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Biomedical subjects

Giuseppe Bianchi

Publications and source records attributed to Giuseppe Bianchi.

At least 55 records · Page 3Linked to original sources
PubMed2004

Glomerular number and size in Milan hypertensive and normotensive rats: their relationship to susceptibility and resistance to hypertension and renal disease.

OBJECTIVE: Structural analysis, including morphometric computation of glomerular size and number, was applied to analyse the divergence between propensity to hypertension and renal damage, expressed by rats of the Milan hypertensive strain (MHS) and Milan normotensive strain (MNS), respectively. DESIGN: MHS, MNS rats and progenitor Wistar rats were investigated at age 9 weeks and 9 months. Classical morphometric methods were complemented by the dissector/fractionator technique to count glomeruli. RESULTS: At 9 weeks, when nephrogenesis was completed and hypertension established, MHS rats exhibited significantly lower kidney weight, cortical volume, glomerular number and volume compared to coeval MNS rats. In Wistar rats, these parameters were similar to those of MNS rats, except for lower glomerular volume. At 9 months, MHS rats showed significantly lower expansion of glomerular volume compared to MNS and Wistar rats. MNS rats had 10% sclerotic glomeruli, which was associated with reduced renal function and heavy proteinuria; conversely, sclerosis was rare in coeval MHS and Wistar rats. Media thickness was higher, whereas lumen diameter was lower, in intrarenal arteries of MHS versus MNS rats at both time points. CONCLUSIONS: These data indicate that structural changes other than a tubular defect may play a role in the development of hypertension in MHS rats. The lack of significant glomerular hypertrophy and damage in this strain, despite reduced glomerular number, could be related to their (haemodynamic) protection from hypertensive renal disease, possibly due to the hypertrophy of intrarenal arteries. The larger size of glomeruli of MNS rats may be linked to their susceptibility to glomerulosclerosis.

Animals↗
PubMed2004

Association of peripheral and central arterial wave reflections with the CYP11B2 -344C allele and sodium excretion.

OBJECTIVE: Angiotensin II and aldosterone, generated by the angiotensin-converting enzyme (ACE) and aldosterone synthase (CYP11B2), respectively, not only regulate sodium and water homeostasis, but also influence vascular remodeling in response to high blood pressure. In the European Project on Genes in Hypertension (EPOGH), we therefore investigated whether the ACE I/D and CYP11B2 C-344T polymorphisms influence early arterial wave reflections, a measure of vascular stiffness. METHODS: We measured the peripheral and central augmentation index of systolic blood pressure by applanation tonometry at the level of the radial artery in 622 subjects (160 families and 64 unrelated individuals) randomly recruited from three European populations, whose average urinary sodium excretion ranged from 196 to 245 mmol/day. In multivariate analyses, with sodium excretion analyzed as a continuous variable, we explored the phenotype-genotype associations by means of generalized estimating equations and the quantitative transmission disequilibrium test. RESULTS: The peripheral and central augmentation indexes were significantly higher in CYP11B2 -344C allele carriers than in -344T homozygotes. In offspring, early wave reflections increased with the transmission of the -344C allele. This effect of the CYP11B2 polymorphism occurred in subjects with a higher than median urinary sodium excretion (210 mmol/day). The ACE I/D polymorphism did not influence augmentation of systolic blood pressure. CONCLUSIONS: The CYP11B2 C-344T polymorphism affects arterial stiffness. However, sodium intake seems to modulate this genetic effect.

Adult↗
PubMed2004

Low-salt diet and diuretic effect on blood pressure and organ damage.

This review focuses on some aspects of the complex relationship among dietary salt intake, BP, organ complication, and genetic factors. First, the reason regarding the debate in the effect of a low-salt diet on BP and organ damage is discussed. Certainly, the lack of controlled long-term studies, taken together with the opposite effect of a low-salt diet on cardiovascular risk factors, justifies the contrasting opinions about the opportunity to reduce the sodium (Na) content in the diet of the general population. Second, the contribution that the genetic polymorphisms may furnish to explain the BP response in studies that apply either a moderate or a brisk reduction of salt intake is considered. Finally, the long-term effects of diuretics that produce a decrease in body Na similar to that achieved by moderate long-term dietary salt reduction are examined. Diuretics are able to reduce organ complications in the general population. However, these beneficial effects may be the net results of opposite effects in a subset of patients. Recently, the results of an observational study on hypertensive patients who were treated with a variety of antihypertensive drugs have been published. These results show that in carriers of the 460Trp ADD1 allele (38% of the population), the administration of diuretics halves the incidence of myocardial infarction and stroke when compared with other antihypertensive treatments that produce similar reduction of BP. These data support the notion that matching of the genetic mechanism with the drug mechanisms of action produces a clear therapeutic benefit.

Blood Pressure↗
PubMed2003

Expression analysis of the human adducin gene family and evidence of ADD2 beta4 multiple splicing variants.

Adducin is a cytoskeleton heterodimeric protein. Its subunits are encoded by three related genes (ADD1, ADD2, and ADD3) which show alternative spliced variants. Adducin polymorphisms are involved in blood pressure regulation in humans and rats. We have analyzed mRNA distribution of ADD gene family in human tissues and cells with Real-Time TaqMan RT-PCR. Whereas ADD1 is ubiquitously distributed, ADD3 is more expressed in kidney medulla and cortex than in fetal kidney, while in adult liver it is less abundant than in fetal liver. ADD2 beta1 and beta4 variants show the same pattern of distribution with the highest expression in brain, fetal liver, and kidney. Conventional RT-PCR identified new beta4 variants. Beta4a is characterized by an in-frame insertion of 21 nucleotides upstream exon 15 predicting a 7 amino acids longer protein with a similar C-terminus region. It is coexpressed with beta1 and beta4 in several tissues. Fetal kidney shows further beta4b, beta4c and beta4d variants containing internal exon deletions that enormously modify the predicted NH(2) and central regions. Our findings could help one to understand the functional role of adducin variants in specific tissues and cells.

Amino Acid Sequence↗
PubMed2003

Essential hypertension.

Hypertension is a frequent, chronic, age-related disorder, which often entails debilitating cardiovascular and renal complications. Blood pressure is usually noted in combination with other cardiovascular risk factors. Diagnosis of hypertension increasingly relies on automated techniques of blood pressure measurement. The pathophysiology of essential hypertension depends on the primary or secondary inability of the kidney to excrete sodium at a normal blood pressure. The central nervous system, endocrine factors, the large arteries, and the microcirculation also have roles in the disorder. Although monogenic forms of blood pressure dysregulation exist, hypertension mostly arises as a complex quantitative trait that is affected by varying combinations of genetic and environmental factors. Non-pharmacological strategies can reduce blood pressure. Antihypertensive drug treatment diminishes the complications of hypertension. The concept that a few major genes will provide the final clue to the pathogenesis of essential hypertension is an oversimplification that contradicts the heterogeneous nature of this disorder. Further integration of genetic, molecular, clinical, and epidemiological research could disclose subsets of patients in whom specific combinations of genetic and environmental factors raise blood pressure, and might lead to more individualised treatment.

Adolescent↗
PubMed2003

Tissue-specific modulation of beta-adducin transcripts in Milan hypertensive rats.

Genetic variants in Adducins, a family of cytoskeleton proteins (alpha, beta, and gamma) encoded by three genes, have been associated with primary hypertension in humans and in Milan hypertensive (MHS) rats. The present paper describes the identification of a rat beta 4 alternative splicing isoform differing from beta subunit for an in-frame insertion of 18 amino acids and showing a polymorphic site (R592W) between MHS and its normotensive control (MNS). Furthermore, we established a quantitative real-time PCR assay for analyzing the tissue expression of adducin gene family and determining whether any subunit transcript demonstrates altered expression during the development of MHS hypertension, especially in tissues relevant for the control of cardiovascular phenotypes (i.e., kidney, left ventricle, and large arteries). Among the three adducins only beta transcripts were modulated, in a tissue-specific manner, during the development of hypertension in MHS, compared to age-matched MNS controls. A 43% decrease in renal outer medulla was already present at the prehypertensive phase; a 70% decrease in femoral artery and 66% increase in left ventricle were observed after the development of hypertension. Surprisingly beta 4-Add, which is a minor component of total beta transcripts, is drastically reduced up to 88% in all MHS tissues. Alteration in beta-Add expression levels may account, at least in part, for the observed phenotypic changes in MHS hypertension.

Alternative Splicing↗
PubMed2003

C1-C2 posterior fusion in growing patients: long-term follow-up.

STUDY DESIGN: A retrospective review of patients undergoing C1-C2 posterior fusion during childhood was undertaken. OBJECTIVES: The aim of this study was to investigate the change in the sagittal curvature of the cervical spine in children after C1-C2 posterior fusion. SUMMARY OF BACKGROUND DATA: There have been only a few reports on postoperative changes in the sagittal curvature of the cervical spine after C1-C2 posterior fusion in children. However, they have all described the onset of sagittal postoperative cervical deformities. METHODS: Between January 1977 and December 1992, a total of 12 children underwent C1-C2 posterior fusion for atlantoaxial instability resulting from congenital malformation in eight, juvenile rheumatoid arthritis in one, and rotatory subluxation in three. The average age at the time of surgery was 10.9 years (range 7-12 years). All children underwent a similar treatment program with gradual preoperative reduction in halo cast, followed by C1-C2 posterior fusion with Mersilene loops in two cases, wiring in eight (Gallie's or Brooks' techniques), and interlaminar clamps in the remaining two. The halo cast made it possible to avoid a hyperextended or hyperflexed C1-C2 position while performing the atlantoaxial fusion, thus ensuring a more anatomic position during C1-C2 fusion. In the postoperative period, the halo cast was maintained for 7 to 9 weeks. RESULTS Follow-up ranged from 7 years to 13 years. Preoperative alignment of the cervical spine was classified into two groups: lordosis (eight patients) and straight (four patients). Postoperative subaxial malalignment (kyphosis) occurred in four cases (33%): these patients showed evidence of spontaneous and gradual sagittal improvement and presented either a straight (two cases) or a lordotic (two cases) cervical spine at follow-up. Immediately after surgery, the cervical spine was normally aligned in the remaining eight patients (lordosis and straight alignment in six and two cases, respectively) and was unchanged at follow-up. At follow-up, none of the 12 patients had a cervical deformity on sagittal plane. CONCLUSION: In children, a spontaneous realignment of the subaxial kyphosis observed after C1-C2 posterior fusion can be noted at follow-up, when a postoperative deformity occurs (33% in the present series). According to the present findings, it is not always mandatory to perform occipitocervical fusion in children with atlantoaxial instability just to prevent subaxial deformity in the cervical spine.

Adolescent↗
PubMed2003

ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy.

Renin-angiotensin system reactivity and the constitutive capacity of the renal tubule to reabsorb sodium play a role in the individual response to diuretic therapy; therefore we evaluated the blood pressure (BP) response to hydrochlorothiazide in 87 never-treated individuals with mild essential hypertension, according to ACE gene I/D and alpha-adducin Gly460Trp polymorphism. These genotypes where chosen because previous data showed their interaction in determining the BP response to salt probably was the result of their involvement in the activation of the renin-angiotensin system (ACE) and in the constitutive capacity of the kidney to reabsorb sodium (alpha-adducin) (treatment for 2 months). BP was measured after 3 run-in visits and after the first and second months of treatment by means of a standardized procedure. Data were analyzed by ANOVA, t test, and multivariate ANOVA for repeated measures (covarying for gender, age, and body mass index). Although basal mean BP (MBP) was similar in the different ACE and alpha-adducin genotypes, patients carrying at least one I allele of ACE and one 460Trp allele of alpha-adducin had the largest MBP decrease with treatment (12.7+/-1.9 mm Hg), the effect of the combination of genotypes being additive but not epistatic. These patients had an odds ratio of 15.75 of being a responder to hydrochlorothiazide compared with patients with Gly460Gly+DD, with the least MBP decrease (3.4+/-1.7 mm Hg). Alpha-adducin and ACE I/D polymorphism may be useful to predict the interindividual degree of response to hydrochlorothiazide; the analysis of the combination of the 2 genotypes increases the accuracy of the prediction of response to the drug.

Antihypertensive Agents↗
PubMed2003

beta-Adducin polymorphisms, blood pressure, and sodium excretion in three European populations.

The associations of the beta-adducin C1797T polymorphism with blood pressure (BP) and various indexes of sodium homeostasis were investigated in 388 men and 456 women, aged 18 to 60 years, recruited from three European populations (Cracow, Poland, n = 300; Novosibirsk, Russian Federation, n = 274; Mirano, Italy; n = 270). Phenotypes included 24-h ambulatory BP and urinary excretion of electrolytes and aldosterone. Subjects were genotyped for the beta-adducin polymorphism. Both a population-based association study and a family-based analysis were performed. Urinary sodium excretion was higher in Cracow than in Mirano (241 v 185 mmol/24 h, P <.05) and intermediate in Novosibirsk (206 mmol/24 h). The beta-adducin T allele (15.2% v 9.1%, P <.0001) was more prevalent in Mirano than in the two Slavic centers. In both population-based and family-based association analyses, there was significant heterogeneity between Slavic and Italian subjects in the phenotype-genotype relationships with beta-adducin. In the Slavic centers, 24-h systolic BP was higher in T allele carriers than in CC homozygotes (122.3 v 119.7 mm Hg, P =.03), whereas this was not the case in Mirano (121.8 v 122.9 mm Hg, P =.42). In Slavic (212.6 v 233.1 mmol/24 h) as well as in Italian (166.1 v 191.5 mmol/24 h) participants, 24-h sodium excretion was lower (P =.01) in T allele carriers than in CC homozygotes. These results were confirmed in the family-based analysis of offspring using a quantitative transmission disequilibrium test. In conclusion, the frequency of the beta-adducin T allele and salt intake differ across European populations. Thus, both variation in genetic background and salt intake may explain the observed heterogeneity in the phenotype-genotype relationships. Genetic determinants of complex quantitative traits such as BP can only be investigated within their epidemiologic context.

Adolescent↗
PubMed2003

Salt, endogenous ouabain and blood pressure interactions in the general population.

OBJECTIVE: Experimental data show that ouabain is a modulator of the sodium-potassium pump, which plays an important role in sodium homeostasis and blood pressure regulation. We investigated the distribution of plasma ouabain in the general population in relation to blood pressure and other determinants of sodium homeostasis. METHODS: In 379 subjects enrolled in a Belgian population study, we measured plasma ouabain, clinical characteristics including blood pressure, serum and urinary electrolytes, urinary aldosterone excretion, various lifestyle factors, and the Gly460Trp polymorphism of the alpha-adducin gene. Our statistical methods included analysis of covariance and multiple linear regression. RESULTS: Plasma ouabain (median, 140 pmol/l) correlated independently and positively with male gender (n = 182, P = 0.002), smoking (n = 116, P = 0.05), urinary potassium excretion (mean 69 mmol/day, P < 0.0001), and mutation of the alpha-adducin gene (n = 161, P < 0.0001). Both before and after adjustment for covariables, continuous as well as categorical analyses revealed a significant interaction (P < or = 0.02) between plasma ouabain and urinary sodium excretion (mean 194 mmol/day) in relation to blood pressure (mean systolic blood pressure/diastolic blood pressure, 123/76 mmHg). In individuals with plasma ouabain values below the median, blood pressure increased by 2.2 mmHg systolic and 1.4 mmHg diastolic for each 50 mmol/day increment in urinary sodium excretion (P < or = 0.01). No association between blood pressure and urinary sodium excretion was found when plasma ouabain exceeded the median. CONCLUSIONS: Plasma ouabain behaves as a blood pressure modulating factor, possibly released in response to potassium, either inhibiting the pressor effect of an excessive salt intake or counteracting the depressor action of sodium depletion.

Adult↗
PubMed2003

Blood pressure phenotypes in relation to the beta-adducin C1797T polymorphism in the European Project on Genes in Hypertension (EPOGH).

METHODS: The association of blood pressure (BP) with the beta-adducin C1797 T polymorphism was investigated in 388 men and 456 women aged 18-60 years recruited from three European populations (Cracow, Poland, n=300; Novosibirsk, Russian Federation, n=274; Mirano, Italy; n=270). Phenotypes included conventional measurements of BP obtained at the second contact with the subjects and 24-h ambulatory BP. Subjects were genotyped for the beta-adducin C1797 T polymorphism. Both a population-based association study and a family-based analysis were performed. RESULTS: Urinary sodium excretion was higher in Cracow than in Mirano (241 versus 185 mmol/day, P<0.05) and intermediate in Novosibirsk (206 mmol/day). The beta-adducin T allele (15.2 versus 9.1%, P<0.0001) was more prevalent in Mirano than in the two Slavic centres. In both population-based and family-based association analyses, there was significant heterogeneity between Slavic and Italian subjects in the phenotype-genotype relationships with beta-adducin. Adjusted population-based analyses demonstrated that in the two Slavic centres, values of systolic pressure obtained by 24-h, daytime and night-time ambulatory monitoring, but not those measured by conventional sphygmomanometry at home, were significantly higher in T allele carriers than in CC homozygotes. These results were confirmed in the family-based analysis of offspring using a quantitative transmission disequilibrium test. CONCLUSIONS: Phenotype-genotype associations involving blood pressure are influenced by the technique and conditions of the BP measurement as well as by the overall ecogenetic context.

Adolescent↗
PubMed2003

Genetics of hypertension: the adducin paradigm.

The following were investigated: (1) how we became interested in studying adducin genes and what we know about adducin; (2) studies in animals and humans supporting the role of adducin polymorphisms in hypertension, including some methodological problems related to the dissection of the role of a given genetic molecular mechanism in a complex multifactorial polygenic disease like hypertension; (3) biochemical mechanisms underlying the effect of adducin and its interaction with the Na-K pump; and (4) future directions.

Animals↗
PubMed2003

Pharmacogenomics of primary hypertension--the lessons from the past to look toward the future.

A number of recent reviews have addressed the issue of the pharmacogenomics of primary hypertension and related complications by considering the data on the genotype-drug response relationship. Here we mainly discuss the methodological aspects of this issue, trying to integrate 'traditional' clinical and experimental pathophysiology and therapy-pharmacology with the 'new' genetics. Such integration is indispensable to: a). define the appropriate 'context' (genetic background, environment, age, gender, phase of hypertension, previous therapy etc.) in which a given genotype-drug response relationship should be tested (it is indeed likely that many discrepancies among published data originate from context's interference); b). assign the correct clinical meaning to the results obtained by statistics and functional genetics methodologies; c). define a novel clinical entity caused by a disease favoring allele, alone or in combination with other alleles, with a consistent clinical picture, prognosis and responsiveness to the appropriate drug; d). estimate the size of the population target amenable to benefit from a therapeutic intervention developed according to the pharmacogenomics' principles; e). develop a novel drug that selectively interferes with the sequence of events triggered by the genetic mechanism(s) underlying the clinical entity. Peculiar to this strategy is to look for consistency among findings gathered from different 'contexts' after having properly accounted for the context's dependency of the results.

Animals↗
PubMed2003

Relationship between mortality and proximal femur fractures in the elderly.

Four hundred ninety-three patients aged > 65 years with proximal femur fractures were examined to assess the mortality rate within 1 year postoperatively. The risk factors that are most often associated with death were identified. Within the inhomogeneous group of patients, mortality was significantly higher in patients with poor mental status, with > or = 2 pre-existing diseases, a 3 or 4 American Society of Anesthetists class rating, and a lateral fracture. Regarding treatment and rehabilitation, special attention needs to be paid to these patients postoperatively.

Aged↗
PubMed2002

Arachidonic acid increases intracellular calcium in erythrocytes.

Recently, we have measured in erythrocytes a voltage-modulated and dihydropyridine-inhibited calcium influx. Since arachidonic acid and other polyunsaturated fatty acids influence the activities of most ion channels, we studied their effects on the erythrocyte Ca(2+) influx. It was measured on fresh erythrocytes, isolated from healthy donors, using the fluorescent dye Fura 2 as indicator of [Ca(2+)](i). AA (5-50 microM) and EPA (20-30 microM) stimulated a concentration-dependent increase in [Ca(2+)](i), deriving from extracellular calcium (1 mM), without affecting the intra- and extracellular pH and membrane voltage. The Ca(2+) influx rate varied from 0.5 to 3 nM Ca(2+)/s in the presence of AA and from 0.9 to 1.7 nM Ca(2+)/s with EPA. The Ca(2+) influx elicited by AA and EPA was not inhibited by dihydropyridines, while cyclooxygenase inhibitors were effective and PGE1 or PGE2 did not produce any effect. We conclude that AA could activate an erythrocyte voltage-independent Ca(2+) transport via an intermediate product of cyclooxygenase pathway; however, a direct interaction with the membrane lipid-protein cannot be excluded.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗