Estradiol and resveratrol stimulating effect on osteocalcin, but not osteonectin and collagen-1alpha gene expression in primary culture of rat calvarial osteoblast-like cells

Evidence is available that some endocrine disruptors, acting as selective estrogen receptor modulators (SERMs), interfere with osteoblast differentiation and function. Therefore, we investigated whether 17beta-estradiol, bisphenol-A (BSP), silymarin, genistein, resveratrol, procymidone, linurone and benzophenone-3 (BP3) modulate differentiation of rat calvarial osteoblast-like (ROB) cells in primary in vitro culture. Disruptors were added at day 18 of culture and cells were harvested 48 h later. Real time-PCR revealed that estradiol and resveratrol enhanced osteocalcin mRNA expression in ROB cells, while other disruptors were ineffective. The expression of osteonectin and collagen-1alpha was not affected by any disruptor. Estradiol, resveratrol, genistein and BSP stimulated the proliferative activity of ROB cells. In contrast, procymidone and linurone inhibited the proliferative activity, and silymarin and BP3 were ineffective. The conclusion is drawn that i) only resveratrol is able, like estradiol, to stimulate the specialized functions of ROB cells, and ii) the proliferative activity of ROB cells is more sensitive to endocrine disruptors, some of which could probably act via a mechanism independent of their SERM activity.     

On-treatment diastolic blood pressure and prognosis in systolic hypertension

BACKGROUND: It has been suggested that low diastolic blood pressure (BP) while receiving antihypertensive treatment (hereinafter called on-treatment BP) is harmful in older patients with systolic hypertension. We examined the association between on-treatment diastolic BP, mortality, and cardiovascular events in the prospective placebo-controlled Systolic Hypertension in Europe Trial. METHODS: Elderly patients with systolic hypertension were randomized into the double-blind first phase of the trial, after which all patients received active study drugs (phase 2). We assessed the relationship between outcome and on-treatment diastolic BP by use of multivariate Cox regression analysis during receipt of placebo (phase 1) and during active treatment (phases 1 and 2). RESULTS: Rates of noncardiovascular mortality, cardiovascular mortality, and cardiovascular events were 11.1, 12.0, and 29.4, respectively, per 1000 patient-years with active treatment (n = 2358) and 11.9, 12.6, and 39.0, respectively, with placebo (n = 2225). Noncardiovascular mortality, but not cardiovascular mortality, increased with low diastolic BP with active treatment (P < .005) and with placebo (P < .05); for example, hazard ratios for lower diastolic BP, that is, 65 to 60 mm Hg, were, respectively, 1.15 (95% confidence interval, 1.00-1.31) and 1.28 (95% confidence interval, 1.03-1.59). Low diastolic BP with active treatment was associated with increased risk of cardiovascular events, but only in patients with coronary heart disease at baseline (P < .02; hazard ratio for BP 65-60 mm Hg, 1.17; 95% confidence interval, 0.98-1.38). CONCLUSIONS: These findings support the hypothesis that antihypertensive treatment can be intensified to prevent cardiovascular events when systolic BP is not under control in older patients with systolic hypertension, at least until diastolic BP reaches 55 mm Hg. However, a prudent approach is warranted in patients with concomitant coronary heart disease, in whom diastolic BP should probably not be lowered to less than 70 mm Hg.     

Immunomediated and ischemia-independent inflammation of coronary microvessels in unstable angina

This study investigated whether the myocardium is involved in the acute inflammatory reaction associated with bursts of unstable angina (UA). We looked for the presence of activated DR+ inflammatory cells and the expression patterns, localization, and immunostaining identification of genes for cytokines (IL-1beta, TNF-alpha, IL-6, and IFN-gamma), MCP-1, and iNOS in the left ventricle biopsies from 2-vessel disease anginal patients, 24 with UA and 12 with stable angina (SA), who underwent coronary bypass surgery. Biopsy specimens from 6 patients with mitral stenosis who underwent valve replacement were examined as control hearts (CHs). Plasma levels of IL-2 soluble receptor (sIL-2R) were measured as a marker of systemic immune reaction. In CHs, DR+ cells were undetectable, and cytokine and iNOS mRNA expression were negligible. UA patients had higher sIL-2R levels than SA patients (P<0.01), and their biopsy specimens showed both numerous DR+ cells identified as lymphocytes, macrophages, endothelial cells, and elevated expression levels of cytokine and iNOS genes (from 2.4- to 6.1-fold vs SA; P<0.01). Cytokine and iNOS genes and proteins were localized in endothelial cells without involvement of myocytes. IL-1beta and MCP-1 mRNAs were nearly undetectable. No significant differences were found in the number of DR+ cells, levels of cytokine, and iNOS genes between potentially ischemic and nonischemic left ventricle areas. In SA specimens, DR+ cells were very rare and only mRNAs for TNF-alpha and iNOS genes were overexpressed versus CHs. These results indicated that an acute immunomediated inflammatory reaction, essentially involving coronary microvessels, is demonstrable in UA patients.     

Aortic smooth muscle cell phenotypic modulation and fibrillar collagen deposition in angiotensin II-dependent hypertension

BACKGROUND: We investigated the effect of nifedipine, AT-1 and ET-1 receptor blockade on arterial smooth muscle cell phenotypes and collagen deposition in TGRen2 transgenic rat (TGR). METHODS: Four-week-old TGR were blood pressure (BP)-matched and allocated to receive a placebo (n=8), the calcium antagonist nifedipine (n=6), the AT-1 specific receptor antagonist irbesartan (n=6), the ET(A)/ET(B) antagonist bosentan (n=6) or the ET(A)-selective antagonist BMS-182874 (n=5). Sprague-Dawley normotensive rats served as controls (n=6). After 4 weeks of treatment animals were euthanized and the left ventricle (LV) and the structural changes in intracardiac arterioles and aorta were assessed histomorphometrically. Smooth muscle cell phenotypes and fibrillar collagen content of the aortic wall were evaluated by immunostaining, using differentiation markers-specific antibodies and Syrius red staining, respectively. The changes in ET(A) and ET(B) receptor density were also assessed with quantitative autoradiography. RESULTS: Compared to placebo, only irbesartan lowered BP (P<0.001) and prevented LV and small resistance artery hypertrophy. The aorta of placebo-treated TGR showed an increase in foetal-type smooth muscle cell content and fibrillar collagen staining, compared to controls. These changes were blunted by irbesartan, which increased ET(A) receptors in the arterial wall, enhanced by BMS-182874 and unaffected by bosentan. Nifedipine also blunted both the VSMC and collagen changes despite having no effect on BP and ET(A) receptors. CONCLUSIONS: In TGRen2, vascular hypertrophy entails both smooth muscle cell phenotypic modulation and collagen deposition. These alterations do not follow closely the BP changes and seem to imply the dihydropyridine-sensitive calcium channels.     

Endothelin receptor blockade lowers plasma aldosterone levels via different mechanisms in primary aldosteronism and high-to-normal renin hypertension

BACKGROUND: Endothelin (ET)-1 contributes to raising blood pressure (BP) and inducing cardiovascular disease by vasoconstriction and potent stimulation of aldosterone secretion. In the rat this latter effect occurs via ET(B) receptors; in humans in vitro studies implicated both ET(A) and ET(B) receptors, but there is no conclusive evidence in vivo. METHODS: We recruited 13 consenting hypertensive patients: six with primary aldosteronism (PA) and seven with high-to-normal renin hypertension (HNRH). They were infused with a low dose (200 nmol/min for 5 min followed by 100 nmol/min for 10 min) of the ET(A)-selective antagonist BQ-123 either alone or, on a different day, together with an identical dose of the ET(B)-selective antagonist BQ-788. Plasma aldosterone, cortisol and ACTH concentration and plasma renin activity (PRA) were measured with radioimmunoassay at -15, 0, 30, 60, 120, 240, 360 min, while BP was recorded non-invasively. RESULTS: BQ-123 alone and combined with BQ-788 significantly lowered mean BP in both PA and HNRH patients (by 6-10 mmHg at nadir; P<0.01). In PA patients, a short-lived decrease of aldosterone was elicited by combined BQ-123 and BQ-788 (-14%; P<0.05), but not by BQ-123 alone; cortisol, ACTH, and PRA were unaffected by either treatment. In HNRH patients, BQ-123 both alone and combined with BQ-788 lowered aldosterone (-39 and -28%, respectively) and PRA (-43 and -16%, respectively), while cortisol and ACTH were unaffected. CONCLUSIONS: Endogenous ET-1 contributes to maintaining the high BP values and the aldosterone secretion in both PA and HNRH patients. In the former patients, the aldosterone secretagogue effect of ET-1 is mediated via ET(B) receptors, while in the latter it occurs mainly via ET(A)-mediated stimulation of renin production.     

Impaired angiotensin II-extracellular signal-regulated kinase signaling in failing human ventricular myocytes

Angiotensin II was reported to induce insulin-like growth factor-I and endothelin-1 gene expression and peptide release by ventricular cardiomyocytes. However, the progression from cardiac hypertrophy to failure in humans is characterized by a reduced myocyte expression of insulin-like growth factor-I and endothelin-1, notwithstanding the enhanced cardiac generation of angiotensin II. In the present study we investigated the functional status of the signaling pathways responsible for angiotensin II-induced endothelin-1 and insulin-like growth factor-I formation in human ventricular myocytes isolated from patients with dilated (n = 19) or ischemic (n = 14) cardiomyopathy and nonfailing donor hearts (n = 6).In human nonfailing ventricular myocytes, angiotensin II (100 nmol/l) induced insulin-like growth factor-I and endothelin-1 gene expression, and peptide release was mediated by extracellular signal-regulated kinase activation and inhibited by extracellular signal-regulated kinase antagonism (PD98059, 30 micromol/l), endothelin-1 formation being partially reduced also by c-Jun N-terminal kinase inhibition (SP600125, 10 micromol/l); insulin-like growth factor-I and endothelin-1 formations were unaffected by the inhibition of p38 mitogen-activated protein kinase (SB203580, 10 micromol/l) and Janus tyrosine kinase 2 (AG490, 10 micromol/l). In failing myocytes, angiotensin II failed to induce insulin-like growth factor-I and endothelin-1 formation; angiotensin II-induced extracellular signal-regulated kinase activation was significantly impaired (-88% vs. controls) although c-Jun NH2-terminal kinase activation was preserved. The impaired extracellular signal-regulated kinase phosphorylation in failing myocytes was associated with increased myocyte levels of mitogen-activated protein kinase phosphatases.Therefore, the altered growth factor production in failing myocytes is associated with a significant derangement in intracellular signaling.     

Metabolic syndrome and target organ damage in untreated essential hypertensives

BACKGROUND: The prevalence and the relationship between metabolic syndrome, and target organ damage (TOD) in essential hypertensive patients has not been fully explored to date. OBJECTIVE: To investigate the association between metabolic syndrome, as defined by the ATP III report, and cardiac and extracardiac TOD, as defined by the 2003 ESH-ESC guidelines for management of hypertension, in a large population of never-treated essential hypertensives. METHODS: A total of 447 grade 1 and 2 hypertensive patients (mean age 46 +/- 12 years) who were attending a hypertension hospital outpatient clinic for the first time underwent the following procedures: (i) physical examination and repeated clinic blood pressure measurements; (ii) routine examinations; (iii) 24-h urine collection for microalbuminuria; (iv) 24-h ambulatory blood pressure monitoring; (v) echocardiography; and (vi) carotid ultrasonography. Metabolic syndrome was defined as involving at least three of the following alterations: increased waist circumference, increased triglycerides, decreased high-density lipoprotein cholesterol, increased blood pressure, or high fasting glucose. Left ventricular hypertrophy (LVH) was defined according to two different criteria: (i) 125 g/m in men and 110 g/m in women; (ii) 51 g/h in men and 47 g/h in women. RESULTS: The 135 patients with metabolic syndrome (group I) were similar for age, sex distribution, known duration of hypertension and average 24-h, daytime and night-time ambulatory blood pressure to the 312 patients without it (group II).The prevalence of altered left ventricular patterns (LVH and left ventricular concentric remodelling) was significantly higher in group I (criterion a = 30%, criterion b = 42%) than in group II (criterion a = 23%, criterion b = 30%, P < 0.05 and P < 0.01, respectively). A greater urinary albumin excretion (17 +/- 35 versus 11 +/- 23 mg/24 h, P = 0.04) was also found in group I compared to group II. There were no significant differences between the two groups in the prevalence of carotid intima-media thickening and plaques. CONCLUSIONS: These results from a representative sample of untreated middle-aged hypertensives show that: (i) the metabolic syndrome is highly prevalent in this setting and (ii) despite similar ambulatory blood pressure values, patients with metabolic syndrome have a more pronounced cardiac and extracardiac involvement than those without it.     

Experimental assessment of a novel robotically-driven endoscopic capsule compared to traditional colonoscopy

BackgroundDespite colonoscopy represents the conventional diagnostic tool for colorectal pathology, its undeniable discomfort reduces compliance to screening programmes.AimsTo evaluate feasibility and accuracy of a novel robotically-driven magnetic capsule for colonoscopy as compared to the traditional technique.MethodsEleven experts and eleven trainees performed complete colonoscopy by robotic magnetic capsule and by conventional colonoscope in a phantom ex vivo model (artificially clean swine bowel). Feasibility, overall accuracy to detect installed pins, procedure elapsed time and intuitiveness were measured for both techniques in both operator groups.ResultsComplete colonoscopy was feasible in all cases with both techniques. Overall 544/672 pins (80.9%) were detected by experimental capsule procedure, while 591/689 pins (85.8%) were detected within conventional colonoscopy procedure (P = ns), thus establishing non-inferiority. With the experimental capsule procedure, experts detected 74.2% of pins vs. 87.6% detected by trainees (P < 0.0001). Overall time to complete colon inspection by robotic capsule was significantly higher than by conventional colonoscopy (556 ± 188 s vs. 194 ± 158 s, respectively; P = 0.0001).ConclusionWith the limitations represented by an ex vivo setting (artificially clean swine bowel and the absence of peristalsis), colonoscopy by this novel robotically-driven capsule resulted feasible and showed adequate accuracy compared to conventional colonoscopy.     

Superior mesenteric artery syndrome (Wilkie Syndrome) with unusual clinical onset: Description of a rare case

Wilkie''s Syndrome is a very rare disease caused by reduction of aorto-mesenteric space with consequent duodenum compression. It can combine with left renal vein stenosis which, when symptomatic, is known as "Nutcracker Syndrome". We describe a clinical onset case with epigastric pain without vomiting in a normal weight patient. 28-year-old woman who came to our observation for intense epigastric pain after a weight loss of 14 kg in 4 months. Multidetector Computed Tomography and Ultrasound revealed gastric and duodenal overdistension with hydro-air levels, severe duodenum stenosis, and left renal vein compression. Wilkie''s Syndrome is common in anorexic individuals suffering from recurrent postprandial vomiting, onset with severe epigastric pain, without vomiting, is quite unusual. High-calorie diet must be first therapeutic approach, in case of failure treatment of first choice should be endovascular stenting and, only in selected cases, surgical treatment should be used because it is very invasive and burdened with numerous complications. Failure to diagnose this disease can expose patients to serious health risks.