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Biomedical subjects

L Fisher

Publications and source records attributed to L Fisher.

At least 145 records · Page 8Linked to original sources
PubMed1991

Retrovirus-mediated gene transduction into long-term repopulating marrow cells of dogs.

Amphotropic helper-free retrovirus vectors containing the bacterial neomycin phosphotransferase gene (neo) and the human adenosine deaminase gene (adenosine aminohydrolase, EC 3.5.4.4; ADA) were used to transduce canine marrow cells. In one approach, dogs were treated for 7 days with recombinant human granulocyte colony-stimulating factor to stimulate hematopoietic cell division. Bone marrow cells were collected and transduced by 24 hours of cocultivation on vector-producing cells followed by incubation in a vector-containing long-term marrow culture system for 4 days. Transduced autologous marrow (0.4 to 1.0 x 10(8) cells/kg) was infused into dogs administered otherwise lethal total body irradiation (TBI) of 920 cGy. Two of four dogs engrafted, and their marrows showed intermittently between 1% and 11% G418-resistant colony-forming unit granulocyte-macrophage (CFU-GM) colonies for up to 2 years after transplantation. In a different experimental approach, autologous marrow, obtained at the time of the PB neutrophil nadir 7 days after a single cyclophosphamide injection (40 mg/kg intravenously), was cocultivated for 24 hours on vector-producing cells and infused at doses of 0.06 to 0.18 x 10(8) cells/kg into dogs administered 920 cGy TBI. One of three dogs engrafted, and the marrow showed intermittently 1% to 10% G418-resistant CFU-GM colonies for at least 2 years. Culture results were confirmed by polymerase chain reaction (PCR) showing the presence of the neo gene in marrow cells, peripheral blood (PB) granulocytes, and PB and lymph node lymphocytes. Dilution experiments indicated that up to 10% of marrow, lymph node, and PB cells contained the neo gene, consistent with the culture results. Samples harboring the neo gene also contained the gene for human ADA. However, repeated analyses of PB and marrow cells for human ADA gene expression by starch gel electrophoresis were negative. PB samples of all dogs were free of helper virus, and no long-term side effects from the transduction were observed.

3T3 Cells↗
PubMed1991

A retrospective analysis of therapy for acute graft-versus-host disease: secondary treatment.

We have reviewed results of secondary therapy in 427 patients with acute graft-versus-host disease (GVHD) who did not have a durable satisfactory response after primary treatment. At the beginning of secondary treatment, 320 patients (75%) had rash, 252 (59%) had liver dysfunction, and 228 (53%) had gut dysfunction. Secondary treatment was with glucocorticoids (n = 249), cyclosporine (n = 80), antithymocyte globulin (n = 114), or monoclonal antibody (n = 19) either singly (n = 390) or in combination (n = 37). Parameters of GVHD severity were recorded weekly, and responses were determined according to values at the initiation of tertiary treatment or, for patients without such treatment, using values on day 29 of secondary treatment or the last recorded values before death, whichever occurred first. Minimal criteria for improvement or deterioration were defined for each organ, but no attempt was made to define liver or gut outcome if another complication such as venocclusive disease or infectious enteritis was present. Improvement or resolution of GVHD in the respective organ was seen in 45% of patients with skin disease, 25% of patients with evaluable liver disease, and in 35% of patients with evaluable gut disease. Overall complete or partial responses were seen in 40% of patients. The highest complete response rate with secondary therapy (23%) was seen when GVHD recurred during the taper phase of primary glucocorticoid treatment and was managed by increasing the dose of glucocorticoids. Multivariate analyses were performed to identify patient, disease, or treatment factors associated with likelihood of complete response or overall improvement. A similar analysis was performed to identify covariates associated with time to treatment failure (defined as initiation of tertiary therapy or death not due to relapse of malignancy). Severe dysfunction in the skin, liver, and gut at the beginning of treatment was associated both with a decreased likelihood of complete response and an increased treatment failure rate. The times to treatment failure and the proportions of patients in various response categories were similar for primary and secondary treatment, suggesting that the potential efficacy of new immunosuppressive agents for treatment of acute GVHD can be assessed meaningfully in patients who have not responded adequately to initial therapy.

Adult↗
PubMed1991

Preventive effects of clomiphene citrate on estrogen-deficiency osteopenia elicited by LHRH agonist administration in the rat.

The estrogen agonist and antagonist clomiphene citrate has been shown to prevent bone loss induced by ovariectomy in the rat. In young women estrogen-deficiency bone loss is a clinical problem associated with the use of luteinizing hormone releasing hormone (LHRH) agonists, such as buserelin, to treat endometriosis. The aim of this study was to determine whether clomiphene citrate (10 mg/kg body weight per week orally) would prevent the osteopenic effect of buserelin (25 micrograms/kg body weight per day SC) in the rat. Four groups of animals with 45Ca-labeled skeletons were studied for 4 weeks: group A, placebo controls; group B, buserelin; group C, clomiphene; and group D, buserelin + clomiphene. Bone resorption was monitored by measuring the urinary excretion of 45Ca and hydroxyproline. Clomiphene slowed bone breakdown and inhibited the osteopenic effect of buserelin. Total-body calcium values (mean +/- SD) were (mg) 2635 +/- 181, 2267 +/- 85, 2566 +/- 126, and 2624 +/- 77 in groups A to D, respectively. Osteopenia was present only in group B (P less than 0.001). Interestingly buserelin lowered blood 17 beta-estradiol and uterine weights to a similar extent in the presence and absence of clomiphene. Because clomiphene inhibited estrogen-deficiency bone loss in buserelin-treated rats without depressing the hypoestrogenic action of this LHRH agonist, it is suggested that the use of clomiphene to protect the skeleton during LHRH agonist therapy of endometriosis warrants further study.

Animals↗
PubMed1991

17 beta-estradiol protects rats from osteopenia associated with administration of the luteinising hormone releasing hormone (LHRH) agonist, buserelin.

Bone loss associated with sustained administration of luteinising hormone releasing hormone (LHRH) agonists, such as buserelin, is attributed to estrogen deficiency. However, the possibility that the LHRH agonists themselves may contribute to the pathogenesis of bone thinning, has not been ruled out. The aim of the present study was to determine whether or not oral 17 beta-estradiol (300 micrograms/kg body wt/week) would fully prevent the osteopenic effect of buserelin (25 micrograms/kg body wt/day s.c.) in the rat. Four groups of animals with 45Ca-labelled skeletons were studied for 4 weeks: group 1, placebo controls; group 2, 17 beta-estradiol; group 3, buserelin; group 4, 17 beta-estradiol + buserelin. Buserelin alone lowered blood estradiol concentrations, increased bone resorption and reduced femur and total body calcium and 45Ca values. Total body calcium values (means +/- SD) were: (mg) 3405 +/- 176; 3250 +/- 282; 2813 +/- 133; 3156 +/- 452 in groups 1 to 4, respectively. Significant osteopenia was present only in group 3 (P less than 0.001). These results support the view that buserelin-mediated bone loss is due to estrogen deficiency. They do not indicate that LHRH agonists per se, play any role in causing bone thinning.

Animals↗
PubMed1991

Use of a probe to repeat sequence of the Y chromosome for detection of host cells in peripheral blood of bone marrow transplant recipients.

In situ hybridization for the Y chromosome (Y-ISH) was used to identify residual host cells in the peripheral blood of 51 recipients of sex-mismatched allogeneic marrow not depleted of T cells following conditioning with high-dose cyclophosphamide and total body irradiation (TBI). One patient who rejected the graft showed rapid reappearance of host cells after transient donor marrow engraftment. Host cells were detected at low levels in 49 of the remaining 50 patients. Host peripheral blood mononuclear cells (PBMC) decreased with time and reached a plateau at 1.0 +/- 0.2% within four weeks after transplantation, while the percentage of host granulocytes (GRAN) reached a plateau at background level. The mean absolute numbers of host PBMC or GRAN were less than 0.015 x 10(9)/L and did not vary significantly over the period studied. Neither the percentages nor the absolute numbers of host PBMC or GRAN were significantly affected by HLA-matching, TBI dose-intensity, pretransplant remission status, subsequent development of acute or chronic graft-versus-host disease or relapse after transplantation. The authors conclude that it is common to find a few residual host cells in the peripheral blood of allogeneic marrow transplant recipients, and the presence of these cells has no clinical significance.

Adolescent↗
PubMed1991

Osteoarthritis of the hip and osteoporosis of the proximal femur.

A negative association has been reported between osteoarthritis and osteoporosis. There are, however, few population based data to support this association. In this study the bone density in the upper femur was compared with the presence and severity of hip osteoarthritis in 314 subjects undergoing radiography for non-skeletal indications. There was a statistically significant negative association between the two disorders. This relation may reflect differences in the cause of these two major musculoskeletal conditions.

Adult↗
PubMed1991

Differential antagonist activity of alpha-helical corticotropin-releasing factor9-41 in three bioassay systems.

Studies were performed in conscious unrestrained rats to compare the ability of the CRF receptor antagonist, alpha-helical CRF9-41, to inhibit the actions of CRF in three in vivo bioassay systems. When both peptides were administered intracerebroventricularly, an antagonist:agonist ratio between 6:1-12:1 was required to abolish CRF-induced elevations of plasma catecholamine levels. When both peptides were administered iv, CRF-induced hypotension and tachycardia were completely prevented by an antagonist:agonist ratio of 6:1, whereas total blockade of CRF-induced elevations of plasma ACTH and beta-endorphin levels required an antagonist:agonist ratio of 3000:1. These results demonstrate marked differences in the ability of alpha-helical CRF9-41 to antagonize various biological actions of CRF and support the existence of multiple CRF receptor subtypes.

Adrenocorticotropic Hormone↗
PubMed1990

A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment.

We have reviewed results of therapy in 740 patients with grades II-IV acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. At the beginning of therapy, 597 patients (81%) had rash, 369 (50%) had liver dysfunction and 396 (54%) had gut dysfunction. Initial treatment was with glucocorticoids (n = 531), cyclosporine (n = 170), antithymocyte globulin (ATG) (n = 156) or monoclonal antibody (n = 3) either singly (n = 633) or in combination (n = 107). Parameters of GVHD severity in each organ were recorded weekly, and evaluation of response was made using values at the initiation of secondary treatment or, for patients without such treatment, using values on day 29 of primary treatment or the last recorded value before death, whichever occurred first. Minimal criteria for improvement or progression were defined for each organ, but no attempt was made to define liver or gut outcome if another complication such as venocclusive disease or infectious enteritis was present. Improvement rates were 43% for skin disease, 35% for evaluable liver disease and 50% for evaluable gut disease. Overall complete or partial responses were seen in 44% of patients. Multivariate analyses were carried out to identify patient, disease or treatment factors associated with likelihood of overall improvement and likelihood of response in at least one organ. A similar analysis was also carried out to identify covariates associated with time to treatment failure (defined as initiation of secondary therapy or death not due to relapse of malignancy). In all three models, GVHD prophylaxis using cyclosporine combined with methotrexate was associated with favorable GVHD treatment outcome compared to prophylaxis with either agent alone, and treatment with glucocorticoids or cyclosporine was more successful than treatment with ATG. Other factors associated with unfavorable outcome in the model of time to treatment failure and also entered in one of the response models were recipient HLA disparity with the donor, presence of a liver complication other than GVHD, and early onset of GVHD. Results of this analysis indicate that glucocorticoids represent the best initial therapy available for treatment of acute GVHD, although much room for improvement remains.

Antibodies, Monoclonal↗
PubMed1990

Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation.

BACKGROUND: Graft-versus-host disease (GVHD) and infection are major complications of allogeneic bone marrow transplantation. Since intravenous immunoglobulin has shown benefit in several immunodeficiency and autoimmune disorders, we studied its antimicrobial and immunomodulatory role after marrow transplantation. METHODS: In a randomized trial of 382 patients, transplant recipients given immunoglobulin (500 mg per kilogram of body weight weekly to day 90, then monthly to day 360 after transplantation) were compared with controls not given immunoglobulin. By chance, the immunoglobulin group included more patients with advanced-stage neoplasms; otherwise, the study groups were balanced for prognostic factors. RESULTS: Control patients seronegative for cytomegalovirus who received seronegative blood products remained seronegative, but seronegative patients who received immunoglobulin and screened blood had a passive transfer of cytomegalovirus antibody (median titer, 1:64). Among the 61 seronegative patients who could be evaluated, none contracted interstitial pneumonia; among the 308 seropositive patients evaluated, 22 percent of control patients and 13 percent of immunoglobulin recipients had this complication (P = 0.021). Control patients had an increased risk of gram-negative septicemia (relative risk = 2.65, P = 0.0039) and local infection (relative risk = 1.36, P = 0.029) and received 51 more units of platelets than did immunoglobulin recipients. Neither survival nor the risk of relapse was altered by immunoglobulin. However, among patients greater than or equal to 20 years old, there was a reduction in the incidence of acute GVHD (51 percent in controls vs. 34 percent in immunoglobulin recipients; P = 0.0051) and a decrease in deaths due to transplant-related causes after transplantation of HLA-identical marrow (46 percent vs. 30 percent; P = 0.023). CONCLUSIONS: Passive immunotherapy with intravenous immunoglobulin decreases the risk of acute GVHD, associated interstitial pneumonia, and infections after bone marrow transplantation.

Adult↗
PubMed1990

Regional responses within the kidney to ischemia: assessment of adenine nucleotide and catabolite profiles.

UNLABELLED: Renal cortex (C) has predominantly aerobic metabolism, whereas inner medulla (IM) has both aerobic and anaerobic capacities. This study was undertaken (1) to assess how well rat IM anaerobic metabolism maintains this region's ATP content during ischemia; and (2) to determine whether regional variations in adenylate pool/catabolite responses to ischemia exist, obscuring interpretation of cellular energetics in rat studies of acute renal failure (ARF). Adenine nucleotides/catabolites were measured in rat C, IM and outer medulla (OM) after 15 and 45 min of ischemia. After 15 min, all regions showed profound ATP depletion, although the IM maintained slightly higher (by 0.23 mumol/g) absolute ATP levels than C/OM tissues (normal ATP value = 8.7 mumol/g). By 45 min, significant differences in regional ATP levels did not exist. Striking regional catabolite differences were apparent at both 15 and 45 min. Most prominent were: (1) intrarenal purine base/inosine gradients, levels falling approx. 22-50% from C to IM; and (2) preferential OM AMP/IMP/adenosine accumulation. To assess whether more homogeneous results might be found in rabbit kidney, possibly making this animal preferable to rats for studies of renal ischemia, rabbit C, OM and IM adenylate pools were analyzed after 15 min of ischemia. C vs. IM ATP differences were greater (approx. 1.3 mumol/g) and large catabolite concentration differences were still apparent. CONCLUSIONS: (1) anaerobic mechanisms support IM ATP levels during ischemia but, in terms of normal concentrations, the impact is small, particularly in the rat; and (2) marked regional differences in adenylate catabolite levels exist within ischemic kidneys. These need to be recognized when analyzing adenylate pool responses in ischemic ARF.

Acute Kidney Injury↗
PubMed1990

Value of day 100 screening studies for predicting the development of chronic graft-versus-host disease after allogeneic bone marrow transplantation.

We prospectively evaluated 169 patients with a number of screening studies performed between 71 to 121 days after allogeneic marrow transplantation to detect the development of chronic graft-versus-host disease (GVHD). Group 1 patients (n = 78) were asymptomatic and had normal physical examinations at the time of screening and, with a minimum of 8 years follow-up, have not developed chronic GVHD. Group 2 patients (n = 38) had signs and symptoms of chronic GVHD at time of testing. Group 3 patients (n = 53) were similar to those in group 1 in having no clinically evident GVHD at the time of testing, but later developed clinical chronic GVHD. Using time to an event analysis, we compared patients in groups 1 and 3 to determine which of 17 clinical and laboratory factors evaluated at screening accurately predicted the development of subsequent chronic GVHD. Multivariate analyses showed several factors to have independent predictive value. In the first model, results of oral biopsies were excluded since these were done only in one half of the patients. Predictive factors in this analysis included: (1) histologic findings of GVHD on skin biopsy, relative risk 3.23 (95% confidence interval 1.75 to 5.94), P = .0002; and (2) history of grade II through IV acute GVHD, relative risk 3.12 (95% confidence interval 1.72 to 5.64), P = .0002. When oral biopsy results were included in the second model, independent risk factors included: (1) histologic findings of GVHD on skin biopsy, relative risk 5.96 (95% confidence interval 1.95 to 18.19), P = .0017; and (2) low numbers of immunoglobulin A (IgA)-bearing plasma cells detected by direct immunofluorescence in salivary gland areas on oral biopsy, relative risk 11.53 (95% confidence interval 2.51 to 52.03), P = .0017. Our study demonstrates the value of day 100 screening studies for predicting subsequent development of clinical chronic GVHD.

Adolescent↗
PubMed1990

Effects of clomiphene and tamoxifen in vivo on the bone-resorbing effects of parathyroid hormone and of high oral doses of calcitriol (1,25(OH)2D3) in rats with intact ovarian function consuming low calcium diet.

Two experiments were undertaken to study the abilities of clomiphene citrate (20 mg/kg body wt/wk s.c.) and tamoxifen citrate (20 mg/kg body wt/wk s.c.) to slow bone resorption mediated by (a) endogenous parathyroid hormone (PTH) and (b) exogenous calcitriol (1,25(OH)2D3) in vivo in rats with intact ovarian function. Groups of rats with 45Ca-labelled bones were fed a low-calcium (0.01% Ca) diet to stimulate secretion of PTH. Neither clomiphene nor tamoxifen showed the mobilization of 45Ca from femoral bone or prevented the reduction in bone calcium induced by feeding this diet. Moreover these drugs did not depress the urinary excretion of 45Ca or hydroxyproline. These observations indicated that clomiphene and tamoxifen did not inhibit PTH-mediated bone resorption. Administering calcitriol (50 ng/day) orally for 14 days raised plasma calcium, increased urinary 45Ca and its specific activity and decreased femur 45Ca: all these responses were similar in animals receiving calcitriol alone and calcitriol with clomiphene or tamoxifen. The femur 45Ca values (dpm X 10(-3) were: (mean +/- SD, n = 8) placebo, 1901 +/- 127; 1,25(OH)2D3, 1727 +/- 96**; clomiphene + 1,25(OH)2D3, 1694 +/- 93**; tamoxifen + 1,25(OH)2D3, 1664 +/- 61**. (** = P less than 0.01). Thus neither clomiphene nor tamoxifen prevented calcitriol-mediated bone resorption in vivo in the rat.

Animals↗
PubMed1990

HLA heterozygosity in insulin-dependent diabetes is most frequent at the DQ locus.

Restriction fragment length polymorphism using an HLA-DQ beta-chain genomic probe showed that 63 children with insulin-dependent (type 1) diabetes mellitus (IDDM) were all (100%) positive for the BamH1 fragments 12 kb and/or 4 kb compared to 98% (62/63) for HLA-DR3 and/or 4 and 75% (47/63) for HLA-B8 and/or 15. The 36 (56%) DR3-positive children were all 4-kb-positive; however, a total of 44 (70%) children were 4-kb-positive (P less than 0.02). The 55 (87%) DR4-positive children were all 12-kb-positive, but a total of 56 (89%) were 12-kb-positive (NS). The heterozygosity at the HLA region increased from 11/63 (18%) for HLA-B8/15 to 29/63 (46%) for HLA-DR3/4 (P less than 0.0004) and to 37/63 (59%) for the HLA-DQ 4 kb/12 kb fragments (P less than 0.02). The test of an equal probability of a positive result under the adjacent pair of tests indicates that the increased risk of developing IDDM in association with HLA-DQ is to a great extent due to heterozygosity at this locus. There were no differences between the 4 kb/12 kb and the DR3/4-positive IDDM children with respect to fasting or meal-stimulated C peptide, insulin requirement, or levels of insulin antibodies formed during the first 12 months of insulin therapy. Our results support the hypothesis that HLA-DQ is closely associated with an increased risk of childhood IDDM, and when typed for at this locus parameters of the clinical course were homogeneous, suggesting that factors other than HLA-DQ may determine previously observed differences between IDDM children in clinical or functional parameters.

Adolescent↗
PubMed1990

Advancing a family perspective in health research: models and methods.

In this essay we review and respond to four problems that have impeded the application of family theory to health research: the difficulty in translating family concepts to empirical health research; the confusion and uncertainty in measuring "wholes" and "parts" of a family in a single health project; the apparent conflict between circular-causal and linear perspectives in model building; and the putative, implicit "violation" of a family perspective by the employment of certain data management and design strategies. We argue that current, complex conceptualizations of the family have to be matched with equally complex research designs and methods, and that techniques are available to reach these goals. We distinguish between theoretical models and research methods, and review several strategies, design issues, and alternatives for data analysis. Throughout, we point to 1) the need to maintain consistency among theory, construct, and indicator, 2) the employment of multidimensional family assessment in health research, and 3) the use of readily available but infrequently used methods and procedures for appreciating the richness of multivariate family data.

Family↗
PubMed1990

An outreach program to low-income, high risk populations through WIC.

Through a special New York State legislative grant, we were able to produce brochures in Spanish and Haitian French, and to train WIC Staff, Public Health Nurses and Healthy Neighborhood staff in poison prevention. This study involved all the WIC sites in our seven county region, who reach a population of over 10,000 families who have been identified as low income, high-risk individuals in a survey conducted by the American Red Cross. Pre-test showed that the staff knew of the Poison Center but had not instructed clients in poison prevention. Post-testing of WIC staff showed a significant increase in knowledge about poison prevention and increase in the frequency of client instruction. The main thrust of this program was to assure that the phone number of the Poison Center was prominently posted in each home and that clients knew that the Poison Center was available 24 h every day in a poison emergency.

Health Education↗
PubMed1990

Continual reassessment method: a practical design for phase 1 clinical trials in cancer.

This paper looks at a new approach to the design and analysis of Phase 1 clinical trials in cancer. The basic idea and motivation behind the approach stem from an attempt to reconcile the needs of dose-finding experimentation with the ethical demands of established medical practice. It is argued that for these trials the particular shape of the dose toxicity curve is of little interest. Attention focuses rather on identifying a dose with a given targeted toxicity level and on concentrating experimentation at that which all current available evidence indicates to be the best estimate of this level. Such an approach not only makes an explicit attempt to meet ethical requirements but also enables the use of models whose only requirements are that locally (i.e., around the dose corresponding to the targeted toxicity level) they reasonably well approximate the true probability of toxic response. Although a large number of models could be contemplated, we look at a particularly simple one. Extensive simulations show the model to have real promise.

Antineoplastic Agents↗