Influence of intragenic CCL3 haplotypes and CCL3L copy number in HIV-1 infection in a sub-Saharan African population.

Two CCL3 haplotypes (HapA1 and Hap-A3) and two polymorphic positions shared by the haplotypes (Hap-2SNP (single nucleotide polymorphism)) were investigated together with CCL3L copy number (CN), for their role in HIV-1 disease. Hap-A1 was associated with protection from in utero HIV-1 infection: exposed uninfected (EU) infants had higher representation of wild type (WT)/Hap-A1 than infected infants (excluding intrapartum (IP)-infected infants), which maintained significance post maternal Nevirapine (mNVP) and viral load (MVL) correction (P=0.04; odds ratio (OR)=0.33). Mother-infant pair analyses showed the protective effect of Hap-A1 is dependent on its presence in the infant. Hap-A3 was associated with increased IP transmission: WT/Hap-A3 was increased in IP-transmitting vs non-transmitting (NT) mothers, and remained significant post mNVP and MVL correction (P=0.02; OR=3.50). This deleterious effect of Hap-A3 seemed dependent on its presence in the mother. Hap-2SNP was associated with lower CD4 count in the NT mothers (P=0.03). CCL3 Hap-A1 was associated with high CCL3L CN in total (P=0.001) and EU infants (P=0.006); the effect was not additive, however, having either Hap-A1 or high CCL3L CN was more significantly (P=0.0008) associated with protection from in utero infection than Hap-A1 (P=0.028) or high CCL3L CN (P=0.002) alone. Linkage disequilibrium between Hap-A1 and high CCL3L CN appears unlikely given that a Nigerian population showed an opposite relationship.

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

BACKGROUND: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. METHODS: We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. RESULTS: A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. CONCLUSIONS: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)

HAART and risk of tuberculosis in HIV-infected South African children: a multi-site retrospective cohort.

SETTING: Four human immunodeficiency virus (HIV) clinics located at South African tertiary hospitals. OBJECTIVE: To assess the effectiveness of highly active antiretroviral therapy (HAART) in reducing incident tuberculosis (TB) in HIV-infected children. DESIGN: Retrospective cohort. RESULTS: A total of 1132 children's records were included in the study. At entry to the cohort, the median (interquartile range [IQR]) age, CD4%, CD4 count and viral load of all children was respectively 6.3 years (4.1-8.8), 15% (9.0-22.2), 576 cells/mm(3) (287-960) and 160 000 copies/ml (54 941.5-449 683); 75.9% were started on HAART. The male:female ratio was 1:1, and median follow-up time was 1.7 years. In children whose follow-up included both pre-HAART and on-HAART periods, the incidence of clinically diagnosed TB was respectively 21.1 per 100 person-years (py; 95%CI 18.2-24.4) and 6.4/100 py (95%CI 4.8-8.1), and when restricted to confirmed cases, respectively 3.1/100 py (95%CI 2.2-4.2) and 0.8/100 py (95%CI 0.5-1.4). Only 23% of all cases of TB were microbiologically confirmed. Multivariate analyses showed that HAART reduced incident TB by approximately 70%, both for confirmed and all TB cases. CONCLUSIONS: In this high TB burden country, the incidence of diagnosis of TB in HIV-infected children is at least as high as that of adults. HAART reduces incident TB, but further prospective TB preventive and diagnostic studies are urgently needed in children.

Sexual risk behaviour of the first cohort undergoing screening for enrollment into Phase I/II HIV vaccine trials in South Africa.

We assessed risk behaviour in a heterosexual cohort undergoing prescreening for the first Phase I/II HIV vaccine trials in Soweto. We developed a survey and collected self-reported data from HIV-negative potential volunteers. Of 488 participants, most were single and approximately half were from households with incomes below the poverty level. Males reported higher rates of heavy alcohol use (P < 0.001), marijuana use (P < 0.001) and other recreational drug use (P < 0.01). Males reported more sex partners than females in the previous six months (P < 0.001), as well as more casual/anonymous partners (P < 0.001) and one-night stands (P < 0.001). Multivariate analyses revealed substance use and male gender predicted higher risk behaviours, including <100% condom use with known/suspected HIV-positive partners, having casual/anonymous partners and having more than two partners. For this population, male volunteers may need increased risk-reduction counselling during Phase I/II trials and additional recruitment methods may be necessary to identify high-risk female volunteers for Phase III efficacy trials.

Identification of new variants within the two functional genes CCL3 and CCL3L encoding the CCL3 (MIP-1alpha) chemokine: implications for HIV-1 infection.

The CC chemokine CCL3 is encoded by two functional genes, namely CCL3 and CCL3L, and has been identified as a key chemokine in HIV-1 susceptibility and disease progression. The complete CCL3 and CCL3L genes and core promoters of 43 African mother-infant pairs (86 samples) and 28 Caucasian adults in South Africa were sequenced and extensively analysed for genetic variations. Africans were found to be more polymorphic in both genes with 25 single nucleotide polymorphisms (SNPs) in the CCL3 gene and 14 gene copy number single nucleotide polymorphisms (gcnSNPs) in the CCL3L gene, compared to nine CCL3 SNPs and eight CCL3L gcnSNPs in Caucasians. A total of 14 polymorphisms across the two genes were newly identified in this study, most (12/14) of which were exclusive to the African population. In addition, two indels were identified and characterized in the CCL3 and CCL3L genes of a small number of individuals. Of the numerous unique intragenic haplotypes found in the two genes, none were shared by the two population groups. A newly identified five-SNP CCL3 haplotype (Hap-C1) found in a high frequency in Caucasians, however, seems to be evolutionarily related to the most prevalent newly identified African seven-SNP CCL3 haplotype (Hap-A1). Hap-A1 also includes an SNP in the core promoter region and previous CCL3 haplotypes that have been reported to be associated with HIV-1 infection appear to be smaller haplotypes within Hap-A1. We thus propose Hap-A1 as a likely candidate for influencing levels of CCL3 production and in turn outcomes of HIV-1 infection.

Migratory paths and phenotypic choices of clonally related cells in the avian optic tectum.

We used retrovirus-mediated gene transfer to study the migration of clonally related cells in the developing chicken optic tectum. Clonal cohorts initially form radial arrays in the ventricular zone (approximately E5), but eventually divide into three separate migratory streams. In the first migration, a minor population of cells migrates tangentially along axon fascicles in medio-laterally directed files (approximately E6-E7); these eventually differentiate into multipolar efferent cells. After E7, the majority of cells in each clone migrate radially along fascicles of radial glia to form the tectal plate, wherein they differentiate into neurons and astrocytes. Around E9, a set of small cells leaves the radial arrays in superficial layers to form a second tangential migration; at least some of these differentiate into astrocytes. Thus, as the tectum develops, cells derived from a single multipotential precursor migrate along three separate pathways, follow separate guidance cues, and adopt distinct phenotypes.

Prevalence and patterns of victimization and polyvictimization among female sex workers in Soweto, a South African township: a cross-sectional, respondent-driven sampling study.

BACKGROUND: Female sex workers (FSWs) are disproportionately affected by violence from multiple partner categories. This increases their vulnerability to HIV. OBJECTIVES: To describe patterns of violence and polyvictimization among female SWs in Soweto. METHODS: A respondent-driven sampling (RDS) recruitment methodology was used to enrol 508 Soweto-based FSWs using a survey instrument. Raw and RDS adjusted data were descriptively analysed, Spearman's correlation and chi2 test of association were used to show associations. Polyvictimization patterns are shown within a modified Venn diagram. RESULTS: The median age of FSWs in Soweto was 31 years, and most had an incomplete education (74.2%). The prevalence of exposure to physical/sexual intimate partner violence (IPV) in the past year was 53.8%, 46.8% by clients, and 18.5% by police. Past year prevalence of sexual/physical violence by any perpetrator category was 70.8% and lifetime exposure was 76.0%. Childhood sexual violence was reported by 44.3%. Lifetime non-partner rape was 55.5% and all rape exposure was 62.4%. As a result of engaging in sex work in the past year, 65.2% women had been discriminated against. Client, police, IPV, and childhood trauma were all significantly associated with one another, with IPV being the most common co-occurrence. Polyvictimization was seen in almost two-thirds of FSWs, and increased with exposure to discrimination. CONCLUSION: In Soweto, FSWs are exposed to high rates of violence in multiple forms across their lifetime. Our findings show that violence continues unabated into adulthood at levels far higher than in the general population and overall at higher levels than previously recorded among SWs in South Africa. We argue that violence against FSWs is rooted in discrimination. The disparate burden of violence on FSWs requires urgent interventions to proactively address and reframe the normalisation of violence against all women.

Changing ratio of breast cancer incidence rates with age of black females compared with white females in the United States.

Age-standardized breast cancer rates were approximately 30% lower in U.S. black women compared to white women. This observation concealed the fact that black women under age 40 years had a higher incidence of breast cancer than did white women, whereas white women over 40 years had a higher incidence. The known risk factors for breast cancer development (early age at menarche, late age at first full-term delivery, and a late age of menopause) differed in black and white populations, which might explain this difference in breast cancer incidence between blacks and whites at different ages.

A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.

BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.

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.

Correlation between CD4+ lymphocyte counts, concurrent antigen skin test and tuberculin skin test reactivity in human immunodeficiency virus type 1-infected and -uninfected children with tuberculosis.

BACKGROUND: HIV-infected children are at high risk of developing tuberculosis after infection by Mycobacterium tuberculosis. Emphasis is placed on tuberculin skin testing (TST) for diagnosing tuberculosis in children; however, its value in HIV-infected children is controversial. OBJECTIVES: To determine whether concurrent antigen testing and/or CD4+ lymphocyte counts help in the interpretation of the TST in children with tuberculosis. METHODS: Children eligible for the study were diagnosed as having tuberculosis on clinical criteria. CD4+ lymphocyte counts and delayed-type hypersensitivity (DTH) test, using the CMI Multitest were performed when tuberculosis was diagnosed. RESULTS: One hundred thirty children were enrolled. Tuberculin reactivity was lower in HIV-infected children at all cutoff levels than in HIV-uninfected children (P < 0.0001). The positive predictive value of normal CD4+ lymphocyte counts in predicting tuberculin reactions of > or =5 mm (in HIV-1-infected) and > or =10 mm (in HIV-uninfected patients) were 50 and 80.3%, respectively (P < 0.0001). An intact DTH reaction to the CMI Multitest in predicting reactions of > or =5 mm and > or =10 mm to tuberculin in HIV-infected and -uninfected children were 55 and 76%, respectively (P < 0.001). Kwashiorkor was responsible for 53.3% of false-negative TST in HIV-uninfected children with normal CD4+ lymphocyte counts. CONCLUSION: TST is of limited value as an adjunct in diagnosing tuberculosis in HIV-infected children. CD4+ lymphocyte counts and concurrent DTH testing are not useful for predicting tuberculin reactivity in HIV-infected patients with tuberculosis.

Asian/non-Asian transcultural tricyclic antidepressant psychopharmacology: a review.

1. Transcultural psychopharmacology is a discipline that seeks to determine the relative importance of society, culture, environment, genetics, and biophysiology on the prescribing and metabolism of, and response to psychotherapeutic medications. 2. Studies and surveys comparing psychotropic medication use in Asian and non-Asian populations suggest that differences may exist in drug dosage requirements, plasma drug concentrations corresponding to therapeutic and toxic effects, and the incidence and severity of adverse drug reactions. 3. This paper reviews and critiques the published controlled studies on Asian/non-Asian transcultural tricyclic antidepressant psychopharmacology, provides guidelines for the use of psychotropic medications in Asian populations, and offers suggestions for future transcultural studies. 4. Anecdotal reports suggest that differences exist between Asian and non-Asian populations in the pharmacokinetics of tricyclic antidepressants. Controlled studies have not consistently supported this view. 5. Studies with larger sample sizes and more rigorous controls are needed to determine if such differences do, in fact, exist.

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.

Anthropometric measurements and their interpretation: principles, practices, and problems.

As many as 50 per cent of hospitalized patients are estimated, in some surveys, to suffer from protein-calorie malnutrition. Anthropometry provides at least one quick and easy way to assess a patient's protein and calorie reserves. The measurements most commonly obtained are height, weight, triceps skinfold thickness, and upper arm circumference. An alternate method is suggested that compares these measurements with percentiles rather than, as in the current method, with percentages of the standard.

Nutritional aspects of psychiatric disorders.

As most diet therapy texts provide little information about psychiatric illnesses and their treatment, this article is intended as a brief introduction for dietitians. Several psychiatric illnesses, including schizophrenia, mood disorders, eating disorders, and substance abuse, may adversely affect food intake and nutritional status. The drugs used to treat those disorders similarly have effects on appetite and gastrointestinal function and interact with food and nutrients. Antipsychotics, antidepressants, and monoamine oxidase inhibitors (MAOIs) cause dry mouth, constipation, and weight gain. Lithium may cause nausea, vomiting, diarrhea, polydipsia, and weight gain. MAOIs have well-known interactions with foods containing tyramine. Lithium interacts with dietary sodium and caffeine; decreasing dietary intakes of those substances may produce lithium toxicity. Despite claims to the contrary, major psychiatric illnesses cannot be cured by nutritional therapies alone. Dietitians can, however, play an important role as part of a multidisciplinary team in the treatment of patients with psychiatric illness. Such a role includes nutrition assessment and monitoring, nutrition interventions, patient and staff education, and some forms of psychotherapy, including supportive and behavioral therapies for patients with eating disorders.

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.

Can total parenteral nutrition reverse hypoalbuminemia in oncology patients?

To determine if hypoalbuminemia is a consequence of protein-energy malnutrition rather than an associated feature of cancer, we reviewed results when vigorous nutritional support was given to 13 men and 9 women who had solid tumors (head and neck [10], gastrointestinal [8], other [4]) and an initial serum albumin less than 3.5 g/dl. Patients had received a minimum of 21 days of nutritional support with total parenteral nutrition (TPN) supplying an average daily energy intake of at least 1.5 x basal energy expenditure (BEE). The TPN was started at a dosage commensurate with the patient's estimated postoperative caloric requirements, and patients had received an average of 2358 kcal/day (1.97 x BEE) and 1.54 g of protein/kg of body weight. Patient body weights increased by an average of 2.75 kg during the 21 days of TPN, but there was no statistically significant change in serum albumin, suggesting that factors other than malnutrition were primarily responsible for the hypoalbuminemia. Although TPN is useful as an adjunct in patients with cancer, it may not reverse the hypoalbuminemia commonly seen in this population.

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.