexually unresponsive, glomerular activation was insignificant in response to either ambient odorants or female stimuli. However, a subtle induction of c-fos took place in the OB of a few Cnga2-mutants which exhibited sexual arousal. Interestingly, very strong glomerular activation was observed in the OB of Cnga2-null male mice after stimulation with either the neutral odor amyl acetate or the predator odor 2, 3, 5-trimethyl-3-thiazoline (TMT). This study shows for the first time that in vivo olfactory stimulation can robustly induce the neuronal IEG Npas4 in the mouse OB and confirms the odor-evoked induction of a number of IEGs. As shown in previous studies, our results indicate that a CNGA2-independent signaling pathway(s) may activate the olfactory circuit in Cnga2-null mice and that neuronal activation which correlates to behavioral difference in individual mice is detectable by in situ hybridization of IEGs. Thus, the in situ hybridization probe set we established for IEG tracing can be very useful to visualize neuronal activity at the cellular level.


Dynamics of Ecosystem Services during Forest Transitions in Reventazón, Costa Rica.
The forest transition framework describes the temporal changes of forest areas with economic development. A first phase of forest contraction is followed by a second phase of expansion once a turning point is reached. This framework does not differentiate forest types or ecosystem services, and describes forests regardless of their contribution to human well-being. For several decades, deforestation in many tropical regions has degraded ecosystem services, such as watershed regulation, while increasing provisioning services from agriculture, for example, food. Forest transitions and expansion have been observed in some countries, but their consequences for ecosystem services are often unclear. We analyzed the implications of forest cover change on ecosystem services in Costa Rica, where a forest transition has been suggested. A review of literature and secondary data on forest and ecosystem services in Costa Rica indicated that forest transition might have led to an ecosystem services transition. We modeled and mapped the changes of selected ecosystem services in the upper part of the Reventazón watershed and analyzed how supply changed over time in order to identify possible transitions in ecosystem services. The modeled changes of ecosystem services is similar to the second phase of a forest transition but no turning point was identified, probably because of the limited temporal scope of the analysis. Trends of provisioning and regulating services and their tradeoffs were opposite in different spatial subunits of our study area, which highlights the importance of scale in the analysis of ecosystem services and forest transitions. The ecosystem services transition framework proposed in this study is useful for analyzing the temporal changes of ecosystem services and linking socio-economic drivers to ecosystem services demand at different scales.


Clinical features and outcome in horses with severe large intestinal thickening diagnosed with transabdominal ultrasonography: 25 cases (2003-2010).
OBJECTIVE To describe clinical features and outcome of horses with severe large intestinal thickening diagnosed with transabdominal ultrasonography. Retrospective case series. ANIMALS 25 horses. PROCEDURES Medical records of horses that underwent transabdominal ultrasonography between 2003 and 2010 were reviewed. Horses were included if the wall of the large intestine was ≥ 9 mm thick in any of 6 abdominal zones. RESULTS Median age was 13 years (range, 3 to 28 years). Horses were initially examined because of colic, diarrhea, inappetence, weight loss, lethargy, fever, or hematuria. Severe large intestinal thickening (range, 9 to 46.6 mm; mean ± SD, 18.8 ± 6.8 mm) was the primary ultrasonographic finding in all horses. Thickened large intestine was more likely to be detected in ventral versus upper (ie, combined paralumbar and intercostal) abdominal zones and in right versus left zones. Eleven horses survived and had resolution of clinical signs, including the l horse treated surgically for colon torsion. An additional horse survived but continued to have intermittent colic. Ten horses were euthanized or died, including 3 horses with neoplasia and 3 with colitis. Three horses were lost to follow-up, including 1 horse with a cecal mass and 1 with hepatosplenic lymphoma. Severity of thickening and number of zones affected were not significantly different between survivors and nonsurvivors. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that in horses undergoing transabdominal ultrasonography, large intestinal wall thickness ≥ 9 mm may be detected in patients with a variety of conditions. Ultrasonographic examination of all abdominal zones was helpful to determine the extent of thickening and identify additional findings that helped prioritize differential diagnoses.


A genome wide survey of SNP variation reveals the genetic structure of sheep breeds.
The genetic structure of sheep reflects their domestication and subsequent formation into discrete breeds. Understanding genetic structure is essential for achieving genetic improvement through genome-wide association studies, genomic selection and the dissection of quantitative traits. After identifying the first genome-wide set of SNP for sheep, we report on levels of genetic variability both within and between a diverse sample of ovine populations. Then, using cluster analysis and the partitioning of genetic variation, we demonstrate sheep are characterised by weak phylogeographic structure, overlapping genetic similarity and generally low differentiation which is consistent with their short evolutionary history. The degree of population substructure was, however, sufficient to cluster individuals based on geographic origin and known breed history. Specifically, African and Asian populations clustered separately from breeds of European origin sampled from Australia, New Zealand, Europe and North America. Furthermore, we demonstrate the presence of stratification within some, but not all, ovine breeds. The results emphasize that careful documentation of genetic structure will be an essential prerequisite when mapping the genetic basis of complex traits. Furthermore, the identification of a subset of SNP able to assign individuals into broad groupings demonstrates even a small panel of markers may be suitable for applications such as traceability.


Evidence of a large novel gene pool associated with prokaryotic genomic islands.
Microbial genes that are "novel" (no detectable homologs in other species) have become of increasing interest as environmental sampling suggests that there are many more such novel genes in yet-to-be-cultured microorganisms. By analyzing known microbial genomic islands and prophages, we developed criteria for systematic identification of putative genomic islands (clusters of genes of probable horizontal origin in a prokaryotic genome) in 63 prokaryotic genomes, and then characterized the distribution of novel genes and other features. All but a few of the genomes examined contained significantly higher proportions of novel genes in their predicted genomic islands compared with the rest of their genome (Paired t test = 4.43E-14 to 1.27E-18, depending on method). Moreover, the reverse observation (i.e., higher proportions of novel genes outside of islands) never reached statistical significance in any organism examined. We show that this higher proportion of novel genes in predicted genomic islands is not due to less accurate gene prediction in genomic island regions, but likely reflects a genuine increase in novel genes in these regions for both bacteria and archaea. This represents the first comprehensive analysis of novel genes in prokaryotic genomic islands and provides clues regarding the origin of novel genes. Our collective results imply that there are different gene pools associated with recently horizontally transmitted genomic regions versus regions that are primarily vertically inherited. Moreover, there are more novel genes within the gene pool associated with genomic islands. Since genomic islands are frequently associated with a particular microbial adaptation, such as antibiotic resistance, pathogen virulence, or metal resistance, this suggests that microbes may have access to a larger "arsenal" of novel genes for adaptation than previously thought.


A multiscale study of electronic structure and quantum transport in C(6n(2))H(6n)-based graphene quantum dots.
We implement a bottom-up multiscale approach for the modeling of defect localization in C(6n(2))H(6n) islands, i.e. graphene quantum dots with a hexagonal symmetry, by means of density functional and semiempirical approaches. Using the ab initio calculations as a reference, we recognize the theoretical framework under which semiempirical methods adequately describe the electronic structure of the studied systems and thereon proceed to the calculation of quantum transport within the nonequilibrium Green function formalism. The computational data reveal an impurity-like behavior of vacancies in these clusters and evidence the role of parameterization even within the same semiempirical context. In terms of conduction, failure to capture the proper chemical aspects in the presence of generic local alterations of the ideal atomic structure results in an improper description of the transport features. As an example, we show wavefunction localization phenomena induced by the presence of vacancies and discuss the importance of their modeling for the conduction characteristics of the studied structures.


Time trends in nutrient intake and dietary patterns among five birth cohorts of 70-year-olds examined 1971-2016: results from the Gothenburg H70 birth cohort studies, Sweden.
Nutrition is a key factor in healthy ageing but there are still gaps in knowledge about risk- and protective factors linking diet and healthy ageing. The aim of this study was to investigate time trends in dietary patterns and nutrient intake in an older population, in order to increase the understanding of whether dietary recommendations are followed and if nutrient needs are met. Cross-sectional data was derived from five samples of 70-year-olds examined 1971-72, 1981-83, 1992-93, 2000-02 and 2014-16 from the Gothenburg H70 birth cohort studies in Sweden. A total of 2246 individuals (56% women) participated. Dietary intake was determined by the diet history method, which is an interview including questions on usual frequencies and portion sizes of food intake during the preceding three months. Recommended values of nutrient intake and determinants of healthful dietary patterns were based on the Nordic Nutrition Recommendations 2012. Statistical analyses were performed using general linear models, student's t-test and chi-square test, stratified by sex. The intake of fruits and vegetables, fish and seafood, whole grain products and nuts and seeds increased during the study period (p < 0.0001), among both sexes. However, there was also an increase in alcohol intake (p < 0.0001), especially from wine and beer, and in 2014-16 more than 30% had an alcohol intake above recommendations. Protein intake increased (p < 0.0001 for women and p = 0.0004 for men), and 48% of the women and 37% of the men had a protein intake above recommended 1.2 g/kg body weight and day in 2014-16. The proportion of participants at risk of inadequate intake of vitamins C, D and folate decreased during the study period, among both sexes (p < 0.0001). However, vitamin D intake from diet was still below average requirement level of 7.5 μg/day for 49% of the women and 32% of the men in 2014-16. Dietary patterns have changed among 70-year-olds during the past five decades, with an increase in healthful foods and a higher nutrient density in later born birth cohorts. However, the intake of alcohol increased, especially among women. Results from this study can be useful as a basis for dietary guidelines and used for prevention strategies involving older adults in population-based and health care settings.


Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 Study.
Purpose Cholesterol-lowering medication (CLM) has been reported to have a role in preventing breast cancer recurrence. CLM may attenuate signaling through the estrogen receptor by reducing levels of the estrogenic cholesterol metabolite 27-hydroxycholesterol. The impact of endocrine treatment on cholesterol levels and hypercholesterolemia per se may counteract the intended effect of aromatase inhibitors. Patients and Methods The Breast International Group (BIG) conducted a randomized, phase III, double-blind trial, BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor-positive invasive breast cancer from 1998 to 2003. Systemic levels of total cholesterol and use of CLM were measured at study entry and every 6 months up to 5.5 years. Cumulative incidence functions were used to describe the initiation of CLM in the presence of competing risks. Marginal structural Cox proportional hazards modeling investigated the relationships between initiation of CLM during endocrine therapy and outcome. Three time-to-event end points were considered: disease-free-survival, breast cancer-free interval, and distant recurrence-free interval. Results Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen-letrozole (n = 189), letrozole-tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer-free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence-free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03). Conclusion Cholesterol-lowering medication during adjuvant endocrine therapy may have a role in preventing breast cancer recurrence in hormone receptor-positive early-stage breast cancer. We recommend that these observational results be addressed in prospective randomized trials.


Addition of intravenous aminophylline to inhaled beta(2)-agonists in adults with acute asthma.
Asthma is a chronic condition in which sufferers may have occasional or frequent exacerbations resulting in visits to the emergency department (ED). Aminophylline has been used extensively to treat exacerbations in acute asthma settings; however, it's role is unclear especially with respect to any additional benefit when added to inhaled beta(2)-agonists. To determine the magnitude of effect of the addition of intravenous aminophylline to inhaled beta(2)-agonists in adult patients with acute asthma treated in the ED setting. We identified trials from the Cochrane Airways Group register (derived from MEDLINE, EMBASE, CINAHL standardised searches) and handsearched respiratory journals and meeting abstracts. Two independent review authors screened and obtained potentially relevant articles and handsearched their bibliographic lists for additional articles. In the original version of this review published in 2000 we included searches of the database up to 1999. The 2012 review was updated with a revised search from inception to September 2012. Randomised controlled trials comparing intravenous aminophylline versus placebo in adults with acute asthma and treated with inhaled beta(2)-agonists. We included patients who were treated with or without corticosteroids or other bronchodilators provided this was not part of the randomised treatment. Two review authors independently extracted data and one review author entered data into RevMan, which was checked by a second review author. Results are reported as mean differences (MD) or odds ratios (OR) with 95% confidential intervals (CI). Fifteen studies were included in the previous version of the review, and we included two new studies in this update, although we were unable to pool new data. Overall, the quality of the studies was moderate; concealment of allocation was assessed as clearly adequate in only seven (45%) of the trials. There was significant clinical heterogeneity between studies as the doses of aminophylline and other medications and the severity of the acute asthma varied between studies.There was no statistically significant advantage when adding intravenous aminophylline with respect to hospital admissions (OR 0.58; 95% CI 0.30 to 1.12; 6 studies; n = 315). In 2000 it was found that there was no statistically significant effect of aminophylline on airflow outcomes at any time period; the addition of two trials in 2012 has not challenged this conclusion. People treated with aminophylline and beta(2)-agonists had similar peak expiratory flow (PEF) values compared to those treated with beta(2)-agonists alone at 12 h (MD 8.30 L/min; 95% CI -20.69 to 37.29 L/min) or (MD -1.21% predicted; 95% CI -14.21% to 11.78% predicted) and 24 h (MD 22.20 L/min; 95% CI -56.65 to 101.05 L/min). Two subgroup analyses were performed by grouping studies according to mean baseline airflow limitation (11 studies) and the use of any corticosteroids (nine studies). There was no relationship between baseline airflow limitation or the use of corticosteroids on the effect of aminophylline. Aminophylline-treated patients reported more palpitations/arrhythmias (OR 3.02; 95% CI 1.15 to 7.90; 6 studies; n = 249) and vomiting (OR 4.21; 95% CI 2.20 to 8.07; 7 studies; n = 321); however, no significant difference was found in tremor (OR 2.60; 95% CI 0.62 to 11.02; 5 studies; n = 249). The use of intravenous aminophylline did not result in significant additional bronchodilation compared to standard care with inhaled beta(2)-agonists in patients experiencing an asthma exacerbation in the ED setting, or in a significant reduction in the risk of hospital admission. For every 100 people treated with aminophylline an additional 20 people had vomiting and 15 people arrhythmias or palpitations. No subgroups in which aminophylline might be more effective were identified. Our update in 2012 is consistent with the original conclusions that the risk-benefit balance of intravenous aminophylline is unfavourable.


Working memory, perceptual priming, and the perception of hierarchical forms: opposite effects of priming and working memory without memory refreshing.
Previous research has shown that stimuli held in working memory (WM) can influence spatial attention. Using Navon stimuli, we explored whether and how items in WM affect the perception of visual targets at local and global levels in compound letters. Participants looked for a target letter presented at a local or global level while holding a regular block letter as a memory item. An effect of holding the target's identity in WM was found. When memory items and targets were the same, performance was better than in a neutral condition when the memory item did not appear in the hierarchical letter (a benefit from valid cuing). When the memory item matched the distractor in the hierarchical stimulus, performance was worse than in the neutral baseline (a cost on invalid trials). These effects were greatest when the WM cue matched the global level of the hierarchical stimulus, suggesting that WM biases attention to the global level of form. Interestingly, in a no-memory priming condition, target perception was faster in the invalid condition than in the neutral baseline, reversing the effect in the WM condition. A further control experiment ruled out the effects of WM being due to participants' refreshing their memory from the hierarchical stimulus display. The data show that information in WM biases the selection of hierarchical forms, whereas priming does not. Priming alters the perceptual processing of repeated stimuli without biasing attention.


Phospholipid metabolism regulated by a transcription factor sensing phosphatidic acid.
Cells regulate the biophysical properties of their membranes by coordinated synthesis of different classes of lipids. Here, we identified a highly dynamic feedback mechanism by which the budding yeast Saccharomyces cerevisiae can regulate phospholipid biosynthesis. Phosphatidic acid on the endoplasmic reticulum directly bound to the soluble transcriptional repressor Opi1p to maintain it as inactive outside the nucleus. After the addition of the lipid precursor inositol, this phosphatidic acid was rapidly consumed, releasing Opi1p from the endoplasmic reticulum and allowing its nuclear translocation and repression of target genes. Thus, phosphatidic acid appears to be both an essential ubiquitous metabolic intermediate and a signaling lipid.


Neuronal remodeling during metamorphosis is regulated by the alan shepard (shep) gene in Drosophila melanogaster.
Peptidergic neurons are a group of neuronal cells that synthesize and secrete peptides to regulate a variety of biological processes. To identify genes controlling the development and function of peptidergic neurons, we conducted a screen of 545 splice-trap lines and identified 28 loci that drove expression in peptidergic neurons when crossed to a GFP reporter transgene. Among these lines, an insertion in the alan shepard (shep) gene drove expression specifically in most peptidergic neurons. shep transcripts and SHEP proteins were detected primarily and broadly in the central nervous system (CNS) in embryos, and this expression continued into the adult stage. Loss of shep resulted in late pupal lethality, reduced adult life span, wing expansion defects, uncoordinated adult locomotor activities, rejection of males by virgin females, and reduced neuropil area and reduced levels of multiple presynaptic markers throughout the adult CNS. Examination of the bursicon neurons in shep mutant pharate adults revealed smaller somata and fewer axonal branches and boutons, and all of these cellular phenotypes were fully rescued by expression of the most abundant wild-type shep isoform. In contrast to shep mutant animals at the pharate adult stage, shep mutant larvae displayed normal bursicon neuron morphologies. Similarly, shep mutant adults were uncoordinated and weak, while shep mutant larvae displayed largely, although not entirely, normal locomotor behavior. Thus, shep played an important role in the metamorphic development of many neurons.


Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL.
To understand the interactions between Notch1 and Ikaros in the evolution of T cell acute lymphoblastic leukemia (T-ALL), we traced the evolution of T-ALL in mice with an inherited Ikaros mutation, Ikzf1(Plstc) which inactivates DNA binding. DNA-binding Ikaros repressed Notch1 response in transfected cell lines and in CD4(+)8(+) (DP) thymocytes from young pre-leukemic Ikzf1(Plstc) heterozygous mice. In DP thymocytes, a 50-1000 fold escalation in mRNA for Notch1 target genes Hes1 and Dtx1 preceded thymic lymphoma or leukemia and was closely correlated with the first detectable differentiation abnormalities, loss of heterozygosity (LOH) eliminating wild-type Ikzf1, and multiple missense and truncating Notch1 mutations. These findings illuminate the early stages of leukemogenesis by demonstrating progressive exaggeration of Notch1 responsiveness at the DP thymocyte stage brought about by multiple mutations acting in concert upon the Notch1 pathway.


Survivorship after childhood cancer: PanCare: a European Network to promote optimal long-term care.
Survival after childhood cancer has improved substantially over recent decades. Although cancer in childhood is rare increasingly effective treatments have led to a growing number of long-term survivors. It is estimated that there are between 300,000 and 500,000 childhood cancer survivors in Europe. Such good survival prospects raise important questions relating to late effects of treatment for cancer. Research has shown that the majority will suffer adverse health outcomes and premature mortality compared with the general population. While chronic health conditions are common among childhood cancer survivors, each specific type of late effect is very rare. Long-term effects must be considered particularly when addressing complex multimodality treatments, and taking into account the interaction between aspects of treatment and genotype. The PanCare Network was set up across Europe in order to effectively answer many of these questions and thereby improve the care and quality of life of survivors. The need for a structured long-term follow-up system after childhood cancer has been recognised for some time and strategies for implementation have been developed, first nationally and then trans-nationally, across Europe. Since its first meeting in Lund in 2008, the goal of the PanCare Network has been to coordinate and implement these strategies to ensure that every European survivor of childhood and adolescent cancer receives optimal long-term care. This paper will outline the structure and work of the PanCare Network, including the results of several European surveys, the start of two EU-funded projects and interactions with relevant stakeholders and related projects.


Cataract in a preterm newborn: a possible side effect of linezolid therapy.
Cataract may cause visual loss especially in the newborn period if early and urgent intervention is not managed. Approximately 1/3 of cases are congenital, 1/3 are related with systemic diseases and the remaining 1/3 are idiopathic or sporadic. The prevalence of congenital cataract in developed countries is estimated as 1 - 3 per 10,000 live births. There are a number of medicines besides systemic and infectious diseases which may cause cataract. Linezolid is a member of the oxazolidinone antibiotic family which can be used in serious infections caused by vancomycin resistant E. faecium (VRE), methicillin resistant S. aureus (MRSA), methicillin resistant coagulase negative staphylococci and penicillin resistant S. pneumonia in infants and children. Side effects are reported as diarrhea, vomiting, headache, transaminase elevation, rashes and optic neuropathy. Herein, we report a preterm newborn who developed thrombocytopenia and bilateral cataracts during linezolid therapy and relieved one week after the discontinuation of the therapy.


Mobile phones and brain tumours: a review of epidemiological research.
There has been a great deal of public concern regarding the possibility that the use of mobile phone-related technologies might result in adverse health effects. Corresponding to this, there has been substantial epidemiological research designed to determine whether the use of mobile phones (MP) has any effect on health, and in particular whether it increases the risk of developing head and neck tumours. Such literature is particularly heterogeneous, which makes it difficult to pool in a meta-analysis. This paper thus reviews the epidemiological literature pertaining to the use of mobile phones and mobile phone-related technologies, and head and neck tumours, in an attempt to consolidate the various reports. Although there have been individual reports of associations between MP-use and tumours, this research is not consistent and on balance does not provide evidence of an association. There are reports of small associations between MP-use ipsilateral to the tumour for greater than 10 years, for both acoustic neuroma and glioma, but the present paper argues that these are especially prone to confounding by recall bias. The reported associations are in need of replication with methods designed to minimise such bias before they can be treated as more than suggestive.


Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial.
Intradermal MVA85A, a candidate vaccine against tuberculosis, induces high amounts of Ag85A-specific CD4 T cells in adults who have already received the BCG vaccine, but aerosol delivery of this vaccine might offer immunological and logistical advantages. We did a phase 1 double-blind trial to compare the safety and immunogenicity of aerosol-administered and intradermally administered MVA85A METHODS: In this phase 1, double-blind, proof-of-concept trial, 24 eligible BCG-vaccinated healthy UK adults were randomly allocated (1:1) by sequentially numbered, sealed, opaque envelopes into two groups: aerosol MVA85A and intradermal saline placebo or intradermal MVA85A and aerosol saline placebo. Participants, the bronchoscopist, and immunologists were masked to treatment assignment. The primary outcome was safety, assessed by the frequency and severity of vaccine-related local and systemic adverse events. The secondary outcome was immunogenicity assessed with laboratory markers of cell-mediated immunity in blood and bronchoalveolar lavage samples. Safety and immunogenicity were assessed for 24 weeks after vaccination. Immunogenicity to both insert Ag85A and vector modified vaccinia virus Ankara (MVA) was assessed by ex-vivo interferon-γ ELISpot and serum ELISAs. Since all participants were randomised and vaccinated according to protocol, our analyses were per protocol. This trial is registered with ClinicalTrials.gov, number NCT01497769. Both administration routes were well tolerated and immunogenic. Respiratory adverse events were rare and mild. Intradermal MVA85A was associated with expected mild local injection-site reactions. Systemic adverse events did not differ significantly between the two groups. Three participants in each group had no vaccine-related systemic adverse events; fatigue (11/24 [46%]) and headache (10/24 [42%]) were the most frequently reported symptoms. Ag85A-specific systemic responses were similar across groups. Ag85A-specific CD4 T cells were detected in bronchoalveolar lavage cells from both groups and responses were higher in the aerosol group than in the intradermal group. MVA-specific cellular responses were detected in both groups, whereas serum antibodies to MVA were only detectable after intradermal administration of the vaccine. Further clinical trials assessing the aerosol route of vaccine delivery are merited for tuberculosis and other respiratory pathogens. The Wellcome Trust and Oxford Radcliffe Hospitals Biomedical Research Centre.


Membrane transporters and protein traffic networks differentially affecting metal tolerance: a genomic phenotyping study in yeast.
The cellular mechanisms that underlie metal toxicity and detoxification are rather variegated and incompletely understood. Genomic phenotyping was used to assess the roles played by all nonessential Saccharomyces cerevisiae proteins in modulating cell viability after exposure to cadmium, nickel, and other metals. A number of novel genes and pathways that affect multimetal as well as metal-specific tolerance were discovered. Although the vacuole emerged as a major hot spot for metal detoxification, we also identified a number of pathways that play a more general, less direct role in promoting cell survival under stress conditions (for example, mRNA decay, nucleocytoplasmic transport, and iron acquisition) as well as proteins that are more proximally related to metal damage prevention or repair. Most prominent among the latter are various nutrient transporters previously not associated with metal toxicity. A strikingly differential effect was observed for a large set of deletions, the majority of which centered on the ESCRT (endosomal sorting complexes required for transport) and retromer complexes, which - by affecting transporter downregulation and intracellular protein traffic - cause cadmium sensitivity but nickel resistance. The data show that a previously underestimated variety of pathways are involved in cadmium and nickel tolerance in eukaryotic cells. As revealed by comparison with five additional metals, there is a good correlation between the chemical properties and the cellular toxicity signatures of various metals. However, many conserved pathways centered on membrane transporters and protein traffic affect cell viability with a surprisingly high degree of metal specificity.


ScreenPro FH: from the Czech MedPed to international collaboration. ScreenPro FH is a participating project of the EAS-FHCS.
This article describes the evolution of our understanding of familial hypercholesterolemia (FH) in the Central, Eastern, and Southern Europe (CESE) region, and the dissemination of this understanding to other countries. Using the ScreenPro FH project as an example, we would like to illustrate the progression from national objectives, to regional networking and, finally, to international collaboration via the Familial Hypercholesterolemia Studies Collaboration (FHSC) project under the leadership of the European Atherosclerosis Society (EAS). It is essential to improve our ability to diagnose FH. In this regard, the EAS and its FHSC project must be commended for their educational and organizational activities which, above all, are dedicated to the creation of a global FH patient registry. In the CESE region, FH diagnostics and treatment situation are markedly different than in Western Europe or North America. Since the Czech MedPed project (Make Early Diagnoses to Prevent Early Deaths in Medical Pedigrees) has been so successful (with results not only comparable to, but, for some parameters, even surpassing the results of many Western countries) we decided to apply the Czech experience to the CESE region. Thus, the ScreenPro FH project was created. The aim of ScreenPro FH is to create a specialist network in the CESE region. The primary objective of the ScreenPro FH project was to dramatically reduce the number of premature deaths due to clinical complications of atherosclerosis in FH patients. At present, ScreenPro FH comprises 18 member countries with a total population of 500,000,000; which, in terms of the FH population, represents 1-2 million patients.


Impact of value added services on patient waiting time at the ambulatory pharmacy Queen Elizabeth Hospital.
Value added services (VAS) are an innovative dispensing system created to provide an alternative means of collecting partial drug supply from our hospital. This in turn was projected to reduce the necessity for patient to visit pharmacy counter and thus reduce the burden of prescription handling. To evaluate the impact of increased VAS uptake following promotional campaign towards patient waiting time and to explore factors that may affect patient waiting time at the Ambulatory Pharmacy, Queen Elizabeth Hospital. A quasi experimental study design was conducted from September 2014 till June 2015 at the Ambulatory Pharmacy. During pre-intervention phase, baseline parameters were collected retrospectively. Then, VAS promotional campaign was carried out for six months and whilst this was done, the primary outcome of patient waiting time was measured by percentage of prescription served less than 30 minutes. A linear regression analysis was used to determine the impact of increased VAS uptake towards patient waiting time. An increased in percentage of VAS registration (20.9% vs 35.7%, p<0.001) was observed after the promotional campaign. The mean percentage of prescription served less than 30 minutes increased from 83.2% SD=15.9 to 90.3% SD=11.5, p=0.001. After controlling for covariates, it was found that patient waiting time was affected by number of pharmacy technicians (b=-0.0349, 95%CI-0.0548 : -0.0150, p=0.001), number of pharmacy counters (b=0.1125, 95%CI 0.0631 : 0.1620, p<0.001), number of prescriptions (b=0.0008, 95%CI 0.0004 : 0.0011, p<0.001), and number of refill prescriptions (b=0.0004, 95%CI 0.0002 : 0.0007, p<0.001). The increased in percentage of VAS registration was associated with reduction in number of refill prescription (b=-2.9838, 95%CI -4.2289 : -1.7388, p<0.001). Patient waiting time at the Ambulatory Pharmacy improved with the increased in VAS registration. The impact of increased VAS uptake on patient waiting time resulted from reduction in refill prescriptions. Patient waiting time is influenced by number of pharmacy technicians, number of pharmacy counters, number of prescriptions and number of refill prescriptions.


Evolutionary dynamics of the cryptocurrency market.
The cryptocurrency market surpassed the barrier of $100 billion market capitalization in June 2017, after months of steady growth. Despite its increasing relevance in the financial world, a comprehensive analysis of the whole system is still lacking, as most studies have focused exclusively on the behaviour of one (Bitcoin) or few cryptocurrencies. Here, we consider the history of the entire market and analyse the behaviour of 1469 cryptocurrencies introduced between April 2013 and May 2017. We reveal that, while new cryptocurrencies appear and disappear continuously and their market capitalization is increasing (super-)exponentially, several statistical properties of the market have been stable for years. These include the number of active cryptocurrencies, market share distribution and the turnover of cryptocurrencies. Adopting an ecological perspective, we show that the so-called neutral model of evolution is able to reproduce a number of key empirical observations, despite its simplicity and the assumption of no selective advantage of one cryptocurrency over another. Our results shed light on the properties of the cryptocurrency market and establish a first formal link between ecological modelling and the study of this growing system. We anticipate they will spark further research in this direction.


Comparative genomics of Gardnerella vaginalis strains reveals substantial differences in metabolic and virulence potential.
Gardnerella vaginalis is described as a common vaginal bacterial species whose presence correlates strongly with bacterial vaginosis (BV). Here we report the genome sequencing and comparative analyses of three strains of G. vaginalis. Strains 317 (ATCC 14019) and 594 (ATCC 14018) were isolated from the vaginal tracts of women with symptomatic BV, while Strain 409-05 was isolated from a healthy, asymptomatic individual with a Nugent score of 9. Substantial genomic rearrangement and heterogeneity were observed that appeared to have resulted from both mobile elements and substantial lateral gene transfer. These genomic differences translated to differences in metabolic potential. All strains are equipped with significant virulence potential, including genes encoding the previously described vaginolysin, pili for cytoadhesion, EPS biosynthetic genes for biofilm formation, and antimicrobial resistance systems, We also observed systems promoting multi-drug and lantibiotic extrusion. All G. vaginalis strains possess a large number of genes that may enhance their ability to compete with and exclude other vaginal colonists. These include up to six toxin-antitoxin systems and up to nine additional antitoxins lacking cognate toxins, several of which are clustered within each genome. All strains encode bacteriocidal toxins, including two lysozyme-like toxins produced uniquely by strain 409-05. Interestingly, the BV isolates encode numerous proteins not found in strain 409-05 that likely increase their pathogenic potential. These include enzymes enabling mucin degradation, a trait previously described to strongly correlate with BV, although commonly attributed to non-G. vaginalis species. Collectively, our results indicate that all three strains are able to thrive in vaginal environments, and therein the BV isolates are capable of occupying a niche that is unique from 409-05. Each strain has significant virulence potential, although genomic and metabolic differences, such as the ability to degrade mucin, indicate that the detection of G. vaginalis in the vaginal tract provides only partial information on the physiological potential of the organism.


Reconciling after civil conflict increases social capital but decreases individual well-being.
Civil wars divide nations along social, economic, and political cleavages, often pitting one neighbor against another. To restore social cohesion, many countries undertake truth and reconciliation efforts. We examined the consequences of one such effort in Sierra Leone, designed and implemented by a Sierra Leonean nongovernmental organization called Fambul Tok. As a part of this effort, community-level forums are set up in which victims detail war atrocities, and perpetrators confess to war crimes. We used random assignment to study its impact across 200 villages, drawing on data from 2383 individuals. We found that reconciliation had both positive and negative consequences. It led to greater forgiveness of perpetrators and strengthened social capital: Social networks were larger, and people contributed more to public goods in treated villages. However, these benefits came at a substantial cost: The reconciliation treatment also worsened psychological health, increasing depression, anxiety, and posttraumatic stress disorder in these same villages. For a subset of villages, we measured outcomes both 9 months and 31 months after the intervention. These results show that the effects, both positive and negative, persisted into the longer time horizon. Our findings suggest that policy-makers need to restructure reconciliation processes in ways that reduce their negative psychological costs while retaining their positive societal benefits.


The bidirectional association between psychiatric disorders and sheltered homelessness.
Psychiatric disorders and homelessness are related, but temporal associations are unclear. We aimed to explore the overlap between hospital-based psychiatric disorders and sheltered homelessness. This population-based cohort study was conducted using the Danish registers e.g., the Danish Homeless Register and the Danish National Patient Register. The study cohort included all individuals aged 15 years or older, living in Denmark at least one day during 2002-2021 (born 1984-2006). First psychiatric diagnosis was used to define psychiatric disorder and first homeless shelter contact to define homelessness. Adjusted incidence rate ratios (IRRs) and cumulative incidences were estimated. Among 1 530 325 individuals accounting for 16 787 562 person-years at risk aged 15-38 years, 11 433 (0.8%) had at least one homeless shelter contact. Among 1 406 410 individuals accounting for 14 131 060 person-years at risk, 210 730 had at least one psychiatric disorder. People with any psychiatric disorder had increased risk of sheltered homelessness relative to individuals with no psychiatric disorder [IRR 9.2, 95% confidence interval (CI) 8.8-9.6]. Ten years after first psychiatric disorder, 3.0% (95% CI 2.9-3.1) had at least one homeless shelter contact. Individuals experiencing homelessness had increased risk of any psychiatric disorder compared to individuals with no homeless shelter contact (IRR 7.0, 95% CI 6.7-7.4). Ten years after first homeless shelter contact, 47.1% (45.3-48.0) had received a hospital-based psychiatric diagnosis. Strong bidirectional associations between psychiatric disorders and homelessness were identified. Health and social care professionals should be aware of and address these high risks of accumulated psychiatric and social problems.


Occult metastases detected by sentinel node biopsy in patients with early oral and oropharyngeal squamous cell carcinomas: impact on survival.
Analysis of the lymphatic drainage pattern, the reliability of a negative sentinel lymph node biopsy (SLNB), as well as the impact of sentinel lymph node (SLN) metastases on regional control and survival in patients with early stage oral and oropharyngeal squamous cell carcinoma (SCC). A prospective consecutive cohort analysis was conducted which included 111 patients diagnosed between 2003 and 2010. Endpoints of the study were neck control rate, overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS), depending on the size of occult metastases. Forty-nine of 111 patients (38%) had positive SLNs, 10 had isolated tumor cells (ITCs), 19 had micrometastases, and 13 had macrometastases. OS, DSS, and DFS at 3 years for SLN-negative and SLN-positive patients was 98% and 71%, 95% and 76%, and 98% and 73%, respectively. Furthermore, there was a statistically significant difference between the SLN-negative group and ITCs in DSS as well as between the SLN-negative group and patients with micrometastases in OS and DSS and between the SLN-negative group and patients with macrometastases in all 3 survival estimates. Our study is the first to demonstrate that even small tumor deposits only detectable by the extensive histopathologic workup of the SLNB protocol have a significant impact on tumor control and survival in early Oropharyngeal SCC. Whether these findings will translate into different treatment strategies based on the upstaged neck has to be further investigated.


Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer.
The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r(2) = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07-1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region.


The functional consequences of generalized joint hypermobility: a cross-sectional study.
Generalized Joint Hypermobility (GJH) has been found to be associated with musculoskeletal complaints and disability. For others GJH is seen as a prerequisite in order to excel in certain sports like dance. However, it remains unclear what the role is of GJH in human performance. Therefore, the purpose of the study was to establish the association between GJH and functional status and to explore the contribution of physical fitness and musculoskeletal complaints to this association. A total of 72 female participants (mean age (SD; range): 19.6 (2.2; 17-24)) were recruited among students from the Amsterdam School of Health Professions (ASHP) (n = 36) and the Amsterdam School of Arts (ASA), Academy for dance and theater (n = 36) in Amsterdam, The Netherlands. From each participant the following data was collected: Functional status performance (self-reported Physical activity level) and capacity (walking distance and jumping capacity: side hop (SH) and square hop (SQH)), presence of GJH (Beighton score ≥4), muscle strength, musculoskeletal complaints (pain and fatigue) and demographic characteristics (age and BMI). GJH was negatively associated with all capacity measures of functional status. Subjects with GJH had a reduced walking distance (B(SE):-75.5(10.5), p = <.0001) and jumping capacity (SH: B(SE):-10.10(5.0), p = .048, and SQH: B(SE):-11.2(5.1), p = .024) in comparison to subjects without GJH, when controlling for confounding: age, BMI and musculoskeletal complaints. In participants with GJH, functional status was not associated with performance measures. GJH was independently associated with lower walking and jumping capacity, potentially due to the compromised structural integrity of connective tissue. However, pain, fatigue and muscle strength were also important contributors to functional status.


Risk factors for persistent cervical intraepithelial neoplasia grades 1 and 2: managed by watchful waiting.
: This study examines risk factors for persistent cervical intraepithelial neoplasia (CIN) and examines whether human papillomavirus (HPV) testing predicts persistent lesions. : Women with histologically diagnosed CIN 1 or CIN 2 (n = 206) were followed up every 3 months without treatment. Human papillomavirus genotyping, plasma levels of ascorbic acid, and red blood cell folate levels were obtained. Cervical biopsy at 12 months determined the presence of CIN. Relative risk (RR) was estimated by log-linked binomial regression models. : At 12 months, 70% of CIN 1 versus 54% of CIN 2 lesions spontaneously regressed (p < .001). Levels of folate or ascorbic acid were not associated with persistent CIN at 12 months. Compared with HPV-negative women, those with multiple HPV types (RRs ranged from 1.68 to 2.17 at each follow-up visit) or high-risk types (RRs range = 1.74-2.09) were at increased risk for persistent CIN; women with HPV-16/18 had the highest risk (RRs range = 1.91-2.21). Persistent infection with a high-risk type was also associated with persistent CIN (RRs range = 1.50-2.35). Typing for high-risk HPVs at 6 months only had a sensitivity of 46% in predicting persistence of any lesions at 12 months. : Spontaneous regression of CIN 1 and 2 occurs frequently within 12 months. Human papillomavirus infection is the major risk factor for persistent CIN. However, HPV testing cannot reliably predict persistence of any lesion.


Health and economic benefits of public financing of epilepsy treatment in India: An agent-based simulation model.
An estimated 6-10 million people in India live with active epilepsy, and less than half are treated. We analyze the health and economic benefits of three scenarios of publicly financed national epilepsy programs that provide: (1) first-line antiepilepsy drugs (AEDs), (2) first- and second-line AEDs, and (3) first- and second-line AEDs and surgery. We model the prevalence and distribution of epilepsy in India using IndiaSim, an agent-based, simulation model of the Indian population. Agents in the model are disease-free or in one of three disease states: untreated with seizures, treated with seizures, and treated without seizures. Outcome measures include the proportion of the population that has epilepsy and is untreated, disability-adjusted life years (DALYs) averted, and cost per DALY averted. Economic benefit measures estimated include out-of-pocket (OOP) expenditure averted and money-metric value of insurance. All three scenarios represent a cost-effective use of resources and would avert 800,000-1 million DALYs per year in India relative to the current scenario. However, especially in poor regions and populations, scenario 1 (which publicly finances only first-line therapy) does not decrease the OOP expenditure or provide financial risk protection if we include care-seeking costs. The OOP expenditure averted increases from scenarios 1 through 3, and the money-metric value of insurance follows a similar trend between scenarios and typically decreases with wealth. In the first 10 years of scenarios 2 and 3, households avert on average over US$80 million per year in medical expenditure. Expanding and publicly financing epilepsy treatment in India averts substantial disease burden. A universal public finance policy that covers only first-line AEDs may not provide significant financial risk protection. Covering costs for both first- and second-line therapy and other medical costs alleviates the financial burden from epilepsy and is cost-effective across wealth quintiles and in all Indian states.


Fine mapping of quantitative trait loci for improved fruit characteristics from Lycopersicon chmielewskii chromosome 1.
The near-isogenic line (NIL) TA1150 contains a 56-cM introgression from Lycopersicon chmielewskii chromosome 1 and has several interesting phenotypic characteristics including fruit with orange color, high levels of soluble solids, thick pericarp, small stem scars, and good firmness. A set of overlapping recombinant lines (subNILs) was developed and field tested to fine map the quantitative trait loci (QTL) controlling these traits. The results indicated that the solids, pericarp thickness, and firmness QTL are distinct from the color locus. Several of the QTL mapped in this study, including the soluble-solids QTL, probably correspond to QTL mapped in other wild species of tomato. However, analysis of a set of TA523 subNILs containing complementary introgressions from Lycopesicon hirsutum chromosome 1 suggests that this wild species may contain a different locus for improved soluble solids. Thus, it might be possible to combine the L. chmielewskii and L. hirsutum alleles for these loci in a single line with the potential for extremely highly soluble solids. The TA1150 subNIL TA1688 contains the smallest introgression of the solids locus (approximately 19 cM), as well as the pericarp thickness and firmness QTL, with a yield that was equivalent to two of the three control lines. Isolation of recombinant subNILs from TA1688 should break the linkage between orange color and high solids and provide a small introgressed segment for marker-assisted breeding and genetic improvement of processing tomato.


Growing Pains at Hospitals: Opportunities and Issues of Service Expansion in Maximum Care.
Due to the demographic change morbidity raises the demand for medical hospital services as well as a need for medical specialization, while economic and human resources are diminishing. Unlike other industries hospitals do not have sufficient data and adequate models to relate growing demands and increasing performance to growth in staff capacity and to increase in staff competences. Based on huge medical data sample covering the years from 2010 to 2014 with more than 150,000 operations of the Department for Anesthesiology at the University Hospital Muenster, Germany, comparisons are drawn between the development of medical services and the development of personnel capacity and expertise. The numbers of surgical operations increased by 21% and "skin incision to closure" time by 17%. Simultaneously, personnel capacity grew by 16% largely resting upon recruiting first-time employees. Expertise measured as "years of professional experience" dwindled from 10 years to 5.4 years on average and staff turnover accelerated. Static benchmark data collected at fixed reference dates do not sufficiently reflect the nexus between capacity and competence and do not reflect the dynamic changes in a hospital's requirements for expertise and specialization, at all. Staff turnover leads to a loss of experience, which jeopardizes patient safety and hampers medical specialization. In consequence of the dramatic shortage of medical specialists, drop-off rates must be reduced and retention rates must be increased. To that end, working conditions need to be fundamentally converted for a multigeneration, multicultural, and increasingly female workforce.


Volitional regulation of emotions produces distributed alterations in connectivity between visual, attention control, and default networks.
The ability to volitionally regulate emotions is critical to health and well-being. While patterns of neural activation during emotion regulation have been well characterized, patterns of connectivity between regions remain less explored. It is increasingly recognized that the human brain is organized into large-scale intrinsic connectivity networks (ICNs) whose interrelationships are altered in characteristic ways during psychological tasks. In this fMRI study of 54 healthy individuals, we investigated alterations in connectivity within and between ICNs produced by the emotion regulation strategy of reappraisal. In order to gain a comprehensive picture of connectivity changes, we utilized connectomic psychophysiological interactions (PPI), a whole-brain generalization of standard single-seed PPI methods. In particular, we quantified PPI connectivity pair-wise across 837 ROIs placed throughout the cortex. We found that compared to maintaining one's emotional responses, engaging in reappraisal produced robust and distributed alterations in functional connections involving visual, dorsal attention, frontoparietal, and default networks. Visual network in particular increased connectivity with multiple ICNs including dorsal attention and default networks. We interpret these findings in terms of the role of these networks in mediating critical constituent processes in emotion regulation, including visual processing, stimulus salience, attention control, and interpretation and contextualization of stimuli. Our results add a new network perspective to our understanding of the neural underpinnings of emotion regulation, and highlight that connectomic methods can play a valuable role in comprehensively investigating modulation of connectivity across task conditions.


Hepatitis B control by 2012 in the WHO Western Pacific Region: rationale and implications.
In 2005, the WHO Western Pacific Region adopted the hepatitis B control goal of reducing the hepatitis B surface antigen seroprevalence in children at least 5 years of age to less than 2% by 2012. Universal infant immunization with three doses of hepatitis B vaccine, including a timely birth dose, is the key recommended strategy. Measuring seroprevalence in children at least 5 years of age takes into account the period when the risk of acquiring a chronic infection is highest and provides an indicator that can be monitored in the short term, within 5 years of vaccine introduction, and which correlates strongly with the long-term consequences of hepatitis B. A time-bound supranational hepatitis B control goal was chosen to create a sense of political urgency for strengthening routine immunization services and improving access to delivery care as well as providing resources for hepatitis B vaccination. Consequently, the programme strategies selected are not stand-alone but also contribute to strengthening health systems. Independent certification of achievement of the control goal, hitherto used mainly for eradication goals, is planned for all countries. Early assessment showed that adopting the regional goal led to greater political commitment, with reduced inequalities in hepatitis B vaccination between and within countries. Previous declining trends in routine immunization coverage also show signs of reversal and there is major progress in providing timely birth doses. A similar approach may be relevant to countries in Africa and South Asia, that have a high hepatitis B disease burden faltering routine immunization and poor access to skilled delivery care.


Cardiovascular disease and periodontitis: an update on the associations and risk.
Associations between periodontitis and cardiovascular diseases have been recognized. New literature since the last European Workshop on Periodontology has been reviewed. The lack of reliable epidemiological data on disease prevalence makes an assessment of the associations and risks between periodontitis and cardiovascular diseases difficult. Two recent meta-analysis reports have identified associations between periodontitis and cardiovascular diseases (odds ratios: 1.1-2.2). Different surrogate markers for both disease entities, including serum biomarkers, have been investigated. Brachial artery flow-mediated dilatation, and carotid intima media thickness have in some studies been linked to periodontitis. Studies are needed to confirm early results of improvements of such surrogate markers following periodontal therapy. While intensive periodontal therapy may enhance inflammatory responses and impair vascular functions, studies are needed to assess the outcome of periodontal therapies in subjects with confirmed cardiovascular conditions. Tooth eradication may also reduce the systemic inflammatory burden of individuals with severe periodontitis. The role of confounders remain unclear. Periodontitis may contribute to cardiovascular disease and stroke in susceptible subjects. Properly powered longitudinal case-control and intervention trials are needed to identify how periodontitis and periodontal interventions may have an impact on cardiovascular diseases.


Integrating the economic and environmental performance of agricultural systems: A demonstration using Farm Business Survey data and Farmscoper.
There is a continued need to monitor the environmental impacts of agricultural systems while also ensuring sufficient agricultural production. However, it can be difficult to collect relevant environmental data on a large enough number of farms and studies that do so often neglect to consider the financial drivers that ultimately determine many aspects of farm management and performance. This paper outlines a methodology for generating environmental indicators from the Farm Business Survey (FBS), an extensive annual economic survey of representative farms in England and Wales. Data were extracted from the FBS for a sample of East Anglian cereal farms and south western dairy farms and converted where necessary to use as inputs in 'Farmscoper'; farm-level estimates of nitrate, phosphorus and sediment loadings and ammonia and greenhouse gas emissions were generated using the Farmscoper model. Nitrate losses to water, ammonia and greenhouse gas emissions were positively correlated with food energy production per unit area for both farm types; phosphorus loading was also correlated with food energy on the dairy farms. Environmental efficiency indicators, as measured by either total food energy or financial output per unit of negative environmental effect, were calculated; greenhouse gas emission efficiency (using either measure of agricultural output) and nitrate loading efficiency (using financial output) were positively correlated with profitability on cereal farms. No other environmental efficiency measures were significantly associated with farm profitability and none were significant on the dairy farms. These findings suggest that an improvement in economic performance can also improve environmental efficiency, but that this depends on the farm type and negative environmental externality in question. In a wider context, the augmentation of FBS-type data to generate additional environmental indicators can provide useful insights into ongoing research and policy issues around sustainable agricultural production.


Identification of KIAA0196 as a novel susceptibility gene for myofibril structural disorganization in cardiac development.
Congenital heart disease is one of the most common cardiac malformation-related diseases worldwide. Some causative genes have been identified but can explain only a small proportion of all cases; therefore, the discovery of novel susceptibility genes and/or modifier genes for abnormal cardiac development remains a major challenge. We used a single nucleotide polymorphism (SNP) array, and next-generation sequencing (NGS) was conducted to screen and quickly identify candidate genes. KIAA0196 knockout zebrafish and mice were generated by CRISPR/Cas9 to detect whether or how KIAA0196 deficiency would influence cardiac development. Homozygous, but not heterozygous, zebrafish and mice showed early embryonic lethality. At the embryonic stage, microscopic examination and dissection revealed pericardial edema and ventricle enlargement in homozygous zebrafish and obviously delayed cardiac development in heterozygous mice, while echocardiography and tissue staining showed that significantly decreased cardiac function, ventricle enlargement, myofibril loss, and significantly reduced trabecular muscle density were observed in adult heterozygous zebrafish and mice. Most importantly, immunostaining and electron microscopy showed that there was a significant increase in sarcomere structural disorganization and myofibril structural integrity loss in KIAA0196 mutants. Furthermore, substantial downregulation in other sarcomeric genes and proteins was detected and verified in a mouse model via transcriptome and proteomics analyses; these changes especially affected the myosin heavy or light chain (MYH or MYL) family genes. We identified KIAA0196 for the first time as a susceptibility gene for abnormal cardiac development. KIAA0196 deficiency may cause abnormal heart development by influencing the structural integrity of myofibrils.


Serial Monitoring of Immune Markers Being Represented Regulatory T Cell/T Helper 17 Cell Ratio: Indicating Tolerance for Tapering Immunosuppression after Liver Transplantation.
Recipients of liver transplantation (LT) require long-term immunosuppressive drug treatment, but lifelong immunosuppressive treatment has severe side effects. It is known that some LT recipients develop immune tolerance, and although the development of such operational tolerance should allow a decrease in the burden of immunosuppressive drug treatment, the factors that indicate operational tolerance are not clear. This study aimed to monitor immunological markers over time in LT recipients to identify those markers indicating the development of operational tolerance. We performed a prospective pilot study measuring immune markers, including the ratio of regulatory T (Treg) and T helper (Th) 17 cells in peripheral blood in the 14 most immunologically stable patients among 70 clinically stable LT recipients. The doses of immunosuppressive drugs given to these 14 LT recipients were tapered over time and they were monitored for immunological markers related to the development of immune tolerance. As the doses of immunosuppressive drugs were reduced, the Treg/Th17, Th1/Th17, and CD8/Th17 ratio in tolerant recipients was significantly increased compared with that of nontolerant recipients. These results suggest that monitoring of changes in the immune makers, including Treg/Th17 ratio during tapering of immunosuppression may allow prediction of the development of tolerance.


Common Bean: Experimental Indicator Plant for Citrus leprosis virus C and Some Other Cytoplasmic-Type Brevipalpus-Transmitted Viruses.
Citrus leprosis (CL) caused by Citrus leprosis virus C (CiLV-C) is present in Latin America from Mexico to Argentina, where citrus plants are grown. CiLV-C is transmitted by the tenuipalpid mite, Brevipalpus phoenicis, causing localized lesions on citrus leaves, fruit, and stems. One limitation to study of the virus-vector-host relationship in this pathosystem is the lack of a suitable assay plant. On Citrus spp. used as susceptible hosts, symptoms may take weeks or months to appear after experimental inoculation by viruliferous mites. Common bean (Phaseolus vulgaris) was found to respond with localized necrotic lesions after inoculation with viruliferous B. phoenicis in 5 days. Thus far, 113 tested common bean varieties and lines and some recent accessions of varied genetic background behaved in a similar way. Black bean 'IAC Una' was adopted as a standard test variety. When inoculated leaves were left at 28 to 30°C, the period for the lesion appearance was reduced to only 2 days. Confirmation that the lesions on common bean leaves are caused by CiLV-C were made by transmission electron microscopy, immunofluorescence, enzyme-linked immunosorbent assay, and reverse-transcription polymerase chain reaction specific for CiLV-C. Common bean plants mite-inoculated with some other cytoplasmic-type Brevipalpus-transmitted viruses (BrTVs) (Passion fruit green spot virus, Solanum violaefolium ringspot virus, Ligustrum ringspot virus, and Hibiscus green spot virus) also responded with necrotic local lesions and may serve as test plants for these viruses. Two nuclear types of BrTV (Coffee ringspot virus and Clerodendrum chlorotic spot virus) were unable to produce symptoms on common bean.


The molecular mechanisms of traditional Chinese medicine ZHENG syndromes on pancreatic tumor growth.
Traditional Chinese medicine (TCM) syndromes (ZHENG in Chinese) are the abstraction from the comprehensive analysis of clinical information gained by the four main diagnostic TCM methods: observation, listening, questioning, and pulse analyses. Proper TCM diagnosis is the most important principle to guide the prescribing of Chinese herbs. To evaluate the specific effect of TCM ZHENG on tumor growth and to examine the molecular mechanisms underlying ZHENG and tumor growth. The authors established subcutaneous tumor models of pancreatic cancer ZHENG syndromes of Damp heat (Shi-Re) and Spleen deficiency (Pi-Xu). Tissue samples of the subcutaneous transplanted tumors from each model were studied versus control tumors. CCR5 and CXCR4 proteins in these tissues were assayed by immunohistochemical staining. The expression of CCR5/CCL5/CCL4/CCL3 and CXCR4/SDF-1 mRNA was investigated by reverse transcriptase-polymerase chain reaction (RT-PCR). SDF-1, CCL4, CCL5, and CCL3, which are ligands of CXCR4 and CCR5, were examined by ELISA. The study found that tumor models with different ZHENG were successfully established in each group; the tumor growth of Shi-Re group was slower than that of the control group. It was found that there was a significant difference in CCR5 mRNA expression levels among the Pi-Xu, Shi-Re, and control groups. The results of immunohistochemistry staining revealed that the positive rate of CCR5 protein in Shi-Re group, Pi-Xu group, and control group was 25.00%, 53.33%, 83.33%, respectively. The Shi-Re group expressed the lowest levels of CCL5 and CCL4. The results of the study suggest that the existence of TCM ZHENG may influence the tumor growth in pancreatic cancer, which might be mediated by the expression of CCR5/CCL5/CCL4. This finding may lead to the development of TCM ZHENG as a prognostic indicator in pancreatic tumor growth.


Acute life-threatening hypoxemia during mechanical ventilation.
To describe current evidence-based practice in the management of acute life-threatening hypoxemia in mechanically ventilated patients and some of the methods used to individualize the care of the patient. Patients with acute life-threatening hypoxemia will often meet criteria for severe ARDS, for which there are only a few treatment strategies that have been shown to improve survival outcomes. Recent findings have increased our knowledge of the physiological effects of spontaneous breathing and the application of PEEP. Additionally, the use of advanced bedside monitoring has a promising future in the management of hypoxemic patients to fine-tune the ventilator and to evaluate the individual patient response to therapy. Treating the patient with acute life-threatening hypoxemia during mechanical ventilation should begin with an evidence-based approach, with the goal of improving oxygenation and minimizing the harmful effects of mechanical ventilation. The use of advanced monitoring and the application of simple maneuvers at the bedside may assist clinicians to better individualize treatment and improve clinical outcomes.


Identification of candidate genes for dyslexia susceptibility on chromosome 18.
Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis. Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L). Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.


Multiscale Structuring of the E. coli Chromosome by Nucleoid-Associated and Condensin Proteins.
As in eukaryotes, bacterial genomes are not randomly folded. Bacterial genetic information is generally carried on a circular chromosome with a single origin of replication from which two replication forks proceed bidirectionally toward the opposite terminus region. Here, we investigate the higher-order architecture of the Escherichia coli genome, showing its partition into two structurally distinct entities by a complex and intertwined network of contacts: the replication terminus (ter) region and the rest of the chromosome. Outside of ter, the condensin MukBEF and the ubiquitous nucleoid-associated protein (NAP) HU promote DNA contacts in the megabase range. Within ter, the MatP protein prevents MukBEF activity, and contacts are restricted to ∼280 kb, creating a domain with distinct structural properties. We also show how other NAPs contribute to nucleoid organization, such as H-NS, which restricts short-range interactions. Combined, these results reveal the contributions of major evolutionarily conserved proteins in a bacterial chromosome organization.


Functional beta cell regeneration in the islets of pancreas in alloxan induced diabetic rats by (-)-epicatechin.
(-)-Epicatechin (1), a naturally occurring flavonoid compound was found to have reversed the diabetogenic action of alloxan in albino rats (2). (-)-Epicatechin administration in doses of 30 mg/kg (i.p.) twice daily for 4-5 days in alloxan induced (150 mg/kg, i.p.) diabetic albino rats (either sex), has brought down the high blood sugar levels to normal values. Concurrent histological studies of the pancreas of these animals showed regeneration of the beta-cell population of the islets which were earlier necrosed by alloxan. Immunoreactive insulin (IRI) studies showed that the regenerated beta-cells of the islets of pancreas are functional in nature.


Characteristics of human basophil sulfidopeptide leukotriene release: releasability defined as the ability of the basophil to respond to dimeric cross-links.
Human basophils release approximately 90 pmol of LTC4/micrograms histamine when challenged with anti-IgE antibody, but donor to donor variation produces a 1000-fold range of response. There is little conversion to LTC4 to LTE4 in purified preparations of basophils, but conversion to LTE4 does occur if cell densities are high during incubation. Like histamine release, leukotriene release is calcium and temperature dependent and is complete in 20 min, with a t1/2 of approximately 8 min. The process of desensitization also ablates leukotriene release, but there is a distinct two phase process where leukotriene release is enhanced after 5 min of desensitization, whereas histamine release is inhibited and total ablation of leukotriene release occurs only after 45 min of desensitization. Human basophils respond well to stimulation with covalently cross-linked trimeric IgE myeloma but respond poorly to dimeric IgE. This differential sensitivity to the two forms of cross-linked IgE is most exaggerated in the context of leukotriene release, where dimer is 30-fold less efficacious and 100- to 1000-fold less potent than trimer on some donors' basophils. This dichotomy of response is also observed in antigen-challenged cells, where the bivalent hapten, BPO2, also poorly induces leukotriene release in accord with the fact that it predominantly induces dimeric cross-links of penicillin-specific IgE. Anti-IgE dose-response curves reveal a region of dimeric cross-link dominance that may explain the peculiar differences observed in pharmacologic studies of basophil release induced with antigen vs anti-IgE. In addition, there is a continuum of "releasability," where some donors' basophils display no response (histamine or leukotriene release) to dimeric IgE, and others' basophils are essentially equally responsive to both dimeric and trimeric IgE. This releasability difference manifests itself by conferring increased sensitivity to antigenic challenge in those donors' basophils capable of responding to dimeric cross-links such that these donors' basophils are capable of releasing histamine upon antigen challenge while possessing only 50 molecules of cell surface antigen-specific IgE; other dimer-insensitive donors' basophils require 6 to 10-fold greater IgE densities for equal histamine release.


Evaluation of the 'Live Life Better Service', a community-based weight management service, for morbidly obese patients.
There is a limited evidence on the effectiveness of lifestyle interventions in achieving and maintaining a significant level of weight loss in morbidly obese patients. This study evaluated the impact on weight loss and psychological well-being of a community-based weight management service for morbidly obese patients [body mass index (BMI) ≥35 with related co-morbidities or BMI >40] in Derbyshire county. Five hundred and fifty-one participants entered the service since 2010, and 238 participants were still active within the service or had completed the 2-year intervention in April 2013. A one-group pre-post design was used to determine average weight loss (kg) and impact on mental health and well-being [using the validated clinical outcomes of routine evaluation-outcome measure (CORE-OM) questionnaire] among participants. Measurements were recorded at baseline, 12 weeks, 24 weeks, 1 year, 18 months and 2 years, and significance (P ≤ 0.05) was determined using the paired sample t-test. Statistically significant weight loss was recorded at each measurement point for those participants who remained engaged with the service (4.9 kg weight loss at 12 weeks to 18.2 kg at 2 years). There was a significant positive impact on psychological well-being demonstrated by CORE-OM score. Findings show clinically and statistically significant weight loss among participants with improvements in physical and mental health.


Preservation of spinal cord function after extensive segmental artery sacrifice: regional variations in perfusion.
Sacrifice of intercostal and lumbar arteries simplifies thoracoabdominal aneurysm surgery and enables endovascular stenting. Little is known about alterations in cord perfusion after extensive segmental artery sacrifice. We explored this question using hypothermia to reduce metabolism. Twelve juvenile Yorkshire pigs (mean weight, 22.3 kg) were randomized to segmental artery sacrifice at 32 degrees C or 37 degrees C. Cord integrity was assessed with myogenic-evoked potential (MEP) monitoring. Stepwise craniocaudal sacrifice of segmental arteries was continued until MEP diminution occurred; the last segmental artery was then reopened. Fluorescent microspheres were used to measure spinal cord blood flow (SCBF) at baseline, 5 minutes, 1 hour, and 3 hours after segmental artery sacrifice. Hind limb function was monitored for 5 days. All animals recovered normal hind limb function. At 32 degrees C, more segmental arteries, 16.5 versus 15 (p = 0.03), could be sacrificed without MEP loss. Baseline SCBF at 32 degrees C was 50% that at 37 degrees C (p = 0.003) and remained fairly stable throughout. At 37 degrees C, SCBF to the craniocaudal extremes of the cord (C1 to T3 and L2 to L6) increased markedly (p = 0.01) at 1 hour and returned toward normal at 3 hours. Concomitantly, SCBF fell in the middle portion of the cord (T9 to T13) at 1 hour before returning to normal at 3 hours. Almost all segmental arteries can be sacrificed with preservation of spinal cord function. No major change occurs in the central cord in normothermic animals, but there is significant transient hyperemia in segments adjacent to extrasegmental vessels. Hypothermia reduces SCBF and abolishes this possible steal phenomenon. Metabolic and hemodynamic manipulation should enable routine sacrifice of all segmental arteries without spinal cord injury.


Cooperative asymmetric reactions combining photocatalysis and enzymatic catalysis.
Living organisms rely on simultaneous reactions catalysed by mutually compatible and selective enzymes to synthesize complex natural products and other metabolites. To combine the advantages of these biological systems with the reactivity of artificial chemical catalysts, chemists have devised sequential, concurrent, and cooperative chemoenzymatic reactions that combine enzymatic and artificial catalysts1-9. Cooperative chemoenzymatic reactions consist of interconnected processes that generate products in yields and selectivities that cannot be obtained when the two reactions are carried out sequentially with their respective substrates2,7. However, such reactions are difficult to develop because chemical and enzymatic catalysts generally operate in different media at different temperatures and can deactivate each other1-9. Owing to these constraints, the vast majority of cooperative chemoenzymatic processes that have been reported over the past 30 years can be divided into just two categories: chemoenzymatic dynamic kinetic resolutions of racemic alcohols and amines, and enzymatic reactions requiring the simultaneous regeneration of a cofactor2,4,5. New approaches to the development of chemoenzymatic reactions are needed to enable valuable chemical transformations beyond this scope. Here we report a class of cooperative chemoenzymatic reaction that combines photocatalysts that isomerize alkenes with ene-reductases that reduce carbon-carbon double bonds to generate valuable enantioenriched products. This method enables the stereoconvergent reduction of E/Z mixtures of alkenes or reduction of the unreactive stereoisomers of alkenes in yields and enantiomeric excesses that match those obtained from the reduction of the pure, more reactive isomers. The system affords a range of enantioenriched precursors to biologically active compounds. More generally, these results show that the compatibility between photocatalysts and enzymes enables chemoenzymatic processes beyond cofactor regeneration and provides a general strategy for converting stereoselective enzymatic reactions into stereoconvergent ones.


The physiological correlates of Kundalini Yoga meditation: a study of a yoga master.
This study explores the physiological correlates of a highly practiced Kundalini Yoga meditator. Thoracic and abdominal breathing patterns, heart rate (HR), occipital parietal electroencephalograph (EEG), skin conductance level (SCL), and blood volume pulse (BVP) were monitored during prebaseline, meditation, and postbaseline periods. Visual analyses of the data showed a decrease in respiration rate during the meditation from a mean of 11 breaths/min for the pre- and 13 breaths/min for the postbaseline to a mean of 5 breaths/min during the meditation, with a predominance of abdominal/diaphragmatic breathing. There was also more alpha EEG activity during the meditation (M = 1.71 microV) compared to the pre- (M = .47 microV) and postbaseline (M = .78 microV) periods, and an increase in theta EEG activity immediately following the meditation (M = .62 microV) compared to the pre-baseline and meditative periods (each with M = .26 microV). These findings suggest that a shift in breathing patterns may contribute to the development of alpha EEG, and those patterns need to be investigated further.


Spongiform encephalopathy in transgenic mice expressing a point mutation in the β2-α2 loop of the prion protein.
Transmissible spongiform encephalopathies are fatal neurodegenerative diseases attributed to misfolding of the cellular prion protein, PrP(C), into a β-sheet-rich, aggregated isoform, PrP(Sc). We previously found that expression of mouse PrP with the two amino acid substitutions S170N and N174T, which result in high structural order of the β2-α2 loop in the NMR structure at pH 4.5 and 20°C, caused transmissible de novo prion disease in transgenic mice. Here we report that expression of mouse PrP with the single-residue substitution D167S, which also results in a structurally well ordered β2-α2 loop at 20°C, elicits spontaneous PrP aggregation in vivo. Transgenic mice expressing PrP(D167S) developed a progressive encephalopathy characterized by abundant PrP plaque formation, spongiform change, and gliosis. These results add to the evidence that the β2-α2 loop has an important role in intermolecular interactions, including that it may be a key determinant of prion protein aggregation.


Cardiac regeneration: current therapies-future concepts.
Cardiovascular disease (CVD) continues to be one of the main causes of death in the western world. A high burden of disease and the high costs for the healthcare systems claim for novel therapeutic strategies besides current conventional medical care. One decade ago first clinical trials addressed stem cell based therapies as a potential alternative therapeutic strategy for myocardial regeneration and repair. Besides bone marrow derived stem cells (BMCs), adult stem cells from adipose or cardiac tissue have been used in current clinical studies with inconsistent results. Although outcomes in terms of safety and feasibility are generally encouraging, functional improvements were mostly disappointingly low and have failed to reach expectations. In the future, new concepts for myocardial regeneration, especially concerning recovery of cardiomyocyte loss, have to be developed. Transplantation of novel stem or progenitor cell populations with "true" regenerative potential, direct reprogramming of scar tissue into functional myocardium, tissue engineering or stimulation of endogenous cardiac repair by pharmacological agents are conceivable. This review summarizes current evidence of stem cell based regenerative therapies and discusses future strategies to improve functional outcomes.


Arthroscopic identification of iliopubic and ilioischial grooves in a single adult acetabulum.
We report the arthroscopic identification of combined morphological variants of the acetabulum in an adult. The combination of iliopubic and ilioischial grooves has not been reported before. Preoperative radiographic and MRI failed to detect the lesions. These grooves strongly suggest incomplete fusion between the three limbs of the triradiate cartilage. When identified, this condition should not be treated as pathological but as a rare anatomical variant. Hip arthroscopy is a competent tool in discovering such asymptomatic cartilage abnormalities and subtle anatomical variations even in the presence of normal preoperative imaging.


The multisensory function of the human primary visual cortex.
It has been nearly 10 years since Ghazanfar and Schroeder (2006) proposed that the neocortex is essentially multisensory in nature. However, it is only recently that sufficient and hard evidence that supports this proposal has accrued. We review evidence that activity within the human primary visual cortex plays an active role in multisensory processes and directly impacts behavioural outcome. This evidence emerges from a full pallet of human brain imaging and brain mapping methods with which multisensory processes are quantitatively assessed by taking advantage of particular strengths of each technique as well as advances in signal analyses. Several general conclusions about multisensory processes in primary visual cortex of humans are supported relatively solidly. First, haemodynamic methods (fMRI/PET) show that there is both convergence and integration occurring within primary visual cortex. Second, primary visual cortex is involved in multisensory processes during early post-stimulus stages (as revealed by EEG/ERP/ERFs as well as TMS). Third, multisensory effects in primary visual cortex directly impact behaviour and perception, as revealed by correlational (EEG/ERPs/ERFs) as well as more causal measures (TMS/tACS). While the provocative claim of Ghazanfar and Schroeder (2006) that the whole of neocortex is multisensory in function has yet to be demonstrated, this can now be considered established in the case of the human primary visual cortex.


Eplerenone prevents salt-induced vascular stiffness in Zucker diabetic fatty rats: a preliminary report.
Aldosterone levels are elevated in a rat model of type 2 diabetes mellitus, the Zucker Diabetic fatty rat (ZDF). Moreover blood pressure in ZDF rats is salt-sensitive. The aim of this study was to examine the effect of the aldosterone antagonist eplerenone on structural and mechanical properties of resistance arteries of ZDF-rats on normal and high-salt diet. After the development of diabetes, ZDF animals were fed either a normal salt diet (0.28%) or a high-salt diet (5.5%) starting at an age of 15 weeks. ZDF rats on high-salt diet were randomly assigned to eplerenone (100 mg/kg per day, in food) (ZDF+S+E), hydralazine (25 mg/kg per day) (ZDF+S+H), or no treatment (ZDF+S). Rats on normal salt-diet were assigned to eplerenone (ZDF+E) or no treatment (ZDF). Normoglycemic Zucker lean rats were also divided into two groups receiving normal (ZL) or high-salt diet (ZL+S) serving as controls. Systolic blood pressure was measured by tail cuff method. The experiment was terminated at an age of 25 weeks. Mesenteric resistance arteries were studied on a pressurized myograph. Specifically, vascular hypertrophy (media-to-lumen ratio) and vascular stiffness (strain and stress) were analyzed. After pressurized fixation histological analysis of collagen and elastin content was performed. Blood pressure was significantly higher in salt-loaded ZDF compared to ZDF. Eplerenone and hydralazine prevented this rise similarily, however, significance niveau was missed. Media-to-lumen ratio of mesenteric resistance arteries was significantly increased in ZDF+S when compared to ZDF and ZL. Both, eplerenone and hydralazine prevented salt-induced vascular hypertrophy. The strain curve of arteries of salt-loaded ZDF rats was significantly lower when compared to ZL and when compared to ZDF+S+E, but was not different compared to ZDF+S+H. Eplerenone, but not hydralazine shifted the strain-stress curve to the right indicating a vascular wall composition with less resistant components. This indicates increased vascular stiffness in salt-loaded ZDF rats, which could be prevented by eplerenone but not by hydralazine. Collagen content was increased in ZL and ZDF rats on high-salt diet. Eplerenone and hydralazine prevented the increase of collagen content. There was no difference in elastin content. Eplerenone and hydralazine prevented increased media-to-lumen ratio in salt-loaded ZDF-rats, indicating a regression of vascular hypertrophy, which is likely mediated by the blood pressure lowering-effect. Eplerenone has additionally the potential to prevent increased vascular stiffness in salt-loaded ZDF-rats. This suggests an effect of the specific aldosterone antagonist on adverse vascular wall remodelling.


The Transient Covalent Bond in Abiotic Nonequilibrium Systems.
Biochemical systems accomplish many critical functions with by operating out-of-equilibrium using the energy of chemical fuels. The formation of a transient covalent bond is a simple but very effective tool in designing analogous reaction networks. This Minireview focuses on the fuel chemistries that have been used to generate transient bonds in recent demonstrations of abiotic nonequilibrium systems (i.e., systems that do not make use of biological components). Fuel reactions are divided into two fundamental classifications depending on whether the fuel contributes structural elements to the activated state, a distinction that dictates how they can be used. Reported systems are further categorized by overall fuel reaction (e.g., hydrolysis of alkylating agents, carbodiimide hydration) and illustrate how similar chemistry can be used to effect a wide range of nonequilibrium behavior, ranging from self-assembly to the operation of molecular machines.