Floating-Harbor Syndrome: Presentation of the First Romanian Patient with a SRCAP Mutation and Review of the Literature.

Floating-Harbor syndrome (FHS) is a rare autosomal dominant syndrome characterized by short stature with delayed bone age, retarded speech development, intellectual disability and dysmorphic facial features. Recently, dominant mutations almost exclusively clustered in the final exon of the Snf2-related CREBBP activator protein (SRCAP) gene were identified to cause FHS. Here, we report a boy with short stature, speech delay, mild intellectual disability, dysmorphic features, and with genetically confirmed FHS. To the best of our knowledge, this is the first molecularly confirmed case with this syndrome reported in Romania. An intensive program of cognitive and speech stimulation, as well as yearly neurological, psychological, ophthalmological, otorhinolaryngological, pediatric and endocrinological monitoring for our patient were designed. We propose a checklist of clinical features suggestive of FHS, based on the main clinical features, in order to facilitate the diagnosis and clinical management of this rare condition.

Prevalence of albuminuria and cardiovascular risk profile in a referred cohort of patients with type 2 diabetes: an Asian perspective.

BACKGROUND: Microalbuminuria (MA) is a risk marker for diabetic nephropathy and cardiovascular (CV) disease (CVD) in patients with diabetes. This study aimed to describe the prevalence of albuminuria, CV risk factors, and treatments for renal and CV protection in an Asian population with type 2 diabetes. METHODS: This cross-sectional study conducted in eight Asian countries enrolled normotensive/hypertensive adults with type 2 diabetes without known proteinuria and/or non-diabetic kidney disease. Exclusion criteria were type 1 diabetes, menstruation, pregnancy, and acute fever. A single random urinary albumin/creatinine test was carried out in all patients. RESULTS: Of 8,561 patients, 14% had diabetic retinopathy, and 17% and 21% had history of CV disease and smoking, respectively. Normoalbuminuria was seen in 44%, MA in 44%, and macroalbuminuria in 12%. Target glycosylated hemoglobin (HbA1c) (<7%) was reached in only 37% of 3,834 patients with available values. Diabetes was managed by diet alone in 6%, while others received oral hypoglycemic drugs and/or insulin. In total, 75% did not reach target blood pressure (BP) of

Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug.

Hydralazine has been shown to reduce mortality in patients with congestive heart failure when given concomitantly with isosorbide dinitrate. Recently, we demonstrated that nitrate tolerance is in part due to enhanced vascular superoxide .O2- production. We sought to determine mechanisms whereby hydralazine may prevent tolerance. Rabbits either received no treatment, nitroglycerin patches (1.5 micrograms/kg/min x 3 d), hydralazine alone (10 mg/kg/d in drinking water), or hydralazine and nitroglycerin. Aortic segments were studied in organ chambers and relative rates of vascular .O2- production were determined using lucigenin-enhanced chemiluminescence. Nitroglycerin treatment markedly inhibited relaxations to nitroglycerin (maximum relaxations in untreated: 92 +/- 1 vs. 64 +/- 3% in nitroglycerin-treated patients and increased vascular .O2- production by over two-fold (P < 0.05). Treatment with hydralazine in rabbits not receiving nitroglycerin significantly decreased .O2- production in intact rabbit aorta and increased sensitivity to nitroglycerin. When given concomitantly with nitroglycerin, hydralazine completely prevented the development of nitrate tolerance and normalized endogenous rates of vascular .O2- production. Studies of vessel homogenates demonstrated that the major source of .O2- was an NADH-dependent membrane-associated oxidase displaying activities of 67 +/- 12 vs. 28 +/- 2 nmol .O2-.min-1.mg protein-1 in nitroglycerin-treated vs. untreated aortic homogenates. In additional studies, we found that acute addition of hydralazine (10 microM) to nitroglycerin-tolerant vessels immediately inhibited .O2- production and NADH oxidase activity in vascular homogenates. The chemiluminescence signal was inhibited by a recombinant heparin-binding superoxide dismutase (HBSOD) demonstrating the specificity of this assay for .O2-. These observations suggest that a specific membrane-associated oxidase is activated by chronic nitroglycerin treatment, and the activity of this oxidase is inhibited by hydralazine, providing a mechanism whereby hydralazine may prevent tolerance. The ability of hydralazine to inhibit vascular .O2- anion production represents a novel mechanism of action for this drug.

Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas.

The biological significance of the differential expression of cytokeratin (CK) polypeptides in breast carcinomas is unclear. We examined the CK profiles of 101 primary infiltrating ductal breast carcinomas using monoclonal antibodies directed against 11 different CKs and against vimentin. Two major CK phenotypes were distinguished: first, a phenotype expressing only the simple-epithelial CKs 7 (variably), 8, 18 and 19, and secondly, a bimodal phenotype co-expressing significant amounts of one or more of the stratified-epithelial CKs 4, 14 and 17. The vast majority of G1 and G2 carcinomas had the simple-epithelium phenotype, as did a subgroup of G3 carcinomas. Interestingly, the majority (62%) of G3 carcinomas exhibited the bimodal phenotype, with the expression of CKs 4, 14 and 17 being statistically correlated with poor histological differentiation and absence of steroid hormone receptors. The distribution of vimentin only partially overlapped with that of these stratified-epithelial CKs. Prognostic analyses suggested that the presence of CKs 4, 14 and/or 17 was associated with short overall and disease-free survival in subgroups comprising G3, oestrogen-receptor-negative and vimentin-negative tumours. In node-positive tumours the correlation between these CKs and a shorter disease-free interval attained statistical significance (log rank, 0.0096). Thus, abnormal CK profiles in ductal breast carcinomas appear to reflect disturbed regulation of differentiation-related gene expression programmes and may prove to be of clinical value.

Treatment of hypertension in the elderly: data from an international cohort of hypertensives treated by cardiologists.

Hypertension in the elderly is a major risk factor for cardiovascular disease. We aimed to analyze determinants of blood pressure (BP) control across different age groups. Population of a large global survey on hypertension treatment and control including 18927 patients was analyzed. A logistic regression analysis was conducted to estimate BP control rates and the prevalence of antihypertensive drug usage according to age. Systolic BP control decreased from 29.6% (95% confidence intervals (CI) 26.0;33.5) at 18-40 years to 22.4% (20.8;24.2) at >75 years (P<0.0001), and diastolic BP control increased from 31.6% (27.9;35.6) to 57.3% (55.2;59.3), respectively (P<0.0001). BP control was worse in diabetic patients, but did not differ substantially with co-morbid conditions, except for a better control in patients with myocardial infarction (MI) (P<0.05). The use of ≥ 3 antihypertensive drugs increased with age from 16.1 to 37.8% (P<0.0001) due to a more frequent use of loop diuretics (P<0.0001), thiazides (P<0.0001), angiotensin-converting enzyme (ACE) inhibitors (P<0.0001) and calcium channel blockers (P<0.0001). About one third of patients received non-guideline-recommended drug-drug combinations. BP control is largely unsuccessful with increasing age. Owing to frequent inadequacies in the combination of antihypertensive drugs, future guidelines and educational programs should devote increased attention to the choice of optimal drug-drug combinations in the elderly.

Antihypertensive drug therapy and blood pressure control in men and women: an international perspective.

Cardiovascular death represents the single largest cause of mortality in women with 70% of deaths attributable to modifiable risk factors, such as hypertension. This analysis aims at evaluating, whether there are gender disparities in antihypertensive drug usage and blood pressure (BP) control. We included 18 017 patients with arterial hypertension from the International Survey Evaluating Microalbuminuria Routinely by Cardiologists in patients with Hypertension (I-SEARCH). The study was conducted between September 2005 and March 2006 in 26 countries, and data on patient demographics, cardiovascular disease and risk factors, BP, and cardiovascular drug treatment were collected. Mean systolic blood pressure (SBP) was 2.1 mm Hg higher in women (150.6+/-0.35 mm Hg, n=8357/18 017) than in men (148.5+/-0.35 mm Hg; P<0.0001, n=9526/18 017), whereas no difference in diastolic BP was seen (88.2+/-0.20 vs 88+/-0.20 mm Hg; P=0.198). Gender differences in SBP were more pronounced in diabetic as compared with non-diabetic patients (3.5 vs 1.7 mm Hg, n=4272 vs n=13 611; P<0.0001) and became evident at an age 55 years old. Overall BP-control rate was 33.6% in men and 30.6% in women (P<0.0001) and was lower in diabetic as compared with non-diabetic patients. In all, 30% of patients used one, 40% used two and 30% used > or = 3 drugs without gender differences. Response rates to different drug regimens appeared to be similar. However, women received more frequently thiazides and beta-blockers, and less frequently ACE-inhibitors as monotherapy. Major efforts are required to improve BP-management, especially in women.

Smoking is associated with a high prevalence of microalbuminuria in hypertensive high-risk patients: data from I-SEARCH.

BACKGROUND: Microalbuminuria (MAU) is a marker of endothelial dysfunction and a predictor of cardiovascular events. The effects of cigarette smoking on the prevalence of MAU in a high-risk population with arterial hypertension are unclear. METHODS: The International Survey Evaluating Microalbuminuria Routinely by Cardiologists in patients with Hypertension (I-SEARCH) documented the clinical profile of 20,364 patients with arterial hypertension and cardiovascular risk factors. In this population, 13,690 patients had no history of smoking, 4,057 patients were former smokers and 2,617 patients were current smokers. RESULTS: The prevalence of MAU was associated with the smoking status. Consumption of 1-20 cigarettes per day leads to an increase of 6.8% in the prevalence of MAU compared to non-smokers (P < 0.001). Smoking of >20 cigarettes per day was associated with a 12.5% higher prevalence of MAU compared to non-smokers, while former smokers had a 4.7% higher prevalence of MAU. Multivariable analysis revealed that smoking was independently associated with MAU [odds ratio (OR) smoking vs. non-smoking 1.16; 95% confidence interval (CI) 1.01-1.33; P < 0.05]. Particularly, a consumption of >20 cigarettes per day was associated with high odds for MAU (OR 1.33; CI 1.01-1.75; P < 0.05). Interestingly, independently of blood pressure, the use of an angiotensin receptor blocker and an ACE was associated with significantly reduced odds ratio for MAU in the smoking group, while there was no significant association in the non-smoking group. CONCLUSION: The prevalence of MAU in hypertensive patients is higher in smokers than in non-smokers with a strong dose dependency.

The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome.

BACKGROUND: Niacin is an agent that significantly increases high-density lipoprotein cholesterol (HDL-C), but its effects on surrogate markers of atherosclerosis and inflammatory markers are less clear. We studied the effects of niacin on carotid intimal media thickness (IMT), brachial artery reactivity as well as markers of inflammation and the metabolic profile of patients with metabolic syndrome. METHODS AND RESULTS: Fifty patients with the metabolic syndrome (Adult Treatment Panel (ATP) III criteria) were randomised to either extended-release niacin (1000 mg/day) or placebo. After 52 weeks of treatment, there was a change of carotid IMT of +0.009 +/- 0.003 mm in the placebo group and -0.005 +/- 0.002 mm in the niacin group (p = 0.021 between groups). Endothelial function improved by 22% in the group treated with niacin (p < 0.001), whereas no significant changes were seen in the placebo group. High sensitivity C-reactive protein decreased by 20% in the group treated with niacin for 52 weeks (p = 0.013). Niacin increased HDL-C (p < 0.001) and decreased low-density lipoprotein cholesterol and triglycerides (p < 0.001) significantly, and there were no adverse effects on fasting glucose levels after 52 weeks of treatment. CONCLUSION: Extended-release niacin therapy effects a regression in carotid intimal medial thickness and improvement in metabolic parameters (increased HDL and reduced triglycerides). Furthermore, extended-release niacin may demonstrate an anti-atherogenic effect in the metabolic syndrome by improving endothelial function and decreasing vascular inflammation.

Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase.

In patients with septic shock or inflammatory cardiac diseases like myocarditis myocardial contractility is depressed. These patients have elevated circulating levels of bacterial endotoxins (lipopolysaccharides, LPS) and pro-inflammatory cytokines like interleukin-1 beta (IL-alpha 1 beta) or tumor necrosis factor-alpha (TNF-alpha). It is not clear, whether LPS and/or cytokines have direct inotropic effects on cardiomyocytes and whether these effects are mediated via the L-arginine-nitric oxide synthase (NOS) pathway as demonstrated in vascular smooth muscle cells. Therefore, we examined the direct effects of LPS. IL-1 beta and TNF-alpha on contractility and cGMP content in isolated guinea-pig ventricular cardiomyocytes. Furthermore, the influence of the NOS inhibitor NG-nitro-L-arginine (L-NNA) and dexamethasone on these effects was studied as well as inducible NOS (iNOS) protein expression. LPS (1000 ng/ml), IL-1 beta (25 ng/ml) and TNF-alpha (100 ng/ml) decreased contractility by 48%, 55% and 65% and augmented cGMP content by 135%, 88% or 70% after long-term treatment (18 h) in cardiomyocytes, without altering contractility or cGMP content after short-term treatment (30 min). These effects were blocked by L-NNA (100 microM) and dexamethasone (3 microM). Furthermore iNOS protein was expressed in LPS- and cytokine-treated cardiomyocytes. These findings demonstrate that LPS. IL-1 beta and TNF-alpha have direct negative inotropic effects on cardiomyocytes, which are accompanied by an increase in cGMP content. These effects are mediated via de novo synthesis of a myocardial iNOS. The direct negative inotropic effects of endotoxins and cytokines on cardiomyocytes may in part contribute to the contractile dysfunction observed in patients with septic shock or inflammatory cardiac diseases.

Endotoxin and cytokines alter contractile protein expression in cardiac myocytes in vivo.

Release of bacterial endotoxin and cytokines induce cardiac failure during sepsis. We investigated the direct effects of E. coli endotoxin (lipopolysaccharide, LPS) and cytokines induced by LPS on the cardiac myocyte gene program. For in vivo-experiments adult Wistar rats were given 600 microg/day LPS i.v. for 24 h or 7 days. In addition, cultured adult rat cardiac myocytes were treated with LPS, interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNFalpha), interferon-gamma (IFNgamma) or IL-6 for 24 h. mRNA expression was evaluated for cardiac-alpha-actin (cAct), skeletal-alpha-actin (skAct), beta- and alpha-myosin heavy chain (MHC). LPS induced betaMHC-mRNA 3.6-fold and repressed alphaMHC 2.7-fold and cAct 2.5-fold after 24 h in vivo. Up-regulation of betaMHC (3-fold) and repression of cAct (2.5-fold) were still observed after 7 days LPS infusion, whereas alphaMHC-mRNA levels had returned to normal. At the protein level, increased expression of betaMHC by LPS treatment occurred already after 24 h and was maintained thereafter. LPS had no influence on skAct-mRNA. Similar changes in contractile protein mRNA expression were observed in LPS-treated cardiomyocytes in culture, whereas the tested cytokines either activated (IL-1beta, IFNgamma) or repressed (TNFalpha, IL-6) both MHC-isoforms and cAct. In conclusion, LPS and proinflammatory cytokines induce changes in contractile protein expression that may contribute to the acute heart failure observed during endotoxaemia.

Expression of inducible nitric oxide synthase in failing and non-failing human heart.

Recently, a significant activity of inducible nitric oxide synthase (iNOS) has been reported in biopsies from failing hearts due to idiopathic dilated cardiomyopathy (IDC). Thus, a potential pathophysiological role of iNOS in IDC has been stated. In order to investigate, whether iNOS expression is of pathophysiological relevance in human heart failure, we measured iNOS protein expression and cGMP content in left ventricular myocardium from non-failing and failing human hearts. Immunoblot analysis revealed iNOS protein expression in four out of six failing hearts from septic patients, whereas no iNOS-protein expression was detected in either non-failing human hearts (n = 6) or failing hearts due to IDC (n = 9), ischemic heart disease (IHD, n = 7), Becker muscular dystrophy (BMD, n = 2) and mitoxantrone-induced toxic cardiomyopathy TCM, n = 1). cGMP content was increased by 130% in septic hearts, whereas there was no cGMP increase in hearts with IDC. IHD and BMD compared to non-failing hearts. We conclude, that the induction of iNOS may play a role in contractile dysfunction observed in septic shock, but is unlikely to be of major pathophysiological importance in end-stage heart failure due to IDC, IHD, BMD and TCM.

Dissociation of the effects of forskolin and dibutyryl cAMP on force of contraction and phospholamban phosphorylation in human heart failure.

Forskolin and dibutyryl cyclic adenosine monophosphate (cAMP) stimulate force of contraction independent of beta-adrenoceptor stimulation. We studied their effects on force of contraction and phosphorylation of regulatory proteins in isolated electrically driven trabeculae carneae from failing human ventricles. The phosphorylation state of the regulatory protein phospholamban was studied because its phosphorylation usually faithfully follows contractility. For comparison, the phosphorylation state of the inhibitory subunit of troponin was studied. The phosphorylation state was inferred from in vitro phosphorylation of homogenates with cAMP-dependent protein kinase in the presence of radioactive gamma[32P]ATP Proteins were separated by electrophoresis, and radioactivity in the proteins of interest was quantified. The maximal positive inotropic effects occurred at 30 microM forskolin and were attenuated in comparison with the maximal effects to dibutyryl cAMP (1 mM). Both forskolin and dibutyryl cAMP enhanced phospholamban phosphorylation. However, phospholamban phosphorylation in intact trabeculae treated with 30 microM forskolin and 1 mM dibutyryl cAMP was comparable. It is suggested that phospholamban phosphorylation can be dissociated from inotropy at least in isolated trabeculae from failing human hearts.