Modulation of fas/fasL in a murine retroviral infection by AZT and methionine enkephalin.
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Animals↗
Biomedical subjects
R Bowden
Publications and source records attributed to R Bowden.
Predictors of participation in genetic research in a primary care physician network.
This study evaluated the process of recruiting women from a primary care physician network into a study of genetic counseling for breast cancer. It also investigated predictors of women's interest in participating in genetic counseling research. Women were recruited in three stages: (a) via an initial contact letter; (b) a telephone screening survey; and (c) a mailed baseline questionnaire. We performed a logistic regression with participation as the outcome. We sent 4690 initial contact letters and conducted 2081 telephone surveys to recruit 340 participants. Number of relatives with cancer, higher interest in taking a genetic test for breast cancer, and lower degree of worry about cancer were strong predictors for women's participation. Recruitment data showed interest in a study on genetic counseling for breast cancer risk. However, interest decreased as study requirements increased. Participation in genetics-related studies is related to psychological differences that must be considered when generalizing findings.
Adult↗
Alteration of cytokine levels in murine retrovirus infection: modulation by combination therapy.
Immunoregulatory cytokines may regulate the resistance or susceptibility of a host to retroviral infection. These cytokines may be therapeutically modulated to prevent or limit the progression of infection. The non-progression to AIDS of some HIV+ patients has been related to a strong type 1 cytokine response (IL-2, IL-12, and IFNgamma). For this reason, we investigated the ability of combination therapeutics to modulate cytokines in vivo towards a type 1 cytokine response in a murine retroviral infection using Friend leukemia virus (FLV). BALB/c mice were infected with FLV and treated with either 3'-azido-3'-deoxythymidine (AZT), the immunomodulator methionine enkephalin (MENK), or a combination of both AZT and MENK starting 3 d post infection. Splenocytes were harvested on days 1, 3, 7, 14, 21 and 28 post treatment initiation and cultured with 1 microg/ml concanavalin A (ConA) for 24 h. Supernatants were examined for IL-2, IL-4, IL-10, IL-12, and IFNgamma cytokine production using cytokine specific ELISAs. The levels of type 2 cytokines were not significantly changed by any treatment group over the course of the disease. However, although decreased in all infected animals, type 1 cytokines were partially maintained by the combination treatment through day 21. RT-PCR for cytokine specific mRNA confirmed these results, with expression of the type 1 cytokines, especially IFNgamma, being maintained through day 21. Establishment of a treatment regime that can maintain protective cytokine activities against disease progression may prove applicable to other retroviral infections.
Adjuvants, Immunologic↗
Treatment of invasive fungal infections with amphotericin B colloidal dispersion in bone marrow transplant recipients.
Amphotericin B colloidal dispersion (ABCD, AMPHOTEC, AMPHOCIL), a lipid complex of amphotericin B, was developed to reduce the nephrotoxicity of amphotericin B while retaining its antifungal efficacy. In this retrospective review, the efficacy and safety of ABCD were evaluated in 220 BMT recipients (167 allogeneic; 53 autologous) with suspected or documented life-threatening fungal infections (primarily Candida or Aspergillus species). Patients were treated in five open-label clinical trials of ABCD therapy. ABCD was administered intravenously once daily, median dose of 4 mg/kg, for up to 409 days (mean 23 days, median 16 days). Successful therapeutic response to treatment (complete or partial) was reported in 52% of the 99 evaluable patients with proven infection, and in 40% of all 220 patients. In the evaluable population, the response and mortality rates were 51% and 73%, respectively, in the allogeneic BMT patients, compared to 52% and 48% in the autologous BMT patients. The response rate for evaluable patients with Candida spp was 65%, 38% for patients with Aspergillus spp, and 42 % for patients with other or multiple fungal infections. In this patient population at high risk of nephrotoxicity due to concomitant cyclosporine and/or other nephrotoxic agents, ABCD did not cause renal dysfunction. Although the majority of patients had pre-existing renal impairment (median baseline serum creatinine 1.8 mg/dl), there was no trend towards increasing serum creatinine. No unexpected toxicities were observed. In conclusion, ABCD appears to be safe and effective for the treatment of severe fungal infections in BMT patients.
Adolescent↗
Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis.
The records of 239 immunosuppressed patients receiving amphotericin B for suspected or proven aspergillosis were reviewed to determine rates of nephrotoxicity, dialysis, and fatality. The mean and median durations of treatment were 20.4 and 15.0 days, respectively. The creatinine level doubled in 53% of patients and exceeded 2.5 mg/dL in 29%; 14.5% underwent dialysis; and 60% died. A multivariate Cox proportional hazards analysis showed that patients whose creatinine level exceeded 2.5 mg/dL (hazard ratio [HR], 42.02; P<.001), allogeneic bone marrow transplantation (BMT) patients (HR, 6.34; P<. 001), and autologous BMT patients (HR, 5.06; P=.024) were at greatest risk for requiring hemodialysis. Use of hemodialysis (HR, 3. 089; P<.001), duration of amphotericin B use (HR, 1.03 per day; P=. 015), and use of nephrotoxic agents (HR, 1.96; P=.017) were associated with greater risk of death, whereas patients undergoing solid organ transplantation were at lowest risk (HR, 0.46; P=.002). These data indicate that elevated creatinine levels during amphotericin B treatment are associated with a substantial risk for hemodialysis and a higher mortality rate, but the risks vary in different patient groups.
Adolescent↗
Human herpesvirus 6 infections after bone marrow transplantation: clinical and virologic manifestations.
Human herpesvirus 6 (HHV-6) DNA levels in peripheral blood mononuclear cells were prospectively evaluated in 20 cytomegalovirus-seronegative allogeneic marrow transplant patients and in 10 healthy control subjects. Blood and saliva specimens obtained weekly for 3 months after transplant were evaluated by quantitative HHV-6 polymerase chain reaction. One of 20 patients experienced primary HHV-6 infection after marrow transplant (seroconversion, HHV-6 viremia, skin rash); 18 of 20 had increased peripheral blood mononuclear cell HHV-6 DNA levels consistent with asymptomatic reactivations, and 1 patient experienced a reactivation-associated skin rash. Genotyping revealed HHV-6 variant B DNA in all cases. Therapy with acyclovir or intravenous immunoglobulin was not correlated with lower HHV-6 DNA levels. Thus, asymptomatic HHV-6 reactivations appear to be common following allogeneic marrow transplantation. Among HHV-6-seronegative and viral DNA-negative patients, primary HHV-6 infection can ensue in association with self-limited clinical symptoms, including diffuse maculopapular rash.
Adult↗
Analysis of murine gammaherpesvirus-68 transcription during lytic and latent infection.
Murine gammaherpesvirus-68 (MHV-68) is a gamma2-herpesvirus that upon experimental infection of laboratory mice establishes a latent infection in B lymphocytes. To date, no virus-encoded gene products have been reported to be expressed during latent infection. In this study, viral transcription has been analysed in a persistently infected B-cell line and abundant and preferential transcription of open reading frame M3 has been identified. Significantly, in situ hybridization analysis of latently infected mouse spleens with probes corresponding to 20 MHV-68 ORFs demonstrated active transcription of a single ORF, corresponding to M3. The kinetics and pattern of transcription of M3 were compared with that of the virally encoded tRNAs (vtRNAs), previously demonstrated to constitute a marker for latent infection in the spleen. Transcription of vtRNAs in splenic tissue could be first detected at 7 days post-inoculation (p.i.) in scattered cells in periarteriolar lymphoid sheaths (PALS). At 10 days p.i., vtRNA transcription was widespread and localized not only to cells in PALS but also to cells within developing germinal centres and from 21 days p.i. expression was detected exclusively within lymphoid follicles. Transcription of vtRNAs could be detected as late as 70 days p.i. In contrast, the histological localization of M3 transcription, which was first detected at 7 days p.i. in scattered cells in PALS, never changed and transcription could not be detected beyond 21 days p.i. These results suggest that M3 is an ORF that is expressed early during the establishment of latency in vivo.
Animals↗
Gene transfer in the gastrointestinal tract.
The maximum in vivo transfer rate of plasmid pAMbeta1 in the gut was 0.03 transconjugant per recipient cell, and this rate could be simulated in vitro only by forced filter mating. Transfer was not detected in liquid culture matings. Our findings demonstrate that in vitro methods, such as forced filter mating and liquid mating, underestimate the in vivo rates of gene transfer.
Animals↗
The impact of candidemia on length of hospital stay, outcome, and overall cost of illness.
Although numerous studies have examined trends in nosocomial fungal infections, few have specifically addressed the cost of care associated with candidemia. This study analyzes the direct medical costs associated with treating candidemia in the United States. The study design was a cost-of-illness analysis estimating the average cost of candidemia for a single episode of care. Data were obtained from three sources: the 1993 Healthcare Cost and Utilization Project of the Agency for Health Care Policy and Research, the relevant literature, and a clinical expert in systemic fungal infections. The estimated cost (1997 U.S.$) of an episode of care for candidemia is $34,123 per Medicare patient and $44,536 per private insurance patient. The major cost associated with candidemia is that of an increased hospital stay. The estimated cost of care for candidemia may change in the future because of the use of more expensive antifungal treatments with improved safety and efficacy profiles.
Adolescent↗
Lymphokine-augmented activation of avian heterophils.
Heterophils are important mediators of innate resistance in poultry, especially in young birds that have not yet developed an acquired immune response. Invasion of the intestinal mucosa by Salmonella spp. initiates the recruitment of large numbers of heterophils to the lamina propria. Thus, the heterophilic response can control, but not eliminate, bacterial numbers in the bird until development of acquired immunity. Unfortunately, chicks and turkey poults are highly susceptible to Salmonella infections during the first 4 d posthatch due to the functional immaturity of both the innate and acquired immune systems. We have previously shown that the administration of Salmonella enteritidis (SE)-immune lymphokines (ILK) into either 18-d-old developing embryos or day-of-hatch chicks and poults conferred increased resistance to SE organ invasion. In this review, we present evidence that the protection induced by ILK is mediated by vigorous recruitment and activation of heterophils. These activated heterophils migrate rapidly to the site of bacterial invasion where they phagocytize and kill the SE. Specifically, in vitro studies demonstrate an enhancement of functional activities of the heterophils including chemotaxis, adherence, phagocytosis, and bacterial killing. In addition, during the activation process, membrane expression of adhesion molecules rapidly changes from L-selectins to beta2 integrins (CB11b/CD18) on the cells that become activated. These results further demonstrate the validity of preventive activation in poultry to induce the migration of large numbers of activated phagocytic cells to the site of infection by a pathogenic organism. Importantly, this immunopotentiation of the inflammatory response by ILK, as described here, induces the functional maturation of heterophils during the first 4 d posthatch.
Animals↗
Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation.
The influence of busulfan (BU) plasma concentration on outcome of transplantation from HLA identical family members for the treatment of chronic myelogenous leukemia (CML) was examined in 45 patients transplanted in chronic phase (CP) (n = 39) or accelerated phase (AP) (n = 6). All patients received the same regimen of BU, 16 mg/kg orally and cyclophosphamide (CY), 120 mg/kg intravenously. Plasma concentrations of BU at steady state (C(SS)BU) during the dosing interval were measured for each patient. The mean C(SS)BU was 917 ng/mL (range, 642 to 1,749; median, 917; standard deviation, 213). Of patients with C(SS)BU below the median, seven (five of 18 in CP and two of four in AP) developed persistent cytogenetic relapse and three of these patients died. There were no relapses in patients with C(SS)BU above the median. The difference in the cumulative incidence of relapse between the two groups was statistically significant (P = .0003). C(SS)BU was the only statistically significant determinant of relapse in univariable or multivariable analysis. The 3-year survival estimates were 0.82 and 0.64 for patients with C(SS)BU above and below the median (P = .33). There was no statistically significant association of C(SS)BU with survival or nonrelapse mortality, although the power to detect a difference in survival between 0.82 and 0.64 was only 0.24, similarly C(SS)BU above the median was not associated with an increased risk of severe regimen-related toxicity. We conclude that low BU plasma levels are associated with an increased risk of relapse.
Adult↗
Retention of herpes simplex virus DNA sequences in the nuclei of mouse footpad keratinocytes after recovery from primary infection.
Persistence of herpes simplex virus (HSV) DNA in mouse footpad keratinocytes was studied by non-isotopic in situ hybridization. HSV DNA was retained in keratinocyte nuclei for more than 2 weeks after disappearance of infectious virus and viral antigens. The anatomical location of viral DNA became more superficial with increasing time post-infection, reflecting the migration of cells from the basal layer of the epidermis towards the stratum granulosum. Latency-associated transcripts (LATs) were not detected in footpad cells at any of the times studied. In contrast, LATs were detected readily in the nuclei of lumbar ganglionic neurons innervating HSV DNA positive footpads. It was concluded that, after termination of productive infection in the skin, HSV DNA persists transiently in keratinocyte nuclei, in the absence of abundant latency-associated transcription. An implication of these data is that detection of HSV DNA in the skin may reflect recent, but not necessarily current, cutaneous virus replication.
Animals↗
Multicenter evaluation of proposed standardized procedure for antifungal susceptibility testing of filamentous fungi.
A multicenter study was conducted to expand the generation and analysis of data that supports the proposal of a reference method for the antifungal susceptibility testing of filamentous fungi. Broth microdilution MICs of amphotericin B and itraconazole were determined in 11 centers against 30 coded duplicate pairs of Aspergillus spp., Fusarium spp., Pseudallescheria boydii, and Rhizopus arrhizus. The effect of inoculum density (approximately 10(3) and 10(4) CFU/ml), incubation time (24, 48, and 72 h), and procedure of MIC determination (conventional and colorimetric [Alamar Blue] evaluation of growth inhibition) on intra- and interlaboratory agreement was analyzed. Based on intra- (97 to 100%) and interlaboratory (94 to 95%) agreement for both drugs, the overall optimal testing conditions identified were determination of colorimetric MICs after 48 to 72 h of incubation with an inoculum density of approximately 10(4) CFU/ml. These testing conditions are proposed as guidelines for a reference broth microdilution method.
Antifungal Agents↗
Legionellosis in a bone marrow transplant center.
We reviewed 10 cases of culture proven legionellosis that occurred at a marrow transplant center (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) over a 6-year period ending in 1993. Infections were caused by four species of Legionella with no apparent clustering of cases. Detection of Legionella using direct fluorescent antibody assays proved unreliable due to the high proportion of rare Legionella species isolated. The clinical presentation, course and outcome of patients varied and did not correlate with underlying disease, type of transplant, transplant day or engraftment status. However, five of the seven patients infected with non-pneumophila species recovered from their pneumonia compared to none of the three patients infected with L. pneumophila. Persistent or relapsed infection after 3 weeks of appropriate therapy was documented in one case suggesting that prolonged antibiotic treatment is indicated in these patients.
Adolescent↗
Cytomegalovirus infection in marrow transplantation.
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Antiviral Agents↗
Fungal liver infection in marrow transplant recipients: prevalence at autopsy, predisposing factors, and clinical features.
To determine the prevalence of fungal liver infection at autopsy in marrow transplant recipients, we reviewed autopsy results for the period 1980-1989. Cases were compared to randomly chosen autopsied controls without fungal infection. Fungal liver infection was found in 67 (9%) of 731 patients. Fungal cultures of liver lesions were positive for 34 of 67 patients, most of whom had been culture-positive for the same fungal species (largely Candida) during life. Multivariate analysis revealed that independent predictors of fungal liver infection were deep fungal infection after transplantation (RR, 35), colonization or superficial infection after transplantation (RR, 13), and severe liver dysfunction caused by veno-occlusive disease of the liver and/or graft-versus-host disease (RR, 7). Clinical and laboratory findings during the last month of life revealed no differences between cases and controls. Liver imaging studies performed during the last 15 days of life had a sensitivity of only 18% for detecting fungal liver lesions.
Adult↗
Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia.
The records were reviewed of 58 patients receiving transplants in Seattle with unmanipulated marrow from HLA-identical siblings during the accelerated phase (AP) of chronic myeloid leukemia. Variables examined for association with survival and relapse included the interval from diagnosis to transplant, the reasons for categorization as AP, age, regimen, and cytomegalovirus serology. Four patients relapsed. The 4-year probabilities of survival, relapse-free survival, nonrelapse mortality, and relapse were 0.49, 0.43, 0.51, and 0.12, respectively. After completion of the stepwise multivariate analysis, age less than 38 years and categorization as AP solely on the basis of chromosomal abnormalities emerged as being independently significantly associated with improved survival. The 4-year probability of survival for the 16 patients categorized as AP because of chromosomal abnormalities and receiving transplant less than 1 year from diagnosis was 0.74. The low probability of relapse in these patients suggests that more aggressive preparative regimens are not indicated for patients receiving transplants in AP because of the increased risk of transplant-related mortality.
Acute Disease↗
Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide.
A prospective randomized study was conducted comparing two conditioning regimens for the treatment of patients with chronic myeloid leukemia in chronic phase by marrow transplantation from HLA identical siblings. Sixty-nine patients received 60 mg/kg of cyclophosphamide on each of 2 successive days followed by 6 fractions of total body irradiation each of 2.0 Gy (CY-TBI), and 73 patients received 16 mg/kg of busulfan delivered over 4 days followed by 60 mg/kg CY on each of 2 successive days (BU-CY). There was no significant difference between the CY-TBI and the BU-CY groups in the 3-year probabilities of survival (0.80 for both), relapse (0.13 for both), or event-free survival (CY-TBI, 0.68; BU-CY, 0.71) or in speed of engraftment or incidence of venocclusive disease of the liver. The 4-year probabilities of survival and event-free survival for patients transplanted within 1 year of diagnosis were 0.86 and 0.72, respectively, for each group. Significantly more patients in the CY-TBI group experienced major creatinine elevations. There was significantly more acute graft-versus-host disease in the CY-TBI group. Fever days, positive blood cultures, hospitalizations, and inpatient hospital days were significantly more common in the CY-TBI group than in the BU-CY group. In conclusion, the BU-CY regimen was better tolerated than, and associated with survival and relapse probabilities that compare favorably with, the CY-TBI regimen.
Adolescent↗