Preliminary profiling of blood transcriptome in a rat model of hemorrhagic shock.

Hemorrhagic shock is a leading cause of morbidity and mortality worldwide. Significant blood loss may lead to decreased blood pressure and inadequate tissue perfusion with resultant organ failure and death, even after replacement of lost blood volume. One reason for this high acuity is that the fundamental mechanisms of shock are poorly understood. Proteomic and metabolomic approaches have been used to investigate the molecular events occurring in hemorrhagic shock but, to our knowledge, a systematic analysis of the transcriptomic profile is missing. Therefore, a pilot analysis using paired-end RNA sequencing was used to identify changes that occur in the blood transcriptome of rats subjected to hemorrhagic shock after blood reinfusion. Hemorrhagic shock was induced using a Wigger's shock model. The transcriptome of whole blood from shocked animals shows modulation of genes related to inflammation and immune response (Tlr13, Il1b, Ccl6, Lgals3), antioxidant functions (Mt2A, Mt1), tissue injury and repair pathways (Gpnmb, Trim72) and lipid mediators (Alox5ap, Ltb4r, Ptger2) compared with control animals. These findings are congruent with results obtained in hemorrhagic shock analysis by other authors using metabolomics and proteomics. The analysis of blood transcriptome may be a valuable tool to understand the biological changes occurring in hemorrhagic shock and a promising approach for the identification of novel biomarkers and therapeutic targets. Impact statement This study provides the first pilot analysis of the changes occurring in transcriptome expression of whole blood in hemorrhagic shock (HS) rats. We showed that the analysis of blood transcriptome is a useful approach to investigate pathways and functional alterations in this disease condition. This pilot study encourages the possible application of transcriptome analysis in the clinical setting, for the molecular profiling of whole blood in HS patients.

The -665 C>T polymorphism in the eNOS gene predicts cardiovascular mortality and morbidity in white Europeans.

We recently identified rs3918226 as a hypertension susceptibility locus (-665 C>T), TT homozygosity being associated with higher hypertension risk. T compared with C allele transfected cells had lower endothelial nitric oxide synthase (eNOS) expression. In the family-based Flemish Study on Environment, Genes and Health Outcomes (50.9% women; mean age 40.3 years), we investigated whether 32 TT homozygotes had worse outcomes than 2787 C allele carriers. Over 15 years (median), total and cardiovascular mortality and cardiovascular and coronary events amounted to 269 (9.5%), 98 (3.5%), 247 (8.8%) and 120 (4.3%), respectively. While accounting for family clusters, the hazard ratios associated with TT homozygosity were 4.11 (P=0.0052) for cardiovascular mortality (4 deaths), 2.75 (P=0.0067) for cardiovascular events (7 endpoints) and 3.10 (P=0.022) for coronary events (4 endpoints). With adjustment for cardiovascular risk factors, these hazard ratios were 6.01 (P=0.0003), 2.64 (P=0.0091) and 2.89 (P=0.010), respectively. Analyses unadjusted for blood pressure and antihypertensive treatment produced consistent results. For all fatal plus nonfatal cardiovascular events, the positive predictive value, attributable risk and population-attributable risk associated with TT homozygosity were 21.9, 61.5 and 2.0%, respectively. In conclusion, TT homozygosity at the position -665 in the eNOS promoter predicts adverse outcomes, independent of blood pressure and other risk factors.

From endothelial dysfunction to atherosclerosis.

It has recently emerged that endothelial dysfunction is an early step in the development of atherosclerosis and is mainly characterised by a reduction in the bioavailability of nitric oxide. All of the traditional cardiovascular (CV) risk factors (dyslipidemia, arterial hypertension, hyperglycemia and diabetes) are associated with endothelial dysfunction, and oxidised low-density lipoproteins, the renin-angiotensin axis and insulin resistance play important roles in the pathogenesis of impaired endothelial function. The increased expression of adhesion molecules and pro-inflammatory cytokines leads to abnormal endothelium-dependent vasodilation which could be investigated using vasoreactivity tests such as flow-mediated dilation in the brachial artery. Recently, new evidences showed that the immune system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis with a particular regard towards autoimmunity. The high prevalence of the atherosclerotic process in systemic autoimmune diseases supports the hypothesis of the immune pathogenesis. Evaluating coronary microvascular dysfunction by means of transthoracic echocardiography with non-invasive coronary flow reserve assessment is particularly interesting as it could detect preclinical impairment of coronary microvascular function. The discovery that the mechanisms responsible for endothelial damage have a genetic basis could improve the approach to CV diseases. This review summarises the most important aspects of the pathogenesis and development of endothelial dysfunction, with particular attention to the role of traditional CV risk factors, the usefulness of vasoreactivity tests, and the future perspectives opened by genetic studies.

Carotid and femoral artery stiffness in relation to three candidate genes in a white population.

Different genetic polymorphisms influence cardiovascular disease. We recently discovered a relationship between the intima-media thickness of the muscular femoral artery, but not the elastic common carotid artery, and the combined ACE (ACE, I/D), alpha-adducin (Gly460Trp),and aldosterone synthase (AS, C-344T) gene polymorphisms. To investigate the relationship between these polymorphisms and functional properties of the carotid artery and femoral artery, a sample of 756 subjects enrolled in a population study were genotyped for the presence of the ACE D, alpha-adducin 460Trp, and aldosterone synthase -344T alleles. Vessel wall properties were assessed using a vessel wall movement detector system in combination with applanation tonometry. Statistical analysis allowed for confounders and interaction among genes. Cross-sectional compliance of the common carotid artery was negatively associated with the ACE D allele. ACE II versus ACE DD homozygotes differed, expressed as a percentage of the population mean (7.0%; 95% confidence interval [CI], 1.6% to 12.4%; P=0.02). In multigene analysis, ACE DD subjects also deviated significantly from the population mean for the distensibility coefficient of the common carotid artery when carrying the AS/T allele (-5.5%; 95% CI, -9.3% to -1.7%; P<0.01), without a change in cross-sectional compliance. ACE DD subjects, when homozygote for alpha-adducin Gly460, had a lower femoral cross-sectional compliance (-10.4%; 95% CI, -1.9% to -18.9%; P<0.03) and a lower distensibility (-9.7%; 95% CI, -2.1% to -17.3%; P<0.02) compared with the population mean. These data show that functional large artery properties are influenced by the ACE I/D polymorphism. Cross-sectional compliance and distensibility coefficients are influenced by the ACE I/D genotype, but this influence depends on the vascular territory and genetic background.

Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population.

BACKGROUND: The genes encoding angiotensin converting enzyme (ACE, I/D), alpha-adducin (ADD, Gly460Trp) and aldosterone synthase (AS, -344C/T) share the potential of influencing blood pressure (BP) via sodium homeostasis. However, most studies in humans focused on single-gene effects and disregarded epistasis, the suppression or potentiation of a gene by other non-allelic genes. METHODS: We studied the singular and combined effects of the aforementioned candidate genes: (1) in relation to BP, plasma renin activity (PRA) and urinary aldosterone in 1461 subjects randomly selected from a Caucasian population; and (2) in relation to the incidence of hypertension in a subgroup of 678 initially normotensive subjects followed up for 9.1 years (median). RESULTS: In cross-sectional analyses, AS/CC homozygosity was associated with slightly lower systolic BP (-1.32 mmHg; P = 0.08). AS/TT homozygotes showed both lower PRA and higher urinary aldosterone excretion (P < or = 0.05). In multiple-gene analyses, compared with the whole study population, ADD/Trp subjects had a higher relative risk of hypertension in the presence of the AS/T allele (1.29; P = 0.05), whereas in combination with AS/CC homozygosity ADD/Trp subjects had the smallest relative risk (0.48; P = 0.003). Hypertension developed in 229 subjects (36.6 cases per 1000 person-years). ACE/DD homozygosity, in comparison with the other ACE genotypes, was associated with increases in the incidence of hypertension, which amounted to 31% (P = 0.005) in single-gene analyses, to 59% (P = 0.004) in carriers of the ADD/Trp allele and to 122% (P = 0.0007) in AS/CC subjects. Among subjects who had both the ADD/Trp allele and the AS/CC genotype, ACE/DD homozygotes manifested a 252% (P = 0.001) higher incidence of hypertension. CONCLUSIONS: Epistatic interactions between the ACE, ADD and AS genes contribute to the prevalence and incidence of hypertension in Caucasians. The clinical relevance of the risk-conferring haplotypes identified in our prospective study was underscored by their positive predictive values, which under the assumption of a 20% life-time risk of hypertension, ranged from 29.8-40.1%.

Alpha-adducin polymorphism in hypertensives of South African ancestry.

The alpha-adducin gene contributes significantly to hypertension in MHS rats (rats of the Milan hypertensive strain) and in some white and Japanese populations, causing a low renin, sodium, and diuretic-sensitive hypertension. No data are available from populations of African ancestry who have a high prevalence of low renin, sodium, and diuretic-sensitive hypertension. We studied the relationship between the 460-Trp variant of alpha-adducin gene with hypertension using a case-control study design in black South Africans. Surprisingly we found that the overall frequency of the 460-Trp allele was low (approximately 6%), but in spite of such relatively low frequency, the 460-Trp allele was 2.5-fold more frequent in hypertensives than normotensives (P = .028), with an odds ratio for hypertension associated to the state of carrier of at least one 460-Trp allele of 2.68. The finding of such low frequency of the 460-Trp allele in individuals of African ancestry points to the substantial ethnic variability of the genes that have been found to be associated with hypertension. On the other hand, it suggests an association of the 460-Trp allele with hypertension also in subjects of African origin.

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.

The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study.

The basic requirement for declaring an association study positive is that the "hypertension-favoring" allele is more frequent in hypertensive cases than in normotensive controls. However, both positive and negative associations with hypertension have been found for the same polymorphism when studied in different populations. In the present study, we addressed the question of the possible cause(s) of this discrepancy among populations by using the alpha-adducin polymorphism as a paradigm. Four hundred ninety hypertensives and 176 normotensives enrolled in Sassari, Italy, and 468 hypertensives and 181 normotensives enrolled in Milano, Italy, were genotyped for the alpha-adducin Gly460Trp polymorphism. The blood pressure response to 2 months of hydrochlorothiazide therapy could be evaluated in 143 (85 in Sassari and 58 in Milano) hypertensives with and without the 460Trp alpha-adducin allele. The alpha-adducin 460Trp allele was not significantly more frequent in hypertensives in the Sassari population but was more frequent in hypertensives than in normotensives in Milano (P=0.019). Basal plasma renin activity was lower and blood pressure fall after diuretic therapy more pronounced (P<0.01) in hypertensives carrying at least one 460Trp allele than in Gly460Gly homozygotes, irrespective of their membership in the Sassari or Milano cohort. The effect of alpha-adducin genotype in predicting basal plasma renin activity and blood pressure decrease with diuretic treatment is similar in Sassari and Milano, despite the lack of association of the alpha-adducin genotype with hypertension in Sassari.

Adducin polymorphism affects renal proximal tubule reabsorption in hypertension.

Abnormalities in renal sodium reabsorption may be involved in the development and maintenance of experimental and clinical hypertension. Adducin polymorphism is thought to regulate ion transport in the renal tubule. It has recently been shown that there is a significant linkage of alpha-adducin locus to essential hypertension and that the 460Trp allele is associated with hypertension. Patients with this allele display larger blood pressure changes with body sodium variation. The aim of this study was to test whether alpha-adducin polymorphism is involved in abnormalities of renal function. Because proximal tubular reabsorption has been shown to be tightly coupled to renal perfusion pressure, this segmental tubular function was investigated in 54 (29 Gly/Gly and 25 Gly/Trp) untreated hypertensive patients in basal conditions with the use of endogenous lithium concentration and uric acid. Fractional excretions of lithium and uric acid were significantly decreased in the Gly/Trp hypertensive patients compared with the Gly/Gly hypertensives. The contribution of alpha-adducin to fractional excretion of lithium was investigated by multiple regression analysis. Adducin genotype was significantly (R2=0.11, F=6.5; P<0.01) and directly related to fraction excretion of lithium; gender, age, urinary Na+, urinary uric acid, mean blood pressure, and plasma renin activity were not related. In conclusion, the adducin gene can be considered to be a 'renal hypertensive gene' that modulates the capacity of tubular epithelial cells to transport Na+ and hence contributes to the level of blood pressure.

Adducin in essential hypertension.

In Milan hypertensive rats (MHS) the sequence of events going from renal function to cell membrane ion transport abnormalities and finally to the molecular defect responsible of hypertension has been established. A polymorphism of the cytoskeletal protein adducin has been identified as a likely culprit for hypertension in these rats. Two point mutations in MHS alpha- (F316Y) and beta- (Q529R) adducin genes have been shown to be associated with hypertension in genetic crosses of MHS and MNS rats. Also in humans, a polymorphism of alpha-adducin gene (Gly460Trp) has been found to be significantly associated both to hypertension and salt sensitivity. Studies aimed at clarifying the functional role of alpha-adducin variants have shown that adducin from the MHS rats is able to stimulate Na-KATPase activity both after transfection in renal tubular cells and after incubation with the enzyme in a cell-free system. Also the human hypertensive alpha-adducin variant displays the same activity of MHS adducin in a cell-free system. Therefore, both in humans and in rats, adducin polymorphisms may affect blood pressure and kidney function by modulating the overall capacity of tubular epithelial cells to transport ions, through variations of the Na-KATPase activity. However adducin polymorphisms account for only a portion of hypertension both in humans and rats. Therefore additive or epistatic interactions with other genes involved in renal sodium handling need to be studied.

Alpha-adducin polymorphisms and renal sodium handling in essential hypertensive patients.

The relationship between blood pressure and sodium (Na) excretion is less steep in hypertension caused by increased renal tubular reabsorption. We recently demonstrated that one mutation in rat alpha-adducin gene: (1) is responsible for approximately 50% of the hypertension of MHS rats, and (2) stimulates tubular Na-K pump activity when transfected in renal epithelial cell, suggesting that its pressor effect may occur because an increased tubular reabsorption. Linkage and association studies demonstrated that the alpha-adducin locus is relevant for human hypertension. A point mutation (G460W) was found in human alpha-adducin gene, the 460W variant (G/W) is more frequent in hypertensives than in normotensives. The aim of this study was to test whether acute changes in body Na may differently affect blood pressure in humans as a function of alpha-adducin genotype. The pressure-natriuresis relationship was analyzed in 108 hypertensive using two different acute maneuvers: Na removal (furosemide 25 mg p.o.) and, two days later, Na load (310 mmoles i.v. in 2 hr). We found that 80 patients were wild-type homozygous (G/G), 26 were G/W heterozygous, and 2 were W/W homozygous with similar blood pressure, age body mass index, gender, plasma and urinary sodium and potassium. In basal condition G/W-W/W patients showed a lower plasma renin activity and fractional excretion of Na. In either case the pressure-natriuresis relationship was less sleep in G/W-W/W than in G/G patients, obviously negative for Na depletion with furosemide (-0.011 +/- 0.004 vs. -0.002 +/- 0.002 mm Hg/mumol/min, P < 0.03), and positive for Na load (0.086 +/- 0.02 vs. 0.027 +/- 0.007 mm Hg/mumol/min, P < 0.001). The finding of reduced slope after Na depletion or Na load supports the hypothesis that, as MHS rats, humans bearing one W alpha-adducin variant display an increased of renal tubular sodium reabsorption.

Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension.

BACKGROUND: Abnormalities in renal sodium transport may be involved in hypertension. Adducin, an alpha/beta heterodimeric protein found in the renal tubule is thought to regulate ion transport through changes in the actin cytoskeleton. We investigated whether an alpha-adducin polymorphism (Gly 460 Trp) is involved in essential hypertension in two separate populations. METHODS: Linkage analysis of three DNA markers at different distances from the alpha-adducin locus (20-2500 kb) was done in 137 hypertensive sibling-pairs. 477 hypertensive and 322 normotensive individuals were genotyped for the alpha-adducin polymorphism. The blood-pressure response to acute and chronic changes in sodium balance was studied in hypertensive individuals with and without the 460 Trp alpha-adducin allele. FINDINGS: Significant linkage was found for all three markers in the sibling-pair study. The extra shared alleles (9.1%, 6.5%, and 4.7%) and the significance level for linkage (p = 0.0006, p = 0.0119, and p = 0.0211) both decreased with increasing distance from the alpha-adducin locus. There was a significant association between the 460 Trp mutation and hypertension (p = 0.0003). In the salt-sensitivity test, to assess the acute blood-pressure response to changes in body sodium in 86 hypertensive patients, the decrease in mean arterial pressure was greater in 65 patients who were heterozygous for the mutant allele (Gly/Trp) than in 21 wild-type homozygotes (Gly/Gly) (mean decrease 15.9 [SE 2.0] vs 7.4 [1.3] mm Hg; p = 0.001). Similarly, 21 heterozygous hypertensive patients showed a greater fall in mean arterial pressure in response to 2 months' treatment with hydrochlorothiazide than did 37 wild-type homozygous hypertensive patients (mean decrease 14.7 [2.2] vs 6.8 [1.4] mm Hg; p = 0.002). INTERPRETATION: Our findings of significant linkage of the alpha-adducin locus to essential hypertension and greater sensitivity to changes in sodium balance among patients with the mutant allele suggest that alpha-adducin is associated with a salt-sensitive form of essential hypertension. We suggest the alpha-adducin polymorphism may identify hypertensive patients who will benefit from diuretic treatment or manoeuvres to reduce total body sodium.

Genetics of renal mechanisms of primary hypertension: the role of adducin.

PURPOSE: To summarize data concerning the identification of adducin as a 'candidate' gene in the Milan hypertensive strain of rats (MHS), a genetic model of essential hypertension, and in human essential hypertension. RESULTS: The sequence of events from renal function to cell membrane ion transports and finally to the molecular defect has been established in MHS rats. This led to the identification of polymorphisms in the cytoskeletal protein adducin. These polymorphisms are involved in blood pressure regulation in these rats. A linkage and an association study on Caucasian populations support the involvement of adducin in human hypertension also. A polymorphism of alpha-adducin gene is significantly associated with human hypertension. In particular, both in humans and in rats, adducin polymorphisms affect kidney function by modulating the overall capacity of tubular epithelial cells to transport ions. CONCLUSIONS: Adducin polymorphisms account for only a portion of hypertension both in humans and rats. Therefore additive or epistatic interactions with other genes involved in renal sodium handling need to be studied.

Alpha-adducin gene polymorphism and cardiovascular phenotypes in a general population.

BACKGROUND: Previous studies have shown that molecular variants of the cytoskeletal protein adducin may be involved in regulation of blood pressure both in genetic rat hypertension and in human essential hypertension. OBJECTIVE: To investigate the relationship of genetic polymorphism of alpha-adducin with blood pressure, cardiovascular structure, and some biochemical indexes of cardiovascular risk in a sample of general population. DESIGN AND METHODS: A sample of 246 subjects (124 men and 122 women, aged 57.7+/-3.7 years) was randomly chosen from a middle-aged population. Twenty-four-hour ambulatory blood pressure, as well as left ventricular mass (by echocardiographic methods) and carotid wall thickness (by B-mode ultrasound methods) were measured. DNA was extracted from peripheral blood samples; the Gly460Trp diallelic variant of human alpha-adducin was genotyped by polymerase chain reaction amplification and then allele-specific oligo hybridization. RESULTS: A trend toward higher 24 h ambulatory blood pressure values in subjects not treated with antihypertensive drugs was observed among carriers of Trp460 allele, although the differences did not attain statistical significance (at closest, P = 0.066 for a dominant effect of Trp460 on systolic blood pressure). When blood pressure was considered a dichotomous variable, allowing the inclusion of treated hypertensives), a higher prevalence of Trp460 allele among hypertensives was observed (0.188 versus 0.106 among normotensives, P= 0.02). There was no evidence of association either of left ventricular mass or of common carotid wall thickness with Gly460Trp polymorphism. CONCLUSIONS: In this sample of a general population, the relationship of a genetic polymorphism of alpha-adducin with blood pressure values was rather weak. However, a population-based case-control analysis indicated that there was an association between Trp460 allele and hypertension, with a relative risk for subjects carrying at least one Trp460 allele of approximately 1.6. Further investigation of larger and different population samples in order to assess the role of adducin gene polymorphism as a marker of genetic predisposition to the development of hypertension is warranted.

[Paraquat-induced acute dermatitis in a child after playing with a discarded container]. / Dermatite acuta da paraquat in bambina che ha utilizzato per gioco un contenitore abbandonato.

The improper use of pesticide waste containers is a significant risk in rural areas, especially where appropriate systems of draining off refuse are lacking. A case is reported of an eight-year-old child who had played with the abandoned Paraquat container. After contamination with the pesticide she showed several II degree caustic lesions on both thighs and knees, associated with a mild erythemato-desquamative cheilitis and a "strawberry tongue". Common laboratory findings did not reveal any kidney, liver and/or red/white cell alterations and the chest X-ray was normal even several months after the accident. No physical consequences ensued, except for hyperchromic pigmentation on the legs. Where empty pesticide containers are not properly collected, they can represent a risk of pesticide exposure for the general population. They can also be a potential source of pollution for superficial water and soil. In the district where the accident was reported it was estimated that empty containers made up 7% of the weight of the 146,330 kg of pesticides sold to local farmers in 1993, of which about 10,400 kg was burned, buried and dispersed in the soil. Within the framework of a global pesticide prevention programme launched by the Regional Government of Lombardy, local health authorities, with the contribution of farmers, are carrying out a project for the proper collection of empty pesticide containers.

Association of the alpha-adducin locus with essential hypertension.

Previous studies on genetic rat hypertension have shown that polymorphism within the alpha-adducin gene may regulate blood pressure. Adducin is a cytoskeletal protein that may be involved in cellular signal transduction and interacts with other membrane-skeleton proteins that affect ion transport across the cell membrane. There is a high homology between rat and human adducin and pathophysiological similarities between the Milan hypertensive rat strain and a subgroup of patients with essential hypertension. Thus, we designed a case-control study to test the possible association between the alpha-adducin locus and hypertension. One hundred ninety primary hypertensive patients were compared with 126 control subjects. All subjects were white and unrelated. Four multiallelic markers surrounding the alpha-adducin locus located in 4p16.3 were selected: D4S125 and D4S95 mapping at 680 and 20 kb centromeric, and D4S43 and D4S228/E24 mapping at 660 and 2500 kb telomeric. Alleles for each marker were pooled into groups. Comparisons between control subjects and hypertensive patients were carried out by testing the allele-disease association relative to the marker genotype. The maximal association occurred for D4S95 (chi 2(1) 13.33), which maps closest to alpha-adducin. These data suggest that a polymorphism within the alpha-adducin gene may affect blood pressure in humans.

alpha-adducin may control blood pressure both in rats and humans.

1. Previous studies on the pathogenetic mechanisms of hypertension in the Milan hypertensive strain of rat (MHS) showed that a polymorphism within the alpha-adducin gene is responsible for up to 50% of the blood pressure difference between MHS and their MNS normotensive control strain. A case-control study has shown also in humans an association between alpha-adducin locus and hypertension using 4 multiallelic markers surrounding the alpha-adducin locus. 2. With a multiple regression approach we provide an estimate of the contribution of the genotype for each marker to the blood pressure variability in comparison to that provided by sex, body mass index and age. 3. While sex, body mass index and age contributed by about 40-45% to the overall blood pressure variability, the inclusion of the genotype for the marker closer to the alpha-adducin locus provided a further increase of the variability explained of about 5%. 4. The contribution independently provided by the other markers decreased exponentially with the increase of distance from alpha-adducin locus.

Genetic models of arterial hypertension--role of tubular ion transport.

The description of pathogenetic mechanisms underlying different genetic models of essential hypertension is a useful way of illustrating the logical sequence needed to dissect a complex phenotypic condition such as hypertension. The abnormalities in renal function observed in spontaneously hypertensive rats of the Okamoto strain and Milan strain will be emphasized. The description may proceed "downward" from alterations that affect the whole body function to cellular and subcellular levels. However, the identification in the Milan strain rats of a point mutation in the gene coding for adducin, a skeletal protein able to modulate transepithelial sodium transport, provides the opportunity to reconstruct, in an "upward" direction, the sequence of events leading from the single point mutation to the final complex phenotype of essential hypertension.

Erythrocyte Na+,K+,Cl- cotransport and kidney function in essential hypertension.

OBJECTIVE: To determine whether essential hypertensive patients with high Na+,K+,Cl- cotransport (COT) display alterations of some indices of kidney tubular reabsorption similar to those observed in Milan hypertensive (MHS) rats, which have high COT in both erythrocytes and kidney tubular cells, and hypertension caused by a primary increase of tubular reabsorption. DESIGN: Two sets of experiments were performed. First, renal function in two subgroups of hypertensive patients (one with 'high' and one with 'normal' COT was compared with that in normotensive controls. Secondly, the natriuretic and diuretic effects of a single oral dose of frusemide (25 mg) were analysed in six high- and in six normal- COT hypertensive patients. RESULTS: Compared with normotensives and with normal-COT hypertensives, high-COT hypertensives had lower fractional uric acid excretion and plasma renin activity with similar glomerular filtration rate and urinary sodium and potassium excretion. COT was negatively correlated with fractional uric acid excretion in the essential hypertensive patients but not in the normotensives. The diuretic natriuretic response to frusemide was much higher in high- than in normal-COT hypertensives. CONCLUSION: These results are consistent with the hypothesis that patients with high COT have abnormal renal handling of sodium similar to that observed in MHS rats.

Control of hepatitis B: evaluation of two different vaccinal schedules in newborns from HBsAg negative mothers.

504 healthy infants, born to HBsAg negative mothers from May 1st to December 31st 1991, were randomly allocated to an accelerated (group A) or traditional (group B) immunization schedule. The group A infants were immunized at 4 days, 1 month and 3 months of life with 10 micrograms of recombinant HBV vaccine (Engerix B, SKF) while the group B infants were immunized at 4 days, 1 month and 6 months of life with the same dose of vaccine. One month after the first dose of vaccine, 9.2% of the infants in both groups had an HBsAb serum level > 10 mIU/ml. One month after the booster dose, at 4 months of life for group A and at 7 months for group B, 97.40% and 98.53% of the infants presented a serum level > 10 mIU/ml respectively. None in group A and only 2 patients in group B could be considered non-responders (serum concentration below 2 mIU/ml) and 4 infants in group A and 4 in group B were considered hypo-responders (serum level between 2.1 and 9.9 mIU/ml). Immunogenetic study performed on the 2 non-responders and 6 of the hypo-responders, revealed the presence in all but two of the HLA haplotypes, classically involved in the lack of hyporesponsiveness to foreign peptides, namely: HLA-DR7; DQ2, DR4; DQ3, DR15; DQ6 and DR3; DQ2. Surprisingly, 2 hypo-responders carried the HLA haplotypes (DR11, DQ7 and DR13, DQ6), usually associated with hyperresponsiveness. Both vaccinal cycles provided evidence that infants respond well to vaccination, started at birth, against hepatitis B virus with a high degree of protection.(ABSTRACT TRUNCATED AT 250 WORDS)