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Biomedical subjects

P Lepage

Publications and source records attributed to P Lepage.

At least 19 recordsLinked to original sources
PubMed1998

Care of human immunodeficiency virus-infected children in developing countries. International Working Group on Mother-to-Child Transmission of HIV.

CONTEXT: There is urgent need to strengthen the area of pediatric HIV/AIDS care in developing countries. Clinical research in this area is also scarce. METHODOLOGY: A literature review and a postal survey were used to obtain updated information on mortality, morbidity and current standards of care of children born to HIV-infected mothers in developing countries. A 2-day workshop was organized to review the available data and to identify the key areas where clinical research should be conducted. MAIN FINDINGS: Rates of mortality and morbidity were very different from one study to another but generally higher than in industrialized countries. Prognostic studies for HIV-1-infected children in developing countries were not available. Based on the report of 14 teams from 11 countries, specific protocols for HIV-infected children with persistent diarrhea or severe malnutrition were documented in fewer than one-half of the cases. Secondary antimicrobial prophylaxis after interstitial pneumonia or recurrent infections was still infrequent, as primary prophylaxis of opportunistic infections. The following list of clinical research priorities was identified by the workshop participants: primary prophylaxis of opportunistic and bacterial infections; case management of persistent diarrhea; reassessment of the performance of p24 antigen for diagnostic and prognosis use; studies on the etiology of pulmonary infections; long term observational pediatric cohorts; current weaning practices and duration of breast-feeding; counseling and HIV testing of children and families; prevention of HIV sexual transmission in children and adolescents.

AIDS Serodiagnosis↗
PubMed1998

Mother-to-child transmission of HIV.

The first children with HIV-1 infection were described in 1983. As of 1998, the global HIV epidemic is having a profound impact on the health and survival of children. Almost all HIV infections among young children are due to vertical transmission, and the intrapartum period appears to provide us with a crucial window of opportunity for prevention. Postnatal transmission through breastfeeding also contributes an estimated one third to one half of vertical transmission worldwide. Carefully conducted epidemiologic studies are elucidating the immunologic, virologic, and behavioral factors affecting the risk of HIV-1 transmission from mother to infant and the natural history of HIV disease in perinatally infected children. Transmission of HIV-1 is influenced by many factors, and a high maternal viral load is insufficient to fully explain vertical transmission of HIV-1. Pediatricians and other providers should counsel HIV-infected women about the means available to decrease the risk of HIV transmission to the infant. However, the majority of HIV-infected children are born in the developing world, and a crucial challenge is to identify safe and effective interventions that are feasible in those countries with the most significant HIV burden.

Adult↗
PubMed1997

High-resolution linkage map in the proximity of the host resistance locus Cmv1.

The mouse chromosome 6 locus Cmv1 controls replication of mouse Cytomegalovirus (MCMV) in the spleen of the infected host. In our effort to clone Cmv1, we have constructed a high-resolution genetic linkage map in the proximity of the gene. For this, a total of 45 DNA markers corresponding to either cloned genes or microsatellites were mapped within a 7.9-cM interval overlapping the Cmv1 region. We have followed the cosegregation of these markers with respect to Cmv1 in a total of 2248 backcross mice from a preexisting interspecific backcross panel of 281 (Mus spretus x C57BL/6J)F1 x C57BL/6J and 2 novel panels of 989 (A/ J x C57BL6)F1 x A/J and 978 (BALB/c x C57BL/6J)F1 x BALB/c segregating Cmv1. Combined pedigree analysis allowed us to determine the following gene order and intergene distances (in cM) on the distal region of mouse chromosome 6: D6Mit216-(1.9)-D6Mit336-(2.2)- D6Mit218-(1.0)-D6Mit52-(0.5)-D6Mit194-(0.2)-Nkrp 1/ D6Mit61/135/257/289/338-(0.4)-Cmv1/Ly49A/D6Mit370++ +- (0.3)-Prp/Kap/D6Mit13/111/219-(0.3)-Tel/D6Mit374/290/ 220/196/195/110-(1.1)-D6Mit25. Therefore, the minimal genetic interval for Cmv1 of 0.7 cM is defined by 13 tightly linked markers including 2 markers, Ly49A and D6Mit370, that did not show recombination with Cmv1 in 1967 meioses analyzed; the proximal limit of the Cmv1 domain was defined by 8 crossovers between Nkrp1/ D6Mit61/135/257/289/338 and Cmv1/Ly49A/D6Mit370, and the distal limit was defined by 5 crossovers between Cmv1/Ly49A/D6Mit370 and Prp/Kap/D6Mit13/111/219. This work demonstrates tight linkage between Cmv1 and genes from the natural killer complex (NKC), such as Nkrp1 and Ly49A, suggesting that Cmv1 may represent an NK cell recognition structure encoded in the NKC region.

3T3 Cells↗
PubMed1996

Natural resistance to intracellular infections: Nramp1 encodes a membrane phosphoglycoprotein absent in macrophages from susceptible (Nramp1 D169) mouse strains.

The mouse Nramp1 gene (Bcg/Ity/Lsh) controls innate defense to infection with intracellular parasites such as Mycobacterium, Salmonella, and Leishmania. Sequence analysis of Nramp1 predicts a hydrophobic, membrane-associated protein expressed exclusively in monocyte/macrophage lineages. A single G169D substitution within the fourth predicted transmembrane domain of Nramp1 is associated with susceptibility to infection (Bcg) in inbred mouse strains. To initiate the biochemical characterization of the Nramp1 protein and to analyze the molecular basis of susceptibility associated with the Nramp1(D169) allele, oligopeptides derived from Nramp1 and two fusion proteins containing the first 54 and the last 35 residues of Nramp1 were used to raise specific anti-Nramp1 antisera. In addition, a c-Myc epitope (EQKLISEEDL) was introduced in-frame at the C terminus of Nramp1 to follow its expression in a yeast heterologous system. Western analysis of crude membrane fractions from yeast demonstrated that Nramp1 is indeed an integral membrane protein (resistant to urea extraction). In resident Bcg(r) (129sv, Nramp1(G169)) macrophages, one of the anti-Nramp1 antisera identified by immunoprecipitation a protein of 90,000 to 100,000 apparent m.w. that was absent in macrophages from knockout mice bearing a null mutation at Nramp1. The Nramp1 protein could be metabolically labeled with orthophosphate and was sensitive to glycosylase treatment, verifying that Nramp1 is an integral membrane phosphoglycoprotein. Parallel analysis of macrophage extracts from Bcg(s) mouse strains (C57BL6/J and BALB/c, Nramp1(D169)) failed to detect mature Nrampl protein in these cells, suggesting that the G169D mutation at Nramp1 prevents proper maturation or membrane integration of the protein, resulting in its rapid degradation.

Amino Acid Sequence↗
PubMed1996

The contribution of lysine-36 to catalysis by human myo-inositol monophosphatase.

The role of lysine residues in the catalytic mechanism of myo-inositol monophosphatase (EC 3.1.3.25) was investigated. The enzyme was completely inactivated by amidination with ethyl acetimidate or reductive methylation with formaldehyde and cyanoborohydride. Activity was retained when the active site was protected with Mg2+, Li+, and D,L-myo-inositol 1-phosphate. Using radiolabeling, peptide mapping, and sequence analysis, Lys-36 was shown to be the protected residue, which is responsible for inactivation. Replacing Lys-36 with glutamine produced a mutant protein, K36Q, with similar affinities for the substrate and the activator Mg2+, but a 50-fold lower turnover number as compared to the wild-type enzyme. Crystallographic studies did not indicate any gross structural changes in the mutant as compared to the native form. Initial velocity data were best described by a rapid equilibrium ordered mechanism with two Mg2+ binding before and a third one binding after the substrate. Inhibition by calcium was unaffected by the mutation, but inhibition by lithium was greatly reduced and became noncompetitive. The pH dependence of catalysis and the solvent isotope effect on kcat are altered in the mutant enzyme. D,L-myo-Inositol 1-phosphate, 4-nitrophenyl phosphate, and D-glucose 6-phosphate are cleaved at different rates by the wild-type enzyme, but with similar efficiency by K36Q. All data taken together are consistent with the hypothesis that modifying or replacing the lysine residue in position 36 decreases its polarizing effect on one of the catalytic metal ions and prevents the efficient deprotonation of the metal-bound water nucleophile.

Base Sequence↗
PubMed1996

Growth of human immunodeficiency type 1-infected and uninfected children: a prospective cohort study in Kigali, Rwanda, 1988 to 1993.

OBJECTIVE: To compare the anthropometric characteristics of children with and without HIV-1 infection. METHODS: In a prospective cohort study of 218 children born to HIV-1 seropositive mothers and 218 children born to HIV-1 seronegative mothers in Kigali, Rwanda, 3 groups were compared: infected children (n = 46); uninfected children born to seropositive mothers (n = 140); and uninfected children born to seronegative mothers (n = 207). Weight, height and head circumference were measured at birth, every 3 months during the first year of life and every 6 months thereafter. The weight-for-age, height-for-age, weight-for-height and head circumference-for-age mean z scores were calculated. RESULTS: The weight-for-age, height-for-age and head circumference-for-age mean z scores were lower among HIV-infected children than among uninfected ones at each time period. The reduction in the weight-for-age mean z score was the greatest between 12 and 36 months. The reduction in the height-for-age mean z score of HIV-infected children was persistently below 2 SD after 9 months of age. On the other hand the weight-for-height mean z score was not consistently lower in HIV-infected children when compared with uninfected ones. The anthropometric characteristics of uninfected children born to seropositive mothers were similar to those of children born to seronegative mothers. CONCLUSIONS: In this study HIV-infected children were more frequently stunted (low height-for-age) than uninfected ones. Wasting (low weight-for-height) was not common among HIV-infected children.

Adult↗
PubMed1996

[Management of febrile infants under 3 years old].

Fever is a common symptom in young infants. However, it is often difficult to differentiate young children with severe bacterial infections (SBI) from those with benign febrile illnesses. Clinical, biological and radiological criteria, alone or combined, do not allow to identify with precision young infants with SBI. Simple criteria--including medical history, clinical and hematological evaluation (the "Rochester criteria")--have been proposed by North American clinicians to identify young febrile children at low risk of SBI. These criteria have been validated on large numbers of children in various countries. Their application in different clinical situation is discussed in this article.

Bacterial Infections↗
PubMed1995

Four years of natural history of HIV-1 infection in african women: a prospective cohort study in Kigali (Rwanda), 1988-1993.

Clinical features and mortality due to human immunodeficiency virus type-1 (HIV-1) infection in women are described as part of a prospective 4-year cohort study on perinatal transmission of HIV in Kigali, Rwanda. Two hundred fifteen HIV-seropositive (HIV+) and 216 HIV-seronegative (HIV-) pregnant women were enrolled at delivery between November 1988 and June 1989. Clinical information collected during systematic quarterly examinations was compared. HIV antibody tests were performed at delivery and CD4/CD8 lymphocyte counts at 15 days' postpartum. HIV--women who seroconverted during the follow-up period were excluded from the analysis of the comparison group starting at the date of seroconversion. At enrollment, all HIV+ women were asymptomatic for acquired immune deficiency syndrome (AIDS). Incidence of tuberculosis was 2.9 per 100 women-years (WY) after 4 years of follow-up in HIV+ women versus 0.2 per 100 WY among HIV- women (relative risk, 18.2; 95% confidence interval 2.4-137.0). Among HIV+ women, the incidence of AIDS (World Health Organization clinical AIDS definition) was 3.5 per 100 WY. The mortality rate was 4.4 per 100 WY among HIV+ women versus 0.5 per 100 WY among HIV- women. Clinical AIDS was present in only half of the fatalities. Tuberculosis was a major cause of morbidity and mortality in these HIV+ African women. An early diagnosis and an appropriate treatment or prevention of tuberculosis should improve the quality of life of HIV-infected patients in Africa.

Adult↗
PubMed1995

Activation of a MMTV/mdr3 fusion transcript from a cryptic viral promoter is stimulated by mdr-derived sequences located in intron I.

In P388/VCR-10 cells, resistance to cytotoxic drugs is caused by the overexpression of the mdr3 gene, in absence of gene amplification. The gene is transcriptionally activated following integration of a full-length mouse mammary tumor virus (MMTV) within intron I, upstream of the coding region of the gene. This integration results in the production of MMTV/mdr3 fusion transcripts that originate from the antisense 5'LTR of the provirus. The mechanism of mdr3 activation in these cells remains unclear since it cannot be accounted for either by activation from the normal MMTV promoter or by activation of the mdr3 promoter by MMTV enhancer sequences. Subcloning and sequence analysis of the genomic region encompassing the 5' LTR of the provirus with adjacent mdr3 sequences up to exon 2 showed that the LTR had not undergone small rearrangements or deletions. Transfections of fusion plasmids containing this genomic fragment and the reporter gene luciferase showed the presence of transcriptionally active sequences in that region. Deletions of 5' and 3' sequences from this fragment have shown that the antisense LTR itself has little contribution to the activation of the luciferase gene, whereas the mdr3 derived sequences that include part of intron I and the beginning of exon 2 strongly activated luciferase expression when inserted in either orientations upstream of the reporter gene. These results suggest the presence of an activator element within intron I of mdr3 capable of activating transcription from a cryptic start site present in the antisense MMTV LTR. Derepression of this activator sequence within intron I by a mechanism involving integration of a transposable element may be a prerequisite to transcriptional activation of the gene which is silent in the parental P388 cells. Further support for a derepression mechanism of activation in P388 cells is provided by the identification of independent genomic rearrangements in the 5' region of mdr3 in additional MDR P388 derivatives analyzed in this study.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Genomic structure, promoter sequence, and induction of expression of the mouse Nramp1 gene in macrophages.

A candidate gene for the mouse chromosome 1 host resistance locus Bcg/Ity/Lsh was recently cloned and designated Nramp (natural resistance-associated macrophage protein). Nramp is part of a small family of at least two genes, Nramp1 and Nramp2. Primer extension and cDNA cloning were used to isolate the complete 5' end of the Nramp1 mRNA. Analysis of genomic cosmid and bacteriophage clones overlapping the complete Nramp1 gene revealed that the gene was composed of 15 exons and spanned 11.5 kb of genomic DNA. Positioning of introns on the coding portion of the mRNA revealed a modular relationship between coding exons and predicted structural domains of the protein, with 8 of the 12 transmembrane (TM) domains encoded by individual exons. Northern blotting analysis indicated that Nramp1 expression was restricted to J774A.1 and RAW 264.7 macrophage lines and was dramatically increased by treatment with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Primer extension and S1 nuclease mapping experiments were used to locate the transcription initiation site of Nramp1 and revealed the presence of one major and several minor initiation sites. Nucleotide sequencing of the corresponding region failed to detect classical TATA and CAAT elements, but identified two putative initiator sequences located near the major initiation site. Consensus sequences for binding of the macrophage and B-cell-specific transcription factor PU.1, as well as several LPS (NF-IL6) and IFN-gamma response elements, were also identified.

Amino Acid Sequence↗
PubMed1995

Rwanda.

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Homicide↗
PubMed1995

[Septic meningitis in children in Rwanda from 1983 to 1990. Retrospective study at the Kigali Hospital Center].

To assess septic meningitis in pediatric units in terms of the bacteriologic distribution, mortality, and groups at risk, we conducted a retrospective study in the pediatric department of the Kigali Hospital Center (Rwanda). Based on bacteriologic study of 1215 cerebrospinal fluid samples, there were 321 cases of septic meningitis due to identifiable germs and 68 involving cloudy fluid with no detectable germs, i.e. 1.5% of admissions to the Pediatric Unit of the Kigali Hospital Center. The most common organisms were pneumococcus (36.5%), Haemophilus influenzae (31%), salmonella (13%), and meningococcus (11.5%). Most of the children (75%) presenting septic meningitis were under the age of 5 years. Overall mortality was 38% with rates of 52% and 39% for cases involving pneumococcus and salmonella respectively. The predominant clinical symptoms of pneumococcus meningitis were coma (p:0.000055) and respiratory compromise (p:0.02). In contrast Haemophilus influenzae meningitis was associated with a lower incidence of coma (p:0.05) and malnutrition (p:0.017). Salmonella meningitis was characterized by a higher incidence of fever over 38.9 degrees C (p:0.025) and malnutrition (p:0.01). In patients with meningococcus meningitis, the incidence of convulsions appeared to be higher, at the threshold of statistical significance (p:0.052), whereas coma (p:0062) and respiratory distress (p:0.0024) were uncommon. Independently of etiology, no clinical symptom was associated with a statistically higher risk for death.

Adolescent↗
PubMed1994

P-glycoprotein homologues.

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ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Seroincidence of HIV-1 infection in African women of reproductive age: a prospective cohort study in Kigali, Rwanda, 1988-1992.

OBJECTIVE: To estimate the seroincidence of HIV-1 infection among women of reproductive age in Kigali, Rwanda. DESIGN: Fixed prospective cohort followed for 36 months between November 1988 and June 1992, as part of an ongoing study of mother-to-child transmission of HIV-1. SETTING: Centre Hospitalier, Kigali, Rwanda. SUBJECTS: A total of 216 HIV-seronegative women were enrolled at delivery between November 1988 and June 1989. METHODS: A blood sample was obtained at delivery to test for HIV antibodies (by enzyme-linked immunosorbent assay and Western blot). Serum was tested every 3 months during follow-up. Incidence density rates of HIV seroconversion were estimated. RESULTS: The follow-up rate after 3 years was 89%, assessed by the maximum person-years method. The seroincidence density rate was 3.5 per 100 women-years (95% confidence interval, 1.9-5.0). It decreased linearly from 7.6 during the first 6-months postpartum to 2.5 per 100 women-years during the last 6 months of the third year of follow-up. Maternal age did not affect HIV incidence rates. We examined the role of the cohort, counselling, and the first 6-month postpartum effects on this estimate. CONCLUSION: This fixed cohort provided an overall estimation of the HIV infection incidence rate and its dynamics. These figures could be used for programming future HIV preventive vaccine efficacy trials in Rwanda.

Adolescent↗
PubMed1994

Will robots ever replace attendants? Exploring the current capabilities and future potential of robots in education and rehabilitation.

This article describes the current capabilities and future potential of robots designed as supplements or replacements for human assistants or as tools for education and rehabilitation. A number of researchers have developed and tested a variety of robot assistants for individuals with disabilities. These robots can usually be classified as educational, vocational or independent-living assistants. Robots in all three categories are reviewed. A brief summary of the critical characteristics of human service robots is also presented and the limitations of current technology are discussed. Finally, current research aimed at addressing these limitations is described. White robots of all kinds have proven much more difficult to develop than people had expected, we conclude that it will eventually be possible to create an effective, reliable robot for human service tasks, but not as quickly as was predicted in the early 1980s.

Activities of Daily Living↗