Biomedical subjects
J W Gnann
Publications and source records attributed to J W Gnann.
Disseminated herpes zoster in the immunocompromised host: a comparative trial of acyclovir and vidarabine. The NIAID Collaborative Antiviral Study Group.
Seventy-three immunocompromised patients with disseminated herpes zoster were evaluated in a double-blind controlled trial of acyclovir (n = 37) versus vidarabine (n = 36) therapy. Acyclovir was administered at 30 mg/kg/day at 8-h intervals and vidarabine was given as a continuous 12-h infusion at 10 mg/kg/day for 7 days (longer if resolution of cutaneous or visceral disease was incomplete). No demographic differences existed between treatment groups. No deaths attributable to varicella-zoster virus infection occurred within 1 month of treatment. Neither rates of cutaneous healing, resolution of acute neuritis, and frequency of postherpetic neuralgia nor adverse clinical and laboratory events differed between treatment groups. Acyclovir recipients were discharged from the hospital more promptly than vidarabine recipients (P = .04, log rank test). These data indicate that disseminated herpes zoster is amenable to therapy with either acyclovir or vidarabine; resultant mortality is low.
Natural history and treatment of varicella-zoster in high-risk populations.
Rigorous clinical trials have established that both acyclovir and vidarabine favourably alter the clinical course of herpes zoster and chicken-pox in immunocompromised patients. In one comparative study, acyclovir was shown to be superior to vidarabine for zoster in bone marrow transplant recipients. These data, plus the fact that acyclovir is easier to administer than vidarabine, and perhaps less toxic, have made intravenous acyclovir the recognized drug of choice for treatment of herpes zoster in immunocompromised patients. Acyclovir sodium sterile powder received Federal Drug Administration (FDA) approval for this indication in 1990 in the United States. Since complications of zoster occur in only a minority of immunocompromised patients, most physicians would prefer to initiate therapy with an orally-administered drug and avoid the cost and inconvenience of hospitalization. Future studies will compare the efficacy and safety of orally administered bromovinyl arabinosyl uracil and acyclovir in treatment of varicella-zoster virus infections.
Therapy for women hospitalized with acute pyelonephritis: a randomized trial of ampicillin versus trimethoprim-sulfamethoxazole for 14 days.
The efficacy of the traditionally recommended ampicillin (Amp) plus gentamicin (GM) regimen was compared with that of a trimethoprim-sulfamethoxazole (TMP/SMZ)-plus-GM regimen and the adequacy of 14 days total therapy for acute uncomplicated pyelonephritis (AUPN). Eighty-five women hospitalized for AUPN were randomly assigned to receive either Amp, 1 g intravenously (iv) every 6 h for 3 days, then 500 mg orally four times daily, or TMP/SMZ, 160/800 mg iv every 12 h for 3 days, then 160/800 mg orally twice daily. Initially, all patients also received GM every 8 h iv (mean, 606 doses). Antimicrobial resistance necessitated modifying therapy of 14 (32%) of the Amp recipients but of none of the TMP/SMZ recipients (P less than .001). Both regimens produced a satisfactory bacteriologic and clinical response in all cases. Reinfection occurred in 11% of Amp and in 8% of TMP/SMZ recipients. No patient experienced relapsing infection. The TMP/SMZ regimen was less costly and less likely to require modification due to antimicrobial resistance.
Acyclovir: the past ten years.
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Regulation and tissue-specific expression of human cytomegalovirus.
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Using synthetic peptide reagents to distinguish infections caused by different HIV strains.
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T cell recognition of HIV synthetic peptides in a natural infection.
Because T cell responses are critical for defense against viral infections, a series of synthetic peptides derived from the predicted sequence for HIV-1 proteins gp41, pg120, gag, and viral polymerase were used to test the T cell proliferative response of HIV-1 seropositive individuals. Of HIV-1-infected donors from various clinical categories 90% (27/30) had sensitized cells that proliferated in response to at least one of 21 HIV peptides tested. Cells from HIV seronegative controls did not proliferate (0/9) in response to these HIV peptides. Individuals with fewer clinical manifestations of HIV-1 disease responded to a greater number of peptides (average for asymptomatic seropositives = 8.1 peptides; AIDS patients averaged 2.0). The number of peptides recognized also correlated with absolute number of CD4+ cells, but not with delayed cutaneous hypersensitivity to a (non-HIV) battery of Ag. However, clinical stage at no time correlated with the response to any particular peptide. Response patterns differed considerably among individuals, and some peptides stimulated proliferation in many (48%) HIV-infected donors (peptides gp41-2 and pol-3), whereas another peptide elicited no T cell response in any donor tested (peptide gp120-8). We have also begun to investigate the basis for individual heterogeneity of T lymphocyte proliferative responses of HIV-infected donors to the 21 HIV synthetic peptides. Peptide structure and HLA class II determinants both influenced patterns of lymphocyte responses. Reactivity correlated with peptide size, the presence of alpha and beta secondary structure and lack of reverse turn potential. Hydropathy and charge had no predictive value. Peptides derived from HIV sequences that vary highly among strains tended to be recognized less frequently. HIV-infected lymphocyte donors were HLA typed to examine the influence of the MHC on T lymphocyte proliferation. Analysis of the frequencies of individuals reacting to specific peptides, when compared to the allele frequencies in the population at large, indicated association of some responses to DR alleles. More DR association was observed with peptides that showed "moderate" reactivity than with those that were "highly" reactive. We suggest that highly reactive peptides are capable of forming a structure closer to an "ideal" T cell epitope that can associate with many DR alleles. In contrast, "moderately" reactive determinants have less favorable structures for interaction, are more limited in their ability to interact and therefore show more restriction to specific class II alleles.
Custom-designed synthetic peptide immunoassays for distinguishing HIV type 1 and type 2 infections.
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Intravenous acyclovir therapy of first episodes of genital herpes: a multicenter double-blind, placebo-controlled trial.
PURPOSE: A collaborative multicenter double-blind, placebo-controlled trial of intravenous acyclovir treatment of first-episode genital herpes was performed in order to substantiate previous findings on the efficacy and safety of this drug, to evaluate the influence of parenteral therapy on recurrence frequency, and to obtain further data on the natural history of genital herpes. PATIENTS AND METHODS: Eighty-two patients with first episodes of genital herpes simplex virus (HSV) infection were randomly assigned in a double-blind fashion to treatment with intravenous acyclovir (5 mg/kg every eight hours) or placebo for five days. Before therapy, all lesions in the genital/perineal area and in extragenital sites were cultured. New lesions appearing in both areas after the onset of therapy were cultured separately. Lesions in all groups were cultured until completely healed. Sera were collected from all patients on entry to the study and on Day 21 to determine presence or absence of antibodies to HSV-1 and HSV-2. Time to healing, time to crusting, time to cessation of viral shedding, and appearance of new lesions during therapy were compared for each treatment group. RESULTS: Patients receiving acyclovir experienced a significant reduction in the median duration of pain (4.3 versus 4.8 days, p = 0.019), viral shedding (1.9 versus 8.4 days, p less than 0.001), and time to healing (8.4 versus 11.5 days, p = 0.02) compared with placebo recipients. These differences were largely attributable to the effect of therapy in the subset of patients with primary disease in whom acyclovir reduced the median duration of pain from 10.6 days to 4.2 days, the median duration of viral shedding from 17.1 days to 1.9 days, and the median time to healing from 14.2 days to 8.3 days. The rate of subsequent recurrence of genital herpes was not altered by acyclovir treatment: 24 of 32 acyclovir recipients (75 percent) experienced one or more recurrences during a mean follow-up of 14 months compared with 19 of 27 placebo recipients (70 percent). Among patients experiencing recurrences, the mean number of recurrences per month among acyclovir recipients was 0.25 compared with 0.19 for patients given placebo. CONCLUSION: This multicenter trial confirms the efficacy of intravenous acyclovir in the management of first-episode genital herpes, especially in patients with primary infection. However, therapy did not alter the frequency of recurrences.
B- and T-lymphocyte responses to an immunodominant epitope of human immunodeficiency virus.
Using synthetic peptides, we characterized the B-lymphocyte (antibody) and T-lymphocyte (proliferation) responses to an immunodominant epitope of human immunodeficiency virus type 1 (HIV-1) located near the amino-terminal end of the transmembrane glycoprotein (env amino acids 598 to 609). Both immunoglobulin M (IgM) and IgG antibodies against this epitope appeared early after primary infection with HIV-1. In an animal model, the IgG response to a synthetic peptide derived from this sequence was T-helper-cell dependent, whereas the IgM response was T-cell independent. In addition, antibody generated by immunization with this peptide had HIV-1-neutralizing activity. Greater than 99% (201 of 203) of patients infected with HIV-1 generated antibody to this peptide in vivo; however, only 24% (7 of 29) had T cells that proliferated in response to this peptide in vitro. These observations suggest that different HIV-1 gp41 epitopes elicit B-cell and T-cell immune responses.
Inflammatory cells in transplanted kidneys are infected by human cytomegalovirus.
To determine which cells in kidney grafts are infected with human cytomegalovirus (HCMV) before and after transplantation, kidney specimens were studied by in situ hybridization with 35S-labeled DNA probes representing HCMV immediate-early and late genes. Pretransplantation biopsies and serial posttransplantation biopsies were obtained from 7 renal grafts. All of the transplant recipients were HCMV-seronegative at the time of transplantation and all developed primary HCMV infections. HCMV nucleic acids were not detected in biopsies taken from the healthy donor kidneys before transplantation. However, biopsies taken at various intervals after transplantation showed abundant hybridization with HCMV immediate-early and late gene probes. Virtually all of the hybridizing cells were mononuclear inflammatory cells in the interstitial spaces of the kidney. Occasional hybridization was seen with renal tubular or glomerular cells. No cytomegalic cells were seen. Biopsy specimens taken after systemic anti-HCMV chemotherapy with phosphonoformate showed no uniform reduction in HCMV gene expression. These studies demonstrate that the principal HCMV-infected cells in kidneys of renal transplant patients with primary HCMV infections are infiltrating inflammatory cells.
Synthetic peptide immunoassay distinguishes HIV type 1 and HIV type 2 infections.
Efforts to solve the epidemiologic puzzle of AIDS in Africa are complicated by the presence of multiple human retroviruses. Simple serologic tests that unambiguously distinguish among infections by these retroviruses are essential. To that end, a partially conserved immunoreactive epitope was identified in the transmembrane glycoproteins of human immunodeficiency viruses (HIV) types 1 and 2. Synthetic peptides derived from these conserved domains were used in sensitive and specific immunoassays that detect antibodies in sera from patients infected with HIV-1 or HIV-2. By making single amino acid substitutions in the HIV-1 peptide, it was possible to demonstrate HIV-1 strain-specific antibody responses to this epitope. Such custom-designed peptides synthesized from this domain are likely to detect newly discovered HIV types, define infection with specific HIV strains, and allow detection of group-common antibodies.
DF-2 bacteremia following cat bites. Report of two cases.
DF-2 is a recently described gram-negative bacillus known to be part of the normal flora of dogs. A variety of serious infections (bacteremia, endocarditis, meningitis, cellulitis) caused by DF-2 have occurred following dog bites. Asplenic patients appear to be especially susceptible to DF-2 infection. Two cases of DF-2 bacteremia occurring after domestic cat bites are reported. Sepsis and meningitis developed in an asplenic patient, and an immunocompetent patient presented with primary cellulitis. Both patients responded promptly to parenteral antibiotic therapy. DF-2 must now be considered along with Pasteurella multocida in the differential of cellulitis or sepsis following bites or scratches from domestic cats.
Diagnosis of AIDS by using a 12-amino acid peptide representing an immunodominant epitope of the human immunodeficiency virus.
We mapped an immunodominant domain of the human immunodeficiency virus (HIV). We selected hydrophilic amino acid sequences encoded by conserved regions of the gag, pol, and env genes of HIV as potential antigenic domains. Eighteen peptides representing these sequences were synthesized; the peptides elicited strong antibody responses in rabbits. Sera from 53 HIV-infected patients and 50 controls were tested against the synthetic peptides. Although no antibodies to peptides from gag, pol, or env gp120 proteins were present, antibodies to four of the six peptides from env gp41 were detected. Epitope mapping using overlapping peptides showed that sera from 53 (100%) of 53 HIV-infected patients (and from none of 50 controls) reacted with peptides aa584-609 and aa598-609 from gp41, sera from 32 (60%) of 53 patients reacted with peptide aa603-614, and sera from 19 (35%) of 53 patients reacted with peptides aa609-620. Thus, amino acid sequence LeuGlyIleTrpGlyCysSerGlyLysLeuIleCys (aa598-609) from the transmembrane glycoprotein is an immunodominant domain of HIV recognized by serum antibodies from HIV-infected patients.
Acute glomerulonephritis following group G streptococcal infection.
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Fine mapping of an immunodominant domain in the transmembrane glycoprotein of human immunodeficiency virus.
Sera from virtually all individuals infected with human immunodeficiency virus contain antibodies against the viral envelope glycoproteins. By using a series of synthetic peptide antigens, we identified an immunodominant domain at amino acid position 598-609 of gp41. The minimal essential epitope is a 7-amino-acid sequence (amino acids 603-609) containing two cysteine residues. Both cysteine residues are required for the antigenic conformation of the sequence, possibly due to creation of a cyclic structure via disulfide bond formation.
Cardiobacterium hominis causing late prosthetic valve endocarditis.
We have described a patient with a prosthetic mitral valve who had endocarditis due to Cardiobacterium hominis 14 years after valve placement. She was cured with a six-week course of antibiotics, and valve replacement was not required. A four- to six-week course of ampicillin or penicillin G appears to be the therapy of choice.