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Electromagnetic (EM) techniques are extremely important as a direct detection geophysical tool utilized in the base metal industry. They were developed in countries such as Canada, whose thin conductive weathering overburden did not hamper the penetration of EM signals and enabled exploration to depths on the order of 300 m. As a result, EM techniques were used widely in North America and Scandinavia for many years before they became common in countries with a thick conductive overburden, such as Australia. The 1980s and 1990s have seen the use of EM methods move from anomaly finding to mapping, as well as the development of better, faster and more accurate computer modelling algorithms. A review of EM papers, for the years 1998 to 2002, showed that most dealt with EM techniques as mapping tools. Airborne, ground and marine EM techniques are still being developed, as are data processing and interpretation software. The advent of robust 2-D and 3-D computer modelling and inversion algorithms has led to the acceptance of EM methods as a mapping tool for many environmental and petroleum industry applications, a trend which is expected to increase.Electromagnetic (EM) techniques are extremely important as a direct detection geophysical tool utilized in the base metal industry. They were developed in countries such as Canada, whose thin conductive weathering overburden did not hamper the penetration of EM signals and enabled exploration to depths on the order of 300 m. As a result, EM techniques were used widely in North America and Scandinavia for many years before they became common in countries with a thick conductive overburden, such as Australia. The 1980s and 1990s have seen the use of EM methods move from anomaly finding to mapping, as well as the development of better, faster and more accurate computer modelling algorithms. A review of EM papers, for the years 1998 to 2002, showed that most dealt with EM techniques as mapping tools. Airborne, ground and marine EM techniques are still being developed, as are data processing and interpretation software. The advent of robust 2-D and 3-D computer modelling and inversion algorithms has led to the acceptance of EM methods as a mapping tool for many environmental and petroleum industry applications, a trend which is expected to increase.

Thin layers of CrO2have been prepared on polycrystalline rutile TiO2supports by thermal decomposition of wet-impregnated Cr(NO3)3in flowing oxygen under ambient pressure conditions. The nanocomposite material has been characterised by a range of techniques including X-ray powder diffraction and X-ray photoelectron spectroscopy; and magnetic properties have been investigated by SQUID magnetometry. The loading of the nitrate on the support is shown to provide a simple way of controlling the CrO2thickness. The saturation magnetisation and the coercivity, and their variation with temperature, show a strong dependence on the layer thickness. The thinnest (1.4 nm) layers investigated display essentially superparamagnetic behaviour with a small magnetic hysteresis even at 5 K and a magnetisation that scales with H/T. By contrast, thicker (20 nm) layers show magnetic behaviour similar to that of bulk CrO2. There is a critical upper CrO2thickness beyond which support assisted promotion of the formation of the thermodynamically unstable CrO2breaks down.

Hong Kong, with a land area of only 1050 sq km and a population of cover 5 million, has developed rapidly in the past 30 years. The Paper reviews the history of quarrying in this land-scarce Territory and provides information on the distribution, operation and control of quarries. It describes the private quarries, government quarries, site crushers and importation of aggregates, and it outlines the planning for future quarries. Information is given on the types, uses and properties of the granite aggregates. Hong Kong, avec une surface de 1.050 km2et une population de plus de 5 millions de personnes, s'est développé très rapidement pendant les derniers 30 ans. Cette communication passe en revue l'histoire des carrières dans ce territoire qui n'a pas une grande superficie et fournit une information sur la répartition, le fonctionnement et le contrôle des carrières. On présente une description de carrières privées et de carrières du gouvernement, de l'équipement de concassage et de l'importation des granulats avec les grands traits de la planification pour les carri⪻res dans l'avenir. Une information est présentée sur les types, les utilisations et les propriétés des granulats de granite.

The treatment of depressed patients with the monoamine oxidase (MAO)-inhibiting antidepressant, phenelzine, was found to be accompanied by an 82 per cent reduction in platelet MAO activity and a 91 per cent reduction in plasma amine oxidase activity. Maximum reductions in enzyme activity occurred after 7 to 14 days of treatment; recovery of enzyme activity post-treatment required an average of 14 days for the platelet MAO and greater than 6 weeks for the plasma enzyme. Marked elevations in urinary tryptamine excretion occurred in conjunction with MAO inhibition during phenelzine treatment, but the magnitude of urinary tryptamine change in individual patients was not closely correlated with the magnitude of enzyme activity reduction. Changes in platelet serotonin content and in urinary catecholamine metabolites also occurred in response to phenelzine treatment.

This collaborative scheme of Early Supported Discharge, involving hospital and community staff and based in the Orthopaedic Directorate, Royal Infirmary of Edinburgh NHS Trust, has improved early rehabilitation, discharge planning and follow-up for trauma patients aged over 70 and admitted from home and has produced substantial reductions in length of hospital stay. Central to the scheme is a dedicated occupational therapist who coordinates discharge arrangements for eligible patients. An evaluation of the experiences of patients, carers, general practitioners and other community staff indicated that shorter stays in hospital have been achieved without undue problems for patients during the immediate post-discharge period.

This Paper describes a liquid electric analogue model and a finite difference model used to establish reliable values for the shape factors of cylindrical piezometers with length/diameter ratios of up to 15. For piezometers with length/diameter ratios greater than 4, it was found that the shape factor is given with negligible error by the relationship: F = 7d + 1·651. An examination of the effect on the shape factor of piezometer proximity to the watertable showed this to be negligible for practical purposes, except where the piezometer is within a few piezometer lengths of the water-table. Shape factors were also established for cylindrical piezometers embedded in cylindrical soil specimens subjected to all five possible boundary conditions. The measured shape factors were higher or lower than the infinite values depending upon the boundary conditions and the proximity of the boundaries to the piezometer. These data give some guidance to theperformance of pore pressure probes used in laboratory specimens, and they are useful in the analysis of steady state flow conditions and for the assessment of response studies of piezometer systems. Cet Article décrit un modèle analogique électrique fluide et un modèle à différence finie servant à établir des valeurs fiables pour les coefficients de forme de piézométres cyhndriques dont les rapports longueur/diamètre peuvent atteindre 15. Pour les piézomètres dont le rapport longueur/daimétre est supérieur à 4, on a trouvé que le coefficient de forme était donné, avec une erreur négligeable, par la relation F = 7d + 1·65. L'influence sur le coefficient de forme de la proximité de la nappc phréatique est pratiquement négligeable sauf lorsque le piézomètre était à quelques longueurs de piézomètre de la nappe phréatique. Les coefficients de forme ont également été établis pour des piézomètres cylindriques enfoncés dans des échantillons de sols cylindriques soumis aux cinq conditions aux limites possibles. Les coefficients de forme mesurés étaient supérieurs ou inférieurs aux valeurs infinies dependant des conditions aux hmites, et de la proximité des limites par rapport au piézomètre. Ces données permettent de se faire une certaine idée de la performance de sondes de pression interstitielle utilisées dans des échantillons de laboratoire et sont utiles pour l'analyse des conditions d'icoulement stationnaire ainsi que pour I'évaluation des réponses des piézomètres.

An in vitro bioassay based on progesterone production by enzymatically-dispersed immature rat ovary cells, was used to investigate the effect of sialidase treatment on the biological activity of human chorionic gonadotrophin (hCG). The potency in this bioassay system and in an ovarian receptor assay were compared, to substantiate possible discrepancies between the effect of this treatment on biological activity and on receptor binding.Ovarian cells responded dose-dependently to the addition of hCG as well as sialidase treated hCG (asialo-hCG). Dose-response curves of hCG and asialo-hCG were parallel and the maximal stimulation levels reached were the same. Sub-maximal doses of hCG and asialo-hCG were additive. The potency of asialo-hCG was 65% of the original preparation. Addition of low concentrations of phosphodiesterase inhibitor resulted in a greatly enhanced sensitivity of the bioassay, but had no effect on the potencies of asialo-hCG and hCG.In contrast to intact gonadotrophins, the receptor assay potency of asialo-hCG was more than three times the bioassay potency. In agreement with this, it was found that when equal amounts of 125I-labelled hCG and asialohCG were specifically bound to the ovarian cells, the latter stimulated progesterone production less effectively.It is concluded that there is a discrepancy between the effect of desialylation on the biological activity and on the receptor-binding ability of hCG.

DISCUSSION Major canal reconstruction in peat areas P. T . Pigott, E. T. Hanrahan and N . Somers Dr E. W.Brand, Civil Engineering appropriate for failures in peat. Is effective Department, Hong Kong Government stress analysis ever employed for this purpose and, if so, how is it applied? would also be In this most interesting Paper, the Authors It present a simple stability analysis the Grand instructive if the Authors could give a general of Canal failure based on the slidingof the failed outline of the shear strength characteristics of mass along a gently inclined failure plane afew the peat in the Irish midlandsbogs since, metres below the ground surface...

The finite difference solutions presented for the fundamental process of pore pressure equalization in a soil piezometer system are the first of their kind to be published for cyhndrical piezometers. The response-time relationships established for cylindrical piezometers (of radius a and length b) are of the same general form as those for spherical piezomelers, the exact shape of a particular relationship being a function of the ratio a/b, the soil compressibility m and the flexibility of the piezometer measuring system V. The soil-pierometer system characteristics can be best represented by a control parameter λ = 47πbm/V. The value of this parameter characterizes the shape of the response-time curve, for which there is a unique time ratio t90/t 50 and time factor ratio T90 /T 50. On this basis, the cylindrical equalization chart is constructed, which provides a direct means for the analysis of equalization tests in cylindrical piezometers. Interpretation of laboratory tests on piezometers embedded in clay triaxial specimens shows that equalization tests can provide reliable in situ measurement of soil permeability and good estimations of coefficients of consolidation. Les solutions de différences finies présentiées relativement au processus fondamental de l'égalisation de la pression interstitielle dans un système sol-piézomètre sont les premières de ce type à être publiées en ce qui concerne les piézométres cylindriques. Les relations réponse-temps établises pour les piézomètres cylindriques (de rayon a et de longueur b) sont de la même forme générale que celles qui correspondent aux piézroméres sphériques, la forme exacte d'une relation donnéé étant fonction du rapport a/b, de la compressibilité du sol m et de la souplesse du système de mesure du piézomètre V. La meilleure façon de représenter les caractéristiques du système sol-piézomètre est de faire appel à un paramètre de contrôle λ = 4π2 bm/V. La valeur de ce paramètre caractérise la forme de la courbe réponse-temps pour ladquelle il existe un rapport unique de temps t 90/t 50 et un rapport de facteur de temps T 90/T 50. L'abaque d'égalisation cylindrique est établi à partir de ces données; cetabaque permet d'analyser directement les essais d'égalisation dans le cas de piézomètres cylindriques. L'interprétation des résultats des essais en laboratoire de piézomètres fichés dans des échantillons triaxiaux d'argle montre que les essais d'égalisation sent capables de fournir des mesures in situ fables de la perméabilité du sol ainsi que de bonnes évaluations de coefficients de consolidation.

The estimation of the effect of desialylation on the biological activity of human chorionic gonadotrophin (hCG), as determined in the ovarian ascorbic acid depletion assay (OAAD), according to the modification in which the animals are used twice, appeared to be dependent on the assay conditions. Animals which received hCG in the first assay (OAAD-1) gave higher potency estimates for hCG and asialo-hCG in the second assay (OAAD-2) than rats which received asialo-hCG in OAAD-1. The results of the experiments indicate that the ovarian sensitivity for hCG and asialo-hCG is increased after administration of hCG and unilateral ovariectomy and decreased after administration of asialo-hCG.

The potency of human chorionic gonadotrophin (hCG) in competition for binding to a gonadal membrane fraction is remarkably enhanced by sialidase treatment. The present study was undertaken to investigate the specificity and characteristics of the binding of sialidase-treated hCG (asialo-hCG) in a particulate hCG-binding system from luteinized rat ovaries.The competitive potency of asialo-hCG relative to hCG was 2.5, irrespective of whether [125I]hCG or [125I]asialo-hCG was used for tracer. This was due to a 2.1 times higher equilibrium association constant for asialo-hCG, whereas the estimated number of binding sites did not differ. There was no apparent difference in the stability of hCG and asialo-hCG, or in the stability of the respective hormone-receptor complexes. The effect of variation of the incubation conditions on the binding of both tracers was similar.In accordance with the difference in the equilibrium association constant, the association velocity of asialo-hCG was more than double that of hCG.With all of the tracers used the dissociation curves were biphasic, the size of the initial fast-dissociating fraction being inversely related to the pre-incubation time. Under identical conditions, the fast-dissociating fraction was smaller for the [125I]asialo-hCG complex than for the [125I]hCG complex. The dissociation velocities of these fractions appeared to be similar.The results indicate that asialo-hCG binds to the hCG receptor in a way similar to the binding of the unmodified hormone, but with a higher affinity. The smaller size of the fast-dissociation form of the asialo-hCG-receptor complex may be related to the lower biological potency of the hormone derivative.

The present study was undertaken to investigate the effect of desialylation on the intrinsic in vivobiological activity of hCG. To block the hepatic uptake of asialo-hCG we investigated asialo-orosomucoid. The biological activity of hCG and asialo-hCG was estimated with the ovarian ascorbic acid depletion assay (OAAD). The uptake studies were performed with [125I]hCG and [125I]asialo-hCG.Desialylation of hCG increased its hepatic uptake, almost completely abolished its ovarian uptake, and reduced its in vivobiological activity to less than 1 %. Administration of asialo-orosomucoid caused a reduction of the hepatic uptake of asialo-hCG to the level observed for hCG. The ovarian uptake increased, but was lower than observed for hCG, due to a considerably higher renal accumulation of asialo-hCG. The in vivobiological activity of asialo-hCG was approximately 1/5 of the activity of hCG when both were tested in the presence of asialo-orosomucoid.To exclude the interference of renal accumulation, binding and biological activity were also investigated after bilateral nephrectomy. The uptake of radioactivity in the ovaries following injection of [512I]asialo-hCG and asialo-orosomucoid was then almost the same as observed after injection of [125I]hCG alone. When both preparations were now tested in the presence of asialo-orosomucoid, the in vivobiological activity of asialohCG appeared to be approximately 1/3 of the value obtained for hCG. It is concluded that the intrinsic in vivobiological activity of hCG is lowered by desialylation.

This Paper examines the process of pore pressure equalization in soil piezometer systems which is governed by the shape factor F of the piezometer, the volume factor V of the measuring system, and the coefficients of permeability and consolidation k and c of the soil. Gibson (1963) obtained a theoretical solution for a spherical piezometer of radius a in a compressible soil in terms of the dimensionless parameter μ(= 4πa3 m/V) and T(= ct/a 2), and this solution was used by the Authors to establish the response-time relationships for a wide range of μ values. These theoretical relationships were verified against those obtained by means of a finite difference method, which was also used for a brief examination of the transient distribution of pore pressure during the equalization process; the radius of influence was found to be a function of the parameter µ. On the basis of Gibson's theory, a greatly simplified procedure was devised for the inter-pretation of the equalization process to enable the soil properties k and c to be determined directly by the use of an Equalization Chart. An experimental programme of equalization tests was carried out on a range of piezometers of different shapes and sizes embedded in clay specimens and connected to a number of measuring systems of different volume factors. Interpretation of the test results by an Equalization Chart provided verification of Gibson's theory and illustrated the usefulness of equalization tests for in situ measurement of k and c. Cet article examine le processus d'étgalisation de la pression interstitielie dans des piézométres in situ, processus régi par le facteur de forme F du piézométre, le facteur de volume V du systéme de mesure et les coefficients de perméabilité et de consolidation k et c du sol. Gibson (1963) a obtenu une solution théorique pour un piézométre sphérique de rayon a dans un sol compressible, en fonction du paramétre adimensionnel μ(= 4πa 3 m/V) et T(= ct/a 2); cette solution a été utilisée par les auteurs pour établir les relations répose-temps pour une large gamme de valeurs μ. Ces relations theoriques ont été vérifiées avec les relations obtenues au moyen d'une méthode de différences finies qui également été utilisée pour un examen sommaire de la distribution transitoire de la pression interstitielle au tours du processus d'égalisation; les résultats ont montré que le rayon d'influence était unc fonction du paramétre μ. Sur la base de la théorie de Gibson. une méthode extrêmement simplifiée a été élaborée pour l'interprétation du processus d'égalisation pour permettre de déterminer les propriétés du sol k et c directement par le moyen d'un Diagramme d'Egalisation. Un programme expérimental d'essais d'égahsation a été réalisé; les essais portaient sur toute une gamme de piézométres de différentes formes et dimensions, encastrés dans des spécimens d'argile et relies a un certain nombre de systèmes de mesure de facteurs de volume différents. L'interprétation des résultats des essais, réalisée au moyen d'un Diagramme d'Egalisation, a permis de vérifier la théorie de Gibson et de démontrer l'utilité des essais d'égahsation pour la mesure in situ de k et c.

Subtypes of children with attentional problems were investigated using cluster analysis. Subjects were 9-year-old-elementary school children (N = 443). The test battery administered to these children comprised a comprehensive set of common attention tests, covering different aspects of attentional functioning, and a test of reading comprehension. Cluster analysis of these data yielded eight stable and reproducible clusters. The test profiles of two subgroups were indicative of distinct attentional problems. One group appeared deficient in speed of processing, the other in attentional control. A third subgroup showed a reading deficit. Two additional clusters had very poor and excellent performance on the whole battery, respectively. Finally, three clusters were found with minor variations approximating average performance. The internal validity, that is, the adequacy and stability of the cluster solution, appeared to be reasonably good, as indicated by a variety of measures. The long-term stability over an 18-month period was also checked and found to be satisfactory.

Pulmonary fibrosis in hard metal grinders has been observed to an increasing degree in recent years. Most authors attribute the cause of this disease to the influence of the cobalt contained in hard metals. The present case dealt with a 36-year-old man who had been exposed to the grinding dust from sintered hard metal parts for more than 10 years. Biopsy of the lung revealed an advanced, active pulmonary fibrosis. In the biopsy specimens cobalt was determined by flameless atomic absorption. The cobalt content in the biological specimens of the patient (urine: 7.5 µg/l; lung: 1010 µg/kg wet weight) was significantly increased compared with the values measured in normal controls.

Transfusion of3HDFP labeled autologous monocytes was performed in healthy probants. Subsequently labeling indices of blood monocytes and of macrophages in skin window exsudates were determined. The results demonstrated that macrophages of acute inflammatory skin reactions are directly recruited from circulating monocytes. In addition, 4 patients suffering from generalized, chronic eczematous skin diseases were examined. Monocyte turnover rates were normal in 3 of these patients and slightly increased in the fourth. Obviously the macrophage pools at the side of these wide spread chronic inflammatory reactions were composed of self-sustaining and self-renewing macrophage populations with low monocyte recruitment rates.

Conclusion From the observations made in this study, it does not appear that oxygen and carbon dioxide treatment of catatonic dementia præcox patients is to be advocated as a general therapeutic procedure. We are unable to draw definite conclusions regarding the role played by this treatment in the recovery of two patients.

In the course of investigations on the excretion of gonad stimulating hormones in the urine of mental patients1, 2the following method was developed for the preparation of concentrates of the follicle stimulating hormone (F.S.H.).The method is based on the observation that the stable aluminum hydroxide C (γ), prepared according to Willstaetter and Kraut3is a satisfactory absorbent for F.S.H. from urine. The effectiveness of this adsorption depends markedly on the pH, a definite maximum occurring at pH 4.5. Evans, Gustus and Simpson4have reported that solutions of the gonadotropic hormone from acetone-dried pregnant mare's serum are more satisfactorily adsorbed at pH 3.5 by aluminum hydroxides of Types A and B, prepared according to an earlier method of Willstaetter and Kraut,5while Type C was considerably less efficient.The urine is collected in glass jars containing 5 cc. of a saturated alcoholic solution of thymol per liter capacity. Insoluble material is removed by filtration and the filtrate is adjusted to exactly pH 4.5 with 5 N HCl using bromcresol green as external indicator. A suspension containing 20 gm. per liter of aluminum hydroxide C (γ) is slowly poured into the urine until 1 gm. of aluminum hydroxide per liter of urine has been added. For 24-hour specimens of 500-1000 cc. a full 1.0 gm. of aluminum hydroxide is added; for samples of less than 500 cc. only 0.5 gm. is used. The resulting mixture is occasionally stirred by hand (mechanical stirring results in poor yields) during 20 minutes so as to maintain a homogeneous suspension; the solids are allowed to settle during 45 minutes. The supernatant fluid is removed by siphoning and centrifugation, readjusted to pH 4.5 and again treated with aluminum hydroxide by the same procedure.

Summary The effect of intravenous glucagon administration on the secretion of human growth hormone (HGH) before, one hour, one day and three days after a surgical stress was investigated in 27 male patients. The concentrations of blood glucose, serum insulin, free glycerol andß-hydroxybutyrate were measured. Glucagon was a potent stimulus of growth hormone secretion. In the postoperative period the secretion of growth hormone was increased. Decreased glucose utilization and insulin sensitivity were observed. Lipolysis was increased after surgery. Based on findings the relationships between growth hormone, insulin and the intermediary metabolism after surgical stress are discussed.

CrO2 has been prepared on polycrystalline rutile (TiO2) supports by thermal decomposition of impregnated Cr(NO3)3 under ambient pressure conditions to give a material whose saturation magnetisation per Cr ion and coercivity at 5 4;K are found to be comparable to those for commercial CrO2 powder used in magnetic recording tape.

Components of the Renin-Angiotensin-Aldosterone-System (RAAS) are expressed and regulated in vascular endothelial cells. In particular, the epithelial Na-channel (ENaC), the mineralocorticoid receptor (MR), and the NaK-ATPase have been reported to regulate endothelial stiffness in response to serum Na. In the current work, we determined the effect of sAC inhibition on endothelial stiffness. Furthermore, we analyzed sAC-dependent CRE-mediated transcriptional activation and the effects of sAC inhibition on ENaC-, NaK-ATPase-- and MR expression on mRNA and protein levels.

Cardiac resynchronization therapy (CRT) can improve ventricular size, shape and mass and reduce mitral regurgitation by reverse remodelling of the failing ventricle. CRT combines right atrial and ventricular pacing with pacing of the left ventricular free wall by a third lead to resynchronize contraction between and within ventricles. About 30 of patients do not respond to this therapy for unknown reasons. In the present study, we aimed at the identification and classification of CRT responder by the use of genetic variants and clinical parameters.

In a previous communication1the daily urinary excretion of gonadal stimulating substances was investigated over prolonged periods of time in a group of 15 mental patients and 5 non-psychiatric subjects. Female patients, in the involutional period, were found to excrete large amounts of follicle-stimulating hormone (F.S.H.). However the high level of excretion was not maintained continuously and on some days no hormone appeared to be excreted.In the present study†the excretion of F.S.H. was investigated in a group of 94 psychotic women in and past the menopause (age 43-108 years). There were 13 patients diagnosed as manic-depressive psychoses, 8 as involutional melancholia, 17 as psychoses with cerebral arteriosclerosis, 39 as paranoid dementia praecox and 17 patients in other diagnostic categories. Three or 4 non-consecutive 24-hour specimens of urine were collected from each patient. Creatinine determinations were carried out on the individual specimens to ascertain the completeness of the collections.A hormone concentrate was prepared from each 24-hour specimen of urine by essentially the same method used in our previous study.1This concentrate was injected twice daily for 3 days into an immature female rat (21-22 days old) from our stock colony. On the fifth day the ovaries were removed, weighed and examined. The ovaries obtained from at least one of the test periods from each patient were sectioned. The patency of the vagina and the uterine reaction were noted.F.S.H. produces an increase in the weight of the ovaries, which increase apparently depends upon the amount of hormone injected. Therefore, the amount of hormone present in a 24-hour specimen of urine was approximated by means of the ovarian weight of the experimental animal. The normal weight of a pair of ovaries from our 24- to 25-day-old rats is 12 to 16 mg.The findings, thus far, of this study, which is still in progress, suggest the following:(1) Patients with manic depressive psychosis and involutional melancholia appear to excrete larger amounts of F.S.H. than those suffering from paranoid dementia praecox and psychoses with cerebral arteriosclerosis.

The genes encoding ACE (I/D), a-adducin (ADD, Gly460Trp) and aldosterone synthase (AS, –344C/T) share the potential of influencing 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. We studied the singular and epistatic effects of the aforementioned candidate genes in relation to BP, plasma renin activity (PRA) and urinary aldosterone in 1461 subjects randomly selected from a Caucasian population and in relation to the incidence of hypertension in a subgroup of 678 initially normotensive subjects followed up for 9.1 years (median). In cross-sectional analyses AS/CC homozygosity was associated with lower SBP (P=0.03). AS/TT homozygotes showed both lower PRA and higher urinary aldosterone excretion (P=0.05). Compared with the whole study population, ADD/Trp subjects had a higher relative risk of hypertension (1.29; P=0.05) in the presence of the AS/T allele, whereas in combination with AS/CC homozygosity they 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 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 occurrence of hypertension. In conclusion, 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% to 40.1%.

We recently found that the incidence of hypertension and femoral intima-media thickness (IMT) are influenced by epistatic interactions between the genes encoding ACE (I/D polymorphism), a-adducin (Gly460Trp) and aldosterone synthase (-344C/T). By interfering with BP or Na+ homeostasis, these genetic polymorphisms may also change renal function. We therefore genotyped a random population sample for these 3 genes. We measured serum creatinine and uric acid and 24-h urinary protein excretion and determined calculated and measured creatinine clearances (CrCl). The 1454 participants (64.3% of those invited) were 43.4 years old and included 744 women (51.2%). The prevalence of renal dysfunction (CrCl =60 mL/min/1.73 m2) was 11%. The BP measured by the study nurses at the subjects homes averaged 123/76 mm Hg. Mean values were 90 µmol/L for serum creatinine, 300 µmol/L for serum uric acid (n=1194), 90 mg/day for proteinuria (n=556), and 84 and 88 mL/min/1.73 m2 for calculated and measured (n=855) CrCls, respectively. In single-gene analyses with adjustment for significant covariates, serum creatinine, proteinuria and the risk of mild renal dysfunction were positively associated with the ACE D allele. However, these relations with the ACE D allele were confined to carriers of the mutated a-adducin Trp allele (40.1% of all subjects), in whom serum creatinine, proteinuria and the relative risk of mild renal dysfunction were 4.3 µmol/L (P=0.003), 20% (P=0.02) and 302% (P<0.001) higher in carriers of the ACE D allele than in II homozygotes. The presence of the aldosterone-synthase T allele did not add to the association between renal function and the ACE D allele. Thus, in our cross-sectional population study, renal function was slightly but consistently impaired when both the ACE D and a-adducin Trp alleles were present. These findings, taken together with experimental studies and our previous reports on the incidence of hypertension and femoral IMT, constitute a growing body of evidence delineating a clinical entity genetically determined by the risk-carrying ACE D and a-adducin Trp alleles.

We recently found that the prevalence of hypertension was significantly higher among subjects carrying both the a-adducin Trp allele (ADD/Trp) and the aldosterone-synthase T allele (AS/T). Carriers of the D allele of the angiotensin-converting enzyme gene (ACE/D) have higher ACE activity, which may promote generation of angiotensin II, a vascular growth factor. We therefore investigated whether intima-media thickening, a precursor of atherosclerosis, is related to these genetic polymorphisms. We used a wall-tracking ultrasound system to measure carotid and femoral intima-media thickness (IMT) in 380 subjects enrolled in a population study. They were genotyped for the presence of the ADD/Trp, AS/T and ACE/D alleles. The statistical analysis allowed for confounders and epistatic interactions among genes. The sample included 188 men (49.5%). Mean age was 39.8 years (range 12-76). IMT of the carotid and femoral arteries averaged 575 µm and 719 µm, respectively. The IMT of the femoral artery – but not carotid artery – increased with the number of ACE/D alleles, whereas none of the other single-gene associations with either artery reached statistical significance. The effect of ACE genotype on femoral IMT was confined to carriers of the ADD/Trp allele and the AS/T allele. Expressed as a percentage of the population mean, the mean differences between II and DD homozygotes averaged 12.5% (95% Cl 5.3–19.8%) in all subjects, 21.4% (8.5–34.3%) in carriers of the ADD/Trp allele, 15.4% (4.4–26.4%) in carriers of the AS/T allele, and 25.7% (18.5–32.9%) if the ADD/Trp and AS/T alleles were both present. In conclusion, complex epistatic interactions between the ACE, ADD and AS genes contribute to the IMT of large muscular arteries. If confirmed, these findings may have important clinical implications for the assessment of cardiovascular risk and the treatment of hypertension.