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Biomedical subjects

F M Stewart

Publications and source records attributed to F M Stewart.

At least 55 records · Page 3Linked to original sources
PubMed1996

The intrinsic rate of increase of HIV/AIDS: epidemiological and evolutionary implications.

A method derived from demographic theory is presented for modeling the epidemiology of an infectious disease. For long-term infections, this method better accounts for host variation in survival and transmission rates than classical compartment models. Examples of the applications of this method focus on a single long-term infectious disease, HIV/AIDS. The method is employed to examine (1) how changes in transmission rates during different stages of infection affect the rate of spread of HIV/AIDS both in wholly susceptible populations and in populations where the number of potential hosts is limited, (2) the way the relative frequencies of the different stages of infection vary over time, (3) how the rate at which the epidemic is growing (or diminishing) affects the fraction of HIV-infected individuals who manifest the symptoms of AIDS, (4) the effect of treatment on the rate of spread of HIV, and (5) the potential effects of natural selection on the virulence of HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1996

The nature and prevalence of memory disorder late after stroke.

This study aimed to investigate the incidence and nature of memory impairment late after stroke. Out of 193 patients between 12 to 36 months post-cerebrovascular accident contacted in a postal survey, 113 replied that they had experienced memory impairment following the stroke. Seventy of these patients were assessed on an adapted version of the Rivermead Behavioural Memory Test, Warrington's Recognition Memory Test for words and faces, and an every day memory questionnaire. The Token Test and the Benton Facial Recognition Test were also administered as measures of language and visuoperceptual processing. Thirty-five of the patients were impaired on one or more of the memory measures. Of these, 16 showed no evidence of dysphasia or visuoperceptual impairment. The 16 cases of selective memory impairment typically had mild to moderate deficits, and only three were impaired across all three tests. The results suggest that memory impairment following stroke does not necessarily involve general memory impairment. The evidence for material-specific memory deficits was much weaker.

Adult↗
PubMed1996

Adaptation to cognitive deficit? An exploration of apparent dissociations between everyday memory and test performance late after stroke.

It is widely believed that spontaneous improvements in functioning late after brain damage are due to processes of adaptation to permanent cognitive deficits. Reports of everyday memory and the pattern of performance on memory tests were investigated in 70 patients more than a year after a stroke. Contrary to the adaptation hypothesis, performance on simulations of everyday tasks (Rivermead Behavioural Memory Test) correlated strongly with performance on a test where there was little scope for compensatory strategies (forced-choice recognition memory for words). In 12 cases, initial assessment with the EMQ20 questionnaire suggested few cognitive failures in everyday life despite poor test performance. However, where further investigation was possible, it seemed that unreliability of measures or subtle everyday effects of non-verbal memory impairment could explain the apparent discrepancies. In addition, patients who did poorly on tests were not reported to make frequent use of memory aids. Adaptation to deficit does not therefore appear to be a major influence on everyday memory performance late after stroke, but it may have subtle effects or may be important in other areas of functioning. Implications for clinical memory assessment are discussed.

Activities of Daily Living↗
PubMed1996

Improved engraftment of human cord blood stem cells in NOD/LtSz-scid/scid mice after irradiation or multiple-day injections into unirradiated recipients.

Human lymphoematopoietic stem cells engraft in irradiated immunodeficient mice that are homozygous for the severe combined immunodeficiency (scid) mutation. Engraftment levels in C.B-17-scid/scid mice, however, have been low and transient, decreasing the utility of this model for investigation of the development potential and function of human stem cells. In the present study, we have used NOD/LtSz-scid/scid mice as recipients and human cord blood as a source of donor stem cells. Our results demonstrate that NOD/LtSz-scid/scid mice support approximately fivefold higher levels of human stem cell marrow engraftment than do C.B-17-scid/scid mice. Human CD34+ cells are present in the marrow of recipient mice, and the engrafted cells readily peripheralize to the circulation of the host. Terminal differentiation of the stem and progenitor cells into mature progeny is limited. Using a multiple-day injection protocol developed in mice, which allows engraftment of stem cells between congenic mice in the absence of irradiation preconditioning, we observed high levels of human cell engraftment in unirradiated NOD/LtSz-scid/scid recipients after three or five consecutive-day injections. These results demonstrate that NOD/LtSz-scid/scid mice support high levels of human stem cell engraftment and that xenogeneic lymphohematopoietic stem cells can engraft in unirradiated hosts without the need for ablative reconditioning. This model will be useful for the in vivo investigation of human stem cells and for the preclinical analysis of human stem cells for transplantation.

Animals↗
PubMed1995

Cytokines in stem cell transplantation.

The use of cytokines in stem cell transplantation is still in the early stages of development. Efficacy has not been established consistently at the present time. When cytokines are employed in the treatment setting, they should be employed in a study setting evaluating whether there has been real patient benefit-palliation without compromise of therapeutic outcome or, preferably, a survival advantage. Cost effectiveness has not been established and, in any case it should not be a consideration until therapeutic efficacy has been established. The determination of various biologic parameters on cells such as cytokine receptors may permit more precise use of HGFs. In some cases there probably are subsets of patients who are benefited, while there are subsets who are harmed. The challenge of the future is to define these subsets.

Bone Marrow Transplantation↗
PubMed1995

Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation.

We report here on a preliminary human autologous transplantation study of retroviral gene transfer to bone marrow (BM) and peripheral blood (PB)-derived CD34-enriched cells. Eleven patients with multiple myeloma or breast cancer had cyclophosphamide and filgrastim-mobilized PB cells CD34-enriched and transduced with a retroviral marking vector containing the neomycin resistance gene, and CD34-enriched BM cells transduced with a second marking vector also containing a neomycin resistance gene. After high-dose conditioning therapy, both transduced cell populations were reinfused and patients were followed over time for the presence of the marker gene and any adverse effects related to the gene-transfer procedure. All 10 evaluable patients had the marker gene detected at the time of engraftment, and 3 of 9 patients had persistence of the marker gene for greater than 18 months posttransplantation. The marker gene was detected in multiple lineages, including granulocytes, T cells, and B cells. The source of the marking was both the transduced PB graft and the BM graft, with a suggestion of better long-term marking originating from the PB graft. The steady-state levels of marking were low, with only 1:1000 to 1:10,000 cells positive. There was no toxicity noted, and patients did not develop detectable replication-competent helper virus at any time posttransplantation. These results suggest that mobilized PB cells may be preferable to BM for gene therapy applications and that progeny of mobilized peripheral blood cells can contribute long-term to engraftment of multiple lineages.

Antigens, CD↗
PubMed1995

Disconnected.

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Clinical Trials as Topic↗
PubMed1994

Esthesioneuroblastoma. Long-term outcome and patterns of failure--the University of Virginia experience.

BACKGROUND: Esthesioneuroblastoma is a rare tumor arising from olfactory epithelium. This retrospective review analyzed the patterns of failure and long term outcome of patients with esthesioneuroblastoma evaluated at a single institution. METHODS: Forty patients with esthesioneuroblastoma were evaluated at the University of Virginia, with a median follow-up of 130 months. In most cases, treatment consisted of combined-modality therapy, including radiotherapy and surgery for Stages A and B disease and the addition of chemotherapy for Stage C disease. Fifteen patients received chemotherapy that included cyclophosphamide plus vincristine. Thirty-eight patients received radiotherapy, with a median dose of 50 Gy. Initial surgery for 23 patients included craniofacial resection, whereas the remainder had less extensive surgery (3 had no initial surgery). Five patients were salvaged with high dose chemotherapy and autologous bone marrow transplantation (CTX/BMT). RESULTS: Actuarial survivals at 5, 10, and 15 years are 78%, 71%, and 65% respectively. Fifty-five percent of patients failed therapy, and 68% of the failures were locoregional. Thirty-nine percent of recurrences occurred later than 5 years from diagnosis. Three of the five patients were successfully salvaged with CTX/BMT compared with four of seventeen patients who underwent conventional salvage therapy. CONCLUSIONS: Esthesioneuroblastoma is associated with long term survival and late recurrences. Multimodality therapy should be used initially. Durable remissions of failures can be achieved with CTX/BMT:

Adolescent↗
PubMed1994

Seasonal variation in heavy metal levels in tissues of common guillemots, Uria aalge from northwest Scotland.

Mercury, cadmium, zinc, and copper concentrations were analyzed in three samples of common guillemot (in April, June, and November). Levels measured were uniformly low, and not enough to have any toxic effects. Adult guillemots had significantly more cadmium in their livers and kidneys than juveniles, with juvenile levels ranging from 25% to 89% of adult levels. Mercury concentrations in liver and kidney were also higher in adults. Juvenile levels represented from 80% to 94% of adults, but there were no age differences in feather and muscle mercury. Mercury levels declined throughout the year in internal tissues from April through June to November. There was a strong seasonal fluctuation in cadmium levels in liver and kidney, rising significantly between April and June and declining in both adult and juvenile birds. The influences of seasonal processes (namely breeding and moult) and seasonal dietary differences as causative factors in the changes in metal burdens are discussed. These findings have implications for the use of seabirds as monitors of heavy metals in the marine environment.

Animals↗
PubMed1994

Fluctuation tests: how reliable are the estimates of mutation rates?

Fifty one years ago, Luria and Delbrück published in Genetics a paper that was to become a classic. In it they proved, beyond all reasonable doubt, that bacteria were mutating to phage resistance long before they could have encountered any bacteriophage. Luria and Delbrück also showed how the same experimental data could be used to estimate bacterial mutation rates. Since that time and in many different contexts the methods that they introduced have been used to estimate mutation rates. However, little seems to be known about the errors to be expected in such estimates. In what follows I examine how much uncertainty in the estimates is to be expected merely on the basis of the stochastic variability inherent in the sampling process. On the basis of this examination I question a few traditional ideas and conclude with some practical suggestions. The results were obtained by stimulation. It is my hope that they may inspire others to provide a rigorous theoretical basis for such calculations.

Bacteria↗
PubMed1994

An update on non-Hodgkin's lymphomas.

The non-Hodgkin's lymphomas are a diverse group of diseases characterized by enlargement of the lymph nodes and are indolent or aggressive. The histopathologic subtype provides the best guide to the nature of these diseases. In most patients the etiology is unknown. Painless peripheral adenopathy is the usual presenting feature. A careful clinical staging without laparotomy is recommended to establish disease extent, prognosis and treatment. In patients with indolent (low grade) lymphomas, a period of observation prior to treatment may be appropriate if the patient is asymptomatic. Symptomatic patients with low grade lymphoma require therapy. For patients with aggressive disease (intermediate or high grade), immediate treatment with curative intent is indicated. High dose therapy with bone marrow transplantation may be used to cure a small number of patients who relapse following initial chemotherapy.

Antineoplastic Agents↗
PubMed1994

Engraftment of normal murine marrow into nonmyeloablated host mice.

When 200 x 10(6) male BALB/c cells are given by tail vein injection to female nonmyeloablated hosts in one injection, a relatively low engraftment percentage is seen, but when the same total number of cells is given over five injections (separated by 24 hours), the observed engraftment is much higher. A further increase in engraftment appears to occur when the same number of cells is given in 10 injections separated by at least 24 hours. These data suggest that somewhere between 5 and 10% of marrow niches are available at intervals of 24 or more hours and that the keys to high levels of engraftment are the cell cycle status of the engrafting stem cell and the schedule of engraftment.

Animals↗
PubMed1994

In vitro and in vivo studies of stromal niches.

Lymphohematopoiesis occurs in the densely packed environment of the intramedullary spaces. Primitive lymphohematopoietic stem cells exist in close apposition to a variety of supportive cells including both hemopoietic and nonhemopoietic lineages. Using an in vitro long-term Dexter liquid culture system, we have established that a variety of cytokines are produced constitutively by such stromal cells in culture. These cytokines include Steel factor, interleukin-6 (IL-6), and colony-stimulating factor (CSF-1). Granulocyte-CSF and granulocyte-macrophage-CSF mRNA can be detected after refeeding of cultures, although in quiescent cultures message for these factors is difficult to detect. Interleukin-3, IL-4, and IL-5 are not detectable by standard Northern blot analysis or bioassay of condition media. However, IL-3--detectable by reverse-transcriptase PCR and biologic activity--was confirmed by growth of factor-dependent cells on stromal cells with IL-3 antibody blocking of such growth. Stem cells resident on such stromal cells are mirrored by the high proliferative potential colony-forming cell assay and are responsive to a relatively large number of cytokines, with Steel factor being of central importance, appearing to be a critical component of various synergistic combinations. Steel factor allows reduced levels of other factors in such combinations and works early in a temporal sequence. Hematopoietic stem cells can engraft in normal nonmyeloablated hosts. Using a male/female BALB/c transplantation model, we have shown high rates of engraftment into normal animals, out after marrow infusion to 25 months, after marrow infusion and that post-5-fluorouracil bone marrow is quite deficient in such engraftment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice.

We report the successful long-term engraftment of normal male donor bone marrow (BM) transfused into noncytoablated female mice, challenging the assumption that "niches" need to be created for marrow to engraft. We have used chromosomal banding and Southern blot analysis to identify transplanted male marrow cells, and shown the long-term stability of the chimeric marrows. Balb/C, BDF1, or CBA-J female hosts (no irradiation) received for 5 consecutive days 40 x 10(6) male cells (per day) of the same strain, and repopulation patterns were observed. Parallel studies were performed using tibia/femur equivalents of normal marrow or marrow from Balb/C mice pretreated 6 days previously with 150 mg/kg 5-fluorouracil (5-FU). Chromosome banding techniques showed that 5% to 46% of marrow cells were male 3 to 9 months posttransplant with normal donor marrow. Southern blot analysis, using the pY2 probe, showed continued engraftment at 21 to 25 months posttransplant, ranging from 15% to 42% male engrafted cells in marrow. Normal donor male marrow engrafted significantly better than 5-FU-pretreated male marrow as shown 1 to 12 months posttransplant in non-cytoablated female recipients. Percentages of male engrafted cells in BM ranged from 23% to 78% for recipients of normal donor marrow and from 0.1% to 39% for recipients of 5-FU marrow. Mean engraftment for 6 mice receiving normal marrow was 38%, whereas that for 6 mice receiving post-5-FU marrow was 8%, as assayed 1 to 3 months posttransplant. At 10 to 12 months, mean engraftment for the normal donor group was 46%, compared with 16% for the 5-FU group. The patterns of engraftment with normal and 5-FU marrow were similar for spleen and thymus. These results show that long-term chimerism can be established after transplantation of normal donor marrow to normal nonirradiated host mice and indicate that marrow spaces do not have to be created for successful engraftment. They suggest that transplanted marrow competes equally with host marrow for marrow space. Finally, these data show that post-5-FU Balb/C male marrow is markedly inferior in the repopulation of Balb/C female host marrow, spleen, and thymus, and suggest that this population of cells may not be the ideal population for gene transfer studies.

Animals↗
PubMed1993

Post-5-fluorouracil human marrow: stem cell characteristics and renewal properties after autologous marrow transplantation.

The effect of 5-fluorouracil (5-FU) pretreatment on human bone marrow (BM) progenitor/stem cells and recovery of hematopoiesis after autologous marrow transplant was studied. Twenty-one patients were treated with 5-FU (15 mg/kg to 45 mg/kg) intravenously (IV) for 1 to 3 days administered 6 to 22 days before BM harvest. Post-FU marrow was infused into 15 patients after high-dose cyclophosphamide, carmustine (BCNU), and VP-16 (CBV). Seventeen patients (historical controls) were treated with CBV and autologous BM transplantation but did not receive 5-FU before marrow harvest. The groups were comparable for diagnosis and prior therapy. In the 5-FU-treated group and control group, median recovery times for platelet count to 50,000/mm3 were 20 and 30 days, respectively (P = .007), and for platelet count to 100,000/mm3, 23 and 38 days, respectively (P = .007), while neutrophil recovery was not significantly altered. In vitro cultures with 1 to 7 growth factors (interleukin-1 [IL-1], IL-3, IL-4, IL-6, colony-stimulating factor-1 [CSF-1], granulocyte-macrophage colony-stimulating factor [GM-CSF], and G-CSF) were performed. In 8 of 10 patients whose marrow was studied before and after 5-FU treatment, the numbers of CFU-C responsive to the combination of GM-CSF and IL-3 was increased 6.15-fold by 5-FU pretreatment. In 4 of these patients, thymidine suicide of GM-CSF- and IL-3-stimulated CFU-C ranged from 17% to 42%. High proliferative potential colony-forming cell (HPP-CFC) was observed in low frequency in normal marrow and patient's marrow before 5-FU treatment. In 11 of 16 patients pretreated with 5-FU, increased numbers of HPP-CFC were noted. GM-CSF and IL-3 interacted synergistically to stimulate HPP-CFC. Multifactor combinations, especially GM-CSF + G-CSF + IL-3 + IL-6 + IL-1 + CSF-1 did not increase total colony count or classic HPP-CFC but did result in altered morphology, producing huge, loose colonies. The marrow from patients pretreated with 5-FU is enriched with multifactor-responsive HPP-CFC, renews in vivo granulopoiesis in a manner comparable with marrow harvests without 5-FU pretreatment, and provides accelerated in vivo platelet recovery. This marrow may be an appropriate target marrow for gene insertion in gene-therapy protocols.

Antineoplastic Combined Chemotherapy Protocols↗