Potential Cost Savings for the Healthcare System by Physical Activity in Different Chronic Diseases: A Pilot Study in the Veneto Region of Italy.
Sedentary behaviour (SB) and physical inactivity (PI) are associated with an increased risk of chronic diseases and a significant economic burden. This pilot study aims to estimate the possible cost savings for the Veneto Regional Health Service (Italy) due to a population-based physical activity (PA) intervention. The PA-related cost-savings were assessed for four chronic diseases in the whole and sedentary populations of the Veneto region. The SB and PA epidemiological data, regarding an additional percutaneous coronary intervention in coronary artery disease, hospitalizations in chronic obstructive pulmonary disease, surgery for colorectal cancer, and femur fracture, were obtained from national and regional administrative sources. A relative risk reduction, due to PA, was obtained from the recent literature. The annual healthcare costs were estimated using the regional diagnosis-related group tariffs. The annual estimated cost-savings for the regional healthcare service related to these four outcomes: an amount between EUR 5,310,179 (if a conservative analysis was performed) and EUR 17,411,317. By a downward estimate, regarding the direct healthcare costs, PA interventions could lead to important cost-savings in the Veneto region. The savings would be greater when considering the cross-sectional impact on other healthcare costs, comorbidities, and indirect costs.


College student mental health: An evaluation of the DSM-5 self-rated Level 1 cross-cutting symptom measure.
The DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure was developed to aid in clinical decision-making for clients seeking psychiatric services and to facilitate empirical investigation of the dimensional nature of mental health issues. Preliminary evidence supports its utility with clinical samples. However, the brief, yet comprehensive structure of the DSM-5 Level 1 measure may benefit a high-risk population that is less likely to seek treatment. College students have high rates of hazardous substance use and co-occurring mental health symptoms, yet rarely seek treatment. Therefore, the current study evaluated the psychometric properties (i.e., construct and criterion-related validity) of the DSM-5 Level 1 measure with a large, diverse sample of non-treatment-seeking college/university students. Data from 7,217 college students recruited from 10 universities in 10 different states across the United States evidenced psychometric validation of the DSM-5 Level 1 measure. Specifically, we found acceptable internal consistency across multi-item DSM-5 domains and moderate to strong correlations among domains (internal validity). Further, several DSM-5 domains were positively associated with longer, validated measures of the same mental health construct and had similar strengths of associations with substance use outcomes compared to longer measures of the same construct (convergent validity). Finally, all DSM-5 domains were negatively associated with self-esteem and positively associated with other theoretically relevant constructs, such as posttraumatic stress (criterion-related validity). Taken together, the DSM-5 Level 1 measure appears to be a viable tool for evaluating psychopathology in college students. Several opportunities for clinical application and empirical investigation of the DSM-5 Level 1 measure are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Superoxide anion impairs contractility in cultured aortic smooth muscle cells.
We examined the effects of superoxide anion (O) generated by xanthine plus xanthine oxidase (X/XO) on the intracellular Ca(2+) concentration ([Ca(2+)](i)) and muscle contractility in cultured bovine aortic smooth muscle cells (BASMC). Cells were grown on collagen-coated dish for the measurement of [Ca(2+)](i). Pretreatment with X/XO inhibited ATP-induced Ca(2+) transient and Ca(2+) release-activated Ca(2+) entry (CRAC) after thapsigargin-induced store depletion, both of which were reversed by superoxide dismutase (SOD). In contrast, Ca(2+) transients induced by high-K(+) solution and Ca(2+) ionophore A-23187 were not affected by X/XO. BASMC-embedded collagen gel lattice, which was pretreated with xanthine alone, showed contraction in response to ATP, thapsigargin, high-K(+) solution, and A-23187. Pretreatment of the gel with X/XO impaired gel contraction not only by ATP and thapsigargin, but also by high-K(+) solution and A-23187. The X/XO-treated gel showed normal contraction; however, when SOD was present during the pretreatment period. These results indicate that O(2)(-) attenuates smooth muscle contraction by impairing CRAC, ATP-induced Ca(2+) transient, and Ca(2+) sensitivity in BASMC.


Compliance and use of the World Health Organization checklist in U.K. operating theatres.
The World Health Organization (WHO) Surgical Safety Checklist is reported to reduce surgical morbidity and mortality, and is mandatory in the U.K. National Health Service. Hospital audit data show high compliance rates, but direct observation suggests that actual performance may be suboptimal. For each observed operation, WHO time-out and sign-out attempts were recorded, and the quality of the time-out was evaluated using three measures: all information points communicated, all personnel present and active participation. Observation of WHO checklist performance was conducted for 294 operations, in five hospitals and four surgical specialties. Time-out was attempted in 257 operations (87.4 per cent) and sign-out in 26 (8.8 per cent). Within time-out, all information was communicated in 141 (54.9 per cent), the whole team was present in 199 (77.4 per cent) and active participation was observed in 187 (72.8 per cent) operations. Surgical specialty did not affect time-out or sign-out attempt frequency (P = 0.453). Time-out attempt frequency (range 42-100 per cent) as well as all information communicated (15-83 per cent), all team present (35-90 per cent) and active participation (15-93 per cent) varied between hospitals (P < 0.001 for all). Meaningful compliance with the WHO Surgical Safety Checklist is much lower than indicated by administrative data. Sign-out compliance is generally poor, suggesting incompatibility with normal theatre work practices. There is variation between hospitals, but consistency across studied specialties, suggesting a need to address organizational culture issues.


The effects of maternal alcohol consumption during pregnancy on adverse fetal outcomes among pregnant women attending antenatal care at public health facilities in Gondar town, Northwest Ethiopia: a prospective cohort study.
The teratogenic effect of fetal alcohol exposure may lead to actual and potential problems, instantly after birth, at infancy; or even later, and mental impairment in life. This study aimed to investigate the effects of maternal alcohol consumption during pregnancy on adverse fetal outcomes at Gondar town public health facilities, Northwest Ethiopia. A facility-based prospective cohort study was performed among 1778 pregnant women who were booked for antenatal care in selected public health facilities from 29 October 2019 to 7 May 2020 in Gondar town. We used a two-stage random sampling technique to recruit and include participants in the cohort. Data were collected using the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) standardized and pre-tested questionnaire. Multivariable analysis was performed to examine the association between reported prenatal alcohol exposure (non-hazardous and hazardous) and interested adverse birth outcomes using log-binomial regression modeling. The burden of outcomes was reported using the adjusted risk ratio and population-attributable risk (PAR). A total of 1686 pregnant women were included in the analysis, which revealed that the incidences of low birth weight, preterm, and stillbirth were 12.63% (95% CI: 11.12, 14.31), 6.05% (95% CI: 5.00, 7.29) and 4.27% (95% CI: 3.4, 5.35), respectively. Non-hazardous and hazardous alcohol consumption during pregnancy was significantly associated with low birth weight (ARR = 1.50; 95% CI: 1.31, 1.98) and (ARR = 2.34; 95% CI: 1.66, 3.30), respectively. Hazardous alcohol consumption during pregnancy was also significantly associated with preterm birth (ARR = 2.06; 95% CI: 1.21, 3.52). The adjusted PAR of low birth weight related to non-hazardous and hazardous alcohol drinking during pregnancy was 11.72 and 8.44%, respectively. The adjusted PAR of hazardous alcohol consumption was 6.80% for preterm. Our findings suggest that there is an increasing risk of adverse birth outcomes, particularly preterm delivery and low birth weight, with increasing levels of alcohol intake. This result showed that the prevention of maternal alcohol use during pregnancy has the potential to reduce low birth weight and preterm birth. Hence, screening women for alcohol use during antenatal care visits and providing advice with rigorous follow-up of women who used alcohol may save the fetus from the potential risks of adverse birth outcomes.


Endosperm and whole grain rye breads are characterized by low post-prandial insulin response and a beneficial blood glucose profile.
Rye products have previously been shown to induce comparatively low post-prandial insulin responses; irrespectively of their glycaemic indices (GI). However, the mechanism behind this lowered insulin demand remains unknown. An improved insulin economy might contribute to the benefits seen in epidemiological studies with whole grain diets on metabolic risk factors and weight regulation. The objective of this study was to explore the mechanism for a reduced post-prandial insulin demand with rye products. 12 healthy subjects were given flour based rye products made from endosperm, whole grain or bran, produced with different methods (baking, simulated sour-dough baking and boiling) as breakfasts in random order in a cross-over design. White wheat bread (WWB) was used as a reference. Blood glucose, serum insulin, plasma ghrelin and subjective satiety were measured during 180 minutes. To evaluate the course of post-meal glycaemia, a measure of the glycaemic profile (GP) was introduced defined as the duration for the incremental post-prandial blood glucose response divided with the blood glucose incremental peak (min/mM). The study shows that whole grain rye breads and endosperm rye products induced significantly (p < 0.05) lower insulinaemic indices (II's) than WWB. Rye bran bread (RBB) produced significantly higher II compared with all the other rye products. Furthermore, the acute insulin response showed better correlations with the GP than with the GI of the products. The endosperm rye bread and the whole grain rye bread with lactic acid induced a significantly higher GP than RBB, WWB, white wheat- and whole grain rye porridge, respectively. A low insulin incremental peak was associated with less severe late post-prandial hypoglycaemia (r = 0.38, p < 0.001), and hypoglycaemia was negatively correlated to subjective satiety at 180 min (r = -0.28, p < 0.05). A low insulin incremental peak was also associated with a milder recovery of plasma ghrelin in the late post-prandial phase (180 min, r = 0.34, p < 0.01). Our study shows that endosperm and whole grain rye products induce low acute insulinaemic responses and improved glycaemic profiles. The results also suggest that the rye products possess beneficial appetite regulating properties. Further studies are needed to identify the unknown property or bioactive component(s) responsible for these beneficial metabolic features of rye.


Annexin II cell surface and mRNA expression in human acute myeloid leukaemia cell lines.
Acute promyelocytic leukaemia (APL) (M3) is associated with both a characteristic t(15;17) and severe bleeding diathesis caused by disseminated intravascular coagulation (DIC) and/or hyperfibrinolysis. It has been suggested that annexin II, a coreceptor for tissue plasminogen activator (t-PA) and plasminogen (PLG), is overexpressed on the surface of promyelocytes, leading to an increased fibrinolytic potential. This study examined the level of annexin II cell surface and mRNA expression in a range of acute myeloid leukaemia (AML) cell lines. The evidence that annexin II levels are higher in APL would lend support to the hypothesis that the bleeding disorder seen in APL is caused by hyperfibrinolysis. Cell surface annexin II was found to be expressed at higher levels on NB4 (promyelocytic) cells than on either KG1a (early myeloid) or HL60 (myelocytic) cells. However, even higher levels were found on U937 and MM6 (histo-monocytic) and HEL (erythroid) cells (p<0.01). MM6 cells showed a threefold increase in annexin II mRNA compared to any of the other cell lines. These findings do not fully support the concept of the coagulopathy associated with APL being caused by hyperfibrinolysis alone. Further investigations are required to identify the significance of annexin II expression and regulation in leukaemia.


Video deraining and desnowing using temporal correlation and low-rank matrix completion.
A novel algorithm to remove rain or snow streaks from a video sequence using temporal correlation and low-rank matrix completion is proposed in this paper. Based on the observation that rain streaks are too small and move too fast to affect the optical flow estimation between consecutive frames, we obtain an initial rain map by subtracting temporally warped frames from a current frame. Then, we decompose the initial rain map into basis vectors based on the sparse representation, and classify those basis vectors into rain streak ones and outliers with a support vector machine. We then refine the rain map by excluding the outliers. Finally, we remove the detected rain streaks by employing a low-rank matrix completion technique. Furthermore, we extend the proposed algorithm to stereo video deraining. Experimental results demonstrate that the proposed algorithm detects and removes rain or snow streaks efficiently, outperforming conventional algorithms.


Cost-effectiveness of a proportionate universal offer of free exercise: Leeds Let's Get Active.
The purpose of this paper is to assess the cost-effectiveness of a proportionate universal programme to reduce physical inactivity (Leeds Let us Get Active (LLGA)) in adults. A continuous-time Markov chain model was developed to assess the cost implications and QALY gains associated with increases in physical activity levels across the adult population. A parametric survival analysis approach was applied to estimate the decay of intervention effect over time. Baseline model data were obtained from previous economic models, population-based surveys and other published literature. A cost-utility analysis was conducted from a health care sector perspective over the programme duration (39 months). Scenario and probabilistic sensitivity analyses were performed to test the robustness of cost-effectiveness results. In total, 51 874 adult residents registered to the programme and provided baseline data,19.5% of which were living in deprived areas. Under base case assumptions, LLGA was found to be likely to be cost-effective. However, variations in key structural assumptions showed sensitivity of the results. Results from this study suggest a non-negligible level of uncertainty regarding the effectiveness, and therefore, cost-effectiveness of a universal offer of free leisure centre-based exercise that targets hard to reach groups. Further data collection and a shift towards prospective evaluations are needed.


Trends in task shifting in HIV treatment in Africa: Effectiveness, challenges and acceptability to the health professions.
Task shifting has been suggested to meet the demand for initiating and managing more patients on antiretroviral therapy. Although the idea of task shifting is not new, it acquires new relevance in the context of current healthcare delivery. To appraise current trends in task shifting related to HIV treatment programmes in order to evaluate evidence related to the effectiveness of this strategy in addressing human resource constraints and improving patient outcomes, challenges identified in practice and the acceptability of this strategy to the health professions. Electronic databases were searched for studies published in English between January 2009 and December 2014. Keywords such as 'task shifting', 'HIV treatment', 'human resources' and 'health professions' were used. Evidence suggests that task shifting is an effective strategy for addressing human resource constraints in healthcare systems in many countries and provides a cost-effective approach without compromising patient outcomes. Challenges include inadequate supervision support and mentoring, absent regulatory frameworks, a lack of general health system strengthening and the need for monitoring and evaluation. The strategy generally seems to be accepted by the health professions although several arguments against task shifting as a long-term approach have been raised. Task shifting occurs in many settings other than HIV treatment programmes and is viewed as a key strategy for governing human resources for healthcare. It may be an opportune time to review current task shifting recommendations to include a wider range of programmes and incorporate initiatives to address current challenges.


Trends in survival after stroke among Medicare beneficiaries.
Most strokes occur among people aged 65 years and older. The increasing proportion of persons who are in this age group underlines the importance for health-care providers to be aware of trends in poststroke survival. We investigated poststroke survival trends from 1985 to 1989 among Medicare beneficiaries. Medicare hospital claim records and enrollment data were obtained on 1 901 439 Medicare patients with a principal diagnosis of stroke occurring during the years 1985 through 1989. Cox proportional hazard techniques were used to compare the 2-year poststroke survival for strokes occurring in 1986, 1987, 1988, and 1989 relative to strokes occurring in 1985. Poststroke survival trends were examined among groups defined by age, race, region, type of stroke, and, for a 20% subset, history of stroke. We observed a modest improvement in poststroke survival from 1985 to 1989 (1989:1985 hazard ratio, 0.96; P < .05). Trends for persons with hemorrhagic stroke showed more improvement (hazard ratio, 0.88; P < .05) than those for persons with ischemic stroke (hazard ratio, 0.98; P < .05). Improvement was also greater among persons without known prior hospitalization for stroke (hazard ratio, 0.94; P < .05) and during periods of follow-up shorter than 2 years. The variations in poststroke survival among subgroups of the population have important implications for the quality of life of stroke survivors and for the future medical and nursing needs of these populations.


Risk equations to predict life expectancy of people with Type 2 diabetes mellitus following major complications: a study from Western Australia.
To develop a model for predicting life expectancy following major diabetes-related complications and to summarize these results by age and gender in the form of a simple table. Equations for forecasting mortality were derived using an observational cohort of 12,792 patients who had one of the following complications of diabetes: myocardial infarction, stroke, heart failure, amputation or renal failure, recorded in administrative health and mortality data from the state of Western Australia between 1990 and 1999. Logistic regression was used to estimate mortality within the first month post-event and a Gompertz proportional hazards model was used to estimate survival over the patients' remaining lifetime. After examining the internal validity over a 5-year period, these equations were used to estimate remaining life expectancy by age and sex following specific complications. Of the complications examined, renal failure had most impact on life expectancy at all ages, followed by heart failure; the best prognosis was following stroke, myocardial infarction and amputation. For a 60-year-old male, life expectancy immediately post-event ranged from 10.1 years (95% CI 9.4-10.8 years) for stroke to 4.3 years (95% CI 3.1-6.1 years) for renal failure. Life expectancies for women at 60 and 70 years of age were significantly lower than men following myocardial infarction and significantly higher than men following heart failure and amputation at 70 and 80 years of age. The model allows estimation of both survival probability and life expectancy post-event for men and women of any age. The summary table may provide a useful and simple reference for clinicians and diabetes specialists.


Cytosine arabinoside in addition to VCAA-based protocols for the treatment of canine lymphoma with bone marrow involvement: does it make the difference?
Cytosine arabinoside (ara-C) is a component of many protocols for the treatment of acute leukaemia and non-Hodgkin lymphomas in humans. The aim of the study was to prospectively evaluate the efficacy of ara-C in a myeloablative regimen in a cohort of canine lymphomas with bone marrow involvement. Seventeen dogs were enrolled. Eight were treated with a VCAA-based protocol (Group 1) and nine with the same regimen added with ara-C (Group 2). Ara-C was administered on a 5-day schedule as an i.v. continuous infusion at the dose of 150 mg m(-2) per day for five consecutive days. During treatment complete remission (CR) was achieved in two dogs in Group 1 and in eight dogs in Group 2. CR rate was significantly higher in Group 2 (P < 0.01). Median survival was 72.5 days (range 6-174) in Group 1 and 243 days (range 73-635) in Group 2. Survival was significantly longer in Group 2 (P < 0.001). Both protocols were well tolerated, with a low incidence of adverse events. Ara-C added to a VCAA-based protocol appears to be safe and beneficial in dogs with stage V lymphoma. Incorporation of the nucleoside analogue might be crucial for the development of future therapeutic strategies in dogs.


Nanoscale topography and chemistry affect embryonic stem cell self-renewal and early differentiation.
Adherent cells respond to a wide range of substrate cues, including chemistry, topography, hydrophobicity, and surface energy. The cell-substrate interface is therefore an important design parameter in regenerative medicine and tissue engineering applications, where substrate cues are used to influence cell behavior. Thin films comprising 4.5 nm (average diameter) gold nanoparticles coated with a mixture of two alkanethiols can confer hemispherical topography and specific chemistry to bulk substrates. The behavior of murine embryonic stem cells (ESCs) on the thin films can then be compared with their behavior on self-assembled monolayers of the same alkanethiols on vapor-deposited gold, which lack the topographical features. Cells cultured both with and without differentiation inhibitors are characterized by immunofluorescence for Oct4 and qPCR for Fgf5, Foxa2, Nanog, Pou5f1, and Sox2. Nanoscale chemistry and topography are found to influence stem cell differentiation, particularly the early differentiation markers, Fgf5 and Foxa2. Nanoscale topography also affects Oct4 localization, whereas the chemical composition of the substrate does not have an effect. It is demonstrated for the first time that ESCs can sense topographical features established by 4.5 nm particles, and these findings suggest that nanoscale chemistry and topography can act synergistically to influence stem cell differentiation. This study furthers the understanding of the effects of these substrate properties, improving our ability to design materials to control stem cell fate.


Fuzzy error diffusion.
Quantization errors are generally hidden by performing a dithering operation on the image. A common method is to utilize error diffusion. However, this method is prone to error accumulation, resulting in color impulses and streaks. This paper presents a new approach to error diffusion dithering through a fuzzy error diffusion algorithm. In this method, the amount of error to be diffused is determined by considering the relative location of the pixel not only to the closest codebook vector, but to all other palette entries. The goal is to hide the quantization errors by error diffusion, while preventing the excess accumulation of errors. This is achieved through an attraction-repulsion schema according to a fuzzy membership function. We also explored methods to speed up the fuzzy error diffusion process through a L-filter approach by determining a fixed set of membership values. We have implemented the fuzzy error diffusion algorithm for color images and achieved drastic improvements, resulting in superior quality dithered images and significantly lower mean squared error values. A different error measure modeling the characteristic of the human visual system also indicates the superiority of our method.


Realisation and optical engineering of linear variable bandpass filters in nanoporous anodic alumina photonic crystals.
We present the first realisation of linear variable bandpass filters in nanoporous anodic alumina (NAA-LVBPFs) photonic crystal structures. NAA gradient-index filters (NAA-GIFs) are produced by sinusoidal pulse anodisation and used as photonic crystal platforms to generate NAA-LVBPFs. The anodisation period of NAA-GIFs is modified from 650 to 850 s to systematically tune the characteristic photonic stopband of these photonic crystals across the UV-visible-NIR spectrum. Then, the nanoporous structure of NAA-GIFs is gradually widened along the surface under controlled conditions by wet chemical etching using a dip coating approach aiming to create NAA-LVBPFs with finely engineered optical properties. We demonstrate that the characteristic photonic stopband and the iridescent interferometric colour displayed by these photonic crystals can be tuned with precision across the surface of NAA-LVBPFs by adjusting the fabrication and etching conditions. Here, we envisage for the first time the combination of the anodisation period and etching conditions as a cost-competitive, facile, and versatile nanofabrication approach that enables the generation of a broad range of unique LVBPFs covering the spectral regions. These photonic crystal structures open new opportunities for multiple applications, including adaptive optics, hyperspectral imaging, fluorescence diagnostics, spectroscopy, and sensing.


Mass-dependent predation risk and lethal dolphin-porpoise interactions.
In small birds, mass-dependent predation risk (MDPR) is known to make the trade-off between avoiding starvation and avoiding predation dependent on individual mass. This occurs because carrying increased fat reserves not only reduces starvation risk but also results in a higher predation risk due to reduced escape flight performance and/or the increased foraging exposure needed to maintain a higher body mass. In principle, the theory of MDPR could also apply to any animal capable of storing energy reserves to reduce starvation and whose escape performance decreases with increasing mass. We used a unique situation along certain parts of coastal Britain, where harbour porpoises (Phocoena phocoena) are pursued and killed but crucially not eaten by bottlenose dolphins (Tursiops truncatus), to investigate whether a MDPR effect can occur in non-avian species. We show that where high levels of dolphin 'predation' occur, porpoises carry significantly less energy reserves than would otherwise be expected and this equates to reducing by approximately 37% the length of time that a porpoise could survive without feeding. These results provide the first evidence that a mass-dependent starvation-predation risk trade-off may be a general ecological principle that can apply to widely different animal types rather than, as is currently thought, only to birds.


Nutrition in early life and the risk of asthma and allergic disease.
The prevalence of reported cases of asthma and allergic disease has seen a marked increase throughout the world since the 1960s, particularly in more developed, westernised countries. A key focus of research in this area has been the possible adverse effects of foetal and infant exposure to food allergens. There is some evidence that foetal and infant exposure to a range of allergens via the mother and her breast milk is important in the development of normal immune tolerance. Current advice is that pregnant and breastfeeding women do not need to avoid potential food allergens unless they are allergic themselves, or are advised to modify their diet by a health professional. Delaying the introduction of common food allergies beyond 6 months is unlikely to reduce the likelihood of food allergy and allergic disease. The findings of current ongoing trials investigating the potential benefits of early introduction on allergenic foods into the diet of children-as well as the comprehensive review of complementary and young-child feeding advice currently being conducted by the Scientific Advisory Committee on Nutrition-will help inform guidance in this area.


Enzymatic hydrolysis of cellulose in a membrane bioreactor: assessment of operating conditions.
The optimization of operating conditions for cellulose hydrolysis was systemically undertaken using an ultra-scaled down membrane bioreactor based on the parameter scanning ultrafiltration apparatus. The bioconversion of cellulose saccharification was carried out with freely suspended cellulase from Aspergillus niger as the biocatalyst. The polyethersulfone ultrafiltration membranes with a molecular weight cutoff of 10 kDa were used to construct the enzymatic membrane bioreactor, with the membrane showing a complete retaining of cellulase and cellobiase. The influence of solution pH, temperature, salt (NaCl) concentration, presence of cellobiase, cellulose-to-enzyme ratio and stirring speed on reducing sugar production was examined. The results showed that the addition of an appropriate amount of NaCl or cellobiase had a positive effect on reducing sugar formation. Under the identified optimal conditions, cellulose hydrolysis in the enzymatic membrane bioreactor was tested for a long period of time up to 75 h, and both enzymes and operation conditions demonstrated good stability. Also, the activation energy (E(a)) of the enzymatic hydrolysis, with a value of 34.11 ± 1.03 kJ mol(-1), was estimated in this study. The operational and physicochemical conditions identified can help guide the design and operation of enzymatic membrane bioreactors at the industrial scale for cellulose hydrolysis.


Methyl α-l-rhamnosyl-(1→2)[α-l-rhamnosyl-(1→3)]-α-l-rhamnoside penta-hydrate: synchrotron study.
The title hydrate, C(19)H(34)O(13)·5H(2)O, contains a vicinally disubstituted tris-accharide in which the two terminal rhamnosyl sugar groups are positioned adjacent to each other. The conformation of the tris-accharide is described by the glycosidic torsion angles ϕ2 = 48 (1)°, ψ2 = -29 (1)°, ϕ3 = 44 (1)° and ψ3 = 4 (1)°, whereas the ψ2 torsion angle represents a conformation from the major state in solution, the ψ3 torsion angle conformation may have been caught near a potential energy saddle-point when compared to its solution structure, in which at least two but probably three conformational states are populated. Extensive inter-molecular O-H⋯O hydrogen bonding is present in the crystal and a water-containing channel is formed along the b-axis direction.


Receptor tyrosine kinase-like orphan receptor 2 (Ror2) expression creates a poised state of Wnt signaling in renal cancer.
Expression of the receptor tyrosine kinase-like orphan receptor 2 (Ror2) has been identified in an increasing array of tumor types and is known to play a role as an important mediator of Wnt signaling cascades. In this study, we aimed to clarify Ror2 interactions with the Wnt pathways within the context of renal cell carcinoma (RCC). An examination of Ror2 expression in primary human RCC tumors showed a significant correlation with several Wnt signaling genes, including the classical feedback target gene Axin2. We provide evidence that Ror2 expression results in a partially activated state for canonical Wnt signaling through an increased signaling pool of β-catenin, leading to an enhancement of downstream target genes following Wnt3a stimulation in both renal and renal carcinoma-derived cells. Additionally, inhibition of low-density lipoprotein receptor-related protein 6 (LRP6) with either siRNA or dickkopf decreased the response to Wnt3a stimulation, but no change was seen in the increased β-catenin pool associated with Ror2 expression, suggesting that LRP6 cofactor recruitment is necessary for a Wnt3a-induced signal but that it does not participate in the Ror2 effect on β-catenin signaling. These results highlight a new role for Ror2 in conveying a tonic signal to stabilize soluble β-catenin and create a poised state of enhanced responsiveness to Wnt3a exogenous signals in RCC.


Flavisolibacter nicotianae sp. nov., isolated from rhizosphere soil of Nicotiana tabacum L.
A Gram-stain-negative, aerobic, non-motile and rod-shaped bacterium, designated strain X7XT, was isolated from a rhizosphere soil sample of Nicotiana tabacum L. collected from a tobacco factory located in Kunming, south-western China. The cells showed oxidase-positive and catalase-positive reactions. Growth occurred at 20-40 °C and pH 6.0-8.0, with optimal growth at 30 °C and pH 7.0. The predominant respiratory quinone was MK-7. The major fatty acids were identified as iso-C15 : 0, iso-C17 : 0 3OH and summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c). The cellular polar lipids contained phosphatidylethanolamine, an unidentified aminophospholipid, two unidentified glycolipids, four unidentified aminolipids and four unidentified lipids. The genomic DNA G+C content was 49.7 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain X7XT should be affiliated to the genus Flavisolibacter. Results from further analysis showed that strain X7XT had highest 16S rRNA gene sequence similarity to Flavisolibacter metallilatus TX0661T (96.4 %) and 'Flavisolibacter swuensis' SR2-4-2T (96.4 %), followed by other species of the genus Flavisolibacter. The polyphasic taxonomic characteristics indicated that strain X7XT represents a novel species of the genus Flavisolibacter, for which the name Flavisolibacternicotianae sp. nov. (type strain X7XT=KCTC 62326T=CGMCC 16451T) is proposed.


Assessment of treatment response in chronic constipation clinical trials.
While chronic constipation (CC) clinical trials have focused primarily on bowel symptoms (symptoms directly related to bowel movements), abdominal symptoms are also prevalent among patients. The United States Food and Drug Administration's (FDA's) guidance on the use of patient-reported outcome measures to support product approvals or labeling claims recommends that endpoints be developed with direct patient input and include all symptoms important to patients. To identify a comprehensive set of CC symptoms that are important to patients for measurement in clinical trials. Following a targeted literature review to identify CC symptoms previously reported by patients, 28 patient interviews were conducted consistent with the FDA's guidance on patient-reported outcomes. Subsequent to open-ended questions eliciting descriptions of all symptoms, rating and ranking methods were used to identify those of greatest importance to patients. All 67 studies reviewed included bowel symptoms; more than half also addressed at least one abdominal symptom. Interview participants reported 62 potentially distinct concepts: 12 bowel symptoms; 21 abdominal symptoms; and 29 additional symptoms/impacts. Patients' descriptions revealed that many symptom terms were highly related and/or could be considered secondary to CC. The rating and ranking task results suggest that both bowel (for example, stool frequency and consistency) and abdominal symptoms (for example, bloating, abdominal pain) comprise patients' most important symptoms. Further, improvements in both bowel and abdominal symptoms would constitute an improvement in patients' CC overall. Abdominal symptoms in CC patients are equal in relevance to bowel symptoms and should also be addressed in clinical trials to fully evaluate treatment benefit.


Review: the use of sodium hypochlorite in endodontics--potential complications and their management.
Aqueous sodium hypochlorite (bleach) solution is widely used in dental practice during root canal treatment. Although it is generally regarded as being very safe, potentially severe complications can occur when it comes into contact with soft tissue. This paper discusses the use of sodium hypochlorite in dental treatment, reviews the current literature regarding hypochlorite complications, and considers the appropriate management for a dental practitioner when faced with a potentially adverse incident with this agent.


Determining in vivo sternoclavicular, acromioclavicular and glenohumeral joint centre locations from skin markers, CT-scans and intracortical pins: A comparison study.
To describe shoulder motion the sternoclavicular, acromioclavicular and glenohumeral joint centres must be accurately located. Within the literature various methods to estimate joint centres of rotation location are proposed, with no agreement of the method best suited to the shoulder. The objective of this study was to determine the most reliable non-invasive method for locating joint centre locations of the shoulder complex. Functional methods using pin mounted markers were compared to anatomical methods, functional methods using skin mounted markers, imaging-based methods using CT-scan data, and regression equations. Three participants took part in the study, that involved insertion of intracortical pins into the clavicle, scapula and humerus, a CT-scan of the shoulder, and finally data collection using a motion analysis system. The various methods to estimate joint centre location did not all agree, however suggestions about the most reliable non-invasive methods could be made. For the sternoclavicular joint, the authors suggest the anatomical method using the most ventral landmark on the sternoclavicular joint, as recommended by the International Society of Biomechanics. For the acromioclavicular joint, the authors suggest the anatomical method using the landmark defined as the most dorsal point on the acromioclavicular joint, as proposed by van der Helm. For the glenohumeral joint, the simple regression equation of Rab is recommended.


Multisensory spatial attention deficits are predictive of phonological decoding skills in developmental dyslexia.
Although the dominant approach posits that developmental dyslexia arises from deficits in systems that are exclusively linguistic in nature (i.e., phonological deficit theory), dyslexics show a variety of lower level deficits in sensory and attentional processing. Although their link to the reading disorder remains contentious, recent empirical and computational studies suggest that spatial attention plays an important role in phonological decoding. The present behavioral study investigated exogenous spatial attention in dyslexic children and matched controls by measuring RTs to visual and auditory stimuli in cued-detection tasks. Dyslexics with poor nonword decoding accuracy showed a slower time course of visual and auditory (multisensory) spatial attention compared with both chronological age and reading level controls as well as compared with dyslexics with slow but accurate nonword decoding. Individual differences in the time course of multisensory spatial attention accounted for 31% of unique variance in the nonword reading performance of the entire dyslexic sample after controlling for age, IQ, and phonological skills. The present study suggests that multisensory "sluggish attention shifting"-related to a temporoparietal dysfunction-selectively impairs the sublexical mechanisms that are critical for reading development. These findings may offer a new approach for early identification and remediation of developmental dyslexia.


Attitudes towards child restrains and seat belts usage in the learned population of Karachi, Pakistan.
Motor vehicles crashes (MVCs) are the leading cause of injury related morbidity and mortality in developed countries. Recent evidence proves that properly used child seat belts can dramatically reduce the risk of severe and life-threatening injury from MVCs. There are rarities of thought and inspiration regarding the use of child seat belts in our society and region, therefore we lack of data regarding factors and paucity of usage of child seat belts in motor vehicles. This study aimed to assess the knowledge and attitudes of child seat belt usage among the educated population in Karachi, Pakistan. Altogether 304 employees were investigated. They were employees of Aga Khan University who were using their cars and having children younger than 10 years old. A cross sectional observational study was designed, and a 36-item questionnaire in English was used to collect data on participants' demographic details, designation, educational level, economic status, validity of driving license, number of children and cars, availability of adult seat belts and child seat belts along with their functionality, awareness, knowledge and attitude toward its use, and reason of not using these devices. SPSS version 20 for Windows was used to analyze the data and the Chi-square test was used. Totally 290 participants were recruited with a response rate of 72% (212). Of 212 participants, 126 (59%) were male. 154 (72.6%) participants had valid driver licenses, and 154 (72.6%) had adult seat belts in their vehicles. Only 32 (15%) reported regular use of adult seat belts. Although 168 (79.2%) participants had some knowledge about child restrains (CRs), only 65 (22%) had CRs in their cars. Eighty-two (38.7%) participants got the knowledge about CRs and seat belts from media. Mothers were more concerned about the use of CRs than fathers. Only 14 (6.6%) parents were found to use both adult and child seat belts all the time. Of the 157 parents who did not us use CRs, 42 considered unnecessary, 35 lacked relevant knowledge. But 15 parents used CR against their children's wills. The pattern of CR usage among the employees at Aga Khan University, Karachi is dictated by the unavailability of CR, followed by ignorance, inconvenience, and non-acceptance by their children. The important issue of CR has consistently been ignored over the years and it has never gained enough popularity in Pakistan.


Multiple global change stressor effects on phytoplankton nutrient acquisition in a future ocean.
Predicting the effects of multiple global change stressors on microbial communities remains a challenge because of the complex interactions among those factors. Here, we explore the combined effects of major global change stressors on nutrient acquisition traits in marine phytoplankton. Nutrient limitation constrains phytoplankton production in large parts of the present-day oceans, and is expected to increase owing to climate change, potentially favouring small phytoplankton that are better adapted to oligotrophic conditions. However, other stressors, such as elevated pCO2, rising temperatures and higher light levels, may reduce general metabolic and photosynthetic costs, allowing the reallocation of energy to the acquisition of increasingly limiting nutrients. We propose that this energy reallocation in response to major global change stressors may be more effective in large-celled phytoplankton species and, thus, could indirectly benefit large-more than small-celled phytoplankton, offsetting, at least partially, competitive disadvantages of large cells in a future ocean. Thus, considering the size-dependent responses to multiple stressors may provide a more nuanced understanding of how different microbial groups would fare in the future climate and what effects that would have on ecosystem functioning. This article is part of the theme issue 'Conceptual challenges in microbial community ecology'.


Treatment with exenatide once weekly or twice daily for 30 weeks is associated with changes in several cardiovascular risk markers.
Cyslipidemia and type 2 diabetes are two of the most significant risk factors for the development of cardiovascular disease. Measurement of lipoprotein subclasses provides important information about derangements in lipid metabolism and helps refine cardiovascular risk assessment. Exenatide, a glucagon-like peptide 1 receptor agonist, improved glycemic control, obesity, hypertension, and dyslipidemia in patients with type 2 diabetes in clinical trials. In the DURATION-1 trial, patients with type 2 diabetes were treated with exenatide once weekly or twice daily for 30 weeks. This post hoc analysis evaluated the impact of exenatide on lipoprotein subclasses in 211 DURATION-1 patients using vertical auto profile methodology and the Statistical Package for the Social Sciences general linear model adjusted for glycosylated hemoglobin (HbA(1c)) and weight. Baseline lipids and high sensitivity C-reactive protein were normal overall based on the standard lipid panel. Once-weekly exenatide reduced apolipoprotein B and the apolipoprotein B to apolipoprotein A1 ratio (P < 0.05), independent of glycemic improvement and weight loss. A significant shift in lipoprotein pattern away from small, dense low-density lipoprotein-4 cholesterol was also observed (P < 0.05). Exenatide once weekly increased high-density lipoprotein-2 cholesterol, even after adjustment for changes in HbA(1c) and weight (P < 0.05). Triglycerides, very low-density lipoprotein cholesterol, and high sensitivity C-reactive protein were reduced with both the once-weekly and twice-daily exenatide regimens (P < 0.05). In this post hoc analysis, exenatide significantly improved a number of cardiovascular risk markers. Continuous exenatide exposure with exenatide once weekly elicited a greater response than did immediate-release exenatide twice daily, generally independent of glycemic improvement and weight loss. Thus, in addition to improving glycemic control, exenatide induced favorable changes in lipid and lipoprotein metabolism and decreased systemic inflammation.


Methods of suicide: international suicide patterns derived from the WHO mortality database.
Accurate information about preferred suicide methods is important for devising strategies and programmes for suicide prevention. Our knowledge of the methods used and their variation across countries and world regions is still limited. The aim of this study was to provide the first comprehensive overview of international patterns of suicide methods. Data encoded according to the International Classification of Diseases (10th revision) were derived from the WHO mortality database. The classification was used to differentiate suicide methods. Correspondence analysis was used to identify typical patterns of suicide methods in different countries by providing a summary of cross-tabulated data. Poisoning by pesticide was common in many Asian countries and in Latin America; poisoning by drugs was common in both Nordic countries and the United Kingdom. Hanging was the preferred method of suicide in eastern Europe, as was firearm suicide in the United States and jumping from a high place in cities and urban societies such as Hong Kong Special Administrative Region, China. Correspondence analysis demonstrated a polarization between pesticide suicide and firearm suicide at the expense of traditional methods, such as hanging and jumping from a high place, which lay in between. This analysis showed that pesticide suicide and firearm suicide replaced traditional methods in many countries. The observed suicide pattern depended upon the availability of the methods used, in particular the availability of technical means. The present evidence indicates that restricting access to the means of suicide is more urgent and more technically feasible than ever.


Metabolomic studies of radiation-induced apoptosis of human leukocytes by capillary electrophoresis-mass spectrometry and flow cytometry: adaptive cellular responses to ionizing radiation.
There is growing interest in the development of new methods for elucidating the biological effects of low-dose exposure to ionizing radiation (IR) on human health. Herein, we introduce a strategy for assessment of the impact of radiation-induced oxidative stress on the intra-cellular metabolism of human leukocytes. Untargeted metabolomic analyses were performed by CE-ESI-MS on irradiated leukocytes exposed to increasing doses of -radiation emitted from a Taylor source, which were subsequently incubated for 44 h to allow for cellular recovery. Flow cytometry with dual fluorescence staining revealed a major shift from early- to late-stage apoptosis associated with cell membrane permeability changes as radiation dosage was increased relative to the control, but with a significant attenuation measured at intermediate dose levels. CE-ESI-MS analysis of filtered white blood cell lysates was also performed to quantify changes associated with 22 intra-cellular metabolites, which were consistently measured in leukocytes across all radiation levels. Preliminary experiments demonstrated that there was an overall depletion in metabolites with extended exposure to IR; however, there was a non-linear upregulation of specific metabolites at the 4 Gy level relative to pre-irradiated levels, notably for arginine, glutamine, creatine, proline and reduced glutathione. Our studies demonstrate that leukocytes require a minimum threshold level of IR to induce a cytoprotective response in metabolism associated with antioxidant defense, energy homeostasis and cell signaling, which is relevant to improved understanding of the mechanisms of oxidative stress in radiobiology and cancer therapy.


High efficacy of combined rituximab and gemcitabine on Epstein-Barr virus-associated human B-cell lymphoma obtained after Hodgkin's xenograft in immunodeficient mice.
The objectives were to characterize an Epstein-Barr virus-associated human B-cell lymphoma obtained from Hodgkin's xenograft, and to evaluate the in-vivo combination of rituximab and/or gemcitabine. A lymph node biopsy sample from a patient with Hodgkin's disease was xenografted into Rag gamma(c)(-/-) mice. Immunohistochemical, cytogenetic and genetic analyses were performed on both the human biopsy and xenografted tumor from severe combined immunodeficient mice. Tumor-bearing mice were then treated with rituximab and/or gemcitabine. Histologic features of the patient's biopsy concluded on classical CD15/CD30-positive Hodgkin's disease without expression of Epstein-Barr virus proteins. In contrast, morphologic and immunophenotypic examination of the xenograft showed diffuse proliferation of large B cells with high Epstein-Barr virus protein expression. Comparative genomic hybridization showed a normal pattern in the first case and a gain of chromosomal 12 in the xenografted tumor. Finally, polymerase chain reaction detected an immunoglobulin heavy chain rearrangement in the xenografted tumor. Altogether, these results indicate that the xenograft grew from the patient's Epstein-Barr virus-infected B-lymphoid cells and could be assimilated to posttransplant lymphoproliferative disease. In-vivo treatments of xenografted tumors showed significant tumor growth inhibition induced either by rituximab or gemcitabine alone and an impressive efficacy of combined treatment. This result therefore indicates that combined rituximab and gemcitabine could be an alternative approach in patients with posttransplant lymphoproliferative disease.


Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors.
Selective serotonin reuptake inhibitors (SSRIs), in addition to their antidepressant effects, have been reported to have antiinflammatory effects. The aim of this study was to assess the antiarthritic potential of 2 SSRIs, fluoxetine and citalopram, in murine collagen-induced arthritis (CIA) and in a human ex vivo disease model of rheumatoid arthritis (RA). Following therapeutic administration of SSRIs, paw swelling was assessed and clinical scores were determined daily in DBA/1 mice with CIA. Joint architecture was examined histologically at the end of the treatment period. Cultures of human RA synovial membranes were treated with SSRIs, and cytokine production was measured. Toll-like receptor (TLR) function was examined in murine and human macrophages, human B cells, and human fibroblast-like synovial cells treated with SSRIs. Both SSRIs significantly inhibited disease progression in mice with CIA, with fluoxetine showing the greatest degree of efficacy at the clinical and histologic levels. In addition, both drugs significantly inhibited the spontaneous production of tumor necrosis factor, interleukin-6, and interferon-gamma-inducible protein 10 in human RA synovial membrane cultures. Fluoxetine and citalopram treatment also inhibited the signaling of TLRs 3, 7, 8, and 9, providing a potential mechanism for their antiinflammatory action. Fluoxetine and citalopram treatment selectively inhibit endosomal TLR signaling, ameliorate disease in CIA, and suppress inflammatory cytokine production in human RA tissue. These data highlight the antiarthritic potential of the SSRI drug family and provide further evidence of the involvement of TLRs in the pathogenesis of RA. The SSRIs may provide a template for potential antiarthritic drug development.


Multiple growth periods predict unfavourable pathology in patients with small renal masses.
To use the number of positive growth periods as a characterization of the growth of small renal masses in order to determine potential predictors of malignancy. Patients who underwent axial imaging at multiple time points prior to surgical resection for a small renal mass were queried. Patients were categorized based on their pathological tumour grade and stage: favourable (benign, chromophobe and low-grade pT1-2 renal cell carcinoma [RCC]) vs unfavourable (high-grade of any stage and low-grade pT3-4 RCC). A positive growth period was counted each time the difference in greatest tumour diameters between two images was positive. The Cochran-Armitage trend test and Somers' D association were used to determine if the number of positive growth periods was correlated with unfavourable pathology. Of the 124 patients, 86 (69.4%) had favourable pathology and 38 (30.6%) had unfavourable pathology. Those who had favourable pathology were younger than those who had unfavourable pathology: median (interquartile range [IQR]) 61.0 (52.2-66.0) vs 68.5 (61.5-77.0); P < 0.001. The overall growth rate was higher in the unfavourable group, but was not statistically significant: mean (sd) 0.7 (1.7) vs 1.6 (2.8) cm/year; P = 0.07. There was a significant trend difference in the number of positive growth periods between favourability groups (P = 0.02). An association between increased number of positive growth periods and unfavourable pathology was observed: 0.15 (95% confidence interval 0.02, 0.29). The ratios of favourable to unfavourable pathology were 1.8, 1.0, 0.66, 0.59 and 0 as the number of positive growth periods increased from 0 to 4, respectively. While overall growth rate was not predictive of pathology favourability, there was a positive association between the number of positive growth periods and unfavourable pathology. The number of positive growth periods may be a potential parameter for malignant potential in patients undergoing active surveillance for small renal masses.


The CD44+/CD24- phenotype is enriched in basal-like breast tumors.
Human breast tumors are heterogeneous and consist of phenotypically diverse cells. Breast cancer cells with a CD44+/CD24- phenotype have been suggested to have tumor-initiating properties with stem cell-like and invasive features, although it is unclear whether their presence within a tumor has clinical implications. There is also a large heterogeneity between tumors, illustrated by reproducible stratification into various subtypes based on gene expression profiles or histopathological features. We have explored the prevalence of cells with different CD44/CD24 phenotypes within breast cancer subtypes. Double-staining immunohistochemistry was used to quantify CD44 and CD24 expression in 240 human breast tumors for which information on other tumor markers and clinical characteristics was available. Gene expression data were also accessible for a cohort of the material. A considerable heterogeneity in CD44 and CD24 expression was seen both between and within tumors. A complete lack of both proteins was evident in 35% of the tumors, while 13% contained cells of more than one of the CD44+/CD24-, CD44-/CD24+ and CD44+/CD24+ phenotypes. CD44+/CD24- cells were detected in 31% of the tumors, ranging in proportion from only a few to close to 100% of tumor cells. The CD44+/CD24- phenotype was most common in the basal-like subgroup--characterized as negative for the estrogen and progesterone receptors as well as for HER2, and as positive for cytokeratin 5/14 and/or epidermal growth factor receptor, and particularly common in BRCA1 hereditary tumors, of which 94% contained CD44+/CD24- cells. The CD44+/CD24- phenotype was surprisingly scarce in HER2+ tumors, which had a predominantly CD24+ status. A CD44+/CD24- gene expression signature was generated, which included CD44 and alpha6-integrin (CD49f) among the top-ranked overexpressed genes. We demonstrate an association between basal-like and particularly BRCA1 hereditary breast cancer and the presence of CD44+/CD24- cells. Not all basal-like tumors and very few HER2+ tumors, however, contain CD44+/CD24- cells, emphasizing that a putative tumorigenic ability may not be confined to cells of this phenotype and that other breast cancer stem cell markers remain to be identified.


Comparative Safety of Testosterone Dosage Forms.
Increases in testosterone use and mixed reports of adverse events have raised concerns about the cardiovascular safety of testosterone. Testosterone is available in several delivery mechanisms with varying pharmacokinetics; injections cause spikes in testosterone levels, and transdermal patches and gels cause more subtle but sustained increases. The comparative cardiovascular safety of gels, injections, and patches has not been studied. To determine the comparative cardiovascular safety of testosterone injections, patches, and gels. A retrospective cohort study was conducted using administrative claims from a commercially insured (January 1, 2000, to December 31, 2012) and Medicare (January 1, 2007, to December 31, 2010) population in the United States and general practitioner records from the United Kingdom (January 1, 2000, to June 30, 2012). Participants included men (aged ≥18 years) who initiated use of testosterone patches, gels, or injections following 180 days with no testosterone use. Our analysis was conducted from December 11, 2013, to November 12, 2014. New initiation of a testosterone dosage form, with use monitored for up to 1 year. Inpatient or outpatient medical records, diagnoses, or claims for cardiovascular and cerebrovascular events including myocardial infarction (MI), unstable angina, stroke, and composite acute event (MI, unstable angina, or stroke); venous thromboembolism (VTE); mortality; and all-cause hospitalization. We identified 544,115 testosterone initiators between the 3 data sets: 37.4% injection, 6.9% patch, and 55.8% gel. The majority of men in the Medicare cohort were injection initiators (51.2%), most in the US commercially insured population were gel initiators (56.5%), and the UK database included equal proportions of injections and gel users (approximately 41%). With analysis conducted using hazard ratios and 95% CIs, compared with men using gels, injection initiators had higher hazards of cardiovascular events (ie, MI, unstable angina, and stroke) (1.26; 1.18-1.35), hospitalization (1.16; 1.13-1.19), and death (1.34; 1.15-1.56) but not VTE (0.92; 0.76-1.11). Compared with gels, patches did not confer increased hazards of cardiovascular events (1.10; 0.94-1.29), hospitalization (1.04; 1.00-1.08), death (1.02; 0.77-1.33), or VTE (1.08; 0.79-1.47). Testosterone injections were associated with a greater risk of cardiovascular events, hospitalizations, and deaths compared with gels. Patches and gels had similar risk profiles. However, this study did not assess whether patients met criteria for use of testosterone and did not assess the safety of testosterone among users compared with nonusers of the drug.


Seroprevalence and Risk Factors of Brucellosis in Ruminants in Dhofar Province in Southern Oman.
The aim of the present work was to raise awareness of Brucella infection and emphasize the use of serological tests for screening and confirmation of the presence of the infection in different localities in the Dhofar region in the Sultanate of Oman. A seroprevalence of Brucella infection in naturally infected livestock was undertaken in 50 farms (a total of 434 sera, 207 goats, 84 sheep, 54 cattle, and 89 camels) from different wilayat of the Dhofar region in the southern part of Oman. Rose Bengal (RBT), complement fixation (CFT), and indirect enzyme-linked immunosorbent assay (I-ELISA) tests were used to determine the presence of Brucella antibodies. Statistical analysis (Pearson chi-square, binary logistic regression, and univariate logistic regression) was used to investigate the significance between the prevalence and the categorical risk factors individually, with two or more levels (animal species, animal condition, and or location). Our results show that the overall seroprevalence based on CFT, RBT, and I-ELISA was 3% (13/424, CI: 1.8-5.1%), 4.8% (21/434, CI: 3.1-7.3%), and 8% (35/434, CI: 5.8-10.9%), respectively. The highest seroprevalence was reported in goats (13% (27/207)) and animals from East Jabal (13% (21/161)), whereas the lowest was recorded in camels (3.4% (3/89)) and animals from deserts (1.4% (1/69)). Parameters such as the positive predictive value (PPV) and the negative predictive value (NPV) showed that the sensitivity of I-ELISA and CFT based on the RBT test was 61.9% and 57.1%, respectively, whereas the specificity of I-ELISA (94.6%) was less than that of CFT (97.33%). We concluded that three tests are confirmatory for the presence of Brucella infection.


Understanding quantitative genetics in the systems biology era.
Biology is now entering the new era of systems biology and exerting a growing influence on the future development of various disciplines within life sciences. In early classical and molecular periods of Biology, the theoretical frames of classical and molecular quantitative genetics have been systematically established, respectively. With the new advent of systems biology, there is occurring a paradigm shift in the field of quantitative genetics. Where and how the quantitative genetics would develop after having undergone its classical and molecular periods? This is a difficult question to answer exactly. In this perspective article, the major effort was made to discuss the possible development of quantitative genetics in the systems biology era, and for which there is a high potentiality to develop towards "systems quantitative genetics". In our opinion, the systems quantitative genetics can be defined as a new discipline to address the generalized genetic laws of bioalleles controlling the heritable phenotypes of complex traits following a new dynamic network model. Other issues from quantitative genetic perspective relating to the genetical genomics, the updates of network model, and the future research prospects were also discussed.


Management and outcomes of pituitary apoplexy.
This study was undertaken to analyze the predisposing factors, clinical presentation, therapeutic management, and clinical recovery in patients with pituitary apoplexy, with an emphasis on the long-term visual, endocrine, and functional outcomes. The authors performed a retrospective analysis of consecutive cases involving patients treated at Mayo Clinic between 1992 and 2013. Patients were included in the study only if they had 1) abrupt onset of severe headache or visual disturbance in the presence of a pituitary adenoma and 2) radiological or surgical confirmation of a pituitary mass. The primary endpoints of analysis were the visual (ocular motility, visual fields, and visual acuity), endocrine, and functional outcomes (using the modified Rankin Scale). Eighty-seven patients were identified (57 males and 30 females, mean age 50.9 years, range 15-91 years). Twenty-two patients (25.3%) had a known pituitary adenoma. Hypertension was the most common associated factor (39%). Headache was the most frequent presenting symptom (89.7%), followed by visual abnormalities (47.1%). Cranial nerve palsies were present in 39% and visual field defects in 34.1%. MRI detected hemorrhage in 89% patients, as compared with 42% detected by CT scan. Sixty-one patients (70.1%) underwent surgery during acute hospitalization (median time from apoplexy 5 days, IQR 3-10 days), 8 (9.2%) had delayed surgery, and 18 (20.7%) were treated conservatively. Histopathological examination revealed adenoma with pure necrosis in 18 (30%), pure hemorrhage in 4 (6.7%), and both in 6 (10%) patients. Four patients died during hospitalization. The average duration of follow-up was 44.2 ± 43.8 months. All survivors were independent and had complete resolution or substantial improvement in eye movements and visual fields at the last follow-up. Many patients needed long-term hormonal replacement with levothyroxine (62.7%) and cortisol (60%). Daily desmopressin was needed in 23% of all surgical patients at 3 months (versus none of the medically treated) and this requirement decreased slightly over time. Regrowth of pituitary adenoma was seen in 7 patients (8.6%). There were no statistically significant differences in any of the outcome measures across the treatment groups. The outcome of most patients with pituitary apoplexy is excellent. Selected patients can be managed conservatively, and patients with severe neuro-ophthalmological deficits treated with early surgery can achieve an excellent recovery.


Cryopreserved deglycerolized blood is safe and achieves superior tissue oxygenation compared with refrigerated red blood cells: a prospective randomized pilot study.
During preservation, donated liquid red blood cells (RBCs) experience multiple functional and structural changes known as the storage lesion. Increased RBC age is associated with increased infection rates, organ failure, and mortality. This prospective, randomized, double-blinded pilot study enrolled stable trauma patients who required RBC transfusion. Patients were randomly assigned to receive standard or cryopreserved RBCs. Continuous tissue oxygenation (StO2) monitoring was performed during the peritransfusion period. Hematocrit and thrombelastography before and after transfusion were evaluated. Patients were monitored for transfusion reactions and clinical outcomes. Fifty-seven patients were randomized, and groups were well matched for demographics and Injury Severity Score (ISS). No statistically significant differences were noted in hematocrit change, thrombelastography parameters, transfusion reactions, or clinical outcomes. StO2 was found to be higher in the cryopreserved group. Cryopreserved RBCs are equally safe and efficacious to refrigerated RBCs. This storage technique extends the life span of RBCs to 10 years, potentially preserving a precious resource and preventing the storage lesion. StO2 was superior in patients receiving cryopreserved RBCs. This finding has the potential to drive a paradigm shift in transfusion practices. Therapeutic study, level II.


Is There Room for SERMs or SARMs as Alternative Therapies for Adult Male Hypogonadism?
Hypogonadotropic hypogonadism (HH) can be sustained by organic or functional alterations of the hypothalamic-pituitary-testicular axis. Functional HH is related to systemic alterations, such as obesity or chronic inflammatory diseases, but could contribute to a negative course of the illness. For such situation, according to results obtained in infertile women, the administration of selective estrogen receptor modulators (SERMs) has been proposed in males too, with positive results on both metabolic and sexual function. This class of medications increases gonadotropin levels via antagonism to the estrogenic receptor; similar biological effects are also exerted by aromatase inhibitors (AIs), despite different mechanism of action. After a brief review of trials regarding SERMs and AIs use in male HH, we describe the structure and function of the androgen receptor (AR) as a basis for clinical research about compounds able to bind to AR, in order to obtain specific effects (SARMs). The tissue selectivity and different metabolic fate in comparison to testosterone can potentiate anabolic versus androgenic effects; therefore, they might be a valid alternative to testosterone replacement therapy avoiding the negative effects of testosterone (i.e., on prostate, liver, and hematopoiesis). Trials are still at an early phase of investigation and, at the moment, the application seems to be more useful for chronic disease with catabolic status while the validation as replacement for hypogonadism requires further studies.


Chronic inflammation alters production and release of glutathione and related thiols in human U373 astroglial cells.
Neurons rely on glutathione (GSH) and its degradation product cysteinylglycine released by astrocytes to maintain their antioxidant defences. This is particularly important under conditions of inflammation and oxidative stress, as observed in many neurodegenerative diseases including Alzheimer's disease (AD). The effects of inflammatory activation on intracellular GSH content and the extracellular thiol profile (including cysteinylglycine and homocysteine) of astrocytes were investigated. U373 astroglial cells exposed to IL-1β and TNF-α for up to 96 h showed a dose-dependent increase in IL-6 release, indicative of increasing pro-inflammatory cellular activation. With increasing concentrations of IL-1β and TNF-α (0.01-1 ng/ml), an increase in both intracellular and extracellular GSH levels was observed, followed by a return to control levels in response to higher concentrations of IL-1β and TNF-α. Extracellular levels of cysteinylglycine decreased in response to all concentrations of IL-1β and TNF-α. In contrast, levels of the neurotoxic thiol homocysteine increased in a dose-dependent manner to IL-1β and TNF-α-induced activation. Our results suggest that chronically activated astrocytes in the brain might fail to adequately maintain GSH substrate delivery to neurons, thus promoting neuronal vulnerability. They might also explain the elevated levels of homocysteine found in the brains and serum of patients with AD.


Stress effects on working memory, explicit memory, and implicit memory for neutral and emotional stimuli in healthy men.
Stress is a strong modulator of memory function. However, memory is not a unitary process and stress seems to exert different effects depending on the memory type under study. Here, we explored the impact of social stress on different aspects of human memory, including tests for explicit memory and working memory (for neutral materials), as well as implicit memory (perceptual priming, contextual priming and classical conditioning for emotional stimuli). A total of 35 young adult male students were randomly assigned to either the stress or the control group, with stress being induced by the Trier Social Stress Test (TSST). Salivary cortisol levels were assessed repeatedly throughout the experiment to validate stress effects. The results support previous evidence indicating complex effects of stress on different types of memory: A pronounced working memory deficit was associated with exposure to stress. No performance differences between groups of stressed and unstressed subjects were observed in verbal explicit memory (but note that learning and recall took place within 1 h and immediately following stress) or in implicit memory for neutral stimuli. Stress enhanced classical conditioning for negative but not positive stimuli. In addition, stress improved spatial explicit memory. These results reinforce the view that acute stress can be highly disruptive for working memory processing. They provide new evidence for the facilitating effects of stress on implicit memory for negative emotional materials. Our findings are discussed with respect to their potential relevance for psychiatric disorders, such as post traumatic stress disorder.


Common mental disorders and mortality in the West of Scotland Twenty-07 Study: comparing the General Health Questionnaire and the Hospital Anxiety and Depression Scale.
While various measures of common mental disorders (CMD) have been found to be associated with mortality, a comparison of how different measures predict mortality may improve our understanding of the association. This paper compares how the Hospital Anxiety and Depression Scale (HADS) and the 30-item General Health Questionnaire (GHQ-30) predict all cause and cause-specific mortality. Data on 2547 men and women from two cohorts, aged approximately 39 and 55 years, from the West of Scotland Twenty-07 Study who were followed up for mortality over an average of 18.9 (SD 5.0) years. Scores were calculated for HADS depression (HADS-D), HADS Anxiety (HADS-A) and GHQ-30. Cox Proportional Hazards Models were used to determine how each CMD measure predicted mortality. After adjusting for serious physical illness, smoking, social class, alcohol, obesity, pulse rate and living alone, HRs (95% CI) per SD increase in score for all-cause mortality were: 1.15 (1.07 to 1.25) for HADS-D; 1.13 (1.04 to 1.23) for GHQ-30 and 1.05 (0.96 to 1.14) for HADS-A. After the same adjustments, cardiovascular disease mortality was also related to HADS-D (HR 1.24 (1.07 to 1.43)), to GHQ-30 (HR 1.24 (1.11 to 1.40)) and to HADS-A (HR 1.15 (1.01 to 1.32)); respiratory mortality to GHQ-30 (HR 1.33 (1.13 to 1.55)) and mortality from other causes, excluding injuries, to HADS-D (HR 1.28 (1.05 to 1.55)). There were associations between CMD and both all-cause and cause-specific mortality which were broadly similar for GHQ-30 and HADS-D and were still present after adjustment for important confounders and mediators.


News Portrayal of Cancer: Content Analysis of Threat and Efficacy by Cancer Type and Comparison with Incidence and Mortality in Korea.
How the news media cover cancer may have profound significance for cancer prevention and control; however, little is known about the actual content of cancer news coverage in Korea. This research thus aimed to examine news portrayal of specific cancer types with respect to threat and efficacy, and to investigate whether news portrayal corresponds to actual cancer statistics. A content analysis of 1,138 cancer news stories was conducted, using a representative sample from 23 news outlets (television, newspapers, and other news media) in Korea over a 5-year period from 2008 to 2012. Cancer incidence and mortality rates were obtained from the Korean Statistical Information Service. Results suggest that threat was most prominent in news stories on pancreatic cancer (with 87% of the articles containing threat information with specific details), followed by liver (80%) and lung cancers (70%), and least in stomach cancer (41%). Efficacy information with details was conveyed most often in articles on colorectal (54%), skin (54%), and liver (50%) cancers, and least in thyroid cancer (17%). In terms of discrepancies between news portrayal and actual statistics, the threat of pancreatic and liver cancers was overreported, whereas the threat of stomach and prostate cancers was underreported. Efficacy information regarding cervical and colorectal cancers was overrepresented in the news relative to cancer statistics; efficacy of lung and thyroid cancers was underreported. Findings provide important implications for medical professionals to understand news information about particular cancers as a basis for public (mis)perception, and to communicate effectively about cancer risk with the public and patients.


Manganese binding properties of human calprotectin under conditions of high and low calcium: X-ray crystallographic and advanced electron paramagnetic resonance spectroscopic analysis.
The antimicrobial protein calprotectin (CP), a hetero-oligomer of the S100 family members S100A8 and S100A9, is the only identified mammalian Mn(II)-sequestering protein. Human CP uses Ca(II) ions to tune its Mn(II) affinity at a biologically unprecedented hexahistidine site that forms at the S100A8/S100A9 interface, and the molecular basis for this phenomenon requires elucidation. Herein, we investigate the remarkable Mn(II) coordination chemistry of human CP using X-ray crystallography as well as continuous-wave (CW) and pulse electron paramagnetic resonance (EPR) spectroscopies. An X-ray crystallographic structure of Mn(II)-CP containing one Mn(II), two Ca(II), and two Na(I) ions per CP heterodimer is reported. The CW EPR spectrum of Ca(II)- and Mn(II)-bound CP prepared with a 10:0.9:1 Ca(II):Mn(II):CP ratio is characterized by an unusually low zero-field splitting of 485 MHz (E/D = 0.30) for the S = 5/2 Mn(II) ion, consistent with the high symmetry of the His6 binding site observed crystallographically. Results from electron spin-echo envelope modulation and electron-nuclear double resonance experiments reveal that the six Mn(II)-coordinating histidine residues of Ca(II)- and Mn(II)-bound CP are spectroscopically equivalent. The observed (15)N (I = 1/2) hyperfine couplings (A) arise from two distinct classes of nitrogen atoms: the coordinating ε-nitrogen of the imidazole ring of each histidine ligand (A = [3.45, 3.71, 5.91] MHz) and the distal δ-nitrogen (A = [0.11, 0.18, 0.42] MHz). In the absence of Ca(II), the binding affinity of CP for Mn(II) drops by two to three orders of magnitude and coincides with Mn(II) binding at the His6 site as well as other sites. This study demonstrates the role of Ca(II) in enabling high-affinity and specific binding of Mn(II) to the His6 site of human calprotectin.


Cultured representatives of two major phylogroups of human colonic Faecalibacterium prausnitzii can utilize pectin, uronic acids, and host-derived substrates for growth.
Faecalibacterium prausnitzii is one of the most abundant commensal bacteria in the healthy human large intestine, but information on genetic diversity and substrate utilization is limited. Here, we examine the phylogeny, phenotypic characteristics, and influence of gut environmental factors on growth of F. prausnitzii strains isolated from healthy subjects. Phylogenetic analysis based on the 16S rRNA sequences indicated that the cultured strains were representative of F. prausnitzii sequences detected by direct analysis of fecal DNA and separated the available isolates into two phylogroups. Most F. prausnitzii strains tested grew well under anaerobic conditions on apple pectin. Furthermore, F. prausnitzii strains competed successfully in coculture with two other abundant pectin-utilizing species, Bacteroides thetaiotaomicron and Eubacterium eligens, with apple pectin as substrate, suggesting that this species makes a contribution to pectin fermentation in the colon. Many F. prausnitzii isolates were able to utilize uronic acids for growth, an ability previously thought to be confined to Bacteroides spp. among human colonic anaerobes. Most strains grew on N-acetylglucosamine, demonstrating an ability to utilize host-derived substrates. All strains tested were bile sensitive, showing at least 80% growth inhibition in the presence of 0.5 μg/ml bile salts, while inhibition at mildly acidic pH was strain dependent. These attributes help to explain the abundance of F. prausnitzii in the colonic community but also suggest factors in the gut environment that may limit its distribution.


ITS2 as a molecular marker for the identification of Diatraea saccharalis and D. flavipennella and possible infection with Cotesia spp.
In Brazil, the species Diatraea flavipennella and D. saccharalis play an important role in the sugar and alcohol agribusiness by causing many damages in sugarcane fields. The egg, larva, pupa, and adult stages are very morphologically similar between these species, and the identification can be confused. The internal transcribed spacer 2 (ITS 2) from ribosomal DNA has important features as evolutionary divergence. It is a good marker for species identification, participates in the rDNA processing, and has been applied in phylogenetic and population studies. This study aimed to make available a molecular marker to assist on the identification method of pests' species of Diatraea and to identify possible traces of Cotesia in the resistant host. The DNA was extracted from the egg, larva, and adult samples. PCR amplicons were purified and sequenced. The sequences were analyzed in MEGA 5.01. The ITS 2 length was 410 bp in D. flavipennella and 448 bp in D. saccharalis. The GC content was similar between the species. Three microsatellite loci were present in D. saccharalis and absent in D. flavipennella, contributing to differences in ITS 2 length in the species. An additional 367-bp band was attributed to Cotesia spp. The differences among ITS 2 from D. flavipennella, D. saccharalis, and Cotesia sp were sufficient to identify them on electrophoresis gel and sequencing. The presence of Cotesia sp traits in adult D. flavipennella showed possible host refractoriness, but further studies are necessary.


Direct formation of S-nitroso silica nanoparticles from a single silica source.
Nitric oxide (NO) is a ubiquitous molecule in the body. Because of its multiple pathophysiologic roles, the potential for treating various diseases by the exogenous administration of NO has been under intensive investigation. However, the unstable, radical nature of NO poses a major challenge to the effective delivery of NO. Previously, silica nanoparticles synthesized by the traditional method have been developed into NO-carrying systems. In the present study, for the first time NO-carrying silica nanoparticles were prepared from a single silica precursor using a simple nanoprecipitation method. (3-Mercaptopropyl)-trimethoxysilane (MPTMS) was used as the sole silane source, which was subjected to acid-catalyzed S-nitrosation and condensation reactions in a one-pot organic phase. S-Nitroso silica nanoparticles (SNO-SiNPs) were then produced by injecting a smaller quantity of the organic phase into a larger amount of water without surfactants. Various preparation parameters were tested to obtain optimized conditions. Moreover, a phase diagram demonstrating the ouzo effect was constructed. The prepared SNO-SiNPs were spherical particles with a tunable size in the range of 100-400 nm. The nanoparticles in aqueous dispersions exhibited high colloid stability, possibly resulting from highly negatively charged surfaces. The result of solid-state (29)Si NMR shows the predominance of T(2) and T(3) silicon structures, suggesting that nanoparticles were formed from polycondensed silica species. In conclusion, NO-loaded silica nanoparticles have been directly prepared from a single silane precursor using a surfactant-free, low-energy, one-step nanoprecipitation approach. The method precludes the need for the initial formation of bare particles and subsequent functionalization steps.


Anti-proliferative activity and apoptotic effect of tick salivary gland extracts on human HeLa cells.
The anti-proliferative and apoptotic potential of salivary gland extracts (SGE) of unfed and partially fed adult ixodid ticks were screened using human HeLa cells. Cell growth inhibition activity of SGE was measured by the MTT assay. Cell cycle analysis and quantification of DNA fragmentation was performed by DNA staining with propidium iodide. Annexin V-FITC was used to detect apoptotic cells. SGE of all ticks examined suppressed HeLa cell proliferation in a dose dependent manner. Extracts from 2-day fed R. appendiculatus females (IC(50) 0.22 mg/ml SGE soluble protein) and 9-day fed A. variegatum females (IC(50) 0.30 mg/ml) were most potent. Species-specific differences in the anti-proliferative effects of SGE were revealed, suggesting that the amount of active compounds in tick salivary glands change during feeding. Total apoptosis (about 12%) and no significant alteration in cell cycle were confirmed for SGE of A. variegatum and R. appendiculatus, and additionally SGE of 5-day fed I. ricinus females (IC(50) 0.64 mg/ml). The study shows that tumour cell growth suppressant(s) and/or apoptotic triggers are present in tick salivary glands, however, further research into the characteristics and mode of action of such natural substances is necessary.


Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium.
Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for heterogeneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies.


Desiccation-tolerant flowering plants in southern Africa.
The South African flora contains a unique abundance of higher plants which withstand virtually complete desiccation. Water potentials of fielddry leaves corresponded to 30 to 40 percent relative humidity. Mature leaves survived from 15 to approximately 0 percent relative humidity. Known examples were increased from 4 to 15 species, which for the first time included grasses.


GaAs Nanowire pn-Junctions Produced by Low-Cost and High-Throughput Aerotaxy.
Semiconductor nanowires could significantly boost the functionality and performance of future electronics, light-emitting diodes, and solar cells. However, realizing this potential requires growth methods that enable high-throughput and low-cost production of nanowires with controlled doping. Aerotaxy is an aerosol-based method with extremely high growth rate that does not require a growth substrate, allowing mass-production of high-quality nanowires at a low cost. So far, pn-junctions, a crucial element of solar cells and light-emitting diodes, have not been realized by Aerotaxy growth. Here we report a further development of the Aerotaxy method and demonstrate the growth of GaAs nanowire pn-junctions. Our Aerotaxy system uses an aerosol generator for producing the catalytic seed particles, together with a growth reactor with multiple consecutive chambers for growth of material with different dopants. We show that the produced nanowire pn-junctions have excellent diode characteristics with a rectification ratio of >105, an ideality factor around 2, and very promising photoresponse. Using electron beam induced current and hyperspectral cathodoluminescence, we determined the location of the pn-junction and show that the grown nanowires have high doping levels, as well as electrical properties and diffusion lengths comparable to nanowires grown using metal organic vapor phase epitaxy. Our findings demonstrate that high-quality GaAs nanowire pn-junctions can be produced using a low-cost technique suitable for mass-production, paving the way for industrial-scale production of nanowire-based solar cells.


High-level expression of Notch1 increased the risk of metastasis in T1 stage clear cell renal cell carcinoma.
Although metastasis of clear cell renal cell carcinoma (ccRCC) is basically observed in late stage tumors, T1 stage metastasis of ccRCC can also be found with no definite molecular cause resulting inappropriate selection of surgery method and poor prognosis. Notch signaling is a conserved, widely expressed signal pathway that mediates various cellular processes in normal development and tumorigenesis. This study aims to explore the potential role and mechanism of Notch signaling in the metastasis of T1 stage ccRCC. The expression of Notch1 and Jagged1 were analyzed in tumor tissues and matched normal adjacent tissues obtained from 51 ccRCC patients. Compared to non-tumor tissues, Notch1 and Jagged1 expression was significantly elevated both in mRNA and protein levels in tumors. Tissue samples of localized and metastatic tumors were divided into three groups based on their tumor stages and the relative mRNA expression of Notch1 and Jagged1 were analyzed. Compared to localized tumors, Notch1 expression was significantly elevated in metastatic tumors in T1 stage while Jagged1 expression was not statistically different between localized and metastatic tumors of all stages. The average size of metastatic tumors was significantly larger than localized tumors in T1 stage ccRCC and the elevated expression of Notch1 was significantly positive correlated with the tumor diameter. The functional significance of Notch signaling was studied by transfection of 786-O, Caki-1 and HKC cell lines with full-length expression plasmids of Notch1 and Jagged1. Compared to the corresponding controls, all cell lines demonstrated significant promotion in cell proliferation and migration while cell cycle remained unaffected. High-level expression of Notch signaling increased the risk of metastasis in T1 stage ccRCC by stimulating the proliferation and migration of tumor cells, which may be helpful for the selection of suitable operation method and prognosis of ccRCC.


Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation.
The risks associated with new-onset atrial fibrillation (AF) among middle-aged women and populations with a low comorbidity burden are poorly defined. To examine the association between incident AF and mortality in initially healthy women and to evaluate the influence of associated cardiovascular comorbidities on risk. Between 1993 and March 16, 2010, 34,722 women participating in the Women's Health Study underwent prospective follow-up. Participants were 95% white, older than 45 years (median, 53 [interquartile range {IQR}, 49-59] years), and free of AF and cardiovascular disease at baseline. Cox proportional hazards models with time-varying covariates were used to determine the risk of events among women with incident AF. Secondary analyses were performed among women with paroxysmal AF. Primary outcomes included all-cause, cardiovascular, and noncardiovascular mortality. Secondary outcomes included stroke, congestive heart failure, and myocardial infarction. During a median follow-up of 15.4 (IQR, 14.7-15.8) years, 1011 women developed AF. Incidence rates per 1000 person-years among women with and without AF were 10.8 (95% confidence interval [CI], 8.1-13.5) and 3.1 (95% CI, 2.9-3.2) for all-cause mortality, 4.3 (95% CI, 2.6-6.0) and 0.57 (95% CI, 0.5-0.6) for cardiovascular mortality, and 6.5 (95% CI, 4.4-8.6) and 2.5 (95% CI, 2.4-2.6) for noncardiovascular mortality, respectively. In multivariable models, hazard ratios (HRs) of new-onset AF for all-cause, cardiovascular, and noncardiovascular mortality were 2.14 (95% CI, 1.64-2.77), 4.18 (95% CI, 2.69-6.51), and 1.66 (95% CI, 1.19-2.30), respectively. Adjustment for nonfatal cardiovascular events potentially on the causal pathway to death attenuated these risks, but incident AF remained associated with all mortality components (all-cause: HR, 1.70 [95% CI, 1.30-2.22]; cardiovascular: HR, 2.57 [95% CI, 1.63-4.07]; and noncardiovascular: HR, 1.42 [95% CI, 1.02-1.98]). Among women with paroxysmal AF (n = 656), the increase in mortality risk was limited to cardiovascular causes (HR, 2.94; 95% CI, 1.55-5.59). Among a group of healthy women, new-onset AF was independently associated with all-cause, cardiovascular, and noncardiovascular mortality, with some of the risk potentially explained by nonfatal cardiovascular events.


[Leptomeningeal carcinomatosis as the primary manifestation of a carcinoma of probable renal origin].
Leptomeningeal carcinomatosis (LC) is commonly observed in malignant lymphoproliferative diseases (leukemias and lymphomas), and it can rarely be the presenting feature of a solid tumour. The types of tumour most commonly associated with that condition are breast, lung and gastrointestinal carcinomas and malignant melanoma. We report a patient with a carcinoma of probable renal origin who presented with meningeal carcinomatosis, without any symptom attributable to the initial tumour. We review and discuss the diagnostic criteria, the pathophysiology and the therapeutic outlook of this relatively uncommon type of metastatic disease.


Digitized Spiral Drawing: A Possible Biomarker for Early Parkinson's Disease.
Pre-clinical markers of Parkinson's Disease (PD) are needed, and to be relevant in pre-clinical disease, they should be quantifiably abnormal in early disease as well. Handwriting is impaired early in PD and can be evaluated using computerized analysis of drawn spirals, capturing kinematic, dynamic, and spatial abnormalities and calculating indices that quantify motor performance and disability. Digitized spiral drawing correlates with motor scores and may be more sensitive in detecting early changes than subjective ratings. However, whether changes in spiral drawing are abnormal compared with controls and whether changes are detected in early PD are unknown. 138 PD subjects (50 with early PD) and 150 controls drew spirals on a digitizing tablet, generating x, y, z (pressure) data-coordinates and time. Derived indices corresponded to overall spiral execution (severity), shape and kinematic irregularity (second order smoothness, first order zero-crossing), tightness, mean speed and variability of spiral width. Linear mixed effect adjusted models comparing these indices and cross-validation were performed. Receiver operating characteristic analysis was applied to examine discriminative validity of combined indices. All indices were significantly different between PD cases and controls, except for zero-crossing. A model using all indices had high discriminative validity (sensitivity = 0.86, specificity = 0.81). Discriminative validity was maintained in patients with early PD. Spiral analysis accurately discriminates subjects with PD and early PD from controls supporting a role as a promising quantitative biomarker. Further assessment is needed to determine whether spiral changes are PD specific compared with other disorders and if present in pre-clinical PD.


Genetic variability of the mouse hepatoma cells MH-22a revealed by RAPD-PCR-fingerprinting under different conditions of cultivation.
to study genetic variability in clonal lines of the mouse hepatoma MH-22a and the dependence of the capability of different clonal line cells for differentiation on the amount of genetic disturbances revealed by the RAPD-PCR method. The hepatoma MH-22a and its ten clonal lines were transplanted into subcutaneous connective tissue (SCT) and the eye anterior chamber (EAC) by injection of the cells to syngenic C3HA mice. The growth of transplants was checked in 15-20 days after transplantation. The tumors were fixed in neutral paraformaldehyde (10%), passed through ethanol of increasing concentrations, embedded in paraffin and stained by hematoxiline and eosine and Van Gisone. The genetic heterogeneity in the hepatoma cell population MH-22a and its clonal lines in vitro and in vivo was revealed by random amplified polymorphic DNA (RAPD-PCR). For the estimation of genetic variability revealed in the fingerprints was used the genetic variability index (GVI), based on the Bootstrep and Mikulinskaya's statistic programme. The comparative analysis of the genetic structure of the clonal line populations in vitro and in vivo has revealed that the amount of clones with the high, intermediate, and low variability is approximately the same in both cases. It was also shown that GVI in various clonal lines in vitro correlated with their vital ability: the clones yielding clone lines had the lowest GVI. The same GVI value was found in the clonal lines proliferated in the EAC regardless of their capability for differentiation. Intraclonal analysis has shown that the highest values of changes revealed on fingerprints of the amplification of DNA products do not prevent from differentiation of tumor hepatoma cells in the EAC. These data allow concluding that the mouse hepatoma cells MH-22a can preserve ability for differentiation in spite of significant changes in their genome.


Electrodes with high power and high capacity for rechargeable lithium batteries.
New applications such as hybrid electric vehicles and power backup require rechargeable batteries that combine high energy density with high charge and discharge rate capability. Using ab initio computational modeling, we identified useful strategies to design higher rate battery electrodes and tested them on lithium nickel manganese oxide [Li(Ni(0.5)Mn(0.5))O2], a safe, inexpensive material that has been thought to have poor intrinsic rate capability. By modifying its crystal structure, we obtained unexpectedly high rate-capability, considerably better than lithium cobalt oxide (LiCoO2), the current battery electrode material of choice.