Inhibition of dendritic cell maturation by malaria is dose dependent and does not require Plasmodium falciparum erythrocyte membrane protein 1

Red blood cells infected with Plasmodium falciparum (iRBCs) have been shown to modulate maturation of human monocyte-derived dendritic cells (DCs), interfering with their ability to activate T cells. Interaction between Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and CD36 expressed by DCs is the proposed mechanism, but we show here that DC modulation does not require CD36 binding, PfEMP1, or contact between DCs and infected RBCs and depends on the iRBC dose. iRBCs expressing a PfEMP1 variant that binds chondroitin sulfate A (CSA) but not CD36 were phagocytosed, inhibited lipopolysaccharide (LPS)-induced phenotypic maturation and cytokine secretion, and abrogated the ability of DCs to stimulate allogeneic T-cell proliferation. CD36- and CSA-binding iRBCs showed comparable inhibition. P. falciparum lines rendered deficient in PfEMP1 expression by targeted gene knockout or knockdown also inhibited LPS-induced phenotypic maturation, and separation of DCs and iRBCs in transwells showed that inhibition was not contact dependent. Inhibition was observed at an iRBC:DC ratio of 100:1 but not at a ratio of 10:1. High doses of iRBCs were associated with apoptosis of DCs, which was not activation induced. Lower doses of iRBCs stimulated DC maturation sufficient to activate autologous T-cell proliferation. In conclusion, modulation of DC maturation by P. falciparum is dose dependent and does not require interaction between PfEMP1 and CD36. Inhibition and apoptosis of DCs by high-dose iRBCs may or may not be physiological. However, our observation that low-dose iRBCs initiate functional DC maturation warrants reevaluation and further investigation of DC interactions with blood-stage P. falciparum.     

T lymphocytes expressing CCR3 are increased in allergic rhinitis compared with non-allergic controls and following allergen immunotherapy

BACKGROUND: In T cell-associated allergic inflammation, homing of T-helper 2 (Th2) effector cells to mucosal sites may be influenced by chemokine receptor expression. Previous studies have identified CCR3 and CCR4 as putative markers of Th2 cells and CCR5 and CXCR3 as markers of Th1 cells. The aim of this study was to assess differential chemokine receptor expression from symptomatic atopic grass pollen-sensitive subjects, compared with patients on high-dose allergen injection immunotherapy (IT) and healthy controls. METHODS: We examined chemokine receptor expression (CCR1-7 and CXCR1-4) by flow cytometry of peripheral blood CD4+ and CD8+ T cells. We also depleted peripheral blood mononuclear cell (PBMC) populations of CCR3+ CD4+ cells by magnetic bead separation and cells were stimulated with grass pollen allergen for 6 days. Cytokine production was measured by enzyme-linked immunosorbent assay. RESULTS: On freshly isolated PBMC, atopic individuals exhibited increased numbers of CCR3+ CD4+ cells compared with normal controls (P < 0.01). CCR3 expression in IT patients was reduced compared with matched atopic rhinitic controls (P < 0.05) and comparable with that observed in normal subjects. Depletion of CCR3+ CD4+ cells from allergen-stimulated PBMC cultures resulted in decreased interleukin (IL)-5 production compared with whole CD4+ populations (P < 0.05). Freshly isolated CCR3+ CD4+ cells have significantly higher intracellular IL-4 and lower IFN-gamma levels than CCR3- CD4+ cells. CD4+ T cells cultured from both peripheral cells and nasal biopsies demonstrated increased expression of CCR3 in the presence of IL-4 (P < 0.05). CONCLUSION: CCR3+ CD4+ T cells are increased in allergic rhinitis, are reduced by allergen IT, have a Th2 phenotype and contribute to allergen-specific responses. Strategies against CCR3+ T cells may be effective in human allergic diseases.     

Evaluation of matrix metalloproteinase 7 in plasma and pancreatic juice as a biomarker for pancreatic cancer.

Differentiating between periampullary carcinoma and chronic pancreatitis with an inflammatory mass is difficult. Consequently, 6% to 9% of pancreatic resections for suspected carcinoma are done inappropriately for chronic pancreatitis. Here, we test if matrix metalloproteinase 7 (MMP-7), a secreted protease frequently expressed in pancreatic carcinoma, can be measured in plasma, pancreatic, and duodenal juice, and if it can distinguish between periampullary carcinoma and chronic pancreatitis. Ninety-four patients who underwent pancreatic surgery for a (peri)pancreatic neoplasm (n = 63) or chronic pancreatitis (n = 31) were analyzed. Median plasma MMP-7 levels were significantly higher in carcinoma (1.95 ng/mL; interquartile range, 0.81-3.22 ng/mL) compared with chronic pancreatitis and benign disease (0.83 ng/mL; interquartile range, 0.25-1.21 ng/mL; P < 0.01). MMP-7 levels in pancreatic juice were higher, although not significantly, in carcinoma (62 ng/mg protein; interquartile range, 18-241 ng/mg protein) compared with chronic pancreatitis and benign disease (23 ng/mg protein; interquartile range, 8.5-99 ng/mg protein; P = 0.17). MMP-7 levels in duodenal juice were universally low. At an arbitrary cutoff of 1.5 ng/mL in plasma, positive and negative predictive values were 83% and 57%, respectively, values comparable to those of today's most common pancreatic tumor marker, carbohydrate antigen 19-9 (CA19-9; 83% and 53%, respectively). Positive and negative likelihood ratios for plasma MMP-7 were 3.35 and 0.52, respectively. The area under the receiver operating characteristic curve for MMP-7 was 0.73 (95% confidence interval, 0.63-0.84) and for CA19-9, 0.75 (95% confidence interval, 0.64-0.85). Combined MMP-7 and CA19-9 assessment gave a positive predictive value of 100%. Thus, plasma MMP-7 levels discriminated between patients with carcinoma and those with chronic pancreatitis or benign disease. The diagnostic accuracy of plasma MMP-7 alone is not sufficient to determine treatment strategy in patients with a periampullary mass, but combined evaluation of plasma MMP-7 with CA19-9 and other markers may be clinically useful.     

Population and antenatal-based HIV prevalence estimates in a high contracepting female population in rural South Africa

Background  

To present and compare population-based and antenatal-care (ANC) sentinel surveillance HIV prevalence estimates among women in a rural South African population where both provision of ANC services and family planning is prevalent and fertility is declining. With a need, in such settings, to understand how to appropriately adjust ANC sentinel surveillance estimates to represent HIV prevalence in general populations, and with evidence of possible biases inherent to both surveillance systems, we explore differences between the two systems. There is particular emphasis on unrepresentative selection of ANC clinics and unrepresentative testing in the population.     

Integration of chiropractic education into a hospital setting: A South African experiences

This article examines differences between chiropractic and medical internship experiences, both internationally and in South Africa. The South African hospital experience is described, and the future is discussed.     

Is oxygen supply the only regulator of erythropoietin levels? Serum immunoreactive erythropoietin during the first 4 months of life in term infants with different levels of arterial oxygenation

Serum immunoreactive erythropoietin (siEp) levels were measured in 35 full-term infants aged 0-13 weeks, 31 of whom had congenital heart disease. The infants displayed a wide range in arterial oxygen tension (PaO2) and oxygen saturation (SaO2). During the first days of life siEp varied widely with a range from less than 3 to more than 10,000 mIU/ml. The wide variation is consistent with findings in cord blood at term. The siEp levels did not correlate significantly with haemoglobin, haematocrit, PaO2, SaO2, or arterial oxygen content in the total sample, nor when the cohort was split up into different age groups. Cyanotic infants aged 2-13 weeks had significantly higher siEp concentrations than normal adults (p less than 0.001) and than children with cyanotic congenital heart disease, aged 4 months-10 years (p less than 0.001). The raised siEp levels in cyanotic children aged 2-13 weeks found in this study and the normal levels found in their older counterparts (4 months-10 years) (reported elsewhere) are consistent with the pattern observed in man and animals exposed to prolonged hypobaric hypoxia, in which after an initial rise in erythropoietin concentrations the levels fall to normal while increased erythropoiesis is sustained.     

Risks to the public from historical releases of radionuclides and chemicals at the Rocky Flats Environmental Technology Site

This paper summarizes the methods and results of estimating risks of cancer incidence resulting from plutonium, carbon tetrachloride, and beryllium releases from operations at the Rocky Flats Environmental Technology Site, near Denver, Colorado, from 1953 through 1989. The key findings show that people who lived near the facility were exposed to plutonium mainly through inhalation during routine operations, from a major fire in 1957, and from plutonium resuspended from contaminated soil from an outdoor drum storage area, called the 903 Area. Results were presented for five exposure scenarios that were location-independent. Individuals described by the laborer scenario received the highest risk of all scenarios considered. Upper bound (95th percentile) incremental lifetime cancer incidence risks for the laborer scenario were in about the 10(-4) range (1 chance in 10,000) for developing cancer from Rocky Flats plutonium releases during a lifetime. At the 5th percentile level, the maximum cancer risk was about 10(-7) (1 chance in 10 million) for developing cancer during a lifetime. Estimated cancer risks at the 95th percentile level are within the range of for acceptable risks established by the US Environmental Protection Agency of 10(-6) to 10(-4). Carbon tetrachloride was found to be the chemical that presented the highest risk to the public. The 5th and 95th percentile risk values for exposure to carbon tetrachloride were 9.2x10(-7) and 2.5x10(-5), respectively.