Association of fluorescein angiographic features with visual acuity and with optical coherence tomographic and stereoscopic color fundus photographic features of diabetic macular edema in a randomized clinical trial.
Fluorescein angiography (FA) has been performed as part of the management of diabetic macular edema for many years. Its current role relative to the role of optical coherence tomography (OCT) is not well defined. To evaluate the associations of FA features with visual acuity (VA) and with OCT and fundus photographic characteristics in eyes with diabetic macular edema. In a clinical trial, conducted by the Diabetic Retinopathy Clinical Research Network to compare two methods of laser photocoagulation to treat diabetic macular edema, FA (film and digital), color photographs, OCT, and VA measurements were obtained at baseline and at 1 year. Grading of morphologic features was performed at a reading center. Reproducibility of FAs was assessed, and the correlations of FA features with VA, OCT, and color photograph features were computed. From 79 clinical sites, data of 323 study eyes and 203 fellow nonstudy eyes were analyzed. Fluorescein leakage area at baseline was associated with reduced VA, increased OCT measures of retinal thickness and volume, and color photographic measurements of retinal thickening (r = 0.33-0.58). No important associations were found with changes from baseline to 12 months in these parameters or with any of the other variables analyzed. Fluorescein leakage is associated with VA and some OCT and color photographic variables. We did not identify any unique FA variables that had a stronger association with VA than OCT measures of retinal thickness. These data may be useful to investigators planning future diabetic macular edema clinical trials.


Heritability and genetic correlations of heart rate variability at rest and during stress in the Oman Family Study.
Individual differences in heart rate variability (HRV) can be partly attributed to genetic factors that may be more pronounced during stress. Using data from the Oman Family Study (OFS), we aimed to estimate and quantify the relative contribution of genes and environment to the variance of HRV at rest and during stress; calculate the overlap in genetic and environmental influences on HRV at rest and under stress using bivariate analyses of HRV parameters and heart rate (HR). Time and frequency domain HRV variables and average HR were measured from beat-to-beat HR obtained from electrocardiogram recordings at rest and during two stress tests [mental: Word Conflict Test (WCT) and physical: Cold Pressor Test (CPT)] in the OFS - a multigenerational pedigree consisting of five large Arab families with a total of 1326 participants. SOLAR software was used to perform quantitative genetic modelling. Heritability estimates for HRV and HR ranged from 0.11 to 0.31 for rest, 0.09-0.43 for WCT, and 0.07-0.36 for CPT. A large part of the genetic influences during rest and stress conditions were shared with genetic correlations ranging between 0.52 and 0.86 for rest-WCT and 0.60-0.92 for rest-CPT. Nonetheless, genetic rest-stress correlations for most traits were significantly smaller than 1 indicating some stress-specific genetic effects. Genetic factors significantly influence HRV and HR at rest and under stress. Most of the genetic factors that influence HRV at rest also influence HRV during stress tests, although some unique genetic variance emerges during these challenging conditions.


Label-Free Electrochemical Immunoassay for C-Reactive Protein.
C-reactive protein (CRP) is one of the most expressed proteins in blood during acute phase inflammation, and its minute level increase has also been recognized for the clinical diagnosis of cardio vascular diseases. Unfortunately, the available commercial immunoassays are labour intensive, require large sample volumes, and have practical limitations, such as low stability and high production costs. Hence, we have developed a simple, cost effective, and label-free electrochemical immunoassay for the measurement of CRP in a drop of serum sample using an immunosensor strip made up of a screen printed carbon electrode (SPE) modified with anti-CRP functionalized gold nanoparticles (AuNPs). The measurement relies on the decrease of the oxidation current of the redox indicator Fe3+/Fe2+, resulting from the immunoreaction between CRP and anti-CRP. Under optimal conditions, the present immunoassay measures CRP in a linear range from 0.4-200 nM (0.047-23.6 µg mL-1), with a detection limit of 0.15 nM (17 ng mL-1, S/N = 3) and sensitivity of 90.7 nA nM-1, in addition to a good reproducibility and storage stability. The analytical applicability of the presented immunoassay is verified by CRP measurements in human blood serum samples. This work provides the basis for a low-priced, safe, and easy-to-use point-of-care immunosensor assay to measure CRP at clinically relevant concentrations.


Spontaneous postural sway predicts the strength of smooth vection.
This study asked whether individual differences in the influence of vision on postural stability could be used to predict the strength of subsequently induced visual illusions of self-motion (vection). In the experiment, we first measured spontaneous postural sway while subjects stood erect for 60 s with their eyes both open and both closed. We then showed our subjects two types of self-motion display: radially expanding optic flow (simulating constant velocity forwards self-motion) and vertically oscillating radially expanding optic flow (simulating constant velocity forwards self-motion combined with vertical head oscillation). As expected, subjects swayed more with their eyes closed (compared to open) and experienced more compelling illusions of self-motion with vertically oscillating (as opposed to smooth) radial flow. The extent to which participants relied on vision for postural stability-measured as the ratio of sway with eyes closed compared to that with eyes open-was found to predict vection strength. However, this was only the case for displays representing smooth self-motion. It seems that for oscillating displays, other factors, such as visual-vestibular interactions, may be more important.


Spontaneous hepatic decompensation in patients coinfected with HIV and hepatitis C virus during interferon-ribavirin combination treatment.
Spontaneous hepatic decompensation was observed in 7 of 383 patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who were receiving treatment with interferon and ribavirin. Multivariate analysis identified the following risk factors: didanosine use (odds ratio [OR], 8.8; 95% confidence interval [CI], 1.2-102.3; P < .02), cirrhosis, (OR, 8.8; 95% CI, 1.2-104.2; P<.02), and elevated total bilirubin level (OR, 7.9; 95% CI, 1.08-93.3; P<.03). Didanosine should thus not be given to patients with cirrhosis, particularly when treatments for HCV and HIV infections have to be administered concomitantly.


Characterization of the metastasis-associated protein, S100A4. Roles of calcium binding and dimerization in cellular localization and interaction with myosin.
Elevated S100A4 protein expression is associated with metastatic tumor progression and appears to be a strong molecular marker for clinical prognosis. S100A4 is a calcium-binding protein that is known to form homodimers and interacts with several proteins in a calcium-dependent manner. Here we show that S100A4 localizes to lamellipodia structures in a migrating breast cancer-derived cell line and colocalizes with a known S100A4-interacting protein, myosin heavy chain IIA, at the leading edge. We demonstrate that S100A4 mutants that are defective in either their ability to dimerize or in calcium binding are unable to interact with myosin heavy chain IIA. An S100A4 mutant that is deficient for calcium binding retains the ability to form homodimers, suggesting that S100A4 can exist as calcium-free or calcium-bound dimers in vivo. However, a calcium-bound S100A4 monomer only interacts with another calcium-bound monomer and not with an S100A4 mutant that does not bind calcium. Interestingly, despite the calcium dependence for interaction with known protein partners, calcium binding is not necessary for localization to lamellipodia. Both wild type and a mutant that is deficient for calcium binding colocalize with known markers of actively forming leading edges of lamellipodia, Arp3 and neuronal Wiskott-Aldrich syndrome protein. These data suggest that S100A4 localizes to the leading edge in a calcium-independent manner, and identification of the proteins that are involved in localizing S100A4 to the lamellipodial structures may provide novel insight into the mechanism by which S100A4 regulates metastasis.


Relative intakes of tar, nicotine, and carbon monoxide from cigarettes of different yields.
The relative intakes of tar, nicotine, and carbon monoxide were estimated in 2455 cigarette smokers, who freely smoked their usual brands of cigarette. The estimates were derived by using an objective index of inhaling based on the measurement of carboxyhaemoglobin divided by the carbon monoxide yield of the cigarettes smoked, after background and carry over carboxyhaemoglobin effects had been allowed for. Separate analyses were performed according to the yield and type (plain, filter, etc) of cigarette smoked. The analyses based on yield indicated that the extent of inhaling was adjusted sufficiently to achieve similar intakes of nicotine/carbon monoxide regardless of the nicotine/carbon monoxide yield. It was not, however, sufficiently increased to achieve a similar intake of tar as the tar yield of the cigarette decreased. The analyses based on type of cigarette indicated that the extent of inhaling was adjusted to achieve similar intakes of tar and nicotine regardless of the type of cigarette smoked, but that this led to a greater intake of carbon monoxide among filter cigarette smokers than that among smokers of plain cigarettes--more so than would have been expected from their relative carbon monoxide yields. Two conclusions arise from these results. Firstly, any harmful effects of nicotine/carbon monoxide are unlikely to be materially reduced by smoking cigarettes with lower yields of nicotine/carbon monoxide, but the harmful effects of tar are likely to be reduced by smoking cigarettes with lower tar yields. These predictions appear to be borne out by epidemiological observations. Secondly, any harmful effects of carbon monoxide on the cardiovascular system will be greater in smokers of modern filter cigarettes than in smokers of modern plain cigarettes, provided that these two groups of smokers are otherwise similar with respect to risk of cardiovascular disease.


Very-Heavy Sled Training for Improving Horizontal-Force Output in Soccer Players.
Sprint running acceleration is a key feature of physical performance in team sports, and recent literature shows that the ability to generate large magnitudes of horizontal ground-reaction force and mechanical effectiveness of force application are paramount. The authors tested the hypothesis that very-heavy loaded sled sprint training would induce an improvement in horizontal-force production, via an increased effectiveness of application. Training-induced changes in sprint performance and mechanical outputs were computed using a field method based on velocity-time data, before and after an 8-wk protocol (16 sessions of 10- × 20-m sprints). Sixteen male amateur soccer players were assigned to either a very-heavy sled (80% body mass sled load) or a control group (unresisted sprints). The main outcome of this pilot study is that very-heavy sled-resisted sprint training, using much greater loads than traditionally recommended, clearly increased maximal horizontal-force production compared with standard unloaded sprint training (effect size of 0.80 vs 0.20 for controls, unclear between-groups difference) and mechanical effectiveness (ie, more horizontally applied force; effect size of 0.95 vs -0.11, moderate between-groups difference). In addition, 5-m and 20-m sprint performance improvements were moderate and small for the very-heavy sled group and small and trivial for the control group, respectively. Practical Applications: This brief report highlights the usefulness of very-heavy sled (80% body mass) training, which may suggest value for practical improvement of mechanical effectiveness and maximal horizontal-force capabilities in soccer players and other team-sport athletes. This study may encourage further research to confirm the usefulness of very-heavy sled in this context.


Furfural induces reactive oxygen species accumulation and cellular damage in Saccharomyces cerevisiae.
Biofuels offer a viable alternative to petroleum-based fuel. However, current methods are not sufficient and the technology required in order to use lignocellulosic biomass as a fermentation substrate faces several challenges. One challenge is the need for a robust fermentative microorganism that can tolerate the inhibitors present during lignocellulosic fermentation. These inhibitors include the furan aldehyde, furfural, which is released as a byproduct of pentose dehydration during the weak acid pretreatment of lignocellulose. In order to survive in the presence of furfural, yeast cells need not only to reduce furfural to the less toxic furan methanol, but also to protect themselves and repair any damage caused by the furfural. Since furfural tolerance in yeast requires a functional pentose phosphate pathway (PPP), and the PPP is associated with reactive oxygen species (ROS) tolerance, we decided to investigate whether or not furfural induces ROS and its related cellular damage in yeast. We demonstrated that furfural induces the accumulation of ROS in Saccharomyces cerevisiae. In addition, furfural was shown to cause cellular damage that is consistent with ROS accumulation in cells which includes damage to mitochondria and vacuole membranes, the actin cytoskeleton and nuclear chromatin. The furfural-induced damage is less severe when yeast are grown in a furfural concentration (25 mM) that allows for eventual growth after an extended lag compared to a concentration of furfural (50 mM) that prevents growth. These data suggest that when yeast cells encounter the inhibitor furfural, they not only need to reduce furfural into furan methanol but also to protect themselves from the cellular effects of furfural and repair any damage caused. The reduced cellular damage seen at 25 mM furfural compared to 50 mM furfural may be linked to the observation that at 25 mM furfural yeast were able to exit the furfural-induced lag phase and resume growth. Understanding the cellular effects of furfural will help direct future strain development to engineer strains capable of tolerating or remediating ROS and the effects of ROS.


Recent advances in semiconductors for photocatalytic and photoelectrochemical water splitting.
Photocatalytic and photoelectrochemical water splitting under irradiation by sunlight has received much attention for production of renewable hydrogen from water on a large scale. Many challenges still remain in improving energy conversion efficiency, such as utilizing longer-wavelength photons for hydrogen production, enhancing the reaction efficiency at any given wavelength, and increasing the lifetime of the semiconductor materials. This introductory review covers the fundamental aspects of photocatalytic and photoelectrochemical water splitting. Controlling the semiconducting properties of photocatalysts and photoelectrode materials is the primary concern in developing materials for solar water splitting, because they determine how much photoexcitation occurs in a semiconductor under solar illumination and how many photoexcited carriers reach the surface where water splitting takes place. Given a specific semiconductor material, surface modifications are important not only to activate the semiconductor for water splitting but also to facilitate charge separation and to upgrade the stability of the material under photoexcitation. In addition, reducing resistance loss and forming p-n junction have a significant impact on the efficiency of photoelectrochemical water splitting. Correct evaluation of the photocatalytic and photoelectrochemical activity for water splitting is becoming more important in enabling an accurate comparison of a number of studies based on different systems. In the latter part, recent advances in the water splitting reaction under visible light will be presented with a focus on non-oxide semiconductor materials to give an overview of the various problems and solutions.


Investigating predictability of in vitro toxicological assessments of cigarettes: analysis of 7 years of regulatory submissions to Canadian regulatory authorities.
A wealth of in vitro toxicological information on different types of tobaccos and tobacco products has been acquired and published, although the link between in vitro data and impact on human health remains elusive. The present study investigates the possibility of establishing quantitative models for the in vitro toxicological endpoint responses to cigarette smoke. To this end, it relies on information submitted to Canadian health authorities during the period 2006-2012. To our knowledge, this is the first time that published results concerning the influence of such factors as cigarette blend, diameter and filter type on in vitro toxicity are confirmed at the level of a representative range of products on a market. Taking these cigarette design features into account and adding a limited amount of quantitative mainstream smoke composition information, it is shown that, within the boundaries of the considered cigarette design parameters, the in vitro toxicological response can be effectively predicted. In vitro tests of tobacco products are an invaluable initial comparative product assessment tool. The present results reveal the limited value of data from repeated tests on products which do not undergo significant modifications.


A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours.
Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy. This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed. Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks). Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.


Erythrocyte Inosine triphosphatase activity: A potential biomarker for adverse events during combination antiretroviral therapy for HIV.
The purine analogues tenofovir and abacavir are precursors of potential substrates for the enzyme Inosine 5'-triphosphate pyrophosphohydrolase (ITPase). Here, we investigated the association of ITPase activity and ITPA genotype with the occurrence of adverse events (AEs) during combination antiretroviral therapy (cART) for human immunodeficiency virus (HIV) infection. In 393 adult HIV-seropositive patients, AEs were defined as events that led to stop of cART regimen. ITPase activity ≥4 mmol IMP/mmol Hb/hour was considered as normal. ITPA genotype was determined by testing two ITPA polymorphisms: c.94C>A (p.Pro32Thr, rs1127354) and c.124+21A>C (rs7270101). Logistic regression analysis determined odds ratios for developing AEs. In tenofovir-containing regimens decreased ITPase activity was associated with less AEs (p = 0.01) and longer regimen duration (p = 0.001). In contrast, in abacavir-containing regimens decreased ITPase activity was associated with more AEs (crude p = 0.02) and increased switching of medication due to AEs (p = 0.03). ITPA genotype wt/wt was significantly associated with an increase in the occurrence of AEs in tenofovir-containing regimens. Decreased ITPase activity seems to be protective against occurrence of AEs in tenofovir-containing cART, while it is associated with an increase in AEs in abacavir-containing regimens.


The Importance of Temperament for Understanding Early Manifestations of Autism Spectrum Disorder in High-Risk Infants.
The present study investigated the relationship between infant temperament characteristics and autism spectrum disorder (ASD) risk status. Temperament was examined at 6, 12, and 24 months in 282 infants at high familial risk for ASD and 114 low-risk controls using the Infant Behavior Questionnaire-Revised and Early Childhood Behavior Questionnaire. Infants were divided into three groups at 24 months: High-Risk Positive-classified as ASD (HR Pos), High-Risk Negative (HR Neg), and Low-Risk Negative (LR Neg). At 6 and 12 months HR Pos infants exhibited lower Surgency and Regulatory Capacity than LR Neg infants. By 12 months they also demonstrated increased Negative Affect. Group differences remained, when early signs of ASD were controlled for, suggesting that temperament differences could be useful targets for understanding the development of ASD.


A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide.
Pulmonary diffusing capacity (DL) for carbon monoxide (CO) and nitric oxide (NO) were simultaneously measured in man using the single breath method, by adding 4O ppm of NO to the inspired gas and analysing the expirate for NO by a chemiluminescent method. The mean ratio of DLNO to DLCO in thirteen subjects was 4.3 (SD 0.3), mean DLNO = 49 mmol.min-1.kPa-1 (SD 10) and mean DLCO = 11 mmol.min-1.kPa-1 (SD 2). An increase in alveolar oxygen concentration from a mean of 18 to 68% in five subjects was associated with a 54% fall in DLCO but no change in DLNO. A reduction of lung volume from total lung capacity (TLC) (mean of 7 l) to a mean volume of 3.9 l in five subjects caused a fall in both DLNO (by 34%) and DLCO (by 8%). With 175 watts cycle exercise in three subjects the DLCO rose by 45% and DLNO by 25%. Since NO reacts much faster with haemoglobin than CO, DLNO should be influenced much less by reaction with haemoglobin, and perhaps represents a better index for the diffusing capacity of the alveolar-capillary membrane (Dm) than DLCO.


Bisphenol A promotes human prostate stem-progenitor cell self-renewal and increases in vivo carcinogenesis in human prostate epithelium.
Previous studies in rodent models have shown that early-life exposure to bisphenol A (BPA) reprograms the prostate and enhances its susceptibility to hormonal carcinogenesis with aging. To determine whether the human prostate is similarly sensitive to BPA, the current study used human prostate epithelial stem-like cells cultured from prostates of young, disease-free donors. Similar to estradiol-17β (E2), BPA increased stem-progenitor cell self-renewal and expression of stem-related genes in a dose-dependent manner. Further, 10 nM BPA and E2 possessed equimolar membrane-initiated signaling with robust induction of p-Akt and p-Erk at 15 minutes. To assess in vivo carcinogenicity, human prostate stem-progenitor cells combined with rat mesenchyme were grown as renal grafts in nude mice, forming normal human prostate epithelium at 1 month. Developmental BPA exposure was achieved through oral administration of 100 or 250 μg BPA/kg body weight to hosts for 2 weeks after grafting, producing free BPA levels of 0.39 and 1.35 ng/mL serum, respectively. Carcinogenesis was driven by testosterone plus E2 treatment for 2 to 4 months to model rising E2 levels in aging men. The incidence of high-grade prostate intraepithelial neoplasia and adenocarcinoma markedly increased from 13% in oil-fed controls to 33% to 36% in grafts exposed in vivo to BPA (P < .05). Continuous developmental BPA exposure through in vitro (200 nM) plus in vivo (250 μg/kg body weight) treatments increased high-grade prostate intraepithelial neoplasia/cancer incidence to 45% (P < .01). Together, the present findings demonstrate that human prostate stem-progenitor cells are direct BPA targets and that developmental exposure to BPA at low doses increases hormone-dependent cancer risk in the human prostate epithelium.


Analysis of Erythrocyte Invasion Mechanisms of Plasmodium falciparum Clinical Isolates Across 3 Malaria-Endemic Areas in Ghana.
Plasmodium falciparum invades human erythrocytes by using an array of ligands that interact with several receptors, including sialic acid (SA), complement receptor 1 (CR1), and basigin. We hypothesized that in malaria-endemic areas, parasites vary invasion pathways under immune pressure. Therefore, invasion mechanisms of clinical isolates collected from 3 zones of Ghana with different levels of endemicity (from lowest to highest, Accra, Navrongo, and Kintampo) were compared using standardized methods. Blood samples were collected from children aged 2-14 years in whom malaria was diagnosed, and erythrocyte invasion phenotypes were determined using the enzymes neuraminidase, chymotrypsin, and trypsin, which differentially cleave receptors from the erythrocyte surface. In addition, antibodies against CR1 and basigin were used to determine the contributions of these receptors to invasion. Gene expression levels of P. falciparum invasion ligands were also examined. The parasites generally expressed SA-independent invasion phenotypes across the malaria-endemic areas, with parasites from Kintampo showing the highest invasion rates in neuraminidase-treated erythrocytes. CR1 was a major mediator of SA-independent invasion, while basigin was essential for both SA-dependent and SA-independent invasion mechanisms. Furthermore, expression of the basigin ligand PfRh5 was the best predictor of donor parasitemia. Erythrocyte invasion phenotypes expressed by P. falciparum are influenced by endemicity levels, and the PfRh5-basigin pathway is a potential vaccine target.


A Mediterranean Diet Rich in Extra-Virgin Olive Oil Is Associated with a Reduced Prevalence of Nonalcoholic Fatty Liver Disease in Older Individuals at High Cardiovascular Risk.
Adherence to a Mediterranean diet (MedDiet) is thought to reduce liver steatosis. To explore the associations with liver steatosis of 3 different diets: a MedDiet + extra-virgin olive oil (EVOO), MedDiet + nuts, or a control diet. This was a subgroup analysis nested within a multicenter, randomized, parallel-group clinical trial, PREvención con DIeta MEDiterránea (PREDIMED trial: ISRCTN35739639), aimed at assessing the effect of a MedDiet on the primary prevention of cardiovascular disease. One hundred men and women (mean age: 64 ± 6 y), at high cardiovascular risk (62% with type 2 diabetes) from the Bellvitge-PREDIMED center were randomly assigned to a MedDiet supplemented with EVOO, a MedDiet supplemented with mixed nuts, or a control diet (advice to reduce all dietary fat). No recommendations to lose weight or increase physical activity were given. Main measurements were the percentage of liver fat and the diagnosis of steatosis, which were determined by NMR imaging. The association of diet with liver fat content was analyzed by bivariate analysis after a median follow-up of 3 y. Baseline adiposity and cardiometabolic risk factors were similar among the 3 treatment arms. At 3 y after the intervention hepatic steatosis was present in 3 (8.8%), 12 (33.3%), and 10 (33.3%) of the participants in the MedDiet + EVOO, MedDiet + nuts, and control diet groups, respectively (P = 0.027). Respective mean values of liver fat content were 1.2%, 2.7%, and 4.1% (P = 0.07). A tendency toward significance was observed for the MedDiet + EVOO group compared with the control group. Median values of urinary 12(S)-hydroxyeicosatetraenoic acid/creatinine concentrations were significantly (P = 0.001) lower in the MedDiet + EVOO (2.3 ng/mg) than in the MedDiet + nuts (5.0 ng/mg) and control (3.9 ng/mg) groups. No differences in adiposity or glycemic control changes were seen between groups. An energy-unrestricted MedDiet supplemented with EVOO, a food with potent antioxidant and anti-inflammatory properties, is associated with a reduced prevalence of hepatic steatosis in older individuals at high cardiovascular risk.


A DFT study on the relative affinity for oxygen of the alpha and beta subunits of hemoglobin.
DFT calculations are carried out on computational models of the active center of the alpha and beta subunits of hemoglobin in both its oxygenated (R) and deoxygenated (T) states. The computational models are defined by the full heme group, including all porphyrin substituents, and the four amino acids closer to it. The role of the protein environment is introduced by freezing the position of the alpha carbon atom of each of the four amino acids to the positions they have in the available PDB structures. Oxygen affinity is then evaluated by computing the energy difference between the optimized structures of the oxygenated and deoxygenated forms of each model. The results indicate a higher affinity of the alpha subunits over the beta ones. Analysis of the computed structures points out to the strength of the hydrogen bond between the distal histidine and the oxygen molecule as a key factor in discriminating the different systems.


Prevalence of anaemia before major joint arthroplasty and the potential impact of preoperative investigation and correction on perioperative blood transfusions.
Preoperative investigation and treatment of anaemia is recommended before orthopaedic surgery. We measured the prevalence of anaemia among admissions presenting for elective major joint arthroplasty (MJA), assessed their transfusion requirements, and investigated factors associated with perioperative blood transfusion. All admissions to a dedicated elective orthopaedic hospital during 2000-2001 were studied. The patients' database was merged with the haematology and transfusion databases. Population estimates for different types of anaemia and their blood transfusion requirements were generated using local reference ranges (males <130 g litre(-1); females <115 g litre(-1)). One thousand three hundred and twenty-two admissions were included; haematology data were complete for 1142 (544 primary hip, 490 primary knee, 77 revision hip, 31 revision knee). About 19.6% were anaemic [7.1% haemoglobin (Hb) <110 g litre(-1); 1.6% Hb<100 g litre(-1)]. Overall, 21.3% of admissions were transfused (mean 0.58 units per case: 95% CI 0.50-0.61). For anaemic admissions, 42.0% were transfused (mean 1.11 units per case: 95% CI 0.90-1.32). Mean red cell use for admissions with normocytic normochromic anaemia (12.7% of admissions) and hypochromic anaemia (4.6%) was 1.04 (95% CI 0.78-1.31) and 1.14 (95% CI 0.71-1.57) units per admission, respectively. Factors strongly associated independently with transfusion were preoperative haemoglobin </=110 g litre(-1) [odds ratio: 13.92 (95% CI 7.77-24.9) and revision hip surgery (OR: 17.80 (9.59-33.02)]. The prevalence of preoperative anaemia among admissions undergoing elective MJA is approximately 20%. Patients most likely to avoid transfusions with preoperative intervention are those with low haemoglobin undergoing revision hip surgery.


Perinatal mortality in relation to birthweight and gestational age: a registry-based comparison of Northern Norway and Murmansk County, Russia.
The objective was to explore how perinatal mortality relates to birthweight, gestational age and optimal perinatal survival weight for two Arctic populations employing an existing and a newly established birth registry. A medical birth registry for all births in Murmansk County of North-West Russia became operational on 1st January 2006. Its primary function is to provide useful information for health care officials pertinent to improving perinatal care. The cohort studied consisted of 17,302 births in 2006-07 (Murmansk County) and 16,006 in 2004-06 (Northern Norway). Birthweight probability density functions were analysed, and logistic regression models were employed to calculate gestational-age-specific mortality ratios. The perinatal mortality rate was 10.7/1000 in Murmansk County and 5.7/1000 in Northern Norway. Murmansk County had a higher proportion of preterm deliveries (8.7%) compared to Northern Norway (6.6%). The odds ratio (OR) of risk of mortality (Northern Norway as the reference group) was higher for all gestational ages in Murmansk County, but the largest risk difference occurred among term deliveries (OR 2.45, 95% confidence interval 1.45, 4.14) which hardly changed on adjustment for maternal age, parity and gestation. Proportionately, more babies were born near (± 500 g) the optimal perinatal survival weight in Murmansk County (67.2%) than in Northern Norway (47.6%). The observed perinatal mortality was higher in Murmansk County at all birthweight strata and at gestational ages between weeks 25 and 42, but the adjusted risk difference was most significant for term deliveries.


Dendrite and spine modifications in autism and related neurodevelopmental disorders in patients and animal models.
Dendrites and spines are the main neuronal structures receiving input from other neurons and glial cells. Dendritic and spine number, size, and morphology are some of the crucial factors determining how signals coming from individual synapses are integrated. Much remains to be understood about the characteristics of neuronal dendrites and dendritic spines in autism and related disorders. Although there have been many studies conducted using autism mouse models, few have been carried out using postmortem human tissue from patients. Available animal models of autism include those generated through genetic modifications and those non-genetic models of the disease. Here, we review how dendrite and spine morphology and number is affected in autism and related neurodevelopmental diseases, both in human, and genetic and non-genetic animal models of autism. Overall, data obtained from human and animal models point to a generalized reduction in the size and number, as well as an alteration of the morphology of dendrites; and an increase in spine densities with immature morphology, indicating a general spine immaturity state in autism. Additional human studies on dendrite and spine number and morphology in postmortem tissue are needed to understand the properties of these structures in the cerebral cortex of patients with autism. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017.


Perspective-taking across cultures: shared biases in Taiwanese and British adults.
The influential hypothesis by Markus & Kitayama (Markus, Kitayama 1991. Psychol. Rev. 98, 224) postulates that individuals from interdependent cultures place others above self in interpersonal contexts. This led to the prediction and finding that individuals from interdependent cultures are less egocentric than those from independent cultures (Wu, Barr, Gann, Keysar 2013. Front. Hum. Neurosci. 7, 1-7; Wu, Keysar. 2007 Psychol. Sci. 18, 600-606). However, variation in egocentrism can only provide indirect evidence for the Markus and Kitayama hypothesis. The current study sought direct evidence by giving British (independent) and Taiwanese (interdependent) participants two perspective-taking tasks on which an other-focused 'altercentric' processing bias might be observed. One task assessed the calculation of simple perspectives; the other assessed the use of others' perspectives in communication. Sixty-two Taiwanese and British adults were tested in their native languages at their home institutions of study. Results revealed similar degrees of both altercentric and egocentric interference between the two cultural groups. This is the first evidence that listeners account for a speaker's limited perspective at the cost of their own performance. Furthermore, the shared biases point towards similarities rather than differences in perspective-taking across cultures.


Impaired ABCA1-dependent lipid efflux and hypoalphalipoproteinemia in human Niemann-Pick type C disease.
The cholesterol trafficking defect in Niemann-Pick type C (NPC) disease leads to impaired regulation of cholesterol esterification, cholesterol synthesis, and low density lipoprotein receptor activity. The ATP-binding cassette transporter A1 (ABCA1), which mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, is also regulated by cell cholesterol content. To determine whether the Niemann-Pick C1 protein alters the expression and activity of ABCA1, we determined the ability of apolipoprotein A-I (apoA-I) to deplete pools of cellular cholesterol and phospholipids in human fibroblasts derived from NPC1+/+, NPC1+/-, and NPC1-/- subjects. Efflux of low density lipoprotein-derived, non-lipoprotein, plasma membrane, and newly synthesized pools of cell cholesterol by apoA-I was diminished in NPC1-/- cells, as was efflux of phosphatidylcholine and sphingomyelin. NPC1+/- cells showed intermediate levels of lipid efflux compared with NPC1+/+ and NPC1-/- cells. Binding of apoA-I to cholesterol-loaded and non-cholesterol-loaded cells was highest for NPC1+/- cells, with NPC1+/+ and NPC1-/- cells showing similar levels of binding. ABCA1 mRNA and protein levels increased in response to cholesterol loading in NPC1+/+ and NPC1+/- cells but showed low levels at base line and in response to cholesterol loading in NPC1-/- cells. Consistent with impaired ABCA1-dependent lipid mobilization to apoA-I for HDL particle formation, we demonstrate for the first time decreased plasma HDL-cholesterol levels in 17 of 21 (81%) NPC1-/- subjects studied. These results indicate that the cholesterol trafficking defect in NPC disease results in reduced activity of ABCA1, which we suggest is responsible for the low HDL-cholesterol in the majority of NPC subjects and partially responsible for the overaccumulation of cellular lipids in this disorder.


Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity.
Autoimmune diseases are thought to result from imbalances in normal immune physiology and regulation. Here, we show that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2). In order to test directly that an approximately twofold reduction in IL-2 underpins the Idd3-linked destabilization of immune homeostasis, we show that engineered haplodeficiency of Il2 gene expression not only reduces T cell IL-2 production by twofold but also mimics the autoimmune dysregulatory effects of the naturally occurring susceptibility alleles of Il2. Reduced IL-2 production achieved by either genetic mechanism correlates with reduced function of CD4(+) CD25(+) regulatory T cells, which are critical for maintaining immune homeostasis.


Cell adhesion on polyelectrolyte multilayer coated polydimethylsiloxane surfaces with varying topographies.
This article demonstrates that the micro-topography of the surface with respect to the pattern size and pitch influences cell adhesion and proliferation. Extensive research has shown the dependence of cell proliferation on substrate chemistry, but the influence of substrate topography on cell attachment has only recently been appreciated. To evaluate the effect of substrate physical properties (i.e., periodic microstructures) on cell attachment and morphology, we compared the response of several cell types (fibroblasts, HeLa, and primary hepatocytes) cultured on various polydimethylsiloxane (PDMS) patterns. PDMS has been used as an artificial construct to mimic biological structures. Although PDMS is widely used in biomedical applications, membrane technology, and microlithography, it is difficult to maintain cells on PDMS for long periods, and the polymer has proved to be a relatively inefficient substrate for cell adhesion. To improve adhesion, we built polyelectrolyte multilayers (PEMs) on PDMS surfaces to increase surface wettability, thereby improving attachment and spreading of the cells. Micrographs demonstrate the cellular response to physical parameters, such as pattern size and pitch, and suggest that surface topography, in part, regulates cell adhesion and proliferation. Therefore, varying the surface topography may provide a method to influence cell attachment and proliferation for tissue-engineering applications.


Air pollution and risk of chronic obstructed pulmonary disease: The modifying effect of genetic susceptibility and lifestyle.
The effect of long-term exposure to air pollution on the development of chronic obstructive pulmonary disease (COPD) is still controversial, and the role of the interactions of air pollution with genetic risk and lifestyle in COPD risk is unclear. We included 452762 participants derived from the UK Biobank. Annual concentrations of air pollutions, including particle matter (PM2.5, PM10), nitrogen oxides (NOx), and nitrogen dioxide (NO2), were assessed using land-use regression model. We applied Cox proportional hazard model to evaluate the associations between air pollution and COPD risk. In addition, we constructed a polygenic risk score and a lifestyle score, and assessed whether genetic susceptibility and lifestyle modified the effect of air pollution on the COPD risk. Each interquartile range (IQR) increase in annual concentrations of PM2.5, PM10, NOx, and NO2 was associated with 1.17 (95% CI: 1.15,1.19), 1.05 (95% CI: 1.03,1.06), 1.13 (95% CI: 1.11,1.14), and 1.19 (95% CI: 1.16,1.21) times the risk of COPD, respectively. We observed an additive interaction between PM2.5 and genetic risk (P-interact=0.095), and a negative interaction between PM2.5 and lifestyle (P-interact=0.062). The HRs for each IQR increase in PM2.5 were 1.21, (95% CI: 1.16-1.25) and 1.24, (95% CI: 1.21-1.26) in individuals with healthy and unfavourable lifestyle, respectively; and 1.16, (95% CI: 1.13-1.19) and 1.19, (95% CI: 1.16-1.22) in those with low genetic risk and high genetic risk, respectively. Participants with high air pollution exposure, high genetic risk and unfavourable lifestyle showed the highest risk of COPD. Long-term exposure to air pollution was associated with increased risk of COPD, especially in those with high genetic risk and unfavourable lifestyle. None.


Giant Muscle Fibers in a Barnacle, Balanus nubilus Darwin.
Cross-striated muscle fibers of very large size have been found in the scutal-tergal adductor and depressor muscles of the large barnacle B. nubilus. Adductor muscle fibers are up to 2 mm thick. They are innervated by separate nerves, each supplying one end, but not the central region, with terminals; each fiber receives two or three excitor axons. Depressor muscle fibers are up to 1.4 mm thick and receive multiterminal innervation along their entire length; they are innervated by two excitor axons. Postsynaptic potentials are of small or large size and lead to small or large twitches; they do not show facilitation. The muscle fibers shorten to as little as one-sixth resting length.


Noninvasive estimation of the pressure profile in the male urethra using ultrasound imaging.
Decreased prostatic compliance as a result of benign prostatic enlargement can result in bladder outlet obstruction. This changes the urethral pressure profile during voiding. In this study, the authors propose noninvasive estimation of this pressure profile. In four soft tissue mimicking models of the urethra with increasing degree of obstruction, the authors measured deformation of the wall during flow, using ultrasound imaging. Combined with estimates of the model compliance, the authors were able to estimate the pressure profile. First, the compliances (Young's moduli) of the four models were derived by applying static luminal pressure and measuring the resulting strain of the tissue using an ultrasound imaging system. Next, continuous flow was applied to the models and the strain in the urethral wall was measured similarly. The luminal pressure profile was estimated from the strain (measured under continuous flow conditions) and the derived compliance (measured under static pressure conditions). The estimated pressures up- and downstream of the obstruction were compared with the corresponding measured pressures. In the obstructed region, the strain gradient was estimated using linear regression. The luminal pressure values estimated from the ultrasound data up- and downstream of the obstruction were not significantly different from the corresponding measured pressures. The general pressure profile showed a decrease along the length of the obstruction followed by a small increase after the obstruction. The strain gradient in the obstructed region reflected the decrease in urethral pressure and increased with flow rate and degree of obstruction. The results from this model study illustrate the feasibility of noninvasive estimation of the urethral pressure profile using ultrasound. This offers the prospect of a noninvasive, ultrasound based diagnostic tool for assessment of bladder outlet obstruction in men with lower urinary tract symptoms.


Personalised nutrition: status and perspectives.
Personalised, genotype-based nutrition is a concept that links genotyping with specific nutritional advice in order to improve the prevention of nutrition-associated, chronic diseases. This review describes the current scientific basis of the concept and discusses its problems. There is convincing evidence that variant genes may indeed determine the biological response to nutrients. The effects of single-gene variants on risk or risk factor levels of a complex disease are, however, usually small and sometimes inconsistent. Thus, information on the effects of combinations of relevant gene variants appears to be required in order to improve the predictive precision of the genetic information. Furthermore, very few associations between genotype and response have been tested for causality in human intervention studies, and little is known about potential adverse effects of a genotype-derived intervention. These issues need to be addressed before genotyping can become an acceptable method to guide nutritional recommendations.


Providing research results to participants: attitudes and needs of adolescents and parents of children with cancer.
There is an increasing demand for researchers to provide research results to participants. Our aim was to define an appropriate process for this, based on needs and attitudes of participants. A multicenter survey in five sites in the United States and Canada was offered to parents of children with cancer and adolescents with cancer. Respondents indicated their preferred mode of communication of research results with respect to implications; timing, provider, and content of the results; reasons for and against providing results; and barriers to providing results. Four hundred nine parents (including 19 of deceased children) and 86 adolescents responded. Most parents (n = 385; 94.2%) felt that they had a strong right to research results. For positive results, most wanted a letter or e-mail summary (n = 238; 58.2%) or a phone call followed by a letter (n = 100; 24.4%). If the results were negative, phone call (n = 136; 33.3%) or personal visits (n = 150; 36.7%) were preferred. Parents wanted the summary to include long-term sequelae and suggestions for participants (n = 341; 83.4%), effect on future treatments (n = 341; 83.4%), and subsequent research steps (n = 284; 69.5%). Understanding the researcher was a main concern about receiving results (n = 145; 35.5%). Parents felt that results provide information to support quality of life (n = 315; 77%) and raise public awareness of research (n = 282; 68.9%). Adolescents identified similar preferences. Parents of children with cancer and adolescents with cancer feel strongly that they have a right to be offered research results and have specific preferences of how and what information should be communicated.


Wafer-scale reliable switching memory based on 2-dimensional layered organic-inorganic halide perovskite.
Recently, organic-inorganic halide perovskite (OHP) has been suggested as an alternative to oxides or chalcogenides in resistive switching memory devices due to low operating voltage, high ON/OFF ratio, and flexibility. The most studied OHP is 3-dimensional (3D) MAPbI3. However, MAPbI3 often exhibits less reliable switching behavior probably due to the uncontrollable random formation of conducting filaments. Here, we report the resistive switching property of 2-dimensional (2D) OHP and compare switching characteristics depending on structural dimensionality. The dimensionality is controlled by changing the composition of BA2MAn-1PbnI3n+1 (BA = butylammonium, MA = methylammonium), where 2D is formed from n = 1, and 3D is formed from n = ∞. Quasi 2D compositions with n = 2 and 3 are also compared. Transition from a high resistance state (HRS) to a low resistance state (LRS) occurs at 0.25 × 106 V m-1 for 2D BA2PbI4 film, which is lower than those for quasi 2D and 3D. Upon reducing the dimensionality from 3D to 2D, the ON/OFF ratio significantly increases from 102 to 107, which is mainly due to the decreased HRS current. A higher Schottky barrier and thermal activation energy are responsible for the low HRS current. We demonstrate for the first time reliable resistive switching from 4 inch wafer-scale BA2PbI4 thin film working at both room temperature and a high temperature of 87 °C, which strongly suggests that 2D OHP is a promising candidate for resistive switching memory.


Clinic-Based Delivery of the Young Men's Health Project (YMHP) Targeting HIV Risk Reduction and Substance Use Among Young Men Who Have Sex with Men: Protocol for a Type 2, Hybrid Implementation-Effectiveness Trial.
Young men who have sex with men (YMSM) are disproportionately at risk for HIV and sexually transmitted infections. Adapting and testing the effectiveness of the Young Men's Health Project (YMHP), an efficacious intervention designed to reduce substance use and condomless anal sex (CAS) among YMSM, at clinics in Miami, Detroit, and Philadelphia has the potential to reduce HIV and STI disparities among urban YMSM. This study (Adolescent Medicine Trials Network for HIV/AIDS Interventions [ATN] 145 YMHP) aims to adapt YMHP for clinic and remote delivery by existing clinic staff and compare their effectiveness in real-world adolescent HIV clinics. This protocol is part of the ATN Scale It Up program described in a recently published article by Naar et al. This is a comparative effectiveness hybrid type-2 trial of the YMHP intervention with 2 delivery formats-clinic-based versus remote delivery-offered following HIV counseling and testing. Phase 1 includes conducting focus groups with youth to obtain implementation feedback about the delivery of the YMHP intervention and intervention components to ensure culturally competent, feasible, and scalable implementation. Phase 2 includes recruitment and enrollment of 270 YMSM, aged 15 to 24 years, 90 at each of the 3 sites. Enrollment will be limited to HIV-negative YMSM who report recent substance use and either CAS or a positive STI test result. Participants will be randomized to receive the YMHP intervention either in person or by remote delivery. Both conditions involve completion of the 4 YMHP sessions and the delivery of pre-exposure prophylaxis information and navigation services. A minimum of 2 community health workers (CHWs) will be trained to deliver the intervention sessions at each site. Sessions will be audio-recorded for Motivational Interviewing Treatment Integrity (MITI) fidelity coding, and CHWs and supervisors will be given implementation support throughout the study period. Phase 1 focus groups were completed in July 2017 (n=25). Feedback from these focus groups at the 3 sites informed adaptations to the YMHP intervention manual, implementation of the intervention, and recruitment plans for phase 2. Baseline enrollment for phase 2 began in November 2018, and assessments will be at immediate posttest (IP)-, 3-, 6-, 9-, and 12-months after the intervention. Upon collection of both baseline and follow-up data, we will compare the effectiveness and cost-effectiveness of clinic-based versus remote delivery of YMHP in the context of health care access. We are conducting YMHP in 3 cities with high rates of YMSM at risk for HIV and STIs. When adapted for real-world clinics, this study will help substance-using YMSM at risk for HIV and STIs and allow us to examine differences in effectiveness and cost by the method of delivery. ClinicalTrials.gov NCT03488914; https://clinicaltrials.gov/ct2/show/NCT03488914 (Archived by WebCite at http://www.webcitation.org/770WaWWfi). DERR1-10.2196/11184.


Identification of significant ego networks and pathways in rheumatoid arthritis.
The objective of this paper is to identify ego networks and pathways in rheumatoid arthritis (RA) based on EgoNet algorithm and pathway enrichment analysis. The ego networks were identified based on the EgoNet algorithm which was comprised four steps: inputting gene expression data and protein-protein interaction data, identifying ego genes based on topological features of genes in background network, collecting ego networks by conducting snowball sampling for each ego gene, and estimating statistical significance of ego networks utilizing permutation test. To further explore the gene compositions of significant ego networks, pathway enrichment analysis was performed for each of them to investigate ego pathways in the progression of RA. We detected 9 ego genes from the background network, such as CREBBP, SMAD2, and YY1. Starting with each ego gene and ending with prediction accuracy dropped, a total of 9 ego networks were identified. Statistical analysis identified two significant ego networks (ego-networks 2 and 4). Ego-network 2 with ego gene SNW1 and ego-network 4 whose ego gene was YY1 both included 10 genes. The results of pathway enrichment analysis showed that signaling by NOTCH (P = 1.11E-07) and oncogene-induced senescence (P = 3.48E-04) were the two ego pathways for RA. Ego networks and pathways identified in this work might be potential therapeutic markers for RA treatment and give a hand for further studies of this disease.


Emergent Quantum Mechanics: David Bohm Centennial Perspectives.
Emergent quantum mechanics (EmQM) explores the possibility of an ontology for quantum mechanics. The resurgence of interest in realist approaches to quantum mechanics challenges the standard textbook view, which represents an operationalist approach. The possibility of an ontological, i.e., realist, quantum mechanics was first introduced with the original de Broglie-Bohm theory, which has also been developed in another context as Bohmian mechanics. This Editorial introduces a Special Issue featuring contributions which were invited as part of the David Bohm Centennial symposium of the EmQM conference series (www.emqm17.org). Questions directing the EmQM research agenda are: Is reality intrinsically random or fundamentally interconnected? Is the universe local or nonlocal? Might a radically new conception of reality include a form of quantum causality or quantum ontology? What is the role of the experimenter agent in ontological quantum mechanics? The Special Issue also includes research examining ontological propositions that are not based on the Bohm-type nonlocality. These include, for example, local, yet time-symmetric, ontologies, such as quantum models based upon retrocausality. This Editorial provides topical overviews of thirty-one contributions which are organized into seven categories to provide orientation.


Mediation of proliferating cell nuclear antigen (PCNA)-dependent DNA replication through a conserved p21(Cip1)-like PCNA-binding motif present in the third subunit of human DNA polymerase delta.
The subunit that mediates binding of proliferating cell nuclear antigen (PCNA) to human DNA polymerase delta has not been clearly defined. We show that the third subunit of human DNA polymerase delta, p66, interacts with PCNA through a canonical PCNA-binding sequence located in its C terminus. Conversely, p66 interacts with the domain-interconnecting loop of PCNA, a region previously shown to be important for DNA polymerase delta activity and for binding of the cell cycle inhibitor p21(Cip1). In accordance with this, a peptide containing the PCNA-binding domain of p21(Cip1) inhibited p66 binding to PCNA and the activity of native three-subunit DNA polymerase delta. Furthermore, pull-down assays showed that DNA polymerase delta requires p66 for interaction with PCNA. More importantly, only reconstituted three-subunit DNA polymerase delta displayed PCNA-dependent DNA replication that could be inhibited by the PCNA-binding domain of p21(Cip1). Direct participation of p66 in PCNA-dependent DNA replication in vivo is demonstrated by co-localization of p66 with PCNA and DNA polymerase delta within DNA replication foci. Finally, in vitro phosphorylation of p66 by cyclin-dependent kinases suggests that p66 activity may be subject to cell cycle-dependent regulation. These results suggest that p66 is the chief mediator of PCNA-dependent DNA synthesis by DNA polymerase delta.


Peripheral cholinergic function in humans with chronic fatigue syndrome, Gulf War syndrome and with illness following organophosphate exposure.
In the present study, we have investigated whether the peripheral cholinergic abnormalities that we have reported previously [Spence, Khan and Belch (2000) Am. J. Med. 108, 736-739] in patients with chronic fatigue syndrome (CFS) are also present in those with Gulf War syndrome (GWS) and agricultural workers exposed to organophosphate pesticides, where cholinesterase inhibition is specifically implicated. We also looked at whether these abnormalities might be due to a reduction in the activity of cholinesterase expressed on the vascular endothelium. We used laser Doppler imaging to measure the forearm skin blood flow responses to iontophoresis of acetylcholine and of methacholine (which is resistant to breakdown by cholinesterase) in patients with CFS, GWS and those with a history of ill health after definite organophosphate exposure, as well as in matched healthy controls. The response to acetylcholine was significantly higher in patients with CFS than in controls ( P =0.029, repeated-measures ANOVA), but was normal in those with GWS and those exposed to organophosphates. The methacholine response was higher than the acetylcholine response in all patient groups except for those with CFS, where there was no difference between the responses. Although there are many clinical similarities between these three illnesses, our results indicate peripheral cholinergic abnormalities in the vascular endothelium of only patients with CFS, suggesting that this syndrome has a different aetiology, which might involve inhibition of vascular cholinesterase.


Influence of aerobic exercise training on the neural correlates of motor learning in Parkinson's disease individuals.
Aerobic exercise training (AET) has been shown to provide general health benefits, and to improve motor behaviours in particular, in individuals with Parkinson's disease (PD). However, the influence of AET on their motor learning capacities, as well as the change in neural substrates mediating this effect remains to be explored. In the current study, we employed functional Magnetic Resonance Imaging (fMRI) to assess the effect of a 3-month AET program on the neural correlates of implicit motor sequence learning (MSL). 20 healthy controls (HC) and 19 early PD individuals participated in a supervised, high-intensity, stationary recumbent bike training program (3 times/week for 12 weeks). Exercise prescription started at 20 min (+ 5 min/week up to 40 min) based on participant's maximal aerobic power. Before and after the AET program, participants' brain was scanned while performing an implicit version of the serial reaction time task. Brain data revealed pre-post MSL-related increases in functional activity in the hippocampus, striatum and cerebellum in PD patients, as well as in the striatum in HC individuals. Importantly, the functional brain changes in PD individuals correlated with changes in aerobic fitness: a positive relationship was found with increased activity in the hippocampus and striatum, while a negative relationship was observed with the cerebellar activity. Our results reveal, for the first time, that exercise training produces functional changes in known motor learning related brain structures that are consistent with improved behavioural performance observed in PD patients. As such, AET can be a valuable non-pharmacological intervention to promote, not only physical fitness in early PD, but also better motor learning capacity useful in day-to-day activities through increased plasticity in motor related structures.


Choroidal Osteoma Deossification Visualized by Enhanced Depth Imaging Spectral-Domain Optical Coherence Tomography.
Choroidal osteoma (CO) is a rare, benign ossifying lesion of the choroid found in otherwise healthy patients. Although associated with good visual prognosis, tumor deossification in choroidal osteoma has been linked with vision loss, presumably due to overlying photoreceptor degeneration. Here the authors present a case of CO in an elderly male demonstrating tumor deossification and photoreceptor atrophy during a 3-year follow-up using enhanced depth imaging optical coherence tomography (EDI-OCT). Visual acuity was maintained due to the tumor's noncentral location. Patients with CO should undergo regular imaging with EDI-OCT to screen for tumor deossification and impending vision loss. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:87-90.].


Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity.
Fluorine's unique physicochemical properties make it a key element for incorporation into pharmacologically active compounds. Its presence in a drug can alter a number of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailablility and how the effects observed are related to the physicochemical characteristics of the element. Examples of more recently used larger scale synthetic methods for introduction of fluorine into drug leads are detailed and the potential for using biological systems for fluorinated drug production is discussed. The synthetic procedures for carbon-fluorine bond formation largely still rely on decades-old technology for the manufacturing scale and new reagents and methods are required to meet the demands for the preparation of structurally more complex drugs. The improvement of in vitro and computational methods should make fluorinated drug design more efficient and place less emphasis on approaches such as fluorine scanning and animal studies. The introduction of new fluorinated drugs, and in particular those that have novel fluorinated functional groups, should be accompanied by rigorous environmental assessment to determine the nature of transformation products that may cause ecological damage.


A 3D monolithic CNT block structure as a reductant, support and scavenger for nanoscopic gold, platinum and zinc oxide.
ZnO (8-10 nm), gold (10-50 nm), and platinum (2-5 nm) nanoparticles were deposited on monoliths of regularly arranged three-dimensional (3D) carbon nanotubes of 40 nm diameter and length up to 30 microm. The single-source precursor complex di-aqua-bis[2-(methoxyimino)propanato](2)Zn(ii) in dimethylformamide was used for the deposition of nanoparticulate ZnO on an ordered 3D CNT scaffold by solution-phase deposition at temperatures as low as 150 degrees C. Au and Pt nanoparticles were deposited by the spontaneous reduction of aqueous solutions of HAuCl(4) and K(2)PtCl(4) on the surface of the macroscopic 3D CNT scaffolds. X-Ray diffraction (XRD) and transmission electron microscopy (TEM) indicate the crystalline nature and nanosize structure of the deposited ZnO, Au and Pt nanoparticles. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) investigations revealed a dense and homogeneous decoration of the individual CNTs throughout the 3D CNT scaffold structure. Thus the nanovoids of the carbon scaffold structure are therefore completely accessible leading to a homogenous particle deposition on the complete CNT outer surface. The kinetics of the spontaneous reduction of gold(iii) and platinum(ii) ions on the CNTs of the scaffold was followed by UV-vis spectroscopy and indicate (i) first-order reaction kinetics with respect to Au(3+) and Pt(2+) concentration and (ii) that the rate of reduction of Au(3+) is one order of magnitude slower than that of Pt(2+).


Leishmanicidal activity of polyphenolic-rich extract from husk fiber of Cocos nucifera Linn. (Palmae).
The available therapy for leishmaniasis, which affects 2 million people per annum, still causes serious side effects. The polyphenolic-rich extract from the husk fiber of Cocos nucifera Linn. (Palmae) presents antibacterial and antiviral activities, also inhibiting lymphocyte proliferation, as shown by our group in previous works. In the present study, the in vitro leishmanicidal effects of C. nucifera on Leishmania amazonensis were evaluated. The minimal inhibitory concentration of the polyphenolic-rich extract from C. nucifera to completely abrogate parasite growth was 10 microg/ml. Pretreatment of peritoneal mouse macrophages with 10 microg/ml of C. nucifera polyphenolic-rich extract reduced approximately 44% the association index between these macrophages and L. amazonensis promastigotes, with a concomitant increase of 182% in nitric oxide production by the infected macrophage in comparison to nontreated macrophages. These results provide new perspectives on drug development against leishmaniasis, since the extract of C. nucifera at 10 microg/ml is a strikingly potent leishmanicidal substance which inhibited the growth of both promastigote and amastigote developmental stages of L. amazonensis after 60 min, presenting no in vivo allergenic reactions or in vitro cytotoxic effects in mammalian systems.


Critical control points of complementary food preparation and handling in eastern Nigeria.
To investigate microbial contamination and critical control points (CCPs) in the preparation and handling of complementary foods in 120 households in Imo state, Nigeria. The Hazard Analysis Critical Control Point (HACCP) approach was used to investigate processes and procedures that contributed to microbial contamination, growth and survival, and to identify points where controls could be applied to prevent or eliminate these microbiological hazards or reduce them to acceptable levels. Food samples were collected and tested microbiologically at different stages of preparation and handling. During cooking, all foods attained temperatures capable of destroying vegetative forms of food-borne pathogens. However, the risk of contamination increased by storage of food at ambient temperature, by using insufficiently high temperatures to reheat the food, and by adding contaminated ingredients such as dried ground crayfish and soybean powder at stages where no further heat treatment was applied. The purchasing of contaminated raw foodstuffs and ingredients, particularly raw akamu, from vendors in open markets is also a CCP. Although an unsafe environment poses many hazards for children's food, the hygienic quality of prepared food can be assured if basic food safety principles are observed. When many factors contribute to food contamination, identification of CCPs becomes particularly important and can facilitate appropriate targeting of resources and prevention efforts.


Meta-analysis of the family-based association between the PTPN22 C1858T polymorphism and type 1 diabetes.
The aim of this study was to determine whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism (rs2476601) confers susceptibility to type 1 diabetes (T1D). We conducted a meta-analysis of the transmission disequilibrium test (TDT) examining preferential transmission of the T allele of the PTPN22 C1858T polymorphism to children with T1D. A total of 11 studies were included in this meta-analysis, which contained 3,946 families and 2,024 transmissions of the PTPN22 T allele in 11 European populations. The frequencies of the transmitted and non-transmitted T allele were 1,250 (61.8 %) and 774 (38.2 %), respectively. The T allele was transmitted to T1D offspring more often than expected. Meta-analysis showed a significant association between the PTPN22 T allele and T1D (OR 1.611, 95 % CI 1.421, 1.827, p < 1 × 10(-8)) without between-study heterogeneity (I(2) = 32.5, p = 0.138). Publication bias was observed in this meta-analysis (Egger's regression test, p-values = 0.061), but the adjusted OR calculated using the trim and fill technique remained significant (OR 1.577, 95 % CI 1.392, 1.785). This meta-analysis of TDT confirms that the PTPN22 C1858T polymorphism is associated with T1D susceptibility in Europeans.


Effects of guided imagery on blood pressure in pregnant women with hypertension: a pilot randomized controlled trial.
Hypertension occurs in nearly 10 percent of pregnancies, and is associated with higher risk of infant and maternal morbidity and mortality than in normal pregnancies. Previous studies have suggested that relaxation therapies reduce blood pressure in nonpregnant adults. The objectives of this pilot randomized trial were to provide preliminary evidence of whether relaxation by means of guided imagery would reduce blood pressure in hypertensive pregnant women, and to assess the feasibility of a larger trial. A total of 69 pregnant women with hypertension were randomized to periods of guided imagery or of quiet rest, twice daily for 4 weeks or until delivery, whichever came first. Daytime ambulatory mean arterial pressure, systolic and diastolic blood pressure, and anxiety were measured weekly for up to 4 weeks. Women allocated to guided imagery had lower mean arterial pressure elevations over time than those allocated to quiet rest (guided imagery: M = 1.58 mmHg, SD = 7.63; quiet rest: M = 5.93 mmHg, SD = 6.55; t = 2.36, p = 0.02). However, when adjusted for baseline mean arterial pressure and gestation, the effect was not significant (p = 0.14). Numbers of women prescribed antihypertensive medication postrandomization were similar (guided imagery: n = 16; quiet rest: n = 13, χ(2) = 0.74, p = 0.46). There was also no evidence of an effect on women's anxiety. Nearly 90 percent (n = 26) of the guided imagery group indicated that they would use it again. Further rigorous study is warranted to determine effects of guided imagery on maternal blood pressure and perinatal health outcomes.


Organised genome dynamics in the Escherichia coli species results in highly diverse adaptive paths.
The Escherichia coli species represents one of the best-studied model organisms, but also encompasses a variety of commensal and pathogenic strains that diversify by high rates of genetic change. We uniformly (re-) annotated the genomes of 20 commensal and pathogenic E. coli strains and one strain of E. fergusonii (the closest E. coli related species), including seven that we sequenced to completion. Within the approximately 18,000 families of orthologous genes, we found approximately 2,000 common to all strains. Although recombination rates are much higher than mutation rates, we show, both theoretically and using phylogenetic inference, that this does not obscure the phylogenetic signal, which places the B2 phylogenetic group and one group D strain at the basal position. Based on this phylogeny, we inferred past evolutionary events of gain and loss of genes, identifying functional classes under opposite selection pressures. We found an important adaptive role for metabolism diversification within group B2 and Shigella strains, but identified few or no extraintestinal virulence-specific genes, which could render difficult the development of a vaccine against extraintestinal infections. Genome flux in E. coli is confined to a small number of conserved positions in the chromosome, which most often are not associated with integrases or tRNA genes. Core genes flanking some of these regions show higher rates of recombination, suggesting that a gene, once acquired by a strain, spreads within the species by homologous recombination at the flanking genes. Finally, the genome's long-scale structure of recombination indicates lower recombination rates, but not higher mutation rates, at the terminus of replication. The ensuing effect of background selection and biased gene conversion may thus explain why this region is A+T-rich and shows high sequence divergence but low sequence polymorphism. Overall, despite a very high gene flow, genes co-exist in an organised genome.


Do Performance-based Health Measures Reflect Differences in Frailty Among Immigrants Age 50+ in Europe?
Life course influences, including country of residence and country of birth, are associated with frailty index scores. We investigated these associations using performance-based health measures. Among 33,745 participants age 50+ (mean age 64.8 ± 10.1; 55% women) in the Survey of Health, Ageing, and Retirement in Europe, grip strength, delayed word recall, and semantic verbal fluency were assessed. Participants were grouped by country of residence (Northern/Western Europe or Southern/Eastern Europe), and by country of birth (native-born, immigrants born in low- and middle-income countries [LMICs], or immigrants born in high-income countries [HICs]). Participants in Southern/Eastern Europe had lower mean test scores than those in Northern/Western Europe, and their scores did not differ by country of birth group. In Northern/Western Europe, compared with native-born participants, LMIC-born immigrants demonstrated lower mean grip strength (32.8 ± 7.6 kg vs. 35.7 ± 7.7 kg), delayed recall (2.9 ± 1.9 vs. 3.6 ± 1.9), and verbal fluency scores (16.0 ± 6.9 vs. 20.3 ± 7.0). HIC-born immigrants had mean scores higher than LMIC-born immigrants, but lower than native-born participants (all p<.001). Cognitive and motor performance, measured from late middle age, were associated with national income levels of both country of residence and country of birth. This was similar to previously observed differences in frailty index scores.


Improving Emergency Department flow through optimized bed utilization.
Over the last decade, patient volumes in the emergency department (ED) have grown disproportionately compared to the increase in staffing and resources at the Toronto Western Hospital, an academic tertiary care centre in Toronto, Canada. The resultant congestion has spilled over to the ED waiting room, where medically undifferentiated and potentially unstable patients must wait until a bed becomes available. The aim of this quality improvement project was to decrease the 90th percentile of wait time between triage and bed assignment (time-to-bed) by half, from 120 to 60 minutes, for our highest acuity patients. We engaged key stakeholders to identify barriers and potential strategies to achieve optimal flow of patients into the ED. We first identified multiple flow-interrupting challenges, including operational bottlenecks and cultural issues. We then generated change ideas to address two main underlying causes of ED congestion: unnecessary patient utilization of ED beds and communication breakdown causing bed turnaround delays. We subsequently performed seven tests of change through sequential plan-do-study-act (PDSA) cycles. The most significant gains were made by improving communication strategies: small gains were achieved through the optimization of in-house digital information management systems, while significant improvements were achieved through the implementation of a low-tech direct contact mechanism (a two-way radio or walkie-talkie). In the post-intervention phase, time-to-bed for the 90th percentile of high-acuity patients decreased from 120 minutes to 66 minutes, with special cause variation showing a significant shift in the weekly measurements.


Longevity of the adult codling moth, Cydia pomonella, and the obliquebanded leafroller, Choristoneura rosaceana, in Washington apple orchards.
The longevity of adult codling moth (Cydia pomonella (L.) Lepidoptera: Tortricidae) and obliquebanded leafroller (Choristoneura rosaceana (Harris) Lepidoptera: Tortricidae) held in shaded vials in the tree canopy was measured during the normal flight periods during 2004 and 2005. In both years all codling moths were dead by 130 degree-days (DD) (21 d) in the spring and 121 DD (8 d) in the summer. On a degree-day basis, data were similar across sex, generation, and year, and a common curve adequately predicted the survival distribution. For the obliquebanded leafroller, there were longevity differences between the sexes, but not between generations or years. Use of empirical quantile-quantile plots showed that the female obliquebanded leafroller lived an average of 32% longer than males. Maximum longevity observed in these studies for obliquebanded leafrollers was 117 DD (11 d) across both generations. The implications of these data for population biology studies and quarantine requirements are discussed.


Effects of perceived and objective neighborhood crime on walking frequency among midlife African American women in a home-based walking intervention.
Crime may be a significant barrier to physical activity for urban African American women, yet few studies have examined this relationship in intervention studies. This study examines relationships among neighborhood crime incidents, perceptions of crime and safety, and adherence in a walking intervention among urban, midlife African-American women. The sample includes 148 women living in the City of Chicago. Violent crimes, disorder crimes, gun violence, and crime-related safety were examined. Adherence to walking frequency was measured as the percentage of recommended walks completed. Controlling for demographic characteristics and treatment group, multivariate regression analyses showed walking adherence was not associated with any of the crime measures or crime-related safety (R(2) = 0.130 to 0.147). The effect of enhanced treatment did not differ by levels of objective or perceived neighborhood crime or safety. Weak to moderate bivariate correlations were observed between objective crime measures and perceived disorder crime and crime-related safety (r = 0.04 to 0.25). Weak correlations between perceived and objective crime measures suggest they are measuring different aspects of the crime environment. Future studies should examine perceived and objective measures in other populations and settings and other neighborhood social factors which may moderate crime and safety effects on outcomes of physical activity interventions.


Activity and subcellular distribution of cathepsins in primary human monocytes.
Cathepsins (Cat) in antigen presenting cells (APC) control antigen processing as well as major histocompatibility complex class II transport and function. The set of active Cat and the subcellular architecture of the class II antigen presentation compartment are largely unknown in primary human APC, including peripheral blood monocytes. We used novel chemical tools to visualize Cat in an activity-dependent manner. Primary human monocytes contained active CatS, -B, and -H, while CatL was absent. Expression and activity patterns of Cat in human myelo-monocytoid cell lines were distinct from those found in primary cells. On a subcellular scale, the bulk of active Cat was concentrated in lysosomes in primary monocytes. In late endosomes, only active CatS was found in sizable amounts, colocalizing with C-terminal processing of the class II invariant chain and with cystatin C, the major endogenous Cat inhibitor. Late endosomes of human peripheral blood monocytes contain a well-controlled proteolytic machinery distinct from lysosomes, which is likely to play a key role in class II function.


Establishing neonatal networks: the reality.
Managed clinical networks for neonatal care were established in England from 2004. Their structure and effectiveness varies widely over the country. Changes in medical manpower and the scarcity of neonatal nurses make the move towards networks urgent, but there is little evidence of a coordinated approach to improving capacity in the tertiary centres, who will have to absorb the activity that follows reconfiguration. Changes in the governance of hospitals, NHS authority boundaries and in commissioning specialist services, with the drive towards reducing health costs, places the process at some considerable risk. Despite these challenges, the development of coordinated clinical networks will be an important force in improving outcome for very preterm babies in the UK. The development of some form of national coordination of network activities and greater sharing of good practice would enhance the value of the managed clinical neonatal networks.


Rare association of human herpesvirus 6 DNA with human papillomavirus DNA in cervical smears of women with normal and abnormal cytologies.
We investigated by nested PCR the possible association of human herpesvirus 6 (HHV-6) and human papillomavirus (HPV) genomes in the cervixes of 109 women with normal and abnormal cytological smears. HPV DNA was detected in 8.33% of 24 women with normal cytologies and in 41.1% of 85 women with abnormal cytologies; the proportion of HPV DNA was directly related to the severity of the lesions. HHV-6 DNA was found in only one patient, who had a cytological pattern of koilocytosis. The HHV-6 genome was classified by restriction enzyme analysis as variant B. The study indicates that detection of the HHV-6 genome in the cervixes of women with a wide spectrum of gynecological complaints is a rare event and rules out the possible association between HHV-6 and HPV genomes in cervical cancer lesions.


The effect of pain relief on dynamic changes in lumbar curvature.
Lumbar curvature is important in the assessment of low back pain (LBP). It is often reported that changes in curvature seen in LBP sufferers are an adaptive response to pain. Studies investigating this hypothesis employing an experimental pain relief model have failed to isolate pain relief in their interventions. Therefore the purpose of this study was to investigate the immediate effects of pain relief on dynamic lumbar curvature. Twenty acute and 20 chronic LBP sufferers had their dynamic curvature measured using a novel fibre-optic device during flexion, extension and lifting before and after administration of oral analgesics. Peak curvature changes were examined using paired t-tests, numbers of responders to pain relief and changes in lumbar curvature sequencing were compared between groups using Chi-squared testing. A significant reduction in movement evoked pain was achieved. A significant reduction in kyphosis at end range flexion and lifting was identified for the acute LBP group following pain relief. No significant differences were observed for the chronic low back pain (CLBP) group. Neither the acute nor chronic LBP group were more likely to respond to pain relief by demonstrating alterations in peak curvature or in lumbar sequencing behaviour. These results demonstrate simple targeted pain relief did not result in gains in peak curvature challenging the assumption of movement alteration being possible through pain relief. Dynamic changes in curvature as displayed by sequencing showed that neither acute nor chronic LBP sufferers were more likely to respond to pain relief.


Mitochondrial defects in cancer.
Mitochondria play important roles in cellular energy metabolism, free radical generation, and apoptosis. Defects in mitochondrial function have long been suspected to contribute to the development and progression of cancer. In this review article, we aim to provide a brief summary of our current understanding of mitochondrial genetics and biology, review the mtDNA alterations reported in various types of cancer, and offer some perspective as to the emergence of mtDNA mutations, their functional consequences in cancer development, and therapeutic implications.


Effect of weight loss on blood pressure and drug consumption in normal weight patients.
The effect of weight loss on blood pressure and on antihypertensive drug consumption was examined in 81 nonobese subjects with essential hypertension who had been chronically treated with antihypertensive drugs. A hypocaloric diet was prescribed for 5 months. A weight loss greater than 2 kg in 5 months was considered significant. Quality and quantity of antihypertensive medications were scored according to a formula. In the subjects whose medication and weight did not change, mean arterial pressure remained unchanged, whereas it decreased significantly (-7.1 +/- 1.9 mm Hg) in those who showed significant weight loss (-3.28 +/- 0.34 kg) with no change in medication. Among the subjects whose antihypertensive medication remained constant during the diet program there was a significant correlation between the change in weight and mean arterial pressure (r = 0.45, p less than 0.01). Mean arterial pressure increased significantly (+5.1 +/- 1.7 mm Hg) in subjects whose weight remained unchanged with a decrease in medication, whereas it remained significantly lower than the control (by -3.1 +/- 2.0 mm Hg) in those whose weight decreased significantly (-4.57 +/- 0.69 kg) with the decrease in medication. The weight loss-induced decrease in blood pressure occurred independently of the initial degree of obesity and the initial level of mean arterial pressure. Urinary sodium excretion in the control period and at the end of the diet program did not differ significantly between subgroups. These results indicate that, even in subjects of normal weight with essential hypertension, weight loss can induce a fall in blood pressure that leads to a reduction of antihypertensive medication.(ABSTRACT TRUNCATED AT 250 WORDS)


Multi-level control of adaptive camouflage by European cuttlefish.
To camouflage themselves on the seafloor, European cuttlefish Sepia officinalis control the expression of about 30 pattern components to produce a range of body patterns.1 If each component were under independent control, cuttlefish could produce at least 230 patterns. To examine how cuttlefish deploy this vast potential, we recorded cuttlefish on seven experimental backgrounds, each designed to resemble a pattern component, and then compared their responses to predictions of two models of sensory control of component expression. The body pattern model proposes that cuttlefish integrate low-level sensory cues to categorize the background and co-ordinate component expression to produce a small number of overall body patterns.2-4 The feature matching model proposes that each component is expressed in response to one (or more) local visual features, and the overall pattern depends upon the combination of features in the background. Consistent with the feature matching model, six of the backgrounds elicited a specific set of one to four components, whereas the seventh elicited eleven components typical of a disruptive body pattern. This evidence suggests that both modes of control are important, and we suggest how they can be implemented by a recent hierarchical model of the cuttlefish motor system.5,6.


Nursing care delivery models and nurse satisfaction.
The relative impact of various nursing care delivery models and management interventions on nurse satisfaction was assessed in 37 New Jersey hospitals. Nurses ranked pay as the most important factor, followed by autonomy and professional status. Changes in scores between pilot and comparison units were significantly different for satisfaction with interactions and task requirements. Change in satisfaction with interaction was significant for all initiatives in aggregate, as well as for each of the five types of initiatives separately. The change in satisfaction with task requirements was significant for all initiatives taken as a group and for those units that implemented reorganization, computer, and education initiatives. Even among nurses who eventually liked the new environment there was a period of initial dissatisfaction.


Immunological persistence in 5 y olds previously vaccinated with hexavalent DTPa-HBV-IPV/Hib at 3, 5, and 11 months of age.
The combined diphtheria-tetanus-acellular pertussis-hepatitis B-poliomyelitis/Haemophilus influenza vaccine (DTPa-HBV-IPV/Hib: Infanrix™ hexa, GlaxoSmithKline Vaccines) is used for primary vaccination of infants in a range of schedules world-wide. Antibody persistence after 4 DTPa-HBV-IPV/Hib doses in the first 2 y of life has been documented, but long-term persistence data following the 3, 5, 11-12 months (3-5-11) infant vaccination schedule, employed for example in Nordic countries, are limited. We assessed antibody persistence in 57 5-year-old children who had received either DTPa-HBV-IPV/Hib or DTPa-IPV/Hib (Infanrix™-IPV/Hib, GlaxoSmithKline Vaccines) in the 3-5-11 schedule. Among DTPa-HBV-IPV/Hib recipients, 7/12 retained seroprotective antibody concentrations for diphtheria, 10/12 for tetanus, 5/12 for hepatitis and 10/12 for Hib. Detectable antibodies were observed for 0/12 children for pertussis toxin (PT), 12/12 for filamentous haemagglutinin (FHA) and 8/12 for pertactin (PRN). Among DTPa-IPV/Hib recipients, 28/45 retained seroprotective anti-diphtheria concentrations, 34/44 for tetanus and 40/45 for Hib. Detectable antibodies were observed for 9/45 children for PT, 41/45 for FHA and 34/45 for PRN. Antibody persistence in DTPa-HBV-IPV/Hib and DTPa-IPV/Hib-vaccinees appeared similar in 5 y olds to that previously observed in children of a similar age who had received 4 prior doses of DTPa-HBV-IPV/Hib (or DTPa-IPV/Hib). As in subjects primed with 4 prior doses, we observed that antibodies markedly declined by 5 y of age, calling for the administration of a pre-school booster dose in order to ensure continued protection against pertussis.


Predicted Impact of the Food and Drug Administration's Menu-Labeling Regulations on Restaurants in 4 New Jersey Cities.
To determine the proportion of restaurants that will be required to post calorie information under the Food and Drug Administration's menu-labeling regulations in 4 New Jersey cities. We classified geocoded 2014 data on 1753 restaurant outlets in accordance with the Food and Drug Administration's guidelines, which will require restaurants with 20 or more locations nationwide to post calorie information. We used multivariate logistic regression analyses to assess the association between menu-labeling requirements and census tract characteristics. Only 17.6% of restaurants will be affected by menu labeling; restaurants in higher-income tracts have higher odds than do restaurants in lower-income tracts (odds ratio [OR] = 1.55; P = .02). Restaurants in non-Hispanic Black (OR = 1.62; P = .02) and mixed race/ethnicity (OR = 1.44; P = .05) tracts have higher odds than do restaurants in non-Hispanic White tracts of being affected. Additional strategies are needed to help consumers make healthy choices at restaurants not affected by the menu-labeling law. These findings have implications for designing implementation strategies for the law and for evaluating its impact.


Endogenous retroviruses lead to the expression of a histocompatibility antigen detectable by skin graft rejection.
Mov mouse strains differ from their respective, coisogenic partner strains by the embryonic, germ-line introduction of Moloney murine leukemia virus genomes. The possibility that retroviral insertions into the mouse genome resulted in gain or loss mutations at non-H-2 histocompatibility loci was investigated by reciprocal skin grafting between Mov mice and mice from coisogenic, background strains. Two B6-derived and eight 129-derived Mov strains were analyzed. B6 mice rejected skin from the viremic Mov-3 and Mov-14 strains, indicating that these mice had new histocompatibility antigens. No rejections were observed with reciprocal skin grafts exchanged between mice of the 129 background strain and 129-derived Mov strains, one of which (Mov-9) is viremic. To investigate the potential viral origin of the new histocompatibility antigen in Mov-14, lymphocytes from B6 mice primed in vivo with Mov-14 cells or skin were restimulated in vitro with Mov-14 spleen cells and with two retroviral-induced B6 lymphomas, MBL-2 and RBL-5. All three cell types stimulated cytotoxic lymphocytes that lysed Mov-14 Con A lymphoblasts, MBL-2 and RBL-5. The same cytotoxic lymphocytes lysed only lymphoblasts from the viremic Mov-9 strain when tested on cells from 129 and 129 Mov mice. Thus the insertion and expression of exogenous Moloney murine leukemia virus results in the appearance of a new histocompatibility antigen as defined by its stimulation of skin-graft rejection and cytotoxic effector T-cell generation. The non-H-2 histocompatibility antigen identified in this study has been designated H-43 and is encoded by genes mapping to different loci in different Mov strains. These observations suggest that at least a subgroup of non-H-2 histocompatibility antigens is encoded by endogenous retroviruses; the implications of these results for understanding the origin and the identity of non-H-2 histocompatibility antigens are discussed.


Bibliometric analysis of the volume and visibility of Saudi publications in leading anesthesia journals.
The quantity and quality of publications by a country indicates its contribution towards scientific development. To examine the volume and impact of the Saudi anesthesia publications in leading anesthesia journals. Fifteen leading anesthesia journals were identified. Saudi publications in these journals from 1991 to 2011 were searched in the databases of Pubmed and Web of Knowledge. For each article, the journal and time of publication, the type of the article and the affiliation of the first author were analysed. The visibility of the publications was related to the number of citations and was analysed for the years 2000 to 2008. Data were compared with selected Arab countries. Two visibility indices were used. The first relates the average citations per Saudi articles in the years following publication to the average global citations. The second relates the average citations per Saudi article in the two years following publication to the impact factor of the journal of publication. The h-index was used as a measure of both volume and visibility. Anesthesiologists from Saudi affiliations published 173 documents in leading 15 anesthesia journals betweent the years 1991-2011, with a marked increase in the last 6 years. Anesthesia and Analgesia journal published 24% of Saudi articles. Saudi universities contributed to 55% of Saudi publications. The visibility of the Saudi articles was 0.7 of the international figures. Saudi anesthesia publications are increasing in recent years. Although the visibility of Saudi publications is below international figures, it compares favourably to Arab countries.


Identification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1).
Recent research suggests that variation in the gene encoding dystrobrevin binding protein (DTNBP1) confers susceptibility to schizophrenia. Thus far, no specific risk haplotype has been identified in more than 1 study. To confirm DTNBP1 as a schizophrenia susceptibility gene, to identify and replicate specific risk and protective haplotypes, and to explore relationships between DTNBP1 and the phenotype. Genetic association study based on mutation detection and case-control analysis. All subjects were unrelated and ascertained from general (secondary care) psychiatric inpatient and outpatient services. The Cardiff, Wales, sample included 708 white subjects from the United Kingdom and Ireland (221 females) who met DSM-IV criteria for schizophrenia and were individually matched for age, sex, and ethnicity to 711 blood donor controls (233 females). Mean +/- SD age at first psychiatric contact for cases was 23.6 +/- 7.7 years; mean age at ascertainment was 41.8 +/- 13.5 years. The Dublin, Ireland, sample included 219 white subjects from the Republic of Ireland who met DSM-III-R criteria for schizophrenia or schizoaffective disorder and 231 controls. The mean age of the Irish cases was 46.0 +/- 8.5 years; mean age at first psychiatric contact was 25.2 +/- 12.4 years. Evidence for association between the DTNBP1 locus and schizophrenia. In the Cardiff sample, there was no evidence for association with previously implicated haplotypes but strong evidence for association with multiple novel haplotypes. Maximum evidence was found for a novel 3-marker haplotype (global P<.001), composed of 1 risk haplotype (P =.01) and 2 protective haplotypes, 1 common (P =.006) and 1 rare (P<.001). Specific risk and protective haplotypes were replicated in the Dublin sample (P =.02,.047, and.006, respectively). The only phenotypic variable associated with any haplotype was between the common protective haplotype and higher educational achievement (P =.02, corrected for multiple tests). DTNBP1 is a susceptibility gene for schizophrenia. Specific risk and protective haplotypes were identified and replicated. Association with educational achievement may suggest protection mediated by IQ, although this needs to be confirmed in an independent data set.