Treatment outcomes of pre- and extensively drug-resistant tuberculosis in Johannesburg, South Africa.

BACKGROUND: Extensively drug-resistant tuberculosis (XDR-TB) has a poor treatment success rate and high mortality. Multidrug-resistant TB (MDR-TB) has worse outcomes when there is added resistance to second-line injectable drugs (pre-XDR-TBSLID) or fluoroquinolones (pre-XDR-TBFQ). OBJECTIVES: Treatment outcomes in patients with pre-XDR-TB and XDR-TB in a high HIV prevalence area were compared. METHODS: A retrospective medical record review was conducted of patients with pulmonary pre-XDR-TB and XDR-TB managed from 2008 to 2010 at Sizwe Tropical Disease Hospital, Johannesburg, South Africa. Standardised MDR-TB treatment was instituted and was subsequently individualised when further second-line susceptibility results became available. RESULTS: Of 86 patients studied, 95% were sputum smear-positive at baseline, 73% had sputum culture conversion, and 65% were human immunodeficiency virus (HIV) infected, with a median CD4 count of 201 cells/mm³. Of 53 patients with XDR-TB, 26 with pre-XDR-TBFQ and 7 with pre-XDR-TBSLID, respectively 13%, 12% and 29% were cured, 21%, 23% and 57% had a favourable outcome, and 26%, 23% and 14% died. Clofazimine (P < 0.001) and linezolid (P = 0.044) impacted on favourable outcomes. CONCLUSION: Patients with pre-XDR-TBFQ did not have better outcomes than those with XDR-TB. In countries with standardised regimens for resistant TB, patients with pre-XDR-TBFQ may need to receive XDR-TB treatment.

8-Oxo-7,8-dihydro-2'-deoxyguanosine, reactive oxygen species and ambulatory blood pressure in African and Caucasian men: the SABPA study.

Various studies indicate a relationship between increased oxidative stress and hypertension, resulting in increased DNA damage and consequent excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). The aim of this study was to compare urinary 8-oxodG levels in African and Caucasian men and to investigate the association between ambulatory blood pressure (BP) and pulse pressure (PP) with 8-oxodG in these groups. We included 98 African and 92 Caucasian men in the study and determined their ambulatory BP and PP. Biochemical analyses included, urinary 8-oxodG, reactive oxygen species (ROS) (measured as serum peroxides), ferric reducing antioxidant power (FRAP), total glutathione (GSH), glutathione peroxidase (GPx) and glutathione reductase (GR) activity. The African men had significantly higher systolic (SBP) and diastolic blood pressure (DBP) (both p < 0.001). Assessment of the oxidative stress markers indicated significantly lower 8-oxodG levels (p < 0.001) in the African group. The African men also had significantly higher ROS (p = 0.002) with concomitant lower FRAP (p < 0.001), while their GSH levels (p = 0.013) and GR activity (p < 0.001) were significantly higher. Single and partial regression analyses indicated a negative association between urinary 8-oxodG levels with SBP, DBP and PP only in African men. These associations were confirmed in multiple regression analyses (SBP: R(2) = 0.41; ß = -0.25; p = 0.002, DBP: R(2) = 0.30; ß = -0.21; p = 0.022, PP: R(2) = 0.30; ß = -0.19; p = 0.03). Our results revealed significantly lower urinary 8-oxodG in African men, accompanied by a negative association with BP and PP. We propose that this may indicate a dose-response relationship in which increased oxidative stress may play a central role in the up-regulation of antioxidant defence and DNA repair mechanisms.

Potency of progestogens used in hormonal therapy: toward understanding differential actions.

Progestogens are widely used in contraception and in hormone therapy. Biochemical and molecular biological evidence suggests that progestogens differ widely in their affinities and transcriptional effects via different steroid receptors, and hence cannot be considered as a single class of compounds. Consistent with these observations, recent clinical evidence suggests that, despite their similar progestogenic actions, these differences underlie different side-effect profiles for cardiovascular disease and susceptibility to infectious diseases. However, choice of progestogen for maximal benefit and minimal side-effects is hampered by insufficient comparative clinical and molecular studies to understand their relative mechanisms of action, as well as their relative potencies for different assays and clinical effects. This review evaluates the usage, meaning and significance of the terms affinity, potency and efficacy in different models systems, with a view to improved understanding of their physiological and pharmacological significance. This article is part of a Special Issue entitled 'Menopause'.

Prevalence and incidence of symmetrical symptomatic peripheral neuropathy in patients with multidrug-resistant TB.

BACKGROUND: Symptomatic symmetrical peripheral neuropathy (SSPN) is common in patients with HIV infection. It is also a common adverse event associated with both tuberculosis (TB) treatment and antiretroviral therapy (ART), particularly stavudine. While tenofovir is the one of recommended first-line nucleotide reverse transcriptase inhibitors (NRTIs), there is a risk of nephrotoxicity when using tenofovir together with the aminoglycosides needed to treat multidrug-resistant (MDR) TB. Thus, stavudine is often chosen as a treatment option for the HIV-infected MDR TB patient. OBJECTIVE: To assess whether use of stavudine both before and during treatment for MDR TB increased the prevalence and incidence of SSPN. METHOD: MDR TB patients at Sizwe Tropical Disease Hospital were examined for signs of prevalent SSPN. Age, gender, HIV status, alcohol use, TB and HIV treatment regimens both prior to admission and current, and concomitant medications were recorded. RESULTS: In this cohort of 246 patients, we found that 24.4% of patients with MDR TB had SSPN at time of admission for treatment of MDR TB. They were more likely to be HIV-infected (odds ratio (OR) 3.21; 95% CI 1.25 - 8.21) and tended to have longer (>7 months) exposure to stavudine (OR 1.81; 95% CI 0.90 - 3.63). Incident SSPN occurred in 17% of patients and was associated with older age (hazard ratio (HR) 3.00; 95% CI 1.30 - 6.89) and exposure to terizidone (HR 2.98; 95% CI 0.94 to 4.61) or, to a lesser extent, with stavudine (crude HR 1.62; 95% CI 0.65 - 4.01) in the first 6 months of MDR TB treatment. This common adverse event emphasises the need for the development of less toxic drugs for the treatment of MDR TB.

Associations between reactive oxygen species, blood pressure and arterial stiffness in black South Africans: the SABPA study.

Many mechanisms, including oxidative stress, contribute to hypertension. This study investigated the possible associations between oxidative stress, blood pressure and arterial stiffness in black South Africans. Ambulatory blood pressure measurements were taken for 101 black South African men and 99 women. The stiffness indices included ambulatory arterial stiffness index (AASI) and pulse pressure (PP). Reactive oxygen species (ROS) levels (P<0.0001) were higher in the African women compared with men. ROS levels were also higher in hypertensive compared with normotensive men. The 24 h systolic blood pressure (SBP; P<0.01), 24 h diastolic blood pressure (DBP; P<0.0001) and pulse wave velocity (PWV; P<0.01) were significantly higher in African men compared with women. There were unadjusted positive associations of 24 h SBP (r=0.33; P=0.001), 24 h DBP (r=0.26; P=0.008) and 24 h PP (r=0.29; P=0.003) with ROS in African men only. A positive association between AASI and ROS existed only in hypertensive men (r=0.27; P=0.035), but became nonsignificant (B=0.0014; P=0.14) after adjustments. Adjusted, positive associations of 24 h SBP (B=0.181; P=0.018) and 24 h PP (B=0.086; P=0.050) with ROS were again only evident in African men. ROS is positively associated with SBP and PP in African men, suggesting that increased ROS levels may contribute to hypertension in this population group.

The involvement of metallothioneins in mitochondrial function and disease.

Mitochondrial oxidative phosphorylation deficiency is accompanied by various down-stream, adaptive responses which play a key role in the varied phenotypes observed when mitochondrial dysfunction occurs. These responses are often accompanied by the induction of genes involved in defense mechanisms against oxidative stress. Among these responses, metallothioneins (MTs) has been identified to be responsive to mitochondrial dysfunction. MTs, which are expressed in four different isoforms, are small, cysteine rich, metal binding proteins that have been associated with a protective effect in cells under numerous diseased and stressed states. Their diverse functionality and protective roles can be ascribed to their three basic abilities or primary functions which are metal homeostasis, heavy metal detoxification and free radical scavenging. The involvement of MTs with numerous cellular processes, organelles and cells has received much attention while notice of their involvement with the function of mitochondria has been lacking. It is believed that MTs promote the survival of mitochondrial dysfunctional cells by acting as highly efficient reducing elements against the damaging properties of reactive oxygen species (ROS) and by limiting apoptosis. In addition to their role in mitochondrial disease, convincing evidence exist, albeit with conflicting results, of its involvement in some key functions of the mitochondrion, including redox modulation, metal homeostasis and enzyme and transcription factor regulation.

Teratogenicity of 3-hydroxynorvaline in chicken and mouse embryos.

3-Hydroxynorvaline (HNV; 2-amino-3-hydroxypentanoic acid), a microbial L-threonine analogue, is toxic to mammalian cells and displays antiviral properties. In view of this, we investigated the toxicity and/or potential teratogenicity of HNV in developing chicken and mouse embryos. HNV was administered to chicken embryos (in ovo; dose 75-300 mumole/egg; 48 h post-incubation) and pregnant Hanover NMRI mice (per os; total dose 900-1800 mg/kg body mass; gestation days 7-9). Control animals received sterile saline solutions. Harvested embryos (chicken embryos, 10 days post-incubation; mouse embryos; gestation day 18) were fixed in glutaraldehyde and stereomicroscopically inspected for signs of dysmorphogenesis. Body mass, body and toe length and mortality of chicken embryos, and the body mass and mortality of mouse embryos were recorded. HNV exposure significantly increased the incidence of embryotoxic (growth retardation, toxic mortality) and congenital defects in both chicken and mouse embryos. All the observed effects were dose-dependent. In conclusion, HNV is an embryotoxic and teratogenic compound, which caused significant developmental delay and congenital defects in developing chicken and mouse embryos.

The Effect of Formal Exposure to Developmental Care Principles on the Implementation developmental Care Positioning and Handling of Preterm Infants by Neonatal Nurses

The preterm infant requires developmental care that is designed to minimise the stress that the infant experiences within the neonatal intensive care unit (NICU). The aim of the study was to determine the effect of formal exposureto developmental care principles on the implementation of developmental care positioning and handling of the preterm infant by neonatal nurses. The first objective of the study was to compile an accurate scale for measuring the implementation of these principles with respect to the handling and positioning of the infant. Secondly; the study aimed at determining changes in the implementation of developmental care principles within a selected NICU after neonatal nurses were formally exposed to developmental care training. A quasi-experimental research design and a one-group pre-test-post-test approach were followed; and the Wilcoxon matched-pair signed-rank tests were used toexamine the changes. Results were statistically significant and indicated improvement with respect to the developmental care components that were measured. The recommendation was that developmental care principles be integrated into formal neonatal courses. Follow-up studies should be conducted to determine the reliability of the instrument for possible inclusion in routine assessment of the quality of the implementation of developmental care in the NICU

On the possible role of acetylene in gas-phase dioxin formation.

The slow combustion of benzene/phenol gives rise to dibenzofuran (DBF) as major product of incomplete combustion, with negligible proportions of dibenzo-p-dioxin (DBD), or benzofuran (BF). Contrary to a recent proposal that acetylene growth reactions, e.g. BF-->DBF, are important in dioxin formation, co-combustion of benzene/phenol with acetylene--around 550 degrees C--did not alter this product pattern. Also, BF was identified as a product from degradation of DBF.

Determinants of polychlorinated biphenyls (PCBs) in human milk.

In a longitudinal pilot study on the course of the PCB concentration in human milk during six months of lactation, some important PCB determinants could be studied in 23 women and their infants. PCB values were within the range of those found in the literature. Pearson correlation coefficients were calculated to investigate the association of the mean PCB concentration over the first half year of lactation with maternal parameters, such as age, height, weight, previous lactation period, education, occupation, residence, smoking, drinking and dietary habits as well as the infant parameters gestational age, birthweight and weight gain in the first six months of life. Since the PCB concentration on fat basis and the fat content of the milk were strongly inversely related, statistical analyses were carried out both on fat and on milk basis. In univariate analyses the PCB concentration on fat basis was most strongly associated with pre- versus post-pregnancy weight gain, age and occupation. After multiple regression analysis PCB concentration on fat basis remained significantly associated with weight gain changes and remained borderline (p less than 0.10) significantly related with occupation. The pre-pregnancy Quetelet Index of the mother (height/weight) and the estimated PCB content of the diet (primarily fish) were strongly correlated with the PCB concentration on milk basis. Only the Quetelet Index remained significantly related after multiple regression analysis.