Dyslipidemia and Risk of Cardiovascular Events in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Therapy: Insights From the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) Trial.
Dyslipidemia is a major risk factor for cardiovascular events. The prognostic importance of lipoproteins in patients with atrial fibrillation is not well understood. We aimed to explore the association between apolipoprotein A1 (ApoA1) and B (ApoB) and cardiovascular events in patients with atrial fibrillation receiving oral anticoagulation. Using data from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, ApoA1 and ApoB plasma levels were measured at baseline in 14 884 atrial fibrillation patients. Median length of follow-up was 1.9 years. Relationships between continuous levels of ApoA1 and ApoB and clinical outcomes were evaluated using Cox models adjusted for cardiovascular risk factors, medication including statins, and cardiovascular biomarkers. A composite ischemic outcome (ischemic stroke, systemic embolism, myocardial infarction, and cardiovascular death) was used as the primary end point. Median (25th, 75th) ApoA1 and ApoB levels were 1.10 (0.93, 1.30) and 0.70 g/L (0.55, 0.85), respectively. In adjusted analyses, higher levels of ApoA1 were independently associated with a lower risk of the composite ischemic outcome (hazard ratio, 0.81; P<0.0001). Similar results were observed for the individual components of the composite outcome. ApoB was not significantly associated with the composite ischemic outcome (P=0.8240). Neither apolipoprotein was significantly associated with major bleeding. There was no interaction between lipoproteins and randomized treatment for the primary outcome (both P values ≥0.2448). In patients with atrial fibrillation on oral anticoagulation, higher levels of ApoA1 were independently associated with lower risk of ischemic cardiovascular outcomes. Investigating therapies targeting dyslipidemia may thus be useful to improve cardiovascular outcomes in patients with atrial fibrillation. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.


Face Rejuvenation: a new combinated protocol for biorevitalization.
The slowing of the aging process is subject of great research and attention in modern society, particularly aging of face. Processes involved are very complex. Mesotherapy. hyaluronic acid and carbon dioxide injection can be used for biorevitalization and skin rejuvenation. Three groups were made and 62 patients were enrolled. Patients with superficial wrinkles of the face, neck and/or décolleté, without presence of nasolabial folds and marionette wrinkles were included in group 1. Patients with superficial/medium depth wrinkles of the face, neck and/or décolleté, with moderate nasolabial folds but no marionette wrinkles were included in group 2. Patients with deep wrinkles of the face, with deep nasolabial folds and marionette wrinkles were included in group 3. Patients were treated with three different protocols that included injections of amino acids, vitamins and hyaluronic acid in association with carbon dioxide injection. We submitted the PAIS and GAIS scales and we analyzed the scores obtained with Wilcoxon's and Kolmogorov-Smirnov's tests. Statistical Product and Service Solutions (SPSS) softare was used. The p-value was considered acceptable if inferior to 0,05 (p>0,05). In according with these tests, the differences of values at one week and at the end of the study are significant (p<0,05) for both PAIS and GAIS. No side effects were reported. Protocol treatment used in this study gave statistically valid results in the rejuvenation of face for mild, moderate and severe aging.


Efficacy of the 'Stand and Move at Work' multicomponent workplace intervention to reduce sedentary time and improve cardiometabolic risk: a group randomized clinical trial.
Sedentary time is associated with chronic disease and premature mortality. We tested a multilevel workplace intervention with and without sit-stand workstations to reduce sedentary time and lower cardiometabolic risk. Stand and Move at Work was a group (cluster) randomized trial conducted between January 2016 and December 2017 among full-time employees; ≥18 years; and in academic, industry/healthcare, and government worksites in Phoenix, Arizona and Minneapolis/St. Paul, Minnesota, USA. Eligible worksites were randomized to (a) MOVE+, a multilevel intervention targeting reduction in sedentary time and increases in light physical activity (LPA); or (b) STAND+, the MOVE+ intervention along with sit-stand workstations to allow employees to sit or stand while working. The primary endpoints were objectively-measured workplace sitting and LPA at 12 months. The secondary endpoint was a clustered cardiometabolic risk score (blood pressure, glucose, insulin, triglycerides, and HDL-cholesterol) at 12 months. Worksites (N = 24; academic [n = 8], industry/healthcare [n = 8], and government [n = 8] sectors) and employees (N = 630; 27 ± 8 per worksite; 45 ± 11 years of age, 74% female) were enrolled. All worksites were retained and 487 participants completed the intervention and provided data for the primary endpoint. The adjusted between arm difference in sitting at 12 months was - 59.2 (CI: - 74.6,-43.8) min per 8 h workday, favoring STAND+, and in LPA at 12 months was + 2.2 (- 0.9,5.4) min per 8 h workday. Change in the clustered metabolic risk score was small and not statistically significant, but favored STAND+. In an exploratory subgroup of 95 participants with prediabetes or diabetes, the effect sizes were larger and clinically meaningful, all favoring STAND+, including blood glucose, triglycerides, systolic blood pressure, glycated hemoglobin, LDL-cholesterol, body weight, and body fat. Multilevel workplace interventions that include the use of sit-stand workstations are effective for large reductions in sitting time over 12 months. Among those with prediabetes or diabetes, clinical improvements in cardiometabolic risk factors and body weight may be realized. ClinicalTrials.gov Identifier: NCT02566317 . Registered 2 October 2015, first participant enrolled 11 January 2016.


Negative regulation of the RLH signaling by the E3 ubiquitin ligase RNF114.
The retinoic acid-inducible gene-I (RIG-I)-like helicases (RLH)s are cytoplasmic pattern recognition receptors expressed in both immune and non-immune cells that are essential for detection of intracellular RNA products, primarily of viral origin. Upon binding to viral RNA, RLHs interact with mitochondrial antiviral signaling protein (MAVS) to activate interferon (IFN)-mediated antiviral responses. The RLH/MAVS signaling pathway is regulated by ubiquitination/deubiquitination, in which several ubiquitin-editing proteins play critical roles. The really interesting new gene (RING) finger protein 114 (RNF114) was originally identified as a psoriasis susceptibility gene broadly expressed in human tissues. Earlier studies implicated RNF114 in regulating cellular dsRNA responses, cell cycle progression, NF-κB activity and T-cell activation. We found that RNF114 inhibited cellular dsRNA responses and RLH-mediated IFN production. RNF114 functioned as an E3 ubiquitin ligase, and MAVS was identified as a potential target for RNF114-mediated polyubiquitination and degradation. Splenocytes and blood harvested from RNF114 KO showed increased basal IFN level and sensitized responses to dsRNA. However, RNF114 knockout mice failed to exhibit enhance resistance to infection by two acute RNA viruses. These data suggested the potential physiological function of RNF114 in inflammation and host antiviral responses, but demonstrate complexity in the regulation of innate immunity by ubiquitin ligases.


Socioeconomic factors and all cause and cause-specific mortality among older people in Latin America, India, and China: a population-based cohort study.
Even in low and middle income countries most deaths occur in older adults. In Europe, the effects of better education and home ownership upon mortality seem to persist into old age, but these effects may not generalise to LMICs. Reliable data on causes and determinants of mortality are lacking. The vital status of 12,373 people aged 65 y and over was determined 3-5 y after baseline survey in sites in Latin America, India, and China. We report crude and standardised mortality rates, standardized mortality ratios comparing mortality experience with that in the United States, and estimated associations with socioeconomic factors using Cox's proportional hazards regression. Cause-specific mortality fractions were estimated using the InterVA algorithm. Crude mortality rates varied from 27.3 to 70.0 per 1,000 person-years, a 3-fold variation persisting after standardisation for demographic and economic factors. Compared with the US, mortality was much higher in urban India and rural China, much lower in Peru, Venezuela, and urban Mexico, and similar in other sites. Mortality rates were higher among men, and increased with age. Adjusting for these effects, it was found that education, occupational attainment, assets, and pension receipt were all inversely associated with mortality, and food insecurity positively associated. Mutually adjusted, only education remained protective (pooled hazard ratio 0.93, 95% CI 0.89-0.98). Most deaths occurred at home, but, except in India, most individuals received medical attention during their final illness. Chronic diseases were the main causes of death, together with tuberculosis and liver disease, with stroke the leading cause in nearly all sites. Education seems to have an important latent effect on mortality into late life. However, compositional differences in socioeconomic position do not explain differences in mortality between sites. Social protection for older people, and the effectiveness of health systems in preventing and treating chronic disease, may be as important as economic and human development.


The non-obese diabetic mouse sequence, annotation and variation resource: an aid for investigating type 1 diabetes.
Model organisms are becoming increasingly important for the study of complex diseases such as type 1 diabetes (T1D). The non-obese diabetic (NOD) mouse is an experimental model for T1D having been bred to develop the disease spontaneously in a process that is similar to humans. Genetic analysis of the NOD mouse has identified around 50 disease loci, which have the nomenclature Idd for insulin-dependent diabetes, distributed across at least 11 different chromosomes. In total, 21 Idd regions across 6 chromosomes, that are major contributors to T1D susceptibility or resistance, were selected for finished sequencing and annotation at the Wellcome Trust Sanger Institute. Here we describe the generation of 40.4 mega base-pairs of finished sequence from 289 bacterial artificial chromosomes for the NOD mouse. Manual annotation has identified 738 genes in the diabetes sensitive NOD mouse and 765 genes in homologous regions of the diabetes resistant C57BL/6J reference mouse across 19 candidate Idd regions. This has allowed us to call variation consequences between homologous exonic sequences for all annotated regions in the two mouse strains. We demonstrate the importance of this resource further by illustrating the technical difficulties that regions of inter-strain structural variation between the NOD mouse and the C57BL/6J reference mouse can cause for current next generation sequencing and assembly techniques. Furthermore, we have established that the variation rate in the Idd regions is 2.3 times higher than the mean found for the whole genome assembly for the NOD/ShiLtJ genome, which we suggest reflects the fact that positive selection for functional variation in immune genes is beneficial in regard to host defence. In summary, we provide an important resource, which aids the analysis of potential causative genes involved in T1D susceptibility. Database URLs: http://www.sanger.ac.uk/resources/mouse/nod/; http://vega-previous.sanger.ac.uk/info/data/mouse_regions.html#Idd


The yeast homologue of the microtubule-associated protein Lis1 interacts with the sumoylation machinery and a SUMO-targeted ubiquitin ligase.
Microtubules and microtubule-associated proteins are fundamental for multiple cellular processes, including mitosis and intracellular motility, but the factors that control microtubule-associated proteins (MAPs) are poorly understood. Here we show that two MAPs-the CLIP-170 homologue Bik1p and the Lis1 homologue Pac1p-interact with several proteins in the sumoylation pathway. Bik1p and Pac1p interact with Smt3p, the yeast SUMO; Ubc9p, an E2; and Nfi1p, an E3. Bik1p interacts directly with SUMO in vitro, and overexpression of Smt3p and Bik1p results in its in vivo sumoylation. Modified Pac1p is observed when the SUMO protease Ulp1p is inactivated. Both ubiquitin and Smt3p copurify with Pac1p. In contrast to ubiquitination, sumoylation does not directly tag the substrate for degradation. However, SUMO-targeted ubiquitin ligases (STUbLs) can recognize a sumoylated substrate and promote its degradation via ubiquitination and the proteasome. Both Pac1p and Bik1p interact with the STUbL Nis1p-Ris1p and the protease Wss1p. Strains deleted for RIS1 or WSS1 accumulate Pac1p conjugates. This suggests a novel model in which the abundance of these MAPs may be regulated via STUbLs. Pac1p modification is also altered by Kar9p and the dynein regulator She1p. This work has implications for the regulation of dynein's interaction with various cargoes, including its off-loading to the cortex.


Chiari I malformation in asymptomatic young children with Williams syndrome: clinical and MRI study.
We report clinical and magnetic resonance imaging findings in two young children, aged 2 years 4 months and 3 years, with Williams syndrome. Both showed a mild global delay, although their neurological examination was completely normal. Their magnetic resonance imaging, however, showed Chiari I malformation and some non-specific changes in the centrum semiovale and in the white matter posterior to the lateral ventricles. Cerebellar tonsils were displaced through the foramen magnum 8.5 and 7.5 mm respectively. Our results suggest that Chiari I malformation can also be a frequent feature in subjects with Williams syndrome even in the absence of overt neurological signs suggestive of it. Whether these children might develop acute signs later is not known at present. Further studies are needed not only to evaluate the incidence of these findings in the global population of subjects with Williams syndrome but also to identify the children who are at risk for developing acute neurological signs.


Economic burden of work injuries and diseases: a framework and application in five European Union countries.
Estimates of the economic burden of work injuries and diseases can help policymakers prioritize occupational health and safety policies and interventions in order to best allocate scarce resources. Several attempts have been made to estimate these economic burdens at the national level, but most have not included a comprehensive list of cost components, and none have attempted to implement a standard approach across several countries. The aim of our study is to develop a framework for estimating the economic burden of work injuries and diseases and implement it for selected European Union countries. We develop an incidence cost framework using a bottom-up approach to estimate the societal burden of work injuries and diseases and implement it for five European Union countries. Three broad categories of costs are considered-direct healthcare, indirect productivity and intangible health-related quality of life costs. We begin with data on newly diagnosed work injuries and diseases from calendar year 2015. We consider lifetime costs for cases across all categories and incurred by all stakeholders. Sensitivity analysis is undertaken for key parameters. Indirect costs are the largest part of the economic burden, then direct costs and intangible costs. As a percentage of GDP, the highest overall costs are for Poland (10.4%), then Italy (6.7%), The Netherlands (3.6%), Germany (3.3%) and Finland (2.7%). The Netherlands has the highest per case costs (€75,342), then Italy (€58,411), Germany (€44,919), Finland (€43,069) and Poland (€38,918). Costs per working-age population are highest for Italy (€4956), then The Netherlands (€2930), Poland (€2793), Germany (€2527) and Finland (€2331). Our framework serves as a template for estimating the economic burden of work injuries and diseases across countries in the European Union and elsewhere. Results can assist policymakers with identifying health and safety priority areas based on the magnitude of components, particularly when stratified by key characteristics such as industry, injury/disease, age and sex. Case costing can serve as an input into the economic evaluation of prevention initiatives. Comparisons across countries provide insights into the relevant performance of health and safety systems.


Validation of a computational docking methodology to identify the non-covalent binding site of ligands to DNA.
Despite the biomedical consequences of carcinogen-DNA interactions and the potential of DNA as a drug target in medicinal chemistry, only a small number of studies have validated or used docking methods for the prediction of the physical binding of small molecules to DNA. Knowledge of the DNA-physically-bound ligand geometry can lead to the elucidation of the molecular-level mechanism of drugs as well as predicting the subsequent chemical interactions that lead to DNA damage from carcinogens. We sought to validate AutoDock 4.2, a docking method that includes a physics-based free energy function and a Lamarckian Genetic Algorithm, for the prediction of ligand geometries upon physical binding to DNA. We performed simulations by systematically changing the length of the search process for a comprehensive set of 32 ligand-DNA molecular systems with different physico-chemical properties, and we used a free-energy-based convergence criterion to terminate our simulations. For 11 out of 28 molecular systems for which convergence was achieved, the lowest binding free energy geometries were within 2 Å of the experimentally determined geometry. Considering all predicted sites with free energy changes within 20% of the lowest binding free energy site, we found a site within 2 Å of the experimentally determined geometry for 24 out of the 28 systems. However, the predicted hydrogen bonding interactions were different for most molecular systems compared to the same interactions in the experimentally determined geometry. We discuss reasons for the successes and failures, implications, and the importance of ensuring an adequate search in docking calculations. Overall, we concluded that AutoDock 4.2 can be used to predict the non-covalent binding geometry of a small molecule to DNA with some limitations.


Competence of oat ( Avena sativa L.) shoot apical meristems for integrative transformation, inherited expression, and osmotic tolerance of transgenic lines containing hva1.
Three oat ( Avena sativa L.) cultivars have been successfully transformed using an efficient and reproducible in vitro culture system for differentiation of multiple shoots from shoot apical meristems. The transformation was performed using microprojectile bombardment with two plasmids (pBY520 and pAct1-D) containing linked ( hva1-bar) and non-linked ( gus) genes. The hva1 and bar genes cointegrated with a frequency of 100% as expected, and 61.6% of the transgenic plants carried all three genes. Molecular and biochemical analyses in R0, R1 and R2 progenies confirmed stable integration and expression of all transgenes. Localization of the GUS protein in R0 and R1 plants revealed that high-expression of gus occurred in vascular tissues and in the pollen grains of mature flowers. The constitutive expression of HVA1 protein was observed at all developmental stages of transgenic plants, and was particularly stronger during the early seedling stages. R2 progeny of five independent transgenic lines was tested in vitro for tolerance to osmotic (salt and mannitol) stresses. As compared to non-transgenic control plants, transgenic plants maintained a higher growth and showed significantly ( P < 0.05) increased tolerance to stress conditions. Less than 10% of transgenic plants showed symptoms of wilting or death of leaves and, when these symptoms present were delayed in transgenic plants as compared to 80% of non-transgenic plants, either wilted or died. These symptoms confirmed the increased in vitro tolerance in hva1-expressing transgenic plants to non-transgenic plants, providing strong evidence that the HVA1 protein may play an important role in the protection of oats against salinity and possible water-deficiency stress conditions.


Seedlings of subtropical rainforest species from similar successional guild show different photosynthetic and morphological responses to varying light levels.
Restoration using rainforest species in Australia and elsewhere has been limited to a small number of widely known species, mainly pioneer or early successional species, Using the presumed successional status as a guideline for species selection in reforestation should be taken with a caveat since a species' capacity to adjust to light gradients is not easily predicted. This study examined the photosynthetic and growth responses of four Australian subtropical rainforest species in the context of using late successional species in restoration programs. Since the selected species [Sloanea australis ((Benth.) F. Muell.), Cinnamomum oliveri (F. M. Bailey),Caldcluvia paniculosa ((F. Muell.) Hoogland) and Geissois benthamiana (F. Muell.)] are considered late-successional species, this study also discussed the possibility of separating these species according to their acclimation level towards light gradients. Seedlings of four species were grown under four light treatments using neutral density shade cloth (5, 33, 64 and 80% irradiance) during summer November 2014 to February 2015. All species demonstrated a narrow range of photosynthetic acclimation to different light levels, experienced photoinhibition and photodamage in 80% irradiance and allocated more biomass to leaves in 5% irradiance, supporting their classification as late successional species. Cinnamomum oliveri was the only species able to utilize higher irradiance, with a higher light saturated rate of photosynthesis than the other species. Canonical analysis of principal coordinates revealed that the degree of plasticity of each species in response to contrasting irradiance levels varied. This analysis separated the species into three light tolerance classes: obligate shade-adapted species (S. australis and G. benthamiana), high light-adapted species (C. paniculosa) and the generalist (C. oliveri). Overall, this study suggests that the four species can be planted and will grow well under 33-64% irradiance since either lower or higher irradiance inhibits growth, and additionally that C. paniculosa and C. oliveri can be possibly planted in early phase of restoration planting with other early-successional species.


Singing for children and adults with bronchiectasis.
Bronchiectasis is a common respiratory disease, especially in developing countries. Its cause varies from chronic infection to rare immune deficiencies. Bronchiectasis can be present with other respiratory diseases, such as chronic obstructive pulmonary disease (COPD). People with bronchiectasis may suffer from chronic cough, fatigue, shortness of breath, chest pain and coughing up blood. Their lung function may decline with time. These can also have a negative impact on their quality of life. Thus, a holistic management is needed to provide treatment and support. Therapies which include breathing manoeuvres, such as singing, may have health benefits for respiratory function and psychological well being. To evaluate the effects of a singing intervention as a therapy on the quality of life, morbidity, respiratory muscle strength and pulmonary function of children and adults with bronchiectasis. We searched the Cochrane Airways Group (CAG) trials register, the Cochrane Central Register of Controlled Trials, major allied complementary databases, and clinical trials registers. Professional organisations and individuals were also contacted. CAG performed searches in February, and additional searches were carried out in June 2009. Randomised controlled trials in which singing (as an intervention) is compared with either a sham intervention or no singing in patients with bronchiectasis. Two authors independently reviewed the titles, abstracts and citations to assess potential relevance for full review. No eligible trials were identified and thus no data were available for analysis. No meta-analysis could be performed. In the absence of data, we cannot draw any conclusion to support or refute the adoption of singing as an intervention for people with bronchiectasis. Given the simplicity of the potentially beneficial intervention, future randomised controlled trials are required to evaluate singing therapy for people with bronchiectasis.


Graphene Electronic Tattoo Sensors.
Tattoo-like epidermal sensors are an emerging class of truly wearable electronics, owing to their thinness and softness. While most of them are based on thin metal films, a silicon membrane, or nanoparticle-based printable inks, we report sub-micrometer thick, multimodal electronic tattoo sensors that are made of graphene. The graphene electronic tattoo (GET) is designed as filamentary serpentines and fabricated by a cost- and time-effective "wet transfer, dry patterning" method. It has a total thickness of 463 ± 30 nm, an optical transparency of ∼85%, and a stretchability of more than 40%. The GET can be directly laminated on human skin just like a temporary tattoo and can fully conform to the microscopic morphology of the surface of skin via just van der Waals forces. The open-mesh structure of the GET makes it breathable and its stiffness negligible. A bare GET is able to stay attached to skin for several hours without fracture or delamination. With liquid bandage coverage, a GET may stay functional on the skin for up to several days. As a dry electrode, GET-skin interface impedance is on par with medically used silver/silver-chloride (Ag/AgCl) gel electrodes, while offering superior comfort, mobility, and reliability. GET has been successfully applied to measure electrocardiogram (ECG), electromyogram (EMG), electroencephalogram (EEG), skin temperature, and skin hydration.


The reason for the amelioration of N-methyl-N-nitrosourea-induced retinitis pigmentosa in rats by hydrogen-rich saline.
To investigate the effects of hydrogen-rich saline (HRS) on microglia activation and Sirtuin type 1 (Sirt1) in rats with N-methyl-N-nitrosourea (MNU)-induced retinitis pigmentosa (RP). Rats were divided into norm (N) group, model (M) group and HRS (H) group. Rats in M and H groups were given saline and HRS respectively prior to and after administration of MNU. At one day (d1) and d3 afterwards, electroretinogram and histological examination were performed to confirm the effects of HRS on retinal function and structure of MNU-induced RP. Immunofluorescence staining of anti-ionized calcium-binding adapter molecule 1 (Iba1), a maker of microglia cells, was performed, with quantitative real-time polymerase chain reaction (qRT-PCR) for its mRNA quantification. Moreover, Sirt1 mRNA and protein expression in the retinas were detected by Western blot and qRT-PCR. HRS preserved the retinal function and mitigated the reduction of photoreceptor degeneration in MNU-treated retinas. The presence of microglia cells was somewhat more obvious in H group than that in M group at d1. HRS suppressed the further activation of microglia cells, with the number of microglia cells less than that of M group at d3. Results of qRT-PCR of Iba1 were consistent with those of immunofluorescence staining, with the mRNA expression of Iba1 in H group more intensive than that of M group at d1 (P<0.05), while less than that of M group at d3 (P<0.05). Furthermore, the Sirt1 mRNA and protein expression decreased after MNU administration, while HRS mitigated the MNU-induced downregulation of Sirt1. HRS can effectively keep microglia activation induced by MNU to an appropriate extent, while upregulate Sirt1 in MNU-induced RP.


Studies of defective tolerance induction in NZB mice. Evidence for a marrow pre-T cell defect.
NZB mice manifest a defect in tolerance induction by deaggregated heterologous gamma globulins. We have used an adoptive transfer system to study the defect. Thymectomized, intact, or thymectomized recipients given thymic epithelial grafts were studied after lethal irradiation and reconstitution with NZB, DBA/2, or (NZB x DBA(F1 marrow depleted of mature T cells. NZB thymocytes were responsible for the tolerance defect of NZB mice. The information for the defect was present in the NZB marrow prethymocyte. That defect could only be expressed when there was further maturation in association with a thymus. However, the normal DBA/2 thymic epithelium served as well as the abnormal NZB thymic epithelium. These studies resolve existing conflicts as to whether the NZB marrow or thymus is responsible for the loss of tolerance in association with autoimmunity.


The case of the religious network group.
GenCorp, a Connecticut-based paper-goods manufacturer, has long supported employee-organized network groups. Its social support group for African-Americans, in fact, has been a particular success, having provided black employees with opportunities to further enhance their careers and helped the company retain top talent, meet its EEO goals, and gain favorable publicity. So when Alice Lawrence, a top accountant at GenCorp, called general manager Bill Thompson about the Christian network group being organized in one of the company's southern plants, Bill hardly flinched. After all, the Christian group was being organized by Russell Kramer, one of the company's most effective plant managers. What could be the problem there? But a couple of years ago, Alice noted, Russell had sent around a companywide letter that talked about the sinful nature of homosexuality. And that letter has made her and other gay and lesbian employees terribly uneasy. To complicate matters, the issue of "Christian rights" in the workplace was being widely discussed on radio talk shows, and several books on the topic had recently been published. An employee had even called the new region's head of human resources to get clarification on the topic. Up until now, GenCorp hadn't placed a lot of restrictions on network groups. But the emergence of a religious group was raising new questions for GenCorp's managers. Should the company accept religious groups or try to stop them? What policy, if any, should GenCorp adopt toward these network groups? Five experts comment on this fictional case study.


[The influence of separate and combined supplementation with curcumin and quercetin on the protective capacity in rats].
The purpose of the study was to determine the effects of curcumin (CUR) and quercetin (QUER) on the expression of genes and activity of prototypical Nrf2/ARE- and AhR/ XRE-regulated enzymes. Investigation was carried out on male Wistar rats with initial body weight (230-235 g b.w.) that received for 14 days CUR (200 mg/kg b.w.) and QUER (200 mg/kg b.w.) separately or in combination within the standard semi-synthetic diet. The expression of genes and activity of Nrf2/ARE - regulated enzymes - heme oxygenase- 1(HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), AhR/XRE-regulated CYP1A1, CYP1A2 enzymes and the mRNA level of transcription factors Nrf2 and AhR were determined in rats liver. Also the expression of gene CYP3A1 and activity of CYP3A, UDP-glucuronosyltransferase, glutathione transferase were studied in rats liver. Along with this the total antioxidant activity (AOA), malondialdehyde and lipid hydroperoxides levels were determined in blood plasma and liver. The reduced and oxidized glutathione level, total and unsedimentable activity of lysosomal enzymes were investigated in rats' liver. QUER, especially in combination with CUR, increased the AOA of blood plasma and reduced the content of lipid hydroperoxides in it. CUR and QUER did not affect NQO1 activity, but the combined action caused an increase in the HO-1 activity without affecting the expression of the corresponding gene (Hmox1) and Nrf2 gene. CUR and, to a lesser extent QUER, had a strong inducing effect on CYP1A1, CYP1A2, CYP3A activity, but only the CYP1A1 activation was accompanied by the induction of CYP1A1 gene. The inducing effect of CUR and QUER on the activity of CYP450 enzymes greatly enhanced by their combined action. Membrane stabilizing action of CUR and QUER was also strongly expressed under its combined intake. Thus, we can conclude that CUR and QUER, especially in combination, contribute to the protective and adaptive capacity.


Proliferating cells in HIV and pamidronate-associated collapsing focal segmental glomerulosclerosis are parietal epithelial cells.
Collapsing focal segmental glomerulosclerosis (cFSGS) is characterized by hyperplasia of glomerular epithelial cells. In a mouse model of FSGS and in a patient with recurrent idiopathic FSGS, we identified the proliferating cells as parietal epithelial cells (PECs). In the present study, we have evaluated the origin of the proliferating cells in cFSGS associated with human immunodeficiency virus (HIV) and pamidronate. We performed a detailed study of glomerular lesions in biopsies of two patients with HIV-associated cFSGS and a nephrectomy specimen of a patient with pamidronate-associated cFSGS. Glomeruli were studied by serial sectioning using light and electron microscopy and immunohistochemistry to determine the epithelial cell phenotype. We used Synaptopodin, vascular endothelial growth factor, and CD10 as podocyte markers, CK8 and PAX2 as PEC markers and Ki-67 as marker of cell proliferation. The newly deposited extracellular matrix was characterized using antiheparan sulfate single-chain antibodies. The proliferating cells were negative for the podocyte markers, but stained positive for the PEC markers and the cell proliferation marker Ki-67. The proliferating PAX-2 and CK8 positive cells that covered the capillary tuft were always in continuity with PAX-2/CK8 positive cells lining Bowman's capsule. The matrix deposited by these proliferating cells stained identically to Bowman's capsule. Our study demonstrates that PECs proliferate in HIV and pamidronate-associated cFSGS. Our data do not support the concept of the proliferating, dedifferentiated podocyte.


Phocid seals, seal lice and heartworms: a terrestrial host-parasite system conveyed to the marine environment.
Adaptation of pinnipeds to the marine habitat imposed parallel evolutions in their parasites. Ancestral pinnipeds must have harboured sucking lice, which were ancestors of the seal louse Echinophthirius horridus. The seal louse is one of the few insects that successfully adjusted to the marine environment. Adaptations such as keeping an air reservoir and the ability to hold on to and move on the host were necessary, as well as an adjustment of their life cycle to fit the diving habits of their host. E. horridus are confined to the Northern Hemisphere and have been reported from 9 species of northern phocids belonging to 4 genera, including land-locked seal species. The transmission from seal to seal is only possible when animals are hauled-out on land or ice. Lice are rarely found on healthy adult seals, but frequently on weak and young animals. The seal louse is suggested to play an important role as an intermediate host transmitting the heartworm Acanthocheilonema spirocauda among seals. However, the evidence is restricted to a single study where the first 3 larval stages of the heartworm were shown to develop in the louse. The fourth-stage larvae develop in the blood system of seals and eventually transform into the adult stage that matures in the heart. Since all other studies failed to confirm the presence of heartworm larvae in seal lice, other unknown intermediate hosts could be involved in the transmission of the heartworm. Transplacental transmission of microfilariae in seals has been suggested as an additional possibility, but is not likely to be important since the occurrence of heartworms in adult seals is very rare compared with juveniles. Furthermore, there are no findings of the first 3 larval stages in seals. This review shows that the heartworm infects nearly the same species of seals as the seal louse, except for the grey seal Halichoerus grypus, where the heartworm is absent. Prevalence and intensity of infection differ among regions in the Northern Hemisphere. As for seal lice, heartworms mainly infect immature seals, and after infection the prevalence seems to decrease with increasing age of the host.


Access to Affordable Housing Promotes Health and Well-Being and Reduces Hospital Visits.
Clinical interventions can only partially mitigate homelessness and housing insecurity, which are threats to health and well-being. Clinicians have several opportunities to address these problems: They can refer patients who are homeless or housing insecure to support services, advocate for their employer or care group to commit resources to end homelessness and housing insecurity, and/or work with government and private sector community organizations to address and eliminate these problems. Citing examples from around the US, we will illustrate how clinics, hospitals, health plans, and public health organizations work to engage in initiatives to end homelessness and housing insecurity.


Systemic Immediate Hypersensitive Reactions after Treatment with Sweet Bee Venom: A Case Report.
A previous study showed that bee venom (BV) could cause anaphylaxis or other hypersensitivity reactions. Although hypersensitivity reactions due to sweet bee venom (SBV) have been reported, SBV has been reported to be associated with significantly reduced sensitization compared to BV. Although no systemic immediate hypersensitive response accompanied by abnormal vital signs has been reported with respect to SBV, we report a systemic immediate hypersensitive response that we experienced while trying to use SBV clinically. The patient had undergone BV treatment several times at other Oriental medicine clinics and had experienced no adverse reactions. She came to acupuncture & moxibustion department at Semyung university hospital of Oriental medicine (Je-cheon, Korea) complaining of facial hypoesthesia and was treated using SBV injections, her first SBV treatment. SBV, 0.05 cc, was injected at each of 8 acupoints, for a total of 0.40 cc: Jichang (ST4), Daeyeong (ST5), Hyeopgeo (ST6), Hagwan (ST7), Yepung (TE17), Imun (TE21), Cheonghoe (GB2), and Gwallyeo (SI18). The patient showed systemic immediate hypersensitive reactions. The main symptoms were abdominal pain, nausea and perspiration, but common symptoms associated with hypersensitivity, such as edema, were mild. Abdominal pain was the most long-lasting symptom and was accompanied by nausea. Her body temperature decreased due to sweating. Her diastolic blood pressure could not be measured on three occasions. She remained alert, though the symptoms persisted. The following treatments were conducted in sequence; intramuscular epinephrine, 1 mg/mL, injection, intramuscular dexamethasone, 5 mg/mL, injection, intramuscular buscopan, 20 mg/mL, injection, oxygen (O2) inhalation therapy, 1 L/minutes, via a nasal prong, and intravascular injection of normal saline, 1 L. After 12 hours of treatment, the symptoms had completely disappeared. This case shows that the use of SBV does not completely eliminate the possibility of hypersensitivity and that patients who received BV treatment before may also be sensitized to SBV. Thus, a skin test should be given prior to using SBV.


Diversity in Older Adults' Care Networks: The Added Value of Individual Beliefs and Social Network Proximity.
Policy reforms in long-term care require an increased share of informal caregivers in elderly care. This may be more feasible for older adults who (believe they) can organize the care themselves and have a local social network. This study describes care network types, how they vary in the share of informal caregivers, and examines associations with characteristics of community-dwelling older adults, including individual beliefs and network proximity. Latent class analyses were applied to a subsample of older care receivers (N = 491) from the Longitudinal Aging Study Amsterdam, in order to identify homogeneous subgroups of people with similar care networks. Multinomial regression analysis explored associations between network type and care receiver characteristics. Privately paid, coresidential, large informal, and publicly paid care network types were distinguished. Variation in informal care appeared mostly related to health, partner status, income, and proximity of children. Proximity of other potential informal caregivers did not affect the network type. Perceived control of care was highest in the privately paid network. The results suggest that local (non-)kin could be mobilized more often in coresidential networks. Increasing informal or alternative care in publicly paid networks is less likely, due to limited social and financial resources.


Combined carrier status of prothrombin 20210A and factor XIII-A Leu34 alleles as a strong risk factor for myocardial infarction: evidence of a gene-gene interaction.
Studies associating the prothrombin 20210G>A (FII 20210A), factor V Leiden (FVL), and factor XIII Leu34 (FXIII-A Leu34) alleles with myocardial infarction (MI) have yielded conflicting results. Complicated gene-gene interactions, small sample sizes, and heterogeneous genetic and environmental backgrounds may contribute to opposing findings. Simultaneous analysis of multiple gene variants in a large sample size from a genetically isolated population may overcome these weaknesses. Genotyping was performed in 500 MI patients and 500 control subjects from the genetically isolated Newfoundland population to determine the prevalence of the FII 20210A, FVL, and FXIII-A Leu34 variants and their association with MI. Gene-gene interactions were also analyzed. The prevalence of the FII 20210A allele was higher in MI patients (3.2%) than in control subjects (1.0%; P =.015). The FII 20210A allele was also 5.6-fold higher in MI patients younger than 51 years than in age-matched control subjects (P =.04). FVL showed 3.9-fold higher prevalence in young patients than in patients older than 50 years (P =.004) and 2.7-fold higher than in age-matched control subjects (P =.007). Furthermore, the prevalence of combined carriers of the FXIII-A L34 and FII 20210A alleles was 12-fold higher in MI patients than in control subjects (P =.002) and with 92% penetrance. There was disequilibrium of the FXIII-A Leu34 allele to MI patients carrying the FII 20210A allele as a genetic background. Based on our data, we determined that (1) the FII 20210A allele is a risk factor for MI, possibly important for early onset; (2) FVL may predispose for early-onset MI; (3) the FXIII-A Leu34 allele predisposes for MI in males only; however, (4) interaction between the FII 20210A and FXIII-A Leu34 alleles forms a synergistic coeffect that strongly predisposes for MI, placing combined carriers at high risk for MI.


Biostatistic tools in pharmacogenomics--advances, challenges, potential.
Inter-individual variations in drug response are all-too common and, throughout medical history have often posed problems, many of them serious ones. The variations could stem from multiple factors, which include those of both the host (age, genetic and environmental factors) and disease (pathophysiological phenotypes, somatic mutations in case of cancers). The complex interplay of these factors can influence pharmacodynamic responses, such as adverse effects and efficacy, as well as pharmacokinetic manifestations through variability in drug absorption, distribution, metabolism and excretion. Recently, several potentially powerful tools to decipher such intricacies are emerging in various fields of science, and the translation of such knowledge to personalized medicine, called, in general, pharmacogenomics, has been promoted and has occasioned strong expectations from almost every sector of health care. However, at present, few biomarkers can predict which group of patients will respond positively, which will be non-responders and who might experience adverse reactions from the same medication and dosage. This review highlights several important aspects related to the design and statistical analysis for pharmacogenomics studies or clinical trials, which incorporate biomarkers. First, we review biomarker development: how biomarkers may be used as targets and the difference between prognostic and predictive markers. Second, in confirmatory clinical trials, we focus on issues related to study design for evaluating biomarkers and how they can be used to determine which patients might optimally benefit from a specific therapy. Finally, we review exploratory statistical screening techniques for detecting biomarkers in Phase I or pharmacokinetics studies.


Isolated cardiac sarcoidosis: clinical characteristics, diagnosis and treatment.
Sarcoidosis is a systemic disease characterized by the development of noncaseating epithelioid granulomas in multiple organs. Despite extensive investigations over a long period of time, the etiology of this disease remains unknown. Cardiac involvement of this disease is the most ominous complication leading to fatal outcome. Recently, attention has been focused on isolated cardiac sarcoidosis, which exists without clinically apparent sarcoidosis elsewhere. One of the critical issues of isolated cardiac sarcoidosis is difficulty in diagnosis, since existence of the cardiac lesion should be detected from cardiac manifestations alone. Because specificity of biomarkers or sensitivity of histological examination of biopsied sample is very low, diagnosis of isolated cardiac sarcoidosis mainly depends on imaging modalities. In this review article we summarized current knowledge on the pathogenesis of sarcoidosis, clinical features of cardiac sarcoidosis especially that isolated to the heart by showing some typical cases. Utilities and problems of diagnostic imaging tests for this condition including echocardiography, cardiac magnetic resonance imaging, and fluorodeoxyglucose-positron emission tomography are discussed. Advances in pharmacological and nonpharmacological treatment for cardiac sarcoidosis have improved the prognosis of cardiac sarcoidosis to a great deal; however, there are many issues that remain to be solved in the management of isolated cardiac sarcoidosis.


One hundred million years of interhemispheric communication: the history of the corpus callosum.
Analysis of regional corpus callosum fiber composition reveals that callosal regions connecting primary and secondary sensory areas tend to have higher proportions of coarse-diameter, highly myelinated fibers than callosal regions connecting so-called higher-order areas. This suggests that in primary/secondary sensory areas there are strong timing constraints for interhemispheric communication, which may be related to the process of midline fusion of the two sensory hemifields across the hemispheres. We postulate that the evolutionary origin of the corpus callosum in placental mammals is related to the mechanism of midline fusion in the sensory cortices, which only in mammals receive a topographically organized representation of the sensory surfaces. The early corpus callosum may have also served as a substrate for growth of fibers connecting higher-order areas, which possibly participated in the propagation of neuronal ensembles of synchronized activity between the hemispheres. However, as brains became much larger, the increasingly longer interhemispheric distance may have worked as a constraint for efficient callosal transmission. Callosal fiber composition tends to be quite uniform across species with different brain sizes, suggesting that the delay in callosal transmission is longer in bigger brains. There is only a small subset of large-diameter callosal fibers whose size increases with increasing interhemispheric distance. These limitations in interhemispheric connectivity may have favored the development of brain lateralization in some species like humans.


The protective value of a defensive display varies with the experience of wild predators.
Predation has driven the evolution of diverse adaptations for defence among prey, and one striking example is the deimatic display. While such displays can resemble, or indeed co-occur with, aposematic 'warning' signals, theory suggests deimatic displays may function independently of predator learning. The survival value of deimatic displays against wild predators has not been tested before. Here we used the mountain katydid Acripeza reticulata to test the efficacy of a putative deimatic display in the wild. Mountain katydids have a complex defence strategy; they are camouflaged at rest, but reveal a striking red-, blue-, and black-banded abdomen when attacked. We presented live katydids to sympatric (experienced) and allopatric (naive) natural predators, the Australian magpie Cracticus tibicen, and observed bird reactions and katydid behaviors and survival during repeated interactions. The efficacy of the katydids' defence differed with predator experience. Their survival was greatest when faced with naïve predators, which provided clear evidence of the protective value of the display. In contrast, katydid survival was consistently less likely when facing experienced predators. Our results suggest that sympatric predators have learned to attack and consume mountain katydids despite their complex defense, and that their post-attack display can be an effective deterrent, particularly against naïve predators. These results suggest that deimatism does not require predator learning to afford protection, but that a predator can learn to expect the display and subsequently avoid it or ignore it. That sympatric predators learn to ignore the defense is a possible explanation for the mountain katydid's counter-intuitive behavior of revealing warning colors only after tactile stimuli from predator attack.


Reactions of aluminium(i) with transition metal carbonyls: scope, mechanism and selectivity of CO homologation.
Over the past few decades, numerous model systems have been discovered that create carbon-carbon bonds from CO. These reactions are of potential relevance to the Fischer-Tropsch process, a technology that converts syngas (H2/CO) into mixtures of hydrocarbons. In this paper, a homogeneous model system that constructs carbon chains from CO is reported. The system exploits the cooperative effect of a transition metal complex and main group reductant. An entire reaction sequence from C1 → C2 → C3 → C4 has been synthetically verified. The scope of reactivity is broad and includes a variety of transition metals (M = Cr, Mo, W, Mn, Re, Co), including those found in industrial heterogeneous Fischer-Tropsch catalysts. Variation of the transition metal fragment impacts the relative rate of the steps of chain growth, allowing isolation and structural characterisation of a rare C2 intermediate. The selectivity of carbon chain growth is also impacted by this variable; two distinct isomers of the C3 carbon chain were observed to form in different ratios with different transition metal reagents. Based on a combination of experiments (isotope labelling studies, study of intermediates) and calculations (DFT, NBO, ETS-NOCV) we propose a complete mechanism for chain growth that involves defined reactivity at both transition metal and main group centres.


Maternal Marijuana Use and Adverse Neonatal Outcomes: A Systematic Review and Meta-analysis.
To estimate whether marijuana use in pregnancy increases risks for adverse neonatal outcomes and clarify if any increased risk is attributable to marijuana use itself or to confounding factors such as tobacco use. Two authors performed a search of the data through August 2015 utilizing PubMed, Embase, Scopus, Cochrane reviews, ClinicalTrials.gov, and Cumulative Index to Nursing and Allied Health. We looked at observational studies that compared rates of prespecified adverse neonatal outcomes in women who used marijuana during pregnancy with women who did not. Two authors independently extracted data from the selected studies. Primary outcomes were low birth weight (less than 2,500 g) and preterm delivery at less than 37 weeks of gestation. Secondary outcomes were birth weight, gestational age at delivery, small for gestational age, level II or greater nursery admission, stillbirth, spontaneous abortion, low Apgar score, placental abruption, and perinatal death. DerSimonian-Laird random-effects models were used. We assessed heterogeneity using the Q test and I statistic. Stratified analyses were performed for the primary outcomes and pooled adjusted estimates were calculated. We included 31 studies that assessed the effects of maternal marijuana use on adverse neonatal outcomes. Based on pooled unadjusted data, marijuana use during pregnancy was associated with an increased risk of low birth weight (15.4% compared with 10.4%, pooled relative risk [RR] 1.43, 95% confidence interval [CI] 1.27-1.62) and preterm delivery (15.3% compared with 9.6%, pooled RR 1.32, 95% CI 1.14-1.54). However, pooled data adjusted for tobacco use and other confounding factors showed no statistically significant increased risk for low birth weight (pooled RR 1.16, 95% CI 0.98-1.37) or preterm delivery (pooled RR 1.08, 95% CI 0.82-1.43). Maternal marijuana use during pregnancy is not an independent risk factor for adverse neonatal outcomes after adjusting for confounding factors. Thus, the association between maternal marijuana use and adverse outcomes appears attributable to concomitant tobacco use and other confounding factors.


Physiologic Factors Influencing the Arterial-To-End-Tidal CO2 Difference and the Alveolar Dead Space Fraction in Spontaneously Breathing Anesthetised Horses.
The arterial to end-tidal CO2 difference (P(a-ET)CO2) and alveolar dead space fraction (VDalvfrac = P(a-ET)CO2/PaCO2), are used to estimate Enghoff's "pulmonary dead space" (V/QEng), a factor which is also influenced by venous admixture and other pulmonary perfusion abnormalities and thus is not just a measure of dead space as the name suggests. The aim of this experimental study was to evaluate which factors influence these CO2 indices in anesthetized spontaneously breathing horses. Six healthy adult horses were anesthetized in dorsal recumbency breathing spontaneously for 3 h. Data to calculate the CO2 indices (response variables) and dead space variables were measured every 30 min. Bohr's physiological and alveolar dead space variables, cardiac output (CO), mean pulmonary pressure (MPP), venous admixture [Formula: see text], airway dead space, tidal volume, oxygen consumption, and slope III of the volumetric capnogram were evaluated (explanatory variables). Univariate Pearson correlation was first explored for both CO2 indices before V/QEng and the explanatory variables with rho were reported. Multiple linear regression analysis was performed on P(a-ET)CO2 and VDalvfrac assessing which explanatory variables best explained the variance in each response. The simplest, best-fit model was selected based on the maximum adjusted R2 and smallest Mallow's p (Cp). The R2 of the selected model, representing how much of the variance in the response could be explained by the selected variables, was reported. The highest correlation was found with the alveolar part of V/QEng to alveolar tidal volume ratio for both, P(a-ET)CO2 (r = 0.899) and VDalvfrac (r = 0.938). Venous admixture and CO best explained P(a-ET)CO2 (R2 = 0.752; Cp = 4.372) and VDalvfrac (R2 = 0.711; Cp = 9.915). Adding MPP (P(a-ET)CO2) and airway dead space (VDalvfrac) to the models improved them only marginally. No "real" dead space variables from Bohr's equation contributed to the explanation of the variance of the two CO2 indices. P(a-ET)CO2 and VDalvfrac were closely associated with the alveolar part of V/QEng and as such, were also influenced by variables representing a dysfunctional pulmonary perfusion. Neither P(a-ET)CO2 nor VDalvfrac should be considered pulmonary dead space, but used as global indices of V/Q mismatching under the described conditions.


Effectiveness of screening for amblyopia and other eye disorders in a prospective birth cohort study.
To establish whether the current vision screening practice in the Netherlands is effective in preventing permanent visual loss and to estimate the sensitivity of the programme. In the Netherlands, all children are invited for preverbal (1, 3, 6-9 and 14-24 months) and preschool (36, 45, and 60-72 months) vision screening. Screening attendance is high, but the effectiveness in reducing amblyopia is unknown. In a 7-year cohort study, 4624 children born in the city of Rotterdam between 16 September 1996 and 15 May 1997 were followed through all routine vision screening examinations. At age seven, visual acuity (VA) of children still living in Rotterdam was assessed by study orthoptists. In case of VA > 0.1 logMAR in one or both eyes, two or more logMAR lines of interocular difference or eye disorders like strabismus, children underwent a more intensive eye examination. Attendance at the 9-month screening was 89%, decreasing to about 75% at later examinations. Of preverbal tests, 2.5% were positive, and of preschool tests, 10%. In total, 19% of children had a positive vision screening test at least once. Amblyopia prevalence was 3.4%. Sensitivity of the vision screening programme was 73% and specificity 83%. At age seven, 0.7-1.2% (confirmed vs final exam) of the children had a VA > 0.3 logMAR in the worse eye compared with 2-3.9% (in literature) reported prevalence in non-screening situations. Children who were less frequently screened had a higher chance of poor vision (>0.3 logMAR) at age seven. The Dutch child vision screening programme may reduce the risk of persistent amblyopia (VA > 0.3 logMAR) at age seven by more than half.


Metaphase I arrest and spontaneous parthenogenetic activation of strain LTXBO oocytes: chimeric reaggregated ovaries establish primary lesion in oocytes.
Oocytes of strain LT mice, and related strains such as LTXBO, exhibit a high incidence of arrest in the progression of meiosis at metaphase I (MI) and in spontaneous parthenogenetic activation. Activation of these oocytes within the ovary leads to the formation of ovarian teratomas. In this study, the role of the oocyte's companion granulosa cells, the cumulus cells, was investigated using fully grown oocytes matured in vitro after isolation from LTXBO mice. Results showed that the role of cumulus cells in MI arrest is dichotomous. Cumulus cells temporarily helped to sustain MI arrest, but they also promoted a delayed progression to metaphase II. Cumulus cells also promoted parthenogenetic activation that occurred in association with the delayed progression to metaphase II. Next, the question of whether the lesion(s) promoting MI arrest and spontaneous activation is due to defects in the somatic cells or is intrinsic to the oocyte was addressed using chimeric reaggregated ovaries. An improved method for completely exchanging the germ cell and the somatic cell compartments of ovaries from newborn mice is described. These chimeric reaggregated ovaries, grafted beneath the renal capsule of SCID mice, allowed the complete development of LTXBO oocytes to occur in association with somatic cells from control (B6SJLF(1)) ovaries and development of control oocytes in association with LTXBO somatic cells. Oocyte growth and follicular development appeared generally normal in reaggregated ovaries. High incidences of MI arrest and spontaneous activation of LTXBO oocytes occurred regardless of the genotype of the somatic cells. Moreover, there was a low incidence of MI arrest and spontaneous activation of control oocytes, even though they underwent complete development and maturation associated with LTXBO somatic cells. It is concluded that the phenotypes of MI arrest and parthenogenetic activation in LTXBO oocytes are defects caused by lesions intrinsic to the oocyte. Nevertheless, the oocyte's companion somatic cells play crucial roles in the expression of these lesions.


PEEK (Polyether-ether-ketone) Based Cervical Total Disc Arthroplasty: Contact Stress and Lubrication Analysis.
This paper presents a theoretical analysis of the maximum contact stress and the lubrication regimes for PEEK (Polyether-ether-ketone) based self-mating cervical total disc arthroplasty. The NuNec(®) cervical disc arthroplasty system was chosen as the study object, which was then analytically modelled as a ball on socket joint. A non-adhesion Hertzian contact model and elastohydrodynamic lubrication theory were used to predict the maximum contact stress and the minimum film thickness, respectively. The peak contact stress and the minimum film thickness between the bearing surfaces were then determined, as the radial clearance or lubricant was varied. The obtained results show that under 150 N loading, the peak contact stress was in the range 5.9 - 32.1 MPa, well below the yield and fatigue strength of PEEK; the calculated minimum film thickness ranged from 0 to 0.042 µm and the corresponding lambda ratio range was from 0 to 0.052. This indicates that the PEEK based cervical disc arthroplasty will operate under a boundary lubrication regime, within the natural angular velocity range of the cervical spine.


A study of rivastigmine liposomes for delivery into the brain through intranasal route.
The present study is mainly aimed at delivering a drug into the brain via the intranasal route using a liposomal formulation. For this purpose, rivastigmine, which is used in the management of Alzheimer's disease, was selected as a model drug. Conventional liposomes were formulated by the lipid layer hydration method using cholesterol and soya lecithin as lipid components. The concentration of rivastigmine in brain and plasma after intranasal liposomes, free drug and per oral administration was studied in rat models. A significantly higher level of drug was found in the brain with intranasal liposomes of rivastigmine compared to the intranasal free drug and the oral route. Intranasal liposomes had a longer half-life in the brain than intranasally or orally administered free drug. Delivering rivastigmine liposomes through the intranasal route for the treatment of Alzheimer's disease might be a new approach to the management of this condition.


Estimating health care-associated infections and deaths in U.S. hospitals, 2002.
The purpose of this study was to provide a national estimate of the number of healthcare-associated infections (HAI) and deaths in United States hospitals. No single source of nationally representative data on HAIs is currently available. The authors used a multi-step approach and three data sources. The main source of data was the National Nosocomial Infections Surveillance (NNIS) system, data from 1990-2002, conducted by the Centers for Disease Control and Prevention. Data from the National Hospital Discharge Survey (for 2002) and the American Hospital Association Survey (for 2000) were used to supplement NNIS data. The percentage of patients with an HAI whose death was determined to be caused or associated with the HAI from NNIS data was used to estimate the number of deaths. In 2002, the estimated number of HAIs in U.S. hospitals, adjusted to include federal facilities, was approximately 1.7 million: 33,269 HAIs among newborns in high-risk nurseries, 19,059 among newborns in well-baby nurseries, 417,946 among adults and children in ICUs, and 1,266,851 among adults and children outside of ICUs. The estimated deaths associated with HAIs in U.S. hospitals were 98,987: of these, 35,967 were for pneumonia, 30,665 for bloodstream infections, 13,088 for urinary tract infections, 8,205 for surgical site infections, and 11,062 for infections of other sites. HAIs in hospitals are a significant cause of morbidity and mortality in the United States. The method described for estimating the number of HAIs makes the best use of existing data at the national level.


The relationship between parental socio-economic status and episodes of drunkenness among adolescents: findings from a cross-national survey.
Behavioral factors such as (excessive) alcohol consumption play a major role in the explanation of social inequalities in health. The unequal distribution of health risk behaviors among socio-economic groups has important consequences for both the current and future health status of the younger generation. However, little is known about socio-economic differences in unhealthy lifestyles during adolescence. The purpose of the present study is to investigate socio-economic differences in adolescent drinking behaviour among 11-15 year old adolescents in Europe and North America. Data was obtained from the Health Behaviour in School-aged Children (HBSC) study 2001/02, a cross-national survey conducted in collaboration with the World Health Organization. The present analysis is based on 69249 male and 73619 female students from 28 countries. The effect of parental occupation and family affluence on episodes of drunkenness was assessed using separate logistic regression models controlling for age. Socio-economic circumstances of the family had only a limited effect on repeated drunkenness in adolescence. For girls only in one out of 28 countries a significant association between family affluence and repeated drunkenness was observed, while boys from low and/or medium affluent families in nine countries faced a lower risk of drunkenness than boys from more affluent families. Regarding parental occupation, significant differences in episodes of drunkenness were found in nine countries for boys and in six countries for girls. Compared to family affluence, which was positively related to risk of drunkenness, a decreasing occupational status predicted an increasing risk of drunkenness. This pattern was identified within a number of countries, most noticeably for boys. Parental socio-economic status is only of limited importance for episodes of drunkenness in early adolescence, and this very limited role seems to apply for girls more than for boys and for parental occupation more than family affluence. For future studies it might be important to look at the effects of socio-economic status within the context of other peer, family and school related factors in order to assess to what extent those factors might mediate the effects of social class background.


Sporadic hemangioblastomas are characterized by cryptic VHL inactivation.
Hemangioblastomas consist of 10-20% neoplastic "stromal" cells within a vascular tumor cell mass of reactive pericytes, endothelium and lymphocytes. Familial cases of central nervous system hemangioblastoma uniformly result from mutations in the Von Hippel-Lindau (VHL) gene. In contrast, inactivation of VHL has been previously observed in only a minority of sporadic hemangioblastomas, suggesting an alternative genetic etiology. We performed deep-coverage DNA sequencing on 32 sporadic hemangioblastomas (whole exome discovery cohort n = 10, validation n = 22), followed by analysis of clonality, copy number alteration, and somatic mutation. We identified somatic mutation, loss of heterozygosity and/or deletion of VHL in 8 of 10 discovery cohort tumors. VHL inactivating events were ultimately detected in 78% (25/32) of cases. No other gene was significantly mutated. Overall, deep-coverage sequence analysis techniques uncovered VHL alterations within the neoplastic fraction of these tumors at higher frequencies than previously reported. Our findings support the central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas.


Mastication Evaluation With Unsupervised Learning: Using an Inertial Sensor-Based System.
There is a direct relationship between the prevalence of musculoskeletal disorders of the temporomandibular joint and orofacial disorders. A well-elaborated analysis of the jaw movements provides relevant information for healthcare professionals to conclude their diagnosis. Different approaches have been explored to track jaw movements such that the mastication analysis is getting less subjective; however, all methods are still highly subjective, and the quality of the assessments depends much on the experience of the health professional. In this paper, an accurate and non-invasive method based on a commercial low-cost inertial sensor (MPU6050) to measure jaw movements is proposed. The jaw-movement feature values are compared to the obtained with clinical analysis, showing no statistically significant difference between both methods. Moreover, We propose to use unsupervised paradigm approaches to cluster mastication patterns of healthy subjects and simulated patients with facial trauma. Two techniques were used in this paper to instantiate the method: Kohonen's Self-Organizing Maps and K-Means Clustering. Both algorithms have excellent performances to process jaw-movements data, showing encouraging results and potential to bring a full assessment of the masticatory function. The proposed method can be applied in real-time providing relevant dynamic information for health-care professionals.


Zanamivir use during transmission of amantadine-resistant influenza A in a nursing home.
To describe the use of zanamivir during an influenza A outbreak. Residents of a 176-bed long-term-care facility for the elderly in Newmarket, Ontario, Canada, 90% of whom received influenza vaccine in the fall of 1998. When respiratory illness due to influenza A was confirmed, infection control measures and amantadine prophylaxis were initiated. Despite these measures, transmission of influenza A continued. Zanamivir inhalations, 10 mg daily for prophylaxis and 10 mg twice daily for treatment of influenza. There were 13 definite and 66 probable outbreak-associated cases of influenza A. Twelve (15%) cases developed pneumonia, 7 (9%) were hospitalized, and 2 (2.6%) died. All 12 culture-positive cases yielded influenza A/Sydney/H3N2/05/97-like virus, a 1998/99 vaccine component. The three isolates obtained prior to the initiation of amantadine were amantadine-susceptible; all nine obtained after prophylaxis was instituted were amantadine-resistant. One hundred twenty-nine (92%) of 140 residents who were offered zanamivir accepted it and were able to attempt inhalations. Of these 129, 78% (100) had no difficulty in complying with inhalations. Difficulty with inhalations was associated with decreased functional and mental status. Fifteen (58%) of 26 residents fully dependent in activities of daily living had difficulty compared to 14 (14%) of 100 others (P<.001). Twenty-two (45%) of 49 residents not oriented to person, place, or time had difficulty compared to 7 (10%) of 77 others (P<.001). In the 2 weeks after zanamivir prophylaxis, only 2 new cases of respiratory illness occurred, neither confirmed as influenza. No side effects were identified in 128 zanamivir-treated residents. A minority of nursing home residents have difficulty following instructions for zanamivir inhalations. Zanamivir was well tolerated, and its use was temporally associated with termination of an outbreak that amantadine had failed to control.


Unexpected infant deaths associated with use of cough and cold medications.
The objective of this study was to determine whether caregivers had given infants who died unexpectedly over-the-counter cough and cold medications before the infant deaths to identify sociodemographic risk factors for their use. The Arizona Child Fatality Review Program reviews the circumstances surrounding every child death that occurs in the state each year. By statute, the multidisciplinary review teams have access to all medical charts, autopsy reports, law enforcement reports, and other records for their review and use these data to determine the cause of death and its preventability. The data on all infants who died unexpectedly in 2006 and had an autopsy and postmortem toxicologic studies were reviewed for this analysis. Ten unexpected infant deaths that were associated with cold-medication use were identified. The infants ranged in age from 17 days to 10 months. Postmortem toxicology testing found evidence of recent administration of pseudoephedrine, antihistamine, dextromethorphan, and/or other cold-medication ingredients in these infants. The families who used these medications were poor and publicly insured, and 50% of them had limited English proficiency. Only 4 of these infants had received medical care for their current illness before their death. The over-the-counter cough and cold medication had been prescribed by a clinician for only 1 of these infants. Review of these infants' deaths raises concern about the role of the over-the-counter cough and cold medications in these deaths. These findings support the recommendation that such medications not be given to infants. In addition, these findings suggest that warnings on these medications "to consult a clinician" before use are not being followed by parents. Educational campaigns to decrease the use of over-the-counter cough and cold medications in infants need to be increased.


Multiple paternity in reptiles: patterns and processes.
The evolution of female promiscuity poses an intriguing problem as benefits of mating with multiple males often have to arise via indirect, genetic, effects. Studies on birds have documented that multiple paternity is common in natural populations but strong evidence for selection via female benefits is lacking. In an attempt to evaluate the evidence more broadly, we review studies of multiple paternity in natural populations of all major groups of nonavian reptiles. Multiple paternity has been documented in all species investigated so far and commonly exists in over 50% of clutches, with particularly high levels in snakes and lizards. Marine turtles and lizards with prolonged pair-bonding have relatively low levels of multiple paternity but levels are nevertheless higher than in many vertebrates with parental care. There is no evidence that high levels of polyandry are driven by direct benefits to females and the evidence that multiple paternity arises from indirect genetic benefits is weak. Instead, we argue that the most parsimonious explanation for patterns of multiple paternity is that it represents the combined effect of mate-encounter frequency and conflict over mating rates between males and females driven by large male benefits and relatively small female costs, with only weak selection via indirect benefits. A crucial step for researchers is to move from correlative approaches to experimental tests of assumptions and predictions of theory under natural settings, using a combination of molecular techniques and behavioural observations.


Abomasal amino acid infusion in postpartum dairy cows: Effect on whole-body, splanchnic, and mammary glucose metabolism.
Nine Holstein cows fitted with rumen cannulas and indwelling catheters in splanchnic blood vessels were used to study the effects of supplementing AA on milk lactose secretion, whole-body rate of appearance (WB-Ra) of glucose, and tissue metabolism of glucose, lactate, glycerol, and β-OH-butyrate (BHBA) in postpartum dairy cows according to a generalized randomized incomplete block design with repeated measures in time. At calving, cows were blocked according to parity (second and third or greater) and were allocated to 2 treatments: abomasal infusion of water (n=4) or abomasal infusion of free AA with casein profile (AA-CN; n=5) in addition to the same basal diet. The AA-CN infusion started with half the maximal dose at 1 d in milk (DIM) and then steadily decreased from 791 to 226 g/d from DIM 2 to 29 to cover the estimated essential AA deficit. On DIM 5, 15, and 29, D[6,6-(2)H2]-glucose (23.7 mmol/h) was infused into a jugular vein for 5h, and 6 blood samples were taken from arterial, portal, hepatic, and mammary sources at 45-min intervals, starting 1h after the initiation of the D[6,6-(2)H2]glucose infusion. Trans-organ fluxes were calculated as veno-arterial differences times plasma flow (splanchnic: downstream dilution of deacetylated para-aminohippurate; mammary: Fick principle using Phe+Tyr). Energy-corrected milk and lactose yields increased on average with AA-CN by 6.4 kg/d and 353 g/d, respectively, with no DIM × treatment interaction. Despite increased AA supply and increased demand for lactose secretion with AA-CN, net hepatic release of glucose remained unchanged, but WB-Ra of glucose tended to increase with AA-CN. Portal true flux of glucose increased with AA-CN and represented, on average, 17% of WB-Ra. Splanchnic true flux of glucose was unaltered by treatments and was numerically equivalent to WB-Ra, averaging 729 and 741 mmol/h, respectively. Mammary glucose utilization increased with AA-CN infusion, averaging 78% of WB-Ra, and increased gradually as lactation advanced. Net portal, hepatic, splanchnic, and mammary fluxes of lactate, glycerol, and BHBA were not affected by AA infusion. Increasing the supply of AA in postpartum dairy cows elevated the WB-Ra of glucose without affecting the true liver glucose release. The greater WB-Ra of glucose with abomasal AA infusion seemed to originate mainly from greater true portal-drained viscera release of glucose. Glucose utilization by the portal-drained viscera was unaffected by abomasal AA infusion, but the exact mechanism behind the greater true portal glucose release could not be assessed in the current study. The increased mammary glucose uptake was in line with the increased milk lactose yield. In early postpartum lactation, the demand for AA seems to be so high that even with increased AA supply, cows have metabolic priorities for AA other than hepatic gluconeogenesis.


Exploring the influence of vocal emotion expression on communicative effectiveness.
This study explores whether speaker emotion influences communicative effectiveness. Two hundred participants rated their current emotional state and gave a description of a route on a simple map. The quality of the linguistic content of the descriptions was assessed using Latent Semantic Analysis. Six hundred participants provided route drawings based on the map descriptions. Median route deviation served as a measure of communicative effectiveness. Eighty additional participants rated invariant parts of the descriptions for perceived speaker happiness. Path analysis revealed that while speaker emotion did not affect the linguistic content of the descriptions, it had an effect on communicative effectiveness both through the effects of vocal cues directly as well as mediated by perceived happiness of speech. Specifically, higher first formants were associated with higher reported and perceived happiness as well as higher communicative effectiveness. Jitter, on the other hand, was negatively related to the perception of happiness and positively related to communicative effectiveness. These findings suggest that mood-related modulation of phonation and articulation can influence the effectiveness of communication in addition to message content.


Insights into Membrane Protein-Lipid Interactions from Free Energy Calculations.
Integral membrane proteins are regulated by specific interactions with lipids from the surrounding bilayer. The structures of protein-lipid complexes can be determined through a combination of experimental and computational approaches, but the energetic basis of these interactions is difficult to resolve. Molecular dynamics simulations provide the primary computational technique to estimate the free energies of these interactions. We demonstrate that the energetics of protein-lipid interactions may be reliably and reproducibly calculated using three simulation-based approaches: potential of mean force calculations, alchemical free energy perturbation, and well-tempered metadynamics. We employ these techniques within the framework of a coarse-grained force field and apply them to both bacterial and mammalian membrane protein-lipid systems. We demonstrate good agreement between the different techniques, providing a robust framework for their automated implementation within a pipeline for annotation of newly determined membrane protein structures.


Maintenance of neovascularization at the implantation site of an artificial device by bFGF and endothelial cell transplant.
Development of a subcutaneously implantable bioartificial pancreas (BAP) with immunoisolatory function could have a great impact on the treatment of diabetes mellitus. We have developed an implantable BAP device with an ethylene vinyl alcohol (EVAL) membrane. In the present study, we used basic fibroblast growth factors (bFGF), which was incorporated in a carrier for sustained release, in order to induce neovascularization when the device was implanted subcutaneously. To maintain the vasculature thus formed, a cell infusion port was attached to the BAP device, through which the device was filled with human liver vascular endothelial cell line TMNK-1, and the vasculature could be adequately maintained. Mice were divided into the following three groups. In group 1, a bFGF-free BAP device was implanted subcutaneously. In group 2, a sustained-release bFGF-impregnated BAP device was implanted. In group 3, a sustained-release bFGF-impregnated BAP device was implanted, and 3 x 10(6) TMNK-1 cells were infused into the implanted device every week. Neovascularization induced in the subcutaneous tissue around the implanted BAP device was macroscopically examined and histologically evaluated. In addition, the tissue blood flow was measured using a laser blood flow meter. In mice in group 3, neovascularization was significantly induced and maintained until week 8 postimplantation. It was confirmed by scanning electron microscopy that infused TMNK-1 cells adhered to the inner polyethylene surface of the device. It was demonstrated that the use of bFGF and vascular endothelial TMNK-1 cells induced and maintained adequate vasculature and tissue blood flow surrounding the implantable bag-type BAP device. We believe that the present study will contribute to BAP development for the treatment of diabetes.


Preventive effects of ethyl pyruvate on endotoxin-induced uveitis in rats.
Recent studies indicate that ethyl pyruvate (EP) exerts anti-inflammatory properties; however, the effect of EP on ocular inflammation is not known. The efficacy of EP in endotoxin-induced uveitis (EIU) in rats was investigated. EIU in Lewis rats was developed by the subcutaneous injection of lipopolysaccharide (LPS; 150 μg). EP (30 mg/kg body weight) or its carrier was injected intraperitoneally 1 hour before or 2 hours after lipopolysaccharide injection. Animals were killed after 3 and 24 hours followed by enucleation of eyes and collection of the aqueous humor (AqH). The number of infiltrating cells and levels of proteins in the AqH were determined. The rat cytokine/chemokine multiplex method was used to determine level of cytokines and chemokines in the AqH. TNF-α and phospho-nuclear factor kappa B (NF-κB) expression in ocular tissues were determined immunohistochemically. Human primary nonpigmented ciliary epithelial cells (HNPECs) were used to determine the in vitro efficacy of EP on lipopolysaccharide-induced inflammatory response. Compared to controls, AqH from the EIU rat eyes had a significantly higher number of infiltrating cells, total protein, and inflammatory cytokines/chemokines, and the treatment of EP prevented EIU-induced increases. In addition, EP also prevented the expression of TNF-α and activation of NF-κB in the ciliary bodies and retina of the eye. Moreover, in HNPECs, EP inhibited lipopolysaccharide-induced activation of NF-κB and expression of Cox-2, inducible nitric oxide synthase, and TNF-α. Our results indicate that EP prevents ocular inflammation in EIU, suggesting that the supplementation of EP could be a novel approach for the treatment of ocular inflammation, specifically uveitis.


Antibacterial activity of varying UMF-graded Manuka honeys.
Honey has been used as a traditional remedy for skin and soft tissue infections due to its ability to promote wound healing. Manuka honey is recognized for its unusually abundant content of the antibacterial compound, methylglyoxal (MGO). The Unique Manuka Factor (UMF) grading system reflects the MGO concentration in Manuka honey sold commercially. Our objective was to observe if UMF values correlated with the antibacterial activity of Manuka honey against a variety of pathogens purchased over the counter. The antibacterial effect of Manuka honey with UMF values of 5+, 10+, and 15+ from the same manufacturer was assessed by the broth microdilution method. Minimum inhibitory concentration (MIC) values were determined against 128 isolates from wound cultures representing gram-positive, gram-negative, drug-susceptible, and multi-drug resistant (MDR) organisms. Lower MICs were observed with UMF 5+ honey for staphylococci (n = 73, including 25 methicillin-resistant S. aureus) and Pseudomonas aeruginosa (n = 22, including 10 MDR) compared to UMF 10+ honey (p<0.05) and with UMF 10+ compared to UMF 15+ (p = 0.01). For Enterobacteriaceae (n = 33, including 14 MDR), MIC values were significantly lower for UMF 5+ or UMF 10+ compared to UMF 15+ honey (p<0.01). MIC50 for UMF 5+, UMF 10+, and UMF 15+ honey against staphylococci was 6%, 7%, and 15%, and for Enterobacteriaceae was 21%, 21%, and 27%, respectively. For Pseudomonas aeruginosa MIC50 was 21% and MIC90 was 21-27% for all UMFs. Manuka honey exhibited antimicrobial activity against a spectrum of organisms including those with multi-drug resistance, with more potent activity overall against gram-positive than gram-negative bacteria. Manuka honey with lower UMF values, in our limited sampling, paradoxically demonstrated increased antimicrobial activity among the limited samples tested, presumably due to changes in MGO content of honey over time. The UMF value by itself may not be a reliable indicator of antibacterial effect.


Recurrent miscarriage is associated with increased numbers of CD5/20 positive lymphocytes and an increased incidence of thyroid antibodies.
The aim of this study was to determine whether recurrent miscarriage (three or more miscarriages, no live children) was associated with an increased incidence of autoantibodies. Five groups were enrolled into the study; healthy non-pregnant women, healthy first-trimester pregnant women, women suffering spontaneous abortion, those undergoing termination of pregnancy and those with a previous history of miscarriage. The number of total B cells and the numbers of the antibody producing B cell subset CD5+/CD20+ were determined for each group. Samples were tested for anticardiolipin antibodies, antinuclear antibodies and thyroid microsomal and thyroglobulin antibodies. The results showed that compared to normal pregnancy or spontaneous abortion, recurrent miscarriage was associated with a significant increase in the number of CD5+/20+ positive cells (0.8 +/- 0.3 vs 0.5 +/- 0.1 vs 1.1 +/- 0.3 x 10(8)/l; p < 0.001). These women were also found to have a higher incidence of thyroid antibodies, with four out of the 11 patients being positive for thyroid microsomal antibodies. These results suggest that there may be an association between autoimmunity and recurrent miscarriage.


Crystal structure of a thermophilic fungal cyanase and its implications on the catalytic mechanism for bioremediation.
Cyanase catalyzes the bicarbonate-dependent degradation of cyanate to produce ammonia and carbon dioxide, and ammonia is a considerable alternative nitrogen source. Strikingly, the cyanase from the thermophilic fungus Thermomyces lanuginosus (Tl-Cyn) has the highest catalytic efficiency reported among these enzymes. However, its molecular mechanism of action is not clearly understood, because currently there is no structural information available on fungal cyanases. Here we report the crystal structure of Tl-Cyn in complex with inhibitors malonate and formate at 2.2 Å resolution. The structure reveals extensive interactions at the subunit interfaces in a dimer, and a decamer is formed by a pentamer of these dimers. Our biochemical, kinetic and mutagenesis studies confirm the structural observations on the complex and provide further insights into its catalytic mechanism and inhibition. The structure has also aided the creation of a mutant enzyme with enhanced catalytic activity, and such enzymes may have the potential for biotechnological applications, including biotransformation and bioremediation. Moreover, other fungal cyanases with potentially high catalytic activity could also be predicted based on the Tl-Cyn structure, as the active site region among fungal cyanases are highly conserved.


The structural dynamics and energetics of an immunodominant T cell receptor are programmed by its Vbeta domain.
Immunodominant and public T cell receptor (TCR) usage is relatively common in many viral diseases yet surprising in the context of the large naive TCR repertoire. We examined the highly conserved Vbeta17:Valpha10.2 JM22 T cell response to the influenza matrix peptide (58-66)-HLA-A*0201 (HLA-A2-flu) through extensive kinetic, thermodynamic, and structural analyses. We found several conformational adjustments that accompany JM22-HLA-A2-flu binding and identified a binding "hotspot" within the Vbeta domain of the TCR. Within this hotspot, key germline-encoded CDR1 and CDR2 loop residues and a crucial but commonly coded residue in the hypervariable region of CDR3 provide the basis for the substantial bias in the selection of the germline-encoded Vbeta17 domain. The chances of having a substantial number of T cells in the naive repertoire that have HLA-A2-flu-specific Vbeta17 receptors may consequently be relatively high, thus explaining the immunodominant usage of this clonotype.


Inhibitory effects of flavonoids extracted from licorice on lipopolysaccharide-induced acute pulmonary inflammation in mice.
Airway inflammation plays important roles in the pathogenesis of acute respiratory distress syndrome (ARDS), asthma and chronic obstructive pulmonary disease (COPD), and anti-inflammatory treatment effectively improves the symptoms of these diseases. To develop the potentially therapeutic compounds for the treatment of pulmonary inflammation, we investigated the effects of licorice flavonoids (LF) extracted from the roots of Glycyrrhiza uralensis (licorice) on lipopolysaccharide (LPS)-induced acute pulmonary inflammation in mice. Acute pulmonary inflammation was induced by intracheal instillation with LPS, treatment with LF at dosages of 3, 10 and 30 mg/kg significantly reduced the LPS-induced inflammatory cells, including neutrophils, macrophages and lymphocytes accumulation in bronchoalveolar lavage fluids (BALF), among these inflammatory cells, LF predominately inhibited neutrophil infiltration, and the maximal effect (30 mg/kg) was as comparable as dexamethasone treatment at 1 mg/kg. Consistent with its effects on neutrophil infiltration, LF treatment significantly increased LPS-induced BALF superoxide dismutase activity, and significantly decreased lung myeloperoxidase activity as well. Furthermore, treatment with LF at 30 mg/kg significantly reduced LPS-induced lung TNFalpha and IL-1beta mRNA expression at 6 h and 24 h after LPS instillation, respectively. Finally, LF at different dosages not only significantly decreased the elevation of lung water content, but also markedly attenuated LPS-induced histological alteration. Therefore, we suggest that LF effectively attenuates LPS-induced pulmonary inflammation through inhibition of inflammatory cells infiltration and inflammatory mediator release which subsequently reduces neutrophil recruitment into lung and neutrophil-mediated oxidative injury, and this study provides with the potential rationale for development of anti-inflammatory compounds from flavonoid extracts of licorice.


Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial.
Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection. This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369. Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; absolute difference 39% [95% CI 27-53]; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy. Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery. Daiichi Sankyo.


Optical nondestructive dynamic measurements of wafer-scale encapsulated nanofluidic channels.
Nanofluidic channels are of great interest for DNA sequencing, chromatography, and drug delivery. However, metrology of embedded or sealed nanochannels and measurement of their fill-state have remained extremely challenging. Existing techniques have been restricted to optical microscopy, which suffers from insufficient resolution, or scanning electron microscopy, which cannot measure sealed or embedded channels without cleaving the sample. Here, we demonstrate a novel method for accurately extracting nanochannel cross-sectional dimensions and monitoring fluid filling, utilizing spectroscopic ellipsometric scatterometry, combined with rigorous electromagnetic simulations. Our technique is capable of measuring channel dimensions with better than 5-nm accuracy and assessing channel filling within seconds. The developed technique is, thus, well suited for both process monitoring of channel fabrication as well as for studying complex phenomena of fluid flow through nanochannel structures.


A counselee-oriented perspective on risk communication in genetic counseling: explaining the inaccuracy of the counselees' risk perception shortly after BRCA1/2 test result disclosure.
Genetic counseling may help counselees understand their genetic risk of developing breast/ovarian cancer. However, many studies have shown that their perception of their risks is inaccurate. Information-oriented variables often predicted the level of accuracy, focusing on specific processes of receiving and processing risks. We examined counselee-oriented predictors about how counselees embed cancer risks in their lives. These predictors reflect the personal meaning of genetic risks and are expected to explain/mediate the impact of genetic counseling on risk-perception-accuracy. We analyzed 248 questionnaires of a prospective study, filled in by probands with breast/ovarian cancer and pathogenic mutations, unclassified variants, or uninformative results (n = 30, 16, and 202, respectively). Mediation regression analyses were performed to examine whether counselee predictors mediated/explained the influence of information predictors on the accuracy. Information-oriented predictors regarded presentation format, communicated information, question format, education, pedigree information, cancer experience, and cognitive processes/heuristics. Counselee-oriented predictors regarded their self/personality, life/existence, and need for certainty about DNA test result, heredity, and cancer. Both information-oriented and counselee-oriented variables significantly predicted the accuracy of the counselees' risk perception, with moderate to large effect sizes. Counselee-oriented variables completely mediated/explained the effects of information-oriented variables on the accuracy. Counselees seemed to transform objective cancer risks into personally relevant information. Only through this personal meaning of genetic information, information-oriented processes seemed to cause inaccurate perceptions. Genetic counselors are suggested to focus communication on these personal processes.