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Biomedical subjects

L Kuhn

Publications and source records attributed to L Kuhn.

At least 19 recordsLinked to original sources

Metabolomic, proteomic and biophysical analyses of Arabidopsis thaliana cells exposed to a caesium stress. Influence of potassium supply.

The incorporation and localisation of 133Cs in a plant cellular model and the metabolic response induced were analysed as a function of external K concentration using a multidisciplinary approach. Sucrose-fed photosynthetic Arabidopsis thaliana suspension cells, grown in a K-containing or K-depleted medium, were submitted to a 1 mM Cs stress. Cell growth, strongly diminished in absence of K, was not influenced by Cs. In contrast, the chlorophyll content, affected by a Cs stress superposed to K depletion, did not vary under the sole K depletion. The uptake of Cs was monitored in vivo using 133Cs NMR spectroscopy while the final K and Cs concentrations were determined using atomic absorption spectrometry. Cs absorption rate and final concentration increased in a K-depleted external medium; in vivo NMR revealed that intracellular Cs was distributed in two kinds of compartment. Synchrotron X-ray fluorescence microscopy indicated that one could be the chloroplasts. In parallel, the cellular response to the Cs stress was analysed using proteomic and metabolic profiling. Proteins up- and down-regulated in response to Cs, in presence of K+ or not, were analysed by 2D gel electrophoresis and identified by mass spectrometry. No salient feature was detected excepting the overexpression of antioxidant enzymes, a common response of Arabidopsis cells stressed whether by Cs or by K-depletion. 13C and 31P NMR analysis of acid extracts showed that the metabolome impact of the Cs stress was also a function of the K nutrition. These analyses suggested that sugar metabolism and glycolytic fluxes were affected in a way depending upon the medium content in K+. Metabolic flux measurements using 13C labelling would be an elegant way to pursue on this line. Using our experimental system, a progressively stronger Cs stress might point out other specific responses elicited by Cs.

Arabidopsis↗

PsrA is a positive transcriptional regulator of the type III secretion system in Pseudomonas aeruginosa.

The type III secretion system (TTSS) of Pseudomonas aeruginosa is induced in vivo upon contact with eukaryotic cells and in vitro by calcium depletion in culture medium. We have observed a previously identified protein, PsrA, necessary for full activation of TTSS gene expression in P. aeruginosa. Electrophoretic mobility shift assays showed that recombinant PsrA could bind to the exsCEBA promoter region. A mutant with a deletion in the psrA gene was constructed. Using transcriptional fusions, we demonstrated that PsrA is required for the full activation of transcription of the TTSS regulatory operon exsCEBA and effector exoS, although the deletion mutant still responded to calcium depletion, to serum, and to host cell contact. The psrA mutant showed a marked decrease in the secretion of the type III effectors and weak resistance to phagocyte-like PLB-985 cells. The defect in TTSS transcription and secretion in the psrA mutant could be complemented by expression in trans of psrA. PsrA was previously identified as a transcriptional activator of RpoS, a central regulator during stationary phase. We confirmed with our strain that RpoS has a negative effect on TTSS gene expression. Taken altogether, these results suggest that PsrA is a newly identified activator that is involved in the expression of the TTSS by enhancing the exsCEBA transcriptional level.

ADP Ribose Transferases↗

Size and shape of mineralites in young bovine bone measured by atomic force microscopy.

Atomic force microscopy (AFM) was used to obtain three-dimensional images of isolated mineralites extracted from young postnatal bovine bone. The mean mineralite size is 9 nm x 6 nm x 2.0 nm, significantly shorter and thicker than the mineralites of mature bovine bone measured by the same technique. Mineralites of the young postnatal bone can be accommodated within the hole zone regions of a quasi-hexagonally packed collagen fibril in the fashion described by Hodge [9] in which laterally adjacent hole zone regions form continuous "channels" across the diameter of a fibril for a distance of at least 10 nm. Deposition of mineralites of the size noted above in this void volume of the fibrils would result in little or no distortion of the collagen molecules or supramolecular structure of the collagen fibril. The new AFM data supporting this claim is consistent with findings obtained by electron microscopy and low-angle x-ray and neutron diffraction that mineralites formed within collagen fibrils during initial stages of calcification occur within the hole zone region. However, the deposition of additional mineralites in the intermolecular spaces between collagen molecules in the overlap region of the fibrils would significantly distort the fibrils since the space available between adjacent molecules is considerably less than even the smallest dimension of the mineralites.

Animals↗

Quantitation of human immunodeficiency virus type 1 in breast milk.

The distribution and stability of human immunodeficiency virus type 1 (HIV-1) in breast milk (BM) components remain largely unknown. Inhibitory effects, if any, of BM on HIV RNA and DNA PCR amplification are poorly understood. We have addressed these issues by using virus-spiked BM samples from HIV-negative women. BM samples from HIV-negative women were spiked with HIV-1 virions or cells containing a single integrated copy of HIV DNA (8E5/LAV). After incubation under different experimental conditions, viral RNA was detected by the Roche Amplicor UltraSensitive assay in whole-milk, skim milk, and lipid fractions. We found excellent correlation between HIV-1 input copy and recovery in whole milk (r = 0.965, P < 0.0001), skim milk (r = 0.972, P < 0.0001), and the lipid fraction (r = 0.905, P < 0.001). PCR inhibition was observed in less than 10% of the spiked samples. Similar levels of inhibition were noted in BM samples collected from HIV-infected women. HIV proviral DNA was detected in BM samples using real-time PCR (linear correlation between the threshold cycle versus log DNA copy number, >0.982). The effects of incubation duration and temperature and repeated freeze-thaw cycles on HIV RNA recovery were analyzed. HIV RNA levels were remarkably stable in whole milk after three freeze-thaw cycles and for up to 30 h at room temperature. Our findings improve the understanding of the dynamics of HIV detection in BM and the conditions for BM sample collection, storage, and processing.

DNA, Viral↗

Mother-to-child discordance in HLA-G exon 2 is associated with a reduced risk of perinatal HIV-1 transmission.

Definitive genetic parameters correlating with mother-to-child transmission (MCT) of HIV have not been fully established. We screened for the potential correlation between HLA-G variants and MCT, in a cohort of mother-child pairs. Discordance in exon 2 of HLA-G was significantly more common among non-transmitting (93%) than transmitting mother-child pairs (40%). Our results suggest that mother-child pairs both carrying the identical mutation in HLA-G exon 2 may be at higher risk of MCT of HIV-1.

DNA, Viral↗

Human immunodeficiency virus type 1 envelope-stimulated interleukin-2 production and survival of infected children with severe and mild clinical disease.

Interleukin (IL)-2 production after stimulation with human immunodeficiency virus type 1 (HIV-1) envelope (Env) peptides, tetanus toxoid, and phytohemagglutinin was measured in peripheral blood mononuclear cells (PBMC) from 25 HIV-1-infected children with mild and 24 with severe clinical disease and from 15 uninfected children. Env-specific IL-2 production was detected in PBMC of 26.5% of HIV-1-infected children but in none of the uninfected. The absence of Env-specific responses at enrollment among infected children was associated with a 6-fold increased risk of mortality within a year, adjusting for clinical severity (P=.04). Among those with severe clinical disease, Env-stimulated IL-2 reactivity in PBMC was negatively correlated with HIV-1 RNA copy numbers in plasma at enrollment and was positively correlated with CD4 T cell percentages 1 year later. HIV-specific cellular immune responses may play a role in containing progression of HIV-1 infection in children, despite early deficits in cell-mediated immunity.

Child↗

Policy analysis of cervical cancer screening strategies in low-resource settings: clinical benefits and cost-effectiveness.

CONTEXT: Cervical cancer is a leading cause of cancer-related death among women in developing countries. In such low-resource settings, cytology-based screening is difficult to implement, and less complex strategies may offer additional options. OBJECTIVE: To assess the cost-effectiveness of several cervical cancer screening strategies using population-specific data. DESIGN AND SETTING: Cost-effectiveness analysis using a mathematical model and a hypothetical cohort of previously unscreened 30-year-old black South African women. Screening tests included direct visual inspection (DVI) of the cervix, cytologic methods, and testing for high-risk types of human papillomavirus (HPV) DNA. Strategies differed by number of clinical visits, screening frequency, and response to a positive test result. Data sources included a South African screening study, national surveys and fee schedules, and published literature. MAIN OUTCOME MEASURES: Years of life saved (YLS), lifetime costs in US dollars, and incremental cost-effectiveness ratios (cost per YLS). RESULTS: When analyzing all strategies performed as a single lifetime screen at age 35 years compared with no screening, HPV testing followed by treatment of screen-positive women at a second visit, cost $39/YLS (27% cancer incidence reduction); DVI, coupled with immediate treatment of screen-positive women at the first visit was next most effective (26% cancer incidence reduction) and was cost saving; cytology, followed by treatment of screen-positive women at a second visit was least effective (19% cancer incidence reduction) at a cost of $81/YLS. For any given screening frequency, when strategies were compared incrementally, HPV DNA testing generally was more effective but also more costly than DVI, and always was more effective and less costly than cytology. When comparing all strategies simultaneously across screening frequencies, DVI was the nondominated strategy up to a frequency of every 3 years (incremental cost-effectiveness ratio, $460/YLS), and HPV testing every 3 years (incremental cost-effectiveness ratio, $11 500/YLS) was the most effective strategy. CONCLUSION: Cervical cancer screening strategies that incorporate DVI or HPV DNA testing and eliminate colposcopy may offer attractive alternatives to cytology-based screening programs in low-resource settings.

Adult↗

Method of feeding and transmission of HIV-1 from mothers to children by 15 months of age: prospective cohort study from Durban, South Africa.

OBJECTIVE: To determine the risk of HIV transmission by infant feeding modality. DESIGN AND SETTING: A prospective study in two hospitals in Durban, South Africa. PARTICIPANTS: A total of 551 HIV-infected pregnant women enrolled in a randomized trial of vitamin A. INTERVENTIONS: Women self-selected to breastfeed or formula feed after being counselled. Breastfeeders were encouraged to practice exclusive breastfeeding for 3-6 months. MAIN OUTCOME MEASURES: Cumulative probabilities of detecting HIV over time were estimated using Kaplan-Meier methods and were compared in three groups: 157 formula-fed (never breastfed); 118 exclusively breastfed for 3 months or more; and 276 mixed breastfed. RESULTS: The three feeding groups did not differ in any risk factors for transmission, and the probability of detecting HIV at birth was similar. Cumulative probabilities of HIV detection remained similar among never and exclusive breastfeeders up to 6 months: 0.194 (95% CI 0.136-0.260) and 0.194 (95% CI 0.125-0.274), respectively, whereas the probabilities among mixed breastfeeders soon surpassed both groups reaching 0.261 (95% CI 0.205-0.319) by 6 months. By 15 months, the cumulative probability of HIV infection remained lower among those who exclusively breastfed for 3 months or more than among other breastfeeders (0.247 versus 0.359). CONCLUSION: Infants exclusively breastfed for 3 months or more had no excess risk of HIV infection over 6 months than those never breastfed. These findings, if confirmed elsewhere, can influence public health policies on feeding choices available to HIV-infected mothers in developing countries.

Breast Feeding↗

Secretory leukocyte protease inhibitor in vaginal fluids and perinatal human immunodeficiency virus type 1 transmission.

The presence of both viral particles and antiviral mucosal proteins may represent critical determinants of perinatal human immunodeficiency virus type 1 (HIV-1) transmission. In 60 HIV-1-infected women, concentrations of the innate mucosal protein, secretory leukocyte protease inhibitor (SLPI), were lower in vaginal fluid samples from 17 women whose babies became infected than in samples from nontransmitting women (mean+/-SE, 57+/-11 vs. 557+/-177 ng/mL, respectively; P=.01). Rates of transmission among women with higher SLPI concentrations (>100 ng/mL) were lower than those among women with lower concentrations (<100 ng/mL; 8.7% vs. 40.5%, respectively; P=.01). Concentrations of other putative HIV-1-inhibitory innate immune factors were similar in both groups. Concentrations of vaginal HIV-1 tended to be higher in transmitting than in nontransmitting women (407 vs. 174 virions/mL; P=.09). Increased concentrations of selected innate mucosal immune factors, such as SLPI, seem to be associated with reduced rates of perinatal HIV-1 transmission and may contribute to natural antiretroviral defense.

CD4 Lymphocyte Count↗

T-helper cell responses to HIV envelope peptides in cord blood: protection against intrapartum and breast-feeding transmission.

BACKGROUND: Acquired HIV-specific cell-mediated immune responses have been observed in exposed-uninfected individuals, and it has been inferred, but not demonstrated, that these responses constitute a part of natural protective immunity to HIV. This inference was tested prospectively in the natural exposure setting of maternal-infant HIV transmission in a predominantly breast-fed population. METHODS: Cord blood from infants of HIV-seropositive women in Durban, South Africa, were tested for in vitro reactivity to a cocktail of HIV envelope peptides (Env) using a bioassay measuring interleukin-2 production in a murine cell line. Infants were followed with repeat HIV RNA tests up to 18 months of age to establish which ones acquired HIV-infection. RESULTS: T-helper cell responses to Env were detected in 33 out of 86 (38%) cord blood samples from infants of HIV-seropositive women and in none of nine samples from seronegative women (P = 0.02). Among infants of HIV-seropositive mothers, three out of 33 with T-helper responses to Env were already infected before delivery (HIV RNA positive on the day of birth), two were lost to follow-up, and none of the others (out of 28) were found to be HIV infected on subsequent tests. In comparison, six out of 53 infants unresponsive to Env were infected before delivery, and eight out of 47 (17%) of the others were found to have acquired HIV infection intrapartum or post-partum through breast-feeding (P = 0.02). CONCLUSIONS: T-helper cell responses to HIV envelope peptides were detected in more than one-third of newborns of HIV-infected women; no new infections were acquired by these infants at the time of delivery or post-natally through breast-feeding if these T-helper cell responses were detected in cord blood.

Animals↗

Shape and size of isolated bone mineralites measured using atomic force microscopy.

The inorganic phase of bone is comprised primarily of very small mineralites. The size and shape of these mineralites play fundamental roles in maintaining ionic homeostasis and in the biomechanical function of bone. Using atomic force microscopy, we have obtained direct three-dimensional visual evidence of the size and shape of native protein-free mineralites isolated from mature bovine bone. Approximately 98% of the mineralites are less than 2 nm thick displaying a plate-like habit. Distributions of both thickness and width show single peaks. The distribution of lengths may be multimodal with distinct peaks separated by approximately 6 nm. Application of our results is expected to be of use in the design of novel orthopaedic biomaterials. In addition, they provide more accurate inputs to molecular-scale models aimed at predicting the physiological and mechanical behavior of bone.

Animals↗

Altered expression of L-selectin (CD62L) on polymorphonuclear neutrophils of children vertically infected with human immunodeficiency virus type 1.

The expression of the leukocyte adhesion molecule L-selectin (CD62L) on polymorphonuclear neutrophils (PMN) and circulating levels of the soluble form of the receptor (sCD62L) were determined for a group of HIV-1-infected children, categorized as having mild or severe disease, and a group of uninfected control children. The fluorescence intensity of CD62L on PMN was significantly reduced in the HIV-1-infected children with mild disease compared to the uninfected controls. The proportion of lymphocytes expressing CD62L, as well as their corresponding fluorescence intensities, was significantly reduced in both the mild and the severe disease groups compared to the uninfected children, while peripheral levels of sCD62L were significantly elevated in the HIV-1-infected children with mild and severe disease compared to the controls. Altered cell migration resulting from reduced expression of CD62L may be an important contributor to the increased susceptibility to secondary microbial infections seen in HIV-1-infected children.

AIDS-Related Opportunistic Infections↗

Reduced HIV-stimulated T-helper cell reactivity in cord blood with short-course antiretroviral treatment for prevention of maternal-infant transmission.

T-helper cell responses to HIV have been associated with protection against maternal-infant HIV transmission in the absence of antiretroviral treatment, but the effects of antiretroviral treatment, now widely used for prevention, on development of these cell-mediated responses is unknown. We tested whether development of T-helper cell responses to HIV and other antigens would be affected by exposure to short-course regimens of zidovudine-lamivudine (ZDV-3TC) given to prevent maternal-infant HIV transmission. Cord blood samples were collected from 41 infants of HIV-infected mothers enrolled in a clinical trial in which they were treated with regimens of ZDV-3TC and from 29 infants whose HIV-infected mothers were not treated with any antiretroviral drugs. T-helper cell reactivity to HIV envelope peptides and other antigens was measured in vitro using a sensitive culture supernatant titration assay based on IL-2-dependent proliferation. Infants in the clinical trial were followed to 18 months to determine their HIV infection status, and venous blood samples were re-tested at 4.5 and 9 months for T-cell reactivity to HIV. HIV-stimulated T-helper cell reactivity in cord blood was detected 10-fold less frequently among those exposed to antiretroviral prophylaxis (2.4%) than among those unexposed (24.1%) (P = 0.007). Reductions in HIV-stimulated responses in cord blood occurred despite detectable HIV RNA (mean 3.38 standard deviation 0.76 log(10) copies per ml) at delivery among treated women and occurred independent of treatment duration. Our results suggest that short-course antiretroviral treatment given to prevent maternal-infant HIV transmission may attenuate HIV-stimulated T-cell memory responses in the neonate.

Amino Acid Sequence↗

Defective neutrophil degranulation induced by interleukin-8 and complement 5a and down-regulation of associated receptors in children vertically infected with human immunodeficiency virus type 1.

The polymorphonuclear neutrophils (PMNs) of patients infected with human immunodeficiency virus type 1 (HIV-1) show impaired microbicidal responses. The present study assessed the functional integrity of PMN degranulation responses and the expression of specific receptors that mediate these responses in a group of children vertically infected with HIV-1. PMN degranulation in response to interleukin-8 (IL-8) and complement 5a (C5a) was measured in a group of HIV-1-infected children with mild and severe clinical disease and in an uninfected control group. In addition, the expression of CXCR1, CXCR2, and CD88 on whole-blood PMNs was quantified by flow cytometry. Although CXCR1 expression was found to be largely unaltered in the HIV-1-infected children relative to that in the control children, the intensity of CXCR2 expression was significantly reduced in those with severe disease. Furthermore, there was a significant reduction in the percentage of cells expressing CD88 and in the intensity of CD88 fluorescence in the HIV-1-infected children compared to that in control children, with CD88 fluorescence intensity more significantly reduced in the presence of severe disease. PMNs from a large proportion of the HIV-1-infected children either showed reciprocal degranulation responses or were unresponsive to IL-8 and C5a, whereas the PMNs from the uninfected children showed positive responses. Inefficient agonist-induced degranulation may contribute to the increased susceptibility of HIV-1-infected children to secondary microbial infections. Furthermore, reduced expression of CXCR2 and CD88 may be suggestive of defects in other functions of PMNs from HIV-1-infected children.

Age Factors↗

Interferon-gamma and interleukin-10 production among HIV-1-infected and uninfected infants of HIV-1-infected mothers.

Immunologic consequences of exposure to HIV-1 in utero are still poorly understood. This study investigates relationships between type-1 [interferon-gamma (IFN-gamma)] and type-2 (IL-10) cytokine production and maternal-infant HIV-1 transmission. Cord blood leukocytes from deliveries of 71 HIV-1-infected and 11 uninfected mothers were tested for in vitro IFN-gamma and IL-10 production after phytohemagglutinin (PHA) stimulation. The infants of these HIV-1-infected mothers were followed prospectively after birth to determine HIV vertical transmission, and IFN-gamma and IL-10 production was measured again at 6 mo. Median PHA-stimulated IFN-gamma production was 210 pg/mL in cord blood cells from infected and 73 pg/mL from uninfected mothers (p = 0.12), and median PHA-stimulated IL-10 production was 491 pg/mL in cord blood cells from infected and 161 pg/mL from uninfected mothers (p = 0.004). PHA-stimulated IFN-gamma and IL-10 production alone were not significantly associated with transmission, but relationships between the two cytokines differed among infected and uninfected infants of HIV-1-infected mothers. PHA-stimulated IFN-gamma and IL-10 production was positively correlated among infected (r = 0.7, p = 0.12 in cord blood and r = 0.66, p = 0.03 at 6 mo) but not uninfected infants, and stronger relative production of IFN-gamma to IL-10 was observed among exposed uninfected than among infected infants (p = 0.04). Exposure in utero to HIV-1 may augment production of IL-10 detectable in fetal cord blood. Stronger relative production of IFN-gamma to IL-10 in cord blood cells from infants of HIV-1-infected mothers may be associated with protection against perinatal HIV infection.

Female↗

Effects of vitamin A supplementation during pregnancy and early lactation on body weight of South African HIV-infected women.

Effects of vitamin A supplementation during pregnancy and early lactation on maternal weight among HIV-1-seropositive South African women were examined. Three hundred twelve HIV-seropositive pregnant women between 28 and 32 weeks gestation were studied as part of a randomized, double-blind, placebo-controlled trial at the King Edward VIII Hospital in Durban, South Africa. Patients were randomized to receive placebo or 5,000 IU of retinyl palmitate and 30 mg of beta-carotene daily during pregnancy. At delivery, patients received placebo or 200,000 IU of retinyl palmitate. The main outcome measures were prenatal and postnatal maternal weight and weight loss at three months after delivery as measured in body mass index (BMI). Supplementation of vitamin A was not associated with improvements in prepartum weight gain but was significantly associated with improved weight retention three to six months after delivery (p = 0.02). The benefit of vitamin A supplementation appeared to be confined to subgroups with baseline CD4+ count < 200 cells/microL and serum retinol 0-20 micrograms/dL. Similar trends were observed in maintenance of postpartum BMI. However, no statistically significant associations were observed. Although there was no benefit of vitamin A supplementation on prepartum weight gain, a benefit on maintenance of postnatal weight was observed. The benefit was highest among those who were vitamin A-deficient or whose CD4+ count was < 200 cells/microL presupplementation. In populations for whom antiretroviral therapy is not readily available or accessible, the finding that vitamin A may improve postpartum weight lends some hope to a relatively inexpensive treatment which could be used for helping ameliorate some weight loss which is common during HIV infection.

Adult↗