Linkage of the US National Health Interview Survey to air monitoring data: an evaluation of different strategies.
The goal of this study is to describe linkages between the National Health Interview Survey (NHIS) and Environmental Protection Agency (EPA) air monitoring data, specifically how the linkage method affects characteristics and exposure estimates of study samples and estimated associations between exposure and health. In the USA, nationally representative health data are collected in the NHIS and annual air quality data are collected by the EPA. The linkage of these data for research is not straightforward and the choices made may introduce bias into results. The 2000-2003 NHIS and air quality data for six air pollutants were linked by residential block group and monitor location, which differ by pollutants. For each pollutant, three annual exposure variables were assigned to respondents: (1) average of all monitors in the county, (2) of monitors within a 5-mile radius of the distance between block group and monitor, and (3) within a 20-mile radius. Exposure estimates, study sample characteristics, and association between fine particle exposure and respondent-reported health status were compared for different geographic linkage methods. The results showed that study sample characteristics varied by geographic linkage method and pollutant linked. Generally, the fewer the NHIS respondents linked, the higher is the pollution exposure and lower is the percentage of non-Hispanic whites. After adjustment for sociodemographic and geographic factors, associations between fine particles and health status were generally comparable across study samples. Because exposure information is not available for all potential participants in an epidemiological study, selection effects should be considered when drawing inferences about air quality-health associations. With the current monitoring data system, the study sample is substantially reduced when linkage to multiple pollutants is performed.


Conformational properties of intrinsically disordered proteins bound to the surface of silica nanoparticles.
Protein-nanoparticle (NP) interactions dictate properties of nanoconjugates relevant to bionanotechnology. Non-covalent adsorption generates a protein corona (PC) formed by an inner and an outer layer, the hard and soft corona (HC, SC). Intrinsically disordered proteins (IDPs) exist in solution as conformational ensembles, whose response to the presence of NPs is not known. Three IDPs (α-casein, Sic1 and α-synuclein) and lysozyme are compared, describing conformational properties inside HC on silica NPs by circular dichroism (CD) and Fourier-transform infrared (FTIR) spectroscopy. IDPs inside HC are largely unstructured, but display small, protein-specific conformational changes. A minor increase in helical content is observed for α-casein and α-synuclein, reminiscent of membrane effects on α-synuclein. Frozen in their largely disordered conformation, bound proteins do not undergo folding induced by dehydration, as they do in their free forms. While HC thickness approaches the hydrodynamic diameter of the protein in solution for lysozyme, it is much below the respective values for IDPs. NPs boost α-synuclein aggregation kinetics in a dose-dependent manner. IDPs maintain structural disorder inside HC, experiencing minor, protein-specific, induced folding and stabilization against further conformational transitions, such as formation of intermolecular beta-sheets upon dehydration. The HC is formed by a single layer of protein molecules. SC likely plays a key role stabilizing amyloidogenic α-synuclein conformers. Protein-NP interactions can mimic those with macromolecular partners, allowing dissection of contributing factors by rational design of NP surfaces. Application of NPs in vivo should be carefully tested for amyloidogenic potential.


A comparison of exposure assessment approaches: lung cancer and occupational asbestos exposure in a population-based case-control study.
In attempts to overcome the limitations of self-reported data in occupational health research, job-exposure matrices, which assign exposure by occupation, have emerged as an objective approach for assessing occupational exposures. On the basis of a lung cancer case-control study conducted in the Greater Toronto Area, 1997-2002, assessment of occupational exposure to asbestos was compared using self-reports and a general population job-exposure matrix (DOM-JEM). Cases and frequency matched controls provided life-time job histories and self-reported exposures to potential lung carcinogens including asbestos through a detailed questionnaire. Exposure to asbestos was also assigned to each job by linking occupational histories with DOM-JEM. Agreement in classification of exposed and unexposed jobs according to self-reports and DOM-JEM was evaluated using Cohen's κ. Risks for lung cancer were estimated using unconditional logistic regression for each exposure assessment approach. The prevalence of occupational asbestos exposure was greater when based on DOM-JEM than when based on self-reports. Agreement in classifying exposure to jobs between the two assessment approaches was poor. The risk of lung cancer was not elevated among workers who self-reported asbestos exposure, whereas workers considered exposed on the basis of DOM-JEM were almost twice as likely as unexposed workers to be diagnosed with lung cancer (OR 1.9, 95% CI 1.3 to 2.7). It is generally assumed by epidemiologists that self-reported exposure assessments result in inflated risk estimates. In this study, self-reports found no association with a well-established risk factor, whereas a high-quality job-exposure matrix revealed relative risk estimates that are more consistent with previous findings.


HIV incidence, risk factors, and motivation for biomedical intervention among gay, bisexual men, and transgender persons in Northern Thailand.
HIV prevalence among men who have sex with men (MSM) and transgender (TG) persons is high and increasing in Chiang Mai, northern Thailand. To describe demographic, socioeconomic, sexual behavior and interest in future HIV prevention trials among gay and bisexual MSM and TG presenting for HIV testing (VCT) and pre-screening for the iPrEx pre-exposure chemoprophylaxis trail. In 2008-09, MSM/TG participants attending VCT were interviewed and tested for HIV and STI. Univariate and multivariate regression analyses were done to assess associations with HIV infection. A total of 551 MSM clients (56.1% gay, 25.4% TG, and 18.5% bisexual (BS)) were enrolled. The mean age was 23.9 years. HIV prevalence among MSM overall was 12.9% (71/551); 16.5% among gay men, 9.3% among TG, and 6.9% among BS. Consistent use of condom was low, 33.3% in insertive anal sex and 31.9% in receptive anal sex. Interest in participation was high, 86.3% for PrEP, 69.7% for HIV vaccine trials, but 29.9% for circumcision. HIV was independently associated with being gay identified, aOR 2.8, p = 0.037 and with being aged 25-29, aOR 2.7, p = 0.027. Among repeat testers, HIV incidence was 8.2/100 PY, 95% CI, 3.7/100PY to 18.3/100PY. HIV risks and rates varied by self-reported sexual orientation and gender identity. HIV was associated with sexual practices, age, and being gay-identified. These are populations are in need of novel prevention strategies and willing to participate in prevention research.


Retirement intentions of general practitioners aged 45-65 years.
To ascertain the retirement intentions of a cohort of Australian general practitioners. Postal questionnaire survey of members of four Divisions of General Practice in Western Australia, sent out November 2007 - January 2008. A sample of 178 GPs aged 45-65 years. Intention to work in general practice until retirement; reasons for retiring before age 65 years; factors that might encourage working beyond chosen retirement age; and perceived obstacles to working in general practice. 63% of GPs intended to work to at least age 65 years, with men more likely to retire early. Of 63 GPs intending to retire early, 46% gave pressure of work, exhaustion and burnout as reasons for early retirement. Better remuneration, better staffing levels and more general support were incentives to continue working for 46% of the 64 GPs who responded to the question about incentives, and more flexible working hours, part-time work and reduced workload for 41%. Of 169 participants, 65% gave increasing bureaucracy, poor job satisfaction and disillusionment with the medical system or Medicare as obstacles to working in general practice in Australia, whereas workforce shortage, increasing patient demands and diminishing lifestyle through overwork were obstacles named by 48%. Many GPs are planning to retire early, reflecting an emerging trend among professionals and society generally. Declining job satisfaction, falling workforce numbers, excessive workload and increasing bureaucracy were recurrent concerns of older WA GPs considering premature retirement.


Discovery of 2-aminoimidazole and 2-amino imidazolyl-thiazoles as non-xanthine human adenosine A3 receptor antagonists: SAR and molecular modeling studies.
A small-molecule combinatorial library of 24 compounds with 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives was synthesized using a 2-chloro trityl resin. The generated compound library was tested against all the human adenosine receptors subtypes. The 2-aminoimidazole derivatives (6a-6l) showed weak to moderate affinity towards the human adenosine receptors. Further modification to 2-aminoimidazolyl-thiazole derivatives (12a-12l) resulted in an improvement of affinity at adenosine A1, A2A and A3 receptor subtypes. Compound 12b was the most potent and selective non-xanthine human adenosine A3 receptor antagonist of this series. A receptor-based modeling study was performed to explore the possible binding mode of these novel 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives into human adenosine A1, A2A and A3 receptor subtypes.


Novel poly(vinyl alcohol)-based amphiphilic nanogels by non-covalent boric acid crosslinking of polymeric micelles.
In this work, we report a new type of poly(vinyl alcohol)-g-poly(N-isopropylacrylamide) (PVA-g-PNiPAAm) amphiphilic nanogel produced by the non-covalent crosslinking of PVA polyol domains in preformed polymeric micelles with boric acid. The nanomaterials showed sizes in the 100-250 nm range (DLS) and a spherical morphology (HR-SEM). We demonstrated that the size of the polymeric micelles could be fine-tuned by changing the concentration (and the aggregation pattern) of the polymeric amphiphile in water. Upon crosslinking, the polymeric micelles turned into physically stable amphiphilic nanogels that displayed both size and size distribution similar to the micellar precursor for up to two weeks, even under disfavored conditions of concentration and temperature that, in the case of non-crosslinked counterparts, resulted in quick disassembly. In addition, we show for the first time the feasibility of spray-drying technology to consolidate the 3D network formed between PVA and boric acid and to produce stable powders that can be reconstituted upon use at any desired concentration. Moreover, the formation of a borated surface conferred the nanogels with good mucoadhesiveness in vitro. Finally, these novel nanomaterials showed optimal cell compatibility in a model of the intestinal epithelium, the Caco2 cell line. Overall results demonstrate the unprecedented versatility of the proposed modular approach and opens completely new horizons in the application of polymeric micelles and other self-assembled polymeric nanomaterials in diagnostics and therapeutics.


Effects of daily temperature highs on development of Phakopsora pachyrhizi on soybean.
Although considerable information exists regarding the importance of moisture in the development of soybean rust, little is known about the influence of temperature. The purpose of our study was to determine whether temperature might be a significant limiting factor in the development of soybean rust in the southeastern United States. Soybean plants infected with Phakopsora pachyrhizi were incubated in temperature-controlled growth chambers simulating day and night diurnal temperature patterns representative of the southeastern United States during the growing season. At 3-day intervals beginning 12 days after inoculation, urediniospores were collected from each plant and counted. The highest numbers of urediniospores were produced when day temperatures peaked at 21 or 25°C and night temperatures dipped to 8 or 12°C. When day temperatures peaked at 29, 33, or 37°C for a minimum of 1 h/day, urediniospore production was reduced to 36, 19, and 0%, respectively, compared with urediniospore production at the optimum diurnal temperature conditions. Essentially, no lesions developed when the daily temperature high was 37°C or above. Temperature data obtained from the National Climatic Data Center showed that temperature highs during July and August in several southeastern states were too high for significant urediniospore production on 55 to 77% of days. The inhibition of temperature highs on soybean rust development in southeastern states not only limits disease locally but also has implications pertaining to spread of soybean rust into and development of disease in the major soybean-producing regions of the Midwestern and northern states. We concluded from our results that temperature highs common to southeastern states are a factor in the delay or absence of soybean rust in much of the United States.


Pimpinella anisum in modifying the quality of life in patients with functional dyspepsia: A double-blind randomized clinical trial.
We aimed to assess the effects of anise on quality of life (QOL) of patients with functional dyspepsia (FD) in a double-blind randomized clinical trial. Of 180 patients attending the gastroenterology clinic, 107 ones with the diagnosis of postprandial distress syndrome according to Rome III criteria were enrolled. They were randomized into two groups, anise and placebo. Anise group involved 47 patients and received anise powders, 3 g after each meal (3 times/day) for 4 weeks. Control group had 60 patients who received placebo powders (cornstarch), 3 g after each meal (3 times/day) for 4 weeks. The QOL was assessed by short-form (SF)-36 questionnaire. Mean scores of eight health domains of the two groups were compared at baseline and at the end of study. The age, sex, body mass index, smoking history, tea and coffee drinking patterns of the two groups were not significantly different. All domains of SF-36 were similar between the two groups at baseline but were significantly different at week 12. At baseline, mean score of physical component summary was 159 in placebo group and 167 in anise group (P = 0.1). At week 12, the score was 141 in placebo group and 251 in anise group (P = 0.0001). Mean baseline score of mental component summary was 172 and 165 in placebo and anise groups, respectively (P = 0.1). At week 12, the score was 135 in placebo group and 233 in anise group (P = 0.0001). The current study revealed the effectiveness of anise in improvement of QOL in patients with FD.


Dual-modality probe intended for prostate cancer detection combining Raman spectroscopy and tactile resonance technology--discrimination of normal human prostate tissues ex vivo.
Prostate cancer is the most common cancer for men in the western world. For the first time, a dual-modality probe, combining Raman spectroscopy and tactile resonance technology, has been used for assessment of fresh human prostate tissue. The study investigates the potential of the dual-modality probe by testing its ability to differentiate prostate tissue types ex vivo. Measurements on four prostates show that the tactile resonance modality was able to discriminate soft epithelial tissue and stiff stroma (p < 0.05). The Raman spectra exhibited a strong fluorescent background at the current experimental settings. However, stroma could be discerned from epithelia by integrating the value of the spectral background. Combining both parameters by a stepwise analysis resulted in 100% sensitivity and 91% specificity. Although no cancer tissue was analysed, the results are promising for further development of the instrument and method for discriminating prostate tissues and cancer.


A novel banded structure ceramic phosphor for high-power white LEDs.
A novel banded structure ceramic phosphor has been fabricated in this research. This structure provides a convenient and effective method for regulating the full spectrum. It has the advantage of being able to adjust the intensity of all three primary colors independently, regardless of the mutual absorption among different active ions.


Pairwise Operator Learning for Patch-Based Single-Image Super-Resolution.
Motivated by the fact that image patches could be inherently represented by matrices, single-image super-resolution is treated as a problem of learning regression operators in a matrix space in this paper. The regression operators that map low-resolution image patches to high-resolution image patches are generally defined by the left and right multiplication operators. The pairwise operators are, respectively, used to extract the raw and column information of low-resolution image patches for recovering high-resolution estimations. The patch-based regression algorithm possesses three favorable properties. First, the proposed super-resolution algorithm is efficient during both training and testing, because image patches are treated as matrices. Second, the data storage requirement of the optimal pairwise operator is far less than most popular single-image super-resolution algorithms, because only two small sized matrices need to be stored. Last, the super-resolution performance is competitive with most popular single-image super-resolution algorithms, because both raw and column information of image patches is considered. Experimental results show the efficiency and effectiveness of the proposed patch-based single-image super-resolution algorithm.


A fourth-order Runge-Kutta in the interaction picture method for numerically solving the coupled nonlinear Schrodinger equation.
A fourth-order Runge-Kutta in the interaction picture (RK4IP) method is presented for solving the coupled nonlinear Schr odinger equation (CNLSE) that governs the light propagation in optical fibers with randomly varying birefringence. The computational error of RK4IP is caused by the fourth-order Runge-Kutta algorithm, better than the split-step approximation limited by the step size. As a result, the step size of RK4IP can have the same order of magnitude as the dispersion length and/or the nonlinear length of the fiber, provided the birefringence effect is small. For communication fibers with random birefringence, the step size of RK4IP can be orders of magnitude larger than the correlation length and the beating length of the fibers, depending on the interaction between linear and nonlinear effects. Our approach can be applied to the fibers having the general form of local birefringence and treat the Kerr nonlinearity without approximation. Our RK4IP results agree well with those obtained from Manakov-PMD approximation, provided the polarization state can be mixed enough on the Poincar e sphere.


The evaluation of an inexpensive, 2D, video based gait assessment system for clinical use.
The purpose of this study was to investigate the clinical potential of an augmented-video-based-portable-system (AVPS). The AVPS included a walkway grid mat made of vinyl flooring, flat paper bull's eye markers, four photoswitches mounted on tripods, a light-indicator, a video camera, and a computer with ProTrainer System software. The AVPS output was compared to a "gold standard" 3D Vicon Motion Analysis System both statically and dynamically over a fixed range (-90° to +90°) using a two-segment-goniometric-rig marked with both bull's eye and retroreflective markers. At each segment angle position, three trials of data were captured. The reliability of the AVPS was also tested using three raters. Further twelve, young, healthy subjects participated in a concurrent validity study in which they performed six gait trials which were simultaneously recorded by both systems. Both motion analysis systems showed low levels of intra subject variability in all kinematic variables indicated by the size of the standard deviations across the six trials. There were no significant differences between the motion systems with respect to the kinematic variables (P>0.05). The results showed a high intra- and inter-rater reliability for both the kinematic and temporo-spatial parameters. With respect to gait events the lowest ICC value for the intra-rater reliability test was 0.993 for the kinematic variables, and ranged from 0.941 to 0.956 for the temporo-spatial variables and 0.731 to 0.954 for the tibia inclination angles. The validation data suggest the AVPS is capable of generating highly reliable and repeatable data when applied to normal subjects and could be used within the clinical setting.


Simultaneous imaging of two-photon absorption and stimulated Raman scattering by spatial overlap modulation nonlinear optical microscopy.
Imaging of simultaneous two-photon absorption and stimulated Raman scattering is accomplished by detecting the intensity changes of the two-color pulses simultaneously and the mathematical operations of addition and subtraction. The stimulated Raman scattering is quantitatively separated from the two-photon absorption, generated in a mixed solution in which a glycerin solution is miscible in various proportions with a quantum dot solution. Our technique is applied to simultaneous two-photon absorption and stimulated Raman scattering imaging.


The impact of heterochromatin on DSB repair.
DNA NHEJ (non-homologous end-joining) is the major DNA DSB (double-strand break) repair pathway in mammalian cells. Although NHEJ-defective cell lines show marked DSB-repair defects, cells defective in ATM (ataxia telangiectasia mutated) repair most DSBs normally. Thus NHEJ functions independently of ATM signalling. However, approximately 15% of radiation-induced DSBs are repaired with slow kinetics and require ATM and the nuclease Artemis. DSBs persisting in the presence of an ATM inhibitor, ATMi, localize to heterochromatin, suggesting that ATM is required for repairing DSBs arising within or close to heterochromatin. Consistent with this, we show that siRNA (small interfering RNA) of key heterochromatic proteins, including KAP-1 [KRAB (Krüppel-associated box) domain-associated protein 1], HP1 (heterochromatin protein 1) and HDAC (histone deacetylase) 1/2, relieves the requirement for ATM for DSB repair. Furthermore, ATMi addition to cell lines with genetic alterations that have an impact on heterochromatin, including Suv39H1/2 (suppressor of variegation 3-9 homologue 1/2)-knockout, ICFa (immunodeficiency, centromeric region instability, facial anomalies syndrome type a) and Hutchinson-Guilford progeria cell lines, fails to have an impact on DSB repair. KAP-1 is a highly dose-dependent, transient and ATM-specific substrate, and mutation of the ATM phosphorylation site on KAP-1 influences DSB repair. Collectively, the findings show that ATM functions to overcome the barrier to DSB repair posed by heterochromatin. However, even in the presence of ATM, gamma-H2AX (phosphorylated histone H2AX) foci form on the periphery rather than within heterochromatic centres. Finally, we show that KAP-1's association with heterochromatin is diminished as cells progress through mitosis. We propose that KAP-1 is a critical heterochromatic factor that undergoes specific modifications to promote DSB repair and mitotic progression in a manner that allows localized and transient chromatin relaxation, but precludes significant dismantling of the heterochromatic superstructure.


Comparison of six-month outcomes for primary percutaneous revascularization for acute myocardial infarction with drug-eluting versus bare metal stents (from the APEX-AMI study).
We evaluated the use and outcomes of drug-eluting stents (DESs) and bare metal stents (BMSs) in a large primary percutaneous coronary intervention (PCI) acute ST-elevation myocardial infarction (MI) trial. Recently concerns have been raised with "off-label" use of DESs for short- and long-term clinical outcomes. Limited randomized data exist evaluating DESs versus BMSs in ST-elevation MI. Patients (n=5,745) in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial were categorized by stent type used. Baseline variables and clinical outcomes were collected at 90 days and 6 months. Outcomes by stent type were adjusted for using conventional multivariable predictors of 90-day mortality (age, anterior location, total ST-segment deviation, and Killip class), time to PCI, and Thrombolysis In Myocardial Infarction grade flow. Stents were deployed (at the investigator's discretion) in 5,124 patients (89.2%) with acute MI, with DES use in 2,221 (43.3%) and BMS use in 2,903 (56.7%). Patients receiving DESs were younger (median 59 vs 63 years of age, p<0.001), had left anterior descending coronary artery PCI (57.9% vs 48.1%, p<0.001), and often were treated in the United States (58.2%). DES-treated patients had a lower adjusted mortality at 90 days (hazard ratio 0.73, 95% confidence interval [CI] 0.54 to 0.99, p=0.046) and trended toward lower mortality (hazard ratio 0.77, 95% CI 0.58 to 1.03, p=0.084) and recurrent MI (hazard ratio 0.81, 95% CI 0.59 to 1.11, p=0.186) at 6 months compared with BMSs. In conclusion, in this observational analysis of stent use from a large primary percutaneous intervention for acute MI trial, DESs appear as safe as BMSs with similar 6-month clinical outcomes with regard to death and recurrent MI.


Beyond care burden: associations between positive psychological appraisals and well-being among informal caregivers in Europe.
The burden of caring for a family member or friend can have a negative impact on caregiver health and well-being, yet caring can also have positive consequences. Understanding the factors that may enhance caregiver well-being is merited. We used data gathered from the European Quality of Life Survey (EQLS). Using complete case analysis followed by multiple imputation analysis, a series of multilevel regression models were developed to systematically explore the role of three distinct blocks of factors in predicting caregiver well-being as measured by the WHO-5 well-being index: (1) sociodemographic and health factors, (2) care and burden-related factors, and (3) psychological and social appraisals. Differences between frequent caregivers and the general population were also compared on all measures. 36,908 respondents took part in EQLS, with 4171 (11%) identifying as frequent carers. While frequent caregivers reported lower well-being compared to the remaining population, most were happy with the amount of time spent caring. Our model explained approximately 32% of variance in well-being scores. After examining the role of known risk factors, all positive psychological appraisals were associated with higher well-being (p < .001). In order of magnitude these were optimism, perceived autonomy, sense of purpose, resilience, and perceived levels of social inclusion. Self-rated health was the strongest predictor of well-being while female carers and those with high levels of various burden measures reported lower well-being. Findings suggest that caregiver well-being is influenced by more than simply the burden of care. As well as attempting to reduce burden, interventions aimed at supporting caregivers could focus on fostering more positive appraisals to enhance well-being in this group.


Clinical value of multidetector CT coronary angiography as a preoperative screening test before non-coronary cardiac surgery.
Myocardial scintigraphy and/or conventional angiography (CA) are often performed before cardiac surgery in an attempt to identify unsuspected coronary artery disease which might result in significant cardiac morbidity and mortality. Multidetector CT coronary angiography (MDCTCA) has a recognised high negative predictive value and may provide a non-invasive alternative in this subset of patients. The aim of this study was to evaluate the clinical value of MDCTCA as a preoperative screening test in candidates for non-coronary cardiac surgery. 132 patients underwent MDCTCA (Somatom Sensation 16 Cardiac, Siemens) in the assessment of the cardiac risk profile before surgery. Coronary arteries were screened for > or = 50% stenosis. Patients without significant stenosis (Group 1) underwent surgery without any adjunctive screening tests while all patients with coronary lesions > or = 50% at MDCTCA (Group 2) underwent CA. 16 patients (12.1%) were excluded due to poor image quality. 72 patients without significant coronary stenosis at MDCTCA were submitted to surgery. 30 out of 36 patients with significant (> or = 50%) coronary stenosis at MDCTCA and CA underwent adjunctive bypass surgery or coronary angioplasty. In 8 patients, MDCTCA overestimated the severity of the coronary lesions (> 50% MDCTCA, < 50% CA). No severe cardiovascular perioperative events such as myocardial ischaemia, myocardial infarction or cardiac failure occurred in any patient in Group 1. MDCTCA seems to be effective as a preoperative screening test prior to non-coronary cardiac surgery. In this era of cost containment and optimal care of patients, MDCTCA is able to provide coronary vessel and ventricular function evaluation and may become the method of choice for the assessment of a cardiovascular risk profile prior to major surgery.


Comparative effects on blood lipids and faecal steroids of five legume species incorporated into a semi-purified, hypercholesterolaemic rat diet.
The cholesterolaemic effects in rats of a diet (VS) containing Bambara groundnuts (Vigna subterranea), a popular legume eaten in Nigeria, were compared with diets PV, PS, LC and PL, containing baked beans (Phaseolus vulgaris), marrowfat peas (Pisum sativum), lentils (Lens culinaris Medik.) and butter beans (Phaseolus lunatus) respectively. Sixty Sprague-Dawley rats were fed on hypercholesterolaemic semi-purified diets supplemented with 10 g cholesterol and 5 g cholic acid/kg and formulated to provide 40% of energy from fat, as in a typical Western-type human diet. Legumes were substituted for 330 g/kg of the semi-purified diet on a dry-matter basis, which was modified to maintain the same contribution of energy sources as the control diet C3. Another ten rats were fed on control diet C2, which was similar to diet C3 but with no added cholesterol. The rats were fed for 8 weeks and plasma cholesterol levels were measured at weeks 4 and 8. The diets incorporating the five different legume species produced very different cholesterolaemic effects. Diets PV and PL were more potent at lowering raised plasma cholesterol levels than diets PS and LC. Inclusion of the Bambara groundnut into the semi-purified diet resulted in an exaggeration of hypercholesterolaemia. Differences in cholesterol-lowering capacity of the various legume diets in this experiment could not be related to concentrations of faecal bile acids or neutral sterols. However, there was evidence that the inclusion of legumes in the diets reduced the faecal excretion of secondary bile acids.


Humoral immune response against epidermal growth factor encapsulated in dehydration rehydration vesicles of different phospholipid composition.
We investigated the influence of dehydration-rehydration vesicles (DRV) phospholipid composition and the addition of other components on human recombinant epidermal growth factor (hrEGF) encapsulation efficiency and its release from liposomes. Encapsulation of EGF into DRV composed of phosphatidylcholine with different unsaturation levels was around 20-35%. The best result was obtained with dipalmitoyl phosphatidylcholine: cholesterol (DPPC:Ch) liposomes (35%) corresponding to the lowest hrEGF release during one month of storage. Even with this phospholipid composition, modification of the DRV procedure by including an extrusion step did not improve hrEGF encapsulation efficiency, rendering less stable particles. The inclusion of recombinant P64k from Neisseria meningitidis (rP64k), as such or conjugated to hrEGF, decreased the encapsulation efficiency of the latter protein into DRV or freeze and thaw multilamellar vesicles (FATMLV). The hrEGF release from liposomes could be related to the interaction between this polypeptide and the bilayer, as evidenced by increased carboxyfluorescein release from hrEGF-DRV; less susceptibility to fluorescence quenching by acrylamide in the presence of liposomes; and a measurable decrease of phospholipid phase transition Delta enthalpy (DeltaH). DRV comprising saturated phospholipids (DPPC:Ch or distearoyl phosphatidylcholine [DSPC]:Ch) and containing the conjugate EGF-P64k induced a more efficient immune response against hrEGF than unsaturated phospholipid and alum in terms of total IgG, IgG(2a), and IgG(2b) subclasses and the ability of antibody to inhibit the interaction of the EGF receptor with hrEGF.


Waiting time to parapatric speciation.
Using a weak migration and weak mutation approximation, I studied the average waiting time to parapatric speciation. The description of reproductive isolation used is based on the classical Dobzhansky model and its recently proposed multilocus generalizations. The dynamics of parapatric speciation are modelled as a biased random walk performed by the average genetic distance between the residents and immigrants. If a small number of genetic changes is sufficient for complete reproductive isolation, mutation and random genetic drift alone can cause speciation on the time-scale of ten to 1,000 times the inverse of the mutation rate over a set of loci underlying reproductive isolation. Even relatively weak selection for local adaptation can dramatically decrease the waiting time to speciation. The actual duration of the parapatric speciation process (that is the duration of intermediate forms in the actual transition to a state of complete reproductive isolation) is shorter by orders of magnitude than the overall waiting time to speciation. For a wide range of parameter values, the actual duration of parapatric speciation is of the order of one over the mutation rate. In general, parapatric speciation is expected to be triggered by changes in the environment.


Factors motivating individuals to take precautionary action for an expected earthquake in Istanbul.
Istanbul is expected to experience an earthquake in the near future, but individuals show limited interest in preparing for it. This study aims to identify the factors associated with taking action to prepare for an earthquake and mitigate its effects at the individual level. A field survey was carried out in 2007 in two districts of Istanbul with different levels of earthquake risk. Within these districts, three socioeconomic levels were considered. A total of 1,123 people were interviewed face to face. Analysis indicated that the educational level of the respondents was the leading factor associated with taking at least three measures, followed by living in a higher earthquake risk area, having participated in rescue and solidarity activities in previous earthquakes, a higher level of knowledge about earthquakes, home ownership, a higher score for action-stimulating attitudes, being younger, and a higher general safety score, in that order. The findings pointed to the role of knowledge about earthquakes and possible mitigation/preparedness measures, and thus the importance of developing effective awareness programs. Such programs should also consider the characteristics of different groups in the population. Motivated individuals, such as those who have participated in rescue and solidarity activities in previous earthquakes, could be involved in reaching other people.


Attitude of medical students towards general practice and general practitioners.
The stimuli for this work came from the need to identify and understand the origin of students' attitudes towards general practice in the context of undergraduate curriculum reform and concerns about recruitment. To evaluate attitudes of medical students towards general practice as a specialty and general practitioners (GPs) as doctors and explore factors influencing students' attitudes and intended career choice. Cross-sectional survey. Final-year students at two London medical schools. Questionnaires were distributed to 984 students and the results analysed using SPSS analysis. The mean response rate was 72% (700/984). Medical students had a positive attitude towards general practice as a specialty (mean Likert score = 3.90/5, 95% confidence interval [CI] = 3.86 to 3.94) and towards GPs as doctors (mean Likert score = 3.62/5, 95% CI = 3.59 to 3.66). They rated personal experience of GPs as the most important factor influencing their attitude. Students' attitudes towards general practice and GPs were more positive (P<0.001) in the fifth year. First-year students perceived the media to have a more important role in influencing their attitude than those in the fifth year(P<0.001). General practice was the only career option to significantly increase in popularity between the first and final year(P < 0.001). Medical students end their undergraduate years with a more positive attitude towards general practice than has been reported elsewhere recently. This may be partially explained by the greater contact with GPs and suggests that efforts by medical schools to ensure a more balanced, community-based curriculum promotes positive attitudes to general practice. The influence of the media on the first years of medical school requiresfurther investigation.


Economics of children's environmental health.
Economic analyses are increasingly appearing in the children's environmental-health literature. In this review, an illustrative selection of articles that represent cost analyses, cost-effectiveness analyses, and cost-benefit analyses is analyzed for the relative merits of each approach. Cost analyses remain the dominant approach due to lack of available data. Cost-effectiveness and cost-benefit analyses in this area face challenges presented by estimation of costs of environmental interventions, whose costs are likely to decrease with further technological innovation. Benefits are also more difficult to quantify economically and can only be partially alleviated through willingness-to-pay approaches. Nevertheless, economic analyses in children's environmental health are highly informative and important informants to public-health and policy practice. Further attention and training in their appropriate use are needed.


Noninvasive Electromagnetic Source Imaging and Granger Causality Analysis: An Electrophysiological Connectome (eConnectome) Approach.
Combined source-imaging techniques and directional connectivity analysis can provide useful information about the underlying brain networks in a noninvasive fashion. Source-imaging techniques have been used successfully to either determine the source of activity or to extract source time-courses for Granger causality analysis, previously. In this work, we utilize source-imaging algorithms to both find the network nodes [regions of interest (ROI)] and then extract the activation time series for further Granger causality analysis. The aim of this work is to find network nodes objectively from noninvasive electromagnetic signals, extract activation time-courses, and apply Granger analysis on the extracted series to study brain networks under realistic conditions. Source-imaging methods are used to identify network nodes and extract time-courses and then Granger causality analysis is applied to delineate the directional functional connectivity of underlying brain networks. Computer simulations studies where the underlying network (nodes and connectivity pattern) is known were performed; additionally, this approach has been evaluated in partial epilepsy patients to study epilepsy networks from interictal and ictal signals recorded by EEG and/or Magnetoencephalography (MEG). Localization errors of network nodes are less than 5 mm and normalized connectivity errors of ∼20% in estimating underlying brain networks in simulation studies. Additionally, two focal epilepsy patients were studied and the identified nodes driving the epileptic network were concordant with clinical findings from intracranial recordings or surgical resection. Our study indicates that combined source-imaging algorithms with Granger causality analysis can identify underlying networks precisely (both in terms of network nodes location and internodal connectivity). The combined source imaging and Granger analysis technique is an effective tool for studying normal or pathological brain conditions.


Ambulatory Blood Pressure Variability Increases Over a 10-Year Follow-Up in Community-Dwelling Older People.
Greater ambulatory blood pressure variability (ABPV) is associated with end-organ damage and increased mortality. Age-related changes in the cardiovascular and autonomic nervous systems make age-associated increases in ABPV likely. Cross-sectional studies support this hypothesis, showing greater ABPV among older compared to younger adults. The only longitudinal study to examine changes in ABPV, however, found ABPV decreased over 5 years follow-up. This unexpected observation probably reflected the highly selected nature of the study participants. In this longitudinal study, we assessed changes in ABPV over 10 years in a community-cohort of older people. In addition, we examined the extent to which ABPV was predicted by demographics, cardiovascular risk factors, and medication. Clinical examination and 24-hour ambulatory blood pressure monitoring were carried out at baseline and at 10 years follow-up in 83 people, median age 70 years. ABPV was calculated using SD and coefficient of variation (Cv). Three time periods were examined: daytime, nighttime, and 24 hours. Daytime and 24-hour, systolic and diastolic, SD, and Cv were significantly greater at follow-up than at baseline (P < 0.001 in all cases). Mean BP did not change. Multilevel modeling showed follow-up interval had a significant, positive effect on SD and Cv (P < 0.004), independent of age, sex, and medication.ABPV increased over a 10-year follow-up despite stable mean BP. ABPV may therefore be an additional target for treatment in older people. Future studies should examine what degree of ABPV is harmful and if control of ABPV reduces adverse outcome.


Antiepileptic drugs interact with folate and vitamin B12 serum levels.
Antiepileptic drugs (AEDs) are important for the treatment of epilepsy, psychiatric diseases, and pain syndromes. Small studies have suggested that AED treatment reduces serum levels of folate and vitamin B12. This prospective monocenter study aimed at testing the hypothesis that AED treatment is associated with folate and vitamin B12 serum levels in a large population. A total of 2730 AED-treated and 170 untreated patients with epilepsy and 200 healthy individuals were enrolled. Treatment with carbamazepine, gabapentin, oxcarbazepine, phenytoin, primidone, or valproate was associated with lower mean serum folate levels or with a higher frequency of folate levels below the reference range in comparison with the entire group of patients, untreated patients, or controls. Treatment with phenobarbital, pregabalin, primidone, or topiramate was associated with lower vitamin B12 levels compared with the entire group of patients. Vitamin B12 serum levels were higher in patients treated with valproate compared with the entire group of patients, untreated patients, and healthy controls. Folate or vitamin B12 levels below the reference range were associated with higher mean corpuscular volume (MCV) and higher homocysteine plasma levels. Vitamin substitution for 3 months in 141 patients with folate or vitamin B12 levels below the reference range yielded normal vitamin levels in 95% of the supplemented patients and reduced MCV and homocysteine plasma levels. Treatment with most of the commonly used AEDs is associated with reduced folate or vitamin B12 serum levels and is a risk factor for hyperhomocysteinemia. Oral substitution is effective to restore vitamin, MCV, and homocysteine levels.


PLEKHM1 regulates Salmonella-containing vacuole biogenesis and infection.
The host endolysosomal compartment is often manipulated by intracellular bacterial pathogens. Salmonella (Salmonella enterica serovar Typhimurium) secrete numerous effector proteins, including SifA, through a specialized type III secretion system to hijack the host endosomal system and generate the Salmonella-containing vacuole (SCV). To form this replicative niche, Salmonella targets the Rab7 GTPase to recruit host membranes through largely unknown mechanisms. We show that Pleckstrin homology domain-containing protein family member 1 (PLEKHM1), a lysosomal adaptor, is targeted by Salmonella through direct interaction with SifA. By binding the PLEKHM1 PH2 domain, Salmonella utilize a complex containing PLEKHM1, Rab7, and the HOPS tethering complex to mobilize phagolysosomal membranes to the SCV. Depletion of PLEKHM1 causes a profound defect in SCV morphology with multiple bacteria accumulating in enlarged structures and significantly dampens Salmonella proliferation in multiple cell types and mice. Thus, PLEKHM1 provides a critical interface between pathogenic infection and the host endolysosomal system.


Vapor-deposited zeolitic imidazolate frameworks as gap-filling ultra-low-k dielectrics.
The performance of modern chips is strongly related to the multi-layer interconnect structure that interfaces the semiconductor layer with the outside world. The resulting demand to continuously reduce the k-value of the dielectric in these interconnects creates multiple integration challenges and encourages the search for novel materials. Here we report a strategy for the integration of metal-organic frameworks (MOFs) as gap-filling low-k dielectrics in advanced on-chip interconnects. The method relies on the selective conversion of purpose-grown or native metal-oxide films on the metal interconnect lines into MOFs by exposure to organic linker vapor. The proposed strategy is validated for thin films of the zeolitic imidazolate frameworks ZIF-8 and ZIF-67, formed in 2-methylimidazole vapor from ALD ZnO and native CoOx, respectively. Both materials show a Young's modulus and dielectric constant comparable to state-of-the-art porous organosilica dielectrics. Moreover, the fast nucleation and volume expansion accompanying the oxide-to-MOF conversion enable uniform growth and gap-filling of narrow trenches, as demonstrated for 45 nm half-pitch fork-fork capacitors.


Feasibility of a school-based exercise intervention for children with intellectual disability to reduce cardio-metabolic risk.
People with intellectual disabilities (ID) are at increased risk of secondary health conditions, reduced quality of life and life expectancy. Children with ID demonstrate low levels of physical activity in association with a higher prevalence of obesity, a modifiable risk factor associated with secondary health conditions including type 2 diabetes and cardiovascular disease. Despite this, physical activity interventions addressing weight and weight-related complications in this population are limited. This study aimed to establish the feasibility of a school-based group exercise intervention for children with moderate to severe ID. A single-arm intervention study was used to establish the feasibility of a 16-week exercise intervention. Children attending a School for Specific Purposes in Sydney, Australia, participated in two 30-min exercise sessions per week across the intervention period in addition to their regular physical education class. Each exercise session was 60% aerobically based, 20% strength based and 20% targeted towards fundamental movement skill development. We used two facilitation strategies to assist the delivery of the intervention, including the implementation of a variety of communication resources and promotion of social interaction. Feasibility was assessed through recruitment rates, program retention, adverse effects, attendance, group size feasibility and non-compliance. Anthropometric measures included height (m), weight (kg) and waist circumference (cm; umbilicus), with body mass index (BMI) and waist-to-height ratios (WtHR) used to determine cardio-metabolic risk. Aerobic capacity was assessed using the submaximal 6-min walk test (6-MWT). Intensity of physical activity sessions was measured through the use of tri-axial accelerometers and compared to physical activity recommendations. Ten children aged between 9 and 13 years completed the 16-week intervention, with a 55% recruitment rate, 91% program retention, 86% attendance and with no adverse effects reported. Sessions commenced as 1:1 supervisor to child ratios before progressing to established small groups of 2:7 (supervisor : child). Children spent 38.4% (11.5 min) of each session in moderate to vigorous physical activity (MVPA), equating to 20% of their MVPA recommended daily physical activity levels (twice per week). There was a significant change in weight across the intervention period, with a trend towards increased weight between mid-intervention and 3-month follow-up time points. There were no significant changes in child BMI, WtHR or aerobic capacity. A school-based group exercise intervention for children with moderate to severe ID is feasible and safe, with high retention rates and physical activity participation. No significant improvements in body composition or aerobic capacity were determined. The present study demonstrates that engaging children with moderate-severe ID in school-based group exercise is feasible to assist in physical activity participation.


Lickometry: A novel and sensitive method for assessing functional deficits in rats after stroke.
The need for sensitive, easy to administer assessments of long-term functional deficits is crucial in pre-clinical stroke research. In the present study, we introduce lickometry (lick microstructure analysis) as a precise method to assess sensorimotor deficits up to 40 days after middle cerebral artery occlusion in rats. Impairments in drinking efficiency compared to controls, and a compensatory increase in the number of drinking clusters were observed. This highlights the utility of this easy to administer task in assessing subtle, long-term deficits, which could be likened to oral deficits in patients.


Effects of Water Acidification on Senegalese Sole Solea senegalensis Health Status and Metabolic Rate: Implications for Immune Responses and Energy Use.
Increasing water CO2, aquatic hypercapnia, leads to higher physiological pCO2 levels in fish, resulting in an acidosis and compensatory acid-base regulatory response. Senegalese sole is currently farmed in super-intensive recirculating water systems where significant accumulation of CO2 in the water may occur. Moreover, anthropogenic releases of CO2 into the atmosphere are linked to ocean acidification. The present study was designed to assess the effects of acute (4 and 24 h) and prolonged exposure (4 weeks) to CO2 driven acidification (i.e., pH 7.9, 7.6, and 7.3) from normocapnic seawater (pH 8.1) on the innate immune status, gill acid-base ion transporter expression and metabolic rate of juvenile Senegalese sole. The acute exposure to severe hypercapnia clearly affected gill physiology as observed by an increase of NHE3b positive ionocytes and a decrease of cell shape factor. Nonetheless only small physiological adjustments were observed at the systemic level with (1) a modulation of both plasma and skin humoral parameters and (2) an increased expression of HIF-1 expression pointing to an adjustment to the acidic environment even after a short period (i.e., hours). On the other hand, upon prolonged exposure, the expression of several pro-inflammatory and stress related genes was amplified and gill cell shape factor was aggravated with the continued increase of NHE3b positive ionocytes, ultimately impacting fish growth. While these findings indicate limited effects on energy use, deteriorating immune system conditions suggest that Senegalese sole is vulnerable to changes in CO2 and may be affected in aquaculture where a pH drop is more prominent. Further studies are required to investigate how larval and adult Senegalese sole are affected by changes in CO2.


Neuronal processing of translational optic flow in the visual system of the shore crab Carcinus maenas.
This paper describes a search for neurones sensitive to optic flow in the visual system of the shore crab Carcinus maenas using a procedure developed from that of Krapp and Hengstenberg. This involved determining local motion sensitivity and its directional selectivity at many points within the neurone's receptive field and plotting the results on a map. Our results showed that local preferred directions of motion are independent of velocity, stimulus shape and type of motion (circular or linear). Global response maps thus clearly represent real properties of the neurones' receptive fields. Using this method, we have discovered two families of interneurones sensitive to translational optic flow. The first family has its terminal arborisations in the lobula of the optic lobe, the second family in the medulla. The response maps of the lobula neurones (which appear to be monostratified lobular giant neurones) show a clear focus of expansion centred on or just above the horizon, but at significantly different azimuth angles. Response maps such as these, consisting of patterns of movement vectors radiating from a pole, would be expected of neurones responding to self-motion in a particular direction. They would be stimulated when the crab moves towards the pole of the neurone's receptive field. The response maps of the medulla neurones show a focus of contraction, approximately centred on the horizon, but at significantly different azimuth angles. Such neurones would be stimulated when the crab walked away from the pole of the neurone's receptive field. We hypothesise that both the lobula and the medulla interneurones are representatives of arrays of cells, each of which would be optimally activated by self-motion in a different direction. The lobula neurones would be stimulated by the approaching scene and the medulla neurones by the receding scene. Neurones tuned to translational optic flow provide information on the three-dimensional layout of the environment and are thought to play a role in the judgment of heading.


Highly efficient three-level blazed grating in the resonance domain.
We designed, fabricated, and characterized three-level transmission gratings in the resonance domain with reduced shadowing losses based on a three-wave interference mechanism. A new technological approach allows for fabrication of homogeneous and large area multilevel gratings without spurious artifacts. To our knowledge, the measured efficiency of 86% exhibits the largest value yet reported for a multilevel transmission grating in the resonance domain close to normal incidence.


A newly-developed community microarray resource for transcriptome profiling in Brassica species enables the confirmation of Brassica-specific expressed sequences.
The Brassica species include an important group of crops and provide opportunities for studying the evolutionary consequences of polyploidy. They are related to Arabidopsis thaliana, for which the first complete plant genome sequence was obtained and their genomes show extensive, although imperfect, conserved synteny with that of A. thaliana. A large number of EST sequences, derived from a range of different Brassica species, are available in the public database, but no public microarray resource has so far been developed for these species. We assembled unigenes using approximately 800,000 EST sequences, mainly from three species: B. napus, B. rapa and B. oleracea. The assembly was conducted with the aim of co-assembling ESTs of orthologous genes (including homoeologous pairs of genes in B. napus from each of the A and C genomes), but resolving assemblies of paralogous, or paleo-homoeologous, genes (i.e. the genes related by the ancestral genome triplication observed in diploid Brassica species). 90,864 unique sequence assemblies were developed. These were incorporated into the BAC sequence annotation for the Brassica rapa Genome Sequencing Project, enabling the identification of cognate genomic sequences for a proportion of them. A 60-mer oligo microarray comprising 94,558 probes was developed using the unigene sequences. Gene expression was analysed in reciprocal resynthesised B. napus lines and the B. oleracea and B. rapa lines used to produce them. The analysis showed that significant expression could consistently be detected in leaf tissue for 35,386 unigenes. Expression was detected across all four genotypes for 27,355 unigenes, genome-specific expression patterns were observed for 7,851 unigenes and 180 unigenes displayed other classes of expression pattern. Principal component analysis (PCA) clearly resolved the individual microarray datasets for B. rapa, B. oleracea and resynthesised B. napus. Quantitative differences in expression were observed between the resynthesised B. napus lines for 98 unigenes, most of which could be classified into non-additive expression patterns, including 17 that showed cytoplasm-specific patterns. We further characterized the unigenes for which A genome-specific expression was observed and cognate genomic sequences could be identified. Ten of these unigenes were found to be Brassica-specific sequences, including two that originate from complex loci comprising gene clusters. We succeeded in developing a Brassica community microarray resource. Although expression can be measured for the majority of unigenes across species, there were numerous probes that reported in a genome-specific manner. We anticipate that some proportion of these will represent species-specific transcripts and the remainder will be the consequence of variation of sequences within the regions represented by the array probes. Our studies demonstrated that the datasets obtained from the arrays can be used for typical analyses, including PCA and the analysis of differential expression. We have also demonstrated that Brassica-specific transcripts identified in silico in the sequence assembly of public EST database accessions are indeed reported by the array. These would not be detectable using arrays designed using A. thaliana sequences.


Fast associative filtering based on two-dimensional discrete Walsh transform by a volume holographic correlator.
An optical fast associative filtering method based on a multi-channel volume holographic correlator to search the database as a front-end filter is described. The features of searching query are parallelly extracted by a volume holographic correlator based on two-dimensional discrete Walsh transform, and are used to measure the similarity between the query and all the database records. The best matches are picked up for further searching. An experiment is carried out, and the experimental results prove the validity of the method.


Precision tomography of a three-qubit donor quantum processor in silicon.
Nuclear spins were among the first physical platforms to be considered for quantum information processing1,2, because of their exceptional quantum coherence3 and atomic-scale footprint. However, their full potential for quantum computing has not yet been realized, owing to the lack of methods with which to link nuclear qubits within a scalable device combined with multi-qubit operations with sufficient fidelity to sustain fault-tolerant quantum computation. Here we demonstrate universal quantum logic operations using a pair of ion-implanted 31P donor nuclei in a silicon nanoelectronic device. A nuclear two-qubit controlled-Z gate is obtained by imparting a geometric phase to a shared electron spin4, and used to prepare entangled Bell states with fidelities up to 94.2(2.7)%. The quantum operations are precisely characterized using gate set tomography (GST)5, yielding one-qubit average gate fidelities up to 99.95(2)%, two-qubit average gate fidelity of 99.37(11)% and two-qubit preparation/measurement fidelities of 98.95(4)%. These three metrics indicate that nuclear spins in silicon are approaching the performance demanded in fault-tolerant quantum processors6. We then demonstrate entanglement between the two nuclei and the shared electron by producing a Greenberger-Horne-Zeilinger three-qubit state with 92.5(1.0)% fidelity. Because electron spin qubits in semiconductors can be further coupled to other electrons7-9 or physically shuttled across different locations10,11, these results establish a viable route for scalable quantum information processing using donor nuclear and electron spins.


The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors.
All-trans-retinoic acid (ATRA) and its synthetic analogues EC23 and EC19 direct cellular differentiation by interacting as ligands for the retinoic acid receptor (RARα, β and γ) family of nuclear receptor proteins. To date, a number of crystal structures of natural and synthetic ligands complexed to their target proteins have been solved, providing molecular level snap-shots of ligand binding. However, a deeper understanding of receptor and ligand flexibility and conformational freedom is required to develop stable and effective ATRA analogues for clinical use. Therefore, we have used molecular modelling techniques to define RAR interactions with ATRA and two synthetic analogues, EC19 and EC23, and compared their predicted biochemical activities to experimental measurements of relative ligand affinity and recruitment of coactivator proteins. A comprehensive molecular docking approach that explored the conformational space of the ligands indicated that ATRA is able to bind the three RAR proteins in a number of conformations with one extended structure being favoured. In contrast the biologically-distinct isomer, 9-cis-retinoic acid (; 9CRA), showed significantly less conformational flexibility in the RAR binding pockets. These findings were used to inform docking studies of the synthetic retinoids EC23 and EC19, and their respective methyl esters. EC23 was found to be an excellent mimic for ATRA, and occupied similar binding modes to ATRA in all three target RAR proteins. In comparison, EC19 exhibited an alternative binding mode which reduces the strength of key polar interactions in RARα/γ but is well-suited to the larger RARβ binding pocket. In contrast, docking of the corresponding esters revealed the loss of key polar interactions which may explain the much reduced biological activity. Our computational results were complemented using an in vitro binding assay based on FRET measurements, which showed that EC23 was a strongly binding, pan-agonist of the RARs, while EC19 exhibited specificity for RARβ, as predicted by the docking studies. These findings can account for the distinct behaviour of EC23 and EC19 in cellular differentiation assays, and additionally, the methods described herein can be further applied to the understanding of the molecular basis for the selectivity of different retinoids to RARα, β and γ.


Learning to coexist with wildfire.
The impacts of escalating wildfire in many regions - the lives and homes lost, the expense of suppression and the damage to ecosystem services - necessitate a more sustainable coexistence with wildfire. Climate change and continued development on fire-prone landscapes will only compound current problems. Emerging strategies for managing ecosystems and mitigating risks to human communities provide some hope, although greater recognition of their inherent variation and links is crucial. Without a more integrated framework, fire will never operate as a natural ecosystem process, and the impact on society will continue to grow. A more coordinated approach to risk management and land-use planning in these coupled systems is needed.


Global profiling of SRP interaction with nascent polypeptides.
Signal recognition particle (SRP) is a universally conserved protein-RNA complex that mediates co-translational protein translocation and membrane insertion by targeting translating ribosomes to membrane translocons. The existence of parallel co- and post-translational transport pathways, however, raises the question of the cellular substrate pool of SRP and the molecular basis of substrate selection. Here we determine the binding sites of bacterial SRP within the nascent proteome of Escherichia coli at amino acid resolution, by sequencing messenger RNA footprints of ribosome-nascent-chain complexes associated with SRP. SRP, on the basis of its strong preference for hydrophobic transmembrane domains (TMDs), constitutes a compartment-specific targeting factor for nascent inner membrane proteins (IMPs) that efficiently excludes signal-sequence-containing precursors of periplasmic and outer membrane proteins. SRP associates with hydrophobic TMDs enriched in consecutive stretches of hydrophobic and bulky aromatic amino acids immediately on their emergence from the ribosomal exit tunnel. By contrast with current models, N-terminal TMDs are frequently skipped and TMDs internal to the polypeptide sequence are selectively recognized. Furthermore, SRP binds several TMDs in many multi-spanning membrane proteins, suggesting cycles of SRP-mediated membrane targeting. SRP-mediated targeting is not accompanied by a transient slowdown of translation and is not influenced by the ribosome-associated chaperone trigger factor (TF), which has a distinct substrate pool and acts at different stages during translation. Overall, our proteome-wide data set of SRP-binding sites reveals the underlying principles of pathway decisions for nascent chains in bacteria, with SRP acting as the dominant triaging factor, sufficient to separate IMPs from substrates of the SecA-SecB post-translational translocation and TF-assisted cytosolic protein folding pathways.


Biomarker-calibrated dietary energy and protein intake associations with diabetes risk among postmenopausal women from the Women's Health Initiative.
Self-report of dietary energy and protein intakes has been shown to be systematically and differentially underreported. We assessed and compared the association of diabetes among postmenopausal women with biomarker-calibrated and uncalibrated dietary energy and protein intakes from food-frequency questionnaires (FFQs). The analyses were performed for 74,155 participants of various race-ethnicities from the Women's Health Initiative. Uncalibrated and calibrated energy and protein intakes from FFQs were assessed for associations with incident diabetes by using HR estimates based on Cox regression. A 20% increment in uncalibrated energy consumption was associated with increased diabetes risk (HR) of 1.03 (95% CI: 1.01, 1.05), 2.41 (95% CI: 2.06, 2.82) with biomarker calibration, and 1.30 (95% CI: 0.96, 1.76) after adjustment for BMI. A 20% increment in uncalibrated protein (g/d) resulted in an HR of 1.05 (95% CI: 1.03, 1.07), 1.82 (95% CI: 1.56, 2.12) with calibration, and 1.16 (95% CI: 1.05, 1.28) with adjustment for BMI. A 20% increment in uncalibrated protein density (% of energy from protein) resulted in an HR of 1.13 (95% CI: 1.09, 1.17), 1.01 (95% CI: 0.75, 1.37) with calibration, and 1.19 (95% CI: 1.07, 1.32) with adjustment for BMI. Higher protein and total energy intakes (calibrated) appear to be associated with a substantially increased diabetes risk that may be mediated by an increase in body mass over time. Diet-disease associations without correction of self-reported measurement error should be viewed with caution. This trial is registered at clinicaltrials.gov as NCT00000611.


Decision making in controlling virus yellows of sugar beet in the UK.
Virus yellows is an important disease affecting yield in sugar beet in the UK. Myzus persicae (Sulzer) is the most effective and efficient aphid vector of the three viruses causing the disease: beet yellows virus, beet mild yellowing virus and beet chlorosis virus. Control of virus yellows disease is thus focused on the study and control of this aphid species. UK national surveys of virus yellows began in 1946 and these data helped to formulate disease forecasting schemes to optimise control. Over the years, in addition to improvements in farm hygiene, periodic changes and developments in control of the disease have occurred. To accommodate these important developments, virus yellows forecasting schemes have evolved accordingly. The most recent version has been adapted to take account of the current widespread use of imidacloprid seed treatment. Its application offers potential to optimise the rational use of aphicides such as imidacloprid so as to benefit beet growers and the environment by reducing prophylactic use of seed treatment.


State-of-the-art review: stress T1 mapping-technical considerations, pitfalls and emerging clinical applications.
In vivo mapping of the myocardial T1 relaxation time has recently attained wide clinical validation of its potential utility. In this review, we address the basic principles of the T1 mapping techniques, with particular attention to the emerging application of vasodilatory stress agents to interrogate the myocardial microvascular compartment, and differences between commonly used T1 mapping methods when applied in clinical practice.


A polyphenol extract modifies quantity but not quality of liver fatty acid content in high-fat-high-sucrose diet-fed rats: possible implication of the sirtuin pathway.
High-fat or high-fat-high-sucrose diets are known to induce non-alcoholic fatty liver disease and this is emerging as one of the most common liver diseases worldwide. Some polyphenols have been reported to decrease rat hepatic lipid accumulation, in particular those extracted from red grapes such as resveratrol. The present study was designed to determine whether a polyphenol extract (PPE), from red grapes, modulates liver fatty acid composition and desaturase activity indexes in rats fed a high-fat-high-sucrose (HFHS) diet, and to explore whether sirtuin-1 deacetylase activation was implicated in the effect of the PPE against liver steatosis. The effect of this PPE on mitochondriogenesis and mitochondrial activity was also explored. The PPE decreased liver TAG content in HFHS+PPE diet-fed rats in comparison with HFHS diet-fed rats. The PPE had no effect on liver fatty acid composition, desaturase activity indexes and stearoyl-CoA desaturase 1 (SCD1) gene expression. Sirtuin-1 deacetylase protein expression was significantly increased with the PPE; AMP kinase protein expression was higher with the PPE in comparison with the HFHS rats, but no modification of phosphorylated AMP kinase was observed. Protein expression of phospho-acetyl-CoA carboxylase was decreased in HFHS rats and returned to basal values with the PPE. Finally, the PPE modulated PPARγ coactivator-1α (PGC-1α) but did not modify mitochondriogenesis and mitochondrial activity. In conclusion, the PPE partially prevented the accumulation of TAG in the liver by regulating acetyl-CoA carboxylase phosphorylation, a key enzyme in lipid metabolism, probably via sirtuin-1 deacetylase activation. However, the PPE had no effect on the qualitative composition of liver fatty acids.


Regular Latin Dancing and Health Education May Improve Cognition of Late Middle-Aged and Older Latinos.
Disparities exist between Latinos and non-Latino Whites in cognitive function. Dance is culturally appropriate and challenges individuals physically and cognitively, yet the impact of regular dancing on cognitive function in older Latinos has not been examined. A two-group pilot trial was employed among inactive, older Latinos. Participants (N = 57) participated in the BAILAMOS© dance program or a health education program. Cognitive test scores were converted to z-scores and measures of global cognition and specific domains (executive function, episodic memory, working memory) were derived. Results revealed a group × time interaction for episodic memory (p < .05), such that the dance group showed greater improvement in episodic memory than the health education group. A main effect for time for global cognition (p < .05) was also demonstrated, with participants in both groups improving. Structured Latin dance programs can positively influence episodic memory, and participation in structured programs may improve overall cognition among older Latinos.


Replication Study in a Japanese Population to Evaluate the Association between 10 SNP Loci, Identified in European Genome-Wide Association Studies, and Type 2 Diabetes.
We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and 7 susceptibility loci originally identified by European genome-wide association study (GWAS) in 2012: ZMIZ1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, and BCAR1. We also examined the association of 3 additional loci: CCND2 and GIPR, identified in sex-differentiated analyses, and LAMA1, which was shown to be associated with non-obese European type 2 diabetes. We genotyped 6,972 Japanese participants (4,280 type 2 diabetes patients and 2,692 controls) for each of the 10 single nucleotide polymorphisms (SNPs): rs12571751 in ZMIZ1, rs10842994 near KLHDC5, rs2796441 near TLE1, rs459193 near ANKRD55, rs10401969 in CILP2, rs12970134 near MC4R, rs7202877 near BCAR1, rs11063069 near CCND2, rs8108269 near GIPR, and rs8090011 in LAMA1 using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using a logistic regression analysis. All SNPs examined in this study had the same direction of effect (odds ratio > 1.0, p = 9.77 × 10(-4), binomial test), as in the original reports. Among them, rs12571751 in ZMIZ1 was significantly associated with type 2 diabetes [p = 0.0041, odds ratio = 1.123, 95% confidence interval 1.037-1.215, adjusted for sex, age and body mass index (BMI)], but we did not observe significant association of the remaining 9 SNP loci with type 2 diabetes in the present Japanese population (p ≥ 0.005). A genetic risk score, constructed from the sum of risk alleles for the 7 SNP loci identified by un-stratified analyses in the European GWAS meta-analysis were associated with type 2 diabetes in the present Japanese population (p = 2.3 × 10(-4), adjusted for sex, age and BMI). ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population.


A scalable realization of local U(1) gauge invariance in cold atomic mixtures.
In the fundamental laws of physics, gauge fields mediate the interaction between charged particles. An example is the quantum theory of electrons interacting with the electromagnetic field, based on U(1) gauge symmetry. Solving such gauge theories is in general a hard problem for classical computational techniques. Although quantum computers suggest a way forward, large-scale digital quantum devices for complex simulations are difficult to build. We propose a scalable analog quantum simulator of a U(1) gauge theory in one spatial dimension. Using interspecies spin-changing collisions in an atomic mixture, we achieve gauge-invariant interactions between matter and gauge fields with spin- and species-independent trapping potentials. We experimentally realize the elementary building block as a key step toward a platform for quantum simulations of continuous gauge theories.


Clinical outcomes and prognostic factors in patients with breast diffuse large B cell lymphoma; Consortium for Improving Survival of Lymphoma (CISL) study.
The breast is a rare extranodal site of non-Hodgkin lymphoma, and primary breast lymphoma (PBL) has been arbitrarily defined as disease localized to one or both breasts with or without regional lymph nodes involvement. The aim of this study was to evaluate the clinical outcomes in patients with diffuse large B cell lymphoma (DLBCL) and breast involvement, and to find the criteria of PBL reflecting the outcome and prognosis. We retrospectively analyzed data from 68 patients, newly diagnosed with DLBCL and breast involvement at 16 Korean institutions between January 1994 and June 2009. Median age at diagnosis was 48 years (range, 20-83 years). Forty-three (63.2%) patients were PBL according to previous arbitrary criteria, sixteen (23.5%) patients were high-intermediate to high risk of international prognostic index. The patients with one extranodal disease in the breast (OED) with or without nodal disease were 49 (72.1%), and those with multiple extranodal disease (MED) were 19 (27.9%). During median follow-up of 41.5 months (range, 2.4-186.0 months), estimated 5-year progression-free survival (PFS) was 53.7 +/- 7.6%, and overall survival (OS) was 60.3 +/- 7.2%. The 5-year PFS and OS was significantly higher for patients with the OED group than those with the MED group (5-year PFS, 64.9 +/- 8.9% vs. 27.5 +/- 11.4%, p = 0.001; 5-year OS, 74.3 +/- 7.6% vs. 24.5 +/- 13.0%, p < 0.001). In multivariate analysis, MED (hazard ratio [HR], 3.61; 95% confidence interval [CI], 1.07-12.2) and fewer than four cycles of systemic chemotherapy with or without local treatments (HR, 4.47; 95% CI, 1.54-12.96) were independent prognostic factors for worse OS. Twenty-five (36.8%) patients experienced progression, and the cumulative incidence of progression in multiple extranodal sites or other than breasts and central nervous system was significantly different between the OED group and the MED group (5-year cumulative incidence, 9.7 +/- 5.4% vs. 49.0 +/- 15.1%, p = 0.001). Our results show that the patients included in OED group, reflecting different treatment outcome, prognosis and pattern of progression, should be considered as PBL in the future trial. Further studies are warranted to validate our suggested criteria.


Possibilities and limits of imaging endodontic structures with CBCT.
An adequate portrayal of the root canal anatomy by diagnostic imaging is a prerequisite for a successful diagnosis and therapy in endodontics. The introduction of dental cone beam computed tomography (CBCT) has considerably expanded the scope of imaging diagnostics. The aim of the following study was to evaluate the imaging of endodontic structures with CBCT. One hundred and twenty teeth were examined with a CBCT device (ProMax 3D). Subsequently, the findings of the three-dimensional images were evaluated and compared to those of dental radiographs and tangential section preparations of the examined teeth. Results with high prevalence, such as existing roots and root canals, as well as results with low prevalence, e.g., extremely fine anatomical structures of the endodontic tissue, could be visualized precisely by dental CBCT; side canals, ramifications, communications, pulp stones, and obliterations could also be detected. Additionally, the length of curved root canals could be determined accurately. Likewise, root fractures were visualized reliably with CBCT. However, carious lesions could not be diagnosed adequately, and the evaluation of fillings and prosthetic restorations was complicated due to scattered X-ray artifacts. CBCT datasets qualify to visualize and diagnose small anatomical structures of the endodontic tissue.


Risks linked to endogenous retroviruses for vaccine production: a general overview.
Mammalian genomes contain a heavy load of retroelements, which are mobile sequences requiring reverse transcription for their amplification. A significant proportion of these elements is of retroviral origin, with thousands of sequences resembling the integrated form of infectious retroviruses with two LTRs bordering internal regions homologous to the gag, pol, and env genes. These elements, named endogenous retroviruses (ERVs), are thought to be the remnants of ancestral germline infections by active retroviruses, which have thereafter been transmitted in a Mendelian manner. The sequencing of several mammalian genomes has allowed a comprehensive study of their ERVs. They can be grouped according to sequence homologies into 10-100 families per genome, each containing a few to several hundred elements. Strong similarities between ERVs and present-day retroviruses can be inferred from phylogenetic analyses performed on the pol or env genes, suggesting a common history. As a general rule, most ERVs are old and degenerated, with their open reading frames disrupted, but a few proviruses have retained intact genes and the corresponding proteins can thus be expressed. Some elements still contain gag and pol genes that drive the synthesis of viral particles, as well as envelope genes whose product can be incorporated on their cognate or heterologous viral particles. This presentation will review the general properties of endogenous retroviruses, in relation with their possible consequences on vaccine production.


Using major outer membrane protein typing as an epidemiological tool to investigate outbreaks caused by milk-borne Campylobacter jejuni isolates in California.
We describe using major outer membrane protein (MOMP) typing as a screen to compare the Campylobacter jejuni porA gene sequences of clinical outbreak strains from human stool with the porA sequences of dairy farm strains isolated during two milk-borne campylobacteriosis outbreak investigations in California. The genetic relatedness of clinical and environmental strains with identical or closely related porA sequences was confirmed by multilocus sequence typing and pulsed-field gel electrophoresis analysis. The first outbreak involved 1,644 C. jejuni infections at 11 state correctional facilities and was associated with consumption of pasteurized milk supplied by an on-site dairy (dairy A) at a prison in the central valley. The second outbreak involved eight confirmed and three suspect C. jejuni cases linked to consumption of commercial raw milk and raw chocolate colostrum at another central valley dairy (dairy B). Both dairies bottled fluid milk on the farm and distributed the finished product to off-site locations. Altogether, C. jejuni was isolated from 7 of 15 (46.7%) bovine fecal, 12 of 20 (60%) flush alley water, and 1 of 20 (5%) lagoon samples collected on dairy A. At dairy B, C. jejuni was cultured from 9 of 26 (34.6%) bovine fecal samples. Environmental strains indistinguishable from the clinical outbreak strains were found in five flush alley water samples (dairy A) and four bovine fecal samples (dairy B). The findings demonstrate that MOMP typing is a useful tool to triage environmental isolates prior to conducting more labor-intensive molecular typing methods.


A diffusion tensor imaging study on the auditory system and tinnitus.
Tinnitus is an auditory percept in the absence of an external sound source. Mechanisms in the central nervous system are believed to be key in the pathophysiology of tinnitus. Diffusion tensor imaging (DTI) is an MR imaging technique that allows in vivo exploration of white matter tissue in the human brain. Using a probabilistic DTI approach, we determined the characteristics of fiber tracts from the inferior colliculus to the medial geniculate body up to the primary auditory cortex. We also investigated the connections between the auditory system and the amygdala, which may be involved in some forms of tinnitus. White matter tracts were characterized by three quantities: the mean fractional anisotropy, the weighted mean fractional anisotropy and the path strength. All these quantities are measures of the patency of white matter tracts. The most important finding is an increased patency of the white matter tracts between the auditory cortex and the amygdala in tinnitus patients as compared to healthy controls.


Epidemiology, diagnosis and treatment of enteric fever.
Enteric fever continues to be a common and serious problem worldwide, and the need for reliable and cheap alternatives to culture methods for diagnosis remains. Epidemics of different strains may coexist in the same geographical area and the rapid emergence of resistance to fluoroquinolones, independent of plasmid mediated multidrug resistance, means that alternative drugs for chemotherapy are also needed.


GLP-compliant evaluation and standardization of the peripubertal castrate male rat Hershberger assay for oral exposure of test agents.
Since oral exposure is more relevant than the sc route for human exposure to environmental substances, studies to evaluate and standardize this route in the Hershberger assay were conducted in 2001-2003. Interest in environmental androgen agonists is increasing, so the oral route of the Hershberger assay may be useful to quantify agonist activity of these substances. Castrated Sprague-Dawley rats were dosed (PND 60-69) with androgen receptor agonists and/or antagonists, terminated on PND 70, and body, liver, and accessory sex organs (ASOs) weighed. Methyltestosterone (MT) po, at 0.1-50mg/kg/day, resulted in dose-dependent increases in ASO weights at 5-50 mg/kg; 0.1 mg/kg/day was without statistically significant effect. Testosterone propionate (TP) (sc) at 0.1-1.6 mg/kg/day also resulted in dose-dependent increases in ASO weights, at all doses. Detection of putative androgen antagonists by the oral route was confirmed with dose-response curves of antagonism from flutamide (FLU) po at 1, 5, or 10 mg/kg/day, with MT at 5 or 10 mg/kg/day (po, 4h later). These results extend the OECD Hershberger assay evaluation and standardization to the oral route and identify and discuss challenges of the assay to detect (anti)androgen-active compounds.


Geometrically Diverse Lariat Peptide Scaffolds Reveal an Untapped Chemical Space of High Membrane Permeability.
Constrained, membrane-permeable peptides offer the possibility of engaging challenging intracellular targets. Structure-permeability relationships have been extensively studied in cyclic peptides whose backbones are cyclized from head to tail, like the membrane permeable and orally bioavailable natural product cyclosporine A. In contrast, the physicochemical properties of lariat peptides, which are cyclized from one of the termini onto a side chain, have received little attention. Many lariat peptide natural products exhibit interesting biological activities, and some, such as griselimycin and didemnin B, are membrane permeable and have intracellular targets. To investigate the structure-permeability relationships in the chemical space exemplified by these natural products, we generated a library of scaffolds using stable isotopes to encode stereochemistry and determined the passive membrane permeability of over 1000 novel lariat peptide scaffolds with molecular weights around 1000. Many lariats were surprisingly permeable, comparable to many known orally bioavailable drugs. Passive permeability was strongly dependent on N-methylation, stereochemistry, and ring topology. A variety of structure-permeability trends were observed including a relationship between alternating stereochemistry and high permeability, as well as a set of highly permeable consensus sequences. For the first time, robust structure-permeability relationships are established in synthetic lariat peptides exceeding 1000 compounds.


Production of extracellular traps against Aspergillus fumigatus in vitro and in infected lung tissue is dependent on invading neutrophils and influenced by hydrophobin RodA.
Aspergillus fumigatus is the most important airborne fungal pathogen causing life-threatening infections in immunocompromised patients. Macrophages and neutrophils are known to kill conidia, whereas hyphae are killed mainly by neutrophils. Since hyphae are too large to be engulfed, neutrophils possess an array of extracellular killing mechanisms including the formation of neutrophil extracellular traps (NETs) consisting of nuclear DNA decorated with fungicidal proteins. However, until now NET formation in response to A. fumigatus has only been demonstrated in vitro, the importance of neutrophils for their production in vivo is unclear and the molecular mechanisms of the fungus to defend against NET formation are unknown. Here, we show that human neutrophils produce NETs in vitro when encountering A. fumigatus. In time-lapse movies NET production was a highly dynamic process which, however, was only exhibited by a sub-population of cells. NETosis was maximal against hyphae, but reduced against resting and swollen conidia. In a newly developed mouse model we could then demonstrate the existence and measure the kinetics of NET formation in vivo by 2-photon microscopy of Aspergillus-infected lungs. We also observed the enormous dynamics of neutrophils within the lung and their ability to interact with and phagocytose fungal elements in situ. Furthermore, systemic neutrophil depletion in mice almost completely inhibited NET formation in lungs, thus directly linking the immigration of neutrophils with NET formation in vivo. By using fungal mutants and purified proteins we demonstrate that hydrophobin RodA, a surface protein making conidia immunologically inert, led to reduced NET formation of neutrophils encountering Aspergillus fungal elements. NET-dependent killing of Aspergillus-hyphae could be demonstrated at later time-points, but was only moderate. Thus, these data establish that NET formation occurs in vivo during host defence against A. fumigatus, but suggest that it does not play a major role in killing this fungus. Instead, NETs may have a fungistatic effect and may prevent further spreading.


Glycogen synthase kinase 3β sustains invasion of glioblastoma via the focal adhesion kinase, Rac1, and c-Jun N-terminal kinase-mediated pathway.
The failure of current treatment options for glioblastoma stems from their inability to control tumor cell proliferation and invasion. Biologically targeted therapies offer great hope and one promising target is glycogen synthase kinase-3β (GSK3β), implicated in various diseases, including cancer. We previously reported that inhibition of GSK3β compromises the survival and proliferation of glioblastoma cells, induces their apoptosis, and sensitizes them to temozolomide and radiation. Here, we explore whether GSK3β also contributes to the highly invasive nature of glioblastoma. The effects of GSK3β inhibition on migration and invasion of glioblastoma cells were examined by wound-healing and Transwell assays, as well as in a mouse model of glioblastoma. We also investigated changes in cellular microarchitectures, cytoskeletal components, and proteins responsible for cell motility and invasion. Inhibition of GSK3β attenuated the migration and invasion of glioblastoma cells in vitro and that of tumor cells in a mouse model of glioblastoma. These effects were associated with suppression of the molecular axis involving focal adhesion kinase, guanine nucleotide exchange factors/Rac1 and c-Jun N-terminal kinase. Changes in cellular phenotypes responsible for cell motility and invasion were also observed, including decreased formation of lamellipodia and invadopodium-like microstructures and alterations in the subcellular localization, and activity of Rac1 and F-actin. These changes coincided with decreased expression of matrix metalloproteinases. Our results confirm the potential of GSK3β as an attractive therapeutic target against glioblastoma invasion, thus highlighting a second role in this tumor type in addition to its involvement in chemo- and radioresistance.


A review of the emerging potential therapy for neurological disorders: human embryonic stem cell therapy.
The first human embryonic stem cell (hESC) line was developed in the late nineties. hESCs are capable of proliferating indefinitely and differentiate into all the three embryonic germ layers. Further, the differentiation of hESC lines into neural precursor cells and neurons, astrocytes and oligodendrocytes showed their potential in treating several incurable neurological disorders such as spinal cord injury (SCI), cerebral palsy (CP), Parkinson's disease (PD). In this review, we will discuss the global scenario of research and therapeutic use of hESCs in the treatment of neurological disorders. Following this, we will discuss the development of a unique hESC line, how it differs from the other available hESC lines and its use in the treatment of neurological disorders. hESCs were isolated from mixture of neuronal and non-neuronal progenitor cells in their pre progenitor state in a Good Laboratory Practices, Good Tissue Practices and Good Manufacturing Practices compliant laboratory. Blastomere cells have served as a source to derive the hESCs and the xeno-free culture was demonstrated to be more safe and effective in clinical therapeutic application of hESCs. All the patients showed a remarkable improvement in their conditions and no serious adverse events were reported. This study concluded that hESC lines could be scalable and used in the treatment of various neurological disorders such as SCI, CP, and PD.


Type 1 diabetes eHealth psychoeducation: youth recruitment, participation, and satisfaction.
The Internet and other eHealth technologies offer a platform for improving the dissemination and accessibility of psychoeducational programs for youth with chronic illness. However, little is known about the recruitment process and yield of diverse samples in Internet research with youth who have a chronic illness. The purpose of this study was to compare the demographic and clinical characteristics of youth with Type 1 diabetes on recruitment, participation, and satisfaction with 2 eHealth psychoeducational programs. Youth with Type 1 diabetes from 4 sites in the United States were invited to participate (N=510) with 320 eligible youth consenting (mean age=12.3, SD 1.1; 55.3% female; 65.2% white; and mean A1C=8.3, SD 1.5). Data for this secondary analysis included demographic information (age, race/ethnicity, and income), depressive symptoms, and recruitment rates, including those who refused at point of contact (22.0%), passive refusers who consented but did not participate (15.3%), and those who enrolled (62.7%). Participation (80% lessons completed) and a satisfaction survey (ie, how helpful, enjoyable) were also analyzed. Chi-square or analysis of variance (ANOVA) analyses were used. There were significant differences in recruitment rates by income and race/ethnicity such that black, Hispanic, or mixed race/ethnicity and low-income youth were more likely to refuse passively compared to white and higher-income youth who were more likely to enroll (P<.001). Participation in program sessions was high, with 78.1% of youth completing at least 4 of 5 sessions. There were no significant differences in participation by program, age, gender, or race/ethnicity. Low-income youth were less likely to participate (P=.002). Satisfaction in both programs was also high (3.9 of 5). There were significant gender, race/ethnicity, and income differences, in that girls (P=.001), black, Hispanic, or mixed race/ethnicity youth (P=.02), and low-income youth (P=.02) reported higher satisfaction. There were no differences in satisfaction by program or age. Results indicate that black, Hispanic, or mixed race/ethnicity youth and low-income youth with Type 1 diabetes are less likely to enroll in Internet-based research than white and higher-income youth; thus, creative recruitment approaches are needed. Low-income youth were less likely to participate, possibly due to access. However, once enrolled, youth of diverse race/ethnicity and low-income youth with Type 1 diabetes were as highly satisfied with the eHealth programs as white youth and those with higher income. Results suggest that eHealth programs have the potential to reach diverse youth and be appealing to them.


Of little yellow men and a fear of the light.
We report the case of a 65-year-old woman presenting with recurrent vomiting for 3 days. She had been previously diagnosed with an atrial septal defect and was on treatment with diuretics and digoxin for paroxysmal supraventricular tachycardia. The clinical examination was consistent with an atrial septal defect with severe pulmonary hypertension. Electrocardiography showed complete heart block with ST-segment changes suggestive of digitalis toxicity. Transthoracic echocardiography confirmed Eisenmengerisation. Serum digoxin levels were elevated. Following hospitalisation, she was diagnosed with photophobia when she persistently asked for ambient lighting to be switched off. Most interestingly, the patient kept reporting seeing little yellow men, which was how she perceived the attending doctors. Cessation of digoxin therapy led to progressive abatement of her symptoms.


Maintenance of wintertime vitamin D status with cholecalciferol supplementation is not associated with alterations in serum cytokine concentrations among apparently healthy younger or older adults.
Epidemiological studies have shown that low vitamin D status results in impaired immune function and is associated with the prevalence of autoimmune and inflammatory conditions. Vitamin D supplementation has been shown to reduce circulating concentrations of inflammatory markers in such conditions. However, the possible beneficial effect of vitamin D supplementation in the general population, particularly for those individuals living at high latitudes where hypovitaminosis D is common during wintertime, remains unclear. The aim of this study was to assess the effect of vitamin D supplementation using doses of 5, 10, and 15 μg/d cholecalciferol (D3) compared with placebo on cytokine concentrations throughout winter in apparently healthy younger (aged 20-40 y) and older (aged ≥64 y) adults. A total of 211 younger and 202 older adults completed the 22-wk intervention (from October to March) with >85% compliance. Serum concentrations of 25-hydroxycholecalciferol [25(OH)D3], high sensitivity C-reactive protein, IL-6, IL-10, soluble CD40 ligand, TGFβ, TNFα, and fibrinogen were measured using ELISA. 25(OH)D3 concentrations significantly decreased in the placebo and 5 and 10/d μg D3 groups in the younger cohort and in the placebo group in the older cohort. Whereas 15 μg/d D3 supplementation maintained 25(OH)D3 concentrations in the younger cohort (baseline, 75.9 nmol/L; postintervention, 69.0 nmol/L) and significantly increased concentrations in the older cohort (baseline, 55.1 nmol/L; postintervention, 73.9 nmol/L), it had no significant effect on cytokine concentrations (ANCOVA, P > 0.05). The long-term effects of low vitamin D status remain to be elucidated and optimization of vitamin D status in otherwise healthy individuals may potentially have lasting beneficial effects on the immune system.