Specific social influences on the acceptance of novel foods in 2-5-year-old children.
Social influences have been shown to be very important to overcome food neophobia in young children. However, there is no experimental evidence about whether social influences on food acceptance are specific, that is if models eating the same food as the child are more effective in promoting food acceptance than models eating a different food. We assessed children's behavior towards novel foods when an adult model (a) was not eating (Presence condition), (b) was eating a food of a Different color (Different color condition), and (c) was eating a food of the Same color (Same color condition). We tested 27 children (ages 2- to 5-years-old) recruited from The Pennsylvania State University day-care facilities. Results show that children accepted and ate their novel food more in the Same color condition than in the Different color and in the Presence conditions. Therefore, in young children food acceptance is promoted by specific social influences. These data indicate that children are more likely to eat new food if others are eating the same type of food than when others are merely present or eating another kind of food.


3D bioprinting of methacrylated hyaluronic acid (MeHA) hydrogel with intrinsic osteogenicity.
In bone regenerative medicine there is a need for suitable bone substitutes. Hydrogels have excellent biocompatible and biodegradable characteristics, but their visco-elastic properties limit their applicability, especially with respect to 3D bioprinting. In this study, we modified the naturally occurring extracellular matrix glycosaminoglycan hyaluronic acid (HA), in order to yield photo-crosslinkable hydrogels with increased mechanical stiffness and long-term stability, and with minimal decrease in cytocompatibility. Application of these tailor-made methacrylated hyaluronic acid (MeHA) gels for bone tissue engineering and 3D bioprinting was the subject of investigation. Visco-elastic properties of MeHA gels, measured by rheology and dynamic mechanical analysis, showed that irradiation of the hydrogels with UV light led to increased storage moduli and elastic moduli, indicating increasing gel rigidity. Subsequently, human bone marrow derived mesenchymal stromal cells (MSCs) were incorporated into MeHA hydrogels, and cell viability remained 64.4% after 21 days of culture. Osteogenic differentiation of MSCs occurred spontaneously in hydrogels with high concentrations of MeHA polymer, in absence of additional osteogenic stimuli. Addition of bone morphogenetic protein-2 (BMP-2) to the culture medium further increased osteogenic differentiation, as evidenced by increased matrix mineralisation. MeHA hydrogels demonstrated to be suitable for 3D bioprinting, and were printed into porous and anatomically shaped scaffolds. Taken together, photosensitive MeHA-based hydrogels fulfilled our criteria for cellular bioprinted bone constructs within a narrow window of concentration.


Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes.
For many drugs, pharmacogenetic polymorphisms are known affecting biotransformation and clinical outcome. The clinical importance of these variants depends on allele-frequency and the effect size of the clinical outcome parameters. Further, it depends on the therapeutic range of the drug which is affected, on predictability of drug response as well as on duration until onset of therapeutic efficacy. Consequences which arise from genotyping might be: adjustment of dose according to genotype, choice of therapeutic strategy or even choice of drug. In antidepressant drug treatment, most drugs are metabolized via the polymorphic cytochrome P450 enzyme CYP2D6. Huge differences in pharmacokinetic parameters have been consistently shown for many tricyclics, some SSRIs, and other antidepressant drugs whereas the effects on therapeutic efficacy and adverse events have been described controversially. In cardiovascular disease, oral anticoagulants, nonsteroidal anti-inflammatory drugs, oral hypoglycemic drugs and other drugs are affected by genetic polymorphisms of the cytochrome P450 drug metabolizing enzyme CYP2C9. Studies in patients or healthy volunteers revealed up to 10-fold differences in pharmacokinetic parameters due to genetic polymorphisms of CYP2C9. Pharmacogenetics based dose adjustments are one tool to individualize drug treatment according to genetic factors. They can be derived from pharmacokinetic data with the aim to obtain equal drug concentrations in each individual. Prospective validation of dose adjustments based on pharmacogenetics should be performed before routine application of such strategies. A controlled prospective clinical trial with one arm receiving genotype-based dose adjustments and the other arm receiving therapy as usual will elucidate the benefit of pharmacogenomics-based individualization of certain drug therapies.


Skin-related quality of life among migrant farmworkers.
Farmworkers in North America work in an environment likely to produce skin injuries and illnesses that affect quality of life (QOL). We identified the dimensions of skin-related QOL that were most impaired and examined predictors in a cohort of North Carolina farmworkers. We conducted a longitudinal survey of 304 Latino farmworkers across a work season (1,048 interviews). We assessed skin-related QOL using the Dermatology Life Quality Index. Effects on QOL were reported in 38.7% of observations. The greatest impacts of skin impairments were seen in the Symptoms and Feelings and Work and School Subscales. In multivariate analysis, specific work tasks and high temperatures were associated with greater decrements in QOL. Skin disease among farmworkers is sufficiently severe to affect QOL. Future research should test the effectiveness of interventions on modifiable factors such as facilities for personal hygiene and field sanitation on skin-related QOL.


Comparison of [125I]HIPDm and [125I]iodoantipyrine in quantifying regional cerebral blood flow in rats.
We determined regional cerebral blood flow (rCBF) using [125I]HIPDm [N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamin e] and [125I]iodoantipyrine autoradiography under control and pathologic conditions (hypercapnia [acidosis], hypocapnia [alkalosis], and disrupted blood-brain barrier) conditions in 35 rats. In control rats, HIPDm rCBF (indicator fractionation method, n = 5) was lower than the corresponding IAP rCBF (diffusible indicator method, n = 4), most notably in the infratentorial regions and subcortical nuclei. In hypercapnia, rCBF increased by 100% and 37% in the HIPDm (n = 5) and IAP (n = 5) groups, respectively. In hypocapnia, IAP rCBF (n = 4) decreased 34% but HIPDm rCBF (n = 4) did not change. Following disruption of the blood-brain barrier by intracarotid infusion of mannitol in eight rats, both radiotracers (HIPDm n = 4, IAP n = 4) showed decreased rCBF to regions of disruption as defined by trypan blue extravasation. Our work indicates that modeling HIPDm uptake to quantify rCBF using the indicator fractionation method will underestimate blood flow and that HIPDm kinetics are influenced by compartmental pH dynamics that will limit the accuracy of this method in quantifying rCBF in pathologic conditions.


Kruppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids.
Phenotypic switching of vascular smooth muscle cells (SMCs), such as increased proliferation, enhanced migration, and downregulation of SMC differentiation marker genes, is known to play a key role in the development of atherosclerosis. However, the factors and mechanisms controlling this process are not fully understood. We recently showed that oxidized phospholipids, including 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), which accumulate in atherosclerotic lesions, are potent repressors of expression of SMC differentiation marker genes in cultured SMCs as well as in rat carotid arteries in vivo. Here, we examined the molecular mechanisms whereby POVPC induces suppression of SMC differentiation marker genes in cultured SMCs. Results showed that POVPC induced phosphorylation of ERK1/2 and Elk-1. The MEK inhibitors U-0126 and PD-98059 attenuated POVPC-induced suppression of smooth muscle (SM) alpha-actin and SM-myosin heavy chain. POVPC also induced expression of Krüppel-like factor 4 (Klf4). Chromatin immunoprecipitation assays revealed that POVPC caused simultaneous binding of Elk-1 and Klf4 to the promoter region of the SM alpha-actin gene. Moreover, coimmunoprecipitation assays showed a physical interaction between Elk-1 and Klf4. Results in Klf4-null SMCs showed that blockade of both Klf4 induction and Elk-1 phosphorylation completely abolished POVPC-induced suppression of SMC differentiation marker genes. POVPC-induced suppression of SMC differentiation marker genes was also accompanied by hypoacetylation of histone H4 at the SM alpha-actin promoter, which was mediated by the recruitment of histone deacetylases (HDACs), HDAC2 and HDAC5. Coimmunoprecipitation assays showed that Klf4 interacted with HDAC5. Results provide evidence that Klf4, Elk-1, and HDACs coordinately mediate POVPC-induced suppression of SMC differentiation marker genes.


Surface Effects of the HgI(2) Crystal Characterized by Spectroscopic Ellipsometry.
We report on determination of the surface effects of mercuric iodide (HgI(2)) uniaxial HgI(2) optical parameters with a fixed-polarizer, rotating-polarizer, and fixed-analyzer spectroscopic ellipsometer (PRPSE) after chemical polishing. The characteristics of the chemical complex [KHgI(3), H(2)O] that forms on the HgI(2) surface during KI etching have been investigated over the spectral range from 400 to 800 nm. Surface roughness and effects of the ellipsometric parameters of HgI(2) were treated, and the thickness of the layer formed on the surface was determined and analyzed by PRPSE. The surface roughness was modeled with the Bruggeman effective medium approximation.


Assessment of left ventricular parameters in orthotopic heart transplant recipients using dual-source CT and contrast-enhanced echocardiography: comparison with MRI.
To establish the accuracy and reliability of cardiac dual-source CT (DSCT) and two-dimensional contrast-enhanced echocardiography (CE-Echo) in estimating left ventricular (LV) parameters with respect to cardiac magnetic resonance imaging (CMR) as the reference standard. Twenty-five consecutive heart transplant recipients (20 male, mean age 62.7±10.4 years, mean time since transplantation 8.1±5.9 years) were prospectively recruited. Two blinded readers independently assessed LV ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), and stroke volume (SV) for each patient after manual tracing of the endo- and epicardial contours in DSCT, CE-Echo and CMR cine images. Student's t-test for paired samples for differences, and Bland and Altman plots and Lin's concordance-correlation coefficients (CCC) for agreement were calculated. There was no statistical difference between left ventricular parameters determined by DSCT and CMR. CE-Echo resulted in significant underestimation of left ventricular volumes (mean difference EDV: 15.94±14.19 ml and 17.1±17.06 ml, ESV: 8.5±9.3 and 7.32±9.14 ml with respect to DSCT and CMR), and overestimation of EF compared with the cross-sectional imaging modalities (3.78±8.47% and 2.14±8.35% with respect to DSCT and CMR). Concordance correlation coefficients for LV parameters using DSCT and CMR were higher (CCC≥0.75) than CCC values observed between CE-Echo and DSCT- or CMR-derived data (CCC≥0.54 and CCC≥0.49, respectively). Interobserver agreement was higher for DSCT and CMR values (CCC≥0.72 and CCC≥0.87, respectively). In orthotopic heart transplantation cardiac DSCT allows accurate and reliable estimation of LV parameters compared with CMR, whereas CE-Echo seems to be insufficient to obtain precise measurements.


A guided and unguided internet- and mobile-based intervention for chronic pain: health economic evaluation alongside a randomised controlled trial.
This study aims at evaluating the cost-effectiveness and cost-utility of a guided and unguided internet-based intervention for chronic pain patients (ACTonPainguided and ACTonPainunguided) compared with a waitlist control group (CG) as well as the comparative cost-effectiveness of the guided and the unguided version. This is a health economic evaluation alongside a three-arm randomised controlled trial from a societal perspective. Assessments were conducted at baseline, 9 weeks and 6 months after randomisation. Participants were recruited through online and offline strategies and in collaboration with a health insurance company. 302 adults (≥18 years, pain for at least 6 months) were randomly allocated to one of the three groups (ACTonPainguided, ACTonPainunguided, CG). ACTonPain consists of seven modules and is based on Acceptance and Commitment Therapy. ACTonPainguided and ACTonPainunguided only differ in provision of human support. Main outcomes of the cost-effectiveness and the cost-utility analyses were meaningful change in pain interference (treatment response) and quality-adjusted life years (QALYs), respectively. Economic evaluation estimates were the incremental cost-effectiveness and cost-utility ratio (ICER/ICUR). At 6-month follow-up, treatment response and QALYs were highest in ACTonPainguided (44% and 0.280; mean costs = €6,945), followed by ACTonPainunguided (28% and 0.266; mean costs = €6,560) and the CG (16% and 0.244; mean costs = €6,908). ACTonPainguided vs CG revealed an ICER of €45 and an ICUR of €604.ACTonPainunguided dominated CG. At a willingness-to-pay of €0 the probability of being cost-effective was 50% for ACTonPainguided (vs CG, for both treatment response and QALY gained) and 67% for ACTonPainunguided (vs CG, for both treatment response and QALY gained). These probabilities rose to 95% when society's willingness-to-pay is €91,000 (ACTonPainguided) and €127,000 (ACTonPainunguided) per QALY gained. ACTonPainguided vs ACTonPainunguided revealed an ICER of €2,374 and an ICUR of €45,993. Depending on society's willingness-to-pay, ACTonPain is a potentially cost-effective adjunct to established pain treatment. ACTonPainunguided (vs CG) revealed lower costs at better health outcomes. However, uncertainty has to be considered. Direct comparison of the two interventions does not indicate a preference for ACTonPainguided. DRKS00006183.


Noni juice improves serum lipid profiles and other risk markers in cigarette smokers.
Cigarette smoke-induced oxidative stress leads to dyslipidemia and systemic inflammation. Morinda citrifolia (noni) fruit juice has been found previously to have a significant antioxidant activity. One hundred thirty-two adult heavy smokers completed a randomized, double blind, placebo-controlled clinical trial designed to investigate the effect of noni juice on serum cholesterol, triglyceride, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), high-sensitivity C-reactive protein (hs-CRP), and homocysteine. Volunteers drank noni juice or a fruit juice placebo daily for one month. Drinking 29.5 mL to 188 mL of noni juice per day significantly reduced cholesterol levels, triglycerides, and hs-CRP. Decreases in LDL and homocysteine, as well increases in HDL, were also observed among noni juice drinkers. The placebo, which was devoid of iridoid glycosides, did not significantly influence blood lipid profiles or hs-CRP. Noni juice was able to mitigate cigarette smoke-induced dyslipidemia, an activity associated with the presence of iridoids.


A high-throughput screening approach to discovering good forms of biologically inspired visual representation.
While many models of biological object recognition share a common set of "broad-stroke" properties, the performance of any one model depends strongly on the choice of parameters in a particular instantiation of that model--e.g., the number of units per layer, the size of pooling kernels, exponents in normalization operations, etc. Since the number of such parameters (explicit or implicit) is typically large and the computational cost of evaluating one particular parameter set is high, the space of possible model instantiations goes largely unexplored. Thus, when a model fails to approach the abilities of biological visual systems, we are left uncertain whether this failure is because we are missing a fundamental idea or because the correct "parts" have not been tuned correctly, assembled at sufficient scale, or provided with enough training. Here, we present a high-throughput approach to the exploration of such parameter sets, leveraging recent advances in stream processing hardware (high-end NVIDIA graphic cards and the PlayStation 3's IBM Cell Processor). In analogy to high-throughput screening approaches in molecular biology and genetics, we explored thousands of potential network architectures and parameter instantiations, screening those that show promising object recognition performance for further analysis. We show that this approach can yield significant, reproducible gains in performance across an array of basic object recognition tasks, consistently outperforming a variety of state-of-the-art purpose-built vision systems from the literature. As the scale of available computational power continues to expand, we argue that this approach has the potential to greatly accelerate progress in both artificial vision and our understanding of the computational underpinning of biological vision.


The status of tuberculosis infection control measures in health care facilities rendering joint TB/HIV services in "German Leprosy and Tuberculosis Relief Association" supported states in Nigeria.
To assess the status of tuberculosis (TB) infection control practice in health care facilities implementing joint TB/HIV activities. A descriptive survey triangulating self-administered questionnaire (facility survey to Infection Control Officer, individual health worker to general health workers), review of facility case notes and participant observation techniques was carried out. Twelve health facilities from southern Nigeria were assessed. (1) Administrative and work practice control measure: Only 1 (8.3%) facility had a documented TB Infection control policy; 2 (16.7%) facilities had Infection Control Committee; 5 (41.7%) facilities had Infection Control Officer; 2 (16.7%) asked questions at the health records about cough; 1 (8.3%) facility had health workers intermittently checking for patients with cough in the waiting hall; and 2 (16.7%) facilities had Infection Control Officers who have attended some training on infection control. No facility had Information, Education and Communication (IEC) materials reminding patients and health workers of the possibility of TB transmission in the health care setting. While 86.4% of TB patients were screened for HIV, only 54.7% of HIV patients were tested for TB. (2) Environmental control measures: All the waiting halls were well ventilated. Though 66.7% of the consulting rooms were well ventilated, 25% of them were over crowded; 58.3% of the facilities managed sputum smear positive TB patients in the same ward with HIV-positive and other vulnerable patients; no facility had air cleaners. Implementation of the different aspects of the administrative control and work practice component of TB infection control measure range from 8.3% to 41.7% of the facilities. Urgent measures should be taken to reverse this trend in the face of TB burden due to HIV.


Characterization and risk assessment of seasonal and weather dynamics in organic pollutant mixtures from discharge of a separate sewer system.
Sites of wastewater discharge are hotspots for pollution of freshwaters with organic micropollutants and are often associated with adverse effects to aquatic organisms. The assessment, monitoring and managment of these hotspots is challenged by variations in the pollutant mixture composition due to season, weather conditions and random spills. In this study, we unraveled temporal exposure patterns in organic micropollutant mixtures from wastewater discharge and analyzed respective acute and sublethal risks for aquatic organisms. Samples were taken from two components of a separate sewer system i) a wastewater treatment plant (WWTP) and ii) a rain sewer of a medium size town as well as from the receiving river in different seasons. Rain sewer samples were separately collected for rain and dry - weather conditions. We analyzed 149 compounds by liquid chromatography-tandem mass spectrometry (LC-MS/MS). By considering the pollution dynamics in the point sources, we reduced the complexity of pollutant mixtures by k-means clustering to a few emission groups representing temporal and weather-related pollution patterns. From these groups, we derived biological quality element (BQE) - specific risk patterns. In most cases, one main risk driving emission group and a few individual risk driving compounds were identified for each BQE. While acute risk for fish was quite low, algae were exposed to seasonally emitted herbicides (terbuthylazine, spiroxamine) and crustaceans to randomly spilled insecticides (diazinon, dimethoate). Sublethal risks for all BQE were strongly influenced by constantly emitted pollutants, above all, pharmaceuticals. Variability of risks in the river was mainly driven by water discharge of the river rather than by season or peak events. Overall, the studied WWTP represented the major pollution source with a specific emission of agricultural compounds. However, the investigated rain sewer showed to be a constant pollution source due to illicit connections and was an important entry route for high loads of insecticides and biocides due to spills or incorrect disposal. By considering these pollution and risk dynamics, monitoring strategies may be optimized with a special focus on times of low flow conditions in the river, rain events and seasonally emitted risk drivers.


Survey of knowledge, attitude, and practice regarding reproductive health among urban men in China: a descriptive study.
There has been little focus on men's reproductive health (RH) in China. This descriptive study conducted in Yiling District, Yichang, China, surveyed male knowledge of sexual physiology and RH to assess levels of knowledge, attitudes and practices (KAPs) regarding prevention of sexually transmitted diseases (STDs). A total of 3933 men, aged 18-59 years (mean, 40.3 years), were recruited by cluster random sampling. They completed a questionnaire in the presence of an interviewer, with items related to subject characteristics, RH knowledge, and subjective symptoms of the reproductive system. Physical examination and reproductive system disease diagnosis were performed. Participants' occupations were predominantly skilled labor (80.5%). Nearly four-fifths (78.5%) respondents had at least one reproductive disease. Over half of respondents were aware of and declared a positive attitude about sexual physiology and safe sex, and 70% of them selected to visit a doctor when they had a reproductive disorder. However, only 41.9% believed human immunodeficiency virus/acquired immunodeficiency syndrome could be transmitted through breastfeeding, and 64.6% incorrectly thought they could avoid contracting STDs by cleaning their genitals after intercourse. In addition, 45% discriminated against and were unwilling to be friends with infected persons. Nearly 45% of those with a reproductive system disorder refused to discuss it with friends or family members. These results indicate that this cohort of Chinese men had a certain degree of KAP about RH, whereas some aspects require further public health education in the general population. It is necessary to disseminate accurate knowledge of STD risk in China based on sociodemographic characteristics.


Effect of malaria on placental volume measured using three-dimensional ultrasound: a pilot study.
The presence of malaria parasites and histopathological changes in the placenta are associated with a reduction in birth weight, principally due to intrauterine growth restriction. The aim of this study was to examine the feasibility of studying early pregnancy placental volumes using three-dimensional (3D) ultrasound in a malaria endemic area, as a small volume in the second trimester may be an indicator of intra-uterine growth restriction and placental insufficiency. Placenta volumes were acquired using a portable ultrasound machine and a 3D ultrasound transducer and estimated using the Virtual Organ Computer-aided AnaLysis (VOCAL) image analysis software package. Intra-observer reliability and limits of agreement of the placenta volume measurements were calculated. Polynomial regression models for the mean and standard deviation as a function of gestational age for the placental volumes of uninfected women were created and tested. Based on these equations each measurement was converted into a z -score. The z-scores of the placental volumes of malaria infected and uninfected women were then compared. Eighty-four women (uninfected = 65; infected = 19) with a posterior placenta delivered congenitally normal, live born, single babies. The mean placental volumes in the uninfected women were modeled to fit 5th, 10th, 50th, 90th and 95th centiles for 14-24 weeks' gestation. Most placenta volumes in the infected women were below the 50th centile for gestational age; most of those with Plasmodium falciparum were below the 10th centile. The 95% intra-observer limits of agreement for first and second measurements were ± 37.0 mL and ± 25.4 mL at 30 degrees and 15 degrees rotation respectively. The new technique of 3D ultrasound volumetry of the placenta may be useful to improve our understanding of the pathophysiological constraints on foetal growth caused by malaria infection in early pregnancy.


Access to primary health care for immigrants: results of a patient survey conducted in 137 primary care practices in Ontario, Canada.
Immigrants make up one fifth of the Canadian population and this number continues to grow. Adequate access to primary health care is important for this population but it is not clear if this is being achieved. This study explored patient reported access to primary health care of a population of immigrants in Ontario, Canada who were users of the primary care system and compared this with Canadian-born individuals; and by model of primary care practice. This study uses data from the Comparison of Models of Primary Care Study (COMP-PC), a mixed-methods, practice-based, cross-sectional study that collected information from patients and providers in 137 primary care practices across Ontario, Canada in 2005-2006. The practices were randomly sampled to ensure an equal number of practices in each of the four dominant primary care models at that time: Fee-For-Service, Community Health Centres, and the two main capitation models (Health Service Organization and Family Health Networks). Adult patients of participating practices were identified when they presented for an appointment and completed a survey in the waiting room. Three measures of access were used, all derived from the patient survey: First Contact Access, First Contact Utilization (both based on the Primary Care Assessment Tool) and number of self-reported visits to the practice in the past year. Of the 5,269 patients who reported country of birth 1,099 (20.8%) were born outside of Canada. In adjusted analysis, recent immigrants (arrival in Canada within the past five years) and immigrants in Canada for more than 20 years were less likely to report good health compared to Canadian-born (Odds ratio 0.58, 95% CI 0.36,0.92 and 0.81, 95% CI 0.67,0.99). Overall, immigrants reported equal access to primary care services compared with Canadian-born. Within immigrant groups recently arrived immigrants had similar access scores to Canadian-born but reported 5.3 more primary care visits after adjusting for health status. Looking across models, recent immigrants in Fee-For-Service practices reported poorer access and fewer primary care visits compared to Canadian-born. Overall, immigrants who were users of the primary care system reported a similar level of access as Canadian-born individuals. While recent immigrants are in poorer health compared with Canadian-born they report adequate access to primary care. The differences in access for recently arrived immigrants, across primary care models suggests that organizational features of primary care may lead to inequity in access.


Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumour activity.
Intravesical BCG therapy is effective in the treatment of superficial bladder cancer. Both clinical and experimental results suggest a role for cytokines and delayed-type hypersensitivity (DTH) in BCG-induced antitumour immunity. We characterized the modulatory effects of BCG on bladder cytokine expression and determined the relationship between DTH and BCG antitumour activity. The bladders of mice were instilled with BCG through a catheter. Bladder tissue RNA and urine were collected for evaluation of cytokine expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ELISA. IFN-gamma and TNF-alpha, the two major cytokines associated with DTH, were efficiently induced by BCG. IL10, an important down-regulator of DTH, was also induced by BCG. Constitutive levels of IL4 and IL5 were observed, but neither IL4 nor IL5 were modulated by BCG. Similar results were observed in the kinetic analysis of urinary cytokines in patients after intravesical BCG therapy. Production of Th1 (T helper type 1) cytokines (IFN-gamma, IL2 and IL12) preceded that of the Th2 (T helper type 2) cytokine IL10. A tendency toward higher ratios of IFN-gamma versus IL10 for BCG responders also was observed. In animal studies the absence of IL10 abrogated either by antibody inhibition or the use of genetically modified, IL10 deficient (IL10-/-) mice resulted in enhanced DTH responses. Under conditions of enhanced DTH, a significant enhancement in antitumour activity was observed. These data demonstrate that DTH and its associated mononuclear infiltration and cytokine production are important to the antitumour activity of intravesical BCG therapy, and suggest that effects to diminish IL10 production may have therapeutic value.


Population differentiation and Wolbachia phylogeny in mosquitoes of the Aedes scutellaris group.
Mosquito species of the Aedes (Stegomyia) scutellaris (Walker) group (Diptera: Culicidae) are distributed across many islands of the South Pacific and include major regional vectors of filariasis, such as Aedes polynesiensis (Marks). Analysis of populations of Ae. polynesiensis at the extremes of its range, from Fiji and from Moorea, French Polynesia, using the rDNA ITS2 (internal transcribed spacer 2) region and six microsatellite markers showed considerable genetic differentiation between them (F(ST) = 0.298-0.357). Phylogenetic analysis of the Wolbachia endosymbionts in three members of the complex revealed that based on the wsp gene they are all very similar and belong to the Mel subgroup of the A clade, closely related to the Wolbachia strain present in the gall wasp Callyrhytis glandium (Giraud) (Hymenoptera: Cynipidae). By contrast they are only distantly related to the A-clade Wolbachia in Aedes albopictus (Skuse), a species closely allied to the Ae. scutellaris group. There was very low differentiation between the Wolbachia in the Moorea and Fiji populations of Ae. polynesiensis.


Registered nurses' reflections on discussing sexuality with patients: responsibilities, doubts and fears.
To describe registered nurses' reflections on discussing sexuality with patients. It is known that many diseases and treatments have a negative impact on sexual health. Despite these facts, registered nurses typically do not address sexual issues with patients. A descriptive design and a qualitative approach were used. Interviews were conducted in 2010 with 10 registered nurses. The data were analysed using qualitative content analysis. The themes 'Doing the right thing and doing good', 'Could've, would've, should've: a nurse's conflicting feelings' and 'I just don't talk about it: sexuality as a nontopic' confirmed the notion that discussing sexuality in nursing care is still challenging and difficult for nurses, but also revealed that nurses who do talk to patients about sexual issues do so based on their strong sense of wanting to help. They felt a responsibility because of their knowledge in the area, but the topic also brought out conflicting feelings such as fear and embarrassment. Lack of time, support and places to talk to patients in private as well as prejudice were contributing factors to their not addressing sexuality. Some nurses also felt that sexuality was someone else's responsibility and a taboo subject. Patients' sexuality is still surrounded by silence. But factors exist that can facilitate discussion of sexuality. Nurses have a key role in detecting ill-health. This study suggests that when nurses use their knowledge and go beyond their comfort zone and address sexuality, they can identify patients' sexual problems. Nurses need to understand how their knowledge can help patients who are experiencing sexual problems; they also need support from the workplace and to have access to routines that reinforce the notion that sexuality is a topic worth discussing.


The use of physical restraint in patients with cerebral contusion.
Behavioral problems resulting in the use of physical restraint is a clinical problem seen in the acute phase of recovery from cerebral contusion. However, little is known about the frequency of physical restraint, factors that might predispose to its use, the pattern of adjunctive psychotropic drugs used or the outcome for patients needing this form of management. In order to examine these issues, a retrospective study of all patients (N = 34) admitted with cerebral contusion to a neurosurgical service over a one-year period was undertaken. Physical restraint was used in twelve patients (35%) for an average length of 4.3 days. The use of physical restraint was associated with presumptive evidence of alcohol abuse or dependence but not with level of consciousness on admission. Restrained patients were frequently prescribed psychotropic drugs during hospitalization. Patients requiring physical restraint stayed in hospital nearly twice as long as those not needing restraint. Close attention to the identification and treatment of alcohol problems and their complications in this population may reduce the need for physical restraint and shorten length of hospital stay.


Common Hormone Therapies Used to Care for Transgender Patients Influence Laboratory Results.
Many laboratory tests are reported and interpreted with sex-specific reference intervals. However, transgender individuals receiving masculinizing or feminizing hormone therapy experience physiological changes predisposing some laboratory tests to shift outside of existing reference intervals. In this study, we review laboratory testing of a large cohort of transgender individuals who were prescribed hormone therapy for at least 6 months at an academic medical center. Transgender patients were identified using a search function within the electronic health record with gender identity status verified by chart review. Patients were grouped based on type of hormone therapy administered. All laboratory studies were ordered for medical purposes as part of clinical care; as a result, the exact laboratory tests differed among the patients. Some of the patients had sufficient data for both 6- and 12-month comparisons with baseline laboratory values. Statistically significant changes were observed at 6- and 12-month comparisons in basic chemistry, endocrine, and hematologic parameters for transgender individuals receiving masculinizing or feminizing hormones. Chart review demonstrated variation in route of administration of hormone therapy and frequency of gender-affirming surgery within the study population. Transgender individuals receiving hormone therapy experienced significant changes in components of basic chemistry, endocrine, and hematologic parameters following administration of hormone therapy. Variability in hormone dosing and route of administration for gender-affirming treatment warrants further investigation.


Resetting of circadian time in peripheral tissues by glucocorticoid signaling.
In mammals, circadian oscillators reside not only in the suprachiasmatic nucleus of the brain, which harbors the central pacemaker, but also in most peripheral tissues. Here, we show that the glucocorticoid hormone analog dexamethasone induces circadian gene expression in cultured rat-1 fibroblasts and transiently changes the phase of circadian gene expression in liver, kidney, and heart. However, dexamethasone does not affect cyclic gene expression in neurons of the suprachiasmatic nucleus. This enabled us to establish an apparent phase-shift response curve specifically for peripheral clocks in intact animals. In contrast to the central clock, circadian oscillators in peripheral tissues appear to remain responsive to phase resetting throughout the day.


A comparison of oral azithromycin with topical oxytetracycline/polymyxin for the treatment of trachoma in children.
Trachoma, an infectious keratoconjunctivitis caused by Chlamydia trachomatis, is a leading cause of preventable blindness in developing countries. In this study we compared oral azithromycin with oxytetracycline/polymyxin eye ointment (once daily for 5 days every 4 weeks; total of six treatment cycles) for the treatment of active endemic trachoma in 168 rural Egyptian children. A suspension of azithromycin was administered to children as a dose of 20 mg/kg by one of three schedules: a single dose, one dose a week for 3 weeks, and one dose every 4 weeks for a total of six doses. The children's clinical status and chlamydial infection rates were evaluated for 1 year. The clinical cure rates were 35% 2 months after initial treatment, 16% at 8 months (during the annual autumn epidemic of purulent conjunctivitis), and 47% at 1 year. The pretreatment chlamydial infection rate of 33% (determined by direct immunofluorescence) decreased to 5% at 2 months and was 9% at 12 months. There were no significant clinical or laboratory differences among the four treatment groups. Thus, 1-6 doses of azithromycin were equivalent to 30 days of topical oxytetracycline/polymyxin ointment and may offer an effective alternative means of controlling endemic trachoma.


Integration of grid maps in merged environments.
Natural environments are represented by local maps of grid cells and place cells that are stitched together. The manner by which transitions between map fragments are generated is unknown. We recorded grid cells while rats were trained in two rectangular compartments, A and B (each 1 m × 2 m), separated by a wall. Once distinct grid maps were established in each environment, we removed the partition and allowed the rat to explore the merged environment (2 m × 2 m). The grid patterns were largely retained along the distal walls of the box. Nearer the former partition line, individual grid fields changed location, resulting almost immediately in local spatial periodicity and continuity between the two original maps. Grid cells belonging to the same grid module retained phase relationships during the transformation. Thus, when environments are merged, grid fields reorganize rapidly to establish spatial periodicity in the area where the environments meet.


Surveillance and control of rabies in La Reunion, Mayotte, and Madagascar.
Mayotte and La Reunion islands are currently free of animal rabies and surveillance is performed by the French Human and Veterinary Public Health Services. However, dog rabies is still enzootic in Madagascar with 4 to 10 confirmed human cases each year. The number of antirabies medical centres in Madagascar is still scarce to provide easy access to the local population for post-exposure rabies prophylaxis. Furthermore, stray dog populations are considerable and attempts to control rabies by mass campaigns of dog vaccination have not received sufficient attention from the national health authorities. To address these challenges, an expanded program to control rabies needs to be initiated by the Malagasy authorities.


Probing optical excitations in chevron-like armchair graphene nanoribbons.
The bottom-up fabrication of graphene nanoribbons (GNRs) has opened new opportunities to specifically tune their electronic and optical properties by precisely controlling their atomic structure. Here, we address excitation in GNRs with periodic structural wiggles, the so-called chevron GNRs. Based on reflectance difference and high-resolution electron energy loss spectroscopies together with ab initio simulations, we demonstrate that their excited-state properties are of excitonic nature. The spectral fingerprints corresponding to different reaction stages in their bottom-up fabrication are also unequivocally identified, allowing us to follow the exciton build-up from the starting monomer precursor to the final GNR structure.


Investigating alternatives to the fish early-life stage test: a strategy for discovering and annotating adverse outcome pathways for early fish development.
The fish early-life stage (FELS) test (Organisation for Economic Co-operation and Development [OECD] test guideline 210) is the primary test used internationally to estimate chronic fish toxicity in support of ecological risk assessments and chemical management programs. As part of an ongoing effort to develop efficient and cost-effective alternatives to the FELS test, there is a need to identify and describe potential adverse outcome pathways (AOPs) relevant to FELS toxicity. To support this endeavor, the authors outline and illustrate an overall strategy for the discovery and annotation of FELS AOPs. Key events represented by major developmental landmarks were organized into a preliminary conceptual model of fish development. Using swim bladder inflation as an example, a weight-of-evidence-based approach was used to support linkage of key molecular initiating events to adverse phenotypic outcomes and reduced young-of-year survival. Based on an iterative approach, the feasibility of using key events as the foundation for expanding a network of plausible linkages and AOP knowledge was explored and, in the process, important knowledge gaps were identified. Given the scope and scale of the task, prioritization of AOP development was recommended and key research objectives were defined relative to factors such as current animal-use restrictions in the European Union and increased demands for fish toxicity data in chemical management programs globally. The example and strategy described are intended to guide collective efforts to define FELS-related AOPs and develop resource-efficient predictive assays that address the toxicological domain of the OECD 210 test.


Tooth wear in captive giraffes (Giraffa camelopardalis): mesowear analysis classifies free-ranging specimens as browsers but captive ones as grazers.
Captive giraffe (Giraffa camelopardalis) mostly do not attain the longevity possible for this species and frequently have problems associated with low energy intake and fat storage mobilization. Abnormal tooth wear has been among the causes suggested as an underlying problem. This study utilizes a tooth wear scoring method ("mesowear") primarily used in paleobiology. This scoring method was applied to museum specimens of free-ranging (n=20) and captive (n=41) giraffes. The scoring system allows for the differentiation between attrition--(typical for browsers, as browse contains little abrasive silica) and abrasion--(typical for grazers, as grass contains abrasive silica) dominated tooth wear. The dental wear pattern of the free-ranging population is dominated by attrition, resembles that previously published for free-ranging giraffe, and clusters within browsing herbivores in comparative analysis. In contrast, the wear pattern of the captive population is dominated by abrasion and clusters among grazing herbivores in comparative analyses. A potential explanation for this difference in tooth wear is likely related to the content of abrasive elements in zoo diets. Silica content (measured as acid insoluble ash) is low in browse and alfalfa. However, grass hay and the majority of pelleted compound feeds contain higher amounts of silica. It can be speculated that the abnormal wear pattern in captivity compromises tooth function in captive giraffe, with deleterious long-term consequences.


Treatment of the pivot-shift intraarticular versus extraarticular or combined reconstruction procedures. A biomechanical study.
Various surgical procedures for ACL reconstruction (intraarticular, extraarticular, and combined procedures) were performed on ACL-sectioned anatomic knee specimens, and their effects on tibial rotation were investigated by analyzing knee movements under valgus and rotatory torques on five fresh anatomic knee specimens. The movements were measured in three dimensions using biplanar photography, when all the ligament were intact, than after the ACL was sectioned, and finally after each surgical procedure was performed. From the results, the pivot shift, which had been observed when the ACL was sectioned, disappeared after carrying out any of the procedures examined. On the other hand, the range of physiologic rotation of the tibia reduced to less than its normal value when either the extraarticular reconstruction or the combined reconstructive procedure was performed. However, the tibial rotation was restored to almost its normal value when the intraarticular reconstruction was performed. Thus, it would appear that the intraarticular reconstruction of the ACL is the best way for eliminating the pivot shift and restoring the joint mechanics to normality.


Role of position 627 of PB2 and the multibasic cleavage site of the hemagglutinin in the virulence of H5N1 avian influenza virus in chickens and ducks.
Highly pathogenic H5N1 avian influenza viruses have caused major disease outbreaks in domestic and free-living birds with transmission to humans resulting in 59% mortality amongst 564 cases. The mutation of the amino acid at position 627 of the viral polymerase basic-2 protein (PB2) from glutamic acid (E) in avian isolates to lysine (K) in human isolates is frequently found, but it is not known if this change affects the fitness and pathogenicity of the virus in birds. We show here that horizontal transmission of A/Vietnam/1203/2004 H5N1 (VN/1203) virus in chickens and ducks was not affected by the change of K to E at PB2-627. All chickens died between 21 to 48 hours post infection (pi), while 70% of the ducks survived infection. Virus replication was detected in chickens within 12 hours pi and reached peak titers in spleen, lung and brain between 18 to 24 hours for both viruses. Viral antigen in chickens was predominantly in the endothelium, while in ducks it was present in multiple cell types, including neurons, myocardium, skeletal muscle and connective tissues. Virus replicated to a high titer in chicken thrombocytes and caused upregulation of TLR3 and several cell adhesion molecules, which may explain the rapid virus dissemination and location of viral antigen in endothelium. Virus replication in ducks reached peak values between 2 and 4 days pi in spleen, lung and brain tissues and in contrast to infection in chickens, thrombocytes were not involved. In addition, infection of chickens with low pathogenic VN/1203 caused neuropathology, with E at position PB2-627 causing significantly higher infection rates than K, indicating that it enhances virulence in chickens.


Activation of preexisting and acquired face representations: the N250 event-related potential as an index of face familiarity.
Electrophysiological studies using event-related potentials have demonstrated that face stimuli elicit a greater negative brain potential in right posterior recording sites 170 msec after stimulus onset (N170) relative to nonface stimuli. Results from repetition priming paradigms have shown that repeated exposures of familiar faces elicit a larger negative brainwave (N250r) at inferior temporal sites compared to repetitions of unfamiliar faces. However, less is known about the time course and learning conditions under which the N250 face representation is acquired. In the familiarization phase of the Joe/no Joe task, subjects studied a target "Joe" face ("Jane" for female subjects) and, during the course of the experiment, identified a series of sequentially presented faces as either Joe or not Joe. The critical stimulus conditions included the subject's own face, a same-sex Joe ( Jane) face and a same-sex "other" face. The main finding was that the subject's own face produced a focal negative deflection (N250) in posterior channels relative to nontarget faces. The task-relevant Joe target face was not differentiated from other nontarget faces in the first half of the experiment. However, in the second half, the Joe face produced an N250 response that was similar in magnitude to the own face. These findings suggest that the N250 indexes two types of face memories: a preexperimentally familiar face representation (i.e., the "own face" and a newly acquired face representation (i.e., the Joe/Jane face) that was formed during the course of the experiment.


Hepatitis C virus (HCV) hypervariable region 1 complexity does not correlate with severity of liver disease, HCV type, viral load or duration of infection.
Several studies have suggested that infection with a highly heterogeneous population of hepatitis C virus correlates with a low response rate to interferon. It is still debated, however, whether or not this heterogeneity might be associated with liver disease severity. The aim of this study was to analyse hepatitis C virus genome complexity in patients with various stages of liver disease. We used polymerase chain reaction-single strand conformation polymorphism (SSCP) analysis to estimate the degree of complexity of the hypervariable region (HVR1) in 95 anti-HCV and serum HCV-RNA positive patients. They were divided into two groups according to Knodell's histological activity index (HAI) grading: 22 with HAI <4 and 73 with HAI> or =4, including 19 with cirrhosis. The number of visible SSCP bands ranged from 1 to 7. There was no significant difference in the number of SSCP bands between patients with HAI <4 and patients with HAI> or =4 (median number of bands was 4 in both groups). The number of SSCP bands was not correlated to the biochemical activity, the genotype, the HCV-RNA titre or the duration of hepatitis C virus infection. The HCV-HVR1 complexity profile alone does not correlate with the severity of liver disease, whatever the biological and virological profile of the viral infection.


Pt2Ag acetylide-doped silica nanoparticles: enabling luminescence of Pt2Ag complexes in water and sensors for highly sensitive detection of cyanide anions.
Two novel luminescent hetero-trinuclear complexes [Pt2Ag(μ-dpppy)2(C≡CC6H4R-4)4](ClO4) (R = H, 1; R = CH3, 2; dpppy = 2,6-bis(diphenylphosphino)pyridine) were synthesized by the self-assembly reaction between [Pt(C[triple bond, length as m-dash]CC6H4R-4)4](2-) and [Ag2(μ-dpppy)3](2+) and characterized by elemental analyses, electrospray ionization mass spectrometry, and (1)H NMR and (31)P{(1)H} NMR spectroscopy and by X-ray crystallography for complex 2. Two Pt2Ag complexes show strong luminescence in the solid state, but exhibit weak emission in CH2Cl2 solution and in acetonitrile-water (1 : 1, v : v) solution at room temperature. To overcome the limitations of low water solubility and weak emission in solutions, a new kind of luminescent Pt2Ag@SiO2 nanoparticles was prepared by incorporating the new Pt2Ag acetylides into monodisperse silica nanoparticles. It is noted that Pt2Ag@SiO2 nanoparticles exhibit strong luminescence in aqueous solution, and cyanide anions tend to decrease their luminescence intensity in NaHCO3-NaOH buffer solution. Based on this, a novel nanosensor for highly sensitive detection of cyanide anions was developed in the range of 0.1-10.0 μM.


Hydrogen peroxide mediates amyloid beta protein toxicity.
Amyloid beta protein (A beta) is a 40-43 amino acid peptide that is associated with plaques in the brains of Alzheimer's patients and is cytotoxic to cultured neurons. Using both primary central nervous system cultures and clonal cell lines, it is shown that a number of anti-oxidants protect cells from A beta toxicity, suggesting that at least one pathway to A beta cytotoxicity results in free radical damage. A beta causes increased levels of H2O2 and lipid peroxides to accumulate in cells. The H2O2-degrading enzyme catalase protects cells from A beta toxicity. Clonal cell lines selected for their resistance to A beta toxicity also become resistant to the cytolytic action of H2O2. In addition, A beta induces the activity of NF-kappa B, a transcription factor thought to be regulated by oxidative stress. Finally, A beta-induced H2O2 production and A beta toxicity are blocked by reagents that inhibit flavin oxidases, suggesting that A beta activates a member of this class of enzymes. These results show that the cytotoxic action of A beta on neurons results from free radical damage to susceptible cells.


The human Tim-Tipin complex interacts directly with DNA polymerase epsilon and stimulates its synthetic activity.
The Tim-Tipin complex plays an important role in the S phase checkpoint and replication fork stability in metazoans, but the molecular mechanism underlying its biological function is poorly understood. Here, we present evidence that the recombinant human Tim-Tipin complex (and Tim alone) markedly enhances the synthetic activity of DNA polymerase ε. In contrast, no significant effect on the synthetic ability of human DNA polymerase α and δ by Tim-Tipin was observed. Surface plasmon resonance measurements and co-immunoprecipitation experiments revealed that recombinant DNA polymerase ε directly interacts with either Tim or Tipin. In addition, the results of DNA band shift assays suggest that the Tim-Tipin complex (or Tim alone) is able to associate with DNA polymerase ε bound to a 40-/80-mer DNA ligand. Our results are discussed in view of the molecular dynamics at the human DNA replication fork.


Crystal structure of a novel conformational state of the flavivirus NS3 protein: implications for polyprotein processing and viral replication.
The flavivirus genome comprises a single strand of positive-sense RNA, which is translated into a polyprotein and cleaved by a combination of viral and host proteases to yield functional proteins. One of these, nonstructural protein 3 (NS3), is an enzyme with both serine protease and NTPase/helicase activities. NS3 plays a central role in the flavivirus life cycle: the NS3 N-terminal serine protease together with its essential cofactor NS2B is involved in the processing of the polyprotein, whereas the NS3 C-terminal NTPase/helicase is responsible for ATP-dependent RNA strand separation during replication. An unresolved question remains regarding why NS3 appears to encode two apparently disconnected functionalities within one protein. Here we report the 2.75-A-resolution crystal structure of full-length Murray Valley encephalitis virus NS3 fused with the protease activation peptide of NS2B. The biochemical characterization of this construct suggests that the protease has little influence on the helicase activity and vice versa. This finding is in agreement with the structural data, revealing a single protein with two essentially segregated globular domains. Comparison of the structure with that of dengue virus type 4 NS2B-NS3 reveals a relative orientation of the two domains that is radically different between the two structures. Our analysis suggests that the relative domain-domain orientation in NS3 is highly variable and dictated by a flexible interdomain linker. The possible implications of this conformational flexibility for the function of NS3 are discussed.


Use of a near-infrared vein finder to define cortical veins and dural sinuses prior to dural opening.
Near-infrared (NIR) light is commonly used to map venous anatomy in the upper extremities to gain intravenous access for line placement. In this report, the authors describe the use of a common and commercially available NIR vein finder to delineate the cortical venous anatomy prior to dural opening.During a variety of cranial approaches, the dura was directly visualized using an NIR vein finder. The NIR light source allowed for recognition of the underlying cortical venous anatomy, dural sinuses, and underlying pathology before the dura was opened. This information was considered when tailoring the dural opening. When the dura was illuminated with the NIR vein finder, the underlying cortical and sinus venous anatomy was evident and correlated with the observed cortical anatomy. The vein finder was also accurate in locating superficial lesions and pathological dural veins. A complete accordance in the findings on the pre- and post-dural opening images was observed in all cases.This simple, inexpensive procedure is readily compatible with operative room workflow, necessitates no head fixation, and offers a real-time image independent of brain shift.


Alcohol use and immune reconstitution among HIV-infected patients on antiretroviral therapy in Nairobi, Kenya.
Studies on the effects of alcohol use on HIV disease progression have been contradictory, with at least one study finding a positive effect of low alcohol consumption on CD4 count. In addition, most such studies have taken place in the developed West. We investigated the association between alcohol use and immune reconstitution through CD4 count response among HIV-infected individuals on antiretroviral therapy (ART) at an urban sub-Saharan African clinic. This was a retrospective cohort study of treatment-naïve HIV-infected adults initiating ART in Nairobi, Kenya and followed for 12 months between January 2009 and December 2012. At enrollment, a standardized questionnaire was used to collect data on sociodemographic variables and alcohol consumption. CD4 count was measured every six months. Linear regression models assessed the association between CD4 count and alcohol consumption, categorized as abstinent, moderate, or hazardous. Overall, 854 participants were included, 522 of which were women, with 85 (25.6%) men and 50 (9.6%) women reporting any alcohol use, and 8 (2.4%) men and 7 (1.3%) women reporting hazardous drinking. At baseline, alcohol use was associated with higher education and socioeconomic status. Median CD4 count was higher among alcohol users compared to those who abstained at baseline and at 6 and 12 months post-ART initiation, although this was only significant at 6 months. There were no differences in adherence between abstainers and drinkers. While overall alcohol use was significantly associated with higher CD4 counts, moderate and hazardous use treated separately were not. We conclude that, while alcohol use was associated with higher CD4 counts at 12 months post-ART, the mechanism for this association is unclear but may reflect unmeasured socioeconomic or nutritional differences. Additional research is required on the specific drinking patterns of this population and the types of alcoholic beverages consumed to clarify this relationship.


The role of schools in children's physical activity participation: staff perceptions.
The school setting provides a promising environment to increase children's physical activity (PA), however, staff often impact the success of PA within schools. The purpose of this article was to describe the knowledge of elementary school staff related to PA and their perception of the importance of the school environment being conducive to PA prior to the implementation of a recess intervention. Qualitative focus groups were conducted in 12 elementary schools in the Midwest. Grounded theory was used to explore participants' knowledge and perceptions. Participants felt PA was important but believed several factors impacted children's ability to be more active: (i) lack of time due to increasing academic demands, (ii) peer pressure (especially in girls) not to be active and (iii) lack of space and equipment. When discussing recess, staff felt that their encouragement of or active participation in PA with children resulted in more activity. Furthermore, even though participants were aware of PA benefits, they noticed eliminating recess was often used as a punishment for misbehavior. School-based PA promotion and PA opportunities hold great promise for increasing PA in children. However, to maximize these efforts school polices related to training staff about PA are needed.


Interaction between PRP11 and SPP91 yeast splicing factors and characterization of a PRP9-PRP11-SPP91 complex.
Several proteins are involved in the early steps of the spliceosome assembly pathway. Protein-protein interactions have been identified between two Saccharomyces cerevisiae yeast splicing factors, PRP9 and SPP91. Here it is demonstrated that protein-protein interactions occur between SPP91 and PRP11. The combination of the prp9-1 mutant and a truncated prp11 mutant exhibits a synthetic lethal phenotype, suggestive of a common biochemical defect. The PRP9 and PRP11 proteins do not interact directly, but the PRP9 and PRP11 molecules can simultaneously bind SPP91 to form a three-molecule complex. Structurally and functionally related proteins are found in mammalian cells and are associated in a single biochemical fraction. This strongly suggests that the PRP9-SPP91-PRP11 complex is a key element of the splicing machinery.


Older men who use computers have lower risk of dementia.
To determine if older men who use computers have lower risk of developing dementia. Cohort study of 5506 community-dwelling men aged 69 to 87 years followed for up to 8.5 years. Use of computers measured as daily, weekly, less than weekly and never. Participants also reported their use of email, internet, word processors, games or other computer activities. The primary outcome was the incidence of ICD-10 diagnosis of dementia as recorded by the Western Australian Data Linkage System. 1857/5506 (33.7%) men reported using computers and 347 (6.3%) received a diagnosis of dementia during an average follow up of 6.0 years (range: 6 months to 8.5 years). The hazard ratio (HR) of dementia was lower among computer users than non-users (HR = 0.62, 95%CI = 0.47-0.81, after adjustment for age, educational attainment, size of social network, and presence of depression or of significant clinical morbidity). The HR of dementia appeared to decrease with increasing frequency of computer use: 0.68 (95%CI = 0.41-1.13), 0.61 (95%CI = 0.39-0.94) and 0.59 (95%CI = 0.40-0.87) for less than weekly, at least weekly and daily. The HR of dementia was 0.66 (95%CI = 0.50-0.86) after the analysis was further adjusted for baseline cognitive function, as measured by the Mini-Mental State Examination. Older men who use computers have lower risk of receiving a diagnosis of dementia up to 8.5 years later. Randomised trials are required to determine if the observed associations are causal.


Description and Early Outcomes of a Comprehensive Curriculum Redesign at the Northwestern University Feinberg School of Medicine.
In 2012, the Northwestern University Feinberg School of Medicine launched a redesigned curriculum addressing the four primary recommendations in the 2010 Carnegie Foundation for the Advancement of Teaching report on reforming medical education. This new curriculum provides a more standardized evaluation of students' competency achievement through a robust portfolio review process coupled with standard evaluations of medical knowledge and clinical skills. It individualizes learning processes through curriculum flexibility, enabling students to take electives earlier and complete clerkships in their preferred order. The new curriculum is integrated both horizontally and vertically, combining disciplines within organ-based modules and deliberately linking elements (science in medicine, clinical medicine, health and society, professional development) and threads (medical decision making, quality and safety, teamwork and leadership, lifestyle medicine, advocacy and equity) across the three phases that replaced the traditional four-year timeline. It encourages students to conduct research in an area of interest and commit to lifelong learning and self-improvement. The curriculum formalizes the process of professional identity formation and requires students to reflect on their experiences with the informal and hidden curricula, which strongly shape their identities.The authors describe the new curriculum structure, explain their approach to each Carnegie report recommendation, describe early outcomes and challenges, and propose areas for further work. Early data from the first cohort to progress through the curriculum show unchanged United States Medical Licensing Examination Step 1 and 2 scores, enhanced student research engagement and career exploration, and improved student confidence in the patient care and professional development domains.


Reducing Sun Exposure for Prevention of Skin Cancers: Factorial Invariance and Reliability of the Self-Efficacy Scale for Sun Protection.
The Self-Efficacy Scale for Sun Protection consists of two correlated factors with three items each for Sunscreen Use and Avoidance. This study evaluated two crucial psychometric assumptions, factorial invariance and scale reliability, with a sample of adults (N = 1356) participating in a computer-tailored, population-based intervention study. A measure has factorial invariance when the model is the same across subgroups. Three levels of invariance were tested, from least to most restrictive: (1) Configural Invariance (nonzero factor loadings unconstrained); (2) Pattern Identity Invariance (equal factor loadings); and (3) Strong Factorial Invariance (equal factor loadings and measurement errors). Strong Factorial Invariance was a good fit for the model across seven grouping variables: age, education, ethnicity, gender, race, skin tone, and Stage of Change for Sun Protection. Internal consistency coefficient Alpha and factor rho scale reliability, respectively, were .84 and .86 for Sunscreen Use, .68 and .70 for Avoidance, and .78 and .78 for the global (total) scale. The psychometric evidence demonstrates strong empirical support that the scale is consistent, has internal validity, and can be used to assess population-based adult samples.


Specification of dopaminergic subsets involves interplay of En1 and Pitx3.
Mesodiencephalic dopaminergic (mdDA) neurons control locomotion and emotion and are affected in multiple psychiatric and neurodegenerative diseases, including Parkinson's disease (PD). The homeodomain transcription factor Pitx3 is pivotal in mdDA neuron development and loss of Pitx3 results in programming deficits in a rostrolateral subpopulation of mdDA neurons destined to form the substantia nigra pars compacta (SNc), reminiscent of the specific cell loss observed in PD. We show here that in adult mice in which the gene encoding a second homeoprotein, engrailed 1 (En1), has been deleted, dramatic loss of mdDA neurons and striatal innervation defects were observed, partially reminiscent of defects observed in Pitx3(-/-) mice. We then continue to reveal developmental crosstalk between En1 and Pitx3 through genome-wide expression analysis. During development, both En1 and Pitx3 are required to induce expression of mdDA genes in the rostrolateral subset destined to form the SNc. By contrast, Pitx3 and En1 reciprocally regulate a separate gene cluster, which includes Cck, demarcating a caudal mdDA subset in wild-type embryos. Whereas En1 is crucial for induction of this caudal phenotype, Pitx3 antagonizes it rostrolaterally. The combinatorial action of En1 and Pitx3 is potentially realized through at least three levels of molecular interaction: (1) influencing each other's expression level, (2) releasing histone deacetylase-mediated repression of Nurr1 target genes and (3) modulating En1 activity through Pitx3-driven activation of En1 modulatory proteins. These findings show how two crucial mediators of mdDA neuronal development, En1 and Pitx3, interact in dopaminergic subset specification, the importance of which is exemplified by the specific vulnerability of the SNc found in PD.


Peptide-binding motifs associated with MHC molecules common in Chinese rhesus macaques are analogous to those of human HLA supertypes and include HLA-B27-like alleles.
Chinese rhesus macaques are of particular interest in simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) research as these animals have prolonged kinetics of disease progression to acquired immunodeficiency syndrome (AIDS), compared to their Indian counterparts, suggesting that they may be a better model for HIV. Nevertheless, the specific mechanism(s) accounting for these kinetics remains unclear. The study of major histocompatibility complex (MHC) molecules, including their MHC/peptide-binding motifs, provides valuable information for measuring cellular immune responses and deciphering outcomes of infection and vaccine efficacy. In this study, we have provided detailed characterization of six prevalent Chinese rhesus macaque MHC class I alleles, yielding a combined phenotypic frequency of 29 %. The peptide-binding specificity of two of these alleles, Mamu-A2*01:02 and Mamu-B*010:01, as well as the previously characterized allele Mamu-B*003:01 (and Indian rhesus Mamu-B*003:01), was found to be analogous to that of alleles in the HLA-B27 supertype family. Specific alleles in the HLA-B27 supertype family, including HLA-B*27:05, have been associated with long-term nonprogression to AIDS in humans. All six alleles characterized in the present study were found to have specificities analogous to HLA supertype alleles. These data contribute to the concept that Chinese rhesus macaque MHC immunogenetics is more similar to HLA than their Indian rhesus macaque counterparts and thereby warrants further studies to decipher the role of these alleles in the context of SIV infection.


Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs.
Therapeutic drug monitoring (TDM) is widely accepted as a method to improve the effectiveness and safety of the first generation antiepileptic drugs (AEDs) and to identify an individual's optimum concentration. Like the older AEDs, the new AEDs also have significant pharmacokinetic variability. A similar relationship between concentration and effect for the new and old AEDs in experimental seizure models suggests that it is reasonable to use TDM for the new AEDs. With the addition of generic formulations of the new AEDs, TDM can play an important role to validate bioequivalence in patients. There is a history of problems with generics of the older AEDs, primarily carbamazepine and phenytoin. The Biopharmaceutics Classification System, which correlates the solubility and permeability of a drug with oral drug absorption, predicts that there should be no significant problems with the majority of the new AEDs. Because of the controversy over the risk-benefit of generic substitution of AEDs, the use of TDM will provide a way to ensure patient safety while establishing that generics of AEDs proven to be bioequivalent in population studies are also bioequivalent in individuals. The goal of personalized medicine is to use genetic testing to target therapy and identify those individuals unlikely to respond to a drug or likely to respond adversely to the same drug. Of all the AEDs, only phenytoin undergoes significant metabolism by cytochrome P450 isozymes with significant genetic polymorphisms (CYP2C9, CYP2C19). Studies are still needed to identify genetic and biomarkers to identify patients at risk for serious idiosyncratic reactions. There have been significant advances in the understanding of the role of genetics in idiopathic as well as acquired epilepsies. Identification of experimental and clinical evidence linking functional changes associated with gene mutations to epilepsy syndromes will help provide new molecular targets for future AEDs.


Testicular adrenal rest tumors in boys with 21-hydroxylase deficiency, timely diagnosis and follow-up.
Testicular adrenal rest tumors (TARTs) are found in 30-94% of adult males with congenital adrenal hyperplasia (CAH). We sought to explore TART appearance through yearly ultrasound examination of testes in young boys with CAH, and its association with metabolic control and genetic mutations. Twenty-five boys with 21-hydroxylase deficiency in the age group 4-18 years diagnosed during the period 2001-2016 were included in the study. ACTH, 17-hydroxyprogesterone, androstenedione and testosterone were measured at 4-month intervals. Growth and BMI were assessed at the time of evaluation. PCR/ACRS method was used for CYP21A2 gene analysis. Testicular ultrasound examination was performed yearly. TARTs were detected by ultrasound in 8 children at the age of 6-16 years (13.2 years average). Five had salt-wasting form, two had simple virilizing form and one had non-classic form of CAH. Significant differences in the17OHP and androstenedione levels were detected between the boys, adherent and non-adherent to therapy. Inadequate metabolic control was not different in boys with and without TART (11/17 and 5/8 respectively). No significant difference was detected in the distribution of genetic mutations or adherence to therapy between patients with and without TARTs. One patient had a mutation not reported thus far in TART and another developed leukemia. TART is not rare in young boys with CAH, irrespective of the specific mutation or metabolic control. Ultrasound screening helps timely diagnosis and adjustment of therapy.


Absence of correlation between ex vivo susceptibility to doxycycline and pfteQ-pfmdt gene polymorphism in French Guiana.
In French Guiana, doxycycline is used for both chemoprophylaxis and the treatment of malaria. The presence of isolates with reduced ex vivo susceptibility to doxycycline in French Guiana makes it critical to identify any genetic determinants contributing to the chemosusceptibility level of Plasmodium falciparum to doxycycline, such as pfmdt and pftetQ, which were recently identified as potential molecular markers in African isolates. A Bayesian statistical approach was used to define different ex vivo doxycycline phenotypes. The pfmdt and pftetQ gene copy numbers were quantified by quantitative real-time polymerase chain reaction in 129 P. falciparum isolates collected between 2000 and 2010, and pftetQ, pfrps7, pfssurRNA, and pflsurRNA sequences were analysed after amplification by polymerase chain reaction. PftetQ and pfmdt copy numbers were not associated with reduced susceptibility to doxycycline in P. falciparum within French Guiana. Sequence analysis of the genes revealed five known single nucleotide polymorphisms. Three new SNPs were identified in the apicoplast ribosomal RNA long sub-unit (pflsurRNA): C740T, A1875C and A1875T. These polymorphisms were not associated with reduced chemosusceptibility to doxycycline. The present study does not validate pfmdt and pftetQ genes as molecular markers of decreased susceptibility to doxycycline in P. falciparum isolates in French Guiana.


The neural bases of distraction and reappraisal.
Distraction and reappraisal are two commonly used forms of cognitive emotion regulation. Functional neuroimaging studies have shown that each one depends upon interactions between pFC, interpreted as implementing cognitive control, and limbic regions, interpreted as mediating emotional responses. However, no study has directly compared distraction with reappraisal, and it remains unclear whether they draw upon different neural mechanisms and have different emotional consequences. The present fMRI study compared distraction and reappraisal and found both similarities and differences between the two forms of emotion regulation. Both resulted in decreased negative affect, decreased activation in the amygdala, and increased activation in prefrontal and cingulate regions. Relative to distraction, reappraisal led to greater decreases in negative affect and to greater increases in a network of regions associated with processing affective meaning (medial prefrontal and anterior temporal cortices). Relative to reappraisal, distraction led to greater decreases in amygdala activation and to greater increases in activation in prefrontal and parietal regions. Taken together, these data suggest that distraction and reappraisal differentially engage neural systems involved in attentional deployment and cognitive reframing and have different emotional consequences.


Glucose-6-phosphate dehydrogenase and malate dehydrogenase enzyme electrophoretic patterns amongst strains of Bacteroides fragilis.
Fifty-two strains of Bacteroides fragilis were examined for their enzyme electrophoretic patterns of glucose-6-phosphate dehydrogenase (G6PDH) and malate dehydrogenase (MDH). All strains tested possessed high levels of both enzymes but the G6PDH reduced NADP whereas MDH was NAD-dependent. Twenty-seven strains produced single bands of both G6PDH and MDH. In all cases G6PDH migrated faster than MDH. Strains clustered by a single linkage algorithm were recovered in eight clusters at the 77% similarity level. The remaining 25 strains produced multiple bands of one or both enzymes. These were recovered in six clusters at the 72% similarity level using the same algorithm. The results of this study revealed considerable heterogeneity of enzyme patterns within B. fragilis.


A contamination-insensitive probe for imaging specific biomolecules by secondary ion mass spectrometry.
Imaging techniques should differentiate between specific signals, from the biomolecules of interest, and non-specific signals, from the background. We present a probe containing (15)N and (14)N isotopes in approximately equal proportion, for secondary ion mass spectrometry imaging. This probe designed for a precise biomolecule analysis is insensitive to background signals.


Influence of substituents on DNA and protein binding of cyclometalated Ir(iii) complexes and anticancer activity.
Synthesis of terpyridyl based ligands 3-([2,2':6',2''-terpyridin]-4'-yl)-7-methoxy-2-(methylthio)-quinolone, (L1); 3-([2,2':6',2''-terpyridin]-4'-yl)-6-methoxyquinolin-2(1H)-one, (L2); 3-([2,2'-:6',2''-terpyridin]-4'-yl)-6-methylquinolin-2(1H)-one (L3) and cyclometalated iridium(iii) complexes [[Ir(ppy)2L1]+PF6- (1), [Ir(ppy)2L2]+PF6- (2), [Ir(ppy)2L3]+PF6- (3) (2-phenylpyridine = Hppy)] involving these ligands has been described. The ligands L1-L3 and complexes 1-3 have been thoroughly characterized by elemental analyses, spectral studies (IR, 1H, 13C NMR, UV/vis and fluorescence) ESI-MS, and the structure of 3 has been unambiguously authenticated by single crystal X-ray analyses. UV/vis, fluorescence and circular dichroism spectroscopic studies showed rather efficient binding of 1 with CT-DNA (calf thymus DNA) and BSA (bovine serum albumin) relative to 2 and 3. Molecular docking studies unveiled binding of 1-3 with minor groove of CT-DNA via van der Waal's forces and electrostatically with the hydrophobic moiety of HSA (human serum albumin). The ligands and complexes exhibited moderate cytotoxicity towards MDA-MB-231 (breast cancer cell line) and significant influence on HeLa (cervical cancer cell line) cells. Cytotoxicity, morphological changes, and apoptosis have been followed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay, Hoechst 33342/PI (PI = propidium iodide) staining, cell cycle analysis by FACS (fluorescence activated cell sorting), and ROS (reactive oxygen species) generation by DCFH-DA (dichlorodihydrofluorescein diacetate) dye. Confocal microscopy images revealed that the drug efficiently initiates apoptosis in the cell cytosol. The IC50 values showed superior cytotoxicity of 1-3 against the HeLa cell line relative to cisplatin, and their ability to induce apoptosis is in the order 1 > 2 > 3.


Associations between Systemic Sclerosis and Thyroid Diseases.
We have reviewed scientific literature about the association of systemic sclerosis (SSc) and thyroid disorders. A high incidence, and prevalence, of new cases of autoimmune thyroiditis (AT) and/or hypothyroidism have been shown in sclerodermic patients (overall in the female gender). An association among a Th1 immune-predominance, low vitamin D levels, and AT have been also shown in SSc patients. Cases of Graves' disease (GD) have been described in SSc patients, too, according with the higher prevalence of thyroid autoimmunity. It has been also shown a higher prevalence of papillary thyroid cancer (PTC), in association with AT, in SSc patients. However, in order to confirm results about GD and thyroid cancer, studies in larger number of patients with SSc are needed. During the follow-up of SSc patients it would be appropriate to monitor carefully their thyroid status. The abovementioned data strongly suggest a periodic thyroid function follow-up in female SSc patients [showing a borderline high (although in the normal range) thyroid-stimulating hormone level, antithyroid peroxidase antibody positivity, and a small thyroid with a hypoechoic pattern], and, when necessary, appropriate treatments. In conclusion, most of the studies show an association among SSc, AT, and hypothyroidism, such as an increased prevalence of TC overall in SSc patients with AT. Only few cases of GD have been also described in SSc.


Policies Affecting Medicaid Beneficiaries' Smoking Cessation Behaviors.
Smoking rates for Medicaid beneficiaries have remained flat in recent years. Medicaid may support smokers in quitting by covering a broad array of tobacco cessation services without barriers such as copays. This study examines the impact of increasing generosity in Medicaid tobacco cessation coverage policies on smoking and cessation behaviors. We used 2010 and 2015 National Health Interview Survey data merged with information on state tobacco, Medicaid cessation, and Medicaid eligibility policies to estimate state fixed effects models of cessation medication use, counseling use, quit attempts, and current smoking. Smokers living in states that cover cessation medications but not counseling services were less likely to use counseling. Smokers were more likely to report having tried to quit in states with higher rates of use of cessation medications among Medicaid beneficiaries. We found no impact of Medicaid policies on use of cessation medications. States that impose copays had higher rates of smoking, while those that require counseling as a condition of receiving medication had lower rates of smoking. Additionally, we found that expanding Medicaid eligibility under the Affordable Care Act is associated with decreased smoking prevalence among Medicaid beneficiaries. Covering cessation counseling may encourage smokers that want to quit to use this service. Promoting the use of cessation medications may improve the likelihood that smokers try to quit. Medicaid coverage of cessation services is an important but incomplete strategy in addressing smoking among low-income populations. States may be able to improve utilization of cessation counseling by providing Medicaid reimbursement for this service. Encouraging utilization of tobacco cessation medications may help more smokers quit. States should consider how to promote effective cessation methods among clinicians and patients.


Predictive computational modeling of the mucosal immune responses during Helicobacter pylori infection.
T helper (Th) cells play a major role in the immune response and pathology at the gastric mucosa during Helicobacter pylori infection. There is a limited mechanistic understanding regarding the contributions of CD4+ T cell subsets to gastritis development during H. pylori colonization. We used two computational approaches: ordinary differential equation (ODE)-based and agent-based modeling (ABM) to study the mechanisms underlying cellular immune responses to H. pylori and how CD4+ T cell subsets influenced initiation, progression and outcome of disease. To calibrate the model, in vivo experimentation was performed by infecting C57BL/6 mice intragastrically with H. pylori and assaying immune cell subsets in the stomach and gastric lymph nodes (GLN) on days 0, 7, 14, 30 and 60 post-infection. Our computational model reproduced the dynamics of effector and regulatory pathways in the gastric lamina propria (LP) in silico. Simulation results show the induction of a Th17 response and a dominant Th1 response, together with a regulatory response characterized by high levels of mucosal Treg) cells. We also investigated the potential role of peroxisome proliferator-activated receptor γ (PPARγ) activation on the modulation of host responses to H. pylori by using loss-of-function approaches. Specifically, in silico results showed a predominance of Th1 and Th17 cells in the stomach of the cell-specific PPARγ knockout system when compared to the wild-type simulation. Spatio-temporal, object-oriented ABM approaches suggested similar dynamics in induction of host responses showing analogous T cell distributions to ODE modeling and facilitated tracking lesion formation. In addition, sensitivity analysis predicted a crucial contribution of Th1 and Th17 effector responses as mediators of histopathological changes in the gastric mucosa during chronic stages of infection, which were experimentally validated in mice. These integrated immunoinformatics approaches characterized the induction of mucosal effector and regulatory pathways controlled by PPARγ during H. pylori infection affecting disease outcomes.


Essential Japanese guidelines for the prevention of perioperative infections in the urological field: 2015 edition.
After publication of the initial version of the Japanese guidelines for urological surgery in 2007, new surgical techniques have been introduced. Furthermore, several important issues, such as criteria for use of single-dose antimicrobial prophylaxis and control of hospitalized infection, were also established, which led to alterations of the methods used for antimicrobial prophylaxis as well as perioperative management. The purpose of antimicrobial prophylaxis is to protect the surgical wound from contamination by normal bacterial flora. Antimicrobial prophylaxis should be based on penicillins with beta-lactamase inhibitors, or first- or second-generation cephalosporins, though penicillins without beta-lactamase inhibitors should not be prescribed because of the high prevalence of antimicrobial resistance. As an adequate intratissue concentration of the antimicrobial at the surgical site should be accomplished by the time of initiation of surgery, antimicrobial prophylaxis should be started up to 30 min before beginning the operation. Antimicrobial prophylaxis should be terminated within 24 h in clean and clean-contaminated surgery, and within 2 days of surgery using the bowels, because a longer duration is a risk factor for surgical site infection development. Importantly, possible risk factors for surgical site infections include the antimicrobial prophylaxis methodology used as well as others, such as duration of preoperative hospitalization, hand washing, the American Society of Anesthesiologists score, diabetes and smoking history. These guidelines are to be applied only for preoperatively non-infected low-risk patients. In cases with preoperative infection or bacteriuria that can cause a surgical site infection or urinary tract infection after surgery, patients must receive adequate preoperative treatment based on the individual situation.


Modulation of Immunological Pathways in Autistic and Neurotypical Lymphoblastoid Cell Lines by the Enteric Microbiome Metabolite Propionic Acid.
Propionic acid (PPA) is a ubiquitous short-chain fatty acid which is a fermentation product of the enteric microbiome and present or added to many foods. While PPA has beneficial effects, it is also associated with human disorders, including autism spectrum disorders (ASDs). We previously demonstrated that PPA modulates mitochondrial dysfunction differentially in subsets of lymphoblastoid cell lines (LCLs) derived from patients with ASD. Specifically, PPA significantly increases mitochondrial function in LCLs that have mitochondrial dysfunction at baseline [individuals with autistic disorder with atypical mitochondrial function (AD-A) LCLs] as compared to ASD LCLs with normal mitochondrial function [individuals with autistic disorder with normal mitochondrial function (AD-N) LCLs] and control (CNT) LCLs. PPA at 1 mM was found to have a minimal effect on expression of immune genes in CNT and AD-N LCLs. However, as hypothesized, Panther analysis demonstrated that 1 mM PPA exposure at 24 or 48 h resulted in significant activation of the immune system genes in AD-A LCLs. When the effect of PPA on ASD LCLs were compared to the CNT LCLs, both ASD groups demonstrated immune pathway activation, although the AD-A LCLs demonstrate a wider activation of immune genes. Ingenuity Pathway Analysis identified several immune-related pathways as key Canonical Pathways that were differentially regulated, specifically human leukocyte antigen expression and immunoglobulin production genes were upregulated. These data demonstrate that the enteric microbiome metabolite PPA can evoke atypical immune activation in LCLs with an underlying abnormal metabolic state. As PPA, as well as enteric bacteria which produce PPA, have been implicated in a wide variety of diseases which have components of immune dysfunction, including ASD, diabetes, obesity, and inflammatory diseases, insight into this metabolic modulator may have wide applications for both health and disease.


Systematic analysis of palatal transcriptome to identify cleft palate genes within TGFβ3-knockout mice alleles: RNA-Seq analysis of TGFβ3 Mice.
In humans, cleft palate (CP) accounts for one of the largest number of birth defects with a complex genetic and environmental etiology. TGFβ3 has been established as an important regulator of palatal fusion in mice and it has been shown that TGFβ3-null mice exhibit CP without any other major deformities. However, the genes that regulate cellular decisions and molecular mechanisms maintained by the TGFβ3 pathway throughout palatogenesis are predominantly unexplored. Our objective in this study was to analyze global transcriptome changes within the palate during different gestational ages within TGFβ3 knockout mice to identify TGFβ3-associated genes previously unknown to be associated with the development of cleft palate. We used deep sequencing technology, RNA-Seq, to analyze the transcriptome of TGFβ3 knockout mice at crucial stages of palatogenesis, including palatal growth (E14.5), adhesion (E15.5), and fusion (E16.5). The overall transcriptome analysis of TGFβ3 wildtype mice (C57BL/6) reveals that almost 6000 genes were upregulated during the transition from E14.5 to E15.5 and more than 2000 were downregulated from E15.5 to E16.5. Using bioinformatics tools and databases, we identified the most comprehensive list of CP genes (n = 322) in which mutations cause CP either in humans or mice, and analyzed their expression patterns. The expression motifs of CP genes between TGFβ3+/- and TGFβ3-/- were not significantly different from each other, and the expression of the majority of CP genes remained unchanged from E14.5 to E16.5. Using these patterns, we identified 8 unique genes within TGFβ3-/- mice (Chrng, Foxc2, H19, Kcnj13, Lhx8, Meox2, Shh, and Six3), which may function as the primary contributors to the development of cleft palate in TGFβ3-/- mice. When the significantly altered CP genes were overlaid with TGFβ signaling, all of these genes followed the Smad-dependent pathway. Our study represents the first analysis of the palatal transcriptome of the mouse, as well as TGFβ3 knockout mice, using deep sequencing methods. In this study, we characterized the critical regulation of palatal transcripts that may play key regulatory roles through crucial stages of palatal development. We identified potential causative CP genes in a TGFβ3 knockout model, which may lead to a better understanding of the genetic mechanisms of palatogenesis and provide novel potential targets for gene therapy approaches to treat cleft palate.


Pediatric multiple sclerosis.
Multiple sclerosis (MS) occurs at all ages of the pediatric population. Childhood MS may represent up to 10% of all MS cases. Establishing the diagnosis of MS in a child is complicated by the limited diagnostic criteria and the possibility of significant clinical and magnetic resonance imaging (MRI) overlap with acute disseminated encephalomyelitis and other pediatric diseases. Although the clinical profile of MS appears similar to that seen in adults, several features may differ and specific issues arise in children. Sex ratios are different between young children with MS and adolescents--implicating a role for sex hormones in disease pathogenesis and/or modification of disease expression. Younger patients with MS are more likely to have seizures, brainstem, and cerebellar symptoms than adults. Children with MS may have fewer T2 hyperintense areas on MRI scans, therefore not meeting MRI criteria established for adults. It is possible that the pediatric MS course is more indolent than in adult patients but the disease may lead to significant disability at a younger age, e.g., while patients are students, young professionals, or want to start a family. There has been no controlled clinical trial in children with disease modifying therapies approved for adult MS due to the limited number of patients under the age of 18 years compared with the adult contingent. As a result, children are receiving adult therapies in an arbitrary manner and our understanding of pediatric treatment effect and tolerability is limited. Available data on tolerability of approved drugs for adults is reviewed.


Control Effect and Possible Mechanism of the Natural Compound Phenazine-1-Carboxamide against Botrytis cinerea.
To develop new agents against strawberry grey mould and to aid in the development of biological pesticides, we investigated the inhibitory effect of a natural compound, phenazine-1-carboxamide (PCN), against Botrytis cinerea using a growth rate assay. Additionally, indoor toxicity and the in vitro control effect of PCN were further studied to determine its potential mechanisms of action on B. cinerea. PCN was inhibitory against B. cinerea with a 50% effective concentration (EC50) of 108.12 μg/mL; the toxicity of PCN was equivalent to that of carbendazim (CBM). The best in vitro control effect of PCN against grey mould in strawberry (fruit) reached 75.32%, which was slightly higher than that of CBM. The field control effect of PCN against grey mould reached a maximum of 72.31% at a PCN concentration of 700 μg/mL, which was 1.02 times higher than that of CBM. Fungistatic activity was observed at low concentrations of PCN, while high concentrations of PCN resulted in fungicidal activity against B. cinerea. This natural compound strongly inhibited both spore and sclerotium germination of B. cinerea, with the best relative inhibition rates of 77.03% and 82.11%, respectively. The inhibitory effect of PCN on mycelial growth of B. cinerea was significant and reached levels of 87.32%. Scanning electron microscopy observations revealed that after 48 h of PCN treatment, the mycelia appeared loose, locally twisted, and folded, with exudation of contents; the mycelia was withered and twisted, with edge burrs, deformations, ruptures and a sheet-like structure. Transmission electron microscopy observations revealed that after 48 h of PCN treatment, the structure of the cell nucleus was unclear and the vacuoles had ruptured; additionally, various organelles exhibited disordered structures, there were substantial non-membrane transparent inclusions, the cells were plasmolysed, the cell walls were collapsed in some cases, and the hyphal tissue was essentially necrotic. A PCN dosage of 35-140 μg/mL had no effect on the cell membrane permeability of the mycelia, while a PCN dosage of 700 μg/mL resulted in significant permeability. PCN inhibited B. cinerea toxin; the mycotoxin level was approximately 0.41 of the value recorded for the control at a PCN dosage of 700 μg/mL. PCN affected the activity of pectin methylgalacturonase (PMG), polygalacturonase (PG), cellulase (Cx) and β-glucosidase (BG); the lowest activities of PMG, PG, BG and Cx reached 0.3 U/mg, 0.62 U/mg, 0.64 U/mg, and 0.79 U/mg, respectively, after treatment with 700 μg/mL PCN.


High seroprevalence of Babesia antibodies among Borrelia burgdorferi-infected humans in Sweden.
In northern Europe, tick-borne diseases such as Lyme borreliosis (LB) and tick-borne encephalitis (TBE) are well known. The actual incidence of Babesia infections, however, has remained elusive. In this study, the prevalence of antibodies against two Babesia spp. was investigated in a cohort of patients that were seropositive for Borrelia (B.) burgdorferi sensu lato (s.l.). Data were compared to a control group of healthy individuals. Sera were collected from 283 individuals residing in the southernmost region of Sweden, Skåne County. Almost one third of the sera were from patients with a confirmed seropositive reaction against B. burgdorferi s.l. All sera samples were assessed for IgG antibodies against Babesia (Ba.) microti and Ba. divergens by indirect fluorescent antibody (IFA) assays. Seropositive IgG titers for at least one of the Babesia spp. was significantly more common (p < 0.05) in individuals seropositive for Borrelia (16.3%) compared to the healthy control group (2.5%). Our findings suggest that Babesia infections may indeed be quite common among individuals who have been exposed to tick bites. Furthermore, the results indicate that human babesiosis should be considered in patients that show relevant symptoms; particularly for splenectomized and other immunocompromised individuals. Finally, the data challenges current blood transfusion procedures and highlights the current lack of awareness of the parasite in northern Europe.