Host erythrocyte polymorphisms and exposure to Plasmodium falciparum in Papua New Guinea.

BACKGROUND: The protection afforded by human erythrocyte polymorphisms against the malaria parasite, Plasmodium falciparum, has been proposed to be due to reduced ability of the parasite to invade or develop in erythrocytes. If this were the case, variable levels of parasitaemia and rates of seroconversion to infected-erythrocyte variant surface antigens (VSA) should be seen in different host genotypes. METHODS: To test this hypothesis, P. falciparum parasitaemia and anti-VSA antibody levels were measured in a cohort of 555 asymptomatic children from an area of intense malaria transmission in Papua New Guinea. Linear mixed models were used to investigate the effect of alpha+-thalassaemia, complement receptor-1 and south-east Asian ovalocytosis, as well as glucose-6-phosphate dehydrogenase deficiency and ABO blood group on parasitaemia and age-specific seroconversion to VSA. RESULTS: No host polymorphism showed a significant association with both parasite prevalence/density and age-specific seroconversion to VSA. CONCLUSION: Host erythrocyte polymorphisms commonly found in Papua New Guinea do not effect exposure to blood stage P. falciparum infection. This contrasts with data for sickle cell trait and highlights that the above-mentioned polymorphisms may confer protection against malaria via distinct mechanisms.

Assessing and accounting for time heterogeneity in stochastic actor oriented models.

This paper explores time heterogeneity in stochastic actor oriented models (SAOM) proposed by Snijders (Sociological Methodology. Blackwell, Boston, pp 361-395, 2001) which are meant to study the evolution of networks. SAOMs model social networks as directed graphs with nodes representing people, organizations, etc., and dichotomous relations representing underlying relationships of friendship, advice, etc. We illustrate several reasons why heterogeneity should be statistically tested and provide a fast, convenient method for assessment and model correction. SAOMs provide a flexible framework for network dynamics which allow a researcher to test selection, influence, behavioral, and structural properties in network data over time. We show how the forward-selecting, score type test proposed by Schweinberger (Chapter 4: Statistical modeling of network panel data: goodness of fit. PhD thesis, University of Groningen 2007) can be employed to quickly assess heterogeneity at almost no additional computational cost. One step estimates are used to assess the magnitude of the heterogeneity. Simulation studies are conducted to support the validity of this approach. The ASSIST dataset (Campbell et al. Lancet 371(9624):1595-1602, 2008) is reanalyzed with the score type test, one step estimators, and a full estimation for illustration. These tools are implemented in the RSiena package, and a brief walkthrough is provided.

Metabolism of the intervertebral disc: effects of low levels of oxygen, glucose, and pH on rates of energy metabolism of bovine nucleus pulposus cells.

STUDY DESIGN: In vitro measurements of metabolic rates of isolated bovine nucleus pulposus cells at varying levels of oxygen, glucose, and pH. OBJECTIVES: To obtain quantitative information on the interactions between oxygen and glucose concentrations and pH, and the rates of oxygen and glucose consumption and lactic acid production, for disc nucleus cells. SUMMARY OF BACKGROUND DATA: Disc cells depend on diffusion from blood vessels at the disc margins for supply of nutrients. Loss of supply is thought to lead to disc degeneration, but how loss of supply affects nutrient concentrations in the disc is not known; nutrient concentrations within discs can normally only be calculated, because concentration measurements are invasive. However, realistic predictions cannot be made until there are data from measurements of metabolic rates at conditions found in the disc in vivo, i.e., at low levels of oxygen, glucose, and pH. METHODS: A metabolism chamber was designed to allow simultaneous recording of oxygen and glucose concentrations and of pH. These concentrations were measured electrochemically with custom-built glucose and oxygen sensors; lactic acid was measured biochemically. Bovine nucleus pulposus cells were isolated and inserted into the chamber, and simultaneous rates of oxygen and glucose consumption and of lactic acid production were measured over a range of glucose, oxygen, and pH levels. RESULTS: There were strong interactions between rates of metabolism and oxygen consumption and pH. At atmospheric oxygen levels, oxygen consumption rate at pH 6.2 was 32% of that at pH 7.4. The rate fell by 60% as oxygen concentration was decreased from 21 to 5% at pH 7.4, but only by 20% at pH 6.2. Similar interactions were seen for lactic acid production and glucose consumption rates; we found that glycolysis rates fell at low oxygen and glucose concentrations and low pH. Equations were derived that satisfactorily predict the effect of nutrient and metabolite concentrations on rates of lactic acid production rate and oxygen consumption. CONCLUSIONS: Disc cell metabolism in air and at pH 7.4 differs markedly from that found in the disc nucleus in vivo, where low levels of oxygen, glucose, and pH all coexist.

Enhanced expression of the mannose receptor by endothelial cells of the liver and spleen microvascular beds in the macrophage-deficient PU.1 null mouse.

Mice null for the haematopoietic lineage-specific transcription factor PU.1 lack mature Mphi and are compromised in their ability to clear cellular debris from the blood circulation. We investigated the possibility that non-professional phagocytes may partially compensate for the lack of Mphi in clearance functions. In the absence of Kupffer cells (resident liver Mphi) in the PU.1 null mice, electron microscopy revealed ingested debris in sinusoidal endothelial cells and hepatocytes although debris was also seen free in blood vessels. To investigate whether an increased clearance function of non-professional phagocytes might be linked to expression of Mphi-associated phagocytic and pinocytic receptors by other cells in PU.1 null mouse, we examined expression of several candidate proteins by immunocytochemistry and Western blotting. We found mannose receptor (MR) comparably expressed in PU.1 null and PU.1+ mice liver and spleen whereas class A scavenger receptor was substantially reduced and complement receptor 3 was absent in PU.1 null animals. By morphometric analysis, liver and spleen sinusoidal endothelial cells were seen to express significantly more MR in the PU.1 null mouse. This study provides the first evidence of apparently compensatory alterations in the microvasculature of the Mphi-deficient PU.1 null mouse.

Correlates of delayed disease progression in HIV-1-infected Kenyan children.

Without treatment most HIV-1-infected children in Africa die before their third birthday (>89%) and long-term nonprogressors are rare. The mechanisms underlying nonprogression in HIV-1-infected children are not well understood. In the present study, we examined potential correlates of delayed HIV disease progression in 51 HIV-1-infected African children. Children were assigned to progression subgroups based on clinical characterization. HIV-1-specific immune responses were studied using a combination of ELISPOT assays, tetramer staining, and FACS analysis to characterize the magnitude, specificity, and functional phenotype of HIV-1-specific CD8(+) and CD4(+) T cells. Host genetic factors were examined by genotyping with sequence-specific primers. HIV-1 nef gene sequences from infecting isolates from the children were examined for potential attenuating deletions. Thymic output was measured by T cell rearrangement excision circle assays. HIV-1-specific CD8(+) T cell responses were detected in all progression groups. The most striking attribute of long-term survivor nonprogressors was the detection of HIV-1-specific CD4(+) Th responses in this group at a magnitude substantially greater than previously observed in adult long-term nonprogressors. Although long-term survivor nonprogressors had a significantly higher percentage of CD45RA(+)CD4(+) T cells, nonprogression was not associated with higher thymic output. No protective genotypes for known coreceptor polymorphisms or large sequence deletions in the nef gene associated with delayed disease progression were identified. In the absence of host genotypes and attenuating mutations in HIV-1 nef, long-term surviving children generated strong CD4(+) T cell responses to HIV-1. As HIV-1-specific helper cells support anti-HIV-1 effector responses in active disease, their presence may be important in delaying disease progression.

Non-linear survival analysis using neural networks.

We describe models for survival analysis which are based on a multi-layer perceptron, a type of neural network. These relax the assumptions of the traditional regression models, while including them as particular cases. They allow non-linear predictors to be fitted implicitly and the effect of the covariates to vary over time. The flexibility is included in the model only when it is beneficial, as judged by cross-validation. Such models can be used to guide a search for extra regressors, by comparing their predictive accuracy with that of linear models. Most also allow the estimation of the hazard function, of which a great variety can be modelled. In this paper we describe seven different neural network survival models and illustrate their use by comparing their performance in predicting the time to relapse for breast cancer patients.

Growth, morbidity, and mortality in a cohort of institutionalized HIV-1-infected African children.

OBJECTIVE: As a result of the HIV epidemic in Africa, much debate exists on whether institutionalized compared with community-based care provides optimum management of infected children. Previous reports calculated 89% mortality by age 3 years among outpatients in Malawi. No similar data are available for infected children in institutionalized care. We characterized patterns of morbidity and mortality among HIV-1-infected children residing at an orphanage in Nairobi. METHODS: Medical records for 174 children followed over 5 years were reviewed. Mortality was analyzed by Kaplan-Meier methods with adjustment to account for survival in the community before admission. Anthropometric indices were calculated to include mean z scores for weight for length and length for age. Low indices reflected wasting and stunting. Opportunistic infections were documented. RESULTS: Of 174 children, 64 had died. Survival was 70% at age 3 years. Morbidity included recurrent respiratory tract infections, gastroenteritis, parotitis, and lymphoid interstitial pneumonitis. No new cases of tuberculosis disease were noted after admission. Mean z scores for length for age suggested overall stunting (z = -1.65). Wasting was not observed (z = -0.39). CONCLUSION: The optimal form of care for HIV-infected children in resource-poor settings may be the development of similar homes. Absence of tuberculosis disease in long-standing residents may have contributed to improved survival. Stunting in the absence of wasting implied that growth was compromised by opportunistic infections and other cofactors.