Key issues in the clinical development and implementation of TB vaccines in South Africa.

Significant progress has been made in advancing the development pipeline for a new and more effective TB vaccine with some candidate vaccines now in late stage clinical evaluation. However, progress has been hampered by an incomplete understanding of the components of a protective immune response and limited animal models, rendering the field unable to reliably predict vaccine efficacy earlier in preclinical development, including by evaluation in animal models, and limiting the predictive utility of comparing immunogenic effects across vaccine candidates in phase I/II studies. Consequently, new candidate vaccines have to be evaluated for efficacy in large-scale phase II/III trials using clinical endpoints. Apart from the technical challenges of characterising TB incidence in target populations at high risk of acquiring TB disease and standardising case definitions in order to improve both the sensitivity and more importantly the specificity of trial endpoints, there is an urgency in expanding and supporting the considerable trial infrastructure that will be required to evaluate and ultimately license a new TB vaccine. In the longer term, implementation strategies are dependent on what policy makers most value. Economic analyses will be essential to guide policy and implementation. This paper outlines the gaps and challenges and identifies solutions for effectively developing and efficiently introducing a new TB vaccine.

Prospective treatment in carnitine-acylcarnitine translocase deficiency.

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder that results in long-chain fatty acids being unavailable for mitochondrial beta-oxidation and ketogenesis. It can present in the neonatal period or infancy with a severe clinical form, typically with convulsions, hypothermia, encephalopathy, cardiomyopathy and liver dysfunction, or with a milder phenotype with episodes of hypoglycaemia and hyperammonaemia during intercurrent illness. Investigations show hypoketonaemia, intermittent dicarboxyluria and hypocarnitinaemia with grossly elevated acylcarnitines. Enzyme assay or DNA analysis confirms the diagnosis. The severe phenotype results in severe disability or death. The less severe phenotype can also cause significant disability secondary to hypoglycaemia and/or hyperammonaemia at presentation. We report the outcome of two siblings with CACT deficiency. The index patient presented at the age of 2 months during a respiratory illness with hypoglycaemia, hyperammonaemia and cardiorespiratory collapse. Acylcarnitine profiles showed decreased free carnitine but striking elevations of long-chain acylcarnitines. Urine organic acids showed dicarboxylic aciduria. Fatty acid oxidation studies showed reduced oleate and myristate oxidation. His acylcarnitine profile normalized after he was started on a medium-chain triglyceride (MCT) low-fat diet and carnitine supplementation. Low CACT activity on enzyme assay confirmed the diagnosis. He has resulting profound developmental delay and epilepsy. The sibling was prospectively treated with a low-fat MCT diet and carnitine supplementation. Acylcarnitine profile at birth also showed elevated long-chain acylcarnitines. Fatty acid oxidation studies confirmed the diagnosis. To date he has normal development and has not had any significant periods of hypoglycaemia or hyperammonaemia.

Enhancing immunity to nematode parasites in single-bearing Merino ewes through nutrition and genetic selection.

The effectiveness of protein supplementation and genetic selection to enhance the resistance of periparturient Merino ewes to infection from gastrointestinal parasites was tested in a replicated grazing experiment. One hundred and twenty ewes from lines selected for increased resistance (R) to Haemonchus contortus or at random (C) were subjected to one of the three supplement groups that provided 0 or 250 g per day cottonseed meal for 5 weeks prior to, or for 6 weeks after the start of lambing. Faecal egg counts (FEC) of R ewes were consistently lower than those of C ewes but both groups exhibited a periparturient rise in FEC. Supplementation during the pre-partum period reduced FEC and increased ewe body weight gain. The benefits of pre-partum supplementation in reducing FEC continued to be apparent up to 10 weeks after supplementation ceased. There was a strong suggestion that the benefits to parasite resistance from protein supplementation were greatest in C ewes. Wool growth rates (15%) and birth weights (5%) were greater for C ewes but differences between the lines for lamb body weight had disappeared by day 97. The greatest benefit to resistance from protein supplementation was observed when ewes were experiencing a loss of maternal body weight. Conversely, no benefits to resistance were observed when ewes had moderate (78-107 g per day) rates of maternal weight gain. These results suggest that increased resistance as a result of protein supplementation is dependent on the prevailing supply and demand for scarce nutrients such as metabolisable protein (MP). Both genetic selection and protein nutrition are effective strategies to enhance host resistance to nematode infection during the periparturient period.

A review of herbal medicines for psychiatric disorders.

OBJECTIVE: This review examines herbs commonly used for psychiatric symptoms-St. John's wort, kava, ginkgo biloba, and valerian. METHODS: MEDLINE was searched for articles related to the use of herbs in psychiatry published after 1990. A secondary search examined sources cited in articles obtained from the MEDLINE search. RESULTS: Of nine controlled and standardized trials of St. John's wort, five showed the herb's superiority to placebo, and four found no differences in effectiveness when compared with antidepressant drugs. The pharmacologically active components are not known. Several double-blind, placebo-controlled trials have demonstrated the anxiolytic efficacy of kava, but these studies had ill-defined patient populations, small sample sizes, and short treatment duration. All but one of 40 controlled trials of ginkgo extracts in the treatment of dementia found clinically significant improvement in memory loss, concentration, fatigue, anxiety, and depressed mood. Most studies of gingko had poorly defined patient populations and small sample sizes and used nonstandard measures. A recent well-designed multicenter study showed significantly less decline in cognitive function among patients with dementia receiving gingko. Valerian has been shown to decrease sleep latency and nocturnal awakenings and improve subjective sleep quality, but placebo effects were marked in some studies, and in some cases the beneficial effects were not seen until two to four weeks of therapy. CONCLUSIONS: Although evidence of the efficacy of herbal preparations in treating psychiatric conditions is growing, translating the results of efficacy studies into effective treatments for patients is hampered by the chemical complexity of the products, the lack of standardization of commonly available preparations, and the paucity of well-controlled studies.

Pharyngeal colonization prevalence rates for Streptococcus pyogenes and Streptococcus pneumoniae in a respiratory chemoprophylaxis intervention study using azithromycin.

OBJECTIVES: A prospective assessment of the pharyngeal colonization prevalence rates for Streptococcus pyogenes and Streptococcus pneumoniae before and after an azithromycin chemoprophylaxis intervention clinical trial in a cohort of US Marine Corps trainees. In addition, the minimum inhibitory concentrations (MICs) for all streptococcal isolates, for azithromycin, penicillin, erythromycin and cefotaxime are reported. METHODS: Between November 1994 and March 1995, 1108 asymptomatic male US Marine Corps trainees, located in Southern California, were randomly assigned to one of three intervention groups: (1) weekly oral azithromycin, 500 mg (n = 362); (2) 1.2 MU benzathine penicillin G, intramuscularly once (n = 374); or (3) no chemoprophylaxis (n = 372). Subjects provided both a pre- and post-training pharyngeal culture and microbial analysis was conducted to determine the colonization status of each study subject. RESULTS: The pretraining colonization prevalence was 1.2% for S. pneumoniae and 2.4% for S. pyogenes. There was no statistical difference in pretraining prevalence between the three treatment groups for either organism. Post-training pharyngeal cultures revealed an overall prevalence of 1.1% with no difference between treatment arms. However, the overall post-training prevalence of S. pyogenes colonization increased to 4.8%, with the azithromycin group having significant evidence of protection (0.7%) in comparison with the no-treatment group (8.2%). The Etest method demonstrated no significant difference in the MIC50, MIC90, and MIC ranges between pre- and post-training isolates for any of the tested drugs. CONCLUSION: The use of azithromycin as a chemoprophylactic agent to reduce the colonization and subsequent infection of streptococcal respiratory disease among healthy adult male military recruits may be beneficial.

Protein supplementation improves the performance of parasitised sheep fed a straw-based diet.

A study was made of the benefits of protein supplementation for parasitised and non-parasitised lambs. Sixty, 5-month-old crossbred wether lambs were placed in individual pens indoors for 9 weeks. Half of the animals were experimentally dosed with 1500 Haemonchus contortus larvae per head per week and were fed ad libitum and the other half were worm-free, pair-fed controls. Diets were formulated to be iso-energetic (9.0 MJ of calculated metabolisable energy per kg dry matter) with five levels of protein (10, 13, 16, 19 and 22% crude protein). These diets were based on oaten chaff, with barley, cotton-seed meal, urea and mineral mix (except for the 22% crude protein diet which did not contain barley). Dietary crude protein content increased live-weight gain, feed intake, rumen fluid ammonia-N, packed cell volume, eosinophil counts and antibody responses to H. contortus L3 antigen and decreased faecal worm egg counts significantly. Infection did not significantly affect packed cell volume of animals on diets with 16, 19 and 22% crude protein content. We conclude that extra dietary protein can prevent the adverse effects of H. contortus infection on animal production.

How Australia came to have a National Women's Health Policy.

A National Women's Health Policy was launched in Australia in 1989, and Australia became the only country to have a comprehensive policy on women's health. The policy is intended to provide a framework for decision-making in both mainstream and separate women's health services. The author examines the forces and factors that led to the formulation and adoption of the policy, then addresses the question of why Australia is alone in choosing a national policy as a focus for women's health action. A number of key influences, either absent or weaker in comparable countries, worked together to facilitate policy development. The activities of women working in a number of arenas coincided with the election of relatively supportive governments, creation of women's policy machinery in bureaucracies, employment of feminists in key positions, and opportunities for policy expansion afforded by federalism. These influences, within the Australian ideological context of strong support for social liberalism, account for the country's distinctive policy position.

Health care in North must acknowledge Inuit values, traditional medicine.

Dr. Gail Gray spent a week on Baffin Island in a retreat devoted to discussions about health care delivery in the North. She says it is obvious that traditional medical practices and Inuit cultural values must be part of any new health care initiatives if the initiatives are to be successful.

A reinvestigation of Maprounea triterpenes.

Anti-HIV activity and the inhibition of phorbol ester receptor binding activity in two species of Maprounea were traced to small amounts of highly potent phorbol esters of the daphnane type. The triterpenes previously isolated from this genus were found to be devoid of biological activity when scrupulously purified. Four new triterpene esters were elucidated; two [3,4] were found in M. africana, while three [4,6,7] were found in M. membranacea. Nmr assignments have also been made for two previously known compounds [2,5] in this group.

Taurine-supplemented total parenteral nutrition and taurine status of malnourished cancer patients.

The status of plasma taurine and whether its concentration can be influenced by total parenteral nutrition (TPN) was determined in 51 malnourished fasting cancer patients after surgery and 7-14 days after starting TPN providing 41 +/- 2 kcal, 0.30 +/- 0.02 g N kg-1.day-1 and 40 mg pyridoxine. Plasma taurine was 50% lower in patients than in control subjects. Plasma taurine was significantly greater than baseline only after 14 days of TPN. We also studied the effects of surgery and taurine supplementation (8.6 mg.kg-1.day-1) on plasma and urine taurine concentrations in 12 malnourished patients. Preoperatively, all patients had normal plasma taurine concentrations; postoperatively, it was in the deficient range in 4 patients. Taurine-supplemented patients initially had higher than baseline concentrations; by day 10, none had subnormal levels. Subnormal taurine concentrations commonly occur in malnourished postoperative cancer patients; surgery further precipitates their fall. Plasma concentrations were maintained only with taurine-supplemented TPN.

Two new cytotoxic chalcones from Calythropsis aurea.

The crude extract of Calythropsis aurea (Myrtaceae) produced a pattern of differential cytotoxicity in the NCI 60 cell line assay which was similar to those of known tubulin-interactive compounds. Cytotoxicity-guided fractionation led to the isolation of two new chalcones, calythropsin [1] and dihydrocalythropsin [2], which were responsible for the activity. Calythropsin was demonstrated to have a weak effect on mitosis, and presumably also on tubulin polymerization.

Nutrition and dementia.

The nutritional consequences of dementia and the role of diet in the etiology, treatment, and prevention of dementia are the subjects of this review. The major cause of dementia is Alzheimer's disease. Although it has been suggested that aluminum intake may cause this disease, the bulk of scientific evidence suggests that this is unlikely. Dietary supplements of choline and lecithin have been used to treat Alzheimer's disease but are ineffective. Alzheimer's disease patients are at risk of developing protein-energy malnutrition because of poor food intake and increased energy requirements. The second most common cause of dementia is multi-infarct dementia, caused by multiple strokes. Diet may play a role in the prevention of this form of dementia through effects on blood pressure and other risk factors. Control of risk factors may also prevent further progression of the dementia. Patients with multi-infarct dementia often have dysphagia. The third most common cause of dementia appears to be excessive alcohol intake, due both to the direct neurotoxic effects of alcohol and to the effects of alcohol on nutritional status. Alcoholic dementia may be at least partially reversible with abstinence and good nutrition. Other causes are vitamin B-12 and folate deficiencies; these are reversible dementias. In all types of dementia, adequate nutrition may improve physical well-being, help maximize the patient's functioning, and improve the quality of life.

Vitamin supplement use in a Southern California retirement community.

Vitamin supplement were taken regularly by 62% of men and 69% of women surveyed in a Southern California retirement community. Supplement use was associated with more frequent use of health screening procedures and with several other health-related habits. A substantial proportion of residents consumed high levels of vitamins C and E, and 3.2% consumed potentially toxic doses of vitamin A.

Vitamin A and cancer incidence in a retirement community.

The use of vitamin A supplements and the risk of cancer was examined in a cohort of 11,888 residents of a retirement community near Los Angeles, California. After 2 1/2 years of follow-up, 445 incident cancers occurred in 435 of the study participants. Overall, the relative risk of cancer for supplement users versus nonusers was 1.0. In a subset of 32 randomly selected individuals, the 14 supplement users had a significantly higher mean serum retinol level (86 micrograms/dl) than did the 18 nonusers (74 micrograms/dl).

Assessment of three brief methods of estimation of vitamin A and C intakes for a prospective study of cancer: comparison with dietary history.

Three methods of estimating vitamin A and C intakes from food frequency data obtained in June 1981 were compared with estimates obtained from dietary histories taken in September 1982, in 50 elderly residents of a Southern California retirement community. The first method of estimating vitamin A and C intakes (Af and Cf) was to add the products of the frequency of use of foods and the vitamin content of an average serving. The second method of estimating the intakes of these vitamins (Ai and Ci) was to develop an index based on the sum of frequencies of consumption of foods rich in these vitamins. This was then converted to absolute amounts using a regression equation. The third method (Ar and Cr) was to use stepwise multiple regression with the estimated intakes from the history (Ah and Ch) as dependent variables and to develop an equation with a small number of foods as the independent variables. When intakes from food alone were examined, the Spearman correlations between Ah and Af, Ai, and Ar, respectively, were 0.03, 0.16, and 0.43; the correlations between Ch and Cf, Ci, and Cr were 0.29, 0.36, and 0.38. When supplemental vitamin intakes were included, the correlations were between 0.35 and 0.44 for vitamin A and between 0.62 and 0.64 for vitamin C. The results demonstrated the importance of including the contribution of supplemental vitamins in estimating total vitamin A and C intake and suggested that the index and regression approaches may be superior to Af and Cf for estimating dietary vitamin intakes from food frequency questionnaires.

Dietary intake and nutrient supplement use in a Southern California retirement community.

Dietary histories and information concerning the use of nutritional supplements were obtained from 51 randomly selected residents of an Orange County, CA, retirement community. The nutrients for which dietary intakes were most apt to fall below 100% of the 1980 Recommended Dietary Allowance were: calcium, in both sexes; energy, in males; and iron, thiamin, riboflavin, and niacin in females. With the exception of calcium, few subjects had intakes below two-thirds of the Recommended Dietary Allowances. These findings are similar to those reported in previous dietary surveys of the elderly. Vitamin and mineral supplements were consumed by 72% of the subjects; such consumption was unrelated to dietary intake. Supplemental vitamin C was consumed by 67% of the subjects in amounts ranging from 30 to 5200 mg daily; supplemental vitamin E was taken by 51%, with amounts ranging from 8 to 1000 IU daily. Supplement use by this population is one of the highest reported among the elderly, an effect that may result from the affluence of the community, its geographic location, and from a high level of nutritional consciousness among its residents.

Location and activity of ulcerative and Crohn's colitis by indium 111 leukocyte scan. A prospective comparison study.

A prospective blinded study comparing the indium 111 leukocyte scan to barium enema, colonoscopy, or surgery or a combination of these, was carried out in 15 patients (10 with active ulcerative colitis and 5 with active Crohn's colitis). Correlation of disease location to colonic regions between indium scan and other diagnostic studies was excellent in 11 instances, good in 2, and poor in 3. In 2 of the 3 studies where major disagreement occurred, the comparative barium enema was performed greater than 2 mo after the indium scan. Disease activity, estimated by the intensity of radionuclide uptake, was compared to clinical disease activity assessed by the Crohn's Disease Activity Index for both forms of colitis. The relative degree of inflammation estimated by the indium scan correlated well with the independent clinical assessment (correlation coefficient = 0.81). The indium 111 leukocyte scan appears to be an accurate, noninvasive method for assessing the extent and the severity of the inflammation in patients with acute ulcerative or Crohn's colitis.

Long-term antimicrobial prophylaxis for recurrent urinary tract infection in women.

Thirteen women and two preadolescent girls who suffered recurrences after six months of prophylaxis with trimethoprim (TMP; 40 mg) and sulfamethoxazole (SMZ; 200 mg) taken thrice weekly at bedtime were enrolled in a 24-month study of prophylaxis with the same region. During 29.1 cumulative patient-years of prophylaxis, two infections due to Escherichia coli and one each due to Staphylococcus epidermidis and Streptococcus faecalis occurred (0.14 infection/patient-year). MICs for these isolates were less than or equal to 2 micrograms of TMP/ml and greater than 512 micrograms of SMZ/ml. During prophylaxis, 106 of 116 cultures from the periurethral area and 66 of 97 cultures from the anal and canal yielded no aerobic gram-negative bacilli. In three patients, the periurethral area was colonized with aerobic gram-negative bacilli with MICs of greater than or equal to 2 micrograms of TMP/ml. Thirteen patients were followed after the discontinuation of prophylaxis. Eight suffered recurrences, seven with organisms susceptible to TMP. After one year the remaining five had experienced no recurrences. It is concluded that long-term prophylaxis with 40 mg of TMP and 200 mg of SMZ thrice weekly is an effective, well-tolerated regimen that can maintain an infection-free state in women with histories of frequent urinary reinfections.

The possible use of Trypanosoma musculi infection in mice as a screening test for potential Trypanosoma cruzi-active drugs.

The ability of a range of trypanocidal drugs, including a number known to be active in Trypanosoma cruzi infections were tested against Trypanosoma musculi infections in the mouse. The ability of these drugs, particularly in their ability to eliminate the "cryptic phase" of T. musculi infections remaining in the kidneys, was investigated and their activity against this phase of T. musculi largely paralleled their known activity against T. cruzi infections. It is suggested that this could be used as a preliminary screening test for potential T. cruzi-active drugs.