Genetic mechanisms underlying the regulation of urinary sodium excretion and arterial blood pressure: the role of adducin.
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Animals↗
Biomedical subjects
G Bianchi
Publications and source records attributed to G Bianchi.
Synergistic effect of alpha-adducin and ACE genes causes blood pressure changes with body sodium and volume expansion.
BACKGROUND: The genetic dissection of a polygenic, multifactorial, quantitative disease such as arterial hypertension is hampered by a large environmental variance and by genetic heterogeneity. METHODS: To reduce the environmental variance, we measured the pressor response to a saline load (PRSL) and the basal plasma renin activity (PRA) under very controlled conditions in 145 essential hypertensive patients, as they may have the most direct clinical expression of the putative genetic alteration in renal Na handling and blood pressure (BP) regulation caused by the alpha-adducin and angiotensin-converting enzyme (ACE) polymorphism. RESULTS: PRSL was smaller in patients homozygous for the wild-type (Gly460) variant of alpha-adducin compared with that of patients bearing at least one copy of the 460Trp variant (2.5 +/- 0.6 vs. 7.0 +/- 0.9 mm Hg, P = 0.0001), whereas the ACE genotype was not associated with differences in PRSL. Both alpha-adducin and ACE affect PRA, with lower values correlated with the number of 460Trp or D alleles (P = 0.019 and 0.017, respectively). Most important, alpha-adducin and ACE interact epistatically in determining the PRSL, doubling the variance explained when epistasis is taken into account (variance from 7.7 to 15.5%). CONCLUSION: These findings support the involvement of ACE and alpha-adducin in PRSL and PRA control, which are of paramount importance in setting the BP level and its response to therapy.
Adult↗
Synthesis of glutathione in response to methionine load in control subjects and in patients with cirrhosis.
The fasting plasma level of reduced glutathione (GSH), a methionine-derived tripeptide, is reduced in cirrhosis. There is evidence that a reduced activity of S-adenosyl-L-methionine synthetase limiting the flux of methionine along the transmethylation/transsulfuration pathway may contribute to decrease GSH levels. No studies have analyzed plasma GSH in response to a methionine load. In 6 control subjects and in 10 patients with cirrhosis, plasma sulfur amino acid and plasma and erythrocyte GSH levels were measured in response to a L-methionine load (0.1 g/kg). Blood samples were obtained throughout the day after the oral load. Urine was collected for measurement of sulfur excretion. During the study period, all subjects consumed a standard diet of 1,683 kcal containing 2% protein and virtually no methionine. Plasma methionine increased in both groups to a peak level exceeding 20 times the basal value 90 minutes after the load, and declined thereafter. Methionine clearance, calculated on the descending part of the methionine-time curve, was reduced by 50% in cirrhosis (P = .0001). Fasting GSH was higher in controls (mean +/- SD, 3.9 +/- 1.3 v 1.6 +/- 0.7 micromol/L, P = .0004). In response to a methionine load, it peaked at 10.2 +/- 7.2 and 3.2 +/- 1.3 micromol/L, respectively (P = .009). Thereafter, plasma GSH progressively declined, and after 24 hours, it returned to the fasting preinfusion values in both groups. Plasma cysteine and taurine concentrations, as well as the erythrocyte GSH time course, paralleled plasma GSH levels, with less significant differences between groups. Sulfate excretion was delayed. GSH synthesis is stimulated by a methionine load. The reduced flux of methionine along the transmethylation/transsulfuration pathway reduces GSH synthesis in cirrhosis. Defective methionine metabolism also may be responsible for reduced fasting GSH.
Aged↗
Interaction of substance use and risks to sexual health in the Slovak army: general, sociocultural and individual behaviour patterns.
This paper offers an overview about the application of the newly designed WHO/UNAIDS Rapid Assessment and Response Guide (SEX-RAR) for research on interaction between psychoactive substance use and sexual risks in the very specific environment during mandatory military service in the Slovak Republic. Presented results outline general, specific (sociocultural) and individual behaviour patterns concerning interaction of substance (alcohol) use and sexual behaviour, as well as proposed recommendations for intervention activities.
Adult↗
Concurrent pheochromocytoma, diabetes insipidus and cerebral venous thrombosis--a possible unique pathophysiological mechanism.
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Adrenal Gland Neoplasms↗
Hypertension in chronic renal failure and end-stage renal disease patients treated with haemodialysis or peritoneal dialysis.
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Antihypertensive Agents↗
Renal arterial stenosis: prospective comparison of color Doppler US and breath-hold, three-dimensional, dynamic, gadolinium-enhanced MR angiography.
PURPOSE: To compare color Doppler ultrasonography (US) with fast, breath-hold, three-dimensional, gadolinium-enhanced magnetic resonance (MR) angiography in detecting renal arterial stenosis. MATERIALS AND METHODS: Forty-five patients with clinical suspicion of renovascular disease were prospectively examined with intra- and extrarenal color Doppler US and breath-hold, gadolinium-enhanced MR angiography. Digital subtraction arteriography (DSA) was the standard of reference in all patients for the number of renal arteries and degree of stenosis. RESULTS: DSA depicted 103 arteries and 52 stenoses. Color Doppler US was nondiagnostic in two examinations. Significantly more of 13 accessory renal arteries were detected with MR angiography (n = 12) than with color Doppler US (n = 3; P <.05). For assessing all stenoses, the sensitivity and accuracy were 94% and 91%, respectively, for MR angiography and 71% and 76%, respectively, for US (P <.05). The sensitivity was higher for MR angiography (100%) than for US (79%; P <.05) in diagnosing stenoses with at least 50% narrowing. The specificity, accuracy, and negative predictive value in diagnosing stenoses of at least 50% narrowing were 93%, 95%, and 100% for MR angiography and 93%, 89%, and 90% for US. CONCLUSION: Breath-hold, gadolinium-enhanced MR angiography is superior to color Doppler US in accessory renal artery detection. Although the specificity of MR angiography is similar to that of color Doppler US, MR angiography has a better sensitivity and negative predictive value in depicting renal arterial stenoses.
Adult↗
In vitro studies on the trafficking of dendritic cells through endothelial cells and extra-cellular matrix.
Dendritic cells (DC) are antigen presenting cells (APC) with the unique ability to initiate an immune response. Immature DC are localized in peripheral tissues where they exert a sentinel function for incoming antigens (Ag). After Ag capture and exposure to inflammatory stimuli DC undergo maturation and migrate to regional lymph nodes where the presentation of antigenic peptides to T lymphocytes takes place. Thus their correct functioning as APC involves localization in tissues and trafficking via the lymph or blood to lymphoid organs. In the present study we have investigated the ability of DC to interact in vitro with human vascular endothelial cells (EC) and extracellular matrix (ECM). DC are differentiated from monocytes by in vitro exposure to GM-CSF and IL-13 for 7 days. In adhesion assays a considerable proportion of DC binds to resting EC monolayers and this adhesion is inhibited by anti-CD11a and CD11b, but not anti-CD11c mAbs. Binding to a natural ECM, derived from cultured EC involves VLA-4 and VLA-5 integrins. In a transmigration assay, 10% of input cells are able to cross the EC monolayer in the absence of exogenous stimuli. The amount of DC transmigrated through a monolayer of EC was increased of 2-3 fold by C-C chemokines RANTES, MIP1alpha, and MIP-1beta. Most importantly, in view of the trafficking pattern of these cells, a significant proportion of DC can migrate in a reverse transmigration assay, i.e. across the endothelial basement membrane and subsequently, across endothelial cells. Upon exposure to immune or inflammatory signals peripheral DC undergo maturation and migration to lymphoid organs. Functional maturation is associated with loss of responsiveness to chemokines present at sites of inflammation (e.g. MIP1alpha, MIP1beta and RANTES) and acquisition of a receptor repertoire which renders these cells responsive to signals which guide their localization in lymphoid organs (e.g. MIP3beta). A better understanding of the molecular basis of DC trafficking may provide molecular and conceptual tools to direct and modulate DC localization as a strategy to upregulate and orient specific immunity.
Cell Adhesion↗
CA-Repeat polymorphism in intron 1 of HSD11B2 : effects on gene expression and salt sensitivity.
Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11beta-hydroxysteroid dehydrogenase cause apparent mineralocorticoid excess, a form of familial hypertension. Because the hypertension associated with AME is of the salt-sensitive type, it seemed possible that decreases in 11-HSD2 activity might be associated with salt sensitivity. To examine this, Italians with mild hypertension underwent a protocol consisting of a rapid intravenous saline infusion and subsequent furosemide diuresis. To determine whether there were genetic associations between HSD11B2 and salt sensitivity, 198 Italians were genotyped for a CA repeat polymorphism (11 alleles) in the first intron. Increased differences in mean arterial pressure between the sodium loaded and depleted states were correlated with shorter CA repeat length (R=0.214, P=0. 0025). The effect behaved as a recessive trait. This suggested that decreased HSD11B2 expression was associated with shorter CA repeat length. Furthermore, activity of renal 11-HSD2 as measured by an increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89+/-0.04 [mean+/-SE]) compared with 34 salt-resistant subjects (0.71+/-0.04, P<0.001). However, when minigenes containing either 14 or 23 CA repeats were transfected into rabbit or human kidney cortical collecting duct cells, the construct with 14 repeats was instead expressed at levels 50% higher than those of the construct with 23 repeats, as determined by reverse transcription-polymerase chain reaction. We conclude that polymorphisms in HSD11B2 and decreased 11-HSD2 activity are associated with sensitivity to sodium loading, but a functional explanation for these associations remains to be elucidated.
11-beta-Hydroxysteroid Dehydrogenases↗
Genetic mapping of blood pressure quantitative trait loci in Milan hypertensive rats.
In a previous study, by using a candidate gene approach, we detected in both Milan hypertensive rats and humans a polymorphism in the alpha-adducin gene (ADD1) that was associated with blood pressure and renal sodium handling. In the present study, a genomewide search with 264 informative markers was undertaken in 251 (Milan hypertensive strain x Milan normotensive strain) F2 rats to further investigate the contribution of the adducin gene family (Add1, Add2, and Add3) and to identify novel quantitative trait loci (QTLs) that affect blood pressure. The influence of 2 different methods of blood pressure measurement, the intracarotid catheter and the tail-cuff method, was also evaluated. We found evidence that QTLs affected systolic blood pressure (SBP) measured at the carotid (direct SBP) on rat chromosome 1 with a logarithm of the odds (LOD) score peak of 3.3 on D1Rat121 and on rat chromosome 14 on Add1 locus (LOD=3.2). A QTL for SBP measured at the tail (indirect SBP) was found on rat chromosome 10 around D10Rat33 (LOD=5.0). All of these QTLs identified chromosomal regions not detected in other rat studies and harbor genes (Na(+)/H(+) exchanger A3; alpha-adducin; alpha(1B)-adrenergic receptor) that may be involved in blood pressure regulation. Therefore, these findings may be relevant to human hypertension, also in consideration of the biochemical and pathophysiological similarities between MHS and a subgroup of patients of primary hypertension, which led to the identification of alpha-adducin as a candidate gene in both species.
Animals↗
PST 2238: a new antihypertensive compound that modulates the Na-K pump 'in vivo' and 'in vitro'.
A primary renal alteration due to a genetic polymorphism of the cytoskeletal protein adducin associated with an up-regulation of the renal Na-K pump and increased levels of ouabainlike factor (OLF) has been identified as a possible causes of hypertension in Milan rats (MHS). This adducin polymorphism has also been found to be associated with hypertension and the blood pressure changes related to renal Na handling in humans and increased OLF levels have been found in a relevant portion of hypertensive patients. Increased activity and expression of the Na-K pump has also been observed under the following 'in vitro' and 'in vivo' conditions: rat renal cells transfected with the 'hypertensive' variant of adducin, as compared with normal cells; normal rat renal cells incubated for 5 days with 10(-9) M ouabain and normal rats made hypertensive by a chronic infusion of low doses of ouabain (OS rats). An up-regulation of the Na-K pump seems therefore to be a common biochemical alteration induced both by an adducin polymorphism and/or chronic exposure to low concentrations of ouabain (or OLF). A new antihypertensive compound, PST 2238, that selectively antagonizes the pressor effect and the alteration of the renal Na-K pump induced both by an adducin polymorphism and OLF, is described. The ability of PST 2238 to lower blood pressure and normalize the Na-K pump both in MHS and OS rats suggests that this compound could be useful in the treatment of those forms of essential hypertension in which renal Na-handling alterations are associated with either adducin polymorphisms and/or increased OLF levels.
Androstanols↗
The genomics of cardiovascular disorders: therapeutic implications.
Cardiovascular disease (CVD) is a complicated series of disorders that result from the interaction between genetic predisposing mechanisms and environmental factors. Over the last few years substantial progress has been made in defining the molecular basis of several genetically transmitted non-atherosclerotic CVD such as hypertrophic and dilated cardiomyopathies, long-QT syndrome and essential hypertension. This review represents a summary of the current knowledge about the major gene polymorphisms found to be associated with these CVDs. Moreover, we will discuss how the discovery of disease-associated genes will greatly enhance the ability to formulate advanced diagnoses, to define prophylactic therapeutic strategies to prevent or reduce the progression of the disease and, finally, to proceed to the development of new drugs tailored for the specific cellular or molecular functions altered as consequence of the predisposing genes.
Animals↗
Nutritional treatment with branched-chain amino acids in advanced liver cirrhosis.
During the last 20 years there has been much interest in nutritional treatment for patients with advanced cirrhosis. Most studies have measured the potential benefit of nutritional supplements of dietary proteins, generic protein hydrolysates, or specific branched-chain amino acid (BCAA)-enriched formulas in regard to nutritional parameters and hepatic encephalopathy. The issue is not definitively settled; data are conflicting and meta-analyses have failed to produce unequivocal results. A consensus review, recently produced under the auspices of the European Society for Parenteral and Enteral Nutrition, concluded that: (1) patients with cirrhosis tend to be hypermetabolic, and a higher-than-normal supply of dietary proteins is needed to achieve nitrogen balance; (2) most patients tolerate a normal or even increased dietary protein intake, without risk of hepatic encephalopathy; (3) a modified eating pattern, based on several meals and a late evening snack, is useful; (4) in severely malnourished patients, amino acid supplements may be considered to provide the necessary amount of proteins to meet protein requirements; (5) in a few patients intolerant to the required protein intake, BCAA supplements may be considered to provide the necessary nitrogen intake without detrimental effects on the mental state, perhaps even improving it. Future studies are needed to quantify the advantage of nutritional support with amino acids or BCAA supplements on overall well-being, complications, and ultimately survival with a long-lasting disease where self-perceived health-related quality of life is a major outcome.
Amino Acids, Branched-Chain↗
A multicenter cross sectional study on bone mineral density in rheumatoid arthritis. Italian Study Group on Bone Mass in Rheumatoid Arthritis.
OBJECTIVE: To determine the frequency of osteoporosis in a large cohort of women with rheumatoid arthritis (RA) and to investigate the main determinants of bone mineral density (BMD) and risk factors for vertebral fractures in this population. METHODS: We recruited 925 consecutive female patients with RA at 21 Rheumatology Centers in Italy. For each patient pre-registered demographic, disease, and treatment-related variables were collected. BMD was measured at lumbar spine and proximal femur by dual x-ray absorptiometry technique. Collected variables underwent a univariate and multivariate statistical procedure. Osteoporosis was defined as BMD > -2.5 T score. RESULTS: The frequency of osteoporosis in the whole sample was 28.8% at lumbar spine and 36.2% at femoral neck and increased linearly from Steinbrocker's functional stage I to IV (p = 0.0001). Patients with spinal or femoral osteoporosis were significantly older (p = 0.0001), had a lower body mass index (BMI) (p < 0.02), a significantly longer disease duration (p < 0.02) and a significantly higher Health Assessment Questionnaire (HAQ) score (p = 0.0001). These differences were significant, even after adjusting for age. Steroid use was associated with significantly lower lumbar and femoral BMD (p = 0.0001) even after adjusting for the main confounding covariates. Analysis of lateral spine radiographs revealed 74 women with at least one vertebral fracture. These women had a significantly lower lumbar and femoral BMD (p = 0.0001). The generalized linear model showed that steroid use, menopause, BMI, age, and HAQ were all significant independent predictors of lumbar and femoral BMD. The logistic procedure showed that age (OR 1.05, 95% CI 1.03-1.07), HAQ (OR 1.3, 95% CI 1.07-1.7), menopause (OR 1.9, 95% CI 1.1-3.2), use of steroids (OR 1.5, 95% CI 1.07-2.1), and BMI (OR 0.8, 95% CI 0.8-0.9) were significantly associated with the risk for osteoporosis. The only variables associated with an increased risk for vertebral fracture were age (OR 1.04, 95% CI 1.01-1.08), HAQ (OR 1.7, 95% CI 1.08-2.09), and cumulative steroid intake (OR for 1 g of prednisone 1.03, 95% CI 1.006-1.07). CONCLUSION: To prevent osteoporosis and its dramatic complications in RA the therapeutic challenge is to preserve functional capacity using the lowest possible dosage of corticosteroids.
Absorptiometry, Photon↗
Diagnosis of human hydatidosis. Predictive value of a rural ultrasonographic survey in an apparently healthy population.
The usefulness of ultrasonography (US) in the early diagnosis of hydatidosis, applied in large-scale surveys to populations lacking clinical symptoms of the disease, has been amply documented. However, the rate of false positive and negative results is poorly described. Due to this, the present paper is aimed to evaluate the sensitivity, specificity and predictive value of a conventional rural ultrasonographic survey in comparison with higher imaging complexity. Accordingly, during 1997 and 1998 a total of 1054 children from 7 to 14 years of age were evaluated by means of US, in the town of Ingeniero Jacobacci, Province of Rio Negro, Argentina, employing a portable device for population studies. All detected cases were referred to a high complexity center specialized in imaging diagnosis for their re-evaluation with US, CT scanning and X-rays. A control group comprising 3 children negative by US for each positive case in the mass screening survey was selected and reexamined by US and X-rays and CT scanning in doubtful situations. Twenty-seven asymptomatic carriers were referred with images compatible with hydatid cysts, while 66 were classified as disease free. At reexamination, 24 of those diagnosed as carriers and the totality of those classified as healthy were confirmed. On the basis of our results, a sensitivity of 100%, a specificity of 95.6% and a global test value of 96.7% were estimated.
Adolescent↗
Donor and recipient postoperative complications in living related kidney transplantation. A multicentric study.
BACKGROUND: Living related kidney transplantation is considered a gold standard of renal transplantation in order to overcome end-stage renal disease within the same family members. Living donation, albeit decreasing cadaveric donor shortage, exposes donors to the risk of surgical complications. METHODS: In order to assess the postoperative complication rate in donors and recipients, we reviewed retrospectively 90 consecutive living related kidney transplants in a multicentric study. All nephrectomies were performed extraperitoneally through a left flank incision. RESULTS: Major perioperative complications (first 3 weeks after surgery) occurred in 12 subjects: these included bleeding (2.2%), symptomatic pneumothorax (1.1%), iliac thrombophlebitis (3.3%), iliac artery dissection (1.1%), laparotomic dehiscence (2.2%), perirenal hematoma (1.1%), renal artery stenosis (1.1%), urinary fistula (1.1%). Minor perioperative complications took place in 8 cases. One recipient died. Donor postoperative major complications occurred in 2 subjects. CONCLUSIONS: On the basis of these results we conclude that living related kidney transplantation is an important treatment of end stage renal disease, due to the associated low major complication rate and the high feasibility of this methodology.
Adolescent↗
Genomic organization of the human gamma adducin gene.
We report the genomic structure of the human gamma adducin gene (ADD3). Adducin is a protein involved in cytoskeletal assembly and composed of alpha-beta or alpha-gamma subunits which share a high degree of homology between human and rat. Mutations in alpha subunit have been shown associated to both human and rat hypertension. The human ADD3 gene spans over 20 kb and is composed of at least 13 introns and 14 exons covering the entire coding region. The exon size ranges from 81 bp to greater than 293 bp and the intron size from 111 bp to longer than 3.2 kb. We also demonstrate the presence of an alternative splicing event around exon 13, whose sequence, position, and expression is analogous in rat Add3 gene. Moreover, human ADD3 amino acid sequence presents 91.9% of identity compared to rat sequence. Characterization of human ADD3 gene provides an important tool for mutation analysis.
Alternative Splicing↗
A case of bleeding gastric lipoma: US, CT and MR findings.
We report a case of gastric lipoma which manifested with an episode of acute gastrointestinal hemorrhage. Preoperative diagnosis was based on the US, CT, and MRI findings, as the results of gastrointestinal endoscopy were inconclusive. The role of current imaging methods, and particularly of MRI, is discussed.
Anastomosis, Roux-en-Y↗