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Biomedical subjects

K McIntosh

Publications and source records attributed to K McIntosh.

At least 73 records · Page 4Linked to original sources
PubMed1995

A rapid, direct test for zidovudine susceptibility in clinical isolates of human immunodeficiency virus type 1 (HIV-1) from infected children.

BACKGROUND: Existing phenotypic tests of antiretroviral susceptibility in clinical isolates of human immunodeficiency virus (HIV) are expensive and slow, and require passage of virus in cell culture with the possible consequence of selecting variants. OBJECTIVES: We sought to develop a rapid 14-day assay for zidovudine susceptibility of cell-associated HIV performed directly in patient blood samples. STUDY DESIGN: Twenty-three tests were performed prospectively in 21 children, and the results were compared with those of the AIDS Clinical Trials Group/Department of Defense consensus drug susceptibility assay (DSA) as well as certain clinical parameters. RESULTS: Five strains from ZDV-naive children were sensitive by the rapid test. Three were tested by DSA, and all were sensitive. Six strains from children who had received >/=24 months of ZDV were resistant by the rapid assay. Four of these strains were tested by the DSA, and all were shown resistant. The viral strains from children who received <24 months of therapy or who had switched from ZDV to other antiviral therapy exhibited variable sensitivity by both tests. Changes in CD4 cells in the subsequent 6 months, as well as weight gain during this time were both correlated to the results of the rapid test. The syncytium-inducing capacity of the virus strains was analyzed similarly. CONCLUSIONS: The rapid intracellular virus susceptibility assay is a test of drug sensitivity performed on HIV growing in cells obtained directly from an infected patient. The test has a two-week turn-around time and, in this preliminary report, gives results which correlate with both time on zidovudine and also subsequent CD4 cell changes.

Journal Article↗
PubMed1995

Cross-linking of Fc gamma receptors activates HIV-1 long terminal repeat-driven transcription in human monocytes.

Elevation of the levels of circulating immune complexes frequently accompanies HIV-1 infection and is a prognostic indicator of clinical progression from asymptomatic infection to AIDS. Here we report that cross-linking of Fc gamma RI or Fc gamma RII by adherent human IgG or by specific anti-Fc gamma R mAb activates HIV-1 gene expression in the human monocytic cell line BF24 and increased HIV RNA expression in monocytes from HIV infected patients as assayed by reverse transcription-PCR. In THP-1 cells, Fc gamma R cross-linking induced NF-kappa B, which is known to bind to the regulatory region of the long terminal repeat (LTR) of HIV-1 and to activate HIV-1 transcription. Anti-TNF-alpha antibody but not anti-IL-1 beta antibody strongly inhibited both the induction of HIV-1-LTR-driven transcription and the induction of NF-kappa B by Fc gamma R cross-linking. These results indicate that Fc gamma R can mediate a TNF-alpha-dependent induction of HIV-1 gene transcription and suggest that immune complexes may contribute to the pathophysiology of HIV-1 infection by augmenting viral replication in monocytes.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The prenatal exclusion test for Huntington's disease: experience in the west of Scotland, 1986-1993.

Information about the prenatal exclusion test for Huntington's disease (HD) has been given to an unselected series of couples who attended the genetic counselling clinic from 1986 onwards. Ten couples underwent 13 prenatal tests during this period with expressed intention of stopping a pregnancy if the result indicated a high risk (almost 50%) that the fetus carried the HD gene. Nine fetuses at nearly 50% risk of carrying the HD gene were identified but only six such pregnancies were terminated. In each of three high risk pregnancies which continued, the mother made a "final hour" decision not to undergo the scheduled, first trimester termination. In our experience, late reversal of a previous decision to undergo first trimester pregnancy termination for a genetic indication is uniquely frequent among couples who have undergone the prenatal exclusion test for HD.

Adult↗
PubMed1995

Vertical Transmission of HIV-1. Correlation with maternal viral load and plasma levels of CD4 binding site anti-gp120 antibodies.

Almost all childhood HIV-1 is now acquired through vertical transmission. Identifying factors that affect the rate of transmission may lead to the initiation of specific preventive strategies. In this study, antibody levels against different neutralizing epitopes on the envelope glycoprotein of HIV-1 (gp120) were measured in HIV-1-infected pregnant women that either transmitted HIV-1 to their infants (18 women) or did not (29 women). Differences in levels of antibodies directed against the monomeric gp120 molecule and against the V3 loop region of gp120 were not significantly different between the two groups studied. However, significant differences were observed in the levels of CD4 binding site antibodies, as determined by the ability of diluted maternal plasma to inhibit binding of the CD4 binding site monoclonal antibody F105 (mAb F105) to monomeric gp120. In addition, more nontransmitting mothers had low viral load as defined by having two or more negative HIV-1 viral cultures during pregnancy compared with transmitters. This pilot study suggests that in addition to higher viral load, low levels of CD4 binding site antibodies correlate with increased risk of HIV-1 vertical transmission. Passive immunotherapy with broadly neutralizing CD4 binding site antibodies should be considered as a strategy to reduce this risk.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Gastrostomy tube supplementation for HIV-infected children.

OBJECTIVE: Malnutrition is common in pediatric human immunodeficiency virus (HIV) infection, and little is known of effective nutritional interventions. We sought to determine whether enteral supplementation with gastrostomy tube feedings would provide improvements in weight, height, body composition, immune parameters, morbidity, and mortality. METHODS: We collected clinical data on 23 HIV-infected children who were fed chronically by gastrostomy tube. The main outcome measures included weight, height, triceps skinfold thickness (TSF), arm-muscle circumference (AMC), hospital days, caloric intake, and CD4-positive T-lymphocyte count. Each of these parameters was measured or evaluated at four points: 6 months before nasogastric tube feeding, at the time nasogastric tube feeding was initiated, at the time gastrostomy tube feeding was initiated, and 6 months after gastrostomy tube feedings began. RESULTS: Weight z score [-2.1 (0.14) to -1.58 (0.14)] and weight-for-height z score [-0.98 (0.16) to -0.15 (0.17)] improved with gastrostomy tube feedings. There was a trend toward improvement in weight z score with nasogastric tube feedings. Caloric intakes increased progressively with nasogastric and gastrostomy tube feedings. No improvement in height, TSF, AMC, hospital days, or CD4 counts was seen in the follow-up period. However, children who had the greatest increase in weight had the most improvement in fat stores (TSF) (r = .65, P = .002) and a decrease in hospital days after the gastrostomy tube was placed (r = -.48, P = .025). Higher age-adjusted CD4 counts and lower weight-for-height z scores at the time of enteral supplementation were significant predictors of a positive response to gastrostomy tube feedings (r = .85, P = .0001). Children who responded favorably had a 2.8-fold reduction in the risk of dying for every positive unit change in weight z score (P = .005). CONCLUSION: Gastrostomy tube supplementation for HIV-infected children can improve weight and fat mass when other oral methods fail. Weight gain is coincident with greater caloric intakes. HIV-infected children with higher CD4 counts and lower weight-for-height z scores are likely to respond favorably to gastrostomy tube feedings. Early nutritional intervention is indicated for HIV-infected children.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Oral administration of acetylcholine receptor: effects on experimental myasthenia gravis.

The abnormality in myasthenia gravis (MG) is a deficiency of acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune attack. Although immunosuppressive drugs are usually beneficial in MG, they produce generalized suppression of the immune system. Treatment should specifically inhibit the immune response to AChR. Oral administration of an antigen may induce specific tolerance and has recently been tested for treatment of several cell-mediated experimental and human autoimmune diseases. In this study, we investigated the effects of oral administration of AChR in an experimental rat model of MG (EAMG), which is antibody mediated. Lewis rats were fed various doses of purified or unpurified Torpedo AChR, or a control antigen, ovalbumin (OVA). They were then immunized with AChR or OVA. We measured antibody responses to Torpedo AChR or OVA, autoantibody responses to rat AChR, cellular responses, cellular suppressive effects, and clinical status. Our results showed that AChR feeding prevented clinical signs of EAMG. It initially primed, then inhibited, antibody responses to foreign (Torpedo) AChR and self (rat) AChR, with a delayed onset. Cellular responses to AChR, measured by lymphocyte proliferation and interleukin-2 production, were markedly inhibited. The effects were dose dependent. Unpurified AChR given in comparable amounts was far less effective than pure AChR. OVA feeding had similar, but even more potent effects on humoral and cellular immune responses to OVA, but did not inhibit clinical EAMG or AChR responses. Moderate nonspecific suppression by splenic T cells from orally treated animals was demonstrated in vitro. We conclude that oral therapy is beneficial in EAMG and may prove effective in MG patients. Early priming and delayed inhibition suggest that a molecule with less immunogenic potential than intact AChR might be more effective as a therapeutic agent.

Administration, Oral↗
PubMed1994

Limitations of fractional shortening as an index of contractility in pediatric patients infected with human immunodeficiency virus.

Left ventricular fractional shortening (FS) is dependent on left ventricular preload and afterload, as well as contractility. Contractility may therefore not be accurately described by FS, especially in infants and children infected with human immunodeficiency virus (HIV), who tend to have abnormal left ventricular preload and afterload. We therefore examined the magnitude and clinical impact of the discrepancy between FS and contractility by assessment of 177 echocardiograms from 76 HIV-infected pediatric patients (median age, 1.9 years). The studies included simultaneous measurements of left ventricular FS, contractility, preload, and afterload. The correlation between contractility and FS was modest (r = 0.70; p < 0.001), and was weaker in children less than 2 years of age (r = 0.52) than in older children (r = 0.84). FS incorrectly predicted contractility in 46% of the studies; 43% with depressed FS (< 28%) had either normal (17/42) or enhanced (1/42) contractility. For 67% of echocardiograms, FS and contractility differed by > 1 SD, and for 36% the difference was > 2 SD. These differences remained after adjustment of FS for age or body surface area. Afterload was abnormal in 42% and preload in 21% of all echocardiograms. High preload predicted that FS would overestimate contractility (p = 0.002); high afterload predicted that FS would underestimate contractility (p < 0.001). The discrepancy between FS and contractility was larger among children who were younger, had more advanced HIV disease, or were not sedated during echocardiography. One third of children with congestive symptoms had normal contractility and depressed FS; the discrepancy was primarily due to loading conditions. We conclude that the high incidence of abnormal loading conditions in HIV-infected infants and children limits the usefulness of load-dependent FS for assessing contractility. Measurements of loading conditions and load-independent indexes, which more directly reflect contractility, allow a more accurate determination of myocardial status and may lead to better clinical management.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Blood culture in the first 6 months of life for the diagnosis of vertically transmitted human immunodeficiency virus infection. The Women and Infants Transmission Study Group.

Serial blood cultures over the first 6 months of life in 310 infants with vertical exposure to human immunodeficiency virus (HIV) in the Women and Infants Transmission Study were analyzed to determine their value for early diagnosis of HIV infection. Cultures were done at 0-7 days and 1, 2, 4, and 6 months of age: 55 infants were infected. Blood culture sensitivity in infected children was 24% (7/29) during the first week of life and 85%, 91%, 82%, and 88%, respectively, at 1, 2, 4, and 6 months. The sensitivity, specificity, and positive and negative predictive values of a single culture between 1 and 6 months of age were, respectively, 86.9%, 99.6%, 97.9%, and 97.5%. Two negative cultures between 1 and 6 months of age defined an uninfected infant with a specificity of 99.2%-100.0%. Blood culture done between 1 and 6 months of age in children of HIV-positive mothers is a sensitive and specific test for HIV infection, with high positive and negative predictive values.

Blood↗
PubMed1993

Cardiac morbidity and related mortality in children with HIV infection.

OBJECTIVE: Dysrhythmias, hemodynamic instability, congestive heart failure, and sudden death are serious complications of human immunodeficiency virus (HIV) infection that, to our knowledge, have not been studied systematically. We sought to determine the cumulative incidence and clinical predictors of these adverse events in a cohort of HIV-infected children. DESIGN: Historical cohort study. SETTING: University-affiliated, primary and tertiary care pediatric hospital and ambulatory care center. PARTICIPANTS: Eighty-one HIV-infected children who had one or more cardiac evaluations between 1984 and 1991 form the study cohort. The initial cardiac evaluation occurred at a median age of 1.5 years, and children were followed up to a median age of 3.6 years. MAIN OUTCOME MEASURES: Mortality (related to cardiac dysfunction as well as noncardiac causes), tachycardia, bradycardia, hypertension, hypotension, marked sinus arrhythmia, cardiac arrest, and chronic congestive heart failure. RESULTS: Hemodynamic abnormalities and dysrhythmias occurred frequently. Eight unexpected cardiorespiratory arrests occurred in seven children (9%). Chronic congestive heart failure was noted in 10% of patients. Thirty children died, 10 with significant cardiac dysfunction. As HIV-infected children progressed from acquired immunodeficiency syndrome (AIDS)-related complex to AIDS, significant cardiac problems were more likely to occur. Both nonneurologic AIDS and encephalopathy were strongly associated with most severe cardiac outcomes. However, encephalopathy was the strongest correlate of cardiorespiratory arrest (P = .002). Epstein-Barr virus coinfection was the strongest correlate of chronic congestive heart failure (P < .001). CONCLUSIONS: Cardiac morbidity and mortality are more common with advanced HIV infection. The presence of encephalopathy or Epstein-Barr virus coinfection identifies HIV-infected children at especially high risk for adverse cardiac outcomes.

AIDS-Related Opportunistic Infections↗
PubMed1993

Gangliosides elicit a T-cell independent antibody response.

Antibodies to glycolipids have recently been found to be elevated in a substantial proportion of patients with motor neuron diseases, various neuropathies and classical ALS. Several features of these antibody responses suggest that they may be produced by a T-cell independent B lymphocyte response: (1) antibodies are predominantly of IgM class; (2) antibodies against gangliosides are directed against the carbohydrate component of the gangliosides; and (3) antiganglioside antibodies are difficult to suppress. In this study we have asked whether gangliosides can induce T-independent responses, in T-cell deficient and T-cell competent mice. Homozygous nude mice (nu/nu), which lack T-cells, and heterozygous controls (nu/+) with intact T-cells, were immunized and rechallenged with the ganglioside GM1 in liposomes. Antibodies were measured by an ELISA method. Both nude mice and controls produced high titers of IgM class antibodies to the ganglioside GM1. The antibody titers peaked by 7 days after each immunization and declined by 14 days. The maximum titer rose progressively after each immunization. No significant amount of IgG antibody to GM1 was produced by either nu/nu or nu/+ mice, even after repeated immunization. These results suggest that gangliosides elicit prominent T-cell-independent antibody responses. The implications of these findings for neurologic disorders associated with anti-ganglioside antibodies are discussed.

Animals↗
PubMed1993

Growth and body composition in children infected with the human immunodeficiency virus-1.

Anthropometric data were collected on 89 children born to human immunodeficiency virus (HIV)-infected women (37 who seroreverted and 52 who were HIV-infected). The main outcomes included birth weight, gestational age, weight, height, arm muscle circumference (AMC), and triceps skinfold thickness (TSF). Gestational age and birth weight were not different between the two groups. The earliest anthropometric evaluation on seroreverted children (age 19 mo) when compared with HIV-infected children (age 21 mo) revealed that weight and weight-for-height percentiles were significantly different (51% vs 33% and 66% vs 48%, respectively). Height and TSF percentiles were not different, although AMC percentiles were lower in infected children (64% vs 43%). In follow-up evaluations, the weight differences between infected and control children did not change. We conclude that HIV does not affect birth weight, but postnatal events result in altered weight gain in HIV-infected children. Lean body mass is lower than in an HIV-negative comparison group at early stages of HIV infection.

Anthropometry↗
PubMed1993

Report of a workshop on respiratory viral infections: epidemiology, diagnosis, treatment, and prevention.

An international workshop to review the epidemiology, diagnosis, treatment, and prevention of respiratory viral infections was held in Turku, Finland, in May 1991. This workshop emphasized the following points. (1) In epidemiological studies of influenza virus, serological, clinical, and gene-sequencing methods have been used to produce a full picture of genetic evolution. Less complete information exists about other viruses, although new data on respiratory syncytial virus are emerging. (2) Tools for the diagnosis of respiratory viral infections have been developed in conjunction with the use of solid-phase immunoassays. A role remains for tissue culture in surveillance and epidemiological studies. Detection of bacterial involvement in respiratory infections has been more difficult. (3) Treatment of infections due to respiratory viruses has advanced with the use of amantadine and aerosolized ribavirin. On the other hand, many viruses remain refractory to treatment. Means for preventing influenza are established, but barriers to the development of other viral vaccines--including the existence of multiple serotypes, imperfect natural immunity, and paradoxical hypersensitivity--have proven difficult to surmount.

Animals↗