The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension1-3. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene, Slc39a12, as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter, ZIP12. We report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia-dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This entirely novel and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.
BackgroundOnce a list of differentially expressed genes has been identified from a microarray experiment, a subsequent post-analysis task is required in order to find the main biological processes associated to the experimental system. This paper describes two pathways analysis tools, ArrayUnlock and Ingenuity Pathways Analysis (IPA) to deal with the post-analyses of microarray data, in the context of the EADGENE and SABRE post-analysis workshop. Dataset employed in this study proceeded from an experimental chicken infection performed to study the host reactions after a homologous or heterologous secondary challenge with two species of Eimeria.ResultsAnalysis of the same microarray data source employing both commercial pathway analysis tools in parallel let to identify several biological and/or molecular functions altered in the chicken Eimeria maxima infection model, including several immune system related pathways. Biological functions differentially altered in the homologous and heterologous second infection were identified. Similarly, the effect of the timing in a homologous second infection was characterized by several biological functions.ConclusionFunctional analysis with ArrayUnlock and IPA provided information related to functional differences with the three comparisons of the chicken infection leading to similar conclusions. ArrayUnlock let an improvement of the annotations of the chicken genome adding InterPro annotations to the data set file. IPA provides two powerful tools to understand the pathway analysis results: the networks and canonical pathways that showed several pathways related to an adaptative immune response.
Salmonella enterica serovar Typhimurium causes enteric disease and compromises food safety. In pigs, the molecular response of the intestine to S. typhimurium has been traditionally characterized by in vitro models that do not reflect the actual immunological competence of the intestinal mucosa. In this work, we performed an oral S. typhimurium infection study to obtain insight into the in vitro response in three different sections (jejunum, ileum and colon) of the porcine intestine. For this, samples from one-month-old infected piglets were collected during a time course comprising 1, 2, and 6 days post inoculation to evaluate the intestinal response by quantifying the mRNA expression of gene coding for 28 innate immune system molecules using quantitative real-time PCR assays. In addition, samples from non-infected control animals were also employed to establish differences in the steady state gene expression between intestinal sections. The panel of quantified molecules included an assortment of cytokines, chemokines, pattern-recognition receptors, intracellular signaling molecules, transcription factors and antimicrobial molecules. Changes in gene expression occurred in the three different parts of the intestine and during the course of the S. typhimurium infection. Moreover, the high variation observed in expression patterns of genes coding for inflammatory mediators could indicate that each intestinal section responds differently to the infection. Thus, on the contrary to findings in the jejunum and colon, a down-regulation and lack of induction of some proinflammatory cytokine transcripts was observed in the ileum. Nevertheless, all chemoattractant cytokines assayed were up-regulated in the ileum and jejunum whereas only interleukin-8 and MIP-1α mRNA were over expressed in the colon. In conclusion, our results reveal regional differences in gene expression profiles along the porcine intestinal gut as well as regional differences in the inflammatory response to S. typhimurium infection. Taken together, these data should provide a basis for a complete understanding of the porcine intestinal response to bacterial infection.
Somatic cell count (SCC) in monitoring udder health has been described in numerous studies as a useful method for the diagnosis of intramammary infection (IMI), and it is considered in standards of quality and hygiene of cow's milk in many countries. However, several authors have questioned the validity of SCC as a reliable IMI diagnosis tool in dairy goats. This review attempts to reflect the importance of different infectious and non-infectious factors that can modify SCC values in goat milk, and must, therefore, be taken into account when using the SCC as a tool in the improvement of udder health and the quality of milk in this species. In dairy goats, some investigations have shown that mammary bacterial infections are a major cause of increased SCC and loss of production. In goats however, the relationship between bacterial infections and SCC values is not as simple as in dairy cattle, since non-infectious factors also have a big impact on SCC. Intrinsic factors are those that depend directly on the animal: time and number of lactation (higher SCC late in lactation and in aged goats), prolificity (higher SCC in multiple births), milking time (higher SCC in evening compared to morning milking) and number of milkings per day, among others. Extrinsic factors include: milking routine (lower SCC in machine than in manual milking), seasonality and food. In addition, milk secretion in goats is mostly apocrine and therefore characterized by the presence of epithelial debris or cytoplasmic particles, which makes the use of DNA specific counters mandatory. All this information is of interest in order to correctly interpret the SCC in goat milk and to establish differential SCC standards.Additional key words: infectious and non-infectious factors; milk quality; mastitis; benchmarking.
Background One sixth of U.S. dialysis patients older than 65 years have been diagnosed with atrial fibrillation/flutter (AF) and the prevalence is increasing. Little is known, however, about the incidence of AF in this population. Methods and Results From the U.S. Renal Data System, we identified 258,605 older patients (≥67 years) with fee-for-service Medicare initiating dialysis between 1995 and 2007, who had not been diagnosed with AF within the previous 2 years. Patients were followed for newly diagnosed AF, which was ascertained from 1 inpatient or 2 outpatient claims containing an AF code. Multivariable proportional hazards regression was used to examine temporal trends and associations of race and ethnicity with incident AF. We also studied temporal trends in the mortality and risk of ischemic stroke after new AF. Over 514,395 person years of follow-up, 76,252 patients experienced incident AF for a crude AF incidence rate of 148/1,000 person years. Incidence of AF increased by 11% (95%CI: 5%-16%) from 1995-2007. Compared with non-Hispanic whites, African Americans (−30%), Asians (−19%), Native Americans (−42%), and Hispanics (−29%) all had lower rates of incident AF. Mortality after incident AF decreased by 22% from 1995-2008. Even more pronounced reductions were seen for incident ischemic stroke during these years. Conclusions The incidence of AF is high in older patients initiating dialysis in the U.S. and has been increasing over the 13 years of study. Mortality declined during that time, but remained >50% during the first year after newly diagnosed AF. Since data on warfarin use were not available, we were unable to understand whether trends towards better outcomes could be explained by higher rates of oral anticoagulation in more recent years.
SummaryBackground and objectives Hispanic patients undergoing chronic dialysis are less likely to receive a kidney transplant compared with non-Hispanic whites. This study sought to elucidate disparities in the path to receipt of a deceased donor transplant between Hispanic and non-Hispanic whites.Design, setting, participants, & measurements Using the US Renal Data System, 417,801 Caucasians who initiated dialysis between January 1, 1995 and December 31, 2007 with follow-up through 2008 were identified. This study investigated time from first dialysis to first kidney transplantation, time from first dialysis to waitlisting, and time from waitlisting to kidney transplantation. Multivariable Cox regression estimated cause-specific hazard ratios (HR CS ) and subdistribution (competing risk) hazard ratios (HR SD ) for Hispanics versus non-Hispanic whites.Results Hispanics experienced lower adjusted rates of deceased donor kidney transplantation than non-Hispanic whites (HR CS , 0.77; 95% confidence interval [95% CI], 0.75 to 0.80) measured from dialysis initiation. No meaningful differences were found in time from dialysis initiation to placement on the transplant waitlist. Once waitlisted, Hispanics had lower adjusted rates of deceased donor kidney transplantation (HR CS , 0.66; 95% CI, 0.64 to 0.68), and the association attenuated once accounting for competing risks (HR SD , 0.79; 95% CI, 0.77 to 0.81). Additionally controlling for blood type and organ procurement organization further reduced the disparity (HR SD , 0.99; 95% CI, 0.96 to 1.02).Conclusions After accounting for geographic location and controlling for competing risks (e.g., Hispanic survival advantage), the disparity in access to deceased donor transplantation was markedly attenuated among Hispanics compared with non-Hispanic whites. To overcome the geographic disparities that Hispanics encounter in the path to transplantation, organ allocation policy revisions are needed to improve donor organ equity.
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