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Biomedical subjects

E Connor

Publications and source records attributed to E Connor.

At least 19 recordsLinked to original sources
PubMed1998

Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. MEDI-493 Study Group.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants. MEDI-493 (palivizumab) is a humanized monoclonal antibody to the fusion protein of RSV and is active in animal models for prevention of pulmonary RSV replication. OBJECTIVE: To describe the safety, tolerance, immunogenicity and pharmacokinetics of repeat intravenous doses of MEDI-493 in premature infants or infants with bronchopulmonary dysplasia. DESIGN: Phase I/II multicenter, randomized, double blind, placebo-controlled, dose escalation trial. PATIENT POPULATION: Infants born prematurely (< or = 35 weeks of gestation) who were < or = 6 months of age and infants with bronchopulmonary dysplasia who were < or = 24 months of age were eligible for study participation. STUDY AGENTS: Participants received 3, 10 or 15 mg/kg MEDI-493 or 0.9% saline intravenously every 30 days for up to five doses. RESULTS: MEDI-493 was safe and well-tolerated and did not induce a specific anti-MEDI-493 response. The mean half-life of 20 days was comparable with that of other immunoglobulin G preparations. Mean trough serum concentrations 30 days after Infusion 1 were 6.8, 36.1 and 60.6 microg/ml for the 3-, 10- and 15-mg/kg dose groups, respectively. After Infusion 2 the trough concentrations were 11.9, 45.2 and 70.7 microg/ml. After subsequent doses the mean trough values ranged from 14 to 18 microg/ml in those given 3 mg/kg and were > 40 microg/ml for patients who received 10 or 15 mg/kg MEDI-493 (46 to 72 microg/ml and 88 to 96 microg/ml, respectively). CONCLUSIONS: MEDI-493 was safe and well-tolerated in this high risk pediatric population. Mean serum concentrations of MEDI-493 that have been shown to produce a 2-log reduction in pulmonary RSV titer in cotton rats were maintained when 10 or 15 mg/kg MEDI-493 was given every 30 days to pediatric patients at high risk for serious RSV disease. Monthly doses of 15 mg/kg maintained concentrations of > 40 microg/ml for the majority of patients.

Antibodies, Monoclonal↗
PubMed1996

Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism.

Acquired hypoparathyroidism (AH) has been considered to result from an autoimmune process but the self-antigens have not been identified. We studied 25 patients with AH, of which 17 had type I autoimmune polyglandular syndrome and 8 had AH associated with autoimmune hypothyroidism. Five of 25 (20%) AH sera reacted to a membrane-associated antigen of 120-140 kD in human parathyroid gland extracts using immunoblot analysis. This is the exact size of the calcium sensing receptor (Ca-SR). The AH sera were then tested by immunoblot using a membrane fraction of HEK-293 cells transfected with Ca-SR cDNA. Eight of 25 (32%) AH sera reacted to a 120-140-kD protein, which closely matched that recognized by the anti-Ca-SR IgG raised in rabbits. The Ca-SR cDNA was translated in vitro into two parts in order to identify the antigenic epitopes. By using this technique, 14 of 25 (56%) AH sera were positive to the extracellular domain of the Ca-SR, whereas none of the AH patients sera reacted to the intracellular domain. The reactivity of the positive sera was completely removed after pre-absorption with the Ca-SR containing membranes. Sera from 50 patients with various other autoimmune diseases as well as 22 normal controls were also tested, and none of them was positive. In conclusion, the Ca-SR has been identified as an autoantigen in AH.

Autoantibodies↗
PubMed1996

Although DR3-DQB1*0201 may be associated with multiple component diseases of the autoimmune polyglandular syndromes, the human leukocyte antigen DR4-DQB1*0302 haplotype is implicated only in beta-cell autoimmunity.

Human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles were analyzed using a PCR-based sequence-specific priming technique in 16 patients with autoimmune polyglandular syndrome type I (APS-I), 31 patients with APS-II, and 110 patients with component diseases of APS-II, including 9 patients with isolated Addison's disease, 43 patients with Hashimoto's thyroiditis, 22 patients with Graves' disease, and 36 patients with vitiligo. No significant associations was observed between HLA and APS-I patients in our data set, nor was sharing of HLA haplotypes by sibling pairs affected by APS I significantly different from the random expectation. Thus, HLA-DRB1 and -DQB1 genes are probably not involved in APS-I. To delineate the associations between HLA-DRB1, DQB1, and APS-II, we analyzed APS-II patients with or without beta-cell autoimmunity [i.e. insulin-dependent diabetes (IDD) and/or islet cell or glutamic acid decarboxylase autoantibodies]. Our results suggest that the association between DR4-DQB1*0302 and APS-II was entirely due to the presence of pancreatic beta-cell autoimmunity, since this haplotype was otherwise not significantly associated with APS-II or with any other of its component diseases. In contrast, the DR3-DQB1*0201 haplotype was associated not only with IDD, but also with APS-II in the absence of pancreatic beta-cell autoimmunity, as were several its component diseases, including isolated Addison's disease, Graves' disease, and Hashimoto's thyroiditis. Interestingly, the frequency of DQB1*0602, a dominantly protective allele against IDD, was not significantly decreased in the APS-II patients with IDD or beta-cell autoimmunity, albeit the patient numbers were small. This phenomenon may suggest that the development of autoimmunity to nonpancreatic endocrine glands may predispose autoimmunity to the pancreatic beta-cells and involve genes other than those of the MHC.

Adolescent↗
PubMed1996

Cell cycle-specific behavior of erythropoietin.

The murine erythropoietin-dependent erythroleukemia cell line, HCD-57, was employed to study the cell cycle-specific behavior of erythropoietin. Cell cycle duration for HCD-57 cells was approximately 12 hours and was uninfluenced by erythropoietin. Populations of HCD-57 cells synchronized in G1 by centrifugal elutriation were able to pass through one complete cell cycle in the absence of erythropoietin but, thereafter, arrested in G1 as identified by propidium iodide staining and flow cytometry. Analysis of cell cycle behavior using the metachromic dye acridine orange, however, revealed that HCD-57 cells pass through a G0 cell cycle phase and, like serum-deprived 3T3 cells, actually arrest in G0 when deprived of erythropoietin. Expression of the cell cycle regulatory protein p34cdc2 was invariant throughout the cell cycle in HCD-57 cells. p34cdc2 was constitutively phosphorylated in G0 cells, and this effect was not modified by erythropoietin. Erythropoietin receptor distribution was log normal in HCD-57 cells in each phase of the cell cycle. The affinity of these surface receptors for erythropoietin was essentially invariant throughout the cell cycle, but receptor expression was upregulated in G2M cells as compared with cells in G1 or S phase. Taken together, these data indicate that erythropoietin has an important role in the G0-G1 to S phase transition but, based on receptor expression, is involved in other phases of the cell cycle as well.

Animals↗
PubMed1994

The role of tyrosinase in autoimmune vitiligo.

Vitiligo is a common depigmenting skin disease, associated with certain autoimmune endocrinopathies, and autoantibodies to several antigens can be found in melanoma cells. We set out to identify the antigens. We examined 26 patients with vitiligo and associated endocrine disease. Of these, 18 patients (77%) and 8 immediate family members had autoantibodies specific for a 69 kDa protein in HTB-70 human melanoma cells that was not seen in control cells. The autoantibody-positive patient sera reacted with recombinant human tyrosinase expressed in Escherichia coli seen by western blots, as did antibodies raised in rabbits against hamster tyrosinase, but not to recombinant tyrosinase-related protein. Not one of 31 normal controls or 8 patients with alopecia or systemic lupus erythematosus had tyrosinase autoantibodies but a small proportion (12%) of 42 patients with autoimmune endocrine disease without a history of vitiligo had them. The results show that tyrosinase, an enzyme important in melanin formation, is a principal autoantigen of autoimmune vitiligo.

Animals↗
PubMed1994

Treatment of HIV infection in infancy.

Treatment for HIV infection and preventive methods for HIV-associated infections are now routinely available and recommended for the management of HIV-infected children. These strategies have been associated with improvement in the quality and duration of life for HIV-infected adults and children. The institution of these interventions is dependent on recognition of infants at risk for infection (born to mothers with HIV infection), early diagnosis of HIV infection in infants and young children, and careful clinical and immunologic monitoring. As with other chronic illnesses, management of HIV-infected children should be comprehensive and should involve the active participation of both the primary pediatrician and the HIV specialist. Optimization of interventional strategies is dependent on ongoing and planned clinical trials.

AIDS Vaccines↗
PubMed1994

Erythropoietin stimulates serine kinase activity in erythropoietin-dependent cells.

Protein phosphorylation is an early event that follows the interaction of erythropoietin (Epo) with its receptor, even though this receptor lacks a kinase domain. To further define the role of protein kinases in Epo-mediated signal transduction, the effect of Epo on serine-threonine kinase activity was examined in the Epo-dependent cell line, HCD-57, using a kinase renaturation assay. In HCD-57 cells synchronized in G0 phase by centrifugal elutriation, multiple serine-threonine kinases were constitutively active, and exposure to Epo was associated with an increase in the activity of kinases with apparent molecular masses of 170, 120, and 90-95 kD. Phosphoamino acid analysis established the covalent incorporation of 32P into serine and threonine for constitutively active kinases and into serine alone for the 90-95 kD kinase. Reelectrophoresis experiments established that 32P incorporation represented kinase autophosphorylation as opposed to protein substrate phosphorylation. Epo-associated serine kinase autophosphorylation was both hormone concentration and time dependent as well as restricted to the G0, G1, and S phases of the cell cycle. Cell fractionation studies localized the activity of the 90-95 kD serine kinase to the plasma membrane.

Animals↗
PubMed1993

Lack of detectable human immunodeficiency virus infection in antibody-negative children born to human immunodeficiency virus-infected mothers.

More than one-half of the children born to women with human immunodeficiency virus (HIV) infection are not infected with HIV. Most of these children, although born antibody-positive, lose maternal antibody and remain asymptomatic. However, it has been unclear how many antibody-negative children of HIV-infected women may truly be infected despite the loss of passively acquired maternal antibody. One hundred nine children who lost maternal antibody after birth to HIV-infected women recruited in four United States maternal HIV transmission studies were examined for HIV infection. Polymerase chain reaction (PCR) was used to determine whether children had HIV proviral DNA in peripheral blood mononuclear cells. A total of 268 samples from 109 children were tested. Clinical status and other laboratory findings were also evaluated. The median age at last follow-up was 25 months (range, 12 to 48 months). One hundred seven (98%) children were negative by PCR on all samples tested. None (95% confidence interval, 0.0 to 1.9%) of 109 children had a repeatedly positive PCR. Two children had single positive PCR results that could not be confirmed on subsequent testing. No other laboratory or clinical findings supported HIV infection in either of these children. The loss of HIV antibody in an asymptomatic child born to an HIV-infected woman strongly suggests that the child is not infected with HIV. Single positive PCR results, particularly in the absence of other clinical or laboratory evidence of HIV infection, should not be used alone to diagnose HIV infection.

AIDS Serodiagnosis↗
PubMed1993

Safety, tolerance, and pharmacokinetics of systemic ribavirin in children with human immunodeficiency virus infection.

Eleven pediatric patients, aged 1 to 10 years and with symptomatic human immunodeficiency virus infection, were treated with 6 or 10 mg of oral ribavirin per kg of body weight daily for 60 days. Safety and pharmacokinetic parameters were monitored; five children had comprehensive pharmacokinetic evaluations. The children tolerated the drug well, and treatment was not associated with any clinically significant adverse effects. Peak concentrations in plasma of 2.5 and 3.0 microM were reached at 90 min after single oral doses of 6 and 10 mg/kg, respectively. The mean systemic availability of oral ribavirin was 42.3%. After 60 days of ribavirin administration, mean trough concentrations in plasma of 2.6 and 4.1 microM were obtained. Ribavirin penetrated well into the cerebrospinal fluid, achieving 70% of the concentration in plasma at steady state.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Enzyme immunoassay for detection of human immunodeficiency virus-specific immunoglobulin A antibodies.

Early diagnosis of human immunodeficiency virus (HIV) infection may be difficult in adults with acute or recent HIV infection and in infants with perinatally acquired HIV. Detection of HIV-specific immunoglobulin A (IgA) antibodies in infant serum by Western blot (immunoblot) has been suggested as a reliable method to identify HIV-infected infants, especially those over the age of 6 months, and as an adjunct to diagnosis of acute HIV infection in adults. We developed a simple enzyme immunoassay for detection of HIV-specific IgA, using standard commercially available reagents. Enzyme immunoassay was comparable to Western blot for detection of HIV-specific IgA in sera from adults (n = 216), older children (n = 49), and infants born to HIV-infected mothers (n = 65). Specificity was 100% and sensitivity ranged from 80 to 92%. IgA-enzyme immunoassay is a simple, highly sensitive method for detection of HIV-specific IgA antibodies and is easily adapted to the standard clinical laboratory.

Adolescent↗
PubMed1993

Current epidemiology of tuberculosis.

After years of decline, tuberculosis has become an increasing cause of morbidity and mortality in the United States. Chronic problems of poverty, homelessness, substandard housing, and poor access to health care have combined to help maintain a reservoir of infected persons. The addition of HIV-associated immunodeficiency has allowed many of these infected individuals, whose infections ordinarily would have remained dormant, to develop tuberculosis at younger ages. In addition, increasing numbers of cases of tuberculosis are being identified among young foreign-born adults from countries of high tuberculosis prevalence. Transmission from these young adults has occurred in increasing numbers to children. These children form an enlarging pool of infected persons that will continue the cycle of tuberculous infection and disease for future generations. Renewed emphasis and resources need to be placed on tuberculosis, particularly in the public health sector. Only in this manner will early detection and treatment of those with infection and disease occur and the cycle of tuberculosis be broken.

AIDS-Related Opportunistic Infections↗
PubMed1993

Advocacy, guardianship and the GP.

Australians have come to realise that they have a right to access high quality health care through their general practitioner. It is essential that people with cognitive impairments through intellectual disability, psychiatric disorders, senility or brain damage are not denied equity of access through their inability to seek medical attention. Those who cannot make reasonable decisions or who cannot understand and give legal consent to operative procedures may need to have a guardian appointed to protect their rights. In other situations an advocate may be appointed if the person's rights are in jeopardy. The general practitioner is often the first person to become aware of the needs of disabled people and is well placed to intervene to ensure the protection of their rights. This includes the right to good health care.

Australia↗
PubMed1992

Lymphocyte subsets in healthy children during the first 5 years of life.

OBJECTIVE: To assess whether relative and absolute values of CD4 and CD8 lymphocytes and CD4/CD8 ratio change in relation to age, and to estimate the fifth and 95th percentiles for these values in children of various ages. PATIENTS AND METHODS: Phenotypic analysis of lymphocyte subsets was performed on blood samples from 208 healthy children, aged 1 through 59 months, using standard flow cytometric techniques. RESULTS: Regression analysis demonstrated that CD4 and CD8 lymphocyte counts declined significantly with advancing age (P less than .000001 and P = .03, respectively). Since CD4 and CD8 counts depend on total lymphocyte count, the percentage of total lymphocytes of each phenotype was also analyzed and demonstrated that the CD4 percentage was highly age dependent (P less than .000001). The CD8 percentage increased with age (P = .0001) but not as much as the CD4 percentage decreased. Median CD4 counts (fifth and 95th percentiles) for children 2 through 3, 4 through 8, 12 through 23, and 24 through 59 months of age were 2.83 (1.46 to 5.11), 2.95 (1.69 to 4.61), 2.07 (1.02 to 3.60), and 1.80 (0.90 to 2.86) x 10(9)/L, respectively. CONCLUSION: Healthy children's CD4 lymphocyte counts are considerably higher than previously established adult values. These data demonstrate that age is an important consideration in interpretation of lymphocyte subsets in children. This may be especially relevant in children who are infected with the human immunodeficiency virus, where CD4 lymphocyte values play a central role in monitoring disease progression and determining thresholds for medical interventions.

CD4-CD8 Ratio↗
PubMed1992

Nontuberculous mycobacteria in children with acquired immunodeficiency syndrome.

Among 139 children with acquired immunodeficiency syndrome at Children's Hospital of New Jersey, 20 had positive cultures for non-tuberculous mycobacteria. Eighty-five percent had Mycobacterium avium complex isolated and 70% had definite evidence of disseminated disease. Ninety-three percent had CD4 lymphocyte counts less than 100 cells/mm3 and 95% had met acquired immunodeficiency syndrome criteria before the time of first positive culture. Clinical findings included failure to gain weight, anorexia, fever, abdominal pain/tenderness and anemia. The median age at onset of symptoms was 46 months and the median time between onset of symptoms and positive culture was 9 months. Outcome for patients with positive cultures for nontuberculous mycobacteria was poor, with 75% of the children surviving for less than or equal to 10 months. Nontuberculous mycobacteria are increasingly important causes of morbidity and indirect mortality in human immunodeficiency-infected children. Children with severe immunodeficiency are at particular risk. In addition to M. avium complex, other species of nontuberculous mycobacteria may be involved.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Varicella does not appear to be a cofactor for human immunodeficiency virus infection in children.

We performed a retrospective analysis of longitudinal clinical and immunologic data obtained from 22 children in the early stages of infection with human immunodeficiency virus (HIV) when they developed varicella. We studied the course of HIV infection to determine whether clinical deterioration occurred after chickenpox. We examined the following indices: growth and development; neurologic status; helper T lymphocyte counts; blood values of core (p24) antigen of HIV; changes in the stage of HIV infection; and need for administration of zidovudine. We studied children for a mean of 2.8 years and for as long as 9.8 years after onset of varicella. There was little evidence that chickenpox affected HIV infection. Three (14%) children developed clinical zoster, 2 of whom (9%) had evidence of chronic infection with varicella-zoster virus. One additional child (5%) had 2 episodes of chickenpox. These observations suggest that children with early HIV infection could be considered for immunization with live attenuated varicella vaccine, which would be predicted to decrease their morbidity from varicella-zoster virus.

CD4-Positive T-Lymphocytes↗
PubMed1992

Population-based study of measles and measles immunization in human immunodeficiency virus-infected children.

This study reports the course of measles and results of measles immunization in a cohort of human immunodeficiency virus-infected children. Six cases of measles were identified. All had typical clinical manifestations, 5 of 6 developed pneumonia and 3 of 6 died. A measles intervention program consisting of serologic screening and active immunization (measles-mumps-rubella (MMR)) was instituted in 1990. Among 127 children with data available for analysis (mean age, 6.7 years), only 35% had documentation of prior immunization with MMR. Among 80 children who had preimmunization measles serology reported, 56% were measles antibody-negative and 40% were antibody-positive; following intervention 36% remained measles antibody-negative. Six children lost measles antibody over time. MMR nonresponders had lower CD4 lymphocyte counts (303 +/- 394) compared with responders (865 +/- 677; P = 0.0058). Measles is a potentially fatal illness in human immunodeficiency virus-infected children. Prevention strategies are limited by low rates of age-appropriate MMR immunization, poor antibody responses to MMR in older human immunodeficiency virus-infected children and seroreversion.

Child↗