Hypertension: Renin-Angiotensin-Aldosterone System Alterations

Blockers of the renin-angiotensin-aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension

Polymorphisms in gene encoding TRPV1-receptor involved in pain perception are unrelated to chronic pancreatitis

Contains fulltext : 79505.pdf (publisher's version ) (Open Access

Impaired Vascular Contractility and Aortic Wall Degeneration in Fibulin-4 Deficient Mice: Effect of Angiotensin II Type 1 (AT1) Receptor Blockade

Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT1) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4+/R) and 4-fold (homozygous Fibulin-4R/R) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT1 receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4R/R mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT1 receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease

Proprioception deficiency in articular cartilage lesions of the knee

Purpose: The purpose of this study is to investigate the proprioceptive function of patients with isolated articular cartilage lesions of the knee as compared to normal controls. Methods: The Cartilage group consisted of eight subjects with radiologically and arthroscopically confirmed, isolated, unilateral, articular cartilage lesions of the knee (Outerbridge grade III or IV). They were compared to 50 normal controls. Knee proprioception was assessed by dynamic postural stabilometry using the Biodex Balance SD System. Patient-reported outcome measures (PROMs) were used to evaluate all subjects. Results: Proprioception of the injured knee of the Cartilage group was significantly poorer compared to that of the control group (p < 0.001). A significant proprioceptive deficit also was observed when the uninjured knees of the Cartilage group were compared to those in the Control group (p = 0.003). There was no significant proprioceptive difference between the injured and the contra-lateral uninjured knee of the Cartilage group (p = 0.116). A significant correlation was found between the proprioception measurements of the injured and uninjured knee of the Cartilage group (r = 0.76, p = 0.030). A significant difference was observed in all PROMs (p < 0.001) between the Cartilage and Control groups. Conclusions: Patients with isolated articular cartilage lesions of the knee had a significant proprioceptive deficit as compared to normal controls. The deficiency was profound and even affected the proprioceptive function of the contra-lateral uninjured knee. This study has shown that articular cartilage lesions have a major influence on knee proprioception. However, it remains uncertain as to whether a proprioceptive deficit leads to osteoarthritis or is a consequence of it

Recombinational Landscape and Population Genomics of Caenorhabditis elegans

Recombination rate and linkage disequilibrium, the latter a function of population genomic processes, are the critical parameters for mapping by linkage and association, and their patterns in Caenorhabditis elegans are poorly understood. We performed high-density SNP genotyping on a large panel of recombinant inbred advanced intercross lines (RIAILs) of C. elegans to characterize the landscape of recombination and, on a panel of wild strains, to characterize population genomic patterns. We confirmed that C. elegans autosomes exhibit discrete domains of nearly constant recombination rate, and we show, for the first time, that the pattern holds for the X chromosome as well. The terminal domains of each chromosome, spanning about 7% of the genome, exhibit effectively no recombination. The RIAILs exhibit a 5.3-fold expansion of the genetic map. With median marker spacing of 61 kb, they are a powerful resource for mapping quantitative trait loci in C. elegans. Among 125 wild isolates, we identified only 41 distinct haplotypes. The patterns of genotypic similarity suggest that some presumed wild strains are laboratory contaminants. The Hawaiian strain, CB4856, exhibits genetic isolation from the remainder of the global population, whose members exhibit ample evidence of intercrossing and recombining. The population effective recombination rate, estimated from the pattern of linkage disequilibrium, is correlated with the estimated meiotic recombination rate, but its magnitude implies that the effective rate of outcrossing is extremely low, corroborating reports of selection against recombinant genotypes. Despite the low population, effective recombination rate and extensive linkage disequilibrium among chromosomes, which are techniques that account for background levels of genomic similarity, permit association mapping in wild C. elegans strains

The role of health literacy in explaining the association between educational attainment and the use of out-of-hours primary care services in chronically ill people: a survey study

Abstract Background Low socioeconomic status (SES) is persistently associated with poor health and suboptimal use of healthcare services, and more unplanned healthcare use. Suboptimal use of emergency and acute healthcare services may increase health inequalities, due to late diagnosis or lack of continuity of care. Given that health literacy has been associated with healthcare utilisation and with education attainment, we sought to explore whether health literacy is related to the use of out-of-hours (OOH) Primary Care Services (PCSs). Additionally, we aimed to study whether and to what extent health literacy accounts for some of the association between education and OOH PSC use. Methods A survey including measures of education attainment, health literacy (assessed by means of the Dutch version of the nine-dimension Health Literacy Questionnaire) and use of PCS was conducted among a sample of adults diagnosed with (any) somatic chronic condition in the Netherlands (response 76.3%, n = 1811). We conducted linear and logistic regression analyses to examine associations between education level and PCS use in the past year. We performed mediation analyses to assess whether the association between education and PCS use was (partly) explained by different aspects of health literacy. We adjusted the models for patient characteristics such as age and morbidity. Results Higher education attainment was associated with higher scores on the health literacy aspects Appraisal of health information, and Navigating the healthcare system. Additionally, appraisal and navigating the healthcare system partially accounted for educational differences in PCS use. Finally, higher appraisal of health information scores were associated with higher PCS utilisation. Conclusion Several aspects of health literacy were demonstrated to relate to PCS use, and partly accounted for educational differences herein. Accordingly, developing health literacy within individuals or communities may help to reduce inappropriate PCS use among people with low education

Catechol-O-methyltransferase (COMT) gene variants and pain in chronic pancreatitis

Item does not contain fulltextBACKGROUND: Pain is the major symptom of chronic pancreatitis. The role of genetics in pancreatic pain is unclear. Catechol-O-methyltransferase (COMT) regulates enkephalin levels and influences pain perception. The COMT gene contains functional polymorphisms that have been found to influence human pain perception. The aim of our study was to investigate COMT single-nucleotide polymorphisms (SNP s) and diplotypes in chronic pancreatitis patients and healthy controls. METHODS: We genotyped four COMT gene SNP s: c.1-98A>G (rs6269), c.186C>T (p.=) (rs4633), c.408C>G (p.=) (rs4818) and c.472G>A (p.Val158Met) (rs4680) using a dual-colour discrimination assay in 240 chronic pancreatitis patients and 445 controls. We generated five diplotypes with a frequency >0.5% and compared prevalence between patients and controls. RESULTS: There was no significant association between the SNPs in the COMT gene and chronic pancreatitis. The diplotype ATCA/ACCG was more prevalent in controls compared with patients (OR 0.48, 95% CI 0.24 to 0.93, p=0.03) where the most common diplotype GCGG /ATCA served as reference. However, after correction for multiple testing, this is not a significant difference. The distribution of other diplotypes was not significantly different between patients and controls. CONCLUSION: COMT SNP s and diplotypes are not associated with chronic pancreatitis. As a consequence, our results do not support a significant role for the COMT gene in chronic pancreatitis

Is there a conflict between general practitioners applying guidelines for antibiotic prescribing and including their patients&rsquo; preferences?

Anne EM Brabers,1 Thamar EM Van Esch,1 Peter P Groenewegen,1&ndash;3 Karin Hek,1 P&eacute; Mullenders,4 Liset Van Dijk,1 Judith D De Jong11NIVEL, the Netherlands Institute for Health Services Research, Utrecht, 2Department of Sociology, Utrecht University, Utrecht, 3Department of Human Geography, Utrecht University, Utrecht, 4The National Health Care Institute, Diemen, the NetherlandsObjectives: One perceived barrier to guideline adherence is the existence of conflicting patient preferences. We examined whether patient preferences influence the prescription of antibiotics in general practice, and how this affects guideline adherence. We hypothesized that preferences play a larger role in prescribing antibiotics if the guideline allows for preferences to be taken into account, ie, if prescribing antibiotics is an option which can be considered rather than a clear recommendation to prescribe or not. We included three guidelines: acute cough, acute rhinosinusitis, and urinary tract infections.Methods: Data from NIVEL (the Netherlands Institute for Health Services Research) Primary Care Database (NIVEL-PCD) were used to assess antibiotic indications and prescriptions. These data were combined with a questionnaire among members of NIVEL&rsquo;s Dutch Health Care Consumer Panel to examine patient preferences. According to NIVEL-PCD, 286 of these members contacted their general practitioner (GP) in 2015 for acute cough, acute rhinosinusitis or urinary tract infections. A logistic multilevel regression analysis was performed to test our hypothesis.Results: Patient preferences do play a role in GPs&rsquo; prescribing of antibiotics only in situations where, in accordance with the guideline, their use is an option which could be considered (interaction between indication and preference: p=0.049). If patients ask for antibiotics themselves in such situations, then GPs prescribe antibiotics more often.Conclusion: Patient preferences only play a role if the guideline provides room to take preferences into account. Therefore, our results do not suggest a conflict between applying guidelines and including patient preferences. Further research is recommended to examine this possible conflict in other situations.Keywords: antibiotics, clinical practice guidelines, medical practice variation, patient preference