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Biomedical subjects

S E Straus

Publications and source records attributed to S E Straus.

At least 55 records · Page 3Linked to original sources
PubMed2000

Gamma interferon impedes the establishment of herpes simplex virus type 1 latent infection but has no impact on its maintenance or reactivation in mice.

Murine models of gamma interferon (IFN-gamma) deficiency demonstrate the role of this cytokine in attenuating acute herpes simplex virus (HSV) disease; however, the effect of IFN-gamma on the establishment and maintenance of neuronal latency and viral reactivation is not known. Using the IFN-gamma knockout (GKO) model of IFN-gamma deficiency and sensitive quantitative PCR methods, we show that IFN-gamma significantly reduces the ganglion content of latent HSV-1 in BALB/c mice, which in turn delays viral time to reactivation following UV irradiation. Similar effects were not seen in the C57BL/6 strain. These results indicate that IFN-gamma significantly attenuates latent HSV infection in the mouse model of ocular infection but has no impact on the maintenance of latency or virus reactivation.

Acute Disease↗
PubMed2000

Decreased bone mineral density during low dose glucocorticoid administration in a randomized, placebo controlled trial.

OBJECTIVE: While osteoporosis and bone fractures are clearly recognized side effects of high dose glucocorticoids, the effect of low dose glucocorticoids remains controversial. We investigated the effect of 3 months of low dose hydrocortisone on bone mineral density (BMD). METHODS: Subjects, 18 to 55 years old with chronic fatigue syndrome and no medical or psychiatric illness requiring medication, were randomized in a double blind, placebo controlled trial to receive oral hydrocortisone, 13 mg/m2 body surface area every morning and 3 mg/m2 every afternoon (25 to 35 mg/day, equivalent to about 7.5 mg prednisone/day) or placebo for 12 weeks. Before and after treatment BMD of the lumbar spine was measured by dual energy x-ray absorptiometry. RESULTS: We studied 23 subjects (19 women, 4 men). For the 11 hydrocortisone recipients there was a mean decrease in BMD: mean change from baseline of the lateral spine was -2.0% (95% CI -3.5 to -0.6. p = 0.03) and mean change of the anteroposterior spine was -0.8% (95% CI -1.5 to -0.1, p = 0.06). Corresponding changes for the 12 placebo recipients were +1.0% (95% CI -1.0 to 3.0, p = 0.34) and +0.2% (95% CI -1.4 to 1.5, p = 0.76). CONCLUSION: A 12 week course of low dose glucocorticoids given to ambulatory subjects with chronic fatigue syndrome was associated with a decrease in BMD of the lumbar spine. This decrease was statistically significant in lateral spine measurements and nearly so in anteroposterior spine measurements.

Adult↗
PubMed1999

The medical review article revisited: has the science improved?

BACKGROUND: The validity of a review depends on its methodologic quality. OBJECTIVE: To determine the methodologic quality of recently published review articles. DESIGN: Critical appraisal. SETTING: All reviews of clinical topics published in six general medical journals in 1996. MEASUREMENTS: Explicit criteria that have been published and validated were used. RESULTS: Of 158 review articles, only 2 satisfied all 10 methodologic criteria (median number of criteria satisfied, 1). Less than a quarter of the articles described how evidence was identified, evaluated, or integrated; 34% addressed a focused clinical question; and 39% identified gaps in existing knowledge. Of the 111 reviews that made treatment recommendations, 48% provided an estimate of the magnitude of potential benefits (and 34%, the potential adverse effects) of the treatment options, 45% cited randomized clinical trials to support their recommendations, and only 6% made any reference to costs. CONCLUSIONS: The methodologic quality of clinical review articles is highly variable, and many of these articles do not specify systematic methods.

Bibliometrics↗
PubMed1999

A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group.

BACKGROUND AND METHODS: Herpes simplex virus (HSV) infections are endemic, but the clinical characteristics of newly acquired HSV type 1 (HSV-1) and HSV type 2 (HSV-2) infections in adults have not been rigorously defined. We monitored 2393 sexually active HSV-2-seronegative persons for clinical and serologic evidence of new HSV infection. Of the participants, 1508 were seropositive for HSV-1 and 885 were seronegative. Charts were reviewed in a blinded manner for classification of those with genitourinary or oropharyngeal symptoms. Charts were also reviewed for all 174 persons with HSV seroconversion. RESULTS: The rates of new HSV-1 and HSV-2 infections were 1.6 and 5.1 cases per 100 person-years, respectively. Of the 155 new HSV-2 infections, 57 (37 percent) were symptomatic, 47 of which (82 percent) were correctly diagnosed at presentation. Among the 74 patients given a clinical diagnosis of genital HSV-2 during the study, 60 were given a correct diagnosis and 14 were given an incorrect diagnosis of genital herpes, for a ratio of true positive results to false positive results of 4:1. Among the 98 persons with asymptomatic HSV-2 seroconversion, 15 percent had genital lesions at some time during follow-up. Women were more likely than men to acquire HSV-2 (P<0.01) and to have symptomatic infection. Previous HSV-1 infection did not reduce the rate of HSV-2 infection, but it did increase the likelihood of asymptomatic seroconversion, as compared with symptomatic seroconversion, by a factor of 2.6 (P<0.001). Of the 19 new HSV-1 infections, 12 were symptomatic. The rates of symptomatic genital HSV-1 infection and oropharyngeal HSV-1 infection were the same (0.5 case per 100 person-years). CONCLUSIONS: Nearly 40 percent of newly acquired HSV-2 infections and nearly two thirds of new HSV-1 infections are symptomatic. Among sexually active adults, new genital HSV-1 infections are as common as new oropharyngeal HSV-1 infections.

Adolescent↗
PubMed1999

Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment.

CONTEXT: Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered. OBJECTIVE: To determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans. DESIGN: Two randomized, double-blind, placebo-controlled trials conducted between June and July 1997. SETTING: Individual hotel rooms; 2 large US university medical schools. PARTICIPANTS: A total of 117 healthy adult volunteers (aged 18-40 years; median age, 21 years) who were susceptible (hemagglutination-inhibition antibody titer < or =1:8). INTERVENTIONS: All subjects were inoculated intranasally with influenza A/Texas/36/91 (H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n = 12], 100 mg twice daily [n = 12], or matching placebo [n = 13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice daily, 200 mg once daily, or matching placebo [n = 16], in each group starting 28 hours after inoculation). All regimens were continued for 5 days. MAIN OUTCOME MEASURES: Comparing placebo groups with pooled treatment groups, for prophylaxis, outcomes included frequency of infection and viral shedding; for treatment, viral shedding in titers. RESULTS: In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P = .16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment study (n = 69), the viral titer area under the curve of the combined oseltamivir groups (n = 56) was lower (median [interquartile range [IQR]], 80 [23-151] vs 273 [79-306] log10 tissue culture-infective doses50 per milliliter x hour; P = .02) than the placebo group (n = 13), and the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P = .003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P = .05), and nasal proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, -11% to 68%), which was largely prevented by ingestion with food. CONCLUSIONS: In these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza.

Administration, Oral↗
PubMed1999

Treatment of HSV-1 infection with immunoglobulin or acyclovir: comparison of their effects on viral spread, latency, and reactivation.

We compared immunoglobulin (IgG) and acyclovir (ACV) therapies on the establishment, maintenance, and reactivation from latency of HSV-1(McKrae) in a mouse ocular infection model. Mice were given one intraperitoneal (IP) dose of human IgG 24 h after infection (Day 1 p. i.) or ACV in the drinking water from Days 1 to 7 p.i. Both treatments allowed similar percentages of mice to survive the infection and decreased ocular virus shedding as compared with untreated controls. At most time points, there were no differences between IgG- and ACV-treated animals with respect to tissue virus titers or in the rates of virus reactivation during explant cocultivation. However, after ultraviolet exposure, HSV reactivated in 30% of ACV-treated mice compared with 90% of IgG-treated mice (P = 0.02). Also by quantitative PCR, we found more latent HSV-1 DNA copies in IgG-treated mice compared with those given ACV (P = 0.02). IgG treatment protects mice from HSV-1 infection essentially as well as ACV does. Nonetheless, it permits higher levels of latent infection and subsequent in vivo reactivation. These studies have implications for the mechanism by which IgG functions to attenuate HSV infections and for its potential value as a therapeutic agent in humans.

Acute Disease↗
PubMed1999

Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group.

CONTEXT: In the last 3 decades, herpes simplex virus type 2 (HSV-2) infection seroprevalence and neonatal herpes have increased substantially. An effective vaccine for the prevention of genital herpes could help control this epidemic. OBJECTIVE: To evaluate the efficacy of a vaccine for prevention of HSV-2 infection. DESIGN: Two randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 microg each of 2 major HSV-2 surface glycoproteins (gB2 and gD2) against which neutralizing antibodies are directed, administered at months 0, 1, and 6. Control subjects were given a citrate buffer vehicle. Participants were followed up for 1 year after the third immunization. SETTING AND PARTICIPANTS: We enrolled 2393 persons from December 10, 1993, to April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegative. One trial with 18 centers enrolled 531 HSV-2-seronegative partners of HSV-2-infected persons; the other, with 22 centers, enrolled 1862 persons attending sexually transmitted disease clinics. A total of 2268 (94.8%) met inclusion criteria and were included in the analysis with 1135 randomized to placebo and 2012 to vaccine. MAIN OUTCOME MEASURE: Time to acquisition of HSV-2 infection, defined by seroconversion or isolation of HSV-2 in culture during the study period by randomization group. RESULTS: Time-to-event curves indicated a 50% lower acquisition rate among vaccine vs placebo recipients during the initial 5 months of the trial; however, overall vaccine efficacy was 9% (95% confidence interval, -29% to 36%). Acquisition rates of HSV-2 were 4.6 and 4.2 per 100 patient-years in the placebo and vaccine recipients, respectively (P =.58). Follow-up of vaccine recipients acquiring HSV-2 infection showed vaccination had no significant influence on duration of clinical first genital HSV-2 episodes (vaccine, median of 7.1 days; placebo, 6.5 days; P>.10) or subsequent frequency of reactivation (median monthly recurrence rate with vaccine, 0.2; with placebo, 0.3; P>.10). The vaccine induced high levels of HSV-2-specific neutralizing antibodies in vaccinated persons who did and did not develop genital herpes. CONCLUSIONS: Efficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study.

Adolescent↗
PubMed1999

Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II.

Caspases are cysteine proteases that mediate programmed cell death in phylogenetically diverse multicellular organisms. We report here two kindreds with autoimmune lymphoproliferative syndrome (ALPS) type II, characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects, that harbor independent missense mutations in Caspase 10. These encode amino acid substitutions that decrease caspase activity and interfere with death receptor-induced apoptosis, particularly that stimulated by Fas ligand and TRAIL. These results provide evidence that inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS type II.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Transcript mapping and transregulatory behavior of varicella-zoster virus gene 21, a latency-associated gene.

Gene 21 is one of at least four genes transcribed during latent infection of varicella-zoster virus (VZV) in human ganglia. It may encode a nucleocapsid protein, but its function in lytic and latent infection is not clear. To characterize further the structure and the function of the gene 21 open reading frame (ORF 21), precise localization of its transcripts and their termini was determined by using Northern analysis, S1 nuclease or RNase protection, and primer extension assays. One abundant 3.5-kb transcript that spans ORF 21 was identified. A predominant transcription start site was defined at -78 nucleotide (nt) relative to the ORF 21 translation start codon ATG, and two potential TATA elements were identified at 26 and 83 nt upstream of the 5' end of gene 21 transcripts. Transcription was found to terminate 210 nt beyond the ORF 21 translation stop codon and immediately before the start codon of ORF 22. In transient expression assays, the ORF 21 showed no significant transregulatory activity on promoters of diverse kinetic classes. The ORF 21 promoter, however, was transactivated strongly by VZV infection or by ORF 62.

Base Sequence↗
PubMed1999

Recent advances in varicella-zoster virus infection.

Varicella-zoster virus has developed a complex strategy that allows it to remain latent in the body and avoid destruction by the immune system. Although varicella and zoster have been recognized since antiquity, several new clinical syndromes--including chronic chickenpox with persistent verrucous lesions and disseminated varicella without skin lesions--have been noted in patients with AIDS. Acyclovir has been the mainstay for treating severe varicella-zoster virus infections; however, newer antiviral agents, including valacyclovir and famciclovir, have expanded therapeutic options for treating adults with herpes zoster. The recently licensed live attenuated vaccine for varicella-zoster virus is effective in preventing chickenpox, and the vaccine's ability to stimulate immunity in seropositive adults suggests a promising strategy with which to modify the course of herpes zoster.

Adult↗
PubMed1999

Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia.

Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism. We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.

Adaptor Proteins, Signal Transducing↗
PubMed1999

An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome.

The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate apoptosis, or programmed cell death. The timely deletion of lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective lymphocyte apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon "double-negative" CD3+ CD4- CD8- T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective apoptosis may also contribute to a heightened risk for lymphoma.

Apoptosis↗
PubMed1999

Viral gene expression in rat trigeminal ganglia following neonatal infection with varicella-zoster virus.

Newborn rats were injected intraperitoneally with uninfected human cells or cell infected with 56,000 pfu of varicella-zoster virus (VZV). Five to 6 weeks later, trigeminal ganglia were harvested and tested for VZV DNA and RNA by PCR. VZV gene 21 and 40 DNA were detected in most infected animals. Gene 21 RNA also was detected in ganglia from most infected animals, but not gene 40 RNA, paralleling previous observations in latently infected human ganglia. The neonatal rat may represent a useful new model for the study of VZV latency.

Animals↗