Effect of Curcumin and α-Lipoic Acid in Attenuating Weight Gain and Adiposity.
Objective: Obesity is growing at epidemic proportions worldwide. Natural compounds curcumin and α-lipoic acid have been shown to reduce body-weight gain in both preclinical and clinical studies. This study examined the effect of a combination of curcumin and α-lipoic acid on weight gain and adiposity in high-fat-diet (HFD)-fed mice. Methods: C57BL6 mice (7 weeks old) were randomly assigned to receive either HFD (60% fat) or a normal diet (ND, 10% fat) for a 12-week period, following which the mice receiving HFD were further assigned to supplemental curcumin (0.07%), α-lipoic acid (0.2%), or a combination of curcumin and α-lipoic acid formulated into the HFD for a further 12 weeks. Food intake and body mass were determined on a weekly basis. Body fat composition was determined by dual energy X-ray absorptiometry. Results: Treatment with both curcumin and α-lipoic acid significantly reduced body weight gain in HFD-treated mice, and the combination was more effective in attenuating body weight compared to the individual agents. Food intake and caloric intake were significantly lower in the mice that received α-lipoic acid. Percentage body fat and fat mass and lean body mass, which were increased following HFD feeding, were attenuated in the mice receiving curcumin and the combination. Lean mass was also elevated in the mice that were subjected to an HFD, which was unaltered by curcumin or the combination. Conclusions: Taken together, the combination of curcumin and α-lipoic acid exhibits an additive effect in reducing weight gain and adiposity in response to high-fat feeding.


Associations between mode of HIV testing and consent, confidentiality, and referral: a comparative analysis in four African countries.
Recommendations about scaling up HIV testing and counseling highlight the need to provide key services and to protect clients' rights, but it is unclear to what extent different modes of testing differ in this respect. This paper examines whether practices regarding consent, confidentiality, and referral vary depending on whether testing is provided through voluntary counseling and testing (VCT) or provider-initiated testing. The MATCH (Multi-Country African Testing and Counseling for HIV) study was carried out in Burkina Faso, Kenya, Malawi, and Uganda. Surveys were conducted at selected facilities. We defined eight outcome measures related to pre- and post-test counseling, consent, confidentiality, satisfactory interactions with providers, and (for HIV-positive respondents) referral for care. These were compared across three types of facilities: integrated facilities, where testing is provided along with medical care; stand-alone VCT facilities; and prevention of mother-to-child transmission (PMTCT) facilities, where testing is part of PMTCT services. Tests of bivariate associations and modified Poisson regression were used to assess significance and estimate the unadjusted and adjusted associations between modes of testing and outcome measures. In total, 2,116 respondents tested in 2007 or later reported on their testing experience. High percentages of clients across countries and modes of testing reported receiving recommended services and being satisfied. In the unadjusted analyses, integrated testers were less likely to meet with a counselor before testing (83% compared with 95% of VCT testers; p<0.001), but those who had a pre-test meeting were more likely to have completed consent procedures (89% compared with 83% among VCT testers; p<0.001) and pre-test counseling (78% compared with 73% among VCT testers; p = 0.015). Both integrated and PMTCT testers were more likely to receive complete post-test counseling than were VCT testers (59% among both PMTCT and integrated testers compared with 36% among VCT testers; p<0.001). Adjusted analyses by country show few significant differences by mode of testing: only lower satisfaction among integrated testers in Burkina Faso and Uganda, and lower frequency of referral among PMTCT testers in Malawi. Adjusted analyses of pooled data across countries show a higher likelihood of pre-test meeting for those testing at VCT facilities (adjusted prevalence ratio: 1.22, 95% CI: 1.07-1.38) and higher satisfaction for stand-alone VCT facilities (adjusted prevalence ratio: 1.15; 95% CI: 1.06-1.25), compared to integrated testing, but no other associations were statistically significant. Overall, in this study most respondents reported favorable outcomes for consent, confidentiality, and referral. Provider-initiated ways of delivering testing and counseling do not appear to be associated with less favorable outcomes for clients than traditional, client-initiated VCT, suggesting that testing can be scaled up through multiple modes without detriment to clients' rights. Please see later in the article for the Editors' Summary.


Effects of age, adipose percent, and reproduction on PCB concentrations and profiles in an extreme fasting North Pacific marine mammal.
Persistent organic pollutants, including polychlorinated biphenyls (PCBs), are widely distributed and detectable far from anthropogenic sources. Northern elephant seals (Mirounga angustirostris) biannually travel thousands of kilometers to forage in coastal and open-ocean regions of the northeast Pacific Ocean and then return to land where they fast while breeding and molting. Our study examined potential effects of age, adipose percent, and the difference between the breeding and molting fasts on PCB concentrations and congener profiles in blubber and serum of northern elephant seal females. Between 2005 and 2007, we sampled blubber and blood from 58 seals before and after a foraging trip, which were then analyzed for PCBs. Age did not significantly affect total PCB concentrations; however, the proportion of PCB congeners with different numbers of chlorine atoms was significantly affected by age, especially in the outer blubber. Younger adult females had a significantly greater proportion of low-chlorinated PCBs (tri-, tetra-, and penta-CBs) than older females, with the opposite trend observed for hepta-CBs, indicating that an age-associated process such as parity (birth) may significantly affect congener profiles. The percent of adipose tissue had a significant relationship with inner blubber PCB concentrations, with the highest mean concentrations observed at the end of the molting fast. These results highlight the importance of sampling across the entire blubber layer when assessing contaminant levels in phocid seals and taking into account the adipose stores and reproductive status of an animal when conducting contaminant research.


Community participation in rural health: a scoping review.
Major health inequities between urban and rural populations have resulted in rural health as a reform priority across a number of countries. However, while there is some commonality between rural areas, there is increasing recognition that a one size fits all approach to rural health is ineffective as it fails to align healthcare with local population need. Community participation is proposed as a strategy to engage communities in developing locally responsive healthcare. Current policy in several countries reflects a desire for meaningful, high level community participation, similar to Arnstein's definition of citizen power. There is a significant gap in understanding how higher level community participation is best enacted in the rural context. The aim of our study was to identify examples, in the international literature, of higher level community participation in rural healthcare. A scoping review was designed to map the existing evidence base on higher level community participation in rural healthcare planning, design, management and evaluation. Key search terms were developed and mapped. Selected databases and internet search engines were used that identified 99 relevant studies. We identified six articles that most closely demonstrated higher level community participation; Arnstein's notion of citizen power. While the identified studies reflected key elements for effective higher level participation, little detail was provided about how groups were established and how the community was represented. The need for strong partnerships was reiterated, with some studies identifying the impact of relational interactions and social ties. In all studies, outcomes from community participation were not rigorously measured. In an environment characterised by increasing interest in community participation in healthcare, greater understanding of the purpose, process and outcomes is a priority for research, policy and practice.


Differences in HLA antigens between patients with mixed connective tissue disease and systemic lupus erythematosus.
Patients with mixed connective tissue disease (MCTD, n = 32) or systemic lupus erythematosus (SLE, n = 60) were typed for HLA-A, B, C, Dw, and DR antigens. All patients with SLE fulfilled at least four criteria of SLE and the patients with MCTD met the criteria proposed by Alarcon-Segovia (1989). The presence of antibodies to Sm was not considered as an exclusion for MCTD. In the patients with SLE, Dw3, DR3, and the associated B8 and A1 antigens were increased, whereas in the patients with MCTD an increased frequency of Dw4 was found (45 v 18% in controls v 14% in SLE). Of the subtypes of DR4, Dw4 was present in all but one of the DR4 positive patients. The frequency of DR4 in patients with MCTD (52%) differed significantly from that of controls (28%). The strong association of MCTD to one DR4 subtype was further seen in the significantly increased frequency of the B15, DR4 combination. Thus the genetic background seems to be different in patients with MCTD from that in patients with SLE. This could partly explain the clinical differences between these diseases.


Ecological knowledge is lost in wealthier communities and countries.
Accumulated knowledge about nature is an important part of people's capacityto manage and conserve the environment. But this ecological knowledge is now being increasingly lost. There have been few cross-cultural and quantitative studies to describe the phenomenon of its loss. Here we show a strong inverse correlation between ecological knowledge and income levels in and among India, Indonesia, and the U.K. (n=1095 interviews). Knowledge acquisition and subsequent saturation occurs at an early age in the most resource-dependent communities, but not in the U.K., where knowledge levels are low and acquisition is slow. Knowledge variance within communities increases in association with ecological knowledge decline and a scale of progressive knowledge loss was revealed with the most rapid rates of loss in industrialized regions. Various studies have described the mutually exclusive relationship between economic growth and environmental conservation; however this is the first to consider the association between economic growth and social capacity to manage the environment. Understanding ecological knowledge loss is importantto understanding the declining capacities of communities undergoing economic development to manage their natural resources and the future of ecosystem diversity in the light of current patterns of economic growth.


Genotyping of Brucella species using clade specific SNPs.
Brucellosis is a worldwide disease of mammals caused by Alphaproteobacteria in the genus Brucella. The genus is genetically monomorphic, requiring extensive genotyping to differentiate isolates. We utilized two different genotyping strategies to characterize isolates. First, we developed a microarray-based assay based on 1000 single nucleotide polymorphisms (SNPs) that were identified from whole genome comparisons of two B. abortus isolates , one B. melitensis, and one B. suis. We then genotyped a diverse collection of 85 Brucella strains at these SNP loci and generated a phylogenetic tree of relationships. Second, we developed a selective primer-extension assay system using capillary electrophoresis that targeted 17 high value SNPs across 8 major branches of the phylogeny and determined their genotypes in a large collection ( n = 340) of diverse isolates. Our 1000 SNP microarray readily distinguished B. abortus, B. melitensis, and B. suis, differentiating B. melitensis and B. suis into two clades each. Brucella abortus was divided into four major clades. Our capillary-based SNP genotyping confirmed all major branches from the microarray assay and assigned all samples to defined lineages. Isolates from these lineages and closely related isolates, among the most commonly encountered lineages worldwide, can now be quickly and easily identified and genetically characterized. We have identified clade-specific SNPs in Brucella that can be used for rapid assignment into major groups below the species level in the three main Brucella species. Our assays represent SNP genotyping approaches that can reliably determine the evolutionary relationships of bacterial isolates without the need for whole genome sequencing of all isolates.


Sulforaphane potentiates the efficacy of 17-allylamino 17-demethoxygeldanamycin against pancreatic cancer through enhanced abrogation of Hsp90 chaperone function.
Heat shock protein 90 (Hsp90), an essential molecular chaperone that regulates the stability of a wide range of oncogenic proteins, is a promising target for cancer therapeutics. We investigated the combination efficacy and potential mechanisms of sulforaphane, a dietary component from broccoli and broccoli sprouts, and 17-allylamino 17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, in pancreatic cancer. MTS assay demonstrated that sulforaphane sensitized pancreatic cancer cells to 17-AAG in vitro. Caspase-3 was activated to 6.4-fold in response to simultaneous treatment with sulforaphane and 17-AAG, whereas 17-AAG alone induced caspase-3 activity to 2-fold compared to control. ATP binding assay and coimmunoprecipitation revealed that sulforaphane disrupted Hsp90-p50(Cdc37) interaction, whereas 17-AAG inhibited ATP binding to Hsp90. Concomitant use of sulforaphane and 17-AAG synergistically downregulated Hsp90 client proteins in Mia Paca-2 cells. Co-administration of sulforaphane and 17-AAG in pancreatic cancer xenograft model led to more than 70% inhibition of the tumor growth, whereas 17-AAG alone only suppressed the tumor growth by 50%. Our data suggest that sulforaphane potentiates the efficacy of 17-AAG against pancreatic cancer through enhanced abrogation of Hsp90 function. These findings provide a rationale for further evaluation of broccoli/broccoli sprout preparations combined with 17-AAG for better efficacy and lower dose-limiting toxicity in pancreatic cancer.


Like parent, like child: intergenerational transmission of partner violence in Cebu, the Philippines.
This study investigates the prevalence of partner violence perpetration and receipt among a sample of young men and women in the Philippines, as well as the relationship between witnessing interparental violence during childhood and current violence in partnerships. We used 1994, 2002, and 2005 data from 472 married or cohabiting young adults from the Cebu Longitudinal Health and Nutrition Survey in Cebu, the Philippines. This is a longitudinal data set following more than 2000 Filipino women and their index children since the child's birth in 1983-1984. Prevalence of partner violence perpetration was 55.8% for female and 25.1% for male respondents. Prevalence of victimization was 27.7% for females and 30.5% for males. In all, 45% of females and 50% of males reported having witnessed their parents/caretakers physically hurt one another during childhood. Multinomial logistic regression analysis showed that witnessing interparental violence significantly predicted report of violent act victimization and reciprocal violent acts. Greater parental joint decision making and being male were independently associated with a lower risk of report of both reciprocal violent acts and violent act victimization. Duration of marriage or cohabitation was associated with report of violent act victimization and reciprocal violent acts. There were gender interaction effects for several factors, including mother's church attendance and household purchase of alcohol at age 11 years. Implications for further research and violence prevention programs include early intervention with adolescents and focus on gender differences in violence determinants.


Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes.
International standardization and coordination of the nomenclature of variants of hepatitis C virus (HCV) is increasingly needed as more is discovered about the scale of HCV-related liver disease and important biological and antigenic differences that exist between variants. A group of scientists expert in the field of HCV genetic variability, and those involved in development of HCV sequence databases, the Hepatitis Virus Database (Japan), euHCVdb (France), and Los Alamos (United States), met to re-examine the status of HCV genotype nomenclature, resolve conflicting genotype or subtype names among described variants of HCV, and draw up revised criteria for the assignment of new genotypes as they are discovered in the future. A comprehensive listing of all currently classified variants of HCV incorporates a number of agreed genotype and subtype name re-assignments to create consistency in nomenclature. The paper also contains consensus proposals for the classification of new variants into genotypes and subtypes, which recognizes and incorporates new knowledge of HCV genetic diversity and epidemiology. A proposal was made that HCV variants be classified into 6 genotypes (representing the 6 genetic groups defined by phylogenetic analysis). Subtype name assignment will be either confirmed or provisional, depending on the availability of complete or partial nucleotide sequence data, or remain unassigned where fewer than 3 examples of a new subtype have been described. In conclusion, these proposals provide the framework by which the HCV databases store and provide access to data on HCV, which will internationally coordinate the assignment of new genotypes and subtypes in the future.


Sexual and asexual oogenesis require the expression of unique and shared sets of genes in the insect Acyrthosiphon pisum.
Although sexual reproduction is dominant within eukaryotes, asexual reproduction is widespread and has evolved independently as a derived trait in almost all major taxa. How asexuality evolved in sexual organisms is unclear. Aphids, such as Acyrthosiphon pisum, alternate between asexual and sexual reproductive means, as the production of parthenogenetic viviparous females or sexual oviparous females and males varies in response to seasonal photoperiodism. Consequently, sexual and asexual development in aphids can be analyzed simultaneously in genetically identical individuals. We compared the transcriptomes of aphid embryos in the stages of development during which the trajectory of oogenesis is determined for producing sexual or asexual gametes. This study design aimed at identifying genes involved in the onset of the divergent mechanisms that result in the sexual or asexual phenotype. We detected 33 genes that were differentially transcribed in sexual and asexual embryos. Functional annotation by gene ontology (GO) showed a biological signature of oogenesis, cell cycle regulation, epigenetic regulation and RNA maturation. In situ hybridizations demonstrated that 16 of the differentially-transcribed genes were specifically expressed in germ cells and/or oocytes of asexual and/or sexual ovaries, and therefore may contribute to aphid oogenesis. We categorized these 16 genes by their transcription patterns in the two types of ovaries; they were: i) expressed during sexual and asexual oogenesis; ii) expressed during sexual and asexual oogenesis but with different localizations; or iii) expressed only during sexual or asexual oogenesis. Our results show that asexual and sexual oogenesis in aphids share common genetic programs but diverge by adapting specificities in their respective gene expression profiles in germ cells and oocytes.


Role of oxidative stress & antioxidant defence in ulcerative colitis patients from north India.
Oxidative stress contributes to severity of ulcerative colitis (UC) but the status of erythrocyte antioxidant defence remains unknown. The present study was aimed to study the role of oxidative stress and antioxidant levels in erythrocytes of UC patients from north India. A total of 81 adult UC patients and 85 age and sex matched apparently healthy controls were included in this study. Levels of lipid peroxidation (LPO), reduced glutathione (GSH), catalase and superoxide dismutase (SOD) were measured in erythrocytes. Mean age of UC patients was 43.5 yr (range 18-64 yr) while in the control group this was 45.3 yr (range 20-64 yr). LPO, catalase and SOD levels in UC patients were significantly increased (P< 0.05) compared to healthy controls, while GSH levels in UC patients were significantly decreased (P< 0.05) compared to healthy controls Ulcerative colitis activity score (UCAI) was 157.4±27.6 in UC patients. Increased levels of LPO, SOD, catalase and a decreased level of GSH represent that oxidative stress plays a significant role in pathophysiology of UC. Further, the levels of LPO, GSH, catalase and SOD remained same during different UCAI.


Estimation of Pregnant Women Possibly Left Behind in Tsunami Predicted Areas of Nagoya City: A Simulation for Rescue Planning.
In case of an outbreak of Nankai Trough Mega-earthquake, it is predicted that a tsunami would invade Nagoya City within 100 minutes, hitting about one third of the City of Nagoya. If the administrative plan of the city and midwives' expertise are coordinated, pregnant women's chances of survival will increase. The authors carried out this simulation study in an attempt to improve consistency of the two efforts. We estimated the number of pregnant women using a machine learning model. The evacuation distance of pregnant women was estimated on the basis of the data of road center line. Through this simulation study, it became clear that preparation for approximately 2600 pregnant women escaping from tsunami predicted area and for about 1200 pregnant women possibly left in the area is needed. Our study suggests that triage point planning is needed in areas where pregnant women are evacuated. The triage makes it possible to transport women to appropriate hospitals.


Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2.
Enhancer of zeste homologue 2 (EZH2), a histone methyltransferase, plays a key role in transcriptional repression through chromatin remodeling. Our objectives were to determine the expression pattern of EZH2 and to assess the anticancer effect of EZH2 depletion in pancreatic cancer cells. Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the expression pattern of EZH2 in normal pancreas and human pancreatic tumors. We used RNA interference, Western blotting, reverse transcription-PCR, and chromatin immunoprecipitation to study the effect of EZH2 depletion on pancreatic cancer cell proliferation and survival. We detected nuclear overexpression of EZH2 in pancreatic cancer cell lines and in 71 of 104 (68%) cases of human pancreatic adenocarcinomas. EZH2 nuclear accumulation was more frequent in poorly differentiated pancreatic adenocarcinomas (31 of 34 cases; P<0.001). We found that genetic depletion of EZH2 results in reexpression of p27(Kip1) and decreased pancreatic cancer cell proliferation. Moreover, we showed that EZH2 depletion sensitized pancreatic cancer cells to doxorubicin and gemcitabine, which leads to a significant induction of apoptosis, suggesting that the combination of EZH2 inhibitors and standard chemotherapy could be a superior potential treatment for pancreatic cancer. Our results show nuclear accumulation of EZH2 as a hallmark of poorly differentiated pancreatic adenocarcinoma; identify the tumor suppressor p27(Kip1) as a new target gene of EZH2; show that EZH2 nuclear overexpression contributes to pancreatic cancer cell proliferation; and suggest EZH2 as a potential therapeutic target for the treatment of pancreatic cancer.


Liar, a novel Lyn-binding nuclear/cytoplasmic shuttling protein that influences erythropoietin-induced differentiation.
Erythropoiesis is primarily controlled by erythropoietin (Epo), which stimulates proliferation, differentiation, and survival of erythroid precursors. We have previously shown that the tyrosine kinase Lyn is critical for transducing differentiation signals emanating from the activated Epo receptor. A yeast 2-hybrid screen for downstream effectors of Lyn identified a novel protein, Liar (Lyn-interacting ankyrin repeat), which forms a multiprotein complex with Lyn and HS1 in erythroid cells. Interestingly, 3 of the ankyrin repeats of Liar define a novel SH3 binding region for Lyn and HS1. Liar also contains functional nuclear localization and nuclear export sequences and shuttles rapidly between the nucleus and cytoplasm. Ectopic expression of Liar inhibited the differentiation of normal erythroid progenitors, as well as immortalized erythroid cells. Significantly, Liar affected Epo-activated signaling molecules including Erk2, STAT5, Akt, and Lyn. These results show that Liar is a novel Lyn-interacting molecule that plays an important role in regulating intracellular signaling events associated with erythroid terminal differentiation.


Informing hot flash treatment decisions for breast cancer survivors: a systematic review of randomized trials comparing active interventions.
Patient-centered decision making about hot flash treatments often incorporates a balance of efficacy and side effects in addition to patient preference. This systematic review examines randomized controlled trials (RCTs) comparing at least two non-hormonal hot flash treatments in breast cancer survivors. In July 2015, PubMed, SCOPUS, CINAHL, Cochrane, and Web of Science databases were searched for RCTs comparing active, non-hormonal hot flash treatments in female breast cancer survivors. Thirteen trials were included after identifying 906 potential studies. Four trials were dose comparison studies of pharmacologic treatments citalopram, venlafaxine, gabapentin, and paroxetine. Hot flash reduction did not differ by tamoxifen or aromatase inhibitor use. Citalopram 10, 20, and 30 mg daily had comparable outcomes. Venlafaxine 75 mg daily improved hot flashes without additional side effects from higher dosing. Gabapentin 900 mg daily improved hot flashes more than 300 mg. Paroxetine 10 mg daily had fewer side effects than 20 mg. Among four trials comparing different pharmacologic treatments, venlafaxine alleviated hot flash symptoms faster than clonidine; participants preferred venlafaxine over gabapentin. Five trials compared pharmacologic to non-pharmacologic treatments. Acupuncture had similar efficacy to venlafaxine and gabapentin but may have longer durability after completing treatment and fewer side effects. We could not perform a pooled meta-analysis because outcomes were not reported in comparable formats. Clinical trial data on non-hormonal hot flash treatments provide comparisons of hot flash efficacy and other patient important outcomes to guide clinical management. Clinicians can use the information to help patients select hot flash interventions.


The reliability of routine anthropometric data collected by health workers: a cross-sectional study.
Reliable data on child growth is a prerequisite for monitoring and improving child health. Despite the extensive resources invested in recording anthropometry, there has been little research into the reliability of these data. If these measurements are unreliable growth may be misreported, and health problems may go undetected. To assess the reliability of routine infant growth data, following anthropometric training of health workers responsible for collecting these data, in Bradford, UK. To determine whether being observed by an external administrator influenced reliability. A test-retest design was used. All health workers (n=192) responsible for growth monitoring in Bradford were included in the study, of which 36.5% (n=70) had complete data. Following training in basic anthropometry all health workers were asked to complete a test-retest study, using infants aged 0-2 years. Health workers took two recordings of weight, length, head circumference, and abdominal circumferences on five infants. A peer health worker recorded a third set of measurements on each infant. Twenty-two individuals were selected to be observed by an external administrator during data collection. Technical error of measurements (TEMs) were produced to assess intra-observer and inter-observer reliability. Differences between groups were tested to determine whether external observation influences reliability. None of the TEMs were excessively large, and coefficients of reliability ranged from 0.96 to 1.00. All intra-observer and inter-observer TEMs for the observed group were larger than those for the non-observed group. For example, the observed group's intra-observer TEMs for weight, length, abdominal circumference, and head circumference (46.18 g, 0.60 cm, 0.65 cm, 0.47 cm) were larger than the non-observed group's TEMS (9.14 g, 0.35 cm, 0.34 cm, 0.19 cm). TEMs for weight, abdominal circumference, and head circumference were significantly larger for the observed group, compared to the non-observed group (p<0.001). Inter-observer TEMs for length were also significantly larger for the observed group (p=0.031), whilst intra-observer TEMs for length were not significantly different between the two groups (p=0.137). Following training in anthropometry health workers in Bradford can, in general, reliably measure child growth. TEMs were comparable to data from other research studies and all coefficients of reliability were indicative of good quality control. Reliability measurement provides a method of quality assurance for routine data monitoring. If commissioners of health services are to be informed by these data then some form of reliability assessment should be considered, and if employed external observation is recommended to improve validity.


Development of a small implantable right ventricular assist device.
The purpose of this program is to design, develop, and clinically evaluate a new, implantable right ventricular assist device (RVAD) that can be used as a component of an implantable biventricular assist device for patients with severe biventricular heart failure. The initial phase of this program resulted in a prototype RVAD, named DexAide, a modified version of the CorAide left ventricular assist device. In vitro testing was performed in a stand-alone circuit and in a true RVAD mode to evaluate pump performance. Pump flow and power were measured under various afterload and pump speed conditions. The pump performance requirements of 2 to 6 l/min and a pressure rise of 20 to 60 mm Hg were successfully met with pump speeds between 1,800 and 3,200 rpm. The nominal design point of 4 l/min and 40 mm Hg pressure rise was achieved at 2,450 +/- 70 rpm with a power consumption of 3.0 +/- 0.2 W. The initial in vitro testing met the design criteria for the new DexAide RVAD. Initial in vivo testing is under way, which will be followed by preclinical readiness testing and a pilot clinical trial in this 5-year program.


Bioinspired Titanium Drug Eluting Platforms Based on a Poly-β-cyclodextrin-Chitosan Layer-by-Layer Self-Assembly Targeting Infections.
In the field of implantable titanium-based biomaterials, infections and inflammations are the most common forms of postoperative complications. The controlled local delivery of therapeutics from implants through polyelectrolyte multilayers (PEMs) has recently emerged as a versatile technique that has shown great promise in the transformation of a classical medical implant into a drug delivery system. Herein, we report the design and the elaboration of new biodegradable multidrug-eluting titanium platforms based on a polyelectrolyte multilayer bioactive coating that target infections. These systems were built up in mild conditions according to the layer-by-layer (L-b-L) assembly and incorporate two biocompatible polysaccharides held together through electrostatic interactions. A synthetic, negatively charged β-cyclodextrin-based polymer (PCD), well-known for forming stable and reversible complexes with hydrophobic therapeutic agents, was exploited as a multidrug reservoir, and chitosan (CHT), a naturally occurring, positively charged polyelectrolyte, was used as a barrier for controlling the drug delivery rate. These polyelectrolyte multilayer films were strongly attached to the titanium surface through a bioinspired polydopamine (PDA) film acting as an adhesive first layer and promoting the robust anchorage of PEMs onto the biomaterials. Prior to the multilayer film deposition, the interactions between both oppositely charged polyelectrolytes, as well the multilayer growth, were monitored by employing surface plasmon resonance (SPR). Several PEMs integrating 5, 10, and 15 bilayers were engineered using the dip coating strategy, and the polyelectrolyte surface densities were estimated by colorimetric titrations and gravimetric analyses. The morphologies of these multilayer systems, as well as their naturally occurring degradation in a physiological medium, were investigated by scanning electron microscopy (SEM), and their thicknesses were measured by means of profilometry and ellipsometry studies. Finally, the ability of the coated titanium multilayer devices to act as a drug-eluting system and to treat infections was validated with gentamicin, a relevant water-soluble antibiotic commonly used in medicine due to its broad bactericidal spectrum.


Ultrasmall TPGS-PLGA Hybrid Nanoparticles for Site-Specific Delivery of Antibiotics into Pseudomonas aeruginosa Biofilms in Lungs.
Inhaled antibiotic treatment of cystic fibrosis-related bacterial biofilm infections is challenging because of the pathological environment of the lungs. Here, we present an "environment-adaptive" nanoparticle composed of a solid poly lactic-co-glycolic acid (PLGA) core and a mucus-inert, enzymatically cleavable shell of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) for the site-specific delivery of antibiotics to bacterial biofilms via aerosol administration. The hybrid nanoparticles with ultrasmall size were self-assembled via a nanoprecipitation process by using a facile microfluidic method. The interactions of the nanoparticles with the biological barriers were comprehensively investigated by using cutting-edge techniques (e.g., quartz crystal microbalance with dissipation monitoring, total internal reflection fluorescence microscopy-based particle tracking, in vitro biofilm model cultured in a flow-chamber system, and quantitative imaging analysis). Our results suggest that the mucus-inert, enzymatically cleavable TPGS shell enables the nanoparticles to penetrate through the mucus, accumulate in the deeper layer of the biofilms, and serve as sustained release depot, thereby improving the killing efficacy of azithromycin (a macrolide antibiotic) against biofilm-forming Pseudomonas aeruginosa. In conclusion, the ultrasmall TPGS-PLGA hybrid nanoparticles represent an efficient delivery system to overcome the multiple barriers and release antibiotics in a sustained manner in the vicinity of the biofilm-forming bacteria.


Prevalence and antimicrobial resistance of Bacillus cereus isolated from beef products in Egypt.
Foodborne pathogens have the main concern in public health and food safety. Bacillus cereus food poisoning is one of the most important foodborne pathogens worldwide. In the present study, a total of 200 random beef product samples were collected from different supermarkets located at Menofia and Cairo governorates were examined for the presence of B. cereus. In addition, the presence of some virulence encoding genes was evaluated using Multiplex PCR. Finally, the antibiogram testing was conveyed to illustrate the resistance pattern of the confirmed B. cereus. The data showed that B. cereus was recovered from 22.5%, 30%, 25%, 37.5% and 15% of the minced meat, burger, sausage, kofta, and luncheon respectively. Among the 20 examined isolates 18/20 (90%) were harbor hblC enterotoxin encoding gene compared with 20/20 (100) were have cytK enterotoxin encoding gene. The isolated strains of B. cereus were resistant to penicillin G and sensitive to oxacillin, clindamycin, vancomycin, erythromycin, gentamicin, ciprofloxacin, and ceftriaxone. In all, the obtained data showed the importance of emerging B. cereus in disease control and prevention programs, and in regular clinical and food quality control laboratories in Egypt.


Short-term dynamics of diversity patterns: evidence of continual reassembly within lacustrine small eukaryotes.
The short-term variation in the community structure of freshwater small eukaryotes (0.2-5 μm) was investigated in a mesotrophic lake every 2-3 days over one summer by coupling three molecular methods: 454 amplicon pyrosequencing, qPCR and TSA-FISH. The pyrosequencing approach unveiled a much more extensive small-eukaryotic diversity (991 OTUs) than has been described previously. The vast majority of the diversity described was represented by rare OTUs (≤ 0.01% of reads) belonging primarily to Cryptomycota, Dikarya and photosynthetic organisms, which were never detected as abundant in any of the samples. The small eukaryote community was characterized by a continual and important reassembly. These rearrangements involved the 20 'core taxa' (≥ 1% of reads), and, were essentially due to a handful of OTUs that were detected in intermediate abundance (0.01-1% of reads) and sporadically in dominant taxa. Putative bacterivorous (Ciliophora and Cercozoa) as well as parasitic and saprotrophic taxa (Perkinsozoa and Cryptomycota) were involved in these changes of diversity. A putative infection of microalgae by a lacustrine perkinsozoan was also reported for the first time in this study. Open questions regarding both the patterns that govern the rapid small eukaryote reassemblies and the possible biogeography of these organisms arise from this study.


ZEB1-AS1 is associated with poor prognosis in non-small-cell lung cancer and influences cell migration and apoptosis by repressing ID1.
Long non-coding RNAs (lncRNAs) have been reported to play a vital role in non-small-cell lung cancer (NSCLC). ZEB1-AS1 overexpression predicts a poor prognosis in osteosarcoma and colorectal cancers. In the current study, we determined the clinical significance and prognostic value of ZEB1-AS1 in patients with NSCLC. The expression of ZEB1-AS1 and inhibitor of differentiation-1 (ID1) was measured using qRT-PCR and Western blot. Cell growth, migration, and invasion were determined using colony formation assays, Transwell assay, and flow cytometry, respectively. Tumor growth was determined with a xenograft model. ZEB1-AS1 was significantly up-regulated in NSCLC tissues compared with normal samples. ZEB1-AS1 overexpression was significantly associated with advanced tumor, lymph node, and metastases (TNM) stage and tumor size, as well as poorer overall survival. Moreover, ZEB1-AS1 knockdown inhibited NSCLC cell proliferation and migration, and promoted cell apoptosis. In addition, a chromatin immunoprecipitation assay revealed that ZEB1-AS1 interacted with STAT3, thereby repressing ID1 expression. Furthermore, rescue experiments indicated that ZEB1-AS1 functioned as an oncogene partly by repressing ID1 in NSCLC cells. Taken together, our findings indicate that ZEB1-AS1 serves as a promising therapeutic target to predict the prognosis of NSCLC.


Association of Neighborhood Social Context and Perceived Stress Among Mothers of Young Children.
Chronic parental stress may negatively impact health among both parents and children. Adverse neighborhood social conditions like crime may increase stress while a supportive neighborhood may buffer stress and promote well-being. Our objective was to examine associations between neighborhood social factors and stress among mothers of young children. We surveyed 300 mothers/female caregivers of Medicaid-enrolled 2 to 4-year-old children in Philadelphia. Maternal stress was measured via the 10-item Perceived Stress Scale (range 0-40). Mothers' perceived neighborhood safety and collective efficacy were assessed using validated scales. Addresses were geocoded to link census tract-level violent crime rates. We used multivariable linear regression to examine associations of neighborhood safety, collective efficacy, and crime with maternal stress, adjusted for demographics, household socioeconomic status, and neighborhood poverty. Among mothers (mean age 31, 60% Black/African American), higher perceived neighborhood safety and collective efficacy were associated with lower stress scores after adjustment for covariates. Each 1-point increase (on a 5-point scale) in perceived neighborhood safety was associated with a 2.30-point decrease in maternal stress (95% CI: -3.07, -1.53). Similarly, each 1-point increase in perceived collective efficacy was associated with a 3.08-point decrease in maternal stress (95% CI: -4.13, -2.02). Police-recorded violent crime rates were not associated with maternal stress. Mothers of young children who perceive their neighborhood social environment more favorably report less stress compared to those who feel their neighborhood environment is less safe and cohesive. Future work is warranted to investigate whether interventions that increase perceived neighborhood safety and collective efficacy reduce stress.


Dynamic temporal requirement of Wnt1 in midbrain dopamine neuron development.
Wnt1-expressing progenitors generate midbrain dopamine (MbDA) and cerebellum (Cb) neurons in distinct temporal windows and from spatially discrete progenitor domains. It has been shown that Wnt1 and Lmx1a participate in a cross-regulatory loop that is utilized during MbDA neuron development. However, Wnt1 expression dynamically changes over time and precedes that of Lmx1a. The spatial and temporal requirements of Wnt1 in development and specifically its requirement for MbDA neurons remain to be determined. To address these issues, we generated a conditional Wnt1 allele and temporally deleted Wnt1 coupled with genetic lineage analysis. Using this approach, we show that patterning of the midbrain (Mb) and Cb by Wnt1 occurs between the one-somite and the six- to eight-somite stages and is solely dependent on Wnt1 function in the Mb, but not in the Cb. Interestingly, an En1-derived domain persists after the early deletion of Wnt1 and mutant cells express OTX2. However, the En1-derived Wnt1-mutant domain does not contain LMX1a-expressing progenitors, and MbDA neurons are depleted. Thus, we demonstrate an early requirement of Wnt1 for all MbDA neurons. Subsequently, we deleted Wnt1 in the ventral Mb and show a continued late requirement for Wnt1 in MbDA neuron development, but not in LMX1a-expressing progenitors. Specifically, Wnt1 deletion disrupts the birthdating of MbDA neurons and causes a depletion of MbDA neurons positioned medially and a concomitant expansion of MbDA neurons positioned laterally during embryogenesis. Collectively, our analyses resolve the spatial and temporal function of Wnt1 in Mb and Cb patterning and in MbDA neuron development in vivo.


Dietary total antioxidant capacity in relation to endometrial cancer risk: a case-control study in Italy.
To investigate the role of the overall antioxidant activity of diet, we estimated the relation between three dietary indices of total antioxidant capacity (TAC) and endometrial cancer risk We analyzed data from an Italian case-control study including 454 women with incident, histologically confirmed endometrial cancer, and 908 frequency-matched controls admitted to the same hospitals as cases for acute non-neoplastic conditions. A reproducible and valid food frequency questionnaire was used to assess subjects' habitual diet. TAC was measured using Italian food composition tables in terms of Ferric-reducing antioxidant power (FRAP), Trolox equivalent antioxidant capacity (TEAC), and total radical-trapping antioxidant parameter (TRAP). We computed odds ratios (OR) and corresponding 95 % confidence intervals (CIs) using conditional multiple logistic regression models, including terms for recognized endometrial cancer risk factors and total energy intake. TAC was inversely related to endometrial cancer risk with ORs for the highest versus the lowest quartile of 0.69 (95 % CI 0.47-1.00) for FRAP, 0.68 (95 % CI 0.46-0.99) for TEAC, and 0.68 (95 % CI 0.47-0.98) for TRAP. The relations appeared consistent in strata of selected risk factors and decreased when considering TAC without the contribution of coffee. Our findings suggest a favorable role of a diet high in TAC on endometrial cancer risk, which can be partially driven by coffee consumption.


Neural Mechanisms Underlying Time Perception and Reward Anticipation.
Findings suggest that the physiological mechanisms involved in the reward anticipation and time perception partially overlap. But the systematic investigation of a potential interaction between time and reward systems using neuroimaging is lacking. Eighteen healthy volunteers (all right-handed) participated in an event-related functional magnetic resonance imaging (fMRI) experiment that employs a visual paradigm that consists monetary reward to assess whether the functional neural representations of time perception and reward prospection are shared or distinct. Subjects performed a time perception task in which observers had to extrapolate the velocity of an occluded moving object in "reward" vs. "no-reward" sessions during fMRI scanning. There were also "control condition" trials in which participants judged about the color tone change of the stimuli. Time perception showed a fronto-parietal (more extensive in the right) cingulate and peristriate cortical as well as cerebellar activity. On the other hand, reward anticipation activated anterior insular cortex, nucleus accumbens, caudate nucleus, thalamus, cerebellum, postcentral gyrus, and peristriate cortex. Interaction between the time perception and the reward prospect showed dorsolateral, orbitofrontal, medial prefrontal and caudate nucleus activity. Our findings suggest that a prefrontal-striatal circuit might integrate reward and timing systems of the brain.


Cloning and characterization of tRNA (m1A58) methyltransferase (TrmI) from Thermus thermophilus HB27, a protein required for cell growth at extreme temperatures.
N1-methyladenosine (m1A) is found at position 58 in the T-loop of many tRNAs. In yeast, the formation of this modified nucleoside is catalyzed by the essential tRNA (m1A58) methyltransferase, a tetrameric enzyme that is composed of two types of subunits (Gcd14p and Gcd10p). In this report we describe the cloning, expression and characterization of a Gcd14p homolog from the hyperthermophilic bacterium Thermus thermophilus. The purified recombinant enzyme behaves as a homotetramer of 150 kDa by gel filtration and catalyzes the site- specific formation of m1A at position 58 of the T-loop of tRNA in the absence of any other complementary protein. S-adenosylmethionine is used as donor of the methyl group. Thus, we propose to name the bacterial enzyme TrmI and accordingly its structural gene trmI. These results provide a key evolutionary link between the functionally characterized two-component eukaryotic enzyme and the recently described crystal structure of an uncharacterized, putative homotetrameric methyltransferase Rv2118c from Mycobacterium tuberculosis. Interest ingly, inactivation of the T.thermophilus trmI gene results in a thermosensitive phenotype (growth defect at 80 degrees C), which suggests a role of the N1-methylation of tRNA adenosine-58 in adaptation of life to extreme temperatures.


Myostatin dysfunction impairs force generation in extensor digitorum longus muscle and increases exercise-induced protein efflux from extensor digitorum longus and soleus muscles.
Myostatin dysfunction promotes muscle hypertrophy, which can complicate assessment of muscle properties. We examined force generating capacity and creatine kinase (CK) efflux from skeletal muscles of young mice before they reach adult body and muscle size. Isolated soleus (SOL) and extensor digitorum longus (EDL) muscles of Berlin high (BEH) mice with dysfunctional myostatin, i.e., homozygous for inactivating myostatin mutation, and with a wild-type myostatin (BEH+/+) were studied. The muscles of BEH mice showed faster (P < 0.01) twitch and tetanus contraction times compared with BEH+/+ mice, but only EDL displayed lower (P < 0.05) specific force. SOL and EDL of age-matched but not younger BEH mice showed greater exercise-induced CK efflux compared with BEH+/+ mice. In summary, myostatin dysfunction leads to impairment in muscle force generating capacity in EDL and increases susceptibility of SOL and EDL to protein loss after exercise.


Patient factors associated with duration of certified sickness absence and transition to long-term incapacity.
Despite a considerable increase in claims for long-term sickness benefits, and the impact of certifying sickness upon general practitioner (GP) workload, little is known about transition to long-term incapacity for work. To explore the relationship between patient factors and the transition from short-term to long-term work incapacity, in particular focusing on mild mental health and musculoskeletal problems. Nine practices comprising the Mersey Primary Care R&D Consortium. Prospective data collection and audit of sickness certificate details. GPs issued carbonised sickness certificates for a period of 12 months. The resulting baseline dataset included claimant diagnosis, age, sex, postcode-derived deprivation score, and sickness episode duration. Associations of patient factors with sickness duration outcomes were tested. Mild mental disorder accounted for nearly 40% of certified sickness. Relatively few claimants had their diagnosis changed during a sickness episode. Risk factors for longer-term incapacity included increasing age, social deprivation, mild and severe mental disorder, neoplasm, and congenital illness. For mild mental disorder claimants, age, addiction, and deprivation were risk factors for relatively longer incapacity. For musculoskeletal problems, the development of chronic incapacity was significantly related to the nature of the problem. Back pain claimants were likely to return to work sooner than those with other musculoskeletal problems. In addition to the presenting diagnosis, a range of factors is associated with the development of chronic incapacity for work, including age and social deprivation. GPs should consider these when negotiating sickness certification with patients.


A monoclonal antibody that recognizes an antigenic determinant shared by HLA A2 and B17.
A hybridoma monoclonal anti-HLA antibody has been produced by the technique of Kohler and Milstein [1]. This antibody recognizes a new specificity common to HLA A2 and B17. It was shown to be a single antibody by isoelectric focusing and absorption experiments.


AUV SLAM and experiments using a mechanical scanning forward-looking sonar.
Navigation technology is one of the most important challenges in the applications of autonomous underwater vehicles (AUVs) which navigate in the complex undersea environment. The ability of localizing a robot and accurately mapping its surroundings simultaneously, namely the simultaneous localization and mapping (SLAM) problem, is a key prerequisite of truly autonomous robots. In this paper, a modified-FastSLAM algorithm is proposed and used in the navigation for our C-Ranger research platform, an open-frame AUV. A mechanical scanning imaging sonar is chosen as the active sensor for the AUV. The modified-FastSLAM implements the update relying on the on-board sensors of C-Ranger. On the other hand, the algorithm employs the data association which combines the single particle maximum likelihood method with modified negative evidence method, and uses the rank-based resampling to overcome the particle depletion problem. In order to verify the feasibility of the proposed methods, both simulation experiments and sea trials for C-Ranger are conducted. The experimental results show the modified-FastSLAM employed for the navigation of the C-Ranger AUV is much more effective and accurate compared with the traditional methods.


Characterization of dispersed heteropoly Acid on mesoporous zeolite using solid-state 31P NMR spin-lattice relaxation.
Dispersion and quantitative characterization of supported catalysts is a grand challenge in catalytic science. In this paper, heteropoly acid H(3)PW(12)O(40) (HPA) is dispersed on mesoporous zeolite silicalite-1 derived from hydrothermal synthesis using carbon black nanoparticle templates, and the catalytic activity is studied for 1-butene isomerization. The HPAs supported on conventional zeolite and on mesoporous zeolite exhibit very different activities and thus provide good model systems to investigate the structure dependence of the catalytic properties. The HPA on mesoporous silicalite-1 shows enhanced catalytic activity for 1-butene isomerization, while HPA on conventional silicalite-1 exhibits low activity. To elucidate the structural difference, supported HPA catalysts are characterized using a variety of techniques, including (31)P magic angle spinning nuclear magnetic resonance, and are shown to contain a range of species on both mesoporous and conventional zeolites. However, contrary to studies reported in the literature, conventional NMR techniques and chemical shifts alone do not provide sufficient information to distinguish the dispersed and aggregated surface species. The dispersed phase and the nondispersed phase can only be unambiguously and quantitatively characterized using spin-lattice relaxation NMR techniques. The HPA supported on mesoporous zeolite contains a fast relaxation component related to the dispersed catalyst, giving a much higher activity, while the HPA supported on conventional zeolite has essentially only the slow relaxation component with very low activity. The results obtained from this work demonstrate that the combination of spinning sideband fitting and spin-lattice relaxation techniques can provide detailed structural information on not only the Keggin structure for HPA but also the degree of dispersion on the support.


Reliability and validity of a nutrition and physical activity environmental self-assessment for child care.
Few assessment instruments have examined the nutrition and physical activity environments in child care, and none are self-administered. Given the emerging focus on child care settings as a target for intervention, a valid and reliable measure of the nutrition and physical activity environment is needed. To measure inter-rater reliability, 59 child care center directors and 109 staff completed the self-assessment concurrently, but independently. Three weeks later, a repeat self-assessment was completed by a sub-sample of 38 directors to assess test-retest reliability. To assess criterion validity, a researcher-administered environmental assessment was conducted at 69 centers and was compared to a self-assessment completed by the director. A weighted kappa test statistic and percent agreement were calculated to assess agreement for each question on the self-assessment. For inter-rater reliability, kappa statistics ranged from 0.20 to 1.00 across all questions. Test-retest reliability of the self-assessment yielded kappa statistics that ranged from 0.07 to 1.00. The inter-quartile kappa statistic ranges for inter-rater and test-retest reliability were 0.45 to 0.63 and 0.27 to 0.45, respectively. When percent agreement was calculated, questions ranged from 52.6% to 100% for inter-rater reliability and 34.3% to 100% for test-retest reliability. Kappa statistics for validity ranged from -0.01 to 0.79, with an inter-quartile range of 0.08 to 0.34. Percent agreement for validity ranged from 12.9% to 93.7%. This study provides estimates of criterion validity, inter-rater reliability and test-retest reliability for an environmental nutrition and physical activity self-assessment instrument for child care. Results indicate that the self-assessment is a stable and reasonably accurate instrument for use with child care interventions. We therefore recommend the Nutrition and Physical Activity Self-Assessment for Child Care (NAP SACC) instrument to researchers and practitioners interested in conducting healthy weight intervention in child care. However, a more robust, less subjective measure would be more appropriate for researchers seeking an outcome measure to assess intervention impact.


Different binding modes of two flaviolin substrate molecules in cytochrome P450 158A1 (CYP158A1) compared to CYP158A2.
Cytochrome P450 158A2 (CYP158A2) has been shown to catalyze an unusual oxidative C-C coupling reaction to polymerize flaviolin and form highly conjugated pigments (three isomers of biflaviolin and one triflaviolin) in Streptomyces coelicolor A3(2) which protect the soil bacterium from deleterious effects of UV irradiation (Zhao B. et al. (2005) J. Biol. Chem. 280, 11599-11607). The present studies demonstrate that the subfamily partner CYP158A1, sharing 61% amino acid identity with CYP158A2, can also catalyze the same flaviolin dimerization reactions, but it generates just two of the three isomers of biflaviolin that CYP158A2 produces. Furthermore, the two CYP158A1 products have very different molar ratios compared with the corresponding CYP158A2 products, indicating that each enzyme maintains its own stereo- and regiospecificity. To find an explanation for these differences, three CYP158A1 structures have been solved by X-ray crystallography and have been compared with those for CYP158A2. The structures reveal surprising differences. Particularly, only one flaviolin molecule is present close to the heme iron in CYP158A1, and the second flaviolin molecule binds at the entrance of the putative substrate access channel on the protein distal surface 9 A away. Our work describes two members of the same P450 subfamily, which produce the same products by oxidative C-C coupling yet show very different structural orientations of substrate molecules in the active site.


The Gut Microbiota Facilitates Drifts in the Genetic Diversity and Infectivity of Bacterial Viruses.
The intestinal microbiota and human health are intimately linked, but interactions between bacteria and bacteriophages in the context of the mammalian intestine remain largely unexplored. We used comparative population genomics to study a tripartite network consisting of a virulent bacteriophage, its bacterial host, and a phage-insensitive bacterial strain both in vitro and within the murine gut. The bacteriophage adapted to infect the insensitive strain when the three partners co-existed in the gut of conventional mice, but not in dixenic mice or in planktonic cultures. The molecular changes associated with modifications in the bacteriophage host spectrum included single amino acid substitutions and an unusual homologous intragenomic recombination event within the genome of the bacteriophage. An intermediate bacterial host isolated from the murine microbiota mediated bacteriophage adaptation. Our data indicate that by offering access to new hosts, the microbiota shifts the genetic diversity of bacteriophages, thereby promoting long-term persistence of bacteriophage populations.


Profiling of serum proteins influenced by warm partner contact in healthy couples.
Warm physical contact may positively influence our health and well-being; however, it has not been investigated yet whether serum proteins are influenced by warm physical contact in healthy couples. In this study, we focused on psychological and physiological effects of warm partner contact in healthy couples. When participants freely kissed and hugged their romantic partners, they were asked to subjectively evaluate their present emotions. Furthermore, changes of serum proteins were determined by using ProteinChip surface enhanced laser desorption/ionization-time-of-flight-mass spectrometry (SELDI-TOF-MS). We characterized these proteins by using biochemical techniques combined with gel filtration high performance liquid chromatography (HPLC), reverse-phase HPLC, and sequencing analyses. Romantic couples became happier and less irritated after kissing and hugging. Accompanying these psychological changes, SELDI-TOF-MS indicated that the intensities of 66-k Da, 11.7-k Da, and 5.9-k Da serum proteins were increased. These proteins were identified as serum albumin and beta2-microglobulin, and probably fibrinogen fragment. The feeling of happiness positively correlated and the feeling of irritation negatively correlated with intensities of serum albumin and beta2-microglobulin. These results suggest that psychological stress may be reduced and we may feel happiness when we kiss and hug a romantic partner. Furthermore, these results also suggest that warm partner contact influences peripheral circulating proteins, more importantly, may promote health and well-being.


Reference values for body composition and associations with blood pressure in Kenyan adults aged ≥50 years old.
To develop age- and sex-specific centile reference curves for fat-free mass (FFM) and fat mass (FM) adjusted for height in an adult Kenyan population and to investigate the association between FM, FFM and blood pressure (BP). Measures of body composition from bioimpedance analyses and BP were collected in 1995 participants aged ≥50 years in Nakuru County, Kenya. Reference curves were produced using the LMS method. Multivariable linear regression models were used to test the cross-sectional association between body composition indexes and BP. The age- and sex-specific reference curves for body composition (FMI and FFMI) confirmed that FFMI is lower in both men and women with increasing age. FMI declines with age in women while among men the decline starts after 70 years. FFM was higher in men (47.4 ± 7.2 kg) than in women (38.8 ± 5.5 kg), while FM was lower in men (17.3 ± 8.1 kg) than in women (24.4 ± 10.2 kg). FMI, FFMI and BMI were all positively associated with systolic and diastolic BP, and after adjusting for body weight, FFMI remained positively associated with systolic BP and the FMI remained positively associated with diastolic BP. There was no evidence to suggest that FMI and FFMI were superior to measurement of BMI alone. These body composition reference curves provide normative data on body composition for older adults in Kenya. Further research should consider the prospective associations with health, including frailty-related outcomes.


Brief quiet ego contemplation reduces oxidative stress and mind-wandering.
Excessive self-concern increases perceptions of threat and defensiveness. In contrast, fostering a more inclusive and expanded sense of self can reduce stress and improve well-being. We developed and tested a novel brief intervention designed to strengthen a student's compassionate self-identity, an identity that values balance and growth by reminding them of four quiet ego characteristics: detached awareness, inclusive identity, perspective taking, and growth. Students (N = 32) in their first semester of college who reported greater self-protective (e.g., defensive) goals in the first 2 weeks of the semester were invited to participate in the study. Volunteers were randomly assigned to one of three conditions: quiet ego contemplation (QEC), QEC with virtual reality (VR) headset (QEC-VR), and control. Participants came to the lab three times to engage in a 15-min exercise in a 30-days period. The 15-min QEC briefly described each quiet ego characteristic followed by a few minutes time to reflect on what that characteristic meant to them. Those in the QEC condition reported improved quiet ego characteristics and pluralistic thinking, decreases in a urinary marker of oxidative stress, and reduced mind-wandering on a cognitive task. Contrary to expectation, participants who wore the VR headsets while listening to the QEC demonstrated the least improvement. Results suggest that a brief intervention that reduces self-focus and strengthens a more compassionate self-view may offer an additional resource that individuals can use in their everyday lives.


Effect of postprandial insulinemia and insulin resistance on measurement of arterial stiffness (augmentation index).
Arterial stiffness, specifically augmentation index (AIx), is an independent predictor of cardiovascular risk. Previous studies suggest that insulin infusion decreases AIx and that this response is attenuated in insulin resistance. Whether physiological postprandial insulinemia similarly affects AIx measurements, and whether insulin resistance modifies this response, has not been studied. Seven relatively insulin-resistant and seven insulin-sensitive postmenopausal women received low-carbohydrate and high-carbohydrate high-fat meals on separate days. Glucose and insulin levels were measured for 360-min following meal consumption. AIx was measured by radial artery applanation tonometry at regular intervals postprandially. Postprandial increases in glucose and insulin were greater following the high-carbohydrate high-fat meal in both insulin-sensitive and insulin-resistant subjects. AIx decreased in both groups following both meals. In insulin-sensitive subjects, the postprandial reduction (incremental area above the curve) in AIx was greater following the high-carbohydrate vs. low-carbohydrate high-fat meal (-6821+/-1089 vs. -3797+/-1171% x min, respectively, P=0.009). In contrast, in insulin-resistant subjects, postprandial AIx responses were similar following the meals, suggesting that insulin resistance is associated with impaired postprandial arterial relaxation. This study demonstrates that the carbohydrate content of a meal, and, hence, the magnitude of the postprandial glucose and insulin responses it elicits, are important determinants of postprandial AIx measurements. The further observation that insulin resistance modified this effect raises the possibility that this phenomenon is a contributor to increased cardiovascular risk in insulin resistance. The results indicate that future studies of AIx need to control for the effects of these potentially confounding variables and that measurement of AIx should be standardized with respect to meals.


Use Your Noodle to Simulate Tourniquet Use on a Limb With and Without Bone.
The purpose of this study was to simulate first aid by mechanical use of a limb tourniquet on a thigh with and without bone to better understand best caregiving practices. Two investigators studied simulated first aid on a new pool "noodle," a plastic cylinder with a central air tunnel into which we inserted a wood dowel to simulate bone. Data were gathered by group (study and control, n = 12 each). The control group comprised data collected from simulated tourniquet use on the model with bone present. The study group comprised data from simulated tourniquet use on the model without bone. Comparing compression with and without bone, the mean volumes of compressed soft tissues alone were 303mL and 306mL, respectively. When bone was present, the volume of soft tissues was squeezed more, yielding a smaller size by 3mL (1%). The bone had a volume of 41mL and pressed statically outward with an equal force oppositely directed to the inward compression of the overlying soft tissues. With bone removed and compression applied, the mean residual void was 16mL, because 25mL (i.e., 41mL minus 16mL) of soft tissues had collapsed inward. The volume of the limb under the tourniquet with and without bone was 344mL and 322mL, respectively. The collapse volume, 25mL, was 3mL more than the difference of the mean volume of the limb under the tourniquet. More limb squeeze (22mL) looked like better compression, but it was actually worse-an illusion created by collapse of the hidden void. In simulated first aid, mechanical modeling demonstrated how tourniquet compression applied to a limb squeezed the soft tissues better when underlying bone was present. Bone loss altered the compression profile and may complicate control of bleeding in care. This knowledge, its depiction, and its demonstration may inform first-aid instructors.


Dexamethasone Therapy for Septic Arthritis in Children.
Prospective studies of children with septic arthritis report that adding dexamethasone to antibiotic therapy contributes significantly to clinical and laboratory improvement. This study sought to evaluate the effect of this regimen outside of a randomized controlled trial. The sample consisted of children with septic arthritis hospitalized at a tertiary pediatric medical center in 2008 to 2013. Disease course and outcome were compared between children treated with antibiotics alone or with adjuvant dexamethasone, according to the admitting department policy. The cohort included 116 patients, 90 treated with antibiotics alone and 26 treated with antibiotics+dexamethasone. The groups were similar for age, symptom duration before hospitalization, body temperature, acute-phase reactant levels, and rate of positive fluid cultures (21.6% total). Compared with monotherapy, antibiotics+dexamethasone treatment was associated with a shorter duration of fever (mean 2.3 vs 3.9 days, P = .002), more rapid clinical improvement (mean 6.3 vs 10.0 days to no pain/limitation, P < .001), more rapid decrease in C-reactive protein level to <1 mg/dL (mean 5.3 vs 8.4 days, P = .002), shorter duration of parenteral antibiotic treatment (mean 7.1 vs 11.4 days, P < .001), and shorter hospital stay (mean 8.0 vs 10.7 days, P = .004). Recurrent symptoms of fever and joint pain occurred in 4 patients in the antibiotics+dexamethasone group after completion of the steroid course. Children with septic arthritis treated early with a short course of adjuvant dexamethasone show earlier improvement in clinical and laboratory parameters than children treated with antibiotics alone.


Wildlife diseases: from individuals to ecosystems.
1. We review our ecological understanding of wildlife infectious diseases from the individual host to the ecosystem scale, highlighting where conceptual thinking lacks verification, discussing difficulties and challenges, and offering potential future research directions. 2. New molecular approaches hold potential to increase our understanding of parasite interactions within hosts. Also, advances in our knowledge of immune systems makes immunological parameters viable measures of parasite exposure, and useful tools for improving our understanding of causal mechanisms. 3. Studies of transmission dynamics have revealed the importance of heterogeneity in host behaviour and physiology, and of contact processes operating at different spatial and temporal scales. An important future challenge is to determine the key transmission mechanisms maintaining the persistence of different types of diseases in the wild. 4. Regulation of host populations is too complex to consider parasite effects in isolation from other factors. One solution is to seek a unified understanding of the conditions under which (and the ecological rules determining when) population scale impacts of parasites can occur. 5. Good evidence now shows that both direct effects of parasites, and trait mediated indirect effects, frequently mediate the success of invasive species and their impacts on recipient communities. A wider exploration of these effects is now needed. 6. At the ecosystem scale, research is needed to characterize the circumstances and conditions under which both fluxes in parasite biomass, and trait mediated effects, are significant in ecosystem processes, and to demonstrate that parasites do indeed increase 'ecosystem health'. 7. There is a general need for more empirical testing of predictions and subsequent development of theory in the classic research cycle. Experimental field studies, meta-analyses, the collection and analysis of long-term data sets, and data constrained modelling, will all be key to advancing our understanding. 8. Finally, we are only now beginning to understand the importance of cross-scale interactions associated with parasitism. Such interactions may offer key insights into bigger picture questions such as when and how different regulatory factors are important, when disease can cause species extinctions, and what characteristics are indicative of functionally resilient ecosystems.


The effect of assortative mating upon genetic association studies: spurious associations and population substructure in the absence of admixture.
Spurious associations due to confounding factors are an often cited and intensely debated concern for genetic association studies. Great attention has been focused upon the specific threat of confounding due to population stratification. This emphasis has spurred the development of many statistical genetic methods to detect and correct for the potentially confounding effects of admixture. Unfortunately, this emphasis on admixture has led some authors to suggest that if ethnically homogenous populations are used, spurious associations are unlikely to occur. We show that under small and realistic degrees of assortative mating over time, spurious associations arise even in ethnically homogeneous populations. We demonstrate that structured association and genomic control tests can, under certain conditions, correct for these spurious associations. We conclude that investigators should not assume spurious associations will not occur in association studies using ethnically homogenous populations and recommend the use of genomic control methods and/or family-based association tests within genetic association studies.


The soleus muscle: MRI, anatomic and histologic findings in cadavers with clinical correlation of strain injury distribution.
The purpose of this study was to describe the normal anatomy of the soleus muscle using magnetic resonance (MR) imaging, anatomic dissection and histologic correlation in cadavers. The second objective of this study was to analyse the morphometry of the soleus muscle in normal volunteers. The final objective was to undertake a retrospective review of soleal strain injuries confirmed with MR imaging, with correlation made between the cadaveric anatomic findings and the MR imaging features. Eleven fresh cadaveric legs were studied using a high resolution 3.0 T (T) MR imaging scanner to obtain images in the axial, coronal and sagittal planes. After imaging, six specimens were dissected and evaluated by histological analysis, with the remaining five specimens then frozen and cut into axial sections. The corresponding levels on the MR examination were then compared with the levels of anatomic sectioning. MR imaging was also used to examine the soleus muscle in both legs of 20 healthy volunteers. Finally, 55 clinical cases of soleus muscle strains diagnosed between October 2006 and January 2011 that had also previously undergone MR imaging were re-evaluated. The location of strain injury was reviewed and correlated with the anatomic information that had been revealed in the anatomic component of our study. Dissection of the soleus muscle revealed two proximal intramuscular aponeuroses (medial and lateral) that are formed as a direct continuation of the surrounding epimysium. From an anatomic, functional and pathologic perspective, these aponeuroses are considered in this study as intramuscular tendons, however they have been not previously described as such. These tendons penetrate deep into the muscle belly, from which the proximal muscle fibres of the soleus arise. Inferiorly, these muscle fibres insert onto a long distal central tendon that becomes confluent with the overlying distal tendon of gastrocnemius to form the Achilles tendon. Significant differences between the length of the central tendon on the right side (31.35 cm) and the left side (30.36 cm) were observed (p = .002), as well as the length of insertion of this tendon onto the Achilles tendon on the right side (7.19 cm) compared with the left (7.94 cm) (p = .02). The retrospective analysis identified five sites within the soleus where strains were distributed: musculotendinous junction sites (proximal medial strains accounting for 25.5% of all injuries, proximal lateral strains accounting for 12.7% and distal central tendon strains accounting for 18.2%) and myofascial sites (anterior strains accounting for 21.8% of all injuries and posterior strains accounting for 21.8%). Strains of the proximal medial musculotendinous junction were the most common of soleal muscle injuries, comprising 56.4% of all cases. Current information on the detailed anatomy of the soleus muscle in the anatomic and radiological literature is lacking. Knowledge of this anatomy accounts for the distribution of sports-induced injuries within the soleus muscle-tendon unit and therefore assists in the accurate identification of these injuries, with possible prognostic benefit.


The relative roles of density and climatic variation on population dynamics and fecundity rates in three contrasting ungulate species.
The relative influences of density-dependent and -independent processes on vital rates and population dynamics have been debated in ecology for over half a century, yet it is only recently that both processes have been shown to operate within the same population. However, generalizations on the role of each process across species are rare. Using a process-orientated generalized linear modelling approach we show that variations in fecundity rates in populations of three species of ungulates with contrasting life histories are associated with density and winter weather in a remarkably similar manner. However, there are differences and we speculate that they are a result of differences in size between the species. Much previous research exploring the association between vital rates, population dynamics and density-dependent and -independent processes has used pattern-orientated approaches to decompose time-series into contributions from density-dependent and -independent processes. Results from these analyses are sometimes used to infer associations between vital rates, density and climatic variables. We compare results from pattern-orientated analyses of time-series with process-orientated analyses and report that the two approaches give different results. The approach of analysing relationships between vital rates, density and climatic variables may detect important processes influencing population dynamics that time-series methodologies may overlook.


Combined Endovascular and Microsurgical Hybrid Management of Cerebral Aneurysms: The Preliminary Fujita Experience.
A subgroup of complex aneurysms demands multimodal treatment by microscopic and endovascular means. Partial obliteration or remnant postprocedure demands to go further to the other modality. All patients between July 2016 and January 2017 who had to undergo multimodality measures for complete obliteration of the aneurysms were included in the study. The patients who had either undergone clipping or coiling for their aneurysms, but with incomplete obliteration of the aneurysm, were also included in the study. Between July 2016 and January 2017, a total of three patients had to undergo coiling after clipping of the aneurysm for complete obliteration. Two patients had to go for clipping following coiling. All five patients had complete obliteration of the aneurysm sac. Both microscopic and endovascular means are complementary measures instead of competing procedures. It is important to realize the technical difficulties when surgical therapy follows initial endovascular treatment. Similarly, coiling a previously clipped aneurysm can be difficult, if the clip obscures normal working projections.


Robotic enucleation of benign pancreatic tumors.
Robot-assisted enucleation provides the dual benefits of a minimally-invasive technique and pancreatic parenchymal conservation to selected patients with functional pancreatic neuroendocrine tumors (F-pNETs) and serous cystadenomas. Insulinomas, the most common F-pNETs, are ideal candidates for enucleation when <2 cm given the 80% probability of being benign. Current evidence suggests enucleation for the following: benign, isolated lesions with a distance between tumor and main pancreatic duct ≥3 mm (no focal stricture or dilation), insulinomas, gastrinomas <2 cm, and nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) <1-2 cm and low Ki67 mitotic index. Minimally-invasive enucleation is an imaging-dependent procedure that requires recognizable anatomic landmarks for successful completion, including tumor proximity to the pancreatic duct as well as localization relative to major structures such as the gastroduodenal artery, bile duct, and portal vein. Tumor localization often mandates intraoperative ultrasound aided by duplex studies of intratumoral blood flow and frozen section confirmation. Five patients have undergone robot-assisted enucleation at Beth Israel Deaconess Medical Center between January 2014 and January 2017 with median tumor diameter of 1.3 cm (0.9-1.7 cm) located in the pancreatic head [2] and tail [3]. Surgical indications included insulinoma [2] and NF-pNETs [3]. Median operative time was 204 min (range, 137-347 min) and estimated blood loss of 50 mL. There were no conversions to open or transfusions. Robotic enucleation is a safe and feasible technique that allows parenchymal conservation in a minimally-invasive setting, reducing operative time and length of stay with equivalent pathological outcomes compared to open surgery.


Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers.
Resurgence to target L-type voltage-dependent calcium channels has been applied by the synthesis of two series of nifedipine analogues where the ortho- or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking study with a receptor model followed by molecular alignment has been performed on 47 compounds to predict the most active member. The IC50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution of groups at the 3- and 5-positions of the dihydropyridine (DHP) ring gave 3k, which is more active than nifedipine. Our valid three-dimensional quantitative structure-activity relationship (3D-QSAR) model prefigures the influence of lipophilicity, bulkiness and chelating effects of the C3 and C5 substituents. Bulky groups interfere with ring-to-ring hydrophobic interaction with tyrosine (Tyr)4311 and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3- and 5-positions of the DHP ring as an approach to increasing the activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring ensures strong binding to the receptor and hence stabilization of the closed-channel conformation. The validation of 3D-QSAR model indicated its proficiency in predicting activity of newly compounds belonging to the same chemical class.


Public health laboratory systems development in East Africa through training in laboratory management and field epidemiology.
Laboratories are integral to the delivery of quality health care and for public health functions; however laboratory systems and services are often neglected in resource-poor settings such as the East African region. In order to sustainably strengthen national laboratory systems in resource-poor countries, there is a need to train laboratory personnel to work in clinical as well as public health laboratories. In 2004,Kenya, Uganda, Tanzania, and South Sudan began training public health laboratory workers jointly with field epidemiologists in the Kenya Field Epidemiology and Laboratory Training Program (FELTP), and later through the Tanzania FELTP, as a strategy to strengthen public health laboratories. These programs train laboratory epidemiologists through a two-year public health leadership development course, and also offer various types of short course training for frontline staff. The FELTP laboratory graduates in Kenya, Tanzania, Uganda, and South Sudan are working in their respective countries to strengthen public health laboratory systems while the short course participants provide a pool of frontline implementers with the capacity to support the lower tiers of health systems, as well as serve as surge capacity for the regions and the national level. Through training competent public health laboratory workers, the East African ministries of health, in collaboration with other regional partners and stakeholders are now engaged in developing and implementing a holistic approach that will guarantee an overall strengthening of the health system by using well-trained public health laboratory leaders to drive the process. Strengthening public health laboratory medicine in East Africa is critical to improve health-care systems. The experience with the FELTP model in East Africa is a step in the right direction towards ensuring a stronger role for the laboratory in public health.


Regulation of microglia development and homeostasis.
Microglia represent the resident macrophages of the central nervous system (CNS) and account for 10% of the adult glial cell population in the normal brain. Although microglial cells are thought to contribute to most pathological conditions including CNS infections, neuroinflammatory lesions, brain tumors, and neurodegenerative diseases, their exact role in CNS development, homeostasis, and disease remains poorly understood. In contrast to most macrophage populations, microglia survive high-dose ionizing radiation and maintain themselves locally and independently of circulating precursors in the steady state. However, controversies remain on the origin of microglia in the brain and whether they could potentially be repopulated by circulating myeloid precursors after brain injury. Microglia-targeted therapies through the use of genetically modified circulating hematopoietic cells proved to be a promising therapeutic strategy for the treatment of brain diseases. It is thus of great importance to understand the contribution and developmental cues of circulating myeloid cells as potential microglia progenitors to the adult pool of microglia in the steady state and under inflammatory conditions.


Virtual chimera states for delayed-feedback systems.
Time-delayed systems are found to display remarkable temporal patterns the dynamics of which split into regular and chaotic components repeating at the interval of a delay. This novel long-term behavior for delay dynamics results from strongly asymmetric nonlinear delayed feedback driving a highly damped harmonic oscillator dynamics. In the corresponding virtual space-time representation, the behavior is found to develop as a chimeralike state, a new paradigmatic object from the network theory characterized by the coexistence of synchronous and incoherent oscillations. Numerous virtual chimera states are obtained and analyzed, through experiment, theory, and simulations.


Corticotropin-releasing factor acting on corticotropin-releasing factor receptor type 1 is critical for binge alcohol drinking in mice.
The corticotropin-releasing factor (CRF) system has been implicated in the regulation of alcohol consumption. However, previous mouse knockout (KO) studies using continuous ethanol access have failed to conclusively confirm this. Recent studies have shown that CRF receptor type 1 (CRFR1) antagonists attenuate alcohol intake in the limited access "drinking in the dark" (DID) model of binge drinking. To avoid the potential nonspecific effects of antagonists, in this study, we tested alcohol drinking in CRFR1, CRFR2, CRF, and urocortin 1 (Ucn1) KO and corresponding wild-type (WT) littermates using the DID paradigm. On days 1 to 3, the CRFR1, CRFR2, Ucn1, and CRF KO mice and their respective WT littermates were provided with 20% ethanol or 10% sucrose for 2 hours with water available at all other times. On day 4, access to ethanol or sucrose was increased to 4 hours. At the end of each drinking session, the volume of ethanol consumed was recorded, and at the conclusion of the last session, blood was also collected for blood ethanol concentration (BEC) analysis. CRFR1 KO mice had lower alcohol intakes and BECs and higher intakes of sucrose compared with WTs. In contrast, CRFR2 KO mice, while having reduced intakes initially, had similar alcohol intakes on days 2 to 4 and similar BECs as the WTs. To determine the ligand responsible, Ucn1 and CRF KO and WT mice were tested next. While Ucn1 KOs had similar alcohol intakes and BECs to their WTs, CRF KO mice showed reduced alcohol consumption and lower BECs compared with WTs. Our results confirm that CRFR1 plays a key role in binge drinking and identify CRF as the ligand critically involved in excessive alcohol consumption.


Altered monocyte expression and expansion of non-classical monocyte subset in IgA nephropathy patients.
The main defect of immunoglobulin A nephropathy (IgAN) lies within the immune system and in peripheral blood mononuclear cells rather than in the kidney. Previously, we found an altered gene expression in monocytes compared with B and T cells isolated from IgAN patients; thus, our aim here has been to study this subset at a genome-wide and functional level. A total of 39 IgAN patients and 37 healthy blood donors (HBDs) were included in this study, and microarray technology was used to evaluate global gene expression differences in monocytes isolated from IgAN patients and HBDs. Aberrantly expressed genes and pathways were then validated on an independent set of IgAN patients with RT-PCR western blot and flow cytometric analysis. Gene expression differences in monocytes from IgAN patients and HBDs primarily involved apoptosis signalling, mitochondrial dysfunction, tnfr2/1 and death receptor signalling. Both the extrinsic and intrinsic apoptotic pathways seem to be implicated; in particular, the protein levels of NDUFS3 and TNFRSF1A were upregulated thus confirming the altered mitochondrial and death receptor homeostasis. Furthermore, the basal intracellular protein levels of TNF in monocytes were lower in IgAN patients compared with HBDs. We validated at protein level an enhanced apoptotic phenotype and a different subset distribution in monocytes from IgAN patients. We found that the non-classical monocyte subset (CD14(+)CD16(+)) was significantly expanded in all IgAN patients tested even though the total monocyte count remained unchanged. Our findings demonstrate, for the first time, an aberrant modulation of the mitochondrial respiratory system in monocytes isolated from IgAN patients. Furthermore, the aberrant expansion of the (CD14(+)CD16(+)) subset could explain the enhanced apoptotic phenotype seen in these cells thus revealing their potential role in the pathogenesis of IgAN.


Do oestrogens induce chromosome specific aneuploidy in vitro, similar to the pattern of aneuploidy seen in breast cancer?
The study was concerned with investigating the specific effects of non-DNA reactive oestrogens at low "biologically relevant" doses and the causative role they may play in breast cancer through inducing aneuploidy. A review of previous studies identified a non-random pattern of aneuploidy seen in breast cancers. This information was used to select those chromosomes that undergo copy number changes in breast cancer and chromosomes that appear stable. A panel of centromeric specific probes were selected and centromeric specific fluorescence in situ hybridisation (FISH) was carried out on the human lymphoblastoid cell line, AHH-1, which had been pre-treated with the chemical aneugens 17-beta oestradiol, diethylstilbestrol (DES) and bisphenol-A (BP-A). The results suggest that oestrogens may play a causative role in breast cancer by inducing a specific pattern of aneuploidy similar to that seen in breast carcinomas. 17-beta oestradiol appears to induce changes most similar to those seen in breast tumours, BP-A induces the same pattern but at a lower frequency and DES appears to be less chromosome specific in its act.


Influenza Vaccination Rates Among Parents and Health Care Personnel in a German Neonatology Department.
The influenza vaccination is recommended for all German pregnant women and health care personnel (HCP). We are the first to publish vaccination rates of mothers of hospitalized newborns and HCP in neonatal units. Between September 2016 and March 2017, data were collected in our level-III neonatology department in this descriptive multidisciplinary study, using an anonymous questionnaire. As a result, 513 persons were asked to participate, including 330 parents and 183 HCP. We received an 80.3% (412/513) response rate, 87.3% (288/330), and 67.8% (124/183) from parents and HCP, respectively. Ten percent (16/160) of mothers and 4.7% (6/127) of fathers had been vaccinated in 2016-2017 and 54.4% (87/160) mothers and 52.2% (66/127) fathers ever in their lifetime. In 2016-2017, 51.2% (21/41) of physicians had been vaccinated, 25.5% (14/55) of nurses, and 50.0% (14/28) of other staff members. When comparing those who had more than five influenza vaccinations in their life time, physicians were at 43.9% (18/41) versus nurses at 10.9% (6/55) (p < 0.01), and other HCP at 7.4% (2/27) (p < 0.01). The influenza vaccine uptake rate of 10% in mothers of hospitalized neonates is disappointingly low, resulting in 90% of hospitalized neonates being potentially vulnerable to influenza infection at a time where the risk for influenza-related complication can be severe.


Prediction of Ordered Water Molecules in Protein Binding Sites from Molecular Dynamics Simulations: The Impact of Ligand Binding on Hydration Networks.
Water plays a major role in ligand binding and is attracting increasing attention in structure-based drug design. Water molecules can make large contributions to binding affinity by bridging protein-ligand interactions or by being displaced upon complex formation, but these phenomena are challenging to model at the molecular level. Herein, networks of ordered water molecules in protein binding sites were analyzed by clustering of molecular dynamics (MD) simulation trajectories. Locations of ordered waters (hydration sites) were first identified from simulations of high resolution crystal structures of 13 protein-ligand complexes. The MD-derived hydration sites reproduced 73% of the binding site water molecules observed in the crystal structures. If the simulations were repeated without the cocrystallized ligands, a majority (58%) of the crystal waters in the binding sites were still predicted. In addition, comparison of the hydration sites obtained from simulations carried out in the absence of ligands to those identified for the complexes revealed that the networks of ordered water molecules were preserved to a large extent, suggesting that the locations of waters in a protein-ligand interface are mainly dictated by the protein. Analysis of >1000 crystal structures showed that hydration sites bridged protein-ligand interactions in complexes with different ligands, and those with high MD-derived occupancies were more likely to correspond to experimentally observed ordered water molecules. The results demonstrate that ordered water molecules relevant for modeling of protein-ligand complexes can be identified from MD simulations. Our findings could contribute to development of improved methods for structure-based virtual screening and lead optimization.


The effects of Advanced Glycation End Products (RAGE)-374T/A and Gly82Ser variants and soluble-RAGE levels to obesity in children.
In recent years, studies related to advanced glycation end products (AGE) and their interaction with their receptors (RAGE) have advanced our knowledge of the roles of these molecules in different diseases. However, studies concerning AGE-RAGE interaction in obesity are limited and the results are conflicting. RAGE gene is located on 6p21.3, has several polymorphic sites including -374T/A, a functional polymorphism in the promoter region, and Gly82Ser, present within the ligand-binding domain. In the present study, the determination of possible risks in the development of obesity according to RAGE polymorhisms and plasma levels of RAGE (sRAGE) was aimed. 87 obese and 78 healthy children were included in this study. Genomic DNA was isolated with salting-out procedure. RAGE polymorphisms were analyzed by PCR based techniques. In contrast to Gly82Ser, -374T/A allelic and genotypic frequencies were not different between study groups. Ser(SerSer+GlySer genotype) allele frequency was higher in obese cases than controls (74.20%→25.80%,OR:2.573,95%CI:1.789-3.699;p<0.01). In obese cases, blood glycose (92.50±2.80→87.00±1.16; p=0.025) and HDL-C (46.14±2.75→39.84±1.82;p=0.057) levels were higher than TT genotype carriers. As for Gly82Ser polymorphism, HDL-C (p=0.004) and FT4 (p=0.020) levels were different in obese cases, the order was SerSer>GlySer>GlyGly for HDL-C, and opposite for FT4. Besides, Ser carriers had lower insulin (p=0.038) and homa-IR (p=0.081) levels than GG genotype. sRAGE levels were different between obese and control seperately or in combination with RAGE polymorphisms (p<0.05), the order of sRAGE was TT>TA>AA for -374T/A and SerSer>GlyGly>GlySer for Gly82Ser. According to our results SerSer genotype could have significant effects on sRAGE levels, and increased sRAGE levels and Gly82Ser polymorphism either combinatorially or seperately increased the propensity towards obesity.