Antihypertensive action of soluble epoxide hydrolase inhibition in Ren‐2 transgenic rats is mediated by suppression of the intrarenal renin–angiotensin system

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Molecular Characterization of β-Thalassemia in the Czech and Slovak Populations: Mediterranean,Asian and Unique Mutations

β-Thalassemia (β-thal) is considered rare in Central Europe. As in other malaria-free regions, the presence of β-thal in Central Europe reflects historical and recent immigration, and demographic changes that have influenced the genetic variability of the current populations living in this area. This study assesses the frequency and spectrum of mutations on the β-globin gene in Czech and Slovak subjects with clinical symptoms of thalassemia. The results of the initial part of this research were published more than two decades ago; the aim of this study was to update these original reports. During the period from 2002 to 2015, 400 cases from Czech and Slovak hematological centers were analyzed. Twenty-nine β-thal mutations, identified in 356 heterozygotes from 218 unrelated families, involve five unique mutations including a recently described insertion of a transposable L1 element into the β-globin gene. One mutation described here is reported for the first time. Most of the mutations were of Mediterranean origin and accounted for 82.0% of cases. All but one case studied were heterozygous carriers, manifesting β-thal minor, with rare exceptions represented by the rare (β⁰) codons 46/47 (+G) (HBB: c.142_142dupG) mutation associated with an α-globin gene quadruplication and by dominantly inherited β-thal with a more severe phenotype. One double heterozygous β-thal patient was a recent immigrant from Moldavia. The list of δβ-thal alleles (26 carriers, 16 families) contains Hb Lepore and two types of δβ⁰-thal deletions. In the past, genetic drift and migration as well as recent immigrations were responsible for the introduction of Mediterranean alleles, while several mutations described in single families were of local origin.     

Temporal Trends in Preterm Birth,Neonatal Mortality,and Neonatal Morbidity Following Spontaneous and Clinician-Initiated Delivery in Canada, 2009-2016

ObjectiveClinician-initiated deliveries at 34 to 36 weeks gestation have increased in Canada since 2006, but the impacts of clinician-initiated deliveries on the overall preterm birth (PTB) rate and concomitant changes in neonatal outcomes are unknown. This study examined gestational age–specific trends in spontaneous and clinician-initiated PTB and associated neonatal mortality and morbidity.MethodsThis population-based study included 1 880 444 singleton live births in Canada (excluding Québec) in 2009-2016, using hospitalization data from the Canadian Institute for Health Information. The primary outcomes were neonatal mortality and a composite outcome mortality and/or severe neonatal morbidity identified by International Statistical Classification of Diseases and Related Health Problems, 10th revision, Canada codes. Outcomes were stratified by spontaneous and clinician-initiated deliveries and gestational age categories. Logistic regression yielded adjusted odds ratios (aORs) per 1-year change and 95% confidence intervals (CIs) (Canadian Task Force Classification II-2).ResultsThe PTB rate remained stable (6.2%) and the proportion of clinician-initiated PTBs increased from 31.0% to 37.9% (P < 0.001). Although overall neonatal mortality remained stable (1.1%), mortality declined among infants born spontaneously at 28 to 33 weeks gestation (aOR 0.92; 95% CI 0.87–0.97). The composite mortality and/or severe morbidity declined from 12.7% to 12.2% (aOR 0.98; 95% CI 0.97–0.99). Declines were observed in the rates of sepsis (aOR 0.96; 95% CI 0.95–0.98) and respiratory distress syndrome requiring ventilation (aOR 0.97; 95% CI 0.96–0.98), whereas rates of intraventricular hemorrhage increased (aOR 1.03; 95% CI 1.01–1.05).ConclusionWith the increase in clinician-initiated deliveries, the stable rates of PTB and neonatal mortality and the decline in composite mortality and/or severe morbidity are encouraging findings. This study adds to clinical understanding of carefully timed and medically justified early interventions.     

Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D)-39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness.     

The Effect of Maternal Age on Adverse Birth Outcomes: Does Parity Matter?

ObjectivesTo examine the effect of parity on the association between older maternal age and adverse birth outcomes, specifically stillbirth, neonatal death, preterm birth, small for gestational age, and neonatal intensive care unit admission.MethodsWe conducted a retrospective cohort study of singleton births in British Columbia between 1999 and 2004. In the cohort, 69 023 women were aged 20 to 29, 25 058 were aged 35 to 39, and 4816 were aged 40 and over. Perinatal risk factors, obstetric history, and birth outcomes were abstracted from the British Columbia Perinatal Database Registry. Logistic regression was used to calculate adjusted odds ratios (aOR) and 95% confidence intervals for adverse outcomes in the two older age groups compared with the young control subjects.ResultsCompared with younger control subjects, women aged 35 to 39 years had an aOR of stillbirth of 1.5 (95% CI 1.2 to 1.9) and women aged ≥ 40 years also had an aOR of 1.5 (95% CI 1.0 to 2.4). The aOR for NICU admission was 1.2 (95% CI 1.0 to 1.3) in women aged 35 to 39 years and 1.4 (95% CI 1.1 to 17) in women aged ≥ 40 years compared with younger control subjects. The risk of preterm birth and SGA differed by parity. The aOR for preterm birth compared with younger primiparas was 1.5 (95% CI 1.4 to 1.7) for women aged 35 to 39 years and 1.6 (95% CI 1.3 to 2.0) for women aged ≥ 40 years. In multiparas the aOR for preterm birth was 1.1 (95% CI 1.1 to 1.2) in women aged 35 to 39 and 1.3 (95% CI 1.1 to 1.5) in women > 40 years. The aOR for SGA in primiparas was 1.2 (95% CI 1.1 to 1.4) for women aged 35 to 39 and 1.4 (95% CI 1.1 to 1.7) for women aged ≥ 40 years. The risk of neonatal death was not significantly different between groups.ConclusionOlder women were at elevated risk of stillbirth, preterm birth, and NICU admission regardless of parity. Parity modified the effect of maternal age on preterm birth and SGA. Older primiparas were at elevated risk for SGA, but no association between age and SGA was found in multiparas. Older primiparas were at higher risk of preterm birth than older multiparas compared with younger women.     

Osteoporosis risk assessment and management in primary care: focus on quantity and quality

Introduction and hypothesis Early identification of high‐risk patients by general practitioners (GPs) plays the key role in the management of osteoporosis (OP). Methods We conducted a postal questionnaire survey among 1500 Czech GPs to examine their behaviour related to OP. Results The overall questionnaire return rate was 38%. The respondents (mean age 52 years; 61.5% women) did not differ from non‐respondents. OP knowledge correlated negatively with age (P < 0.001). The most common reason for both suspicion of OP and referral for suspected OP is the patient's complaints. When the initial skeletal examination for suspected OP is conducted on the GP's initiative, it is most often X‐ray (76%) followed by osteodensitometry (61%). The respondents address five patients (median) per month about this issue. The number of referrals to a specialist for suspected OP during the last quarter was 5 (median). The most commonly reported barriers to OP management were financial limits set by the health insurance agency (71%) and lack of authorization to prescribe selected drugs (71%). Conclusions The GPs should pay greater attention to risk factors and be more active in the detection of at‐risk patients. It is necessary to motivate the GPs and to overcome the barriers to effective clinical practice.