Cyclooxygenase-2-linked attenuation of hypoxia-induced pulmonary hypertension and intravascular thrombosis

Exogenous prostacyclin is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To explore whether endogenous prostaglandins played a similar role in pulmonary hypertension, we examined the effect of deleting cyclooxygenase (COX)-gene isoforms in a chronic hypoxia model of PH. Pulmonary hypertension, examined by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (n = 8), and hematocrit (n = 3), was induced by 3 weeks of hypobarichypoxia in wild-type and COX-knockout (KO) mice. RVESP was increased in wild-type hypoxic mice compared with normoxic controls (24.4 ± 1.4 versus 13.8 ± 1.9 mm Hg; n = 8; p < 0.05). COX-2 KO mice showed a greater increase in RVESP following hypoxia (36.8 ± 2.7 mm Hg; p < 0.05). Urinary thromboxane (TX)B2 excretion increased following hypoxia (44.6 ± 11.1 versus 14.7 ± 1.8 ng/ml; n = 6; p < 0.05), an effect that was exacerbated by COX-2 gene disruption (54.5 ± 10.8 ng/ml; n = 6). In contrast, the increase in 6-keto-prostacyclin1α excretion following hypoxia was reduced by COX-2 gene disruption (29 ± 3 versus 52 ± 4.6 ng/ml; p < 0.01). Tail cut bleed times were lower following hypoxia, and there was evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The TXA2/endoperoxide receptor antagonist ifetroban (50 mg/kg/day) offset the effect of deleting the COX-2 gene, attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. COX-2 gene deletion exacerbates pulmonary hypertension, enhances sensitivity to TXA2, and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.

Computational fluid dynamic analysis of intracranial aneurysmal bleb formation

Background The management of unruptured aneurysms is controversial with the decision to treat influenced by aneurysm characteristics including size and morphology. Aneurysmal bleb formation is thought to be associated with an increased risk of rupture. Objective To correlate computational fluid dynamic (CFD) indices with bleb formation. Methods Anatomical models were constructed from three-dimensional rotational angiogram (3DRA) data in 27 patients with cerebral aneurysms harbouring single blebs. Additional models representing the aneurysm before bleb formation were constructed by digitally removing the bleb. We characterised haemodynamic features of models both with and without the bleb using CFDs. Flow structure, wall shear stress (WSS), pressure and oscillatory shear index (OSI) were analysed. Results There was a statistically significant association between bleb location at or adjacent to the point of maximal WSS (74.1%, p=0.019), irrespective of rupture status. Aneurysmal blebs were related to the inflow or outflow jet in 88.9% of cases (p<0.001) whilst 11.1% were unrelated. Maximal wall pressure and OSI were not significantly related to bleb location. The bleb region attained a lower WSS following its formation in 96.3% of cases (p<0.001) and was also lower than the average aneurysm WSS in 86% of cases (p<0.001). Conclusion Cerebral aneurysm blebs generally form at or adjacent to the point of maximal WSS and are aligned with major flow structures. Wall pressure and OSI do not contribute to determining bleb location. The measurement of WSS using CFD models may potentially predict bleb formation and thus improve the assessment of rupture risk in unruptured aneurysms.

Three-dimensional dose verification for clinical treatments of small intracranial tumours

Cancers of the brain and central nervous system account for 1.6% of new cancers and 1.8% of cancer deaths globally. The highest rates of all developed nations are observed in Australia and New Zealand. There are known complexities associated with dose measurement of very small radiation fields. Here, 3D dosimetric verification of treatments for small intracranial tumours using gel dosimetry was investigated.

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that 1 of these receptors, 5-HT(2B), is involved in bone marrow stem cell mobilization that participates in the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT(2B) receptors by circulating c-kit(+) precursor cells, whereas mice lacking 5-HT(2B) receptors showed alterations in platelets and monocyte-macrophage numbers, and in myeloid lineages of bone marrow. Strikingly, mice with restricted expression of 5-HT(2B) receptors in bone marrow cells developed hypoxia or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, whereas restricted elimination of 5-HT(2B) receptors on bone marrow cells confers a complete resistance. Moreover, ex vivo culture of human CD34(+) or mice c-kit(+) progenitor cells in the presence of a 5-HT(2B) receptor antagonist resulted in altered myeloid differentiation potential. Thus, we demonstrate that activation of 5-HT(2B) receptors on bone marrow lineage progenitors is critical for the development of PAH.

Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR βgeo/+ mice were generated from embryonic stem (ES) cells with a gene trap integration of a β-galactosidase-neomycin phosphotransferase (βgeo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GRβgeo/+ mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin- aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GRβgeo/+ mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GRβgeo/+ mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.

Obesity and hypertension have differing oxidant handling molecular pathways in age-related chronic kidney disease

Chronic kidney disease (CKD) in ageing is a burden on health systems worldwide. Rat models of age-related CKD linked with obesity and hypertension were used to investigate alterations in oxidant handling and energy metabolism to identify gene targets or markers for age-related CKD. Young adult (3 months) and old (21–24 months) spontaneously-hypertensive (SHR), normotensive Wistar-Kyoto (WKY) and Wistar rats (normotensive, obese in ageing) were compared for renal functional and physiological parameters, renal fibrosis and inflammation, oxidative stress (hemeoxygenase-1/HO-1), apoptosis and cell injury (including Bax:Bcl-2), phosphorylated and non-phosphorylated forms of oxidant and energy sensing proteins (p66Shc, AMPK), signal transduction proteins (ERK1/2, PKB), and transcription factors (NF-κB, FoxO1). All old rats were normoglycemic. Renal fibrosis, tubular epithelial apoptosis, interstitial macrophages and myofibroblasts (all p < 0.05), p66Shc/phospho-p66 (p < 0.05), Bax/Bcl-2 ratio (p < 0.05) and NF-κB expression (p < 0.01) were highest in old obese Wistars. Expression of phospho-FoxO/FoxO was elevated in old Wistars (p < 0.001) and WKYs (p < 0.01). SHRs had high levels in young and old rats. Expression of PKB, phospho-PKB, ERK1/2 and phospho-ERK1/2 were significantly elevated in all aged animals. These results suggest that obesity and hypertension have differing oxidant handling and signalling pathways that act in the pathogenesis of age-related CKD

Ineffective cerebral perfusion related to increased intracranial pressure secondary to subarachnoid haemorrhage : An examination of nursing interventions

Considered a condition of the elderly population, stroke will soon be the leading cause of death globally. In Singapore it is the fourth leading cause of death after cancer and heart disease. Subarachnoid haemorrhage, when compared with an embolic stroke, has a more devastating outcome because of the deleterious complications associated with it. Vasospam, re-bleeding and global cerebral ischemia are three of the most prominent complications. Therefore, nursing care and interventions developed to reduce the incidence of complications and optimise neurological function are critical in the acute phase of this condition. Using a casestudy approach this article will discuss and offer a rationale to a number of key nursing interventions based around a nursing care plan designed to reduce the incidence of complications.

Determinants and treatment of hypertension in South Africans: The first demographic and health survey

Objectives: To identify the groups of patients with high prevalence and poor control of hypertension in South Africa. Methods: In the first national Demographic and Health Survey, 12 952 randomly selected South Africans, aged 15 years and older were surveyed. Trained interviewers completed questionnaires on socio-demographic characteristics, lifestyle and the management of hypertension. This cross-sectional survey also included blood pressure, height and weight measurements. Logistic regression analyses identified the determinants of hypertension and the treatment status in this dataset. Results: A high risk of hypertension was associated with less than tertiary education, older age groups, overweight and obese people, using alcohol in excess, and a family history of stroke and hypertension. Rural Africans had the lowest risk of hypertension, which was significantly higher in obese African women than in women with normal body mass index. Improved hypertension control was found in the wealthy, women, older persons, being Asian, and having medical insurance. Conclusions: Rural African people had lower hypertension prevalence rates than the other groups. The poorer, younger men, without health insurance had the worst level of hypertension control.

Exploring factors influencing adherence to lifestyle modifications in Chinese people with hypertension: The role of concordance during health communication

This study investigated the factors influencing the conduct of modifying unhealthy lifestyles in Chinese people with high blood pressure, and examined the effect of health communication between health professionals and patients on their health behaviours. The thesis proposes a new theoretical framework to explain and predict individuals' behaviours which can be used to design interventions to improve their health behaviours.

Effectiveness of in-office blood pressure measurement by eye care practitioners in early detection and management of hypertension

AIM To investigate the number of hypertensive patients, the optometrist is able to identify by routinely taking blood pressure (BP) measurements for patients in "at -risk" groups, and to sample patients' opinions regarding in -office BP measurement. Many of the optometrists in Saudi Arabia practice in optical stores. These stores are wide spread, easily accessible and seldom need appointments. The expanding role of the optometrist as a primary health care provider (PHCP) and the increasing global prevalence of hypertension, highlight the need for an integrated approach towards detecting and monitoring hypertension. METHODS Automated BP measurements were made twice (during the same session) at five selected optometry practices using a validated BP monitor (Omron M6) to assess the number of patients with high BP (HBP) - in at -risk groups -visiting the eye clinic routinely. Prior to data collection, practitioners underwent a two-day training workshop by a cardiologist on hypertension and how to obtain accurate BP readings. A protocol for BP measurement was distributed and retained in all participating clinics. The general attitude towards cardiovascular health of 480 patients aged 37.2 (依12.4)y and their opinion towards in-office BP measurement was assessed using a self -administered questionnaire. RESULTS A response rate of 83.6% was obtained for the survey. Ninety -three of the 443 patients (21.0% ) tested for BP in this study had HBP. Of these, (62 subjects) 67.7% were unaware of their HBP status. Thirty of the 105 subjects (28.6%) who had previously been diagnosed with HBP, still had HBP at the time of this study, and only 22 (73.3%) of these patients were on medication. Also, only 25% of the diagnosed hypertensive patients owned a BP monitor. CONCLUSION Taking BP measurements in optometry practices, we were able to identify one previously undiagnosed patient with HBP for every 8 adults tested. We also identified 30 of 105 previously diagnosed patients whose BP was poorly controlled, twenty-two of whom were on medication. The patients who participated in this study were positively disposed toward the routine measurement of BP by optometrists.

The influence of family history of hypertension on disease prevalence and associated metabolic risk factors among Sri Lankan adults

Background Hypertension is a major contributor to the global non-communicable disease burden. Family history is an important non-modifiable risk factor for hypertension. The present study aims to describe the influence of family history (FH) on hypertension prevalence and associated metabolic risk factors in a large cohort of South Asian adults, from a nationally representative sample from Sri Lanka. Methods A cross-sectional survey among 5,000 Sri Lankan adults, evaluating FH at the levels of parents, grandparents, siblings and children. A binary logistic regression analysis was performed in all patients with ‘presence of hypertension’ as dichotomous dependent variable and using family history in parents, grandparents, siblings and children as binary independent variables. The adjusted odds ratio controlling for confounders (age, gender, body mass index, diabetes, hyperlipidemia and physical activity) are presented below. Results In all adults the prevalence of hypertension was significantly higher in patients with a FH (29.3 %, n = 572/1951) than those without (24.4 %, n = 616/2530) (p < 0.001). Presence of a FH significantly increased the risk of hypertension (OR:1.29; 95 % CI:1.13-1.47), obesity (OR:1.36; 95 % CI: 1.27–1.45), central obesity (OR:1.30; 95 % CI 1.22–1.40) and metabolic syndrome (OR:1.19; 95 % CI: 1.08–1.30). In all adults presence of family history in parents (OR:1.28; 95 % CI: 1.12–1.48), grandparents (OR:1.34; 95 % CI: 1.20–1.50) and siblings (OR:1.27; 95 % CI: 1.21–1.33) all were associated with significantly increased risk of developing hypertension. Conclusions Our results show that the prevalence of hypertension was significantly higher in those with a FH of hypertension. FH of hypertension was also associated with the prevalence of obesity, central obesity and metabolic syndrome. Individuals with a FH of hypertension form an easily identifiable group who may benefit from targeted interventions.

Identification of common variants associated with human hippocampal and intracranial volumes

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10 -16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10 -12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10 -7).

The prevalence, predictors and associations of hypertension in Sri Lanka: A cross-sectional population based national survey

We studied the community prevalence, patterns and predictors of hypertension in a large sub-population of South Asian adults with a view of identifying differential risk factors. Data were collected between years 2005-2006 and 5000 adults were invited for the study. The sample size was 4485, and about 39.5% were males. Mean systolic and diastolic blood pressures were 127.1 ± 19.8 mmHg and 75.4 ± 11.3 mmHg, respectively. Age-adjusted prevalence in all adults, males and females was 23.7%, 23.4% and 23.8%, respectively. Urban adults had a significantly higher prevalence of hypertension than rural adults. In the binary logistic-regression analysis, male gender (OR: 1.2), increasing age, Sri Lankan Moor ethnicity (OR: 1.6), physical inactivity (OR: 1.7), presence of diabetes (OR: 2.2) and central obesity (OR: 2.3) all were significantly associated with hypertension. In conclusion, nearly one-third of the Sri Lankan adult population is hypertensive. Hence, public health initiatives should encourage healthier lifestyles with emphasis on preventing obesity and increasing physical activity.

Patient reported adherence to hypertension treatment: A revalidation study

Background Adherence to hypertension management in patients with hypertension is known to influence their blood pressure control. It is important to measure patients’ adherence behaviours to assist with designing appropriate interventions to improve blood pressure control. Aims The purposes of this study were to use confirmatory factor analysis to revalidate the Therapeutic Adherence Scale for Hypertensive Patients (TASHP), and to calculate the cut-off score for classifying adherence behaviours into two groups: satisfactory and low adherence behaviours. Methods Systematic random sampling was used to recruit patients with hypertension in China. Demographic characteristics, the TASHP and blood pressure were collected. The psychometric tests of the TASHP included: construct validity, criteria-related validity, internal reliability, and split-half reliability. The area under the receiver operating characteristics curve and Youden index were used to identify the cut-off score of the TASHP for blood pressure control. Results This study involved 366 patients. Confirmatory factor analysis supported the four-component structure of the TASHP proposed in the original scale development study. The TASHP has a satisfactory internal reliability (Cronbach’s α > 0.7) and a satisfactory split-half reliability (Spearman–Brown coefficients > 0.7). The patients with overall scores of the TASHP ⩾ 109 points were considered to have satisfactory adherence behaviours. Conclusion The TASHP is a validated and reliable instrument to measure the adherence to hypertension management in Chinese patients with hypertension. The cut-off score of 109 points can be considered as an effective measure to classify the level of adherence into satisfactory and low adherence behaviours.