Episiotomy: a form of genital mutilation.
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Episiotomy↗
Biomedical subjects
M Girard
Publications and source records attributed to M Girard.
Expression and detection of macrophage-tropic HIV-1 gp120 in the brain using conformation-dependent antibodies.
HIV-1 envelope proteins gp120 and gp41 are likely to play a role in the pathogenesis of HIV-associated neurocognitive disorders. While detection of gp120 in HIV-infected cell cultures is easy, it has not yet been possible to identify gp120 in human or animal brains in situ. The difficulty in detecting gp120 could be due to low expression levels of the protein, to the shedding of gp120 from infected macrophages/microglia, or to the use of inappropriate gp-specific antibodies. We addressed these questions by analyzing the subcellular localization, oligomeric structure, and shedding behavior of gp120 from a macrophage-tropic, CCR5-dependent primary isolate, BX08, expressed by a Semliki Forest virus replicon (SFVenvBX08) in vitro. We used the same SFV system injected in vivo into the rat brain in an attempt to detect gp120 in situ. Our results show that gp120/41 is expressed as monomers, dimers, and trimers in cell culture. Immunocytochemical analysis revealed that intracytoplasmic gp120 can be recognized by an anti-V3 antibody, whereas gp120 at the plasma membrane is detected exclusively by a conformation-dependent antibody. In the rat brain, the SFV vector allows gene expression in neurons from day 3 to day 9 after injection without any apparent brain damage nor reactive astrogliosis. In SFVenvBX08-infected neurons only conformation-dependent antibodies allowed gp120 labeling. These results suggest that previous difficulties in detecting gp120 in brain tissues may be due to the use of antibodies which were unable to recognize gp120 at the plasma membrane.
Animals↗
Role of the HIV type 1 glycoprotein 120 V3 loop in determining coreceptor usage.
Macrophage (M)-tropic HIV-1 isolates use the beta-chemokine receptor CCR5 as a coreceptor for entry, while T cell line-adapted (TCLA) strains use CXCR4 and dual-tropic strains can use either CCR5 or CXCR4. To investigate the viral determinants involved in choice of coreceptor, we used a fusion assay based on the infection of CD4+ HeLa cells that express one or both coreceptors with Semliki Forest virus (SFV) recombinants expressing the native HIV-1 gp160 of a primary M-tropic isolate (HIV-1BX08), a TCLA isolate (HIV-1LAI), or a dual-tropic strain (HIV-1MN). We examined whether the V3 region of these glycoproteins interacts directly with the corresponding coreceptors by assaying coreceptor-dependent cell-to-cell fusion mediated by the different recombinants in the presence of various synthetic linear peptides. Synthetic peptides corresponding to different V3 loop sequences blocked syncytium formation in a coreceptor-specific manner. Synthetic V2 peptides were also inhibitory for syncytium formation, but showed no apparent coreceptor specificity. A BX08 V3 peptide with a D320 --> R substitution retained no inhibitory capacity for BX08 Env-mediated cell-to-cell fusion, but inhibited LAI Env-mediated fusion as efficiently as the homologous LAI V3 peptide. The same mutation engineered in the BX08 env gene rendered it able to form syncytia on CD4+CXCR4+CCR5-HeLa cells and susceptible to inhibition by SDF-1alpha and MIP-1beta. Other substitutions tested (D320 --> Q/D324 --> N or S306 --> R) exhibited intermediate effects on coreceptor usage. These results underscore the importance of the V3 loop in modulating coreceptor choice and show that single amino acid modifications in V3 can dramatically modify coreceptor usage. Moreover, they provide evidence that linear V3 loop peptides can compete with intact cell surface-expressed gp120/gp41 for CCR5 or CXCR4 interaction.
Amino Acid Sequence↗
Hypoxia-induced loss of synaptic transmission is exacerbated in hippocampal slices of transgenic mice expressing C-terminal fragments of Alzheimer amyloid precursor protein.
To investigate the possible involvement of beta-amyloid (A beta) in disrupting neuronal function during ischemia, we examined whether overexpression of C-terminal fragments of beta-amyloid precursor protein (beta-APP) in transgenic (Tg) mice is capable of altering the capacity of hippocampus slices to recover synaptic transmission after transient hypoxic episodes. Recovery of synaptic transmission was monitored in area CA1 of perfused hippocampal slices prepared from both control and Tg mice. The results obtained indicate that hippocampal slices prepared from Tg mice exhibited a much lower level of recovery in synaptic transmission following reoxygenation. This reduction in the capacity of Tg slices to recover from hypoxia-induced impairment of synaptic transmission in the hippocampus does not appear to be related to pre-existing alterations in either functional or biochemical properties of glutamate receptors in Tg mice. The present results provide the first experimental evidence that overexpression of the C-terminal fragment of APP exacerbates functional damage of hippocampal neurons after hypoxic episodes.
Amyloid beta-Protein Precursor↗
Spinal procaine with and without epinephrine and its relation to transient radicular irritation.
PURPOSE: To document the clinical characteristics of procaine with or without the addition of epinephrine. METHODS: In this randomized, prospective, double blind study, 62 patients received spinal anesthesia with 100 mg procaine and either 0.3 mg epinephrine (EPI group) or 0.3 ml NaCl 0.9% (SALINE group). Sensory anesthesia to needle prick was evaluated q 1 min for 10 min, q 3 min for 33 min and q 5 min until regression to L4. Motor block was assessed with the Bromage scale. Patients were questioned, by telephone, for transient radicular irritation (TRI) 48 hr later. RESULTS: Time to reach highest sensory level and number of segments blocked showed no difference. Mean time for regression of the sensory level to T10 was longer in EPI (83 +/- 23 vs 66 +/- 20 min, P < 0.01). Time to recuperate to full flexion of knees and feet (Bromage 4) was longer in EPI (126 +/- 37 vs 100 +/- 30 min, P < 0.01). Patients in EPI received more ephedrine. Eighteen patients had nausea (15 EPI/3 SALINE, P < 0.0015). One patient had TRI, incidence: 1.67%, 95% CI (< 1%-9%). CONCLUSION: Spinal procaine is appropriate for surgery of short duration. Epinephrine prolongs sensory and motor blocks by 25%. However, it is associated with a high incidence of nausea.
Adult↗
New prospects for the development of a vaccine against human immunodeficiency virus type 1. An overview.
During the past few years, definite progress has been made in the field of human immunodeficiency virus type 1 (HIV-1) vaccines. Initial attempts using envelope gp120 or gp140 from T-cell line-adapted (TCLA) HIV-1 strains to vaccinate chimpanzees showed that neutralizing antibody-based immune responses were protective against challenge with homologous TCLA virus strains or strains with low replicative capacity, but these neutralizing antibodies remained inactive when tested on primary HIV-1 isolates, casting doubts on the efficacy of gp120-based vaccines in the natural setting. Development of a live attenuated simian immunodeficiency virus (SIV) vaccine was undertaken in the macaque model using whole live SIV bearing multiple deletions in the nef, vpr and vpx genes. This vaccine provided remarkable protective efficacy against wild-type SIV challenge, but the deletion mutants remain pathogenic, notably in neonate monkeys. Study of the mechanisms of protection in the SIV model unravelled the importance of the T-cell responses, whether in the form of cytotoxic T-lymphocyte (CTL) killing activity, or in that of antiviral factor secretion of cytokines, beta-chemokines and other unidentified antiviral factors by CD8+ T-cells. Induction of such a response is being sought at this time using various live recombinant virus vaccines, either poxvirus or alphavirus vectors or DNA vectors, which can be combined together or with a gp120/gp140 boost in various prime-boost combination strategies. New vectors include attenuated vaccinia virus NYVAC, modified vaccinia strain Ankara (MVA), Semliki Forest virus, Venezuelan equine encephalitis virus, and Salmonellas. Recent DNA prime-poxvirus boost combination regimens have generated promising protection results against SIV or SIV/HIV (SHIV) challenge in macaque models. Emphasis is also put on the induction of a mucosal immune response, involving both a secretory IgA response and a mucosal CTL response which could constitute a 'first line of defence' in the vaccinated host. Finally, a totally novel vaccine approach based on the use of Tat or Tat and Rev antigens has been shown to induce efficient protection from challenge with pathogenic SIV or SHIV in vaccinated macaques. The only vaccine in phase 3 clinical trials in human volunteers is a gp120-based vaccine, AIDSVAX. A prime-boost combination of a recombinant canarypoxvirus and a subunit gp120 vaccine is in phase 2. Emphasis has been put recently on the necessity of testing prototype vaccines in developing countries using immunogens derived from local virus strains. Trial sites have thus been identified in Kenya, Uganda, Thailand and South Africa where phase I trials have begun or are expected to start presently.
AIDS Vaccines↗
Effect of the laryngeal mask airway on oesophageal pH: influence of the volume and pressure inside the cuff.
We studied gastro-oesophageal reflux (GOR) with a face mask and laryngeal mask airway (LMA), and the effects of inflation pressure and volume of the LMA cuff on oesophageal pH, in 60 patients. Patients were managed with either a face mask (group I) or LMA inflated to obtain a seal in the anaesthesia circuit at 7 cm H2O (group II) or 15 cm H2O (group III). A pH-sensitive probe with two electrodes, 10 cm apart, was placed in the oesophagus during anaesthesia and recordings were made continuously until patients awakened. There was a significant difference in the incidence of GOR between the face mask (group I) and the LMA (groups II-III) (P < 0.05) in the lower oesophagus but there was no difference in the mid-oesophagus. No correlation was found between pressure and volume inside the cuff and variations in oesophageal pH. We conclude that LMA use was associated with increased reflux in the low oesophagus but oesophageal pH was not influenced by variations in pressure or volume inside the LMA cuff.
Adult↗
[Antiviral vaccines].
Vaccination has been successful in controlling numerous diseases in man and animals. Smallpox has been eradicated and poliomyelitis is on the verge of being eradicated. The traditional immunization arsenal includes vaccines using live, attenuated, and inactivated organisms. DNA recombinant technology has added two new types of vaccines, i.e. subunit vaccines based on purified antigens produced by genetic engineering in bacterial, yeast, or animal-cell cultures and live recombinant vaccines based on attenuated bacterial or viral vectors. Currently the best known examples of these new vaccines are those using poxvirus vectors (vaccinia virus, canarypox virus, or fowlpox virus) but new vectors are under development. Another application for genetic engineering in the field of vaccinology is the development of DNA vaccines using naked plasmid DNA. This technique has achieved remarkable results in small rodents but its efficacy, safety, and feasibility in man has yet to be demonstrated. Numerous studies are now under way to improve the process. In the field of synthetic vaccines, lipopeptides have shown promise for induction of cell immune response. Development of vaccines for administration by the oral or nasal route may one day revolutionize vaccination techniques. However, effective vaccines against hepatitis C and HIV have stalled in the face of the complexity and pathophysiology of these diseases. These are the greatest challenges confronting scientists at the dawn of the new millennium.
AIDS Vaccines↗
Genital infection of female chimpanzees with human immunodeficiency virus type 1.
To develop an animal model for mucosal HIV-1 infection, adult chimpanzees were inoculated without trauma by depositing the virus inoculum at the entrance to the cervical canal with a rigid catheter to which flexible tubing was attached. By this procedure, persistent infections were established in some chimpanzees with various infectious doses of either cell-associated HIV-1LAI(IIIB) (peripheral blood mononuclear cells from an infected chimpanzee) or with cell-free HIV-1 strains representing subtypes B and E, but not with a subtype A strain. Although some animals did not become infected until after the second or third cervicovaginal exposure, one chimpanzee was clearly infected after one exposure by several criteria, including virus isolation, but this animal did not seroconvert. A second chimpanzee appeared to be resistant to infection despite repeated mucosal exposures at irregular intervals. However, lymphocytes from both of these animals exhibited low-level proliferative responses to HIV-1 but not SIV antigens. Despite these apparently abortive or latent infections, after exposure to HIV-1 by the intravenous route, both animals developed systemic infections and seroconverted. Overall, 8 of 10 chimpanzees were infected systemically after one to three cervicovaginal exposures to HIV-1LAI(IIIB). The results indicate that (1) HIV-1 productive infection of female chimpanzees by the cervicovaginal route generally requires more than one exposure, just as with humans; (2) low level infections without seroconversion can be established after mucosal exposure to HIV; and (3) vaccine efficacy studies involving a single virus challenge of immunized chimpanzees by the cervicovaginal route probably will not be possible.
Animals↗
Fine specificity of anti-V3 antibodies induced in chimpanzees by HIV candidate vaccines.
The fine specificity of the anti-V3 antibody responses induced in chimpanzees immunized by various human immunodeficiency type 1 (HIV-1) candidate vaccines and challenged by heterologous strains of HIV-1 was analyzed by enzyme-linked immunosorbent assay (ELISA) and Pepscan epitope mapping. Two chimpanzees immunized with the recombinant canarypox virus ALVAC-HIV (vCP125) expressing gp160MN and boosted with purified gp160MN/LAI alone, then with both immunogens in combination, were not protected against challenge with HIV-1 SF2. Their sera mainly recognized one epitope of the V3 loop, located in the NH2-terminal half. By contrast, immunization of two other chimpanzees with purified gp160MN/LAI and boosting with a synthetic V3MN peptide elicited a strong anti-V3 antibody response with a broader specificity directed against multiple epitopes all along the V3 loop. These chimpanzees were protected against infection by HIV-1 SF2. However, when these two chimpanzees were challenged later with a HIV-1 clade E strain virus, they became infected. We failed to detect any reactivity with the peptide of the ectodomain of gp41 of sera harvested after immunization with the various immunogens or after challenge with HIV-1 SF2 or HIV-1 90CR402. These results demonstrated that anti-V3 antibodies with a restricted fine specificity were induced in chimpanzees immunized with gp160 purified or expressed by recombinant canarypox confirming our previous results obtained in three different species (human, guinea pig and, macaque). In contrast, a boost with the V3 peptide broadened antibody responses, suggesting that the mode of presentation of the V3 loop to the immune system strongly influences the epitope specificity of the resulting antibody response.
AIDS Vaccines↗
Groundwater contamination by nitrates associated with intensive potato culture in Québec.
In rural areas, groundwater contamination by nitrates is a problem related to the spreading of organic and chemical fertilizers by farmers and, to some extent, to effluents from domestic sewage systems. Health effects of groundwater contamination by nitrates have been assessed several times and may lead to important consequences for infants. Following pressures from citizens in 1990, a survey of well water quality around potato fields of the Portneuf county (Québec) found that nitrate contamination was frequently above the 10 mg-N/1 standard. Because this first survey was limited to areas of intensive potato culture, it was not possible to evaluate the real impact on the groundwater quality for the whole county and the subsequent public health intervention was spread over the entire region. A second survey was carried out in 1995 to reevaluate the situation using random sampling methods. This latter study took into account drinking water habits of the population, the relative importance of potato culture as a source of nitrogen loading, the effects of soil types, and waste-water disposal systems as well as land use on nitrate concentration in private well water. The data analysis was carried out by combining GIS and statistical methods to test hypotheses about the spatial relationship linking measured nitrate concentrations with their immediate environment. This paper presents the major findings from this second study which confirm the impact of intensive potato culture on groundwater nitrate concentrations, mainly localized in sandy soil areas within 2 km of fields. Finally, it illustrates the usefulness of GIS to focus public health interventions.
Agriculture↗
Mercury levels in the Cree population of James Bay, Quebec, from 1988 to 1993/94.
BACKGROUND: High levels of mercury in the Cree population of James Bay, Que., have been a cause of concern for several years. This study examines changes in mercury levels within the Cree population between 1988 and 1993/94 and identifies potential determinants of high mercury levels. METHODS: Data on mercury levels among the Cree were obtained through a surveillance program undertaken by the Cree Board of Health and Social Services of James Bay. In 1988 and again in 1993/94 surveys were carried out in all 9 Cree communities of northern Quebec. Hair samples were obtained and analysed for mercury content. Analyses were carried out to determine the proportion of people who had mercury levels in excess of established norms. Changes in mercury levels between 1988 and 1993/94 and determinants of high levels were estimated by means of regression methods. RESULTS: The proportion of the Cree population with mercury levels in excess of 15.0 mg/kg declined from 14.2% in 1988 to 2.7% in 1993/94. Wide variations in mercury levels were observed between communities: 0.6% and 8.3% of the Eastmain and Whapmagoostui communities respectively had mercury levels of 15.0 mg/kg or greater in 1993/94. Logistic regression analyses showed that significantly higher levels of mercury were independently associated with male sex, increasing age and trapper status. There was a correlation between the mercury level of the head of the household and that of the spouse. INTERPRETATION: Mercury levels in the Cree of James Bay have decreased in the recent past. Nevertheless, this decrease in mercury levels may not be permanent and does not necessarily imply that the issue is definitively resolved.
Adolescent↗
Quinolines as potent 5-lipoxygenase inhibitors: synthesis and biological profile of L-746,530.
Leukotriene biosynthesis inhibitors have potential as new therapeutic agents for asthma and inflammatory diseases. A series of novel substituted 2-cyanoquinolines have been synthesized and the structure activity relationships were evaluated with respect to their ability to inhibit the formation of leukotrienes via the 5-lipoxygenase enzyme. [1S,5R]-2-Cyano-4-(3-furyl)-7-¿3-fluoro-5-[3-(3 alpha-hydroxy-6,8-dioxabicyclo[3.2.1]-octanyl)]phenoxymethyl ¿quinoline (L-746,530) 3 represents a distinct class of inhibitors and possesses in vitro and in vivo potency comparable or superior to naphthalenic analog (L-739,010) 2.
Bridged Bicyclo Compounds↗
Tuohy needles and CSE.
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Anesthesia, Epidural↗
Loss of CD4+ T cells in human immunodeficiency virus type 1-infected chimpanzees is associated with increased lymphocyte apoptosis.
Supportive evidence that apoptosis contributes to loss of CD4+ lymphocytes in human immunodeficiency virus type 1 (HIV-1)-infected humans comes from an apparent lack of abnormal apoptosis in apathogenic lentivirus infections of nonhuman primates, including HIV-1 infection of chimpanzees. Two female chimpanzees were inoculated, one cervically and the other intravenously, with HIV-1 derived from the LAI/LAV-1b strain, which was isolated from a chimpanzee infected with the virus for 8 years. Within 6 weeks of infection, both recipient chimpanzees developed a progressive loss of CD4+ T cells which correlated with persistently high viral burdens and increased levels of CD4+ T-cell apoptosis both in vitro and in vivo. Lymph nodes from both animals also revealed evidence of immune hyperactivation. Intermediate levels of T-cell apoptosis in both peripheral blood and lymph nodes were seen in a third chimpanzee that had been infected with the LAI/LAV-1b strain for 9 years; this animal has maintained depressed CD4/CD8 T-cell ratios for the last 3 years. Similar analyses of cells from 4 uninfected animals and 10 other HIV-1-infected chimpanzees without loss of CD4+ cells revealed no difference in levels of apoptosis in these two control groups. These results demonstrate a correlation between immune hyperactivation, T-cell apoptosis, and chronic loss of CD4+ T cells in HIV-1-infected chimpanzees, providing additional evidence that apoptosis is an important factor in T-cell loss in AIDS. Furthermore, the results show that some HIV-1 strains are pathogenic for chimpanzees and that this species is not inherently resistant to HIV-1-induced disease.
Animals↗
A comprehensive panel of near-full-length clones and reference sequences for non-subtype B isolates of human immunodeficiency virus type 1.
Non-subtype B viruses cause the vast majority of new human immunodeficiency virus type 1 (HIV-1) infections worldwide and are thus the major focus of international vaccine efforts. Although their geographic dissemination is carefully monitored, their immunogenic and biological properties remain largely unknown, in part because well-characterized virological reference reagents are lacking. In particular, full-length clones and sequences are rare, since subtype classification is frequently based on small PCR-derived viral fragments. There are only five proviral clones available for viruses other than subtype B, and these represent only 3 of the 10 proposed (group M) sequence subtypes. This lack of reference sequences also confounds the identification and analysis of mosaic (recombinant) genomes, which appear to be arising with increasing frequency in areas where multiple sequence subtypes cocirculate. To generate a more representative panel of non-subtype B reference reagents, we have cloned (by long PCR or lambda phage techniques) and sequenced 10 near-full-length HIV-1 genomes (lacking less than 80 bp of long terminal repeat sequences) from primary isolates collected at major epicenters of the global AIDS pandemic. Detailed phylogenetic analyses identified six that represented nonrecombinant members of HIV-1 subtypes A (92UG037.1), C (92BR025. 8), D (84ZR085.1 and 94UG114.1), F (93BR020.1), and H (90CF056.1), the last two comprising the first full-length examples of these subtypes. Four others were found to be complex mosaics of subtypes A and C (92RW009.6), A and G (92NG083.2 and 92NG003.1), and B and F (93BR029.4), again emphasizing the impact of intersubtype recombination on global HIV-1 diversification. Although a number of clones had frameshift mutations or translational stop codons in major open reading frames, all the genomes contained a complete set of genes and three had intact genomic organizations without inactivating mutations. Reconstruction of one of these (94UG114.1) yielded replication-competent virus that grew to high titers in normal donor peripheral blood mononuclear cell cultures. This panel of non-subtype B reference genomes should prove valuable for structure-function studies of genetically diverse viral gene products, the generation of subtype-specific immunological reagents, and the production of DNA- and protein-based subunit vaccines directed against a broader spectrum of viruses.
Adolescent↗
Andre Michel Lwoff 8 May 1902-30 September 1994.
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France↗
Mitomycin-vinorelbine as second line chemotherapy in metastatic breast cancer
Fourty-six patients (41 evaluable) were treated in second line chemotherapy of metastatic breast cancer (MBC) by an association of mitomycin (M), vinorelbine (V) (M 8 mg/m2 D1, V 25 mg/m2 D1 and DI 8 every 4 weeks). Median age was 58 years (36-78), median performance status 1 (0-3). Thirty-seven per cent of the tumors were estrogen receptors positive and 17% progesterone receptors positive.eventeen patients received an adjuvant chemotherapy and 39 a first line chemotherapy with anthracyclin (A). The median number of metastatic sites was 2 (1-4) and 27 patients (67%) had visceral metastases. Twelve patients were refractory to anthracyclins and 5 resistant. No toxic death nor hemolytic uremic syndrom were observed.even (3,7%) febrile neutropenias happened responsible for 4 hospitalizations. A grade 3 or 4 neutropenia was noted in 34% of the cycles but no other clinic toxicity nor grade 3 or 4 thrombopenia. The rate of objective response (OR) was 37,5% with 2 complete responses (CR) and 13 partial responses (PR).even patients had stable disease and 18 progressed. The rate of hepatic OR was 31%. Five (40%) A-refractory patients responded but no resistant patient. Median OR time was 10 weeks (8-12) and median OR duration was 5 months (3-6). Median survival was 11,5 months. MV association is well tolerated and effective in second line chemotherapy for MBC even with hepatic metastasis and in patients refractory to anthracyclins.
Journal Article↗