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Biomedical subjects

J McClure

Publications and source records attributed to J McClure.

At least 37 records · Page 2Linked to original sources
PubMed1997

Plasma viremia in macaques infected with simian immunodeficiency virus: plasma viral load early in infection predicts survival.

A reliable method for the quantitation of plasma viremia in nonhuman primates infected with simian immunodeficiency virus (SIV) and related viruses is described. This method is based on an established quantitative-competitive PCR format and includes a truncated control for internal assay calibration. Optimization of assay conditions has significantly improved amplification specificity, and interassay variability is comparable to that of commercially available assays for human immunodeficiency virus (HIV) quantitation. This procedure was used to monitor viral loads in a group of Macaca mulatta animals that were infected with SIVsmE660 for over 2 years. Highly diverse profiles of plasma viremia were observed among animals, and high viral loads were associated with more rapid disease progression. Spearman rank correlation analyses were done for survival versus three parameters of viral load: plasma viremia, p27 core antigen, and frequency of infected peripheral blood mononuclear cells. Plasma viremia had the strongest overall correlation and was significantly (P < 0.05 to P < 0.01) associated with survival at 10 of the 13 time points examined. Plasma viremia did not correlate with survival during the primary viremia phase; however, the strength of this correlation increased with time postinfection and, remarkably, viremia levels as early as week 6 postinfection were highly predictive (P < 0.01) of relative survival. These findings are consistent with the available clinical data concerning viral load correlates early in HIV infection, and they provide further support for the view that disease outcome in lentiviral infection may be largely determined by events that occur shortly after infection.

Animals↗
PubMed1996

In vitro effects of anti-HIV immunotoxins directed against multiple epitopes on HIV type 1 envelope glycoprotein 160.

We have used a panel of anti-gp160 MAbs to construct anti-HIV immunotoxins by coupling antibodies to ricin A chain (RAC). The ability of the immunotoxins to kill HIV-1-infected cells and halt the spread of infection was tested in tissue culture on persistently and acutely infected cell lines and primary lymphocyte cultures stimulated with phytohemagglutinin (PHA blasts). Laboratory strains and clinical isolates of HIV both were tested. The constitution and antigen-binding capacity of the immunotoxins were confirmed by ELISA and indirect immunofluorescence. Immunotoxins that bind epitopes exposed on the cell surface effectively killed persistently infected cells, although killing was not directly proportional to binding of immunotoxin to cell. The activity of anti-gp41, but not anti-gp120, immunotoxins was markedly enhanced in the presence of soluble CD4 or peptides corresponding to the CDR3 region of CD4. CD4-mediated enhancement of anti-gp41 immunotoxin activity was observed for laboratory strains neutralized by sCD4 and for clinical isolates that were resistant to neutralization by sCD4. Immunotoxin action was potentiated by brefeldin A, bafilomycin A1, cortisone, and an amphipathic fusion peptide, but not by cytochalasin D, nocodazol, monodansyl cadaverine, or trans-retinoic acid. Anti-HIV immunotoxins are useful tool with which to study the functional expression of gp120/gp41 antigens on the surface of HIV-infected cells, as well as potential AIDS therapeutics. Because these studies relate to the accessibility of viral antigens to antibody-mediated attack, these studies also have relevance for vaccine development.

Anti-Bacterial Agents↗
PubMed1996

The effect on chick osteoclasts of infection with paramyxoviruses.

The detection of virus in osteoclasts from Pagetic patients is now well known, but it has yet to be shown convincingly that the presence of virus in Pagetic osteoclasts influences their behaviour. In this study, osteoclasts from embryonic chick tibiae were infected with canine distemper virus or measles virus and compared with mock-infected controls. Infection was confirmed using virus-specific fluorescent antibodies. It was found that virus infection did not alter osteoclast morphology or tartrate-resistant acid phosphatase (TRAP) activity. Both infected and mock-infected osteoclasts produced resorption pits on bovine bone slices; these could be divided into two distinct size classes with a computer-based measuring system. Virus infection significantly increased the proportion of the larger size class of resorption pit. These results suggest that virus infection can increase bone resorption by osteoclasts, lending further support to the hypothesis that viruses play a role in Paget's disease of bone.

Acid Phosphatase↗
PubMed1996

Passive immune globulin therapy in the SIV/macaque model: early intervention can alter disease profile.

One of the major questions in AIDS is the role that the host immune system and the virus play in the dynamics of infection and the development of AIDS in an infected individual. In order to test the role of antibody in controlling viral infection, high-dose SIV-immune globulin was passively transferred to infected macaques early in infection. Immune globulin purified from the plasma of an SIV-infected long-term non-progressor macaque (SIVIG) or a pool of normal immune globulin (normal Ig) was infused into SIVsmE660-infected macaques (170 mg/kg) at one and fourteen days post infection. Animals were monitored for SIV-specific antibodies, viremia, plasma antigenemia, and clinical course. All animals were infected by SIV. At 16 months post infection, five macaques in the combined control groups have been euthanized, one as a rapid progressor with debilitating disease at 20 weeks post infection. Four macaques from the comparison groups have signs of AIDS, accompanied by high and increasing levels of virus and p27 antigenemia. One of the ten control animals had a very low virus load in plasma and peripheral blood and lymph node mononuclear cells at all times tested and has remained disease-free. In the SIVIG treatment group, two macaques were euthanized at 18-20 weeks due to AIDS, rapid progressors to disease. Three macaques in the SIVIG group had an initial high level of virus in plasma, peripheral blood mononuclear cells (PBMC), and lymph node mononuclear cells (LNMC), which dropped to baseline at 6 weeks post infection and has remained very low or negative for 16 months, a disease profile which has not been observed in untreated animals in this model to date. These macaques have remained clinically healthy. The sixth treated animal is also healthy, with very low virus burden that is detectable only by nested set polymerase chain reaction (PCR). All SIVIG-treated macaques had no detectable p27 plasma antigenemia for the first 10 weeks of infection, demonstrating that the IgG effectively complexed with the virus. The immunological correlates in the treated animals include development of de novo virus-specific antibodies and/or cytotoxic T cell (CTL), both of which are hallmarks of long term non-progressors. The two SIVIG-treated macaques that progress to disease rapidly had no detectable de novo humoral immune responses, as is often seen in rapid HIV disease in humans. Envelope-specific and virus neutralizing antibodies alone were not sufficient to prevent disease progression, as the plasma of both non-progressors as well as progressors had high titers of envelope-specific and neutralizing antibodies against SIVsmE660. Poor clinical prognosis was associated with moderate to high and increasing virus loads in plasma, PBMC, and lymph nodes. Good clinical prognosis correlated with low or undetectable post acute viremia in the peripheral blood and lymph nodes. We hypothesize that SIVIG reduced the spread of virus by eliminating or reducing plasma virus through immune complexes during the first four to 8 weeks of infection and then maintaining this low level of viremia until the host immune response was capable of virus control. Reduction of virus burden early in infection by passive IgG can alter disease outcome in SIV infection of macaques. Modifications of this strategy may lead to effective early treatment of HIV-1 infection in humans.

Animals↗
PubMed1996

Crystal structure of dimeric HIV-1 capsid protein.

X-ray diffraction analysis of a human immunodeficiency virus (HIV-1) capsid (CA) protein shows that each monomer within the dimer consists of seven alpha-helices, five of which are arranged in a coiled coil-like structure. Sequence assignments were made for two of the helices, and tentative connectivity of the remainder of the protein was confirmed by the recent solution structure of a monomeric N-terminal fragment. The C-terminal third of the protein is mostly disordered in the crystal. The longest helices in the coiled coil-like structure are separated by a long, highly antigenic peptide that includes the binding site of an antibody fragment complexed with CA in the crystal. The site of binding of the Fab, the position of the antigenic loop and the site of cleavage between the matrix protein and CA establish the side of the dimer that would be on the exterior of the retroviral core.

Amino Acid Sequence↗
PubMed1996

Development of a chronically catheterized maternal-fetal macaque model to study in utero mother-to-fetus HIV transmission: a preliminary report.

The lack of a representative animal model that permits frequent in utero fetal blood sampling is a major limiting factor for the study of maternal-fetal HIV transmission. Therefore, we have developed a maternal-fetal virus infection model using chronically catheterized macaques to simultaneously study the time-course of viral infection in the mother and the response of the fetus to maternal HIV infection. Pregnant macaques were infected with 10(3) infectious units of HIV-2(287); every 3 days blood samples from both the mother and the fetus as well as amniotic fluid samples were collected. We found a varying degree of peak and time-to-peak virus load, virus-infected PBMCs, and free virus (determined by QC-RNA-PCR method) in maternal blood. Two of the three mothers with more than 10(8) copies of viral RNA/ml of plasma at peak viremia transmitted the virus to their fetuses at about 14 days post-infection. As observed with HIV-2(287) infected mothers, virus-infected fetuses also produced a rapid rate of CD4+ cell decline in utero.

Animals↗
PubMed1995

The biological reality of the interlacunar network in the embryonic, cartilaginous, skeleton: a thiazine dye/absolute ethanol/LR White resin protocol for visualizing the network with minimal tissue shrinkage.

Third toe phalanges of chicks aged 8-13 days in ovo and 7-day post-natal rat femoral growth plate were examined to determine whether the interlacunar network (IN), a structure with no lipoprotein membrane component or cytoplasmic organelles, is a genuine component of young growth cartilage. In chick phalanges dehydrated by 70% (v/v) ethanol and LR White resin, variable metachromatic staining of the interlacunar network by toluidine blue and red staining by picro-Sirius red indicate the presence of glycosaminoglycans and collagen. The network in phalanges dehydrated by 80% (v/v) ethanol appears little different; however, the network is much less widely detectable in phalanges dehydrated by 90% (v/v) ethanol and, after dehydration by absolute ethanol, is almost completely undetectable. In contrast, when the young cartilage is permeated by a thiazine dye such as toluidine blue, using a solution of dye in the aldehyde fixative, the network is widely detectable, following dehydration by absolute ethanol, both in chick phalanges and in rat growth plate. Comparison of projected areas shows that the extent to which whole chick feet are found to have shrunk, by the time that they are photographed under LR White resin, is determined principally by the extent of dehydration, by 70% (v/v) or absolute ethanol; post-shrinkage areas are 33% or 35% of areas measured in buffer for 70% (v/v) ethanol/LR White resin and 71% or 75% for absolute ethanol/LR White resin (the higher value in each is for the toluidine blue treatment). The network is thus present in radically shrunk tissue, but, significantly, is also fully represented in tissue shrunk by only a conventional margin and is therefore not produced as an artefact by exceptional tissue shrinkage as has been suggested.

Animals↗
PubMed1994

Air quality and respiratory functioning in children with pulmonary disorders.

This study was conducted to examine the relation between daily ambient air conditions, contaminants (eg, aeroallergens such as mold spores and pollen), and respiratory health indices of children with respiratory disorders (eg, asthma) residing in metropolitan Baton Rouge, Louisiana. Daily measures of peak expiratory flow rate (PEFR), respiratory symptoms, and other indices of health were monitored as subjects went about their normal daily activities. The results of this study suggest that high summer temperatures had the greatest impact on children's health status and activity level, with humidity and mold counts also contributing significantly to a decline in respiratory health indices.

Adolescent↗
PubMed1994

Syndromes associated with trichothiodystrophy.

Sparse, brittle, sulphur-deficient hair is an excellent marker for several autosomal recessive neurocutaneous syndromes. The term 'trichothiodystrophy' is commonly used in publications on such syndromes and the best characterized trichothiodystrophy syndrome is associated with skin photosensitivity and intellectual impairment. Patients with these three cardinal signs usually have an underlying DNA repair defect. Here we describe clinical and laboratory findings in two patients with trichothiodystrophy and defective DNA repair alongside findings in three other cases who have different trichothiodystrophy syndromes without defective DNA repair. These patients' features are discussed in the light of a practical classification scheme which is based upon a check-list of clinical abnormalities associated with trichothiodystrophy syndromes (Van Neste, 1991).

Adolescent↗
PubMed1993

Soluble CD4 enhances the efficacy of immunotoxins directed against gp41 of the human immunodeficiency virus.

Monoclonal antibodies specific for the gp120 or gp41 portions of the human immunodeficiency virus (HIV) envelope protein gp160 were conjugated to ricin A chain, and their immunotoxic activities against HIV-infected cells were evaluated in the presence or absence of soluble CD4 (sCD4). Immunotoxin activity was measured in vitro as cytotoxicity and inhibition of secretion of infectious HIV. The efficacy of anti-gp41 immunotoxins was enhanced at least 30-fold in the presence of sCD4. This effect was specific for HIV-infected cells, but not for uninfected cells, and was seen at concentrations of sCD4 as low as 0.1 micrograms/ml. Anti-gp120 immunotoxins were marginally inhibited at higher concentrations of sCD4. Flow cytometry analyses showed that sCD4 increased the expression of gp41 on the surface of infected cells and increased internalization of gp120 and gp41. These data suggest that sCD4 alters the cellular trafficking of HIV envelope proteins. These findings also have important implications for the therapeutic use of anti-HIV immunotoxins and may be generalizable to other immunotoxins as well.

Animals↗
PubMed1993

Cartilage and bone formation in repairing Achilles tendons within diffusion chambers: evidence for tendon-cartilage and cartilage-bone conversion in vivo.

Rodent Achilles tendons were subjected to midpoint tenotomy and allowed to recover for various times in situ before the operated tissue was removed, placed into a Millipore diffusion chamber, and inserted intraperitoneally into syngeneic hosts. Diffusion chambers were then removed at weekly intervals, such that the total time after the operation (i.e., time allowed to recover in situ plus time within the diffusion chamber) was up to 8 weeks, and examined histologically. Ectopic cartilage was produced within the diffusion chamber after a total of 4 weeks but only if the first 2 weeks of recovery were in situ. With increasing time, calcified cartilage, osteoid, and bone were also observed. Overall, the evidence suggests that the cartilage forms via a direct conversion from tendon tissue and that the bone may form as a result of differentiative changes of hypertrophic chondrocytes.

Achilles Tendon↗
PubMed1993

Immunohistochemical localization of articular cartilage proteoglycan and link protein in situ using monoclonal antibodies and lectin-binding methods.

Lectins have specificity for certain carbohydrate structures in macromolecules. Lectins are, therefore, useful histochemical tools for demonstrating the composition and localization of components of connective tissue matrices, such as articular cartilage. In order to assess the significance of observed lectin-binding patterns, experiments were performed in which monoclonal antibodies against chondroitin sulphate- and keratan sulphate-containing proteoglycans and link proteins were applied to sections of bovine articular cartilage after enzymatic digestion with chondroitinase ABC and keratanase. The following conclusions were made: (1) Binding of peanut agglutinin (PNA) in the interterritorial matrix predominantly indicates the presence of keratan sulphate, but may also detect O-linked oligosaccharides of proteoglycans. (2) In normal cartilage wheat germ agglutinin (WGA) binds nearly exclusively to keratan sulphate. In cartilage degraded with chondroitinase ABC and keratanase this lectin may also detect carbohydrates in link protein due to enhanced accessibility. Binding of WGA to O-linked oligosaccharides may eventually occur. (3) In enzymatically digested cartilage matrix, staining with soybean agglutinin (SBA) may be due to link protein, but not to chondroitin sulphate, because specific breakdown of the glycosaminoglycan chain is required for binding of SBA. (4) Ulex europaeus agglutinin I (UEA I) binding sites are only detectable in digested cartilage matrix.

Animals↗
PubMed1993

Multiple primary tumours in a population-based series of patients with histopathologically peer-reviewed sarcomas.

Multiple primary tumours occurring in a three-year population-based series of patients with histopathologically peer-reviewed sarcomas from North West England were ascertained in order to look at the patterns of neoplasms seen. A total of 30 out of the 310 patients entered in the study had additional primary tumours. Very few patients were aged under 60 years at diagnosis of both their malignancies. The youngest was a known case of neurofibromatosis and, although seven patients were diagnosed with a sarcoma and carcinoma of the breast--a combination of cancers characteristic of the Li-Fraumeni cancer family syndrome--no other patients could directly be identified as suffering from any other cancer predisposition syndrome.

Adult↗
PubMed1993

Osteoblast function and osteomalacia in metastatic prostate cancer.

This study has examined the effect of prostate cancer on bone matrix formation and mineralisation by osteoblasts, with special reference to osteomalacia. Sixty-seven patients with prostatic bone metastases underwent transiliac bone biopsy after double tetracycline labelling. Histomorphometric analysis was then undertaken in areas distant from, local to and infiltrated by prostate cancer. In bone free of tumour (n = 45) and bone surrounding metastases (n = 7) both matrix formation and corrected mineral apposition rate were low. By comparison osteoid surface, osteoid volume and mineral apposition rate were markedly increased within metastases (tumor-free bone vs. metastatic bone, p < 0.0001), a finding consistent with a high bone turnover state. Although osteoblast function was disturbed both within metastases and in tumour-free areas, classical osteomalacia was not associated with prostate cancer.

Biopsy, Needle↗
PubMed1993

The effects of orchidectomy on skeletal metabolism in metastatic prostate cancer.

The skeletal metabolic effects of androgen withdrawal have been studied in men with metastatic prostate cancer by using a combination of sequential biochemical measurement, quantitative and subjective bone histology and selective osteoclast inhibition with the bisphosphonate Pamidronate. Results showed dissociation in the levels of biochemical markers of bone formation (alkaline phosphatase and osteocalcin) following castration, whilst markers of bone breakdown (urinary hydroxyproline creatinine (OHP) and calcium excretion (CaE)) increased in the majority of patients. The osteolytic response was inhibited by the bisphosphonate Pamidronate (Aminohydroxypropylidene Bisphosphonate (APD)), thus confirming its osteoclastic origin. Histomorphometry of tumour free bone showed an acute drop in bone volume following surgery (p < 0.05). This effect was blocked by Pamidronate suggesting that osteoclastic activity surges immediately following castration, contributing to the acute bone loss. Histology of metastatic areas showed a marked diminution in bone volume due to decreased osteoblast activity and markedly increased osteoclast mediated osteolysis. In 56% of biopsies there were residual foci of active tumour within metastatic areas after orchidectomy. These disturbed metabolic bone activity in a typically localised manner.

Biopsy↗
PubMed1992

A comparison of moclobemide, amitriptyline and placebo in depression: a Canadian multicentre study.

In a 7-week prospective multicentre study, the efficacy, tolerability and safety of moclobemide were compared to those of amitriptyline and placebo in parallel groups of out-patients (n = 173) fulfilling the DSM III-R criteria for a major depressive episode. Participants were required to have a minimum baseline total score of 18 on the 17-item Hamilton Depression Rating Scale (HAMD). After a 1-week placebo washout, patients were randomly allocated to the three treatment groups. Assessment of efficacy, as judged by the number of responders achieving a 50% reduction in HAMD score by the end of treatment, showed that both moclobemide and amitriptyline were significantly superior to placebo, but that they were not significantly different from each other. Both treatments differed significantly from placebo with respect to the Physician's Global Assessment of Efficacy ('very good' or 'good' response: moclobemide 57%, amitriptyline 60% and placebo 35%). Assessment of tolerance as judged by the spontaneous reporting of adverse events showed a significant superiority of moclobemide over amitriptyline, but there was no significant difference between moclobemide and placebo. At termination of the study, amitriptyline patients showed a significant elevation of heart rate both supine (10.8 beats/min) and standing (15.5 beats/min), as well as significant weight gain (1.7 kg), but no changes were seen in the moclobemide or placebo groups. In conclusion, both moclobemide and amitriptyline were found to be more effective than placebo in the treatment of depression, while moclobemide had fewer side effects.

Adult↗
PubMed1992

Human mesangial cells are resistant to productive infection by multiple strains of human immunodeficiency virus types 1 and 2.

Human immunodeficiency virus-associated nephropathy (HIVAN) is a recognized clinical entity of unknown pathogenesis. A role for viral infection of renal cells in the initiation of this process at present is an intriguing but untested hypothesis. Studies in primate models of acquired immunodeficiency syndrome (AIDS) suggest that injury to the mesangial cell may be central to the sclerosing glomerular lesion characteristic of HIVAN. We therefore tested the infectibility of human mesangial cells (HMC) in vitro by a variety of strains of HIV chosen to include a spectrum of tropisms for different cell types. Productive infection of mesangial cells could not be demonstrated using any of the virus strains. Nonetheless, HIV infection of intrinsic renal cells remains an attractive area of inquiry for understanding the natural history of HIVAN.

AIDS-Associated Nephropathy↗