Development of predictive equations for total body water using the deuterium-dilution method as the gold standard in a population of asymptomatic HIV-positive Zulu women in South Africa

Objectives: The study aimed to derive predictive equations for total body water determinations with bioelectrical impedance and anthropometricmeasurements in a population of asymptomatic human immunodeficiency virus (HIV) -positive Zulu women.Design: Cross-sectional data from within an ongoing prospective study that observed the effect of infant feeding mode on maternal and childhealth in a cohort of asymptomatic HIV-positive women were used for this objective.Setting: A community health centre in Durban.Subjects: Asymptomatic HIV-infected women who were not eligible for antiretroviral therapy. They were resident in the area and were of Zuluethnicity.Outcome measures: Development of predictive equations for total body water.Results: Success was achieved in developing predictive equations for total body water using bioelectrical impedance analysis andanthropometric measurements that were specific to the HIV-positive female Zulu population. These equations were developed using the totalbody water that was obtained from deuterium-dilution method as a gold standard.Conclusion: These predictive equations are likely to be more valid for the HIV-positive female African populations of similar build than thecurrent predictive equations that derive from the Western population

Changes in body composition and other anthropometric measures of female subjects on highly active antiretroviral therapy (HAART): A pilot study in KwaZulu-Natal, South Africa

Background and objectives. An understanding of the effect of highly active antiretroviral therapy (HAART) on various aspects of health, including nutritional status, is needed to ensure that population-specific guidelines can be developed for South Africa. This study aimed to investigate the changes in body composition and other anthropometric measures that occur in HIV-infected women after the initiation of HAART and to explore the relationship between these measures and CD4 lymphocyte count. Design and setting. A longitudinal study was carried out at the Umkhumbane Community Health Centre, KwaZulu-Natal. Subjects. 30 HIV-infected adult women who started HAART between March 2007 and October 2007. Methods. Anthropometric measurements and bioelectrical impedance analysis were performed at baseline and 24 weeks after commencing HAART. CD4 lymphocyte counts were done at baseline and at the 24-week visit. Results. There was a statistically significant increase in all anthropometric measures except waist-hip ratio and lean body mass. The mean weight change (± standard deviation) was 3.4±5.8 kg (p=0.006). Mean body mass index (BMI) (kg/m2) increased from 25.6±5.7 to 27.3±5.6 (p=0.007). Seventy per cent of subjects gained weight, 18.5% had a stable weight and 11.1% lost weight. Subjects with lower CD4 lymphocyte counts experienced greater increases in weight, BMI, fat mass and body fat percentage. No significant association was found between anthropometric changes and change in CD4 count between baseline and the 24-week visit. Conclusions. The findings demonstrate the value of including circumference measurements and body composition techniques as part of nutritional status assessment. Research is needed to determine the best methods of bringing about favourable anthropometric changes to enhance the health of patients on HAART. Southern African Journal of HIV Medicine Vol. 9 (4) 2008: pp. 36-4

Prevention is better than cure – the art of avoiding non-adherence to antiretroviral treatment

The much-used phrase ‘prevention is better than cure’ is applicable to many circumstances, including human mmunodeficiency virus (HIV) infection. In recent years suggestions have been made for a move towards treatment strategies that emphasise prevention of foreseeable adherence problems on a patient-by-patient basis, through focused patient preparation before commencing antiretroviral therapy (ART). This is well elucidated in a statement made in 2004 by Coetzee et al.:1 ‘As it is difficult to ascertain robust predictors of adherence, there has been a move to concentrate on patient preparation before the initiation of ART rather than the use of nonclinical predictors of adherence or selection criteria. A paradigm focused on preparation rather than selection is better suited to the aggressive targets for the scaling up of ART in countries with large epidemics (such as in South Africa), where the view of ART as a very expensive rationed intervention is rapidly changing.&rsquo

Pharmacokinetics and safety of rifabutin in young HIV-infected children receiving rifabutin and lopinavir/ritonavir

ObjectivesCo-treatment of HIV and TB in young children is complicated by limited treatment options and complex drug–drug interactions. Rifabutin is an alternative to rifampicin for adults receiving a ritonavir-boosted PI. We aimed to evaluate the short-term safety and pharmacokinetics of rifabutin when given with lopinavir/ritonavir in children.Patients and methodsWe conducted an open-label study of rifabutin dosed at 5 mg/kg three times a week in HIV-infected children ≤5 years of age receiving lopinavir/ritonavir. Intensive steady-state pharmacokinetic sampling was conducted after six doses. The Division of AIDS 2004, clarification 2009, table for grading severity of adverse events was used to classify drug toxicities. The study was registered with ClinicalTrials.gov, number NCT01259219.ResultsSix children completed the study prior to closure by institutional review boards. The median (range) AUC0–48 of rifabutin was 6.91 (3.52–8.67) μg · h/mL, the median (range) Cmax of rifabutin was 0.39 (0.19–0.46) μg/mL, the median (range) AUC0–48 of 25-O-desacetyl rifabutin was 5.73 (2.85–9.13) μg · h/mL and the median (range) Cmax of 25-O-desacetyl rifabutin was 0.17 (0.08–0.32) μg/mL. The neutrophil count declined in all children; two children experienced grade 4 neutropenia, which resolved rapidly without complications. There was strong correlation between AUC0–48 measures and neutrophil counts.ConclusionsRifabutin dosed at 5 mg/kg three times per week resulted in lower AUC0–48, AUC0–24 and Cmax values for rifabutin and 25-O-desacetyl rifabutin compared with adults receiving 150 mg of rifabutin daily, the current recommended dose. We observed high rates of severe transient neutropenia, possibly due to immaturity of CYP3A4 in young children. It remains unclear whether a safe and effective rifabutin dose exists for treatment of TB in children receiving lopinavir/ritonavir

Human Cardiac-Specific cDNA Array for Idiopathic Dilated Cardiomyopathy: Sex-Related Differences

Idiopathic dilated cardiomyopathy (IDCM) constitutes a large portion of patients with heart failure of unknown etiology. Up to 50% of all transplant recipients carry this clinical diagnosis. Female-specific gene expression in IDCM has not been explored. We report sex-related differences in the gene expression profile of ventricular myocardium from patients undergoing cardiac transplantation. We produced and sequenced subtractive cDNA libraries, using human left ventricular myocardium obtained from male transplant recipients with IDCM and nonfailing human heart donors. With the resulting sequence data, we generated a custom human heart failure microarray for IDCM containing 1,145 cardiac-specific oligonucleotide probes. This array was used to characterize RNA samples from female IDCM transplant recipients. We identified a female gene expression pattern that consists of 37 upregulated genes and 18 downregulated genes associated with IDCM. Upon functional analysis of the gene expression pattern, deregulated genes unique to female IDCM were those that are involved in energy metabolism and regulation of transcription and translation. For male patients we found deregulation of genes related to muscular contraction. These data suggest that 1) the gene expression pattern we have detected for IDCM may be specific for this disease and 2) there is a sex-specific profile to IDCM. Our observations further suggest for the first time ever novel targets for treatment of IDCM in women and men

B cells enhance early innate immune responses during bacterial sepsis

Type I interferon–responsive B cells provide early protection against bacterial sepsis

Type I interferon signaling in hematopoietic cells is required for survival in mouse polymicrobial sepsis by regulating CXCL10

Type I interferon (IFN) α/β is critical for host defense. During endotoxicosis or highly lethal bacterial infections where systemic inflammation predominates, mice deficient in IFN-α/β receptor (IFNAR) display decreased systemic inflammation and improved outcome. However, human sepsis mortality often occurs during a prolonged period of immunosuppression and not from exaggerated inflammation. We used a low lethality cecal ligation and puncture (CLP) model of sepsis to determine the role of type I IFNs in host defense during sepsis. Despite increased endotoxin resistance, IFNAR−/− and chimeric mice lacking IFNAR in hematopoietic cells display increased mortality to CLP. This was not associated with an altered early systemic inflammatory response, except for decreased CXCL10 production. IFNAR−/− mice display persistently elevated peritoneal bacterial counts compared with wild-type mice, reduced peritoneal neutrophil recruitment, and recruitment of neutrophils with poor phagocytic function despite normal to enhanced adaptive immune function during sepsis. Importantly, CXCL10 treatment of IFNAR−/− mice improves survival and decreases peritoneal bacterial loads, and CXCL10 increases mouse and human neutrophil phagocytosis. Using a low lethality sepsis model, we identify a critical role of type I IFN–dependent CXCL10 in host defense during polymicrobial sepsis by increasing neutrophil recruitment and function

MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis

Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1+ cells effectively suppress antigen-specific CD8+ T cell interferon (IFN) γ production but only modestly suppress antigen-specific and nonspecific CD4+ T cell proliferation. GR-1+ cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell–dependent and depression of Th1 cell–dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain–containing adaptor-inducing IFN-β, or the IFN-α/β receptor, is required for complete GR-1+CD11b+ expansion. GR-1+CD11b+ cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization

Quantitation of SPLUNC1 in saliva with an xMAP particle-based antibody capture and detection immunoassay

The short palate lung and nasal epithelial clone 1 (SPLUNC1) protein may be differentially expressed in oral infections, oral inflammatory disorders, or oral malignancies and may be involved in innate immune responses in the oral cavity. However, the actual concentration of SPLUNC1 in saliva has not previously been determined. In this study, we determined the concentrations of SPLUNC1 in saliva using a particle-based antibody capture and detection immunoassay. A commercial goat anti-rhSPLUNC1 polyclonal antibody (AF1897) was linked to fluorescent polystyrene microspheres and used as the capture antibody. A commercial mouse IgG2b anti-rhSPLUNC1 monoclonal antibody (MAB1897) was biotinylated and used as the detection antibody. Western blot and 2-dimensional fluorescence difference gel electrophoresis (2-D DIGE) analysis of immunoprecipitated rhSPLUNC1 and SPLUNC1 from saliva were used to show that the capture AF1897 and detection MAB1897 antibodies both recognized SPLUNC1. Protein concentrations in saliva from 20 subjects ranged from 0.9 to 23.9 mg/ml; SPLUNC1 concentrations ranged from 34.7 ng/ml to 13.8 μg/ml; and SPLUNC concentrations normalized per mg of total salivary protein ranged from 4.7 ng/ml to 5.3 μg/ml. These results show that SPLUNC1 is detected in saliva in a variety of concentrations. This immunoassay may prove to be useful in determining the concentration of SPLUNC1 in saliva for assessing its role in the pathogenesis of oral infections, oral inflammatory disorders, or oral malignancies

Molecular and electronic structure of terminal and alkali metal-capped uranium(V) nitride complexes

Determining the electronic structure of actinide complexes is intrinsically challenging because inter-electronic repulsion, crystal field, and spin–orbit coupling effects can be of similar magnitude. Moreover, such efforts have been hampered by the lack of structurally analogous families of complexes to study. Here we report an improved method to U≡N triple bonds, and assemble a family of uranium(V) nitrides. Along with an isoelectronic oxo, we quantify the electronic structure of this 5f1 family by magnetometry, optical and electron paramagnetic resonance (EPR) spectroscopies and modelling. Thus, we define the relative importance of the spin–orbit and crystal field interactions, and explain the experimentally observed different ground states. We find optical absorption linewidths give a potential tool to identify spin–orbit coupled states, and show measurement of UV···UV super-exchange coupling in dimers by EPR. We show that observed slow magnetic relaxation occurs via two-phonon processes, with no obvious correlation to the crystal field