An HLA-DR alpha promoter DNA-binding protein is expressed ubiquitously and maps to human chromosomes 22 and 5.
The class II major histocompatibility complex antigens are a family of integral membrane proteins whose expression is tissue-specific and developmentally regulated. Three consensus sequences, X1, X2, and Y, separated by an interspace element, is found upstream from all class II genes. Deletion of each of these sequences eliminates expression of class II genes in vitro or in transgenic mice. Here we further characterize the expression of a cDNA encoding a DNA binding protein (human X-box binding protein, hXBP-1) which, like the proteins in whole nuclear extract, recognizes both the X2 promoter element of the human DR alpha and DP beta and mouse A alpha genes. The hXBP-1 cDNA hybridizes to human RNA species of approximately 2.2 kilobases (kb) and 1.6 kb, which are expressed in class II negative as well as class II positive cells. hXBP-1 transcripts are present in several class II deficient mutant B cell lines, although in one such line, 6.1.6, levels were somewhat reduced. Chromosome mapping studies demonstrate that hXBP-1 arises from a small gene family, two of whose members map to human chromosomes 5 and 22. Taken together, these data suggest a high degree of complexity in the transcriptional control of the class II gene family.


Fine structural tuning of styryl-based dyes for fluorescence and CD-based sensing of various ds-DNA/RNA sequences.
A set of styryl- and bis-styryl dyes, varying in length, aromatic surface, net positive charge and steric positioning or bulkiness of substituents, was tested for interactions with various ds-DNA or ds-RNA. Most of the compounds showed strong affinity toward ds-DNA/RNA, directly correlated to the synergistic contribution of the aromatic-conjugated surface and net positive charge. The volume or positioning of terminal aromatic substituents directly controlled the binding mode of the core structure, shifting between DNA/RNA groove binding or DNA/RNA intercalation. Consequently, upon binding to DNA/RNA the fluorimetric and induced CD (ICD) response varied for different compounds, for instance one derivative showed specific fluorescence increase with AT-DNA, while another derivative showed specific ICD response with AU-RNA. Preliminary screening on human tumour cell lines revealed an efficient cellular uptake for all dyes. Only mono-styryl-quinoline derivatives showed a strong antiproliferative activity combined with efficient fluorescent localisation, thus showing promising theragnostic potential, while other compounds were negligibly cytotoxic but still efficient fluorescent markers of cytoplasmic organelles.


Detection of early cartilage damage: feasibility and potential of gagCEST imaging at 7T.
The purpose was to implement a fast 3D glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) sequence at 7 T, test stability and reproducibility in cartilage in the knee in healthy volunteers, and evaluate clinical applicability in cartilage repair patients. Experiments were carried out on a 7-T scanner using a volume transmit coil and a 32-channel receiver wrap-around knee coil. The 3D gagCEST measurement had an acquisition time of 7 min. Signal stability and reproducibility of the GAG effect were assessed in eight healthy volunteers. Clinical applicability of the method was demonstrated in five patients before cartilage repair surgery. Coefficient of variation of the gagCEST signal was 1.9%. The reproducibility of the GAG effect measurements was good in the medial condyle (ICC = 0.87) and excellent in the lateral condyle (ICC = 0.97). GAG effect measurements in healthy cartilage ranged from 2.6%-12.4% compared with 1.3%-5.1% in damaged cartilage. Difference in GAG measurement between healthy cartilage and damaged cartilage was significant (p < 0.05). A fast 3D gagCEST sequence was applied at 7 T for use in cartilage in the knee, acquired within a clinically feasible scan time of 7 min. We demonstrated that the method has high stability, reproducibility and clinical applicability. • gagCEST measurements are stable and reproducible • A non-invasive GAG measurement with gagCEST can be acquired in 7 min • gagCEST is able to discriminate between healthy and damaged cartilage.


Oxidative activation of benzidine and its derivatives by peroxidases.
Benzidine (4,4'-diaminobiphenyl) is a known human carcinogen; exposure to this substance resulted in an epidemic of bladder cancer among workers in the dye industry in Europe and North America. The chemical or enzymatic oxidation of benzidine proceeds via a racial cation detectable by electron spin resonance. Peroxidase-catalyzed oxidation of benzidine generates reactive electrophiles which readily form adducts with phenol and thiol compounds. The structures of these novel metabolites are described. Peroxidases, including prostaglandin synthase, catalyze benzidine binding to protein and nucleic acid; the nature of the resulting adducts is unknown. The relevance of these processes to benzidine carcinogenesis in vivo is the subject of research and debate. A central question remains: is benzidine activated in extra-hepatic target tissues such as bladder epithelium, or transported to these tissues following hepatic oxidative metabolism?


Glucose-dependent insulinotropic polypeptide reduces fat-specific expression and activity of 11β-hydroxysteroid dehydrogenase type 1 and inhibits release of free fatty acids.
Glucose-dependent insulinotropic polypeptide (GIP) has been suggested to have direct effects on nonislet tissues. GIP also reportedly increased glucose uptake and inhibition of lipolysis in adipocytes after inhibition of the intracellular cortisone-cortisol shuttle 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). We here analyzed whether GIP modifies lipid metabolism and further elucidated the relation between GIP, 11β-HSD1, and fatty acid metabolism. GIP reduced activity of 11β-HSD1 promoter constructs and the expression and activity of 11β-HSD1 in differentiated 3T3-L1 adipocytes in a time- and dose-dependent fashion. This was paralleled by a reduction of free fatty acid (FFA) release and a reduced expression of key enzymes regulating lipolysis in adipose tissue. Preinhibition of 11β-HSD1 completely abolished GIP-induced effects on FFA release. To investigate the acute effects of GIP in humans, a randomized clinical trial was performed. GIP lowered circulating FFAs compared with saline control and reduced expression and ex vivo activity of 11β-HSD1 and adipose triglyceride lipase expression in subcutaneous fat biopsies. Our data suggest that GIP reduces FFA release from adipose tissue by inhibition of lipolysis or by increased reesterification. This process appears to depend on a modification of 11β-HSD1 activity. In general, the presented data support that GIP has direct and insulin-independent effects on adipose tissue.


Activity and determinants of cholinesterases and paraoxonase-1 in blood of workers exposed to non-cholinesterase inhibiting pesticides.
Pesticide exposure has been associated with different adverse health effects which may be modulated to some extent by paraoxonase-1 (PON1) activity and genetic polymorphisms. This study assessed seasonal variations in PON1 activity (using paraoxon -POase-, phenylacetate -AREase-, diazoxon -DZOase- and dihydrocoumarin -DHCase- as substrates), erythrocyte acetylcholinesterase (AChE) and plasma cholinesterase (using butyrylthiocholine -BuChE- and benzoylcholine -BeChE- as substrates. The study population consisted of intensive agriculture workers regularly exposed to pesticides other than organophosphates and non-exposed controls from Almería (Southeastern Spain). The effect of common genetic polymorphisms of PON1 and BCHE on paraoxonase-1 and cholinesterase activities toward different substrates was also assessed. Linear mixed models were used to compare esterase activities in agricultural workers and control subjects over the two study periods (high and low exposure to pesticides). The significant decrease in AChE and increase in BuChE and BeChE activities observed in workers with respect to control subjects was attributed to pesticide exposure. Workers also had higher levels of AREase, DZOase and, to a lesser extent, of POase, but showed decreased DHCase activity. While PON1 Q192R and PON1 -108C/T gene polymorphisms were significantly associated with all PON1 activities, PON1 L55M showed a significant association with AREase, DZOase and DHCase. BCHE-K (Karlow variant) was significantly associated with lower BeChE activity (but not with BuChE) and BCHE-A (atypical variant) showed no significant association with any cholinesterase activity. These findings suggest that increased PON1, BuChE and BeChE activities in exposed workers might result from an adaptive response against pesticide exposure to compensate for adverse effects at the biochemical level. This response appears to be modulated by PON1 and BCHE gene polymorphisms.


Inhibition of Ras oncogenic activity by Ras protooncogenes.
Point mutations in ras genes have been found in a large number and wide variety of human tumors. These oncogenic Ras mutants are locked in an active GTP-bound state that leads to a constitutive and deregulated activation of Ras function. The dogma that ras oncogenes are dominant, whereby the mutation of a single allele in a cell will predispose the host cell to transformation regardless of the presence of the normal allele, is being challenged. We have seen that increasing amounts of Ras protooncogenes are able to inhibit the activity of the N-Ras oncogene in the activation of Elk in NIH 3T3 cells and in the formation of foci. We have been able to determine that the inhibitory effect is by competition between Ras protooncogenes and the N-Ras oncogene that occurs first at the effector level at the membranes, then at the processing level and lastly at the effector level in the cytosol. In addition, coexpression of the N-Ras protooncogene in thymic lymphomas induced by the N-Ras oncogene is associated with increased levels of p107, p130 and cyclin A and decreased levels of Rb. In the present report, we have shown that the N-Ras oncogene is not truly dominant over Ras protooncogenes and their competing activities might be depending on cellular context.


Conditional depletion of neurogenesis inhibits long-term recovery after experimental stroke in mice.
We reported previously that ablation of doublecortin (DCX)-immunopositive newborn neurons in mice worsens anatomical and functional outcome measured 1 day after experimental stroke, but whether this effect persists is unknown. We generated transgenic mice that express herpes simplex virus thymidine kinase under control of the DCX promoter (DCX-TK transgenic mice). DCX-expressing and recently divided cells in the rostral subventricular zone (SVZ) and hippocampus of DCX-TK transgenic mice, but not wild-type mice, were specifically depleted after ganciclovir (GCV) treatment for 14 days. Focal cerebral ischemia was induced by permanent distal middle cerebral artery occlusion (MCAO) on day 14 of vehicle or GCV treatment, and mice were killed 12 weeks after MCAO. Infarct volume was significantly increased and neurologic deficits were more severe in GCV- compared to vehicle-treated DCX-TK transgenic mice at first 8 weeks, after depletion of DCX- and bromodeoxyuridine-immunoreactive cells in the SVZ and dentate gyrus following focal ischemia. Our results indicate that endogenous neurogenesis in a critical period following experimental stroke influences the course of long-term recovery.


Parity of indigenous and non-indigenous women in Brazil: does the reported number of children born depend upon who answers national census questions?
Taking parity as the main analytic variable, the objective of this study is to investigate whether the patterns of response to national census questions in Brazil differ when Indigenous and non-Indigenous women are compared, taking into consideration whether the information was provided by the women directly or by a proxy respondent (another household member or a non-resident). We use data on children ever born to Indigenous and non-Indigenous women from two Brazilian regions, the Northeast and the North. Data on the number of household members, total household rooms, interviewee's color/race, educational attainment, age, parity, and type of respondent were obtained from the 2010 Brazilian census. The relation between color/race and reported parity, as well as the impact of the type of respondent on this association were assessed with the Zero-inflated Negative Binomial regression, stratified by region (North and Northeast) and urban/rural status. Just over half of census interviewees answered directly the census questions (51.2% in the North and 54.4% in the Northeast). Indigenous women in the North region had the highest percentage of interviews carried out with a non-resident (12.7% total; 15.0% and 3.0% in rural and urban areas, respectively). Regardless of color/race, parity means were considerably higher when the question was answered by the woman directly (93.5%-101.4% and 15.6%-21.7% higher, compared co-resident and non-resident based answers, respectively). Parity underreporting was particularly strong in Indigenous women living in the rural North (16.0% less in comparison to White women). Proxy respondents tend to underestimate the count of children, particularly among Indigenous women from the North. The implementation of certain methodological alternatives in the Brazilian national censuses, such as the selection and training of census takers to work specifically in Indigenous territories, might be a productive means to improve data collection.


Quantification of the relative contribution of estrogen to bone mineral density in men and women.
The study quantified the relative contributions of estrogen (E2) and total testosterone (TT) to variation in bone mineral density in men and women. This was a cross-sectional study which involved 200 men and 415 women aged 18 to 89 years. BMD at the lumbar spine (LS) and femoral neck (FN) was measured by DXA. Serum levels of E2 and TT were measured by electrochemiluminescence immunoassays. The association between E2, TT, and BMD was analyzed by the multiple linear regression model, adjusting for age and BMI. The contribution of each hormone to the variation in BMD was quantified by the bootstrap method. In women, higher serum levels of E2, but not TT, were significantly associated with greater BMD at the FN (P = 0.001) and LS (P < 0.0001). In men, higher serum levels of E2 were independently associated with greater FNBMD (P = 0.008) and LSBMD (P = 0.086). In the multiple linear regression model, age, body weight and E2 accounted for 50-55% variance in FNBMD, and 25% (in men) and 48% (in women) variance in LSBMD. Variation in E2 accounted for 2.5% (95% CI 0.4-7.8%) and 11.3% (95% CI 8.1-15.3%) variation in FNBMD in men and women, respectively. Moreover, E2 contributed 1.2% (95% CI 0.1-5.8%) and 11.7% (95% CI 8.5-15.9%) variation in LSBMD in men and women, respectively. Estrogen is more important than testosterone in the determination of age-related bone mineral density men and women of Vietnamese background. However, the relative contributions of estrogen to bone mineral density in men are likely modest.


Enamel remineralization on teeth adjacent to Class II glass ionomer restorations.
To examine the in vitro remineralization of incipient carious lesions on teeth adjacent interproximally to teeth with Class II glass ionomer cement restorations. Artificial carious lesions were created at the contact area of 30 teeth. Ten teeth had Class II glass ionomer cement/resin composite restorations placed, 10 teeth had Class II glass ionomer silver cermet restorations placed and 10 teeth had Class II amalgam restorations placed. Sections 100 microns thick were obtained longitudinally through the caries sites and polarized photomicrographs were taken in imbibition media of water and Thoulet's (R.I. 1.41 and 1.47) solutions, representing 5%, 10% and 25% pore volume respectively. Varnish was placed on the section, leaving only the external section site exposed, then sections were situated back into the original tooth. The restored teeth were abutted to the carious tooth so that the restorations came into contact with the adjacent restoration. The specimens were placed into closed environments of artificial saliva for 14 days, then were photographed again under polarized light and areas of the carious lesions were quantitated. An ANOVA indicated significant variance in adjacent tooth remineralization, when comparing the experimental groups, in imbibition media of water (P < 0.05), Thoulet's 1.41 solution (P < 0.008) and Thoulet's 1.47 solution (P < 0.006). Duncan's multiple range test demonstrated the glass ionomer cement/resin composite group to have significantly greater decrease in pore volume (P < 0.05) than the amalgam control group in water imbibition media and Thoulet's 1.47 media. There was no statistically significant difference between the glass ionomer cement/resin composite and glass ionomer silver cermet groups in these two imbibition media. The glass ionomer cement/resin composite group demonstrated significantly more (P < 0.05) decrease in pore volume than both the glass ionomer silver cermet group and amalgam control group in Thoulet's 1.47 imbibition media.


Yeast 5 - an expanded reconstruction of the Saccharomyces cerevisiae metabolic network.
Efforts to improve the computational reconstruction of the Saccharomyces cerevisiae biochemical reaction network and to refine the stoichiometrically constrained metabolic models that can be derived from such a reconstruction have continued since the first stoichiometrically constrained yeast genome scale metabolic model was published in 2003. Continuing this ongoing process, we have constructed an update to the Yeast Consensus Reconstruction, Yeast 5. The Yeast Consensus Reconstruction is a product of efforts to forge a community-based reconstruction emphasizing standards compliance and biochemical accuracy via evidence-based selection of reactions. It draws upon models published by a variety of independent research groups as well as information obtained from biochemical databases and primary literature. Yeast 5 refines the biochemical reactions included in the reconstruction, particularly reactions involved in sphingolipid metabolism; updates gene-reaction annotations; and emphasizes the distinction between reconstruction and stoichiometrically constrained model. Although it was not a primary goal, this update also improves the accuracy of model prediction of viability and auxotrophy phenotypes and increases the number of epistatic interactions. This update maintains an emphasis on standards compliance, unambiguous metabolite naming, and computer-readable annotations available through a structured document format. Additionally, we have developed MATLAB scripts to evaluate the model's predictive accuracy and to demonstrate basic model applications such as simulating aerobic and anaerobic growth. These scripts, which provide an independent tool for evaluating the performance of various stoichiometrically constrained yeast metabolic models using flux balance analysis, are included as Additional files 1, 2 and 3. Yeast 5 expands and refines the computational reconstruction of yeast metabolism and improves the predictive accuracy of a stoichiometrically constrained yeast metabolic model. It differs from previous reconstructions and models by emphasizing the distinction between the yeast metabolic reconstruction and the stoichiometrically constrained model, and makes both available as Additional file 4 and Additional file 5 and at http://yeast.sf.net/ as separate systems biology markup language (SBML) files. Through this separation, we intend to make the modeling process more accessible, explicit, transparent, and reproducible.


A 2-year follow-up of spirometric parameters in workers of a tile and ceramic industry, Yazd, southeastern Iran.
Respiratory diseases cause a considerable amount of morbidity and mortality in the world. Pulmonary function tests are important measures for the diagnosis and management of respiratory disorders. Workers in tile and ceramic industry are exposed to high amounts of respiratory pollutants. To identify the changes in spirometric parameters in a 2-year period among tile and ceramic workers in Yazd and compare it with a control group. The study was conducted in 5 tile and ceramic factories selected by cluster sampling between 2009 and 2011 in Yazd, southeastern Iran. Demographic data and spirometric parameters of participants were recorded. Spirometric parameters were significantly reduced during the 2 years. The largest decrease was observed in FVC (≈500 mL) in ball-mill and grinding after 2 years. Decrease in all spirometric parameters was significantly higher in industrial workers than office workers. Respiratory exposure in tile and ceramic industry can significantly affect pulmonary function tests.


Are overdoses treated by ambulance services an opportunity for additional interventions? A prospective cohort study.
To assess whether people who inject drugs (PWID) and who are treated for overdose by ambulance services have a greater mortality risk compared with other PWID, and to compare mortality risk within potentially critical time-periods (1 week, 1 month, 3 months, 6 months, 1 year, 5 years) after an overdose attendance with the mortality risk within potentially non-critical time-periods (time before and/or after critical periods). A prospective cohort study. Oslo, Norway. A total of 172 PWID street-recruited in 1997 and followed-up until the end of 2004. Interview data linked to data from ambulance records, Norwegian Correctional Services, Opioid Substitution Treatment records and National Cause of Death Registry. Separate Cox regression models (one for each critical time-period) were estimated. Ambulance services treated 54% of the participants for an overdose during follow-up. The mortality rate was 2.8 per 100 person-years for those with an overdose and 3.3 for those without; the adjusted hazard ratio (HR) was 1.3 (95% CI = 0.6, 2.6, P = 0.482). Mortality risk was greater in all but the shortest critical time-period following ambulance attendance than in the non-critical periods. The mortality risk remained significantly elevated during critical periods, even when adjusted for total time spent in prison and substitution treatment. The HR ranged from 9.4 (95% CI = 3.5, 25.4) in the month after an overdose to 13.9 (95% CI = 6.4, 30.2) in the 5-year period. Mortality risk among people who inject drugs is significantly greater in time-periods after an overdose attendance than outside these time-periods.


[Accuracy of waist circumference and waist-to-hip ratio as predictors of dyslipidemia in a cross-sectional study among blood donors in Cuiabá, Mato Grosso State, Brazil].
This study evaluated the accuracy of anthropometric fat location indices (waist circumference and waist-to-hip ratio) as predictors of dyslipidemia, in addition to defining their respective cut-offs. The sample consisted of 416 healthy male blood donors from 20 to 58 years of age at the Blood Center in Cuiabá, capital of Mato Grosso State, Brazil. Serum lipids were determined through the enzymatic method. Data analysis through the ROC curve identified the best indicator and the cut-off with the largest statistically significant area under the ROC curve. The best cut-off points for waist-to-hip ratio and waist circumference were 0.90 and 85cm, respectively. The area under the ROC curve between waist circumference and high cholesterol/HDL relation included the 0.50 value, so waist circumference could not be considered a predictor of dyslipidemia. The best sensitivity and specificity were in the youngest group. Waist-to-hip ratio was a better predictor of dyslipidemia than waist circumference, although the latter showed better discriminating power to detect hypertriglyceridemia. The most accurate cut-off points were lower than those set by the World Health Organization.


Statin-induced changes in mitochondrial respiration in blood platelets in rats and human with dyslipidemia.
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used drugs for lowering blood lipid levels and preventing cardiovascular diseases. However, statins can have serious adverse effects, which may be related to development of mitochondrial dysfunctions. The aim of study was to demonstrate the in vivo effect of high and therapeutic doses of statins on mitochondrial respiration in blood platelets. Model approach was used in the study. Simvastatin was administered to rats at a high dose for 4 weeks. Humans were treated with therapeutic doses of rosuvastatin or atorvastatin for 6 weeks. Platelet mitochondrial respiration was measured using high-resolution respirometry. In rats, a significantly lower physiological respiratory rate was found in intact platelets of simvastatin-treated rats compared to controls. In humans, no significant changes in mitochondrial respiration were detected in intact platelets; however, decreased complex I-linked respiration was observed after statin treatment in permeabilized platelets. We propose that the small in vivo effect of statins on platelet energy metabolism can be attributed to drug effects on complex I of the electron transport system. Both intact and permeabilized platelets can be used as a readily available biological model to study changes in cellular energy metabolism in patients treated with statins.


Histomorphometric analysis following augmentation of the anterior atrophic maxilla with cancellous bone block allograft.
Grafting with bone blocks may be required to restore the alveolar process in extremely atrophic maxillae prior to implant placement to ensure both function and esthetics. The present study was conducted to histologically and histomorphometrically evaluate the application of allograft cancellous bone blocks for the augmentation of the anterior atrophic maxilla. Consecutive patients with severe atrophy in the anterior maxilla underwent augmentation with cancellous bone block allografts. Bony deficiencies of at least 3 mm horizontally and up to 3 mm vertically according to computed tomographic para-axial reconstructions served as inclusion criteria. After 6 months, implants were placed and a cylindric sample core from the graft area was collected. All specimens were prepared for histologic and histomorphometric examination. Forty patients were included in the study. Eighty-three implants were placed in bone that was augmented with 60 cancellous freeze-dried bone block allografts. The implant survival rate was 98.8%. Mean follow-up was 48 ± 22 months (range, 14 to 82 months). The mean percentage of newly formed bone was 33% ± 18%, that of the residual cancellous block allograft was 26% ± 17%, and marrow and connective tissue comprised 41% ± 2%. Statistically significant histomorphometric differences regarding newly formed bone and residual cancellous block allograft were found between younger (< 40 years) and older (≥ 40 years) patients, respectively. Age did not appear to influence the percentage of marrow and connective tissue. Cancellous bone block allograft is biocompatible and osteoconductive, permitting new bone formation following augmentation of extremely atrophic anterior maxillae in a two-stage implant placement procedure. New bone formation was age-dependent.


Prevalence of HIV and HIV-related diseases in the adult medical wards of a tertiary hospital in Durban, South Africa.
Our objective was to determine the prevalence of HIV and the distribution of HIV-related diseases among adult, medical inpatients. Consecutive admissions were recruited and a single ELISA assay was used to determine HIV infection. Demographic and clinical details were extracted from clinical records. Of 507 patients, 54% were infected with HIV of which 84% had AIDS. HIV-infected patients were significantly younger (34.9 years) than uninfected patients (47.1 years) and had significantly higher risks for oral/oesophageal candidiasis (risk ratio [RR] 18.6), generalized lymphadenopathy (RR 7.1), unexplained fever (RR 7.0), chronic diarrhoea (RR 6.2) and pulmonary tuberculosis (RR 3.1). Pulmonary tuberculosis was present in 56% of HIV cases. Mortality was 22% for HIV cases and 9% (P=0.016) for others. The mean length of hospital stay was the same for HIV-infected and uninfected patients. AIDS is the most common reason for admission to adult medical wards and will increasingly limit the number of beds available for non-AIDS patients.


[EuroRotaNet--European rotavirus strain surveillance network established with Hungarian participation].
Group A rotaviruses are the most common cause of severe gastroenteritis worldwide. The incidence and distribution of group A rotavirus sero/genotypes varies between geographical areas during a rotavirus season, and from one season to the next. In addition, cocirculation of genetically diverse multitypic rotaviruses and of intratypic variants in any one place and time is common. Assuming widespread use of rotavirus vaccine in the near future, comprehensive surveillance of natural rotavirus infections is vital. EuroRotaNet has been established in order to gather comprehensive information on the rotavirus types co-circulating throughout Europe. The main objectives of the network are to (i) develop methods and algorithms for effective rotavirus strain typing and characterisation, (ii) describe in detail the molecular epidemiology of rotavirus infections in Europe, (iii) monitor the effectiveness of current genotyping methods and respond to changes associated with genetic drift and shift, and (iv) monitor the emergence and spread of novel rotavirus strains within Europe. This infrastructure may serve as a platform for future surveillance activities and nested studies for evaluating the effectiveness of a rotavirus vaccine in the general population. Studies to monitor the reduction in disease associated with common rotavirus types, the possible vaccine-induced emergence of antibody escape mutants of genotypes other than those included in the vaccine and of reassortment between vaccine and naturally circulating wildtype strains are required.


Factors associated with maternal death from direct pregnancy complications: a UK national case-control study.
To investigate the factors associated with maternal death from direct pregnancy complications in the UK. Unmatched case-control analysis. All hospitals caring for pregnant women in the UK. A total of 135 women who died (cases) between 2009 and 2012 from eclampsia, pulmonary embolism, severe sepsis, amniotic fluid embolism, and peripartum haemorrhage, using data from the Confidential Enquiry into Maternal Death, and another 1661 women who survived severe complications (controls) caused by these conditions (2005-2013), using data from the UK Obstetric Surveillance System. Multivariable regression analyses were undertaken to identify the factors that were associated with maternal deaths and to estimate the additive odds associated with the presence of one or more of these factors. Odds ratios associated with maternal death and population-attributable fractions, with 95% confidence intervals. Incremental risk of death associated with the factors using a 'risk factors' score. Six factors were independently associated with maternal death: inadequate use of antenatal care (adjusted odds ratio, aOR 15.87, 95% CI 6.73-37.41); substance misuse (aOR 10.16, 95% CI 1.81-57.04); medical comorbidities (aOR 4.82, 95% CI 3.14-7.40); previous pregnancy problems (aOR 2.21, 95% CI 1.34-3.62); hypertensive disorders of pregnancy (aOR 2.44, 95% CI 1.31-4.52); and Indian ethnicity (aOR 2.70, 95% CI 1.14-6.43). Of the increased risk associated with maternal death, 70% (95% CI 66-73%) could be attributed to these factors. Odds associated with maternal death increased by three and a half times per unit increase in the 'risk factor' score (aOR 3.59, 95% CI 2.83-4.56). This study shows that medical comorbidities are importantly associated with direct (obstetric) deaths. Further studies are required to understand whether specific aspects of care could be improved to reduce maternal deaths among women with medical comorbidities in the UK.


Evaluation of GeneXpert MTB/RIF for diagnosis of tuberculous meningitis.
Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Microbiological confirmation is rare, and treatment is often delayed, increasing mortality and morbidity. The GeneXpert MTB/RIF test was evaluated in a large cohort of patients with suspected tuberculous meningitis. Three hundred seventy-nine patients presenting with suspected tuberculous meningitis to the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, between 17 April 2011 and 31 December 2012 were included in the study. Cerebrospinal fluid samples were tested by Ziehl-Neelsen smear, mycobacterial growth indicator tube (MGIT) culture, and Xpert MTB/RIF. Rifampin (RIF) resistance results by Xpert were confirmed by an MTBDR-Plus line probe assay and all positive cultures were tested by phenotypic MGIT drug susceptibility testing. Overall, 182/379 included patients (48.0%) were diagnosed with tuberculous meningitis. Sensitivities of Xpert, smear, and MGIT culture among patients diagnosed with TBM were 59.3% (108/182 [95% confidence interval {CI}, 51.8 to 66.5%]), 78.6% (143/182 [95% CI, 71.9 to 84.3%]) and 66.5% (121/182 [95% CI, 59.1 to 73.3%]), respectively. There was one false-positive Xpert MTB/RIF test (99.5% specificity). Four cases of RIF resistance (4/109; 3.7%) were identified by Xpert, of which 3 were confirmed to be multidrug-resistant (MDR) TBM and one was culture negative. Xpert MTB/RIF is a rapid and specific test for the diagnosis of tuberculous meningitis. The addition of a vortexing step to sample processing increased sensitivity for confirmed TBM by 20% (P = 0.04). Meticulous examination of a smear from a large volume of cerebrospinal fluid (CSF) remains the most sensitive technique but is not practical in most laboratories. The Xpert MTB/RIF represents a significant advance in the early diagnosis of this devastating condition.


Management of the third stage of labor in an Egyptian teaching hospital.
The study describes normal labor practices in an Egyptian teaching hospital for the first time, where postpartum hemorrhage is the leading cause of maternal mortality. Third-stage management patterns are described and compared to evidence-based medicine. Reasons for third-stage practices observed are explored. 176 normal births were directly observed. Women were interviewed postpartum and study findings were shared with providers. Third-stage active management was correctly done for 15% of women observed. Most common deviations for the remaining 85% were: giving uterotonic drugs after placental delivery (65%) and without cord traction (49%). Passive management was not done for any observed delivery. The preventive role actively managing the third stage can provide against postpartum hemorrhage was lost to the majority of the deliveries observed. Obstacles to adopting protocols shown to reduce hemorrhage should be explored, given the contribution of postpartum hemorrhage to maternal deaths in Egypt.


Phylogeography of Heliconius cydno and its closest relatives: disentangling their origin and diversification.
The origins of the extraordinary diversity within the Neotropics have long fascinated biologists and naturalists. Yet, the underlying factors that have given rise to this diversity remain controversial. To test the relative importance of Quaternary climatic change and Neogene tectonic and paleogeographic reorganizations in the generation of biodiversity, we examine intraspecific variation across the Heliconius cydno radiation and compare this variation to that within the closely related Heliconius melpomene and Heliconius timareta radiations. Our data, which consist of both mtDNA and genome-scan data from nearly 2250 amplified fragment length polymorphism (AFLP) loci, reveal a complex history of differentiation and admixture at different geographic scales. Both mtDNA and AFLP phylogenies suggest that H. timareta and H. cydno are probably geographic extremes of the same radiation that probably diverged from H. melpomene prior to the Pliocene-Pleistocene boundary, consistent with hypotheses of diversification that rely on geological events in the Pliocene. The mtDNA suggests that this radiation originated in Central America or the northwestern region of South America, with a subsequent colonization of the eastern and western slopes of the Andes. Our genome-scan data indicate significant admixture among sympatric H. cydno/H. timareta and H. melpomene populations across the extensive geographic ranges of the two radiations. Within H. cydno, both mtDNA and AFLP data indicate significant population structure at local scales, with strong genetic differences even among adjacent H. cydno colour pattern races. These genetic patterns highlight the importance of past geoclimatic events, intraspecific gene flow, and local population differentiation in the origin and establishment of new adaptive forms.


Personalized pharmacotherapy in psychiatry.
The hypothesis of each individual being special and different leading to heterogenity of diseases sets the ground for the concept of personalized medicine. Personalized psychiatry follows the principles of personalized medicine. A constituent part of an individually adapted approach towards the psychiatric patient presents itself thorough personalized psychiatry. The development of pharmacogenomics and pharmacogenetics as well as the nanotechnology based on them ensures implementation of personalized medicine principles in psychiatry to a greater extent than other medical disciplines. In the field of pharmacogenomics, the greatest advance was achieved by the study of genetic variability in drug metabolism. All the predispositions are now present for the implementation of pharmacogenetic tests in routine practice. Pharmacogenetic testing for medications which are metabolised thorough two polymorph cytochromes P 450: CYP2D6 and CYP2C19 is of special significance due to their involvement in most adverse and ultrafast metabolism of psychopharmacs. The potential application of personalized medicine in psychiatry, supported by pharmacogenetics and pharmacogenomics, are: personalized medication choice, personalized dosage, anticipation of possible side-effects individually and personalized follow-up treatment with rehabilitation. The authors conclude how the development of pharmacogenomics and pharmacogenetics as well as the nanotechnology based on them, presents a step forward in creating a personalized therapeutic approach in psychiatry. However, the burden of applying the most appropriate therapeutic agent and medication tapering remains based on clinician decision. Pharmacogenetics can only help by making therapeutic decisions with one less unknown element.


Orientation coding: a specific deficit in Williams syndrome?
Williams syndrome (WS) is a rare genetic disorder with a unique cognitive profile in which verbal abilities are markedly stronger than visuospatial abilities. This study investigated the claim that orientation coding is a specific deficit within the visuospatial domain in WS. Experiment 1 employed a simplified version of the Benton Judgement of Line Orientation task and a control, length-matching task. Results demonstrated comparable levels of orientation matching performance in the group with WS and a group of typically developing (TD) controls matched by nonverbal ability, although it is possible that floor effects masked group differences. A group difference was observed in the length-matching task due to stronger performance from the control group. Experiment 2 employed an orientation-discrimination task and a length-discrimination task. Contrary to previous reports, the results showed that individuals with WS were able to code by orientation to a comparable level as that of their matched controls. This demonstrates that, although some impairment is apparent, orientation coding does not represent a specific deficit in WS. Comparison between Experiments 1 and 2 suggests that orientation coding is vulnerable to task complexity. However, once again, this vulnerability does not appear to be specific to the population with WS, as it was also apparent in the TD controls.


Neutrophil Recovery in Breast Cancer Patients Receiving Docetaxel-Containing Chemotherapy with and without Granulocyte Colony-Stimulating Factor Prophylaxis.
The primary outcome of the current study is, whether there is a protective effect of prior chemotherapy or of prior granulocyte colony-stimulating factor (G-CSF) on the next cycle blood cell counts. Hematologic toxicity was evaluated, based on a randomized phase III study in breast cancer patients (n = 167) with >20% risk of febrile neutropenia. The primary endpoint was the nadir blood cell counts for patients treated with G-CSF given during all 6 chemotherapy cycles or limited to the first 2 chemotherapy cycles only. For the present analyses, 47 patients were eligible. In the G-CSF 1-6 arm, the median white blood cell count (WBC) and absolute neutrophil count (ANC) nadir slowly decreased from 10.8 × 109/L in cycle 1 to 7.5 × 109/L in cycle 6 and from 7.1 × 109/L to 5.5 × 109/L, respectively. The median WBC nadir in the G-CSF 1-2 arm decreased from 1.2 × 109/L in cycle 3 to 0.9 × 109/L in cycle 6 and the ANC nadir showed a grade 4 neutropenia of 0.1 × 109/L in cycles 3-6. All patients had ANC recovery to normal levels (≥1.5 × 109/L) without delay on day 1 of the next cycle. We conclude that there is no protective effect of prior G-CSF or prior chemotherapy use on nadir blood cell counts in subsequent cycles.


Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study.
Objective To examine long term cardiorenal outcomes associated with increased concentrations of creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment.Design Population based cohort study using electronic health records from the Clinical Practice Research Datalink and Hospital Episode Statistics.Setting UK primary care, 1997-2014.Participants Patients starting treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers (n=122 363).Main outcome measures Poisson regression was used to compare rates of end stage renal disease, myocardial infarction, heart failure, and death among patients with creatinine increases of 30% or more after starting treatment against those without such increases, and for each 10% increase in creatinine. Analyses were adjusted for age, sex, calendar period, socioeconomic status, lifestyle factors, chronic kidney disease, diabetes, cardiovascular comorbidities, and use of other antihypertensive drugs and non-steroidal anti-inflammatory drugs.Results Among the 2078 (1.7%) patients with creatinine increases of 30% or more, a higher proportion were female, were elderly, had cardiorenal comorbidity, and used non-steroidal anti-inflammatory drugs, loop diuretics, or potassium sparing diuretics. Creatinine increases of 30% or more were associated with an increased adjusted incidence rate ratio for all outcomes, compared with increases of less than 30%: 3.43 (95% confidence interval 2.40 to 4.91) for end stage renal disease, 1.46 (1.16 to 1.84) for myocardial infarction, 1.37 (1.14 to 1.65) for heart failure, and 1.84 (1.65 to 2.05) for death. The detailed categorisation of increases in creatinine concentrations (<10%, 10-19%, 20-29%, 30-39%, and ≥40%) showed a graduated relation for all outcomes (all P values for trends <0.001). Notably, creatinine increases of less than 30% were also associated with increased incidence rate ratios for all outcomes, including death (1.15 (1.09 to 1.22) for increases of 10-19% and 1.35 (1.23 to 1.49) for increases of 20-29%, using <10% as reference). Results were consistent across calendar periods, across subgroups of patients, and among continuing users.Conclusions Increases in creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment were associated with adverse cardiorenal outcomes in a graduated relation, even below the guideline recommended threshold of a 30% increase for stopping treatment.


Ultrasonographic evaluation of reticular motility during rest, eating, rumination and stress in 30 healthy cows.
A 3.5 MHz linear transducer was used to assess the motility of the reticulum in 30 healthy, standing, non-sedated cows while they were at rest, eating, ruminating and under stress. The ultrasonographic examinations were made over periods of nine minutes and video recorded for analysis. The reticulum contracted in a biphasic pattern while the cows were resting, eating or stressed. The first contraction was incomplete and was followed by a period of incomplete relaxation. A complete second contraction occurred immediately afterwards, followed by an interval of complete relaxation and the return of the organ to its original position. When the cows were ruminating, a regurgitation contraction, which was incomplete, occurred immediately before the biphasic contraction. The number of reticular contractions in a nine-minute period was largest when the cows were eating (13.9 contractions, or approximately 1.5 per minute) and smallest when they were stressed (9.3 contractions, or approximately 1 per minute). The duration of the first reticular contraction was shortest during rumination (2.4 seconds) and longest when the cows were eating (3.0 seconds). The interval between two biphasic contractions was shortest when the cows were eating (31.6 seconds) and longest when they were stressed (53.8 seconds).


Heterogeneous Contribution of Insulin Sensitivity and Secretion Defects to Gestational Diabetes Mellitus.
To characterize physiologic subtypes of gestational diabetes mellitus (GDM). Insulin sensitivity and secretion were estimated in 809 women at 24-30 weeks' gestation, using oral glucose tolerance test-based indices. In women with GDM (8.3%), defects in insulin sensitivity or secretion were defined below the 25th percentile in women with normal glucose tolerance (NGT). GDM subtypes were defined based on the defect(s) present. Relative to women with NGT, women with predominant insulin sensitivity defects (51% of GDM) had higher BMI and fasting glucose, larger infants (birth weight z score 0.57 [-0.01 to 1.37] vs. 0.03 [-0.53 to 0.52], P = 0.001), and greater risk of GDM-associated adverse outcomes (57.6 vs. 28.2%, P = 0.003); differences were independent of BMI. Women with predominant insulin secretion defects (30% of GDM) had BMI, fasting glucose, infant birth weights, and risk of adverse outcomes similar to those in women with NGT. Heterogeneity of physiologic processes underlying hyperglycemia exists among women with GDM. GDM with impaired insulin sensitivity confers a greater risk of adverse outcomes.


Warming assessment of the bottom-up Paris Agreement emissions pledges.
Under the bottom-up architecture of the Paris Agreement, countries pledge Nationally Determined Contributions (NDCs). Current NDCs individually align, at best, with divergent concepts of equity and are collectively inconsistent with the Paris Agreement. We show that the global 2030-emissions of NDCs match the sum of each country adopting the least-stringent of five effort-sharing allocations of a well-below 2 °C-scenario. Extending such a self-interested bottom-up aggregation of equity might lead to a median 2100-warming of 2.3 °C. Tightening the warming goal of each country's effort-sharing approach to aspirational levels of 1.1 °C and 1.3 °C could achieve the 1.5 °C and well-below 2 °C-thresholds, respectively. This new hybrid allocation reconciles the bottom-up nature of the Paris Agreement with its top-down warming thresholds and provides a temperature metric to assess NDCs. When taken as benchmark by other countries, the NDCs of India, the EU, the USA and China lead to 2.6 °C, 3.2 °C, 4 °C and over 5.1 °C warmings, respectively.


Hyperbaric Oxygen Therapy to Avoid Blindness From Filler Injection.
The most serious complication of filler or fat injection is blindness. According to a recent systematic review of 98 patients of blindness provoked by filler or fat injection, only 2 patients had the outcome of a complete recovery of vision.In the literature, only 2 papers were found in which hyperbaric oxygen therapy (HBOT) was used in ophthalmic artery obstruction. However, no improvement of vision was obtained in either patient. Recently, the authors treated a patient who had central retinal vein occlusion and cilioretinal artery occlusion with HBOT (daily 2-hour sessions at 253 kPa for 14 days), and his visual acuity returned to normal.In central retinal artery obstruction, if the cilioretinal artery is present, it will maintain the thickness of the retina to a variable extent. Though the size of the cilioretinal artery and the area it supplies varies, 36.2% (32.1-40.2%) of people have a cilioretinal artery.Thereafter, HBOT might be applied to patients with central retinal artery occlusion following filler injection.


Recurrent spontaneous hemarthrosis associated with reflex sympathetic dystrophy.
Reflex sympathetic dystrophy is a mysterious entity with unclear pathogenesis. The diagnosis is largely clinical and based on signs and symptoms of pain and vasomotor dysfunction. Treatment is a challenge because the underlying mechanism remains unknown. Our patient is a 75-year-old woman 2 years after left total knee replacement who presented with her second spontaneous hemarthrosis in 3 months. After arthrocentesis, dusky discoloration, edema, hyperesthesia, and decreased range of motion of the left knee and entire distal extremity were noted. Despite analgesia and physical therapy her symptoms worsened. Radiographs of her left knee showed severe periprosthetic osteopenia and a triple phase bone scan was negative. Clinically, reflex sympathetic dystrophy was considered likely and a lumbar sympathetic block was performed. The patient improved and continued to do well after a series of blocks. This is the first reported case of recurrent atraumatic hemarthrosis associated with reflex sympathetic dystrophy.


Association Between Food Distress and Smoking Among Racially and Ethnically Diverse Adults, Schenectady, New York, 2013-2014.
Smoking and poor nutrition are 2 leading preventable causes of death. This study investigated associations between smoking and indicators of individual- and neighborhood-level food distress among racially and ethnically diverse urban adults. We analyzed data from a health interview survey and a food environment assessment collected in 2013 and 2014 in Schenectady, New York. We constructed logistic regression models for current smoking with 6 indicators of food distress as exposure variables and sociodemographic characteristics, depression, anxiety, perceived stress, alcohol binge drinking, and disability as covariates. The analytic sample consisted of 1,917 adults; 59.4% were female, more than half were racial/ethnic minorities (26.2% non-Hispanic black, 10.3% Hispanic, 10.9% Guyanese, 4.0% multiracial and other), and 37.1% were current smokers. All indicators of food distress remained in the parsimonious final model: consuming 0 or 1 serving of fruits and vegetables daily more than doubled the odds of smoking, compared with consuming 5 or more servings (odds ratio [OR], 2.05). Food insecurity (OR, 1.77), receiving Supplemental Nutrition Assistance Program benefits (OR, 1.79), using a food pantry (OR, 1.41), living in a neighborhood with low access to healthy food (OR, 1.40), and shopping for food often at a store with limited healthy food choices (OR, 1.38) were also associated with significantly higher odds of smoking. Recognizing that smoking and food distress are independently associated would lead to innovative public health intervention strategies. We suggest stronger collaboration between tobacco and nutrition public health professionals to synergistically reduce tobacco use and improve nutrition behavior and food environments in communities.


Long chain n-3 polyunsaturated fatty acids and incidence rate of coronary artery calcification in Japanese men in Japan and white men in the USA: population based prospective cohort study.
To determine whether serum concentrations of long chain n-3 polyunsaturated fatty acids (LCn3PUFAs) contribute to the difference in the incidence rate of coronary artery calcification (CAC) between Japanese men in Japan and white men in the USA. In a population based, prospective cohort study, 214 Japanese men and 152 white men aged 40-49 years at baseline (2002-2006) with coronary calcium score (CCS)=0 were re-examined for CAC in 2007-2010. Among these, 175 Japanese men and 113 white men participated in the follow-up exam. Incident cases were defined as participants with CCS≥10 at follow-up. A relative risk regression analysis was used to model the incidence rate ratio between the Japanese and white men. The incidence rate ratio was first adjusted for potential confounders at baseline and then further adjusted for serum LCn3PUFAs at baseline. Mean (SD) serum percentage of LCn3PUFA was >100% higher in Japanese men than in white men (9.08 (2.49) vs 3.84 (1.79), respectively, p<0.01). Japanese men had a significantly lower incidence rate of CAC compared to white men (0.9 vs 2.9/100 person-years, respectively, p<0.01). The incidence rate ratio of CAC taking follow-up time into account between Japanese and white men was 0.321 (95% CI 0.150 to 0.690; p<0.01). After adjusting for age, systolic blood pressure, low density lipoprotein cholesterol, diabetes, and other potential confounders, the ratio remained significant (0.262, 95% CI 0.094 to 0.731; p=0.01). After further adjusting for LCn3PUFAs, however, the ratio was attenuated and became non-significant (0.376, 95% CI 0.090 to 1.572; p=0.18). LCn3PUFAs significantly contributed to the difference in the incidence of CAC between Japanese and white men.


Use of acupuncture in female infertility and a summary of recent acupuncture studies related to embryo transfer.
During the last five years the use of acupuncture in female infertility as an adjuvant to conventional treatment in assisted reproductive technology (ART) has increased in popularity. The present paper briefly discusses clinical and experimental data on the effect of acupuncture on uterine and ovarian blood flow, as an analgesic method during ART, and on endocrine and metabolic disturbances such as polycystic ovary syndrome (PCOS). Further it gives a summary of recent studies evaluating the effect of acupuncture before and after embryo transfer on pregnancy outcome. Of the four published RCTs, three reveal significantly higher pregnancy rates in the acupuncture groups compared with the control groups. But the use of different study protocols makes it difficult to draw definitive conclusions. It seems, however, that acupuncture has a positive effect and no adverse effects on pregnancy outcome.


Liquid-crystal tunable filter spectral imaging for brain tumor demarcation.
Past studies have demonstrated that combined fluorescence and diffuse reflectance spectroscopy can successfully discriminate between normal, tumor core, and tumor margin tissues in the brain. To achieve efficient, real-time surgical resection guidance with optical biopsy, probe-based spectroscopy must be extended to spectral imaging to spatially demarcate the tumor margins. We describe the design and characterization of a combined fluorescence and diffuse reflectance imaging system that uses liquid-crystal tunable filter technology. Experiments were conducted to quantitatively determine the linearity, field of view, spatial and spectral resolution, and wavelength sensitivity of the imaging system. Spectral images were acquired from tissue phantoms, mouse brain in vitro, and human cortex in vivo for functional testing of the system. The spectral imaging system produces measured intensities that are linear with sample emission intensity and integration time and possesses a 1 in. (2.54 cm) field of view for a 7 in. (18 cm) object distance. The spectral resolution is linear with wavelength, and the spatial resolution is pixel-limited. The sensitivity spectra for the imaging system provide a guide for the distribution of total image integration time between wavelengths. Functional tests in vitro demonstrate the capability to spectrally discriminate between brain tissues based on exogenous fluorescence contrast or endogenous tissue composition. In vivo imaging captures adequate fluorescence and diffuse reflectance intensities within a clinically viable 2 min imaging time frame and demonstrates the importance of hemostasis to acquired signal strengths and imaging speed.


Phylogenetic analysis of migration, differentiation, and class switching in B cells.
B cells undergo rapid mutation and selection for antibody binding affinity when producing antibodies capable of neutralizing pathogens. This evolutionary process can be intermixed with migration between tissues, differentiation between cellular subsets, and switching between functional isotypes. B cell receptor (BCR) sequence data has the potential to elucidate important information about these processes. However, there is currently no robust, generalizable framework for making such inferences from BCR sequence data. To address this, we develop three parsimony-based summary statistics to characterize migration, differentiation, and isotype switching along B cell phylogenetic trees. We use simulations to demonstrate the effectiveness of this approach. We then use this framework to infer patterns of cellular differentiation and isotype switching from high throughput BCR sequence datasets obtained from patients in a study of HIV infection and a study of food allergy. These methods are implemented in the R package dowser, available at https://dowser.readthedocs.io.


Novel touch-induced, Ca(2+)-dependent phobic response in a flagellate green alga.
The biflagellate green alga Spermatozopsis similis exhibits a remarkable avoidance reaction in addition to the photophobic or stop response characteristic of such algae. S. similis normally swims forward with its anteriorly attached flagella directed posteriorly and propagating sine-like waves base to tip. Upon contact with surfaces or other cells, S. similis responds with rapid backward swimming, covering distances of up to 50 microns in 140 to 220 msec. This reaction, which we term the mechanoshock response, also can be triggered by vigorous mechanical stimulation, but not by physiological light intensities. It consists of 3 phases: (1) a rapid acceleration phase with average duration of 31 msec; (2) a phase of about 66 msec with constant high speed (maximal velocities of > 600 microns.sec-1) or slow deceleration; and (3) a deceleration phase of approximately 83 msec, followed by a stop or short period of circling. The cells then resume forward swimming in a random direction. Prior to the mechanoshock response the flagella rapidly are brought together into a close parallel configuration extending anteriorly of the cell body. They then appear to propel the cell by undulatory beating, while the cell describes a pronounced helical path. Small decreases in the extracellular Ca2+ concentration, as well as low concentrations of Ba2+, strongly suppress the probability of this phobic reaction. We conclude that this mechanoshock response involves large Ca2+ influxes, probably mediated by mechanosensitive and/or stretch-activated ion-channel(s).


A 4-gene signature associated with clinical outcome in high-grade gliomas.
Gene expression studies provide molecular insights improving the classification of patients with high-grade gliomas. We have developed a risk estimation strategy based on a combined analysis of gene expression data to search for robust biomarkers associated with outcome in these tumors. We performed a meta-analysis using 3 publicly available malignant gliomas microarray data sets (267 patients) to define the genes related to both glioma malignancy and patient outcome. These biomarkers were used to construct a risk-score equation based on a Cox proportional hazards model on a subset of 144 patients. External validations were performed on microarray data (59 patients) and on RT-qPCR data (194 patients). The risk-score model performances (discrimination and calibration) were evaluated and compared with that of clinical risk factors, MGMT promoter methylation status, and IDH1 mutational status. This interstudy cross-validation approach allowed the identification of a 4-gene signature highly correlated to survival (CHAF1B, PDLIM4, EDNRB, and HJURP), from which an optimal survival model was built (P < 0.001 in training and validation sets). Multivariate analysis showed that the 4-gene risk score was strongly and independently associated with survival (hazard ratio = 0.46; 95% CI, 0.26-0.81; P = 0.007). Performance estimations indicated that this score added beyond standard clinical parameters and beyond both the MGMT methylation status and the IDH1 mutational status in terms of discrimination (C statistics, 0.827 versus 0.835; P < 0.001). The 4-gene signature provides an independent risk score strongly associated with outcome of patients with high-grade gliomas.


Autopsy consent, brain collection, and standardized neuropathologic assessment of ADNI participants: the essential role of the neuropathology core.
Our objectives are to facilitate autopsy consent, brain collection, and perform standardized neuropathologic assessments of all Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who come to autopsy at the 58 ADNI sites in the USA and Canada. Building on the expertise and resources of the existing Alzheimer's Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, MO, a Neuropathology Core (NPC) to serve ADNI was established with one new highly motivated research coordinator. The ADNI-NPC coordinator provides training materials and protocols to assist clinicians at ADNI sites in obtaining voluntary consent for brain autopsy in ADNI participants. Secondly, the ADNI-NPC maintains a central laboratory to provide uniform neuropathologic assessments using the operational criteria for the classification of AD and other pathologies defined by the National Alzheimer Coordinating Center (NACC). Thirdly, the ADNI-NPC maintains a state-of-the-art brain bank of ADNI-derived brain tissue to promote biomarker and multi-disciplinary clinicopathologic studies. During the initial year of funding of the ADNI Neuropathology Core, there was notable improvement in the autopsy rate to 44.4%. In the most recent year of funding (September 1(st), 2008 to August 31(st) 2009), our autopsy rate improved to 71.5%. Although the overall numbers to date are small, these data demonstrate that the Neuropathology Core has established the administrative organization with the participating sites to harvest brains from ADNI participants who come to autopsy. Within two years of operation, the Neuropathology Core has: (1) implemented a protocol to solicit permission for brain autopsy in ADNI participants at all 58 sites who die and (2) to send appropriate brain tissue from the decedents to the Neuropathology Core for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI of the implementation of the NPC is very clear. Prior to the establishment of the NPC in September 2007, there were 6 deaths but no autopsies in ADNI participants. Subsequent to the establishment of the Core there have been 17 deaths of ADNI participants and 10 autopsies. Hence, the autopsy rate has gone from 0% to 59%. The third major accomplishment is the detection of co-existent pathologies with AD in the autopsied cases. It is possible that these co-morbidities may contribute to any variance in ADNI data.


Coffee and caffeine consumption in relation to sex hormone-binding globulin and risk of type 2 diabetes in postmenopausal women.
Coffee consumption has been inversely associated with type 2 diabetes risk, but its mechanisms are largely unknown. We aimed to examine whether plasma levels of sex hormones and sex hormone-binding globulin (SHBG) may account for the inverse association between coffee consumption and type 2 diabetes risk. We conducted a case-control study nested in the prospective Women's Health Study (WHS). During a median follow-up of 10 years, 359 postmenopausal women with newly diagnosed type 2 diabetes were matched with 359 control subjects by age, race, duration of follow-up, and time of blood draw. Caffeinated coffee was positively associated with SHBG but not with sex hormones. Multivariable-adjusted geometric mean levels of SHBG were 26.6 nmol/l among women consuming ≥4 cups/day of caffeinated coffee and 23.0 nmol/l among nondrinkers (P for trend = 0.01). In contrast, neither decaffeinated coffee nor tea was associated with SHBG or sex hormones. The multivariable-adjusted odds ratio (OR) of type 2 diabetes for women consuming ≥4 cups/day of caffeinated coffee compared with nondrinkers was 0.47 (95% CI 0.23-0.94; P for trend = 0.047). The association was largely attenuated after further adjusting for SHBG (OR 0.71 [95% CI 0.31-1.61]; P for trend = 0.47). In addition, carriers of rs6259 minor allele and noncarriers of rs6257 minor allele of SHBG gene consuming ≥2 cups/day of caffeinated coffee had lower risk of type 2 diabetes in directions corresponding to their associated SHBG. Our findings suggest that SHBG may account for the inverse association between coffee consumption and type 2 diabetes risk among postmenopausal women.


Time-related expression profiles for heat shock protein gene transcripts (HSP40, HSP70) in the central nervous system of Lymnaea stagnalis exposed to thermal stress.
Organisms exposed to environmental stressors respond by rapidly synthesising a suite of highly conserved proteins called heat shock proteins (HSPs). Environmental stress can also enhance and/or block memory formation, with long-term memory formation requiring gene activation and protein synthesis. Thermal stress in the pond snail Lymnaea stagnalis can enhance memory formation, and, in this study, the effect of thermal stress on HSP gene expression in the nervous system was investigated. Time-related expression profiles for HSP40 and HSP70 indicated rapid (<30 min) induction for both transcripts. For HSP40, induction was <20 fold relative to control and expression returned to control levels within 8 h, whereas HSP70 induction was >100 fold and expression did not return to control levels within 8 h.


Daily average temperature and mortality among the elderly: a meta-analysis and systematic review of epidemiological evidence.
The impact of climate change on the health of vulnerable groups such as the elderly has been of increasing concern. However, to date there has been no meta-analysis of current literature relating to the effects of temperature fluctuations upon mortality amongst the elderly. We synthesised risk estimates of the overall impact of daily mean temperature on elderly mortality across different continents. A comprehensive literature search was conducted using MEDLINE and PubMed to identify papers published up to December 2010. Selection criteria including suitable temperature indicators, endpoints, study-designs and identification of threshold were used. A two-stage Bayesian hierarchical model was performed to summarise the percent increase in mortality with a 1°C temperature increase (or decrease) with 95% confidence intervals in hot (or cold) days, with lagged effects also measured. Fifteen studies met the eligibility criteria and almost 13 million elderly deaths were included in this meta-analysis. In total, there was a 2-5% increase for a 1°C increment during hot temperature intervals, and a 1-2 % increase in all-cause mortality for a 1°C decrease during cold temperature intervals. Lags of up to 9 days in exposure to cold temperature intervals were substantially associated with all-cause mortality, but no substantial lagged effects were observed for hot intervals. Thus, both hot and cold temperatures substantially increased mortality among the elderly, but the magnitude of heat-related effects seemed to be larger than that of cold effects within a global context.


Neurosurgical control of chronic pain.
The neurosurgeon can play a significant role in the management of chronic pain. This potential is all to often unrealized or distorted by a lack of knowledge about patients who are suffering from chronic pain. Patient selection is the most important determinant of successful surgical therapy. Patients with chronic pain due to a neoplasm should be offered prompt, definitive neurosurgical intervention. Neurosurgical therapy is less likely to be successful if the pain is secondary to benign disease; tic douloureux is an exception to this rule. If chronic pain behavior is not primarily due to noxious peripheral input, surgery is unlikely to yield any long-term benefit. Augmentation of input by skin stimulation or electrical stimulation of various regions in the peripheral and central nervous system may become important therapeutic procedures for the neurosurgeon.


Detection of ocular surface abnormalities in experimental vitamin A deficiency.
Hypovitaminosis A is the major cause of childhood blindness in many developing countries. Unfortunately, serum vitamin A levels do not accurately reflect liver stores, and there is no good objective test for detecting early, physiologically important deficiency. The purpose of this study was to determine if we could detect ocular surface abnormalities in the eyes of vitamin A-deficient rabbits at early stages of xerophthalmia. Cellulose acetate filter strip impressions were taken serially from the bulbar conjunctiva of vitamin A-deficient rabbits every two weeks, beginning eight to 12 weeks before keratinization of the corneal or conjunctival epithelium was clinically apparent. The percentage of light microscopic fields containing goblet cells decreased, and the percentage of fields containing enlarged epithelial cells increased in a linear fashion, beginning at least four to six weeks before the clinical changes. The results indicate that this technique may be of potential usefulness as a screening tool for early xerophthalmia.


[Nursing practice in view of adverse events following vaccination].
The objectives of this article are to identify the adverse events following vaccination, the focus if nursing practice, using the Post-Vaccination Adverse Events Information System database, and discuss on the nurses' practice on the surveillance for those events. Secondary data were those regarding the vaccines applied in the Brazilian public health system, in the period from 1999 to 2008, totaling 65,442 registers, 59,899 of which were confirmed and 1,403 were associated with another vaccine. The 16 nursing practice events totaled 21,727 registers. Although they account for 35.4% of the registers, the data do not reflect the reality, because their reliability depends on the knowledge network that comprises diagnosis, notification and inclusion in the system. Discussions were made on interventions for the most prevalent events: fever and local events. Most interventions established in the adverse events manual was in agreement with the literature, though there were differences in the content between conducts for the same event due to different vaccines.


The Preventive Effect of Coffee Compounds on Dermatitis and Epidermal Pigmentation after Ultraviolet Irradiation in Mice.
Ultraviolet (UV) irradiation is well known to promote inflammation and pigmentation of skin. UVB mainly affects dermatitis and pigmentation. Coffee contains a number of polyphenols, such as caffeic acid (CA) and chlorogenic acid (CGA) but their in vivo bioactivity for photobiology remains unclear. C57BL/6j male mice were irradiated with UVB (1.0 kJ/m2/day) for 3 days. Five days after the final session of UVB irradiation, the dorsal skin, ear epidermis, and blood samples were analyzed to investigate the inflammatory factors, melanogenesis factors and related hormones. After the oral administration of CA (100 mg/day) or CGA (100 mg/day) for 8 days, only CA was found to inhibit dermatitis and pigmentation. The pathway by which CA inhibits dermatitis is related to the mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)1/2/cAMP response element binding protein (CREB) pathway. Otherwise, the pathway by which CA inhibits pigmentation is related to the activation of the β-endorphin-μ-opioid receptor and suppresses the cAMP-microphthalmia-associated transcription factor (MITF) pathway. It is suggested that the oral administration of CA prevented dermatitis and pigmentation after UVB irradiation in mice.


The Pliocene marine megafauna extinction and its impact on functional diversity.
The end of the Pliocene marked the beginning of a period of great climatic variability and sea-level oscillations. Here, based on a new analysis of the fossil record, we identify a previously unrecognized extinction event among marine megafauna (mammals, seabirds, turtles and sharks) during this time, with extinction rates three times higher than in the rest of the Cenozoic, and with 36% of Pliocene genera failing to survive into the Pleistocene. To gauge the potential consequences of this event for ecosystem functioning, we evaluate its impacts on functional diversity, focusing on the 86% of the megafauna genera that are associated with coastal habitats. Seven (14%) coastal functional entities (unique trait combinations) disappeared, along with 17% of functional richness (volume of the functional space). The origination of new genera during the Pleistocene created new functional entities and contributed to a functional shift of 21%, but minimally compensated for the functional space lost. Reconstructions show that from the late Pliocene onwards, the global area of the neritic zone significantly diminished and exhibited amplified fluctuations. We hypothesize that the abrupt loss of productive coastal habitats, potentially acting alongside oceanographic alterations, was a key extinction driver. The importance of area loss is supported by model analyses showing that animals with high energy requirements (homeotherms) were more susceptible to extinction. The extinction event we uncover here demonstrates that marine megafauna were more vulnerable to global environmental changes in the recent geological past than previously thought.


Ambient UVB Dose and Sun Enjoyment Are Important Predictors of Vitamin D Status in an Older Population.
Background: UVB-induced skin synthesis is considered the key source of vitamin D, yet exposure to UVB is poorly accounted for in epidemiological studies.Objectives: The aim of this study was to examine the association of serum 25-hydroxyvitamin D [25(OH)D] concentration with accurately measured ambient UVB dose, sun enjoyment, supplements, and other factors.Methods: An all-Irish cohort of community-dwelling participants aged >60 y [median age: 73; 67% female; median 25(OH)D: 54.5 nmol/L] was used. Participants from this large, cross-sectional study completed a questionnaire to provide information on demographic factors and lifestyle (including supplement use and sun enjoyment). The Tropospheric Emission Monitoring Internet Service database was used to extract the daily ambient UVB dose at wavelengths that could induce vitamin D synthesis (D-UVB) over Ireland (latitude: 51°N-55°N). Blood sampling occurred throughout the year. Ambient exposure at the place of residence was calculated for each participant individually. Associations between determinants and serum 25(OH)D concentration were examined in a multivariate model. Random forest analysis was used to establish prediction models of vitamin D deficiency, and area under the curve (AUC) is shown.Results: In total, 5138 individuals were included. Median D-UVB was 63 mJ/cm2, which varied between seasons and latitudes, despite the small latitude differential. Vitamin D supplementation (β = 27.7; P < 10 × 10-10), D-UVB (β = 1.58 per 1000 mJ/cm2; P < 10 × 10-10), and sun enjoyment (β = 6.6; P < 0.001) were strongly positively associated with serum 25(OH)D. Those who avoided sunshine were largely at risk of deficiency (<40 nmol/L), whereas those who enjoyed sunshine tended to be vitamin D sufficient (≥50 nmol/L). D-UVB and sun enjoyment improved prediction of deficiency in non-supplement-taking individuals; the overall AUC improved by 3.5%.Conclusion: D-UVB and sun enjoyment are important predictors of vitamin D status, even in this elderly population at northern latitudes. Accurate estimation of ambient UVB can help to further clarify the role of other determinants of vitamin D status and inform sunshine recommendation guidelines.


NaV1.5 sodium channel window currents contribute to spontaneous firing in olfactory sensory neurons.
Olfactory sensory neurons (OSNs) fire spontaneously as well as in response to odor; both forms of firing are physiologically important. We studied voltage-gated Na(+) channels in OSNs to assess their role in spontaneous activity. Whole cell patch-clamp recordings from OSNs demonstrated both tetrodotoxin-sensitive and tetrodotoxin-resistant components of Na(+) current. RT-PCR showed mRNAs for five of the nine different Na(+) channel α-subunits in olfactory tissue; only one was tetrodotoxin resistant, the so-called cardiac subtype NaV1.5. Immunohistochemical analysis indicated that NaV1.5 is present in the apical knob of OSN dendrites but not in the axon. The NaV1.5 channels in OSNs exhibited two important features: 1) a half-inactivation potential near -100 mV, well below the resting potential, and 2) a window current centered near the resting potential. The negative half-inactivation potential renders most NaV1.5 channels in OSNs inactivated at the resting potential, while the window current indicates that the minor fraction of noninactivated NaV1.5 channels have a small probability of opening spontaneously at the resting potential. When the tetrodotoxin-sensitive Na(+) channels were blocked by nanomolar tetrodotoxin at the resting potential, spontaneous firing was suppressed as expected. Furthermore, selectively blocking NaV1.5 channels with Zn(2+) in the absence of tetrodotoxin also suppressed spontaneous firing, indicating that NaV1.5 channels are required for spontaneous activity despite resting inactivation. We propose that window currents produced by noninactivated NaV1.5 channels are one source of the generator potentials that trigger spontaneous firing, while the upstroke and propagation of action potentials in OSNs are borne by the tetrodotoxin-sensitive Na(+) channel subtypes.


3d phase-contrast nanotomography of unstained human skin biopsies may identify morphological differences in the dermis and epidermis between subjects.
Enteric neuropathy is described in most patients with gastrointestinal dysmotility and may be found together with reduced intraepidermal nerve fiber density (IENFD). The aim of this pilot study was to assess whether three-dimensional (3d) imaging of skin biopsies could be used to examine various tissue components in patients with gastrointestinal dysmotility. Four dysmotility patients of different etiology and two healthy volunteers were included. From each subject, two 3-mm punch skin biopsies were stained with antibodies against protein gene product 9.5 or evaluated as a whole with two X-ray phase-contrast computed tomography (CT) setups, a laboratory µCT setup and a dedicated synchrotron radiation nanoCT end-station. Two patients had reduced IENFD, and two normal IENFD, compared with controls. µCT and X-ray phase-contrast holographic nanotomography scanned whole tissue specimens, with optional high-resolution scans revealing delicate structures, without differentiation of various fibers and cells. Irregular architecture of dermal fibers was observed in the patient with Ehlers-Danlos syndrome and the patient with idiopathic dysmotility showed an abundance of mesenchymal ground substance. 3d phase-contrast tomographic imaging may be useful to illustrate traits of connective tissue dysfunction in various organs and to demonstrate whether disorganized dermal fibers could explain organ dysfunction.


Variable induction of vitellogenin genes in the varroa mite, Varroa destructor (Anderson & Trueman), by the honeybee, Apis mellifera L, host and its environment.
Transcript levels of vitellogenins (Vgs) in the varroa mite, Varroa destructor (Anderson & Trueman), were variably induced by interactions between the developing honeybee, Apis mellifera L, as a food source and the capped honeybee cell environment. Transcripts for two Vgs of varroa mites were sequenced and putative Vg protein products characterized. Sequence analysis of VdVg1 and VdVg2 proteins showed that each had greater similarity with Vg1 and Vg2 proteins from ticks, respectively, than between themselves and were grouped separately by phylogenetic analyses. This suggests there was a duplication of the ancestral acarine Vg gene prior to the divergence of the mites and ticks. Low levels of transcript were detected in immature mites, males and phoretic females. Following cell invasion by phoretic females, VdVg1 and VdVg2 transcript levels were up-regulated after cell capping to a maximum at the time of partial cocoon formation by the honeybee. During oviposition the two transcripts were differentially expressed with higher levels of VdVg2 being observed. A bioassay based on assessing the transcript levels was established. Increases in VdVg1 and VdVg2 transcripts were induced experimentally in phoretic females when they were placed inside a cell containing an early metamorphosing last instar bee but not when exposed to the metamorphosing bee alone. The variable response of Vg expression to the food source as well as environmental cues within the capped cell demonstrates that perturbation of host-parasite interactions may provide avenues to disrupt the reproductive cycle of the varroa mites and prevent varroasis.


Muscle development is independent of innervation during Drosophila embryogenesis.
We have examined the role of innervation in directing embryonic myogenesis, using a mutant (prospero), which delays the pioneering of peripheral motor nerves of the Drosophila embryo. In the absence of motor nerves, myoblasts fuse normally to form syncytial myotubes, myotubes form normal attachments to the epidermis, and a larval musculature comparable to the wild-type pattern is generated and maintained. Likewise, the twist-expressing myoblasts that prefigure the adult musculature segregate normally in the absence of motor nerves, migrate to their final embryonic positions and continue to express twist until the end of embryonic development. In the absence of motor nerves, myotubes uncouple at the correct developmental stage to form single cells. Subsequently, uninnervated myotubes develop the mature electrical and contractile properties of larval muscles with a time course indistinguishable from normally innervated myotubes. We conclude that innervation plays no role in the patterning, morphogenesis, maintenance or physiological development of the somatic muscles in the Drosophila embryo.


Influence of MCHR2 and MCHR2-AS1 Genetic Polymorphisms on Body Mass Index in Psychiatric Patients and In Population-Based Subjects with Present or Past Atypical Depression.
Obesity development during psychotropic treatments represents a major health issue in psychiatry. Melanin-concentrating hormone receptor 2 (MCHR2) is a central receptor involved in energy homeostasis. MCHR2 shares its promoter region with MCHR2-AS1, a long antisense non-coding RNA. The aim of this study was to determine whether tagging single nucleotide polymorphisms (tSNPs) of MCHR2 and MCHR2-AS1 are associated with the body mass index (BMI) in the psychiatric and in the general population. The influence of MCHR2 and MCHR2-AS1 tSNPs on BMI was firstly investigated in a discovery psychiatric sample (n1 = 474). Positive results were tested for replication in two other psychiatric samples (n2 = 164, n3 = 178) and in two population-based samples (CoLaus, n4 = 5409; GIANT, n5 = 113809). In the discovery sample, TT carriers of rs7754794C>T had 1.08 kg/m2 (p = 0.04) lower BMI as compared to C-allele carriers. This observation was replicated in an independent psychiatric sample (-2.18 kg/m2; p = 0.009). The association of rs7754794C>T and BMI seemed stronger in subjects younger than 45 years (median of age). In the population-based sample, a moderate association was observed (-0.17 kg/m2; p = 0.02) among younger individuals (<45y). Interestingly, this association was totally driven by patients meeting lifetime criteria for atypical depression, i.e. major depressive episodes characterized by symptoms such as an increased appetite. Indeed, patients with atypical depression carrying rs7754794-TT had 1.17 kg/m2 (p = 0.04) lower BMI values as compared to C-allele carriers, the effect being stronger in younger individuals (-2.50 kg/m2; p = 0.03; interaction between rs7754794 and age: p-value = 0.08). This study provides new insights on the possible influence of MCHR2 and/or MCHR2-AS1 on obesity in psychiatric patients and on the pathophysiology of atypical depression.


The Effect of Degree of Temporal Bone Pneumatization on Sound Transmission of Pulsatile Tinnitus Induced by Sigmoid Sinus Diverticulum and/or Dehiscence: A Clinical and Experimental Study.
Although many studies have suggested that air cells may play an important role in sigmoid sinus diverticulum and/or dehiscence (SSDD)-induced pulsatile tinnitus (PT), the exact effects remain unclear. This study aims to quantitatively investigate the effect of different degrees of pneumatization of temporal bone on sound transmission from the sigmoid sinus to the tympanic cavity. In the clinical study, 25 patients were enrolled to measure the sound intensity and frequency of SSDD-induced PT. In the experimental study, sound inputs at different frequencies at the dehiscent sigmoid plate were measured and compared among realistic object models of different degrees of pneumatization, when sound intensity in the tympanic cavity was fixed as the level of the PT sound intensity sensed by patients. The sound intensity sensed by PT patients was 34.0 ± 13.0 dB SPL, which represented the sound intensity in the tympanic cavity transmitted from the dehiscent sigmoid plate. In the experimental study, when sound received in the tympanic cavity was fixed at 34 dB SPL, the mean inputs of sound intensity at the dehiscent sigmoid plate were 46.9, 46.2, 45.2, 47.1, 57, 57.4, and 74.1 dB SPL in a hypo-pneumatized model; 42.6, 43, 41.5, 43.2, 47.3, 58.2, and 78.8 dB SPL in a moderately pneumatized model; 52.6, 52.8, 48.1, 61, 64.2, 82.4, and >87.3 dB SPL in a well-pneumatized model; and 47.2, 46.2, 45.4, 49.4, 54.9, 66.6, and 77.7 dB SPL in hyper-pneumatized model, with increased sound frequencies (125-8000 Hz). The mean sound transmission distances were 41.7 mm, 45.2 mm, 47.6 mm, and 48.4 mm in successively better pneumatized models. Sound reduces while passing through air cells and attenuation is lowest in the moderately pneumatized temporal bone, followed by the hypo- and hyper-pneumatized temporal bones, and the highest in the well-pneumatized temporal bone. Lower-frequency sound attenuation (≤1000 Hz) is less than that of higher-frequency sound (>1000 Hz).


Raising awareness of on-line cancer information: helping providers empower patients.
While the digital divide remains a special problem in health care, providers' reluctance to refer patients to the Internet is an equally important problem. The Bridging the Digital Divide Project: Your Access to Cancer Information was designed with two target audiences in mind-consumers and health care providers. A total of 256 providers from varied health care settings enrolled in workshops over a 10-month period (2001-2002). Results suggest differences in awareness and use of on-line cancer information among providers and confirm that many providers need to become more comfortable with referring patients to on-line information. At completion of the workshops, all participants reported an increased awareness of cancer information websites, increased confidence in making judgments about the reliability and appropriateness of the sites, an increased willingness to discuss Internet information sources with patients and their family members, and an increased awareness of and intention to use the CIS. Providers from the community hospital were more likely than other groups to report that what they had learned about the Internet was helpful and that their comfort level using the Internet had increased. Partnerships between providers and the CIS may help to further increase this comfort level, ultimately benefiting cancer patients.


Comparative effectiveness of beta-blockers in elderly patients with heart failure.
Whether beta-blockers (BBs) other than carvedilol, metoprolol succinate, and bisoprolol fumarate (evidence-based beta-blockers [EBBBs]) improve survival in patients with heart failure (HF) is unknown. We compared the effectiveness of EBBBs vs non-EBBBs on survival. Our study population included North Carolina residents at least 65 years old who were eligible for Medicare and Medicaid with pharmacy benefits and had had at least 1 hospitalization for HF during the period 2001 through 2004. Primary outcome was survival from 30 days to 1 year. Secondary outcomes included number and days of rehospitalizations for HF and number of outpatient visits. Cohorts were defined by BB class (EBBBs, non-EBBBs, or no BBs) in first 30 days after discharge from index hospitalization for HF. Outcomes were analyzed using inverse probability-weighted (IPW) estimators with propensity score adjustment. Of 11,959 patients, 40% were nonwhite, 79% were female, and 26% were at least 85 years old. Fifty-nine percent received no BB, 23% received EBBBs, and 18% received non-EBBBs. One-year adjusted mortality rates were 28.3% (no BBs), 22.8% (non-EBBBs), and 24.2% (EBBBs). The IPW-adjusted comparisons of 1-year mortality outcomes for either non-EBBBs or EBBBs compared with no BBs were statistically significant (P = .002 for both), but there was no statistical difference between the 2 BB groups (P = .43). The IPW-adjusted mean numbers of rehospitalizations for HF were 0.33 (no BBs), 0.29 (non-EBBBs), and 0.41 (EBBBs), with statistically more rehospitalizations in patients receiving EBBBs compared with no BBs (P = .002) and with non-EBBBs (P < .001). In this elderly population, the comparative effectiveness of EBBBs vs non-EBBBs was similar for 1-year survival, whereas the rehospitalization rate was higher for patients receiving EBBBs.


Model-based learning retrospectively updates model-free values.
Reinforcement learning (RL) is widely regarded as divisible into two distinct computational strategies. Model-free learning is a simple RL process in which a value is associated with actions, whereas model-based learning relies on the formation of internal models of the environment to maximise reward. Recently, theoretical and animal work has suggested that such models might be used to train model-free behaviour, reducing the burden of costly forward planning. Here we devised a way to probe this possibility in human behaviour. We adapted a two-stage decision task and found evidence that model-based processes at the time of learning can alter model-free valuation in healthy individuals. We asked people to rate subjective value of an irrelevant feature that was seen at the time a model-based decision would have been made. These irrelevant feature value ratings were updated by rewards, but in a way that accounted for whether the selected action retrospectively ought to have been taken. This model-based influence on model-free value ratings was best accounted for by a reward prediction error that was calculated relative to the decision path that would most likely have led to the reward. This effect occurred independently of attention and was not present when participants were not explicitly told about the structure of the environment. These findings suggest that current conceptions of model-based and model-free learning require updating in favour of a more integrated approach. Our task provides an empirical handle for further study of the dialogue between these two learning systems in the future.


Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria.
A main challenge in chemotherapy is to determine the in cellulo parameters modulating the drug concentration required for therapeutic action. It is absolutely urgent to understand membrane permeation and intracellular concentration of antibiotics in clinical isolates: passing the membrane barrier to reach the threshold concentration inside the bacterial periplasm or cytoplasm is the pivotal step of antibacterial activity. Ceftazidime (CAZ) is a key molecule of the combination therapy for treating resistant bacteria. We designed and synthesized different fluorescent CAZ derivatives (CAZ*, CAZ**) to dissect the early step of translocation-accumulation across bacterial membrane. Their activities were determined on E. coli strains and on selected clinical isolates overexpressing ß-lactamases. The accumulation of CAZ* and CAZ** were determined by microspectrofluorimetry and epifluorimetry. The derivatives were properly translocated to the periplasmic space when we permeabilize the outer membrane barrier. The periplasmic location of CAZ** was related to a significant antibacterial activity and with the outer membrane permeability. This study demonstrated the correlation between periplasmic accumulation and antibiotic activity. We also validated the method for approaching ß-lactam permeation relative to membrane permeability and paved the way for an original matrix for determining "Structure Intracellular Accumulation Activity Relationship" for the development of new therapeutic candidates.


Gene duplication and divergence in the early evolution of vertebrates.
The duplication-degeneration-complementation model of duplicate gene preservation by subfunctionalisation is currently the best explanation for the high level of retention of duplicate genes in early vertebrate evolution. But a direct test of the applicability of this model to such ancient evolutionary events may be difficult. More likely, recent duplications in other lineages will allow us to establish general principles concerning the fate of genes of different types that are duplicated in different ways. These principles may be then extrapolated to understanding the early evolution of the vertebrates.


A phase 1b study of glasdegib + azacitidine in patients with untreated acute myeloid leukemia and higher-risk myelodysplastic syndromes.
This phase 1b study evaluated glasdegib (100 mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug-drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2-14.0) months and 15.8 (9.3-21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits.Trial registration: ClinicalTrials.gov NCT02367456.


Payments for nutrient uptake in the blue bioeconomy - When to be careful and when to go for it.
Harvesting of marine biomass for various applications may generate ecosystem services that currently lack a market price. One of these is nutrient uptake, which could counteract eutrophication. Market-based instruments (MBIs) such as cap & trade, compensatory mitigation, and payment for ecosystem services could help internalize such positive externalities. However, activities of the blue bioeconomy are diverse. We show that identifiable market characteristics can provide guidance concerning when to use these instruments and not. We find that the activities most suitable for MBIs are those that have positive environmental impacts but that are not (yet) financially viable. For activities that are already profitable on the biomass market, ensuring 'additionality' may be a significant problem for MBIs, especially for cap & trade systems or compensatory mitigation. We provide an overview of how some current biomass options fit into this framework and give suggestions on which biomass types to target.


Surgical management of intra-abdominal mislocated intrauterine devices.
We report on our experience in surgical treatment of patients with intra-abdominal intrauterine devices (IUDs). A total of 10 patients were retrospectively analyzed. Diagnosis was based on gynecologic examination, transvaginal sonography, and abdominal X-ray. All of the IUDs were inserted by trained midwives, either in the puerperal period (n=3) or within 1 year after puerperium (n=7). Five women were asymptomatic at the time of diagnosis, three were pregnant and two complained of pelvic pain. Eight patients were managed by laparoscopy, whereas laparotomy was required in two. Abscess formation was present in two cases. The postoperative course was uneventful in all patients. A missing string during gynecologic examination is the first sign of an intra-abdominal IUD in all cases. Transvaginal sonography should be combined with abdominal X-ray to reach a definitive diagnosis. Laparoscopic treatment may be appropriate in most of the cases.