The promoter of cell growth- and RNA protection-associated SND1 gene is activated by endoplasmic reticulum stress in human hepatoma cells

Background: Staphyloccocal nuclease domain-containing protein 1 (SND1) is involved in the regulation of gene expression and RNA protection. While numerous studies have established that SND1 protein expression is modulated by cellular stresses associated with tumor growth, hypoxia, inflammation, heat- shock and oxidative conditions, little is known about the factors responsible for SND1 expression. Here, we have approached this question by analyzing the transcriptional response of human SND1 gene to pharmacological endoplasmic reticulum (ER) stress in liver cancer cells. Results: We provide first evidence that SND1 promoter activity is increased in human liver cancer cells upon exposure to thapsigargin or tunicamycin or by ectopic expression of ATF6, a crucial transcription factor in the unfolded protein response triggered by ER stress. Deletion analysis of the 5'-flanking region of SND1 promoter identified maximal activation in fragment (-934, +221), which contains most of the predicted ER stress response elements in proximal promoter. Quantitative real- time PCR revealed a near 3 fold increase in SND1 mRNA expression by either of the stress- inducers; whereas SND1 protein was maximally upregulated (3.4-fold) in cells exposed to tunicamycin, a protein glycosylation inhibitor. Conclusion: Promoter activity of the cell growth- and RNA-protection associated SND1 gene is up-regulated by ER stress in human hepatoma cells.

Social, economic, and health impact of the respiratory syncytial virus: a systematic search

Background: Bronchiolitis caused by the respiratory syncytial virus (RSV) and its related complications are common in infants born prematurely, with severe congenital heart disease, or bronchopulmonary dysplasia, as well as in immunosuppressed infants. There is a rich literature on the different aspects of RSV infection with a focus, for the most part, on specific risk populations. However, there is a need for a systematic global analysis of the impact of RSV infection in terms of use of resources and health impact on both children and adults. With this aim, we performed a systematic search of scientific evidence on the social, economic, and health impact of RSV infection. Methods: A systematic search of the following databases was performed: MEDLINE, EMBASE, Spanish Medical Index, MEDES-MEDicina in Spanish, Cochrane Plus Library, and Google without time limits. We selected 421 abstracts based on the 6,598 articles identified. From these abstracts, 4 RSV experts selected the most relevant articles. They selected 65 articles. After reading the full articles, 23 of their references were also selected. Finally, one more article found through a literature information alert system was included. Results: The information collected was summarized and organized into the following topics: 1. Impact on health (infections and respiratory complications, mid-to long-term lung function decline, recurrent wheezing, asthma, other complications such as otitis and rhino-conjunctivitis, and mortality; 2. Impact on resources (visits to primary care and specialists offices, emergency room visits, hospital admissions, ICU admissions, diagnostic tests, and treatments); 3. Impact on costs (direct and indirect costs); 4. Impact on quality of life; and 5. Strategies to reduce the impact (interventions on social and hygienic factors and prophylactic treatments). Conclusions: We concluded that 1. The health impact of RSV infection is relevant and goes beyond the acute episode phase; 2. The health impact of RSV infection on children is much better documented than the impact on adults; 3. Further research is needed on mid-and long-term impact of RSV infection on the adult population, especially those at high-risk; 4. There is a need for interventions aimed at reducing the impact of RSV infection by targeting health education, information, and prophylaxis in high-risk populations.

Unveiling the factors shaping the distribution of widely distributed alpine vertebrates, using multi-scale ecological niche modelling of the bat Plecotus macrobullaris

Several alpine vertebrates share a distribution pattern that extends across the South-western Palearctic but is limited to the main mountain massifs. Although they are usually regarded as cold-adapted species, the range of many alpine vertebrates also includes relatively warm areas, suggesting that factors beyond climatic conditions may be driving their distribution. In this work we first recognize the species belonging to the mentioned biogeographic group and, based on the environmental niche analysis of Plecotus macrobullaris, we identify and characterize the environmental factors constraining their ranges. Distribution overlap analysis of 504 European vertebrates was done using the Sorensen Similarity Index, and we identified four birds and one mammal that share the distribution with P. macrobullaris. We generated 135 environmental niche models including different variable combinations and regularization values for P. macrobullaris at two different scales and resolutions. After selecting the best models, we observed that topographic variables outperformed climatic predictors, and the abruptness of the landscape showed better predictive ability than elevation. The best explanatory climatic variable was mean summer temperature, which showed that P. macrobullaris is able to cope with mean temperature ranges spanning up to 16 degrees C. The models showed that the distribution of P. macrobullaris is mainly shaped by topographic factors that provide rock-abundant and open-space habitats rather than climatic determinants, and that the species is not a cold-adapted, but rather a cold-tolerant eurithermic organism. P. macrobullaris shares its distribution pattern as well as several ecological features with five other alpine vertebrates, suggesting that the conclusions obtained from this study might be extensible to them. We concluded that rock-dwelling and open-space foraging vertebrates with broad temperature tolerance are the best candidates to show wide alpine distribution in the Western Palearctic.

The prevalence of diabetes-related complications and multimorbidity in the population with type 2 diabetes mellitus in the Basque Country

Background: Type 2 diabetes mellitus is associated with a diverse range of pathologies. The aim of the study was to determine the incidence of diabetes-related complications, the prevalence of coexistent chronic conditions and to report multimorbidity in people with type 2 diabetes living in the Basque Country. Methods: Administrative databases, in four cross sections (annually from 2007 to 2011) were consulted to analyse 149,015 individual records from patients aged >= 35 years with type 2 diabetes mellitus. The data observed were: age, sex, diabetes-related complications (annual rates of acute myocardial infarction, major amputations and avoidable hospitalisations), diabetes-related pathologies (prevalence of ischaemic heart disease, renal failure, stroke, heart failure, peripheral neuropathy, foot ulcers and diabetic retinopathy) and other unrelated pathologies (44 diseases). Results: The annual incidence for each condition progressively decreased during the four-year period: acute myocardial infarction (0.47 to 0.40%), major amputations (0.10 to 0.08%), and avoidable hospitalisations (5.85 to 5.5%). The prevalence for diabetes-related chronic pathologies was: ischaemic heart disease (11.5%), renal failure (8.4%), stroke (7.0%), heart failure (4.3%), peripheral neuropathy (1.3%), foot ulcers (2.0%) and diabetic retinopathy (7.2%). The prevalence of multimorbidity was 90.4%. The highest prevalence for other chronic conditions was 73.7% for hypertension, 13.8% for dyspepsia and 12.7% for anxiety. Conclusions: In the type 2 diabetes mellitus population living in the Basque Country, incidence rates of diabetes complications are not as high as in other places. However, they present a high prevalence of diabetes related and unrelated diseases. Multimorbidity is very common in this group, and is a factor to be taken into account to ensure correct clinical management.

Alveolar nitric oxide and its role in pediatric asthma control assessment

Resumen Background: Nitric oxide can be measured at multiple flow rates to determine proximal (maximum airway nitric oxide flux; Jaw(NO)) and distal inflammation (alveolar nitric oxide concentration; CA(NO)). The main aim was to study the association among symptoms, lung function, proximal (maximum airway nitric oxide flux) and distal (alveolar nitric oxide concentration) airway inflammation in asthmatic children treated and not treated with inhaled glucocorticoids. Methods: A cross-sectional study with prospective data collection was carried out in a consecutive sample of girls and boys aged between 6 and 16 years with a medical diagnosis of asthma. Maximum airway nitric oxide flux and alveolar nitric oxide concentration were calculated according to the two-compartment model. In asthmatic patients, the asthma control questionnaire (CAN) was completed and forced spirometry was performed. In controls, differences between the sexes in alveolar nitric oxide concentration and maximum airway nitric oxide flux and their correlation with height were studied. The correlation among the fraction of exhaled NO at 50 ml/s (FENO50), CA(NO), Jaw(NO), forced expiratory volume in 1 second (FEV1) and the CAN questionnaire was measured and the degree of agreement regarding asthma control assessment was studied using Cohen's kappa. Results: We studied 162 children; 49 healthy (group 1), 23 asthmatic participants without treatment (group 2) and 80 asthmatic patients treated with inhaled corticosteroids (group 3). CA(NO) (ppb) was 2.2 (0.1-4.5), 3 (0.2-9.2) and 2.45 (0.1-24), respectively. Jaw(NO) (pl/s) was 516 (98.3-1470), 2356.67 (120-6110) and 1426 (156-11805), respectively. There was a strong association (r = 0.97) between FENO50 and Jaw(NO) and the degree of agreement was very good in group 2 and was good in group 3. There was no agreement or only slight agreement between the measures used to monitor asthma control (FEV1, CAN questionnaire, CA(NO) and Jaw(NO)). Conclusions: The results for CA(NO) and Jaw(NO) in controls were similar to those found in other reports. There was no agreement or only slight agreement among the three measure instruments analyzed to assess asthma control. In our sample, no additional information was provided by CA(NO) and Jaw(NO).

Spatial-temporal excess mortality patterns of the 1918-1919 influenza pandemic in Spain

Background: The impact of socio-demographic factors and baseline health on the mortality burden of seasonal and pandemic influenza remains debated. Here we analyzed the spatial-temporal mortality patterns of the 1918 influenza pandemic in Spain, one of the countries of Europe that experienced the highest mortality burden. Methods: We analyzed monthly death rates from respiratory diseases and all-causes across 49 provinces of Spain, including the Canary and Balearic Islands, during the period January-1915 to June-1919. We estimated the influenza-related excess death rates and risk of death relative to baseline mortality by pandemic wave and province. We then explored the association between pandemic excess mortality rates and health and socio-demographic factors, which included population size and age structure, population density, infant mortality rates, baseline death rates, and urbanization. Results: Our analysis revealed high geographic heterogeneity in pandemic mortality impact. We identified 3 pandemic waves of varying timing and intensity covering the period from Jan-1918 to Jun-1919, with the highest pandemic-related excess mortality rates occurring during the months of October-November 1918 across all Spanish provinces. Cumulative excess mortality rates followed a south-north gradient after controlling for demographic factors, with the North experiencing highest excess mortality rates. A model that included latitude, population density, and the proportion of children living in provinces explained about 40% of the geographic variability in cumulative excess death rates during 1918-19, but different factors explained mortality variation in each wave. Conclusions: A substantial fraction of the variability in excess mortality rates across Spanish provinces remained unexplained, which suggests that other unidentified factors such as comorbidities, climate and background immunity may have affected the 1918-19 pandemic mortality rates. Further archeo-epidemiological research should concentrate on identifying settings with combined availability of local historical mortality records and information on the prevalence of underlying risk factors, or patient-level clinical data, to further clarify the drivers of 1918 pandemic influenza mortality.

Insights into mechanism kinematics for protein motion simulation

Background: The high demanding computational requirements necessary to carry out protein motion simulations make it difficult to obtain information related to protein motion. On the one hand, molecular dynamics simulation requires huge computational resources to achieve satisfactory motion simulations. On the other hand, less accurate procedures such as interpolation methods, do not generate realistic morphs from the kinematic point of view. Analyzing a protein's movement is very similar to serial robots; thus, it is possible to treat the protein chain as a serial mechanism composed of rotational degrees of freedom. Recently, based on this hypothesis, new methodologies have arisen, based on mechanism and robot kinematics, to simulate protein motion. Probabilistic roadmap method, which discretizes the protein configurational space against a scoring function, or the kinetostatic compliance method that minimizes the torques that appear in bonds, aim to simulate protein motion with a reduced computational cost. Results: In this paper a new viewpoint for protein motion simulation, based on mechanism kinematics is presented. The paper describes a set of methodologies, combining different techniques such as structure normalization normalization processes, simulation algorithms and secondary structure detection procedures. The combination of all these procedures allows to obtain kinematic morphs of proteins achieving a very good computational cost-error rate, while maintaining the biological meaning of the obtained structures and the kinematic viability of the obtained motion. Conclusions: The procedure presented in this paper, implements different modules to perform the simulation of the conformational change suffered by a protein when exerting its function. The combination of a main simulation procedure assisted by a secondary structure process, and a side chain orientation strategy, allows to obtain a fast and reliable simulations of protein motion.

Altered glutamyl-aminopeptidase activity and expression in renal neoplasms

Background: Advances in the knowledge of renal neoplasms have demonstrated the implication of several proteases in their genesis, growth and dissemination. Glutamyl-aminopeptidase (GAP) (EC. 3.4.11.7) is a zinc metallopeptidase with angiotensinase activity highly expressed in kidney tissues and its expression and activity have been associated wtih tumour development. Methods: In this prospective study, GAP spectrofluorometric activity and immunohistochemical expression were analysed in clear-cell (CCRCC), papillary (PRCC) and chromophobe (ChRCC) renal cell carcinomas, and in renal oncocytoma (RO). Data obtained in tumour tissue were compared with those from the surrounding uninvolved kidney tissue. In CCRCC, classic pathological parameters such as grade, stage and tumour size were stratified following GAP data and analyzed for 5-year survival. Results: GAP activity in both the membrane-bound and soluble fractions was sharply decreased and its immunohistochemical expression showed mild staining in the four histological types of renal tumours. Soluble and membrane-bound GAP activities correlated with tumour grade and size in CCRCCs. Conclusions: This study suggests a role for GAP in the neoplastic development of renal tumours and provides additional data for considering the activity and expression of this enzyme of interest in the diagnosis and prognosis of renal neoplasms.

The Carpathian range represents a weak genetic barrier in South-East Europe

Background: In the present study we have assessed whether the Carpathian Mountains represent a genetic barrier in East Europe. Therefore, we have analyzed the mtDNA of 128 native individuals of Romania: 62 of them from the North of Romania, and 66 from South Romania. Results: We have analyzed their mtDNA variability in the context of other European and Near Eastern populations through multivariate analyses. The results show that regarding the mtDNA haplogroup and haplotype distributions the Romanian groups living outside the Carpathian range (South Romania) displayed some degree of genetic differentiation compared to those living within the Carpahian range (North Romania). Conclusion: The main differentiation between the mtDNA variability of the groups from North and South Romania can be attributed to the demographic movements from East to West (prehistoric or historic) that differently affected in these regions, suggesting that the Carpathian mountain range represents a weak genetic barrier in South-East Europe.

Carbapenem-resistant and carbapenem-susceptible isogenic isolates of Klebsiella pneumoniae ST101 causing infection in a tertiary hospital

Background: In this study we describe the clinical and molecular characteristics of an outbreak due to carbapenem-resistant Klebsiella pneumoniae (CR-KP) producing CTX-M-15 and OXA-48 carbapenemase. Isogenic strains, carbapenem-susceptible K. pneumoniae (CS-KP) producing CTX-M-15, were also involved in the outbreak. Results: From October 2010 to December 2012 a total of 62 CR-KP and 23 CS-KP were isolated from clinical samples of 42 patients (22 had resistant isolates, 14 had susceptible isolates, and 6 had both CR and CS isolates). All patients had underlying diseases and 17 of them (14 patients with CR-KP and 3 with CS-KP) had received carbapenems previously. The range of carbapenem MICs for total isolates were: imipenem: 2 to >32 mu g/ml vs. <2 mu g/ml; meropenem: 4 to >32 mu g/ml vs. <2 mu g/ml; and ertapenem: 8 to >32 mu g/ml vs. <2 mu g/ml. All the isolates were also resistant to gentamicin, ciprofloxacin, and cotrimoxazole. Both types of isolates shared a common PFGE pattern associated with the multilocus sequence type 101 (ST101). The bla(CTX-M-15) gene was detected in all the isolates, whereas the bla(OXA-48) gene was only detected in CR-KP isolates on a 70 kb plasmid. Conclusions: The clonal spread of K. pneumoniae ST101 expressing the OXA-48 and CTX-M-15 beta-lactamases was the cause of an outbreak of CR-KP infections. CTX-M-15-producing isolates lacking the blaOXA-48 gene coexisted during the outbreak.