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Biomedical subjects

J R Wingard

Publications and source records attributed to J R Wingard.

At least 145 records · Page 8Linked to original sources
PubMed1985

Detection of Epstein-Barr virus DNA in mouthwashes by hybridization.

An assay for the presence of Epstein-Barr virus (EBV) DNA was developed by using a cloned EBV DNA probe. After preliminary testing showed the assay to be sensitive and specific, it was applied to 135 mouthwashes from bone marrow transplant recipients, and 21 of these tests were positive. The concentration of EBV DNA in mouthwashes in some cases was as high as 10(8) genome equivalents per ml. When compared with the lymphocyte transformation assay on the same samples, the sensitivity was 75% and the specificity was 97%. In contrast to the lymphocyte transformation assay, the hybridization was semiquantitative and yielded results in 72 h. Potential applications include monitoring the effects of various interventions, such as immunosuppressive and antiviral chemotherapy, on EBV shedding.

Bone Marrow Transplantation↗
PubMed1985

Genetic analysis of the susceptibility of mouse cytomegalovirus to acyclovir.

Eight independently derived mouse cytomegalovirus (MCMV) mutants resistant to acyclovir (ACV) were obtained by the sequential plating of wild-type virus in increasing concentrations of ACV. Results of complementation studies among these eight mutants suggest that all had mutations within the same or closely associated genes. A ninth MCMV mutant resistant to phosphonoacetate (PAA) derived by plating wild-type virus in the presence of 100 micrograms of PAA per ml displayed coresistance to ACV and was unable to complement any of the ACV-derived mutants. Recombination experiments among all combinations of the nine MCMV mutants were performed and supported the complementation data in that no recombination could be detected. Seven of the eight ACV-resistant mutants demonstrated cross-resistance to PAA and hypersensitivity to aphidicolin. The one mutant not coresistant to PAA was more susceptible to PAA than was the parent virus. Only a few mutants demonstrated coresistance when the mutants were tested against 9-beta-D-arabinofuranosyladenine (ara-A). The ACV mutant that demonstrated increased susceptibility to PAA was 30-fold more susceptible to ara-A but remained unchanged in susceptibility to aphidicolin. Two of the parent-mutant combinations were selected for DNA synthesis analysis in the presence of ACV (5 microM). A significant decrease in DNA synthesis was demonstrated for both parent viruses, and there was little effect on mutant virus DNA synthesis at the same drug concentration. These results suggest that susceptibility of MCMV to ACV is confined to a product of a single gene and that a mutation of this gene can lead to an altered phenotype when compared with parent virus in susceptibility of DNA synthesis to PAA, ara-A, and aphidicolin, drugs that are known to inhibit DNA polymerase activity.

Acyclovir↗
PubMed1985

Late-onset interstitial pneumonia following allogeneic bone marrow transplantation.

Although most episodes of interstitial pneumonia (IP) following allogeneic bone marrow transplantation occur during the second or third month, occasional cases occur later. The records of 139 patients transplanted for leukemia over 6 years were reviewed in this study to examine cases of IP occurring beyond 100 days following marrow transplantation. Ten episodes of IP occurred among the 67 patients who survived 100 days (an actuarial probability of 18%). All cases occurred within the first year. An infectious cause was established in 80%. The case fatality rate was 60%. Although most infectious cases of IP occurring before 100 days are caused by cytomegalovirus, the late-onset cases in this study were caused by a heterogeneous group of pathogens, some of which were amenable to specific therapies. Thus, an aggressive approach to establishing a specific diagnosis should be made in cases of IP occurring more than 100 days after marrow transplantation.

Adolescent↗
PubMed1983

Effect of several antiviral agents on human lymphocyte functions and marrow progenitor cell proliferation.

Toxicity to hematopoiesis and lymphocytic function are major considerations in the clinical applicability of antiviral agents. We have examined the toxicities of five antiviral agents showing activity against herpesviruses: vidarabine, acyclovir, (E)-5-(2-bromovinyl)-2'-deoxyuridine, trifluorothymidine, and (S)-9-(2,3-dihydroxypropyl)adenine. The drugs were tested in vitro for inhibition of herpes simplex virus type 1 and human cytomegalovirus replication, effects on marrow progenitor cell growth, effects on lymphocyte responses to mitogen and alloantigen stimulation, and effects on several lymphocyte cytotoxic responses. In general, lymphocyte proliferative responses were inhibited by the various drugs at lower concentrations than were cytotoxic activities. Acyclovir and (E)-5-(2-bromovinyl)-2'-deoxyuridine were the least toxic drugs tested, with antiviral indices exceeding 10,000. Vidarabine and trifluorothymidine were more toxic, with antiviral indices generally between 10 and 100. (S)-9-(2,3-dihydroxypropyl)-adenine was the most toxic, with several antiviral indices between 1 and 10.

Antiviral Agents↗
PubMed1983

The interaction of human and rodent IgE with the human basophil IgE receptor.

The cross-reactivity of the human IgE receptor with mouse and rat IgE was studied. Using leukocytes from a patient with chronic myelogenous leukemia, in which the mononuclear fraction contained up to 75% basophils, both rat and mouse IgE were found to inhibit the binding of 125I-human IgE to the human basophilic leukemia (HBL cells). About 15-fold more rodent IgE was required for 50% inhibition of binding than unlabeled human IgE (hIgE). Dose-response studies using increasing amounts of rodent vs human 125I-IgE indicated that the HBL cells had about 8000 receptors per cell for hIgE and 5500 receptors per cell for rodent IgE. When the HBL cells were surface labeled with 125I and subsequently solubilized with non-ionic detergent, the labeled hIgE receptor could be isolated by either affinity chromatography on IgE-Sepharose (either human or rodent) or by immunoprecipitation with hIgE and anti-IgE. By SDS-PAGE on 10% gels, the receptor had a m.w. of 58,000 daltons. The solubilized receptors exhibited some rebinding to hIgE-Sepharose, and this rebinding could be inhibited by either human or rodent IgE but not by human IgG. Both the HBL cells and normal human basophils could be passively sensitized with murine IgE anti-DNP for antigen-induced histamine release. The minimum concentration of the mouse IgE antibody for sensitizing normal basophils was 20 to 200 ng/ml. Pretreatment of basophils with human IgE, but not human IgG, abrogated the capacity of the murine IgE antibody to sensitize the cells for histamine release, which indicated that the human and rodent IgE were interacting with the same receptor.

Animals↗
PubMed1982

Acyclovir in mouse cytomegalovirus infections.

A virus-specified thymidine kinase appears to be a general requirement for herpes virus susceptibility to the antiviral effect of acyclovir. Surprisingly, mouse cytomegalovirus (MCMV), which does not encode for a thymidine kinase, is exquisitely sensitive to the drug both in vitro and in vivo. The drug is active against the virus in the absence of a cellular thymidine kinase and the antiviral activity is not diminished in the presence of excess thymidine or a variety of nucleosides and deoxynucleosides. Thus, a thymidine phosphorylation pathway is not required for the drug's activation of this infection. The enzyme system responsible for phosphorylation of the drug has not been identified. Mouse cytomegalovirus mutants resistant to the drug have been isolated, indicating that the antiMCMV effect results from selective inhibition of viral replication rather than indirectly through toxicity to the host cell. Eight resistant mutants appear to be in the same complementation group and seven of the mutants demonstrate coresistance to phosphonoacetic acid, a marker for the DNA polymerase locus of herpes viruses. The evidence to date indicates that the MCMV DNA polymerases is the final site of action of the drug. Investigations of the antiMCMV activity of acyclovir should provide insights into the antiviral effects of this drug and other nucleoside analogs in other herpes virus infections in which the virus does not code for a thymidine kinase (for example, human cytomegalovirus and Epstein-Barr virus).

Acyclovir↗
PubMed1982

Differences in virulence of clinical isolates of Candida tropicalis and Candida albicans in mice.

Prior reports from this institution indicated that Candida tropicalis was more pathogenic than C. albicans in oncology patients. Pairs of clinical isolates of C. tropicalis and C. albicans recovered from similar patients at other institutions were examined to determine their relative virulence. After intravenous inoculation in normal mice, three pairs of isolates had no significant differences in the 50% lethal dose, and one C. tropicalis isolate was less virulent than its companion C. albicans isolate. In contrast, in mice treated with antibiotics and cytarabine, an antineoplastic drug which damages the gastrointestinal mucosa and produces granulocytopenia, oral inoculation of yeast cells produced striking differences in the 50% infective dose: each C. tropicalis isolate was more virulent than the companion C. albicans isolate from the same institution. The increased virulence of the C. tropicalis isolates compared with the C. albicans isolates when given orally to compromised mice parallels clinical observations in compromised patients.

Agranulocytosis↗
PubMed1981

Efficacy of acyclovir against mouse cytomegalovirus in vivo.

Acyclovir reduced mortality and organ virus titers in mice inoculated intraperitoneally with 10 50% lethal doses of mouse cytomegalovirus. This susceptibility to acyclovir of a herpesvirus which lacks thymidine kinase is surprising. Alternative phosphorylating enzymes may account for this susceptibility.

Acyclovir↗
PubMed1981

Activity of trifluorothymidine against cytomegalovirus.

Trifluorothymidine (TFT) was tested for antiviral activity against mouse cytomegalovirus (MCMV) and human cytomegalovirus (HCMV) in one-step replication assays. The TFT concentration required to reduce virus yield by 50% (ID50) was 0.22 microM for MCMV and 0.012 microM for HCMV. The antiviral activity of TFT against MCMV was reversed by addition of equimolar thymidine, and no antiviral activity was demonstrable in a host cell line lacking thymidine kinase. Thus, TFT's anti-MCMV activity is dependent on a host cell TK since this herpesvirus lacks thymidine kinase. A continuous subcutaneous infusion of TFT achieving a serum concentration of 1 microM failed to protect mice from lethal MCMV infection, perhaps because serum levels of thymidine were comparable to the drug level. Comparison of the ID50 against HCMV and the ID50 against human bone marrow progenitor cells resulted in an in vitro therapeutic ratio of 108, suggesting that TFT might offer some promise as a clinically useful anti-HCMV agent.

Animals↗
PubMed1981

Thymidine kinase not required for antiviral activity of acyclovir against mouse cytomegalovirus.

Previous studies of herpesvirus infections have indicated that a virus-specified thymidine kinase is required for the initial phosphorylation of acyclovir [acycloguanosine or 9-(2-hydroxyethoxymethyl)guanine] in the formation of acycloguanosine triphosphate. The latter compound accumulates in infected cells and competitively inhibits the viral DNA polymerase. We found that mouse cytomegalovirus, which does not express a thymidine kinase, was sensitive to the antiviral effects of acyclovir at a 50% inhibitory dose of approximately 0.23 microM. Acyclovir was equally effective against mouse cytomegalovirus in normal 3T3 cells and in 3T3 cells deficient in cellular thymidine kinase. Furthermore, the activity of acyclovir could not be reversed by excess thymidine, which easily reversed the antiviral activity of acyclovir against herpes simplex virus. Using a high-pressure liquid chromatography technique that easily detected acycloguanosine triphosphate in cells infected with herpes simplex virus, we could not detect acycloguanosine triphosphate in mouse cytomegalovirus-infected cells. These experiments demonstrated that the activity of acyclovir against mouse cytomegalovirus is not dependent on a thymidine phosphorylation pathway. Additional experiments are underway to determine whether acycloguanosine triphosphate is produced by another pathway in concentrations sufficient to inhibit mouse cytomegalovirus DNA polymerase.

Acyclovir↗
PubMed1981

Spontaneous pneumothorax during adjuvant chemotherapy for soft-tissue sarcoma.

A 21-year-old man with fibrosarcoma of the left thigh, treated with adjuvant chemotherapy following surgery and radiation, presented with bilateral spontaneous pneumothoraces as the initial manifestation of metastatic disease. While the pathogenesis of this condition is uncertain, it is possible that in this patient drug-induced necrosis of peripherally located subclinical metastatic pulmonary nodules led to spontaneous pneumothorax.

Adult↗
PubMed1980

The value of fungal surveillance cultures as predictors of systemic fungal infections.

Fungal surveillance cultures consisting of urine, stool, and respiratory specimens were analyzed from 37 recipients of bone-marrow transplants and 52 patients undergoing chemotherapy for acute leukemia and other hematologic malignancies. All patients had prolonged aplasia. Sixty-seven percent of the patients were colonized by Candida albicans, and 28% were colonized by Candida tropicalis. No patient was colonized with any species of Aspergillus. There were 21 proven systemic fungal infections: three due to C. albicans, 16 due to C. tropicalis, and two due to Aspergillus. Positive surveillance data for C. tropicalis correlate with disease. Multiple positive-culture data yielded high predictive values (67%-83%), and single positive-culture data yielded slightly lower values as a function of body site. Positive surveillance data for C. albicans did not correlate with disease; negative culture data correlate with the absence of systemic disease due to C. tropicalis and C. albicans. Thus, surveillance data for specific fungal species can aid in diagnosis and appropriate therapy.

Aspergillus↗
PubMed1980

Pathogenicity of Candida tropicalis and Candida albicans after gastrointestinal inoculation in mice.

The ability of clinical isolates of Candida albicans and candida tropicalis to invade through normal and damaged gastrointestinal mucosa was determined. Adult mice were treated with either gentamicin or gentamicin and cytarabine. Suspensions of yeast cells (10(7)) were administered through a catheter intraesophageally. Invasion was determined by culturing liver, kidney, and lung tissue from mice sacrificed after 48 h. C. albicans and C. tropicalis were incapable of invading through normal gastrointestinal mucosa in mice treated only with gentamicin. Two isolates of C. tropicalis penetrated the damaged gastrointestinal mucosa in 69% (49 of 71) of mice treated with gentamicin and cytarabine. In contrast, three isolates of C. albicans penetrated he damaged gastrointestinal mucosa in only 23% (14 of 62) of mice. These results suggest that C. tropicalis is more capable of invading through damaged gastrointestinal mucosa than C. albicans. The observations in this mouse model parallel those seen in patients on cytotoxic drugs. Therefore, this model offers a tool for investigation of the pathogenicity of these organisms in a model analogous to the compromised host.

Animals↗
PubMed1979

Candida tropicalis: a major pathogen in immunocompromised patients.

Of 89 consecutive patients undergoing treatment for hematologic malignancies or undergoing allogeneic bone marrow transplantation, 60 were colonized with Candida albicans and 25 with C. tropicalis. However, of the 18 disseminated infections caused by Candida species, 15 infections in 14 patients were caused by C. tropicalis and only three infections in three patients by C. albicans. The setting in which the infection occurred, skin lesions, polyarthralgias, or polymyalgias, and the unexplained deterioration of renal function were features suggestive of the diagnosis. Defervescence occurred in 10 of the 14 treated patients with C. tropicalis infections in 1 to 6 d (mean, 2.5 d) after initiation of therapy, even though all continued to be granulocytopenic. Resolution occurred in eight of the 15 C. tropicalis infections. In one case outcome was indeterminate, four patients died due to the infection, and two died from other causes but with the infection unresolved.

Adolescent↗
PubMedDate not supplied

Low incidence of red cell and HLA antibody formation by bone marrow transplant patients.

BACKGROUND: Bone marrow transplant (BMT) patients, although immunosuppressed, are at risk for the development of red cell (RBC) and HLA antibodies, and they often are given filtered blood in an effort to prevent the latter complication. This study attempts to determine the rate of formation and the specificity of both RBC and HLA alloantibodies in this patient population. STUDY DESIGN AND METHODS: BMT patients (148 received autologous marrow; 45 received allogeneic marrow) from an 18-month period, including patients with leukemia (57 patients), lymphoma (54), breast cancer (68), myeloma (8), myelodysplastic syndrome (5), and aplastic anemia (1), were studied to determine the rate of alloantibody formation to RBC and HLA antigens. A total of 2,410 RBC antibody screens were performed. The patients received 3,921 packed RBCs and 5,915 single-donor platelet units; all were irradiated and administered via white cell-reduction filters. RESULTS: Seven (3.6%) of 193 patients had RBC antibodies upon hospital admission. Four (2.1%) of 193 developed RBC antibodies during the course of BMT: 3 patients had one RBC antibody and 1 patient had two RBC antibodies. RBC antibodies included anti-E (n = 2), anti-M (n = 1), anti-Jkb (n = 1), and anti-Lu14 (n = 1). Thus, 98 percent of patients (189/193) did not develop new (182/186) or additional (7/7) RBC antibodies during BMT. BMT patients were also screened weekly for HLA antibody formation (60-cell panel). Upon admission, 170 (85%) patients were negative. Of these, 8 (4.7%) developed persistent HLA antibodies (mean panel-reactive antibody score, 33 +/- 29%) and 9 (5.3%) were variably positive. Thus, in our setting and population, RBC antibody formation was 0.1 percent per unit transfused, and the HLA alloimmunization rate was 5 to 10 percent. CONCLUSION: As RBC antibody screens are done every Monday, Wednesday, and Friday on this BMT service and as RBC antibody formation is low in these patients, screening for unexpected antibodies might be possible on a more infrequent basis. Also, the rate of HLA alloimmunization in this population receiving filtered blood components is low.

Adult↗
PubMedDate not supplied

Cytomegalovirus infections in bone marrow transplant recipients given intensive cytoreductive therapy.

Cytomegalovirus (CMV) infections were studied in 785 bone marrow transplant recipients given intensive cytoreductive therapy. CMV excretion occurred in 24%, viremia in 9%, seroconversion in 40%, and overall active infection in 47%. CMV disease was much less common. Retinitis, enteritis, and pneumonitis occurred in only one, five (less than 1%), and 55 (7%) of the patients, respectively. Allograft recipients were more likely to develop CMV disease than were autograft patients (P = .0001) despite comparable rates of active CMV infection. CMV disease was rare after primary infection in both autograft and allograft recipients (0 and 1%, respectively). In contrast, CMV disease occurred in 16% of seropositive allograft recipients. Among allograft recipients, risk factors for CMV pneumonitis were seropositivity, age greater than 10 years, and acute graft-vs.-host disease, while the use of cyclosporine as prophylaxis against graft-vs.-host disease was protective. Although active infection rates did not decrease, the rates of CMV pneumonitis in allograft recipients during successive years declined significantly (P less than .001).

Adolescent↗
PubMedDate not supplied

Cerebrospinal fluid cytology in histiocytic proliferative disorders.

Morphologically atypical histiocytes were observed in the cerebrospinal fluid (CSF) of five patients with histiocytic proliferative disorders, including one each classified as Letterer-Siwe disease and Hand-Schüller-Christian disease and three as malignant histiocytosis. In all of these patients except the one with Letterer-Siwe disease, neurologic examination, CSF leukocyte count and protein and glucose concentrations were normal. Necropsy studies in the three fatal cases (one patient with Letterer-Siwe disease and two with malignant histiocytosis) demonstrated leptomeningeal involvement by atypical histiocytes in all three and brain involvement in the patient with Letterer-Siwe disease. These observations suggest that cytologic examination of CSF is warranted in patients with histiocytic proliferative disorders and may be reliable in documenting central nervous system, particularly leptomeningeal, involvement. The atypicality of the histiocytes in the CSF, however, was not indicative of the classification of the histiocytic proliferative disorder. Because the patient with Hand-Schüller-Christian disease continues to have a normal neurologic examination seven years after abnormal histiocytes were initially detected in his CSF, we believe that the clinical condition of the patient and classification of the histiocytic proliferative disorder are of primary importance for initiating aggressive therapy directed at the central nervous system.

Adolescent↗