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Biomedical subjects

F M Stewart

Publications and source records attributed to F M Stewart.

At least 37 records · Page 2Linked to original sources
PubMed1999

Safety and cost of hyperhydration for the prevention of hemorrhagic cystitis in bone marrow transplant recipients.

Hemorrhagic cystitis is a major cause of morbidity after bone marrow transplantation. Traditional methods of prevention have included mesna (2-mercaptoethane sodium sulfonate) and bladder irrigation. We report the use of hyperhydration as an alternative to these prophylactic measures. One hundred consecutive patients who underwent autologous or allogeneic bone marrow transplantation received high dose cyclophosphamide with hyperhydration using 5% dextrose normal saline at the rate of 250 ml/h and furosemide to maintain a urine output of >150 ml/h. Seventy-one of these patients also received high dose cyclophosphamide as mobilization chemotherapy. There were no episodes of hemorrhagic cystitis following mobilization chemotherapy. The incidence of hemorrhagic cystitis after transplant conditioning was 7% with 2 patients developing clinically significant hemorrhagic cystitis; one was a severe episode. The cost of hyperhydration was US$ 20 per course as opposed to US$ 1,500 per course for mesna, based on acquisition costs at our institution. We conclude that hyperhydration is a safe, inexpensive means of preventing hemorrhagic cystitis associated with high dose cyclophosphamide in bone marrow transplant recipients.

Adult↗
PubMed1998

The fluctuating phenotype of the lymphohematopoietic stem cell with cell cycle transit.

The most primitive engrafting hematopoietic stem cell has been assumed to have a fixed phenotype, with changes in engraftment and renewal potential occurring in a stepwise irreversible fashion linked with differentiation. Recent work shows that in vitro cytokine stimulation of murine marrow cells induces cell cycle transit of primitive stem cells, taking 40 h for progression from G0 to mitosis and 12 h for subsequent doublings. At 48 h of culture, progenitors are expanded, but stem cell engraftment is markedly diminished. We have investigated whether this effect on engraftment was an irreversible step or a reversible plastic feature correlated with cell cycle progression. Long-term engraftment (2 and 6 mo) of male BALB/c marrow cells exposed in vitro to interleukin (IL)-3, IL-6, IL-11, and steel factor was assessed at 2-4-h intervals of culture over 24-48 h using irradiated female hosts; the engraftment phenotype showed marked fluctuations over 2-4-h intervals, with engraftment nadirs occurring in late S and early G2. These data show that early stem cell regulation is cell cycle based, and have critical implications for strategies for stem cell expansion and engraftment or gene therapy, since position in cell cycle will determine whether effective engraftment occurs in either setting.

Animals↗
PubMed1998

Lymphohematopoietic engraftment in minimally myeloablated hosts.

The concept that myeloablation to open space was a prerequisite for marrow stem cell engraftment has been challenged by studies showing high rates of engraftment in nonmyeloablated mice (Stewart et al, Blood 81:2566, 1993; Quesenberry et al, Blood Cells 20:97, 1994; Brecher et al, Blood Cells 5:237, 1979; Saxe et al, Exp Hematol 12:277, 1984; and Wu et al, Exp Hematol 21:251, 1993). However, relatively large numbers of marrow cells were necessary to achieve high long-term donor percentages. We have demonstrated, using a BALB/c male/female marrow transplant model and detecting male DNA in host tissues by Southern blot or fluorescent in situ hybridization, that exposure to doses of irradiation that cause minimal myeloablation (50 to 100 cGy) leads to very high levels of donor chimerism, such that relatively small numbers of marrow cells (10 to 40 million) can give donor chimerism in the 40% to 100% range. Studies of radiation sensitivity of long-term engrafting cells have shown that 100 cGy, although not myelotoxic, is stem cell toxic, and indicate that the final host:donor ratios are determined by competition between host and donor stem cells. These data indicate that low levels of irradiation should be an effective approach to nontoxic marrow transplantation in gene therapy or in attempts to create allochimerism to treat such diseases as cancer, sickle cell anemia, or thalassemia.

Animals↗
PubMed1998

Phenotype of the engrafting stem cell in mice.

The present data on engraftment into non-myeloablated mice strongly suggest that engraftment is determined by host-donor ratios as opposed to opening space. Theoretically, if the ratios of donor to host stem cells could be altered, especially without causing toxicity to the host animal, then the phenotypic readout could be increased in a clinically applicable manner. To research this further, we investigated low-dose irradiation (100 cGy) for its effects on marrow, spleen and peripheral blood counts, as well as engrafting stem cell levels. We found a transient but significant depression in the white blood cell and platelet counts in the peripheral blood which returned to normal by two weeks, with no apparent deleterious effect on the animals. However, the same irradiation dose after two months impaired marrow repopulation and reduced engraftment potential to less than 20% capacity. These results suggested that we could obtain much higher phenotypic readouts after engraftment with this model; thus, we assessed the engraftment of 40 million male BALB/c marrow cells into female hosts exposed to 100 cGy at two, five and eight months after cell infusion. The resultant high levels of chimerism, reaching 100% in many cases, strongly suggest that the key to engraftment in these models is host-donor stem cell ratios. One important issue relative to the above finding is whether cytokine-stimulated proliferating stem cells have irreversibly lost engraftment capacity or whether changes in the engraftment capacity are of a plastic nature, possibly related to cell cycle transit. A number of experiments following engraftment have shown that the engraftment defect is reversible and can be repeatedly lost and regained during the initial portions of a cytokine-stimulated culture. The above results suggest that, at least at the more primitive stem cell level, hematopoietic stem cell regulation may in part be based on a cell cycle model rather than a hierarchical system.

Animals↗
PubMed1998

The population genetics of antibiotic resistance. II: Analytic theory for sustained populations of bacteria in a community of hosts.

The phenomenon of antibiotic resistance is of practical importance and theoretical interest. As a foundation for further studies by simulation, experiment, and observation, we here develop a mathematical model for the dynamics of resistance among the bacteria resident in a population of hosts. The model incorporates the effects of natural selection within untreated hosts, colonization by bacteria from the environment, and the rapid increase of resistance in hosts who receive antibiotics. We derive explicit formulas for the distribution of resistance among hosts and for the rise or fall of resistance when the frequency of treatment is changed.

Anti-Bacterial Agents↗
PubMed1998

Spontaneous tibial artery thrombosis associated with varicella pneumonia and free protein S deficiency.

Pneumonia is the most common serious complication of varicella infection in adults. A variety of thrombotic complications including purpura fulminans and disseminated intravascular coagulation have been reported in children with varicella but not in adults. Two men with varicella pneumonia who had profound lower extremity ischemia caused by thrombosis of the profunda femoris and tibial arteries are reported. Both patients had free protein S deficiency and vascular thrombosis in association with varicella pneumonia without overt evidence of disseminated intravascular coagulation or purpura fulminans. Antiphospholipid immunoglobulin G and immunoglobulin M antibodies were present in one, whereas the other had evidence of the lupus anticoagulant. The proposed pathogenesis and management options including intraarterial thrombolytic therapy with urokinase and the need for long-term anticoagulation are discussed.

Adult↗
PubMed1998

Coverage of bone marrow transplant patients: a survey of American and Canadian institutions.

Personnel involved in supportive care of bone marrow transplant (BMT) patients include fellows (F), medical house-staff (HS), nurse practitioners (NP), physician assistants (PA), and moonlighting physicians (MP). We have obtained surveys from 108 American and Canadian transplant centers on the composition of inpatient support teams. Eighty-seven percent of institutions responding to the survey were university-based programs. Eighty-eight percent of the centers performed both allogeneic and autologous transplants, and 60% performed unrelated donor grafts. The mean number of transplants performed annually at each center was 101 (range 4-515). For daytime coverage, the percent of programs involving F, HS, NP, PA, or MP was 57, 50, 35, 25, and 0%, respectively, and for nighttime coverage, the composition was 50, 56, 7, 6, and 13%, respectively. Medical HS were incorporated into the care of BMT patients at some level in 93% of the programs. Involvement by HS included full 24-hour coverage (44%), full nighttime coverage (8%), stat coverage (18%), and code blue only coverage (21%). HS involvement was similar in small and large transplant programs. HS were more involved in university-based programs. Programs on the East Coast had more HS involvement, with 54% of the programs reporting full 24-hour coverage by HS compared with 32% of the programs in the Pacific region. Coverage of transplant patients varies throughout the country, and nonphysician providers are often used. HS are more active in university-based programs, and their role is similar in both large and small programs.

Bone Marrow Transplantation↗
PubMed1998

Chiaroscuro hematopoietic stem cell.

These observations suggest several immediate clinical strategies. In gene therapy, approaches could be targeted to obtain cycling of hematopoietic stem cells and gene-carrying retrovirus vector integration followed by engraftment at an appropriate time interval which favors engraftment. The same type of approach can be utilized for stem cell expansion approaches. Alternatively marrow or peripheral stem cell engraftment can be obtained with minimal to no toxicity in allochimeric strategies in such diseases as sickle cell anemia or thalassemia. A similar approach could be useful in obtaining cell engraftment with minimal toxicity in therapies employing cellular immune (T-cell and NK-cell) attack against cancer. These areas of clinical application are outline in Table 3.

Animals↗
PubMed1997

Late regression of the dilated site after coronary angioplasty: a 5-year quantitative angiographic study.

BACKGROUND: Limited data are available on the changes that occur at the dilated site late after coronary angioplasty. The aim of this study was to evaluate with quantitative angiography the natural history of changes that occur in the dilated segment between "early" (approximately 6 months) and "late" (approximately 5 years) follow-up after angioplasty. METHODS AND RESULTS: Of 127 consecutive patients (174 lesions) with successful angioplasty, 125 underwent early angiography. Three patients subsequently died, and 24 underwent revascularization surgery or repeated angioplasty, giving a study-eligible population of 98 patients. Quantitative angiographic analysis was performed before and immediately after angioplasty and at early and late follow-up in the study population of 84 patients (115 lesions), which was 86% of study-eligible patients. Mean lesion diameter stenosis decreased from 36.3+/-14.2% at early to 29.6+/-13.5% at late follow-up (P<.0001). No lesion developed late restenosis by the 50% diameter loss criterion. Late regression was related to stenosis severity at early angiography (r=-.58, P<.001). Subgroups at early angiography of 40% to 49% stenosis and > or = 50% stenosis showed significant regression at late angiography. CONCLUSIONS: Lesion regression at the dilated site is common late after angioplasty. The more severe a stenosis is at early angiography, the more likely the chance that there will be late regression. A strategy of watchful waiting may be appropriate for patients with restenotic lesions of borderline severity.

Adult↗
PubMed1997

Cytokine-facilitated transduction leads to low-level engraftment in nonablated hosts.

Using a murine bone marrow transplantation model, we evaluated the long-term engraftment of retrovirally transduced bone marrow cells in nonmyeloablated hosts. Male bone marrow was stimulated in a cocktail of interleukin-3 (IL-3), IL-6, IL-11, and stem cell factor (SCF) for 48 hours, then cocultured on the retroviral producer line MDR18.1 for an additional 24 hours. Functional transduction of hematopoietic progenitors was detected in vitro by reverse transcriptase-polymerase chain reaction (RT-PCR) amplification of multiple drug resistance 1 (MDR1) mRNA from high proliferative potential-colony forming cell (HPP-CFC) colonies. After retroviral transduction, male bone marrow cells were injected into nonablated female mice. Transplant recipients received three TAXOL (Bristol-Myers, Princeton, NJ) injections (10 mg/kg) over a 14-month period. Transplant recipient tissues were analyzed by Southern blot and fluorescence in situ hybridization for Y-chromosome-specific sequences and showed donor cell engraftment of approximately 9%. However, polymerase chain reaction amplification of DNAs from bone marrow, spleen, and peripheral blood showed no evidence of the transduced MDR1 gene. RT-PCR analysis of total bone marrow RNA showed that transcripts from the MDR1 gene were present in a fraction of the engrafted donor cells. These data show functional transfer of the MDR1 gene into nonmyeloablated murine hosts. However, the high rates of in vitro transduction into HPP-CFC, coupled with the low in vivo engraftment rate of donor cells containing the MDR1 gene, suggest that the majority of stem cells that incorporated the retroviral construct did not stably engraft in the host. Based on additional studies that indicate that ex vivo culture of bone marrow induces an engraftment defect concomitantly with progression of cells through S phase, we propose that the cell cycle transit required for proviral integration reduces or impairs the ability of transduced cells to stably engraft.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

The population genetics of antibiotic resistance.

Mathematical models are used to ascertain the relationship between the incidence of antibiotic treatment and the frequency of resistant bacteria in the commensal flora of human hosts, as well as the rates at which these frequencies would decline following a cessation of antibiotic use. Recent studies of the population biology of plasmid-encoded and chromosomal antibiotic resistance are reviewed for estimates of the parameters of these models and to evaluate other factors contributing to the fate of antibiotic-resistant bacteria in human hosts. The implications of these theoretical and empirical results to the future of antibacterial chemotherapy are discussed.

Anti-Bacterial Agents↗
PubMed1997

Adoptive immunotherapy.

Some of the most dramatic advances in the treatment of cancer have used the immune system in combination with conventional or transplantation chemotherapy. Adoptive immunotherapy has been used for relapses after allogeneic bone marrow transplantation, and it has been particularly effective for chronic myeloid leukemia. Adoptive immunotherapy also has been used for Epstein-Barr virus-related lymphomas developing after allogeneic marrow transplantations. Cellular therapy, including the infusion of tumor-reactive immune cells, has been used to mediate response of established solid tumors. This has been used for therapeutic benefit for renal cell carcinoma, melanoma, lung cancer, and breast cancer. Current research is focusing on reducing the toxicity of these approaches as well as further defining the appropriate target tissue.

Animals↗
PubMed1997

Clinical impact of chemotherapy dose escalation in patients with hematologic malignancies and solid tumors.

PURPOSE: To review published controlled clinical trials examining the benefit of escalated chemotherapy in patients with hematologic and solid malignancies. METHODS: Studies were obtained by searching Medline and CancerLit and by review of bibliographies of published trials. We reviewed studies that examined dose-intense (DI) chemotherapy alone, in combination with hematopoietic colony-stimulating factors (CSFs), or high-dose therapy (HDT) with autologous bone marrow support (ABMT). RESULTS: DI therapy without CSF or ABMT has not been shown to improve overall outcome in any tumor except consolidative therapy of acute myelogenous leukemia (AML). In solid tumors, many published studies suggest that less than standard-intensity chemotherapy is suboptimal, but few studies that examined higher compared with standard-dose therapy have shown a significant difference in outcome. No studies have convincingly demonstrated improved overall survival (OS) with DI therapy with CSF support. The use of HDT with ABMT has been shown to improve survival in multiple myeloma (MM), as well as relapsed intermediate- and high-grade non-Hodgkin's lymphoma (NHL). High-dose chemotherapy with ABMT is promising in patients with metastatic breast cancer (MBC), but it should not yet be considered a standard approach for these patients. CONCLUSION: DI chemotherapy is an acceptable and standard therapeutic maneuver for patients with AML in first remission, MM, and relapsed aggressive NHL. In solid tumors, the use of DI chemotherapy either alone or with cytokine support has not been shown to improve outcome and should not be considered standard therapy. Current randomized trials should provide definitive answers about the role of DI therapy in solid tumors.

Antineoplastic Agents↗
PubMed1997

Stem cell transplantation in the normal nonmyeloablated host: relationship between cell dose, schedule, and engraftment.

In previous studies we have shown high rates of stable engraftment when 40 million male BALB/c cells were infused intravenously daily for 5 days (a total of 200 million cells) to normal nonmyeloablated female hosts. The present studies evaluate engraftment of male BALB/c bone marrow cells in female host marrow, spleen, and thymus 20-25 weeks after transplantation using varying cell dosages within a 5-day schedule. Engraftment in recipient mice was assessed by detection of male specific sequence in recipient DNA from each organ. When 40 million cells were given per daily injection for 1, 2, 3, 4, or 5 days, engraftment percentages in host marrow were 11 +/- 0.83, 20 +/- 2.0, 23 +/- 2.5, 32 +/- 6.3, and 39% +/- 5.7 (+/- standard error of mean), respectively, yielding engraftment percentages per million cells infused of 0.28, 0.25, 0.19, 0.20, and 0.20%, respectively. When levels of 2.5, 5, 10, 20, or 40 million cells were injected 5 times over a 5-day schedule into normal BALB/c female hosts, progressively increasing levels of engraftment from 3 +/- 0.6 to 39% +/- 5.7 were seen in host marrow. Highest levels of engraftment per million cells injected were obtained on days 1 and 2 of a 5-day schedule and with a level of 10 million cells given daily over 5 days. Engraftment profiles varied with spleen and thymus and percent engraftment was generally lower than for marrow. The present work indicates that regardless of cell level infused or number of infusions, rates of engraftment observed in marrow approached or exceeded the highest rates of engraftment estimated by theoretical calculations based on replacing host cells ("replacement model") or adding to host cells ("incremental model"). Engraftment in spleen and thymus was lower, but also at times approached or exceeded theoretical maxima. These data show extraordinary levels of engraftment in normal hosts, suggesting that rates in this competitive model are superior to those seen in irradiated hosts; alternatively, there may be selective repression of host stem cell proliferation and differentiation.

Animals↗
PubMed1997

Spontaneous splenic rupture following administration of granulocyte colony-stimulating factor (G-CSF): occurrence in an allogeneic donor of peripheral blood stem cells.

Granulocyte colony-stimulating factor (G-CSF) has been used to improve granulocyte count in chronic neutropenia and myelodysplasia, to minimize the incidence and duration of neutropenia during conventional chemotherapy, and to mobilize peripheral blood stem cells prior to leukapheresis for use in autologous and allogeneic marrow transplantation. The most common toxicity is bone pain, and other reactions such as inflammation at the site of injection have also occurred. In patients with chronic neutropenia, splenomegaly has been described with long-term use, and extramedullary hematopoiesis has also been reported. However, thus far, no life-threatening sequelae of these effects are found in the literature. We now describe a case of spontaneous splenic rupture four days following a six-day course of G-CSF therapy in an allogeneic donor of peripheral blood stem cells.

Acute Disease↗
PubMed1996

Sex differences in case fatality before and after admission to hospital after acute cardiac events: analysis of community based coronary heart disease register.

OBJECTIVE: To determine whether the reported higher case fatality in hospital after an acute cardiac event in women can be explained by sex differences in mortality before admission and in baseline risk factors. DESIGN: Analyses of data from a community based coronary heart disease register. SETTING: Auckland region, New Zealand. SUBJECTS: 5106 patients aged 25-64 years with an acute cardiac event leading to coronary death or definite myocardial infarction within 28 days of onset, occurring between 1986 and 1992. MAIN OUTCOME MEASURES: Case fatality before admission, 28 day case fatality for patients in hospital, and total case fatality after an acute cardiac event. RESULTS: Despite a more unfavourable risk profile women tended to have lower case fatality before admission than men (crude odds ratio 0.88; 95% confidence interval 0.77 to 1.02). Adjustment for age, living arrangements, smoking, medical history, and treatment increased the effect of sex (0.72; 0.60 to 0.86). After admission to hospital, women had a higher case fatality than men (1.76; 1.43 to 2.17), but after adjustment for confounders this was reduced to 1.18 (0.89 to 1.58). Total case fatality 28 days after an acute cardiac event showed no significant difference between men and women (0.85; 0.70 to 1.02) CONCLUSIONS: The higher case fatality after an acute cardiac event in women admitted to hospital is largely explained by differences in living status, history, and medical treatment and is balanced by a lower case fatality before admission.

Adult↗
PubMed1996

Relationships between heavy metal and metallothionein concentrations in lesser black-backed gulls, Larus fuscus, and Cory's shearwater, Calonectris diomedea.

Metallothionein, cadmium, zinc, copper, and mercury concentrations were measured in adult lesser black-backed gulls, Larus fuscus; and metallothionein, cadmium, zinc, and copper concentrations were measured in fledgling Cory's shearwaters, Calonectris diomedea. In gulls, metallothionein was positively correlated with cadmium (kidney r = 0.83, liver r = 0.46), zinc (kidney r = 0.46, liver r = 0.37), and copper (kidney r = 0.28, liver r = 0.34). Mercury levels in lesser black-backed gulls showed no correlations with metallothionein or with any other metal. In shearwaters metallothionein was positively correlated with cadmium in the kidney (r = 0.41) but not in liver, zinc in kidney (r = 0.43) and liver (r = 0.52), and copper in kidney (r = 0.55) but not in liver. Cadmium levels were the most important factor determining tissue metallothionein concentrations in adult lesser black-backed gulls demonstrating the role of metallothionein in heavy metal detoxification. In fledgling Cory's shearwaters, the most important factor in determining metallothionein concentrations in kidney was copper concentrations, and in liver, zinc concentrations. During the latter phases of chick growth high levels of zinc are required for feather development, and at this time the binding of cadmium may be masked by the presence of a large amount of zinc- and copper-bound metallothionein. These results illustrate disparate roles of metallothionein, the levels of which will be in a state of flux both seasonally and annually.

Animals↗