High-resolution genome screen for bone mineral density in heterogeneous stock rat

We previously demonstrated that skeletal mass, structure, and biomechanical properties vary considerably in heterogeneous stock (HS) rat strains. In addition, we observed strong heritability for several of these skeletal phenotypes in the HS rat model, suggesting that it represents a unique genetic resource for dissecting the complex genetics underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone mineral density in HS rats. We measured bone phenotypes from 1524 adult male and female HS rats between 17 and 20 weeks of age. Phenotypes included dual-energy X-ray absorptiometry (DXA) measurements for bone mineral content and areal bone mineral density (aBMD) for femur and lumbar spine (L3-L5), and volumetric BMD measurements by CT for the midshaft and distal femur, femur neck, and fifth lumbar vertebra (L5). A total of 70,000 polymorphic single-nucleotide polymorphisms (SNPs) distributed throughout the genome were selected from genotypes obtained from the Affymetrix rat custom SNPs array for the HS rat population. These SNPs spanned the HS rat genome with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent for each genotyped locus from each of the eight founder HS strains. The haplotypes were tested for association with each bone density phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for BMD phenotypes on chromosomes 2, 9, 10, and 13 meeting a conservative genomewide empiric significance threshold (false discovery rate [FDR] = 5%; p < 3 × 10(-6)). Importantly, most QTLs were localized to very small genomic regions (1-3 megabases [Mb]), allowing us to identify a narrow set of potential candidate genes including both novel genes and genes previously shown to have roles in skeletal development and homeostasis

Fine mapping of bone structure and strength QTLs in heterogeneous stock rat

We previously demonstrated that skeletal structure and strength phenotypes vary considerably in heterogeneous stock (HS) rats. These phenotypes were found to be strongly heritable, suggesting that the HS rat model represents a unique genetic resource for dissecting the complex genetic etiology underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone structure and strength phenotypes using 1524 adult male and female HS rats between 17 to 20 weeks of age. Structure measures included femur length, neck width, head width; femur and lumbar spine (L3-5) areas obtained by DXA; and cross-sectional areas (CSA) at the midshaft, distal femur and femoral neck, and the 5th lumbar vertebra measured by CT. In addition, measures of strength of the whole femur and femoral neck were obtained. Approximately 70,000 polymorphic SNPs distributed throughout the rat genome were selected for genotyping, with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent at each locus from each of the 8 HS founder strains. The haplotypes were then tested for association with each structure and strength phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for structure phenotypes on chromosomes 3, 8, 10, 12, 17 and 20, and QTLs for strength phenotypes on chromosomes 5, 10 and 11 that met a conservative genome-wide empiric significance threshold (FDR=5%; P<3×10(-6)). Importantly, most QTLs were localized to very narrow genomic regions (as small as 0.3 Mb and up to 3 Mb), each harboring a small set of candidate genes, both novel and previously shown to have roles in skeletal development and homeostasis

The health and economic burden of bloodstream infections caused by antimicrobial-susceptible and non-susceptible Enterobacteriaceae and <i>Staphylococcus aureus</i> in European hospitals, 2010 and 2011:a multicentre retrospective cohort study

We performed a multicentre retrospective cohort study including 606,649 acute inpatient episodes at 10 European hospitals in 2010 and 2011 to estimate the impact of antimicrobial resistance on hospital mortality, excess length of stay (LOS) and cost. Bloodstream infections (BSI) caused by third-generation cephalosporin-resistant Enterobacteriaceae (3GCRE), meticillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA) increased the daily risk of hospital death (adjusted hazard ratio (HR) = 1.80; 95% confidence interval (CI): 1.34-2.42, HR = 1.81; 95% CI: 1.49-2.20 and HR = 2.42; 95% CI: 1.66-3.51, respectively) and prolonged LOS (9.3 days; 95% CI: 9.2-9.4, 11.5 days; 95% CI: 11.5-11.6 and 13.3 days; 95% CI: 13.2-13.4, respectively). BSI with third-generation cephalosporin-susceptible Enterobacteriaceae (3GCSE) significantly increased LOS (5.9 days; 95% CI: 5.8-5.9) but not hazard of death (1.16; 95% CI: 0.98-1.36). 3GCRE significantly increased the hazard of death (1.63; 95% CI: 1.13-2.35), excess LOS (4.9 days; 95% CI: 1.1-8.7) and cost compared with susceptible strains, whereas meticillin resistance did not. The annual cost of 3GCRE BSI was higher than of MRSA BSI. While BSI with S. aureus had greater impact on mortality, excess LOS and cost than Enterobacteriaceae per infection, the impact of antimicrobial resistance was greater for Enterobacteriaceae

Enhanced Fear Expression in a Psychopathological Mouse Model of Trait Anxiety: Pharmacological Interventions

The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB), or normal (NAB) anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i) for identifying biological factors underlying misguided conditioned fear responses and (ii) for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias

Nutrient retention efficiency in streams receiving inputs from wastewater treatment plants

9 Páginas ; 5 Tablas ; 2 FigurasWe tested the effect of nutrient inputs from wastewater treatment plants (WWTPs) on stream nutrient retention efficiency by examining the longitudinal patterns of ammonium, nitrate, and phosphate concentrations downstream of WWTP effluents in 15 streams throughout Catalonia (Spain). We hypothesized that large nutrient loadings would saturate stream communities, lowering nutrient retention efficiency (i.e., nutrient retention relative to nutrient flux) relative to less polluted streams. Longitudinal variation in ambient nutrient concentration reflected the net result of physical, chemical, or biological uptake and release processes. Therefore, gradual increases in nutrient concentration indicate that the stream acts as a net source of nutrients to downstream environments, whereas gradual declines indicate that the stream acts as a net sink. In those streams where gradual declines in nutrient concentration were observed, we calculated the nutrient uptake length as an indicator of the stream nutrient retention efficiency. No significant decline was found in dilution-corrected concentrations of dissolved inorganic nitrogen (DIN) and phosphate in 40 and 45% of streams, respectively. In the remaining streams, uptake length (estimated based on the decline of nutrient concentrations at ambient levels) ranged from 0.14 to 29 km (DIN), and from 0.14 to 14 km (phosphate). Overall, these values are longer (lower retention efficiency) than those from nonpolluted streams of similar size, supporting our hypothesis, and suggest that high nutrient loads affect fluvial ecosystem function. This study demonstrates that the efficiency of stream ecosystems to remove nutrients has limitations because it can be significantly altered by the quantity and quality of the receiving water.This research was supported by the funding of the Agència Catalana de l'Aigua (ACA), Departament de Medi Ambient, Generalitat de Catalunya, and the STREAMES project (U.E. EVKI-CT-2000-00081).Peer reviewe

Potential prebiotic effect of Cava Lees: changes in gut microbiota

Lees are a winery by-product with a fiber-rich composition that could have a potential prebiotic effect on gut microbiota. Prebiotics cannot be digested by humans but can be used by bacteria found in the large intestine. To evaluate the potential prebiotic effect of lees, they were administered to Wistar rats for 14 days. Feces were collected daily, and DNA was extracted and analyzed by shot gun sequencing. The supplementation with lees did not affect weight, food intake, or water consumption of the studied rats. It was found that lees promoted the increase of relative abundance of probiotic bacteria belonging to the Lactobacillaceae family, as well as other potentially probiotic species such as Blautia hansenii, Roseburia intestinalis, and Ruminococcus obeum. Moreover, lees supplementation also reduced the abundance of certain pathogenic bacteria. In conclusion, lees can improve the presence of beneficial bacteria in the gastrointestinal tract and can be re-valorized as a new ingredient in food formulatio

Fearfulness in a large N/Nih genetically heterogeneous rat stock: differential profiles of timidity and defensive flight in males and females.

Anxiety-related behaviors were evaluated across various tests in a large sample (n=787, both sexes) of genetically heterogeneous (N/Nih-HS) rats, derived from an eight-way cross of inbred strains. These tests either evoke unlearned (black-white box, BWB-; novel-cage activity, NACT-; elevated "zero" maze, ZM-; baseline acoustic startle response, BAS-) or learned (fear-potentiated startle, FPS-; two-way active-shuttle box-avoidance acquisition, SHAV-) anxious/fearful responses. The results showed that, with the exception of fear-potentiated startle, almost all (unlearned and learned) behaviors assessed fit with a pattern of sex effects characterized by male rats as being more fearful than females. We applied factor analyses (oblique rotation) to each sex, with the final two-factor solution showing: (1) a first factor (labelled as "Timidity") comprising BWB, NACT and ZM variables in both sexes, plus SHAV responding in the case of males, and (2) a second factor (called "Defensive Flight") which grouped BAS, FPS, and SHAV responding in both sexes. An additional regression analysis showed significant influences of (unlearned) risk assessment (i.e. stretch-attendance) behavior on SHAV in males, while FPS was the main variable positively influencing SHAV (in the intermediate and advanced phases of acquisition) in females. This indicates, for the first time, that fear-potentiated startle may have a facilitating role in the rat's active responses (at least in females) to the cue in the intermediate to advanced phases (i.e. when the initial "passive avoidance/active avoidance" begins to fade) of shuttle box avoidance acquisition. The results of this first extensive behavioral evaluation of N/Nih-HS rats are discussed in terms of their potential usefulness for present and future neurobehavioral and genetic studies of fearfulness/anxiety