PubMed Health⌕ Search

Biomedical subjects

S A Spector

Publications and source records attributed to S A Spector.

At least 73 records · Page 4Linked to original sources
PubMed1997

Deterioration of detectable human immunodeficiency virus serum p24 antigen in samples stored for batch testing.

Virologic measurements are becoming important surrogate markers for therapeutic efficacy in clinical trials with human immunodeficiency virus (HIV)-infected subjects. One such marker which is inexpensive and easily evaluated is the HIV p-24 antigen. To determine the storage stability of p24 antigen assayed by enzyme-linked immunosorbent assay of serum collected during clinical trials, a retrospective analysis was performed. The p24 antigen results were available from four Adult or Pediatric AIDS Clinical Trials Group protocols: studies 047, 050, 128, and 213. Paired samples (n = 930) which were assayed by ELISA for p24 antigen both in real time and in batch were analyzed for agreement. Batch and real-time values were correlated; however, there was a lack of agreement which increased with prolonged storage time of batched samples and greater p24 antigen levels. The p24 antigen values were significantly lower in the batched samples, which had a maximum storage time of 1,548 days. The degradation rate of p24 antigen per year was 0.052 log10 for samples with less than 30 pg/ml, 0.197 log10 for those with 30 to 100 pg/ml, and 0.245 log10 for those with > 100 pg/ml. Due to degradation over time, use of p24 antigen values from batch assays with long-term storage could bias study results toward a lack of treatment effect. On the basis of these results we make the following recommendations. (i) Samples should be assayed either in real time by laboratories undergoing quality assurance or in batch with short-term storage (less than 1 year). (ii) When real-time assays are to be performed, the serum samples should not be stored at 4 degrees C, but should be frozen immediately after processing and stored frozen until tested.

Adult↗
PubMed1997

A model system for human cytomegalovirus-mediated modulation of human immunodeficiency virus type 1 long terminal repeat activity in brain cells.

Previously, our laboratory showed that human cytomegalovirus (HCMV) activates human immunodeficiency virus type 1 (HIV-1) in brain-derived cells with limited HIV-1 gene expression but inhibits HIV-1 in cells fully permissive for replication of both viruses (F. M. Jault, S. A. Spector, and D. H. Spector, J. Virol. 68:959-973, 1994). To investigate these effects further, we developed a model system that uncouples HIV-1 gene expression from long terminal repeat (LTR) activity. Two monoclonal U373-MG astrocytoma/glioblastoma cell lines (LTRIG and LIGHIVDC) were generated, each containing an integrated copy of an LTR-chloramphenicol acetyltransferase (CAT) construct and the Escherichia coli lacI gene. LIGHIVDC also has an inducible HIV-1 genome controlled by a Rous sarcoma virus promoter with lac operator sequences. Basal LTR-mediated CAT activity is 65-fold higher in LIGHIVDC than in LTRIG, and this activity is further increased (20-fold) following incubation of LIGHIVDC with isopropyl-beta-D-thiogalactopyranoside (IPTG). Tat protein can be detected by immunostaining in LIGHIVDC. However, Rev-mediated transport and subsequent translation of the singly spliced and unspliced HIV-1 mRNAs is inefficient. In the absence of Tat, HCMV stimulated CAT activity approximately 20-fold, and this activation required HCMV gene expression but not viral DNA replication. LTR-directed transcription was unaffected by HCMV infection in LIGHIVDC but was inhibited in these cells when they contained increased Tat levels following IPTG induction. These results support the hypothesis that HCMV can induce the HIV-1 LTR when HIV-1 gene expression is minimal and that a threshold level of HIV-1 gene products is necessary for HCMV to inhibit this promoter.

Brain↗
PubMed1996

Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. Roche Cooperative Oral Ganciclovir Study Group.

BACKGROUND: In the advanced stages of the acquired immunodeficiency syndrome (AIDS), cytomegalovirus (CMV) disease, particularly vision-damaging retinitis due to CMV is common. We evaluated prophylactic treatment with orally administered ganciclovir as a way to prevent CMV disease. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled study of CMV infected persons with AIDS with either CD4+ lymphocyte counts of < or = 50 per cubic millimeter or counts of < or = 100 per cubic millimeter in those with a history of an AIDS defining opportunistic infection. Patients were randomly assigned, in a 2:1 ratio, to receive either oral ganciclovir (1000 mg three times daily) or placebo. RESULTS: The study was stopped after a median 367 days of follow-up. In an intention-to-treat analysis, the twelve month cumulative rates of confirmed CMV disease were 26 percent in the placebo group (n = 239) and 14 percent in the ganciclovir group (n = 486), representing an overall reduction in risk of 49 percent in the ganciclovir group (P < 0.001). The incidence of CMV retinitis after 12 months was 24 percent in the placebo group and 12 percent in the ganciclovir group (P < 0.0001). The prevalence of CMV-positive urine cultures at base line was 42 percent; after two months it was 43 percent in the placebo group and 10 percent in the ganciclovir group (P < 0.0001). The one year mortality rate was 26 percent in the placebo group and 21 percent in the ganciclovir group (P = 0.14). Therapy with granulocyte colony stimulating factor was more frequent in the ganciclovir group (24 percent) than in the placebo group (9 percent). CONCLUSIONS: In persons with advanced AIDS, phophylactic oral ganciclovir significantly reduces the risk of CMV disease.

AIDS-Related Opportunistic Infections↗
PubMed1996

Strength gains without muscle injury after strength training in patients with postpolio muscular atrophy.

We evaluated changes in the dynamic and isometric strength in the newly weakened quadriceps muscles and asymptomatic triceps muscles of 6 patients with postpolio muscular atrophy (PPMA) after 10 weeks of progressive resistance strength training. Alterations in muscle size were determined with magnetic resonance imaging. Serum creatine kinase levels were measured throughout training, and histological signs of muscle injury and changes in muscle fiber size and types were assessed with muscle biopsies before and after training. Exercise training led to an increase in dynamic strength of 41% and 61% for the two knee extensor tests, and 54% and 71% for the two elbow extensor tests. Up to 20% of the improvement was maintained 5 months after cessation of training. Isometric strength, whole muscle cross-sectional areas of quadriceps and triceps muscles, and serum muscle enzymes did not change. No destructive histopathological changes were noted in the repeat muscle biopsies, and no consistent changes in muscle fiber size or fiber type percentages were observed. These results demonstrate that a supervised resistance training program can lead to significant gains in dynamic strength of both symptomatic and asymptomatic muscles of PPMA patients without serological or histological evidence of muscular damage.

Biopsy↗
PubMed1996

Electrophysiologic and histologic studies in clinically unaffected muscles of patients with prior paralytic poliomyelitis.

Macro-electromyography (macro-EMG) studies have provided important information about the size of the motor units and the degree of reinnvervation in clinically affected muscles of patients with a history of poliomyelitis and postpolio syndrome. The study of clinically unaffected muscles and correlation of their electrophysiologic characteristics with the muscle architecture could provide meaningful information about the ongoing subclinical denervation. We performed macro-EMG and concomitantly measured fiber density in the clinically unaffected gastrocnemius muscle of 10 patients with postpolio syndrome and 10 normal subjects of similar age. We also performed biopsies on the gastrocnemius muscle of 8 of the patients. The median amplitude and area of the macro-motor unit potentials (macro-MUPs) were increased in 8 of the 10 patients, and occasionally were five times as large as the mean median value for the normal subjects. Seven biopsy specimens showed moderate to very large fiber-type grouping. In 5 patients, there was correlation between the electrophysiologic and histologic indices of reinnervation. Amplitude and area of the macro-MUPs were associated with the muscle fiber cross-sectional area. We conclude that clinically unaffected muscles of patients with postpolio syndrome often have large motor units as the result of effective reinnervation after the original motor neuron loss. In spite of possible differences in the cytoarchitecture of muscles affected to different degrees, macro-EMG and fiber density measurements are reliable noninvasive techniques for studying the extent and effectiveness of reinnervation in patients with postpolio syndrome.

Adult↗
PubMed1996

Summary of the International Consensus Symposium on Advances in the Diagnosis, Treatment and Prophylaxis and Cytomegalovirus Infection.

CMV infection and CMV disease can be difficult to differentiate and the diagnosis is usually based on a compatible clinical picture and the results of a diagnostic test for CMV. The only exception to this rule is in HIV-infected patients where fundoscopy is sufficient to diagnose CMV retinitis. Of the current diagnostic tests, qualitative and quantitative PCR, branched DNA and Hybrid Capture, are the most promising. The pp65 antigenemia assay has the disadvantage of being more labor-intensive than the DNA based tests. Preliminary data show that a positive qualitative PCR in a HIV-infected patient has a predictive value for the development of CMV retinitis. However, of the patients positive by qualitative PCR, those with high viral loads in quantitative PCR were at the greatest risk of CMV disease. This might make it possible to identify with great certainty the patients who will go on to develop CMV retinitis, thereby decreasing the number of patients eligible for preemptive or prophylactic therapy and increasing the cost-benefit of this therapeutic measure. Quantitative test might also be useful in monitoring response to therapy, but randomized trials comparing the test are needed. Prophylactic antiviral agents should not be used in seronegative transplant recipients receiving organs from seronegative donors. In high-risk transplant recipients, ganciclovir should be used. CMV vaccines are useful for the protection of babies from CMV seronegative mothers against congenital CMV disease. It also may be useful in seronegative transplant recipients receiving a seropositive donor organ, although the benefit of chemo prophylaxis may surpass that of vaccine. HIV-infected patients with CMV retinitis who relapse under either ganciclovir or foscarnet benefit from subsequent combination therapy, rather than switching to the other drug. However, the cost is high in terms of quality of life. Intravitreal therapy for CMV retinitis is very efficacious, suggesting that drug delivery is a problem in systemic therapy. However, intravitreal therapy does not protect against the development of CMV retinitis in the contralateral eye or from CMV disease elsewhere. Therefore, systemic therapy should be added. CMV disease of the CNS should be diagnosed early and treated agressively, possible with combination therapy. A diagnosis of CMV disease should be based on a compatible clinical picture and the demonstration of CMV in CSF by DNA or antigen assays which are more sensitive than culture.

Animals↗
PubMed1996

Polyradiculopathy associated with ganciclovir-resistant cytomegalovirus in an AIDS patient: phenotypic and genotypic characterization of sequential virus isolates.

To investigate the role of antiviral drug resistance in cytomegalovirus (CMV) disease progression, CMV cultured from an AIDS patient who developed progressive CMV disease despite continual anti- CMV treatment was characterized. In 7 CMV isolates, 1 ganciclovir-resistant strain predominated. Ganciclovir-resistant CMV, containing a UL97 mutation, was cultured from blood and urine before clinical indication of CMV central nervous system (CNS) disease, suggesting that the development of ganciclovir resistance preceded the dissemination of CMV to the CNS. Quantitative competitive polymerase chain reaction indicated that the isolation of ganciclovir-resistant CMV was concurrent with increased CMV DNA in plasma. The results suggest that antiviral resistance should be considered when selecting therapy for CMV CNS disease that develops in patients receiving treatment for CMV retinitis. In addition, plasma CMV DNA in AIDS patients receiving anti-CMV therapy may be a useful marker of disease progression and antiviral resistance.

AIDS-Related Opportunistic Infections↗
PubMed1996

Virologic markers of human immunodeficiency virus type 1 in cerebrospinal fluid of infected children.

To identify virologic correlates associated with central nervous system (CNS) abnormalities in children infected with human immunodeficiency virus type 1 (HIV-1), cerebrospinal fluid (CSF) was examined for virologic markers and correlated with neurodevelopmental status and neuroimaging abnormalities. Of 30 children, 18 (60%) had at least 1 culture-positive CSF sample; in total, 21 (55%) of 38 CSF specimens were culture-positive. CSF white blood cell counts were higher in specimens that were culture-positive (P = .01). HIV-1 RNA was detected in 90% of CSF samples, and RNA levels > or = 10,000 copies/mL were found in 6 (75%) of 8 children with severe neurocognitive impairment (P = .08) and 11 (73%) of 15 children with a cognitive index < or = 85 (P = .04). Higher RNA levels were associated with abnormal brain imaging scans (P = .04) and with neurocognitive deficits (P = .04). Thus, HIV-1 is present within the CNS of most infected children, and neurocognitive impairment appears to be associated with increased HIV-1 replication.

Adolescent↗
PubMed1996

Disease patterns and survival after acquired immunodeficiency syndrome diagnosis in human immunodeficiency virus-infected children.

BACKGROUND: The clinical manifestations of HIV infection in children involve a broad spectrum of conditions ranging from mild symptoms to AIDS. Knowledge of the disease and survival patterns of these children are needed to plan for future needs and develop baseline information to evaluate newer prophylactic or therapeutic management options. OBJECTIVES: To identify AIDS-defining conditions and estimate post-AIDS diagnosis survival among HIV-infected children. METHODS: Disease patterns and survival after the diagnosis of AIDS-defining conditions were studied in 126 children who were identified through a multisite university-based active surveillance system in California from January, 1989, through August, 1993. Hospital medical records were periodically reviewed and data were abstracted onto standardized forms designed for pediatric HIV surveillance. We determined the length of survival between AIDS diagnosis and death and evaluated the impact of disease patterns on survival using Kaplan-Meier's product-limit method and Cox proportional hazards regression. RESULTS: The median age at diagnosis was 13 months for children with perinatally acquired infection and 101.5 months for children infected through other routes of transmission. Pneumocystis carinii pneumonia and lymphoid interstitial pneumonia were the most common AIDS-defining conditions among perinatal cases, whereas the disease patterns observed among nonperinatal cases were more varied. The median postdiagnosis survival for the cohort was 26 months. CONCLUSIONS: Survival time did not differ significantly by race/ethnicity, sex or route of transmission. Respiratory candidiasis and wasting syndrome had significant negative impact on survival but P. carinii pneumonia was not associated with shorter survival. Zidovudine or other antiviral therapies was associated with increased survival.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. Syntex Cooperative Oral Ganciclovir Study Group.

BACKGROUND: Cytomegalovirus retinitis, a sight-threatening infection associated with the acquired immunodeficiency syndrome (AIDS), currently requires lifelong intravenous treatment. An effective oral treatment would be an important advance. METHODS: We compared oral with intravenous ganciclovir in an open-label, randomized study in patients with AIDS and newly diagnosed, stable cytomegalovirus retinitis (the disease was stabilized by three weeks of treatment with intravenous ganciclovir). Sixty subjects were randomly assigned to maintenance therapy with intravenous ganciclovir at a dose of 5 mg per kilogram of body weight daily, and 63 to maintenance therapy with oral ganciclovir at a dose of 3000 mg daily. The subjects were followed for up to 20 weeks, with photography of the fundi conducted every other week. The photographs were evaluated at the completion of the study by an experienced grader who was unaware of the subjects' treatment assignments. RESULTS: Efficacy could be evaluated in 117 subjects; photographs were ungradable for 2 of the 117. On the basis of the masked assessment of photographs from 115 subjects, the mean time to the progression of retinitis was 62 days in those given intravenous ganciclovir and 57 days in those given oral ganciclovir (P = 0.63; relative risk [oral vs. intravenous], 1.08; 95 percent confidence interval for the difference in means, -22 to +12 days). On the basis of funduscopy by ophthalmologists who were aware of the subjects' treatment assignments, the mean time to progression was 96 days in subjects given intravenous ganciclovir and 68 days in subjects given oral ganciclovir (P = 0.03; relative risk [oral vs. intravenous], 1.68; 95 percent confidence interval for the difference in means, -45 to -11 days). Survival, changes in visual acuity, the incidence of viral shedding, and the incidence of adverse gastrointestinal events were similar in the two groups. Neutropenia, anemia, intravenous-catheter-related adverse events, and sepsis were more common in the group given intravenous ganciclovir. CONCLUSIONS: Oral ganciclovir is safe and effective as maintenance therapy for cytomegalovirus retinitis and is more convenient for patients to take than intravenous ganciclovir.

AIDS-Related Opportunistic Infections↗
PubMed1995

A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group.

BACKGROUND: We evaluated the effectiveness of three treatment strategies for the prevention of a first episode of Pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus (HIV). METHODS: In an open-label trial, 843 patients with HIV infection and fewer than 200 CD4+ cells per cubic millimeter received zidovudine plus one of three randomly assigned prophylactic agents, beginning with trimethoprim-sulfamethoxazole, dapsone, or aerosolized pentamidine and followed by a defined sequence of other drugs to be used in cases of intolerance. RESULTS: The estimated 36-month cumulative risks of P. carinii pneumonia were 18 percent, 17 percent, and 21 percent in the trimethoprim-sulfamethoxazole, dapsone, and aerosolized-pentamidine groups, respectively (P = 0.22). The difference in risk among treatment strategies was negligible in patients entering the study with 100 or more CD4+ lymphocytes per cubic millimeter. In those entering with fewer than 100 CD4+ cells per cubic millimeter, the risk was 33 percent with aerosolized pentamidine, as compared with 19 percent with trimethoprim-sulfamethoxazole and 22 percent with dapsone (P = 0.04). The lowest failure rates occurred in patients receiving trimethoprim-sulfamethoxazole, and failures were more common with 50 mg of dapsone than with 100 mg. Toxoplasmosis developed in less than 3 percent of patients. Of the patients assigned to the two systemic therapies, only 23 percent were receiving their assigned drug and dose when they completed the study. The median survival was approximately 39 months in all three groups, and the mortality attributable to P. carinii pneumonia was only 1 percent. CONCLUSIONS: In patients with advanced HIV infection, the three treatment strategies we examined have similar effectiveness in preventing P. carinii pneumonia. Strategies that start with trimethoprim-sulfamethoxazole or with high-dose dapsone, rather than aerosolized pentamidine, are superior in patients with fewer than 100 CD4+ lymphocytes per cubic millimeter.

AIDS-Related Opportunistic Infections↗
PubMed1995

Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus.

In these Phase I/II open-label clinical trials, 62 persons with human immunodeficiency virus type 1 (HIV-1) infection and CD4+ cell counts < 400/mm3 received nevirapine at doses of 12.5, 50, and 200 mg/day, alone or in combination with zidovudine, 200 mg q8h. Nevirapine was well tolerated in the doses tested. Mean steady-state trough levels were 0.23, 1.1, and 1.9 micrograms/ml for the 12.5, 50, and 200 mg/day doses, respectively. Early suppression of p24 antigen levels and increase in CD4+ cell count were reversed following rapid emergence of virus less susceptible to nevirapine. Resistant strains were isolated from all participants by 8 weeks. Nevertheless, reduction of p24 antigen levels to < 50% of baseline values persisted for 12 weeks or more in four of seven persons who received 200 mg nevirapine/day in combination with zidovudine: these individuals had been antigenemic on long-term zidovudine therapy. This study demonstrates a direct relationship between drug resistance and effects on surrogate markers in HIV-1 infection.

Adult↗
PubMed1995

Combination therapy with recombinant human soluble CD4-immunoglobulin G and zidovudine in patients with HIV infection: a phase I study.

To determine the effect of zidovudine (ZDV) on the pharmacokinetic disposition of recombinant soluble CD4 immunoglobulin G (rCD4-IgG) and to evaluate the safety and preliminary activity of concurrent administration of ZDV with rCD4-IgG, we undertook an open-label, dose-escalating, 12-week study. The regimens of intravenous rCD4-IgG and oral ZDV we used were (a) 300 micrograms/kg rCD4-IgG twice per week and 300 mg ZDV per day, (b) 300 micrograms/kg rCD4-IgG twice per week and 600 mg ZDV per day, (c) 1,000 micrograms/kg rCD4-IgG twice per week and 300 mg ZDV per day, (d) 1,000 micrograms/kg rCD4-IgG twice per week and 600 mg ZDV per day, and (e) 3,000 micrograms/kg rCD4-IgG twice per week and 300 mg ZDV per day. Subjects were recruited from three AIDS clinical trials units. Forty-one patients with HIV infection who had CD4 cell counts < or = 500 cells/mm3 and < 120 days of previous ZDV therapy participated. Pharmacokinetic interactions were assessed with the second regimen. Mean calculated peak serum rCD4-IgG concentrations were 5.47 micrograms/ml with ZDV and 8.28 micrograms/ml without ZDV, with serum half-lives of 34.2 and 32.0 h, respectively. Antibodies to rCD4-IgG were not detected. Seven episodes of severe adverse events occurred in five patients: one episode each of severe nausea, fever, or abnormal liver function tests and four episodes of severe neutropenia. Mean hemoglobin and neutrophil counts decreased, and mean platelet counts increased in all regimens, but there were no significant differences among regimens, rCD4-IgG dose, or ZDV dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗