Antibody Responses to Vaccination among South African HIV-Exposed and Unexposed Uninfected Infants during the First 2 Years of Life

HIV-exposed but uninfected (HEU) infants born to HIV-infected mothers from areas in the world with a high burden of infectious disease suffer higher infectious morbidity and mortality than their HIV unexposed uninfected (HUU) peers. Vaccination provides protection from infection. The possibility exists that altered response to vaccination contributes to the higher rate of infection in HEU than in HUU infants. While short-term, cross-sectional studies support this notion, it is unclear whether or not HEU infants develop long-term protective immune responses following the WHO extended program on immunization (EPI). Vaccine-specific antibody responses were compared between HEU and HUU infants from 2 weeks until 2 years of age in a longitudinal South African cohort. Total IgG and antibodies specific for Bordetella pertussis, Haemophilus influenzae type b (Hib), tetanus toxoid, hepatitis B virus (HepB), and measles virus were measured at multiple time points throughout the first 2 years of life. Prevaccine antibodies (maternal antibodies passively acquired) specific for tetanus were lower in HEU than in HUU infants, while prevaccine antibodies to HepB were higher in HEU than in HUU infants. Both groups responded similarly to tetanus, Hib, and HepB vaccination. HEU demonstrated stronger pertussis vaccine responses, developing protective titers 1 year earlier than HUU patients, and maintained higher anti-tetanus titers at 24 months of age. Vaccine-induced antibodies to measles virus were similar in both groups at all time points. Our results suggest that the current EPI vaccination program as practiced in South Africa leads to the development of vaccine-specific antibody responses that are equivalent in HEU and HUU infants. However, our data also suggest that a large fraction of both HEU and HUU South African infants have antibody titers for several infectious threats that remain below the level of protection for much of their first 2 years of life.     

Age‐Matched Dendritic Cell Subpopulations Reference Values in Childhood

Dendritic cells (DCs) are the most potent antigen‐presenting cells and are the key link between the innate and adaptive immune response. Only a few reports with study populations of up to 50 individuals have been published with age‐based reference values for DC subpopulations in healthy children. Therefore, we aimed to establish reference ranges in a larger study population of 100 healthy children, which allowed age‐matched subgroups. Most previous studies were performed using a dual‐platform approach. In this study, a single‐platform approach in a lyse no‐wash procedure was used. DC subpopulations were defined as follows: CD45⁺CD85k⁺HLA‐DR⁺CD14^?CD16^?CD33⁺ cells as myeloid DCs (mDCs) and CD45⁺CD85k⁺HLA‐DR⁺CD14^?CD16^?CD123⁺ cells as plasmacytoid DCs (pDCs). Reference ranges were established using a semi‐parametric regression of age‐matched absolute and relative DC counts. We found a significant decline with increasing age in the medians of mDCs (P = 0.0003) and pDCs per μl peripheral blood (PB) (P = 0.004) and in the 50%, 90% and 95% reference ranges. We also identified significantly lower absolute cell counts of mDCs per μl PB in girls than in boys for all age groups (P = 0.0015). Due to the larger paediatric study population and single‐platform approach, this study may give a more precise overview of the normal age‐matched development of DC subpopulations and may provide a basis for analyzing abnormal DC counts in different illnesses or therapies such as post stem cell transplantation.     

Generation of alphabeta T-cell receptor+ CD4- CD8+ cells in major histocompatibility complex class I-deficient mice upon activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Gene-targeted mice lacking the beta2 microglobulin gene (beta2m-/- mice), and hence functional major histocompatibility complex (MHC) class I molecules, do not develop CD4- CD8+ cells. We show here that both in vitro and in vivo treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a trans-activating ligand of the endogenous aryl hydrocarbon receptor (Ah-R), bypasses the need for MHC class I molecules for selection into the CD4- CD8+ cell pool. When beta2m-/- dams were given a single dose of 50 microg of TCDD, approximately 13% of CD4- CD8+ thymocytes could be detected in their newborn pups. In TCDD-exposed fetal thymus organ cultures of beta2m-/- mice, approximately 35% CD4- CD8+ thymocytes were detectable. About 16% of these CD4- CD8+ cells bore the alpha beta T-cell receptor (TCR) and approximately 33% bore CD3. Only a minority of the CD8+ cells were heat-shock antigen positive. The cells possessed killing activity as shown using the 51Cr-release assay comprising gamma delta TCR- CD4- CD8+ thymocytes from 3 to 4-day-old b2m-/- mice. Thus, TCDD leads to a significant increase of mature CD4- CD8+ thymocytes in relative and absolute numbers. High numbers of CD4- CD8+ thymocytes developed also in organ cultures from thymi, lacking both MHC class I and class II molecules, exposed to TCDD. A 10-fold transient increase of Notch1 mRNA in thymocytes from fetal thymus organ culture, exposed for 4 days to TCDD, was detected in CD4+ CD8+ cells compared with controls. We suggest that TCDD affects thymic selection and directs the lineage commitment of CD4+ CD8+ thymocytes towards CD4- CD8+ cells, possibly via up-regulation of the Notch1 gene.     

Sujets « métaboliquement sains », bien qu’obèses. Première partie: diagnostic, physiopathologie et prévalence

Around 30 to 50% of obese subjects are “metabolically normal” (MHO) whereas numerous nonobese subjects are “metabolically abnormal”. The distribution and function of adipose deposits seem to play a crucial role in explaining this apparent paradox. The aim of this first article is to describe the clinical and biological characteristics that lead to the diagnosis of MHO, attempt to discover the etiopathogenesis of this syndrome and analyze the underlying pathophysiological mechanisms and, finally, to assess the prevalence of the MHO phenotype, which may vary according to the definition used and the population studied.     

Elevated vitreous nitric oxide levels in patients with proliferative diabetic retinopathy

PURPOSE: The aim of this study was to determine nitric oxide levels in the vitreous of patients with proliferative diabetic retinopathy. METHODS: Using the spectrophotometric method based on Griess reaction, we measured levels of nitrite, the stable product of nitric oxide, in the vitreous of 21 eyes of 21 patients who underwent vitrectomy for the treatment of proliferative diabetic retinopathy with tractional retinal detachment, prospectively. Three samples were excluded from the study because of blood contamination. The control group was made up of vitreous samples from 15 eyes of 15 normal cadavers and five eyes of five patients who were undergoing vitrectomy for macular hole surgery.RESULTS: Nitrite levels were 0. 524 +/- 0.27 microM and 0.383 +/- 0.17 microM in the vitreous of patients with proliferative diabetic retinopathy of diabetes type I and type II, respectively. In 15 cadaver eyes and five vitreous samples from patients who underwent macular hole surgery, nitrite levels were below the detection limit (less than 0.08 microM). There was no significant difference between nitrite levels in patients with type I and type II diabetes (P =.56), whereas there was a significant difference between diabetes groups and controls (P <. 00001).CONCLUSION: Vitreous nitric oxide levels are elevated in patients with proliferative diabetic retinopathy with tractional retinal detachment. Nitric oxide may play a role in the pathogenesis of proliferative diabetic retinopathy.     

Characterization of CD95 ligand (CD95L)-induced apoptosis in human tenon fibroblasts

Toxic side effects of cytotoxic agents such as 5-fluorouracil or mitomycin-C in glaucomatous filtering procedures call for alternative approaches to control fibroblast proliferation. CD95L is a death ligand that triggers apoptosis in susceptible target cells. Apoptosis allows for the safe disposal of cells without damaging the surrounding tissue. The goal of this study was to characterize and to evaluate the CD95L induced cell death in cultured Tenon fibroblasts.Human Tenon fibroblasts were treated with different concentrations of CD95L. For comparison, murine NIH 3T3 fibroblasts were used. Immunohistochemistry and Western blot were used to investigate the CD95 and CD95L expression. Cytotoxicity was measured by crystal violet assay. Apoptosis was investigated using in situ DNA end labelling (TUNEL). DEVD-AMC caspase 3 like activity was measured and caspase 3 processing was studied by immunoblot and the use of the caspase inhibitor DEVD-CHO in cell culture assays.Tenon and NIH 3T3 fibroblasts express CD95 and CD95L. The authors found concentration dependent inhibition of proliferation after CD95L treatment. Tenon fibroblasts, but not NIH 3T3 fibroblasts, show synergy when combined with actinomycin D or cyclohexamide. CD95L treatment did not alter total protein or RNA synthesis. Cell death induced by CD95L was apoptotic and activated caspase 3, as TUNEL positive cells and the active fragment of caspase 3 were found. CD95L induced cell death could be inhibited by the caspase-inhibitor.Here, it is demonstrated that the CD95L induced cell death in cultured human Tenon fibroblasts is apoptotic and possibly mediated by the caspase 3 pathway. These results suggest that it may be possible to use CD95L in glaucomatous filtering procedures. In vivo studies are necessary for further evaluation.     

Adaptive changes of autoregulation in chronic cerebral hypotension with arteriovenous malformations: an acetazolamide-enhanced single-photon emission CT study.

PURPOSETo evaluate the relationship among feeding arterial pressure, lesion size, and perfusion in cerebral cortex adjacent to cerebral arteriovenous malformations (AVMs).METHODSEleven patients with hemispheric AVMs underwent 99mTc hexamethyl-propyleneamine oxime single-photon emission CT before and after 1 g of acetazolamide was administered intravenously. AVM volume was estimated from MR dimensions and measured according to the method described by Pasqualin. Pressure measurements were obtained in arteries feeding the cortex adjacent to AVMs. Single-photon emission CT regions of interest were defined in cortex adjacent to the AVM and compared with contralateral regions using the Mountz method to estimate a baseline and dynamic (acetazolamide-challenged) perfusion defect volume.RESULTSEight of 11 patients had baseline perfusion defects, but these defects were unrelated to feeding artery pressures (y = -.06x + 9.92, r2 = .04) or the dynamic change in defect volume after acetazolamide administration (y = .01x + .02, r2 = .002). However, there was a correlation between AVM volume and the baseline defect volume (y = .75x - 1.9, r2 = .76). Five patients had increased defect volume after acetazolamide administration; 5 patients had either no change in or improvement of perfusion. Dynamic changes in defect volume were related to feeding artery pressures.CONCLUSIONPerilesional baseline perfusion defects appear to be related to lesion size and not to local arterial pressure. Cerebrovascular reserve generally was preserved, and perfusion defects appeared to be more pronounced with lower arterial pressures in feeding vessels. Although vasodilatory testing can unmask hemodynamic failure with severe local hypotension, baseline perfusion defects near the lesion and distant perfusion changes are more likely attributable to other causes such as mass-related or neurogenic changes.