The effects of the menstrual cycle, pregnancy and early lactation on haematology and plasma biochemistry in the baboon (Papio hamadryas).

The changes in the haematology and clinical biochemistry associated with the different stages of the menstrual cycle, gestation and lactation in the baboon (Papio hamadryas) were evaluated in a prospective longitudinal study. Serial EDTA and heparin blood samples were collected from 12 baboons. Haemoglobin concentration, haematorcrit, red blood cell and white blood cell counts were decreased in the luteal compared to the follicular phase (P<0.001); the reverse effect was observed for platelet count, total protein and albumin concentrations. The changes in plasma concentrations of sodium, potassium, urea, creatinine and cholesterol and plasma osmolality were characterized by reductions (P<0.01) in early pregnancy which were maintained throughout gestation. Plasma concentrations of total protein, albumin and alkaline phosphatase, as well as haemoglobin, haematocrit and red cell count were reduced (P<0.001) from mid-gestation. Platelet count and plasma calcium concentration fell continuously throughout gestation (P<0.001). Plasma triglycerides were lower and plasma iron was higher (P<0.01) in gestation compared to the phases of the menstrual cycle and lactation. By 1 week post partum, all parameters except haemaglobin had returned to pre-conception levels.

Low-dose nitro-L-arginine administration in baboon (Papio hamadryas) pregnancy.

1. The purpose of the present study was to examine the effect of nitric oxide (NO) inhibition on mean arterial pressure (MAP), endothelin (ET) and the renin-aldosterone system in pregnancy in the non-human primate (baboon). 2. Twenty pregnant baboons (Papio hamadryas) were examined prospectively after the administration of an oral NO inhibitor in different phases of pregnancy. Haemodynamic responses to NO inhibition, evidence of pre-eclampsia and the renin-aldosterone system were examined under anaesthesia. 3. Oral NL-nitro-L-arginine (NOLA; 5 or 10 mg/kg) was given for 1 week in early (6-8 weeks gestation), middle (14-16 weeks gestation) and late (22-24 weeks gestation) pregnancy and while non-pregnant. Mean arterial pressure, heart rate, haematology, biochemistry, ET, plasma renin activity (PRA) and aldosterone were measured. Foetal effects of NOLA were also examined by ultrasound and neonatal measurements. 4. Nitric oxide inhibition led to an increase in MAP in non-pregnant animals (9 mmHg) and in middle and later pregnancy (6 and 7 mmHg, respectively). Mean arterial pressure in early pregnancy was not affected. A reduction in PRA occurred after NO inhibition in all stages of pregnancy. Significant proteinuria occurred only in late pregnancy. 5. Nitric oxide is involved in the maintenance of lower blood pressure in late pregnancy and inhibition leads to an increase in blood pressure and proteinuria in the baboon. Nitric oxide insufficiency may contribute to the clinical manifestations of human pre-eclampsia. Nitric oxide was not involved in the normal vasodilation of early primate pregnancy.

Biochemistry and haematology values for the baboon (Papio hamadryas): the effects of sex, growth, development and age.

A retrospective study evaluated the influence of sex and age on plasma biochemistry and haematology parameters in a captive-bred colony of baboons. Over 1,140 ETDA and heparin blood samples were obtained from 160 clinically normal baboons between the ages of 11 months and 11 years. Data for these blood tests were analysed for the effects of sex, age and sex age interactions. Sex, age and sex age interactions were detected for many plasma biochemistry and haematological parameters. The reference range values for platelets, white-blood cells and mean corpuscular volume and plasma chloride, glucose, total protein and iron were higher (P < 0.01) and red blood cell, plasma sodium, potassium, total CO2, creatinine, urea, total bilirubin, albumin, alkaline phosphate, gamma glutamyl transpeptidase and phosphate were lower (P < 0.01) in the female compared to the male population. Sex age interactions (P < 0.05) were seen with haemoglobin, white blood cells, haematocrit, mean corpuscular volume, sodium, creatinine, urea, calcium, phosphate, total bilirubin, total protein alkaline phosphatase, the liver enzymes and triglycerides. Plasma alkaline phosphatase was highest ( > 800 micro/l) in young juveniles of both sexes; creatinine was higher in older ( > 4 years) compared to younger baboons of the same sex (P < 0.05). Plasma cholesterol and triglycerides were greater (P < 0.01) in young baboons compared to older animals.

Hemodialysis: an appropriate therapy in myeloma-induced renal failure.

To determine whether vigorous treatment with dialysis is of benefit to patients with myeloma-induced renal failure at presentation, we retrospectively reviewed outcomes in a group of patients diagnosed with multiple myeloma between January 1986 and September 1993. Increased age (P = 0.003), presence of renal impairment (P = 0.006), and failure to enter plateau phase (P < 0.001) were independently associated with shortened survival. However, there was no difference in outcome between patients with severe renal failure, those treated with dialysis, and those with milder renal impairment (median survival, 22 months in both groups), nor was reversibility of renal failure associated with any survival advantage. The lack of correlation between severity or reversibility of the renal failure and survival suggests that there may be characteristics of some patients or their underlying myeloma that are responsible both for renal impairment and for adverse prognosis. In this study, neither age, clinical stage, labeling index, nor response to treatment was able to account for the difference in outcome between patients with and without renal failure. The prolongation of life achieved in the dialysis patients such that their median survival was identical with that of the group with milder renal impairment was considered to represent a significant benefit to these patients and to justify the offer of dialysis to all patients requiring it.

Cyclical changes in the renin-angiotensin-aldosterone system during the menstrual cycle of the baboon (Papio hamadryas).

This study characterizes the renin-angiotensin-aldosterone system during the normal menstrual cycle in the baboon. Ten animals received a daily dose of an ACE inhibitor or placebo in a randomized blind cross-over design. Data were obtained during the mid-follicular and early luteal phases of normal non-pregnant menstrual cycles. All examinations and blood collections were performed with ketamine sedation: 7-kg by im injection. Blood pressure was recorded by sphygmomanometer. Serum ACE activity was measured by spectrophotometry. Aldosterone (ALDO), angiotensin I (AI), and angiotensin II (AII) were measured by radioimmunoassay. Plasma renin activity (PRA) was measured by AI generation. The renin-angiotensin-aldosterone system was found to be activated in the follicular phase and suppressed during the luteal phase of the normal non-pregnant menstrual cycle in the baboon.

Fetotoxicity of angiotensin-converting enzyme inhibition in primate pregnancy: a prospective, placebo-controlled study in baboons (Papio hamadryas).

OBJECTIVES: Serious concerns have been raised about angiotensin-converting enzyme inhibition in pregnancy. The central question remains: does toxicity of angiotensin-converting enzyme inhibition pertain to pregnant humans? STUDY DESIGN: A prospective, placebo-controlled study was performed to investigate the effect of angiotensin-converting enzyme inhibition on pregnancy outcome in the baboon. Subjects (N = 12) received active and placebo treatments sequentially in a crossover protocol. Data were analyzed with two-sample t tests, analysis of variance, Fisher's exact test, or Kaplan-Meier survival analysis, where appropriate. RESULTS: Chronic administration of enalapril (7.5 mg per day) from before conception achieved moderate but sustained angiotensin-converting enzyme inhibition as determined by repeated measures of renin-angiotensin system parameters (serum angiotensin-converting enzyme activity, plasma renin activity and plasma angiotensin I, angiotensin II, and aldosterone concentrations). Serum angiotensin-converting enzyme activity was significantly reduced throughout (< 10 nmol.ml-1.min-1, p < 0.01), with significant increases in plasma renin activity and angiotensin I (p < 0.01). Angiotensin II and aldosterone were maintained unchanged compared with placebo. There was a significant incidence of fetal death or intrauterine growth retardation in fetuses exposed to enalapril (eight of 13, zero on placebo, p < 0.01). When the definition of adverse pregnancy outcome was restricted to fetal death alone (four of 13) the difference remained significant (p < 0.05). Maternal arterial pressure was unchanged before conception, but a small and significant fall (10 to 15 mm Hg, p < 0.01) was detected throughout pregnancy. There was no fetal malformations. CONCLUSION: The study provides definitive evidence for serious consequences of angiotensin-converting enzyme inhibition in pregnancy of high-order primates.

Elevated plasma vitamers of vitamin B6 in patients with chronic renal failure on regular haemodialysis.

Plasma pyridoxal-5'-phosphate (PL-5'-P), pyridoxal (PL), pyridoxine (PN), and 4-pyridoxic acid (4-PA) were measured by high-performance liquid chromatography (HPLC) in 39 patients (15 male, 24 female) with chronic fenal failure undergoing regular haemodialysis and 46 healthy controls (28 male, 18 female). All three vitamers of vitamin B6 and the metabolite were significantly elevated in the haemodialysis patients. Mean PL-5'-P and PN concentrations were 20 times the mean in controls. Only one patient took a vitamin B6 supplement. In view of the neurotoxicity of supranutritional intakes of PN in normal humans we suggest that supplements of PN be carefully monitored when administered to patients with chronic renal failure.

Inhibition of fibroblast proliferation in L-valine reduced selective media.

A selective cell culture medium, D-valine minimal essential medium (92 mg/l), has been developed to inhibit the proliferation of fibroblasts in cell culture (Gilbert & Migeon 1975). Substitution of D-valine for L-valine prevents fibroblast growth due to the absence of D-amino acid oxidase in these cells. Most cell cultures require foetal bovine serum as an essential component of the culture media, however foetal bovine serum contains L-valine, negating the value of D-valine selective media. To overcome this difficulty, we have produced a modified selective media for cell culture, by the dialysis of foetal bovine serum and confirmed its ability to inhibit fibroblast growth whilst still allowing the proliferation of epithelial cells in culture.

Cyclosporin A blood levels are not influenced by dietary alterations in lipids.

The bioavailability of an oral dose of cyclosporin A (CSA) is variable. CSA is highly lipid soluble with approximately 40% of the CSA in the intravascular compartment bound to lipoproteins. This study was undertaken to determine what effect acute alterations in plasma lipids following a high fat meal would have on CSA whole blood levels 12 to 14 hours after the last dose. Fifteen renal transplant patients with stable renal function and on CSA therapy alone for a minimum of three months were investigated. Anthropometric data was recorded and baseline blood samples were drawn for CSA, liver function, renal function, vitamins A and E. triglycerides, cholesterol and lipoproteins following an overnight fast. The subjects then received a high fat (72.8% of caloric value) or a low fat (12% of caloric value) meal and post-prandial samples were drawn at two and four hours. The correlation between CSA levels (r = 0.72) taken on the two study days (one week apart) was less than expected despite no change in dosage. Cholesterol levels remained unchanged but triglyceride levels rose following the high fat meal. CSA levels did not correlate with the post-prandial changes in triglycerides, nor with any other parameter of lipid metabolism, lipid transport, or total body fat. This study demonstrated that CSA whole blood levels are not influenced by acute variations in lipids following a meal and therefore the time of sampling for a CSA trough level will not be influenced by the proximity to a recent meal.

Early blood pressure control improves pregnancy outcome in primigravid women with mild hypertension.

OBJECTIVE AND DESIGN: The aim of this study was to evaluate treatment of mild to moderate hypertension (less than 170/110 mmHg) in pregnancy in a prospective, randomised, double-blind trial. SETTING AND PATIENTS: Pregnancy outcome was studied for 52 primigravid women, managed in hospital from early in the third trimester. INTERVENTIONS: Patients were randomly allocated either to placebo or to active treatment (clonidine plus hydralazine). MAIN OUTCOME MEASURES AND RESULTS: Maternal deterioration dictated withdrawal from trial therapy for eight patients receiving placebo, but for only one receiving active treatment. Maternal proteinuria occurred only in the placebo group. Intention-to-treat analysis showed a significant increase in premature delivery for complications in the placebo group (P less than 0.05), despite active blood pressure treatment for those withdrawn from the group because of severe hypertension (170/110 mmHg or higher). Neonatal respiratory distress requiring intensive care occurred only in babies born to women in the placebo group. There were no perinatal deaths and no adverse effects of treatment in the neonates. CONCLUSIONS: The study indicates that early control of mild hypertension in pregnancy can prevent progression to emergency premature delivery.

Essential hypertension--investigations and management.

When one is faced with the problem of essential hypertension it is prudent to pay attention to lifestyle factors, especially alcohol, smoking and obesity. Modification of salt intake in the diet is a simple measure. Drug therapy will need to be long-term therapy and ease of treatment is important, which means that drugs given once a day or at most twice a day should be used. Diuretics and beta-blockers are inexpensive and well proven but have many side-effects. Newer agents may have fewer side-effects but are more expensive. The choice will be an individual one.

Evidence that alterations in renal metabolism and lipid peroxidation may contribute to cyclosporine nephrotoxicity.

This study was designed to investigate aspects of renal xenobiotic metabolism and the renal cellular response to drug-induced injury, in mediating cyclosporine nephrotoxicity. The relation between CsA and renal enzyme activity has not previously been investigated. In this study, CsA induced alterations in rat renal cortical microsomal NADPH cytochrome P-450 reductase activity, microsomal and mitochondrial lipid peroxidation, and renal cortical glutathione levels were investigated. CsA, in vivo (50 mg/kg/day for 4 days), increased in vitro lipid peroxidation in microsomes and mitochondria. CsA produced a significant uncompetitive inhibition of renal NADPH cytochrome P-450 reductase activity. The low activity and maximal enzyme velocity (Vmax) suggest that the amount of renal enzyme available for metabolism may be a rate-limiting step and could contribute to the development of toxicity. CsA in vivo reduced the renal cortical glutathione ratio (GSH/GSSG), which may also reduce the renal cellular response to CsA injury. This study has demonstrated that CsA nephrotoxicity may, in part, be mediated by CsA-induced alterations in renal xenobiotic metabolism.

Hemodynamics of conscious unrestrained baboons, including cardiac output.

A method is described for comprehensive hemodynamic study of undisturbed baboons (Papio hamadryas) that incorporates cardiac output measurement by thermodilution. Instrumentation includes arterial, aortic, and central venous catheterization by a surgical technique that does not require entry to peritoneal or thoracic cavities. It provides a means for right atrial indicator delivery with aortic temperature recording of thermodilution curves. Accuracy was confirmed by comparison to measurement by Swan-Ganz catheters. Diurnal variations of systemic arterial pressure in long-term study of conscious baboons were shown to result from significant increases in cardiac output by day (P less than 0.001), despite concomitant falls in systemic vascular resistance. The cardiac output values obtained were 0.13 l.min-1.kg-1 at night and 0.16 l.min-1.kg-1 by day. Comparison of these results to previous reports of cardiac output in baboons highlights the inadequacies of methods that require physical restraint or anesthesia. This technique also leaves the baboons intact for subsequent breeding or experimental use after catheter removal without the need for further surgery.

Energy supplementation and the nutritional status of hemodialysis patients.

Twenty-one patients undergoing regular hemodialysis completed a trial of energy supplementation. Nine patients added the glucose polymer Polycose to their usual diet and 12 acted as control subjects. The supplemented patients were asked to incorporate 100 or 150 g polymer, equivalent to 1600 or 2400 kJ (400 or 600 kcal) into their usual diet, daily for 6 mo. This resulted in a mean increase in energy intake of 1630 kJ (p less than 0.05) and a mean weight gain of 3.1 kg (p less than 0.005). The addition of glucose polymer to the diet resulted in a mean increase in body fat of 1.8 kg and the lean body mass increased by 1.3 kg. No significant effect on plasma triglycerides, urea, or creatinine was detected. The intake of macro- and micronutrients was not adversely affected and no clinical or psychological side effects were reported. Follow-up of these patients showed that the weight gain was maintained after 6 mo. Glucose polymer was an effective energy supplement that had beneficial effects on the nutritional status of hemodialysis patients.

Body protein of patients undergoing haemodialysis.

The total body protein status of 18 patients undergoing regular haemodialysis was assessed by measuring total body nitrogen (TBN) using in vivo neutron activation analysis (NAA). Eighteen healthy controls, who were selected according to their height, age and sex match with the patients were also measured. The male and female patients were both found to have lower mean values for total body protein (P less than 0.01, P less than 0.025 respectively) although they had similar weights compared with their matched controls. Seven patients were measured on further occasions and only two patients showed a change in their body protein. One female showed an increase of 11 per cent in body protein (with an increase of 25 per cent in body weight) after intensive nutritional repletion therapy. In vivo NAA provides a direct means of measuring body protein and is a reliable method to monitor changes with treatment regimes.