Isoniazid exposure and pyridoxine levels in human immunodeficiency virus associated distal sensory neuropathy.

SETTING: Distal sensory polyneuropathy (DSP) may manifest in human immunodeficiency virus (HIV) infected individuals before or after antiretroviral therapy (ART). DSP can also occur in response to isoniazid (INH); this can be prevented by pyridoxine supplementation. N-acetyltransferase 2 (NAT2) polymorphisms influence drug acetylation and possibly the risk for INH-associated DSP. OBJECTIVE: To investigate the relationship between previous/current TB, pyridoxine deficiency and DSP in HIV-infected individuals enrolled in a government-sponsored HIV programme. DESIGN: Neuropathy assessments were performed among 159 adults pre-ART and 12 and 24 weeks thereafter. DSP was defined as ⩾1 neuropathic symptom and sign. NAT2 genotypes predicted acetylation phenotype. Serum pyridoxine levels (PLP) were quantified at baseline and week 12. RESULTS: DSP was present in 16% of individuals pre-ART and was associated with previous/current TB (P = 0.020). Over 50% were pyridoxine deficient (PLP < 25 nmol/l), despite supplementation with vitamin B complex supplements (2-4 mg/day pyridoxine). Those with a history of TB and pre-ART DSP were more likely to be pyridoxine deficient (P = 0.029), and slow/intermediate NAT2 phenotypes impacted on their PLP levels. Incident/worsening DSP after ART developed in 21% of the participants. PLP levels remained low after ART, particularly among those with prior TB, but without an association between DSP or NAT2 phenotypes. CONCLUSION: Adequate pyridoxine supplementation before ART initiation should be prioritised, particularly in those with a history of TB or current TB.

Influence of type of carbohydrate on atherosclerosis in baboons fed semipurified diets plus 0.1% cholesterol.

Five groups of six (three male, three female) baboons (Papio ursinus) were maintained for 17 months on a semipurified diet containing 40% carbohydrate, 25% casein, 13.9% coconut oil, 0.1% cholesterol, 15% cellulose, 5% salt mix (USP XIV) and 1% vitamin mix. The carbohydrates fed were: fructose, sucrose, starch, glucose, and lactose. A fifth group was used as control and was fed bread, fruit, and vegetables. Serum, liver, and tissue lipids were analyzed at the end of the feeding period as were cholesterol absorption (as 3H-cholesterol) and synthesis (from 14C-mevalonic acid). Serum cholesterol and beta-lipoprotein levels were elevated in all the test groups compared to final control levels or to starting levels for all the baboons. Average serum cholesterol levels of the test groups were not significantly different. Liver lipids were elevated in all test groups except that fed glucose. Baboons on the test diets absorbed more exogenous cholesterol (3H) but biosynthesis of this sterol was not inhibited. The ratio of biliary primary/secondary bile acids was below normal levels only in the animals fed fructose and sucrose. Cholesteryl ester fatty acid spectra of serum and liver reflected the dietary fat. Fecal weight was 69% higher in lactose fed animals and 31% lower in sucrose fed animals than in the controls. The ratio of endogenous or exogenous neutral/acid steroids was considerably lower in the fructose-fed baboons than in the other animals. On this diet average aortic sudanophilia (percentage of surface) was: fructose, 11.3; sucrose, 10.4; starch, 21.3; glucose, 17.2 lactose, 65.8; and control, 1.4. Gross atheromatous lesions were seen in five of six baboons fed lactose; three of six baboons fed fructose; two of six baboons fed sucrose, and one of six baboons fed starch. In a second experiment three groups of baboons were fed the control diet, the semipurified diet in which the carbohydrate was lactose, and the semipurified diet containing lactose plus 0.1% cholesterol for 8.5 months. Serum lipids were elevated in the two test groups but liver lipids were not significantly different from control levels. Average aortic sudanophilia (percentage of area) was: lactose, 2.2; lactose-cholesterol, 20.8; and control, 0.3%. One of the six baboons in the lactose-cholesterol group had visible atherosclerotic lesions. These experiments represent the first successful attempt to produce severe atherosclerosis in baboons by dietary means alone.

Effects of dietary fiber in vervet monkeys fed "Western" diets.

Male Vervet monkeys (7/treatment) were fed a "Western" diet containing 46.2% calories as fat, 39.8% as carbohydrate and 14.0% as protein. The diet was augmented with 10% cellulose or 10% pectin. A third (control) group of seven monkeys was fed a commercial ration augmented with fruit and bread. After 34 weeks, serum cholesterol levels were elevated significantly in the two test groups compared with the controls but there was no difference between the two fiber-fed groups. Serum triglycerides were unaffected. Liver cholesterol levels were the same in all three groups but liver triglyceride levels were lower in the monkeys fed cellulose. Biliary lipids were similar in all three groups as were the calculated lithogenic indices. The average aortic sudanophilia (percent of total area) in the three groups was cellulose, 10.6 +/- 2.5; pectin, 8.1 +/- 2.5; and control, 1.1 +/- 0.4. One animal in each of the groups fed "Western" diet exhibited an atherosclerotic plaque. The results indicate that there is no difference between pectin and cellulose with regard to their effects on either lipidemia or aortic sudanophilia in Vervet monkeys fed a Western-type diet.

In vivo nuclear techniques in veterinary medicine.

A description is given of the more relevant procedures of diagnostic nuclear medicine as well as of future trends in this field, especially with regard to in vivo research and clinical applications at the biochemical level. The part played by animal models in the past and present is emphasised. The inclusion of a nuclear medicine facility, as equipped and run by the Atomic Energy Board at the H.A. Grové Animal Research Centre is put into perspective.

Polyneuropathy, anti-tuberculosis treatment and the role of pyridoxine in the HIV/AIDS era: a systematic review.

Tuberculosis (TB) is increasing in incidence in certain parts of the world, particularly where there is a co-epidemic of human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS), and it is associated with a significant degree of morbidity and mortality. One of the most common complications of anti-tuberculosis treatment is the development of a painful isoniazid (INH) associated polyneuropathy (PN), which is preventable with adequate pyridoxine supplementation. As PN is also the most frequent neurological complication associated with HIV infection, subjects who are HIV and TB co-infected may be at increased risk of developing PN. In this review, we explore current knowledge of anti-tuberculosis drug associated PN focusing on INH and its relationship to pyridoxine, as well as the additional impact of antiretroviral treatment and TB-HIV co-infection. It is evident that guidelines established for the prevention and treatment of this problem differ between industrialised and developing countries, and that further research is needed to define the optimum dosing of pyridoxine supplementation in populations where there is a significant burden of TB and HIV.

Circumstances associated with the contamination of food by aflatoxin in a high primary liver cancer area.

The variable incidence of primary liver cancer has been shown to be related to the average daily intake of aflatoxin in various parts of the world. This study was made to detect and report strategic points of contamination of foodstuffs in the region with the highest known incidence of liver cancer. Methods of food production, harvesting, storage and preparation were examined, and defects which promote fungus growth on food were found at each stage. Most meals consisted of a single dish with three basic ingredients -- a protein, bulk carbohydrate and green vegetables. Groundnuts were the main source of protein, but were also the main cause of aflatoxin contamination, since casual traditional methods of agriculture are not suited to the production of this exotic crop. Aflatoxin production appears to occur in the main sources of carbohydrate, such as cassava and maize, during storage. Leaves of various kinds provide substitutes for green vegetables and common methods of handling the crop promote fungal growth. Western-type foods had a particularly low aflatoxin content, or were free of it. Education and economic opportunities external to the subsistence economy structure are contributing to the westerisation of some living habits, a process believed to be responsible for the observed decrease in the incidence of primary liver cancer. Current knowledge indicates that a pertinent but simple educational programme could further markedly reduce the incidence of the disease.

Onyalai--the possible involvement of a mycotoxin produced by Phoma sorghina in the aetiology.

A number of species of fungi were isolated from millet (Pennisetum typhoides Staph and Hubb) and grain sorghum (Sorghum vulgare Pers) obtained from the households of patients suffering from onyalai. Several proved to be toxic to rats and chickens, including Phoma sorghina (Sacc.) which was the predominating fungus. Cultures of P. sorghina grown on maize and wheat were added to standard rations at concentrations of 5-30%. When fed to day-old New Hampshire chickens, the majority died within 4 days, exhibiting traces of blood on the beak and the cloaca. Rats given 10% or more of the mouldered material in the diet developed thrombocytopenia after 14 days which was followed by haematuria, epistaxis, melaena, and death. Pathological, including histological examination, revealed extensive damage to the fascular system which resulted in widespread haemorrhages.

DNA supercoiled domains and radiosensitivity of subpopulations of human peripheral blood lymphocytes.

Enriched human B- and T-lymphocyte subpopulations were isolated by means of a Percoll step gradient centrifugation procedure. 60Co gamma-irradiation dose-response curves for these subpopulations were obtained by applying a modified nucleoid sedimentation technique, which was also employed for the determination of the superhelical content by means of ethidium bromide intercalation. Although a similarity in the average superhelical density of B- and T1-lymphocytes was shown, B-lymphocytes exhibited a more pronounced reduction in sedimentation ratio, suggesting a higher radiosusceptibility than the T1-lymphocytes. By applying the single hit kinetics of the target theory to the dose-response curves, an estimation of the supercoil domain sizes was made: B- cells, 5.5 X 10(9), 1.78 X 10(9) and 7.78 X 10(8) D; T-cells, 4.55 X 10(9), 1.75 X 10(9) and 7.67 X 10(8) D. The differences in radiosensitivity of lymphocyte subpopulations can not, therefore, be entirely ascribed to differences in DNA superstructure.

Carcinoembryonic antigen in patients with breast cancer: an adjunctive tool to monitor response and therapy.

Plasma carcinoembryonic antigen (CEA) levels were performed by radioimmunoassay in 234 patients with histologically proved breast cancer: 181 with advanced metastatic disease and 53 without distant metastases but nodal involvement at time of mastectomy. Four hundred and thirty-four assays were done and correlated with the clinical status of the patients. Values above 2.5 ng/ml were taken as abnormal. Active disease was associated with elevated plasma CEA levels. Very high values were not recorded in 109 patients when they were considered to be in complete remission, while only 22 patients out of 63 patients with progressive disease had normal values. In 16 of these values remained normal despite progression of disease. In 6 patients clinical relapse preceded CEA elevation by 2--5 months. Tumor burden and abnormal serial CEA values showed positive correlation in 38 patients. In 30 patients, change in clinical status and CEA values occurred simultaneously. In only 2 patients an increase in CEA value occurred 2--3 months before clinical documentation of relapse.

Role of plasma carcinoembryonic antigen in evaluating patients with breast cancer treated with adjuvant chemotherapy.

Serial plasma carcinoembryonic antigen (CEA) levels were determined in 84 patients with breast cancer who were receiving postsurgical adjuvant chemoimmunotherapy or adjuvant chemotherapy. CEA values were correlated with clinical status, scintiscans, alkaline phosphatase, LDH, and SGOT. CEA values greater than 2.5 ng/ml were considered abnormal. Thirty patients had normal serial CEA values; all remain disease-free. In 54 patients one or more abnormal CEA values were recorded; nine of 54 developed overt metastatic disease. Relapses occurred in four of 38 patients in whom values up to 5 ng/ml were recorded, in three of 14 patients in whom values up to 10 ng/ml were recorded, and in two of two patients in whom values greater than 10 ng/ml were recorded.

Carcinoembryonic antigen as a marker in patients with breast cancer receiving postsurgical adjuvant chemotherapy.

Serial plasma CEA levels were determined over a period of 1-3 years in 114 patients receiving adjuvant chemotherapy for T1, 2 or 3a N+ MO breast cancer. CEA values were correlated with clinical status, scintiscans, and other biochemical parameters. CEA values greater than 2.5 ng/ml were considered abnormal. Forty-one patients had normal values throughout the adjuvant period. In 73 patients where abnormal values occurred, four different patterns were seen: (1) a statistically significant number (30/73) had initial elevations with a decreasing titer; (2) rising titer (10/73); (3) fluctuating titer of transient elevation (25/73); and (4) persistent elevation (8/73). Seventeen patients developed overt metastases, this was associated with a rising CEA in nine patients (P less than 0.002). CEA was more sensitive for predicting relapse than alkaline phosphatase or LDH. The correlation between CEA determination and the eventual development of metastatic disease is striking, and has implications for the design of future clinical trials. Results indicate that CEA could be used to identify high risk patients, to estimate efficacy of chemotherapeutic regime, and to determine optimal duration of therapy.

Reversibility of the stabilization effect of sodium molybdate on uterine estrogen and progesterone receptors of the vervet monkey.

Sodium molybdate affected the stability of vervet monkey (Cercopithecus aethiops pygerythrus) uterine estrogen (ER) and progesterone (PR) receptors. Yields of receptors were invariably higher (20-40%) when cytosols were prepared in the presence of 10mM sodium molybdate. No changes were observed in the binding affinities for the natural ligands as reflected in dissociation constants. Receptor-ligand association at 0 degrees C and 20 degrees C was not affected in the presence or absence of molybdate. Stability studies at 37 degrees C indicated both receptors to be more resistant to inactivation in the presence of molybdate. Dissociation of ER and PR was biphasic, indicating the existence of slow (SDC), as well as fast dissociating (FDC) complexes. Rate constants of dissociation were significantly affected by the presence of sodium molybdate. Although no significant changes in the sedimentation coefficients were observed, marked differences in the actual gradient profiles could be illustrated in the presence or absence of sodium molybdate. Observed effects could only be partially reversed in sedimentation dialysis experiments. Proteolytic inhibitors phenylmethylsulfonylfluoride (PMSF) and leupeptin had no inhibitive effect on the molybdate stabilization of ER and PR.

Estrogen and progesterone receptors in the uterus of the vervet monkey.

Experimental conditions for the optimal measurement of estrogen (ER) and progesterone (PR) receptors in normal vervet monkey (Cercopithecus aethiops pygerythrus) uteri are described. The uteri of this primate were found to contain relatively high concentrations of both ER and PR. Levels of ER ranged from 151 to 822 femtomoles per mg protein (mean for group assayed is 327 +/- 165 femtomoles per mg protein). PR assays were performed on the same cytosols and the levels ranged from 444 to 2267 femtomoles per mg protein (mean of 1285 +/- 511 femtomoles per mg protein). Mean Kd values for the ER- and PR-ligand complexes were found to be 3.15 +/- 1.4 X 10(-10)M and 2.38 +/- 0.2 X 10(-9)M respectively, within the group analysed (n = 21). The ratio of PR to ER varied between 1.1 and 13.1 with a mean of 4.5 +/- 2.4. Ligand specificity studies revealed that [3H]-17 beta-estradiol binding to the ER could only be inhibited by estrogens or estrogen analogues. The PR however exhibited an affinity for a wider range of ligand types. In low ionic strength buffers both ER and PR sedimented as approximately 8S type molecules in the presence or absence of 10mM sodium molybdate. Both receptors dissociated into smaller components, following a short exposure to 0.4 M KCl and subsequent centrifugation in a gradient containing 0.4 M KCl.

Standardization of radiorenography in dehydrated and rehydrated primates under laboratory conditions.

Radiorenography with 99mTc-labelled diethylenetriaminepentacetic acid ( [99mTc]-DTPA) was performed on chacma baboons (Papio ursinus) and vervet monkeys (Cercopithecus pygerythus) to establish the effects of various states of hydration on the data obtained from the DTPA-renogram. The renogram parameters, which can be related to certain aspects of kidney function, varied significantly with the degree of hydration. It is therefore imperative for clinically directed animal research projects on the urinary system to standardise the experimental procedure for radiorenography. A dehydration of 6 h followed by an hour IU rehydration period using 200 ml of a 0.9% NaCl solution on baboons under thiopentone sodium anaesthetic, was found to be the most suitable procedure for radiorenographic investigations in this primate model.

Hepatocellular carcinoma and dietary aflatoxin in Mozambique and Transkei.

Estimations of the incidence of hepatocellular carcinoma (HCC) for the period 1968-74 in the Province of Inhambane, Mozambique, have been calculated and together with rates observed in South Africa among mineworkers from the same Province indicate very high levels of incidence in certain districts of Inhambane. Exceptionally high incidence levels in adolescents and young adults are not sustained at older ages and suggest the existence of a subgroup of highly susceptible individuals. A sharp decline in incidence occurred during the period of study. Concurrently with the studies of incidence, 2183 samples of prepared food were randomly collected from 6 districts of Inhambane as well as from Manhica-Magude, a region of lower HCC incidence to the south. A further 623 samples were taken during 1976-77 in Transkei, much further south, where an even lower incidence had been recorded. The mean aflatoxin dietary intake values for the regions studied were significantly related to HCC rates. Furthermore, data on aflatoxin B1 contamination of prepared food from 5 different countries showed overall a highly significant relationship with crude HCC rates. In view of the evidence that chronic hepatitis B virus (HBV) infection may be a prerequisite for the development of virtually all cases of HCC and given the merely moderate prevalence of carrier status that has been observed in some high incidence regions, it is likely that an interaction between HBV and aflatoxin is responsible for the exceptionally high rates evident in parts of Africa and Asia. Various indications from Mozambique suggest that aflatoxin may have a late stage effect on the development of HCC. This points to avenues for intervention that could be more rapidly implemented than with vaccination alone.

A modified neutral sucrose centrifugation method for rapid detection of DNA damaged by gamma-radiation and repair in human lymphocytes.

1. The influence of 60Co gamma-radiation on the sedimentation behaviour of human lymphocyte nucleoids in neutral sucrose gradients was studied with the aid of a modified fluorescent monitor system consisting of the DNA-binding dye, Hoechst 33258 and a vertical centrifuge rotor. 2. A combined method employing the sedimentation procedure and the incorporation of tritiated nucleosides was utilized to evaluate the repair of gamma-radiated DNA.