CYP3A5 as a candidate gene for hypertension: no support from an unselected indigenous West African population.

CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) expression stimulates the sodium retentive actions of the mineralocorticoid receptor causative of hypertension, probably by means of its ability to substantially increase the level of 6ß-hydroxylase activity. Most Black individuals are functional CYP3A5 expressers, and this is a candidate gene for the high incidence of hypertension in Black populations. The study investigates whether CYP3A5 expression results in higher blood pressure in a Ghanaian population. Real-time PCR was used to genotype 898 DNA samples for the CYP3A5*3 and CYP3A5*6 single-nucleotide polymorphisms with technically adequate genotyping for 881 samples. Of these, 803 were genetic CYP3A5 expressers, 44 nonexpressers and 34 uncertain (CYP3A5*3/*6). Although there was a trend in the proportion of hypertensive individuals as CYP3A5 expression decreased, using a two-sided t-test, no statistically significant relationship was established between systolic or diastolic pressure and CYP3A5*3 or CYP3A5*6 genotypes, or their haplotypes (Systolic confidence interval: -8.44 to -7.70, P=0.93, Diastolic confidence interval: -4.89 to 4.85, P=0.99). We conclude, therefore, that there is either no association between CYP3A5 expression and blood pressure or, if there is a relationship, the strength of the association is very small.

Prediction of fat-free mass using bioelectrical impedance analysis in young adults from five populations of African origin.

BACKGROUND/OBJECTIVES: Bioelectrical impedance analysis (BIA) is used in population and clinical studies as a technique for estimating body composition. Because of significant under-representation in existing literature, we sought to develop and validate predictive equation(s) for BIA for studies in populations of African origin. SUBJECTS/METHODS: Among five cohorts of the Modeling the Epidemiologic Transition Study, height, weight, waist circumference and body composition, using isotope dilution, were measured in 362 adults, ages 25-45 with mean body mass indexes ranging from 24 to 32. BIA measures of resistance and reactance were measured using tetrapolar placement of electrodes and the same model of analyzer across sites (BIA 101Q, RJL Systems). Multiple linear regression analysis was used to develop equations for predicting fat-free mass (FFM), as measured by isotope dilution; covariates included sex, age, waist, reactance and height(2)/resistance, along with dummy variables for each site. Developed equations were then tested in a validation sample; FFM predicted by previously published equations were tested in the total sample. RESULTS: A site-combined equation and site-specific equations were developed. The mean differences between FFM (reference) and FFM predicted by the study-derived equations were between 0.4 and 0.6 kg (that is, 1% difference between the actual and predicted FFM), and the measured and predicted values were highly correlated. The site-combined equation performed slightly better than the site-specific equations and the previously published equations. CONCLUSIONS: Relatively small differences exist between BIA equations to estimate FFM, whether study-derived or published equations, although the site-combined equation performed slightly better than others. The study-derived equations provide an important tool for research in these understudied populations.

Shortage of healthcare workers in sub-Saharan Africa: a nephrological perspective.

AIMS: The paper assesses the lack of healthcare workers, the consequences, and possible solutions. MATERIALS AND METHODS: Review of existing literature and global health reports. RESULTS: The 47 countries of sub-Saharan Africa have a critical shortage of healthcare workers, the deficit amounting to 2.4 million doctors and nurses. There are 2 doctors and 11 nursing/midwifery personnel per 10,000 population, compared with 19 doctors and 49 nursing/midwifery personnel per 10,000 for the Americas, and 32 doctors and 78 nursing/midwifery personnel per 10,000 for Europe. And, whereas there are 28 doctors and 87 nurses/midwifery personnel per 10,000 in high income regions of the world, there are only 5 doctors and 11 nurses/ midwifery personnel per 10,000 in low income regions. The shortage of nephrologists in Africa, and especially sub-Saharan Africa, remains a critical issue, with many countries having < 1 nephrologist per million population; some have no nephrologists at all. The USA, UK, Canada and Australia have benefitted considerably from the migration of nurses and doctors over the past half century. Opportunities for training as well as employment have attracted doctors from many countries to these developed countries. Since 2006, new legislation in the UK has limited the inflow of health workers. Developing countries are also beginning to take steps to mitigate the problem of health worker loss and are developing strategies to both train increasing numbers of different cadres of healthcare worker and also to retain those already working in these countries. CONCLUSIONS: The forces of globalization are tending to increase the worldwide movement of all types of professionals, including those working in health care. It is this lack of health workers in developing countries that has been such a major constraint in limiting progress on initiatives such as the HIV "3 by 5" and Millennium Development Goals. More specifically, lack of resources, both human and financial, in developing countries has hampered nephrology programs both in the detection and prevention of chronic kidney disease and in the ability of doctors, nurses and other nephrological personnel to provide acute/chronic dialysis and transplantation.

Loss of health professionals from sub-Saharan Africa: the pivotal role of the UK.

The already inadequate health systems of sub-Saharan Africa have been badly damaged by the emigration of their health professionals, a process in which the UK has played a prominent part. In 2005, there are special opportunities for the UK to take the lead in addressing that damage, and in focusing the attention of the G8 on the wider problems of health-professional migration from poor to rich countries. We suggest some practical measures to these ends. These include action the UK could take on its own, with the African countries most affected, and with other developed countries and WHO.

T594M mutation of the beta-subunit of the epithelial sodium channel in Ghanaian populations from Kumasi and London and a possible association with hypertension.

We have tested 186 individuals from Ghana, 95 indigenous and 91 who have settled in the United Kingdom, for the presence of the T594M mutation in the beta-subunit of the epithelial sodium channel, which is associated with hypertension in black populations. The group living in Ghana had a mean age of 27 years and were normotensive, but had an increased frequency of the T allele compared to the London-based population. If this is reflected in larger studies, and the link with hypertension is maintained in the Ghanaian population, this mutation could be a significant cause of hypertension in Ghana.

A community study of health promotion in rural West Africa: details of a household survey and population census.

BACKGROUND: Hypertension is an important problem in sub-Saharan Africa. The low use of processed food in this area makes a population approach to reducing salt intake feasible. AIM: To create an age-sex register for 12 villages in Ghana as the first stage of a community study of the effect of dietary salt reduction on blood pressure and urinary sodium excretion in West African villagers. DESIGN: Household survey and population census. METHODS: Over three months, village maps were sketched and a complete list of total number of households, adults (with age and gender) and children in each village was obtained. RESULTS: The six semi-urban villages were larger than the six rural villages (10368 vs. 6597 inhabitants) and almost half the total population was under 16. CONCLUSIONS: Accurate census data are important in the design, implementation and interpretation of community studies and intervention trials. We outline the methods by which census data can be collected in rural and semi-urban sub-Saharan African villages, and emphasize the importance of painstaking, thorough work in the collection of such data.

Hypertension and renal failure in Kumasi, Ghana.

Hypertension is common in West Africa and likely to become more common as urbanisation increases. There are at present few facilities for the detection and management of hypertension so the influence it has on overall morbidity and mortality in the population is not clear. The objectives of the study were to assess: (a) renal disease and blood pressure related admissions and deaths among acute medical admissions to Komfo Anokye Teaching Hospital, Kumasi, during an 8-month period; and (b) the burden of renal disease among out-patient hypertensives at the same hospital. Ward admission books were examined in the four acute medical wards to ascertain admission diagnosis and cause of death (two 4-month periods in 1995 and 1996). Clinical assessment (blood pressure, plasma creatinine, proteinuria) was also made of 448 consecutive out-patient hypertensives seen between March 1995 and April 1996. Five hundred and ninety-three (17.9%) of 3317 acute medical admissions were ascribable to a cardiovascular cause (hypertension, heart failure, stroke); 171 (28.8%) of these died. One hundred and sixty-six (5.0%) had renal disease of whom 45 (27.1%) died, usually of end-stage renal disease. Among the 448 hypertensive out-patients, 30.2% (110 out of 365) had a plasma creatinine >140 micromol/l (48 > or = 400 micromol/l) and 25.5% (96 out of 376) had proteinuria. Eighty-nine of the 448 had a diastolic blood pressure > or =115 mm Hg; in this group 38 (42.7%) had a plasma creatinine of >140 micromol/l (and 18 or 20.2% > or =400 micromol/l). In conclusion, cardiovascular and renal disease are important contributors to morbidity and mortality among acute medical admissions to a large city hospital in Ghana. Among out-patient hypertensives renal disease is an important complication, especially in those with the more severe hypertension.

Evidence from a Ghanaian population of known African descent to support the proposition that hemochromatosis is a Caucasian disorder.

Mutations in the HFE gene on chromosome 6 are believed to cause the iron overload disorder hemochromatosis, the most common single gene disorder in northern Europeans. Two mutations have been described previously: C282Y, with an allele frequency of between 3% and 10% in the caucasian population, and H63D, which has an allele frequency of 16%. Published data shows that C282Y appears to be causative in the homozygous state, while the frequency of H63D/C282Y compound heterozygotes is much greater than expected in patient groups. There also appears to be a slightly elevated risk for H63D homozygotes. Hemochromatosis has been thought to be primarily a caucasian disorder. We have studied 97 healthy, black Ghanaian subjects, whose parents and grandparents were also African, to find the frequency of the two mutations. C282Y was absent, while H63D occurred in 2 individuals. These differences are significant at the 0.05 and 0.001 levels, respectively. The prevalence of H63D homozygotes in this population at 1 in 10,000 is clearly of no use in studying the effect of this genotype on phenotype. However, this study suggests an absence of the C282Y mutation in African populations, and the possibility that other populations might provide different genotypes and hence an analysis of H63D risk. A possible heterozygote advantage for the mutation is discussed.

Five-year review of diarrheal disease cases admitted to a busy referral hospital in Ghana.

AIM: To evaluate successes in the clinical management of severe diarrheal diseases in a busy referral hospital in Ghana, four years after the introduction of the World Health Organization's protocol for the clinical management of diarrhea and the establishment of an oral rehydration therapy Corner. METHOD: Data on the cases of diarrheal diseases recorded in the hospital from 1992 to 1996 were collected and analyzed. RESULTS: The average overall diarrheal disease mortality over the period was around 20% with twice as much deaths among adults than among children. There was a tendency of decline in childhood mortality, whereas it was much less evident among the adults. The high mortality caused by diarrheal diseases in the hospital and the differences in adult and childhood mortality were related to the problems in case management that stemmed from diarrhea case management training of clinical staff with a bias towards the pediatric staff, and also from the loss of several trained staff members through transfers and other staff replacements within the hospital. There were similarities in the trend of admissions for adults and children over the period, which suggested a possible common etiology for severe diarrheal diseases recorded in the hospital. CONCLUSIONS: Diarrheal mortality in a busy referral hospital should be investigated regularly for lapses in management because some of these deaths may be prevented by simple interventions.

A novel computer-driven, servo-controlled fluid replacement technique and its application to renal function studies in conscious rats.

1. A new rat model has been developed allowing body fluid status to be accurately controlled and maintained throughout experimentation by computer-driven, servo-controlled replacement of spontaneous urinary fluid losses. 2. Experiments in vitro were performed to test the accuracy of the servo system, and experiments in vivo were carried out to re-assess basic renal function in servo-controlled vasopressin-replete Long Evans and vasopressin-deficient Brattleboro rats. The model was further evaluated in water-diuretic Wistar rats with or without administration of a vasopressin V2-receptor agonist, 1-desamino-8-D-arginine vasopressin. 3. The data gained from the present study indicate the suitability of the servo-controlled replacement system for conscious renal function studies in three different rat strains. Haemodynamic and renal function variables measured were demonstrated to be stable throughout a 5 h experimental procedure and reproducible between repeated experimental occasions over a 14 day post-operative period. 4. Using the servo-control technique, the expected action of 1-desamino-8-D-arginine vasopressin on renal water handling was demonstrated, but the natriuretic effect reported by some workers was not evident. 5. Since the servo-controlled fluid replacement technique maintains many of the inherent differences between vasopressin-replete Long Evans and vasopressin-deficient Brattleboro rats and eliminates the changes in body fluid volume during transition from a diuretic to an antidiuretic state, the model confers an advantage over previously employed constant infusion protocols.

Lithium clearance in dogs: effects of water loading, amiloride and lithium dosage.

1. The influences of lithium dosage, urine flow rate and acute administration of amiloride on the renal handling of lithium in normal conscious dogs were investigated. 2. Lithium was administered in the diet at daily doses of 100 mg or 2 mg of lithium carbonate for the 2 days preceding the investigation. Urine flow rate was altered by water loading with and without arginine vasopressin infusion (5 pg min-1 kg-1). Amiloride was administered as an intravenous bolus (130 micrograms/kg) followed by a continuous infusion (1.22 micrograms h-1 kg-1). 3. Glomerular filtration rate (exogenous creatinine clearance) did not change within series and was not different between series; it averaged 3.27 ml min-1 kg-1. Control levels of fractional lithium excretion (12.4 +/- 1.2%, mean +/- SEM) were not influenced by hydration, hydration plus arginine vasopressin administration or the lithium dosage. However, in hydrated dogs having a plasma lithium concentration of 130-140 mumol/l, amiloride administration was associated with a 5% increase in fractional lithium excretion (P less than or equal to 0.01). 4. It is concluded that distal tubular lithium reabsorption may take place in sodium-replete conscious dogs undergoing water diuresis. The low fractional lithium excretion even during amiloride infusion (14.1-16.8%) may well be due to a high fractional reabsorption of lithium in the proximal tubules; however, a significant reabsorption of lithium distal to the proximal straight tubules by amiloride-insensitive pathways cannot be excluded.

Lithium clearance: modification by the loop of Henle in man.

1. The contribution of Li+ reabsorption in the loop of Henle to lithium clearance (CLi) and the possible mechanism(s) involved were assessed in healthy volunteers. Four mechanisms were considered: (a) passive reabsorption in the thin ascending limb, (b) solvent drag in the thin descending limb, (c) the Na+, K+, 2Cl- transporter in the thick ascending limb and (d) paracellular movement in the thick ascending limb. 2. Since alterations in the corticomedullary osmolal concentration gradient produced by fluid restriction (500 ml day-1) and subsequent water loading (15 ml kg-1) did not affect either CLi (28.5 +/- 2.1 vs. 28.2 +/- 1.9 ml min-1) or fractional lithium clearance (FELi; 23.5 +/- 2.0 vs. 23.0 +/- 1.9%), it is unlikely that substantial Li+ reabsorption occurs in the thin limbs by either passive movement or solvent drag. 3. Increasing plasma Li+ with unchanged plasma Na+ in salt-replete volunteers was associated with only small reductions in CLi (32.8 +/- 1.3 ml min-1, P less than 0.05) and FELi (27.3 +/- 1.8 vs. 25.3 +/- 2.0%, P less than 0.05). This suggests that substantial Li+ reabsorption on the Na+, K+, 2Cl- transporter does not occur. 4. Bumetanide increased FELi in salt-depleted (LS) and salt-replete (HS) volunteers and abolished the pre-diuretic difference in FELi between salt intakes (LS, 16.6 +/- 1.5 vs. 38.7 +/- 2.3%, P less than 0.001; HS, 30.1 +/- 1.5 vs. 40.5 +/- 2.0%, P less than 0.001). Changes in CPO4 and CHCO3 were not detected. Acetazolamide produced comparable increases in FELi (LS, 16.6 +/- 1.5 vs. 38.7 +/- 2.2%, P less than 0.001; HS, 30.1 +/- 1.5 vs. 43.1 +/- 2.4%, P less than 0.01); and CPO4 and CHCO3 were increased. When tubular flow to the loop of Henle was increased by acetazolamide, the bumetanide-induced increases in FELi were reduced (LS, 38.7 +/- 2.2 vs. 48.7 +/- 2.3%, P less than 0.001; HS, 43.1 +/- 2.4 vs. 48.1 +/- 2.6%, P less than 0.001). 5. These data are consistent with the view that (a) Li+ is reabsorbed by a bumetanide-sensitive mechanism in the loop of Henle, (b) approximately 20 and 10% of the filtered load, respectively, is reabsorbed in the loop in salt-depleted and salt-replete volunteers, (c) flow-dependent, voltage-driven paracellular movement in the thick ascending limb is the likely mechanism and (d) this mechanism could account for the difference in Li+ reabsorption between low and high salt intakes.