Autoimmunity to histones, ubiquitin, and ubiquitinated histone H2A in NZBxNZW and MRL-lpr/lpr mice. Anti-histone antibodies are concentrated in glomerular eluates of lupus mice

In lupus diseases products of chromatin catabolism releasedfrom dead cells might be involved in the induction of autoantibodyand in the development of glomerulonephritis. While the pathogenicrole of anti-DNA antibodies is recognized, the role of antibodiesdirected against structural proteins of chromatin is still questioned.IgG antibodies to histones, ubiquitin, and ubiquitinated histoneH2A (UH2A) have been investigated both in plasma and in glomerulareluates of NZBxNZW and MRL-lpr/lpr mice. In NZBxNZW mice, anti-ubiquitinand anti-UH2A antibodies were detected at 8 weeks of age, simultaneouslywith anti-double-stranded DNA antibodies, whereas anti-histoneantibodies appeared later. In MRL-lpr/lpr mice, anti-DNA antibodieswere detected at 4 weeks, whereas anti-histone, anti-ubiquitin,and anti-UH2A antibodies were not detected at that age but appearedin plasma rapidly thereafter. In both strains, increased anti-histoneactivity was found in IgG eluted from glomeruli. These resultssupport the suggestion that anti-histone antibodies are likelyto play a pathogenic role in lupus nephritis. They also indicatethat, like human lupus, murine lupus is characterized by theproduction of anti-ubiquitin and anti-UH2A antibodies.     

Developing an evidence-based, preventive care package for persons with HIV in Africa

Currently, 95% of the 40 million persons with HIV live in low and middle income countries; 27 million in sub-Saharan Africa. HIV/AIDS is a leading cause of death in the region, yet access to care and treatment considered standard-of-care in the industrialized world is extremely limited. There is a need for standardized, evidence-based recommendations on preventive measures. We developed a list of potential interventions based, when possible, on documented efficacy in reducing morbidity or mortality among persons with HIV in Africa. We considered the accessibility, affordability, and potential for implementation using existing health care infrastructure. Potential components included cotrimoxazole prophylaxis, safe drinking water, isoniazid prophylaxis, insecticide-treated bed nets, micronutrients, and provision of HIV counseling and testing and condoms to family members of persons with HIV. There are several additional interventions for which further evaluation would be useful before inclusion in a standard package of care, including acyclovir prophylaxis, food supplementation, hand washing, and fluconazole prophylaxis. The provision of a basic care package could be an important step toward reducing health care disparities and gaining more control of the global HIV/AIDS epidemic.     

Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice

Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of cell death and inflammation, and mediates programmed necrosis (necroptosis) via mixed-lineage kinase like (MLKL) protein. Prior studies in experimental intracerebral hemorrhage (ICH) implicated RIPK1 in the pathogenesis of neuronal death and cognitive outcome, but the relevant cell types involved and potential role of necroptosis remain unexplored. In mice subjected to autologous blood ICH, early RIPK1 activation was observed in neurons, endothelium and pericytes, but not in astrocytes. MLKL activation was detected in astrocytes and neurons but not endothelium or pericytes. Compared with WT controls, RIPK1 kinase-dead (RIPK1^D138N/D138N) mice had reduced brain edema (24 h) and blood-brain barrier (BBB) permeability (24 h, 30 d), and improved postinjury rotarod performance. Mice deficient in MLKL (Mlkl^-/-) had reduced neuronal death (24 h) and BBB permeability at 24 h but not 30d, and improved post-injury rotarod performance vs. WT. The data support a central role for RIPK1 in the pathogenesis of ICH, including cell death, edema, BBB permeability, and motor deficits. These effects may be mediated in part through the activation of MLKL-dependent necroptosis in neurons. The data support development of RIPK1 kinase inhibitors as therapeutic agents for human ICH.     

Maternal recall of birthweight and birth size in Entebbe,Uganda

Objectives To assess the reliability of maternally recalled birthweight and size in Entebbe, Uganda. Methods The study population comprised 404 mothers, who were participants in the Entebbe Mother and Baby Study (EMaBS). Mothers were recruited to EMaBS during antenatal care, maternal characteristics were recorded during pregnancy, and birthweight was recorded at delivery. Four to seven years after delivery, mothers were asked to recall the child’s birthweight and size. Their responses were compared with the birthweight recorded in the EMaBS database. Results Of 404 interviewed mothers, 303 (75%) were able to give an estimate of birthweight and for 265 of these EMaBS data on recorded birthweights were available. Women who were educated and whose children had low birth order were more likely to be able to give an estimate: 37 (14%) recalled the exact recorded birthweight; a further 52 (20%) were accurate to within 0.1 kg of the recorded weight. On average, mothers overestimated birthweight by 0.06 kg (95% CI: 0.00–0.13 kg, P = 0.04). Recalled and recorded birthweights showed moderate agreement with an intraclass correlation coefficient of 0.64. Four hundered mothers gave an estimate of birth size: the sensitivity and specificity of recalled birth size for classifying low birthweight were 76% (95% CI: 50–93%) and 70% (95% CI: 65–75%), respectively. Conclusions Mothers’ recall of birthweight was not precise but in absence of other data, recall of birthweight and size may have some value in epidemiological studies in these settings.     

Prevalence of dyslipidemia and dysglycaemia in HIV infected patients

BACKGROUND: Highly active antiretroviral therapy (HAART) has dramatically reduced AIDS morbidity and mortality, however long-term metabolic consequences including dysglycaemia and dyslipidemia have raised concern regarding accelerated cardiovascular disease risk. OBJECTIVE: To determine the period prevalence of dyslipidemia and dysglycaemia in HIV-infected patients. DESIGN: Cross-sectional comparative group study. SETTING: Kenyatta National Hospital, a tertiary HIV dedicated out-patient facility. SUBJECTS: Consecutive HIV- positive adult patients. MAIN OUTCOME MEASURES: Dyslipidemia: presence of raised total or LDL cholesterol or low HDL cholesterol, or raised triglycerides. Dysglycaemia: presence of impaired fasting glucose or impaired glucose tolerance, or diabetes mellitus. Results: Between January and April 2006, out of 342 screened patients, 295 were recruited and 58% were females. One hundred and thirty four (45%) were on HAART, 82% of whom were on stavudine, lamivudine and either nevirapine or efavirenz. Overall prevalence of dyslipidemiawas 63.1% and dysglycaemia was 20.7%. High total cholesterol occurred in 39.2% of HAART and 10.0% HAART naive patients (p<0.0001, OR 5.18, CI 3.11-10.86), whereas high LDL cholesterol occurred in 40.8% and in 11.2% respectively (p<0.0001, OR 5.43, CI 2.973-9.917). HDL levels were low in 14.6% and 51.3% among HAART and HAART naive patients, respectively, (p<0.0001, OR 0.16, CI 0.091-0.29) while high triglycerides occurred in 25.6% and 22.5% respectively (p=0.541 OR 1.184 CI 0.688-2.037). Among patients on HAART compared to HAART naive patients, diabetes was found in 1.5% against 1.2% (p=0.85), impaired fasting in 2.2% against 0.6% (p=0.30) and impaired glucose tolerance in 16.4% against 21.1% (p=0.22), respectively. CONCLUSIONS: HIV- infected patients demonstrated a high prevalence of dyslipidemia. HAART use was associated with high levels of total, and LDL cholesterol and high triglyceride levels, an established athrogenic lipid profile. However, HAART was not associated with low HDL cholesterol and had no significant effect on dysglycaemia.     

The presentation and outcome of HIV-related disease in Nairobi.

The range of clinical presentations of HIV-related disease in Africa has not been adequately described, despite the fact that many hospitals have to rely heavily on clinical diagnosis. Six hundred adult medical patients seen in the Casualty Department of the main Government hospital in Nairobi were enrolled in a study of the presentation and outcome of HIV-related disease: 506 of these patients were admitted, of whom 19 per cent (95) were HIV seropositive. The remaining 94 were dealt with as outpatients: 11 percent (10) of these were seropositive. A history of prior treatment for sexually transmitted disease and, if male, being uncircumcised, were associated with being seropositive. Three presentations were strongly associated with HIV infection: acute fever with no focus except the gastrointestinal tract (enteric fever-like illness), acute cough with fever (community-acquired pneumonia) and chronic diarrhoea with wasting. The WHO clinical case definition (CCD) for AIDS missed a substantial amount of HIV-related morbidity (sensitivity 39 per cent) and misidentified many seronegative patients (positive predictive value 59 per cent). In comparison with the Centers for Disease Control surveillance definition for AIDS, the CCD was specific (91 per cent) and sensitive (79 per cent) but only had a positive predictive values of 30 per cent: the CCD may therefore be a poor surveillance tool for AIDS. Seropositive patients were much more likely to die than were seronegative patients (39 per cent vs. 15 per cent mortality). Enteric fever-like illness was the presentation which most commonly proved fatal. A wider spectrum of disease is associated with underlying HIV immunosuppression than has previously been described in Africa.