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Biomedical subjects

F Fletcher

Publications and source records attributed to F Fletcher.

At least 19 recordsLinked to original sources
PubMed2001

The creation of ergonomic data sheets for hazard communication of work-related musculoskeletal disorders.

Information on human health hazards caused by chemical exposure has traditionally been supplied through Material Safety Data Sheets (MSDS). This report describes development of an analogous Ergonomic Data Sheet (EDS) to address hazards of work-related musculo-skeletal disorders (WRMSD) from use of hand tools. The EDS includes sections on risk factors for WRMSD, design aspects of the tool that decrease risks, precautionary measures, and objective testing of the tool compared to other comparable tools. The EDS can be used within an Ergonomic Communication Program similar to a Hazard Communication Program.

Communication↗
PubMed2000

RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism.

We have generated RANK (receptor activator of NF-kappaB) nullizygous mice to determine the molecular genetic interactions between osteoprotegerin, osteoprotegerin ligand, and RANK during bone resorption and remodeling processes. RANK(-/-) mice lack osteoclasts and have a profound defect in bone resorption and remodeling and in the development of the cartilaginous growth plates of endochondral bone. The osteopetrosis observed in these mice can be reversed by transplantation of bone marrow from rag1(-/-) (recombinase activating gene 1) mice, indicating that RANK(-/-) mice have an intrinsic defect in osteoclast function. Calciotropic hormones and proresorptive cytokines that are known to induce bone resorption in mice and human were administered to RANK(-/-) mice without inducing hypercalcemia, although tumor necrosis factor alpha treatment leads to the rare appearance of osteoclast-like cells near the site of injection. Osteoclastogenesis can be initiated in RANK(-/-) mice by transfer of the RANK cDNA back into hematopoietic precursors, suggesting a means to critically evaluate RANK structural features required for bone resorption. Together these data indicate that RANK is the intrinsic cell surface determinant that mediates osteoprotegerin ligand effects on bone resorption and remodeling as well as the physiological and pathological effects of calciotropic hormones and proresorptive cytokines.

Animals↗
PubMed2000

Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo.

Osteoprotegerin ligand (OPGL) targets osteoclast precursors and osteoclasts to enhance differentiation and activation, however, little is known about OPGL effects on osteoclast survival. In vitro, the combination of OPGL + colony-stimulating factor-1 (CSF-1) is required for optimal osteoclast survival. Ultrastructurally, apoptotic changes were observed in detached cells and culture lysates exhibited elevated caspase 3 activity, particularly in cultures lacking CSF-1. DEVD-FMK (caspase 3 inhibitor) partially protected cells when combined with OPGL, but not when used alone or in combination with CSF-1. CSF-1 maintained NF-kappaB activation and increased the expression of bcl-2 and bcl-X(L) mRNA, but had no effect on JNK activation. In contrast, OPGL enhanced both NF-kappaB and JNK kinase activation and increased the expression of c-src, but not bcl-2 and bcl-X(L) mRNA. These data suggest that aspects of both OPGL's and CSF-1's signaling/survival pathways are required for optimal osteoclast survival. In mice, a single dose of OPG, the OPGL decoy receptor, led to a >90% loss of osteoclasts because of apoptosis within 48 hours of exposure without impacting osteoclast precursor cells. Therefore, OPGL is essential, but not sufficient, for osteoclast survival and endogenous CSF-1 levels are insufficient to maintain osteoclast viability in the absence of OPGL.

Animals↗
PubMed1998

Marrow repopulating cells in mobilized PBPC can be serially transplanted for up to five generations or be remobilized in PBPC reconstituted mice.

We have evaluated the durability of engraftment and the potential of remobilization in mice reconstituted with mobilized peripheral blood progenitor cells (PBPC). Female mice which had been reconstituted with cytokine-mobilized PBPC from male donors were serially transplanted into second, third, fourth and fifth lethally irradiated female recipients at intervals of 6-10 months. Male-derived hematopoiesis was determined in recipient mice at each serial transplantation. Male-positive CFCs were detected after 5 passages for 45 months, but declined from >95% at passage 1 to 74% at passage 2, 33% at passage 4, and 28% at passage 5. Long-term survival also declined from 97% at passage 2 to 53% at passage 4, and 27% at passage 5. The results demonstrated that mobilized PBPC were able to provide engraftment for more than 45 months, but the engraftment provided by mobilized PBPC decreased at each serial passage. In addition, mice reconstituted with mobilized PBPC (at 1 year post transplantation) were treated with the same cytokines as in the primary mobilization (remobilization). The remobilized PBPC were harvested and transplanted into lethally irradiated secondary recipients. Male-derived CFCs were evaluated at 20 months post transplantation. Mice transplanted with PBPC remobilized with rhG-CSF or rhG-CSF plus rrSCF-PEG showed 70% and 89% male-positive CFCs respectively, demonstrating that mice reconstituted with mobilized PBPC could be remobilized and that the remobilized PBPC were also capable of providing long-term hematopoietic reconstitution. Our studies demonstrated that mobilized PBPC have extensive proliferative or self-renewal capacity to provide durable engraftment and that marrow repopulating cells in PBPC reconstituted mice can be remobilized, suggesting that patients who relapse after PBPC transplantation may be remobilized for a second transplantation to support additional chemotherapy.

Animals↗
PubMed1998

Sperm transport in the reproductive tract of female zebra finches (Taeniopygia guttata).

Aspects of sperm transport in the oviducts of female zebra finches were examined by recording the decline in the number of spermatozoa on the outer perivitelline layer of successively laid eggs. Data from a single clutch of eggs from 32 females indicates that the mean per capita rate of loss of spermatozoa was estimated to be 0.0170 +/- 0.002 SEM spermatozoa h-1. However, individual females showed no consistency in the rate at which spermatozoa were lost from their oviduct over five successive clutches. Models of the mechanism of sperm competition in birds assume that the rate of loss of spermatozoa does not differ between inseminations made before or after the start of egg laying. This assumption was found to be valid: the instantaneous per capita rate of loss of spermatozoa did not differ significantly between females inseminated either before (0.01445 +/- 0.0028 SEM spermatozoa h-1) or after (0.01674 +/- 0.0023 SEM spermatozoa h-1) the onset of oviposition. The rate of sperm transport through the infundibulum was determined to be slower than that between the utero-vaginal sperm storage tubules and the infundibulum by comparing the number of spermatozoa associated with the perivitelline layers of eggs laid after a day on which no eggs were laid. Eggs with < 20 spermatozoa on the outer perivitelline layer were found to have a 50% probability of being infertile. The results are compared with data for domestic fowl and turkeys.

Animals↗
PubMed1996

A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation.

We have previously shown that mice induced to overexpress thrombopoietin (TPO) by retroviral-mediated gene transfer into bone marrow (BM) cells develop myelofibrosis and osteosclerosis. It was speculated that these effects were secondary to TPO, resulting from high levels of megakaryocytes and platelets. Also, it was proposed that these mice represent a model for myelofibrosis and osteosclerosis. In this report, we show that levels of both transforming growth factor-beta 1 and platelet-derived growth factor are increased twofold to fivefold in the platelet-poor plasma of TPO overexpressing mice compared with control mice. These data suggest that the increased megakaryocytes produce elevated levels of these cytokines that lead to the pathogenesis of disease. Further, we retransplanted TPO overexpressing mice, at 40 to 42 weeks after primary transplantation, with normal BM cells. After the secondary transplantation, megakaryocytes and platelets returned to normal levels and the myelofibrosis and osteosclerosis were completely corrected. These data extend our initial studies of the effects of overexpression of TPO and show the potential use of this model to explore the underlying cause of myelofibrosis and osteosclerosis and potential treatments for these diseases.

Animals↗
PubMed1996

Dynamic test to diagnose loose uncemented femoral total hip components.

A new computed tomographic rotation study was developed to determine the stability of uncemented femoral components after total hip arthroplasty. The computed tomographic rotation study measures femoral component version with the leg in maximum external and internal rotation. The component is considered rotationally unstable, and thus loose, if these angles differ by more than 2 degrees. The results of the computed tomographic rotation study were confirmed with intraoperative inspection in 50 patients: 13 patients (Group A) with definite radiographic loosening, 22 patients (Group B) with equivocal radiographic loosening, and 15 patients (Group C) with documented stability. The results of the computed tomographic rotation study agreed with intraoperative findings for all patients in Groups A and C, and 20 of 22 patients in Group B (1 false negative and 1 false positive). Statistical analysis of Group B showed that the computed tomographic rotation study had a sensitivity of 91.6% and a specificity of 90.0%. The positive predictive value was 91.6%. These results indicate that the computed tomographic rotation study can supplement equivocal radiographic findings in assessing loosening of an uncemented femoral component.

Biomechanical Phenomena↗
PubMed1995

Male phenotype and ejaculate quality in the zebra finch Taeniopygia guttata.

We tested the idea that female preference for relatively attractive extra-pair males arises because the morphological and behavioural features that females find attractive covary with ejaculate features: Sheldon's (Proc. R. Soc. Lond. B 257 25-30 (1994) phenotype-linked fertility insurance hypothesis. Two phenotypic traits that female zebra finches find attractive in males are song rate and symmetry of chest band plumage, but we found neither of these to be significantly related to any of the following ejaculate features: number of sperm, percentage of live sperm, absolute number of sperm, sperm length or sperm swimming velocity. Furthermore, and surprisingly, we did not find the predicted negative relationship between male song rate and fluctuating asymmetry of chest band plumage. Because most ejaculate features (except sperm numbers in rested males) show low levels of repeatability, it is unlikely that female zebra finches could reliably obtain a better quality ejaculate by choosing to copulate with a more attractive male. There was thus no evidence for the phenotype-linked fertility insurance hypothesis. Nor did we obtain evidence for the more general fertility insurance hypothesis: we found that female zebra finches paired to a vasectomized male, and hence receiving no sperm, were no more likely to seek an extra-pair copulation than females paired to an intact male.

Animals↗
PubMed1995

Chronic exposure to retroviral vector encoded MGDF (mpl-ligand) induces lineage-specific growth and differentiation of megakaryocytes in mice.

Megakaryocyte growth and development factor (MGDF) has recently been identified as a ligand for the c-mpl receptor. Using retroviral-mediated gene transfer, MGDF has been overexpressed in mice to evaluate the systematic effects due to chronic exposure to this growth factor. MGDF overexpressing mice had more rapid platelet recovery than control mice after transplantation. Following this recovery, the platelet levels continued increasing to fourfold to eightfold above normal baseline levels and remained elevated (five-fold above control mice) in these animals, which are alive and well at more than 4 months posttransplantation. Increased megakaryocyte numbers were detected in a number of organs in these mice including bone marrow, spleen, liver, and lymph nodes. Prolonged overexpression of MGDF led to decreased marrow hematopoiesis, especially erythropoiesis, with a shift to extramedullary hematopoiesis in the spleen and liver. All the MGDF overexpressing mice analyzed to date developed myelofibrosis and osteosclerosis, possibly induced by megakaryocyte and platelet produced cytokines. No significant effect on other hematopoietic lineages was seen in the MGDF overexpressing mice, showing that the stimulatory effect of MGDF in vivo is restricted to the megakaryocyte lineage.

Animals↗
PubMed1995

Structural analysis of human and murine flt3 ligand genomic loci.

Both the murine and human genomic loci that encode flt3 ligand have been cloned. flt3 ligand is a hematopoietic growth factor that stimulates the proliferation of stem and progenitor cells. The portions of the murine and human flt3 ligand genomic loci encompassing the coding region of the protein are approximately 4.0 kb and 5.9 kb, respectively. The human genomic locus is larger as a result of the presence of repeated sequences within introns I, II, IV, V and VI. The transmembrane isoform of the murine and human flt3 ligand proteins are each encoded within seven exons (1-5 + 7 and 8). Analyses of flt3 ligand cDNA clones show that alternative splicing of a putative sixth exon results in the generation of a soluble form of the flt3 ligand protein. The sizes of each of the exons are well conserved between species. Murine and human flt3 genomic loci have a similar exon: intron structure compared to the genomic loci encoding Steel factor and colony stimulating factor 1. These proteins, which appear to be ancestrally related, are hematopoietic growth factors that stimulate cells via specific and structurally related tyrosine kinase receptors on the cell surface.

Alternative Splicing↗
PubMed1994

A comparative study of sperm-egg interactions in birds.

A comparative study was made of the number of spermatozoa trapped on the outer perivitelline layer and the number of spermatozoa penetrating the inner perivitelline layer of the eggs of 27 species of bird. The total number of spermatozoa (trapped spermatozoa plus holes made by spermatozoa) varied between 29 and 164,000 per egg among species and was significantly and positively correlated with size of the ovum. In most species, holes formed a 'halo' around the germinal disc area and the density of holes was much greater in this region than elsewhere, especially in passerine birds. In some species, a high proportion of holes occurred at some distance from the germinal disc. This seems to be an artefact due to the fact that some spermatozoa trapped in the outer perivitelline layer undergo proteolytic activity between fertilization and oviposition and create additional holes in the inner perivitelline layer both at and away from the germinal disc. Across all species and within most individual species, the number of trapped spermatozoa was positively correlated with the number of holes in the inner perivitelline layer. Decreases in the total number of spermatozoa on successive eggs of a clutch provided an index of the rate at which spermatozoa were used from the sperm storage tubules.

Animals↗
PubMed1993

Selection and utilization of spermatozoa in the reproductive tract of the female zebra finch Taeniopygia guttata.

The numbers and proportion of spermatozoa reaching different parts of the female reproductive tract after a single natural insemination were investigated in zebra finches Taeniopygia guttata. The number of spermatozoa transferred during a single, natural copulation was estimated by comparing the number of spermatozoa in the seminal glomera of males that had performed a single copulation with control males. The mean number of spermatozoa per ejaculate was 5.8 x 10(6) +/- 1.80 x 10(6) SEM. The mean number of spermatozoa stored in the sperm storage tubules in the uterovaginal junction following a single, natural insemination was 6027 +/- 1874, 0.104% of those inseminated. The mean number of spermatozoa reaching the infundibulum and trapped on the perivitelline layer of all eggs of the clutch after a single copulation was 45.6 +/- 9.18 and a further 36 penetrated the perivitelline layer of the ovum, i.e. 82 in total (1.4% of the spermatozoa in the sperm storage tubules and 0.001% of spermatozoa in the ejaculate). Female zebra finches that completed a natural breeding cycle with a mean of 12 copulations had 404 +/- 111 spermatozoa trapped on the perivitelline layer of all eggs of the clutch, and an estimated further 173 spermatozoa penetrated the perivitelline layer. A smaller proportion of spermatozoa was trapped on the perivitelline layer of zebra finch eggs, than in chicken or turkey eggs.

Animals↗
PubMed1993

Healing of foot ulcers in immunosuppressed renal transplant patients.

Sixteen renal transplant patients were retrospectively studied to determine the time foot ulcerations healed. All patients were taking imuran and medrol. More recently, patients were also on cyclosporine. All were insulin-dependent diabetics. A control group was established from a pool of randomly selected, age-matched, insulin-dependent diabetics who were also observed for foot ulcerations. All treatment was given by one physician. Pulse volume recordings were obtained in all but eight patients, who were clinically believed to have normal vascular supply to the affected extremity. No statistically significant difference was found between these groups in this regard. Cultures were obtained in all patients when indicated; appropriate antibiotics were started. No major differences were noted with respect to infecting organism. The immunosuppressed group had no excellent results, and three good, 14 fair, and 23 poor results. The control group had ten excellent, 14 good, 11 fair, and 17 poor results. A higher failure rate may occur with limb-salvage surgery in the immunosuppressed patient. This observation confirms a long-held clinical suspicion.

Amputation, Surgical↗
PubMed1976

Chronic bronchitis--measurements and observations over 10 years.

A total of 111 patients with chronic bronchitis were selected for study in 1963. By 1974 only 54 patients were available for clinical examination, chest radiography, and pulmonary function measurements. There was a significantly higher mortality compared with men of the same age and in the same locality, and this was due to cardiorespiratory failure and bronchial carcinoma. Reduction of cigarette smoking, declining atmospheric pollution, and antibiotic treatment have reduced the 24-hour sputum volume of these patients. The initial one-second forced expiratory volume (FEV1) and vital capacity were significantly lower in those patients who later died from cardio-respiratory failure. The duration of antibiotic treatment and the smoking record have not significantly affected the decline of the FEV1 with advancing age. The transfer factor (diffusing capacity) for carbon monoxide (TF) has declined more in those who continued to smoke. Of the 54 patients 14 had radiological evidence of emphysema initially. This has shown little change over 10 years.

Adult↗
PubMed1971

Enhanced immunogenicity of chemically-coated syngeneic tumor cells.

The immunogenicity of the EL-4 strain of mouse lymphoid leukemia cells in syngeneic C57BL/6 recipients was enhanced by in vitro coating of the cells with either Concanavalin A or dinitrophenylaminocaproate. The tumor-specific immune response was quantitated using a recently developed assay that involves in vitro cell-mediated cytotoxicity.

Aminocaproates↗