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R F Holcombe

Publications and source records attributed to R F Holcombe.

50 records · Page 3Linked to original sources
PubMed1993

Mini-dose interferon alpha-2a in the treatment of myelodysplasia.

Interferon-alpha has been used as a differentiating agent in the treatment of patients with myelodysplastic syndrome with conflicting results and often significant toxicity. In order to maximize the differentiating effects of this agent and minimize the myelosuppressive effects, a prospective pilot study was initiated utilizing interferon alpha-2a (Roferon A, Roche Laboratories) in the treatment of complicated or poor prognosis myelodysplasia. The study regimen utilized 'mini-dose' interferon alpha-2a at 1 x 10(6) units subcutaneously three-times per week for 16 weeks followed by an 8 week observation period. Nine patients were enrolled between May 1990 and June 1991, of which seven are evaluable. Forty-three percent (3/7) had a partial or clinical response as defined by normalization of one or more of the hemoglobin concentration, white blood cell count, or platelet count, or a decrease in transfusion requirement by > or = 50%. Only one patient was removed from study for interferon-associated toxicity. Mini-dose interferon alpha-2a appears to be an effective regimen for some patients with myelodysplasia which can be administered with minimal toxicity. Further investigation with interferon-alpha for the treatment of myelodysplastic syndrome, at the dosage utilized in this study, is warranted.

Anemia, Refractory↗
PubMed1992

Chediak-Higashi lymphoblastoid cell lines: granule characteristics and expression of lysosome-associated membrane proteins.

Chediak-Higashi syndrome (CHS) is characterized morphologically by the presence of giant lysosomal granules resulting from the dysregulated fusion of primary lysosomes. Lysosome-associated membrane proteins comprise a family of highly glycosylated proteins which are postulated to facilitate many aspects of normal lysosomal function. In this study, Epstein-Barr virus-transformed lymphoblastoid cell lines derived from a patient with CHS were analyzed for the presence of giant granules and the expression of the lysosome-associated membrane proteins lamp1 and lamp2. Giant myeloperoxidase positive granules typical of CHS, which had a complex structure when examined by electron microscopy, could be demonstrated in the lymphoblastoid cell lines. In situ immunofluorescence with antibodies directed against lamp1 and lamp2 demonstrated abundant expression of each of these proteins in the giant CHS granules. Lack of expression of lysosomal cathepsin G in these granules was also noted. These observations suggest that the lymphoblastoid cell lines provide a convenient model for the study of Chediak-Higashi granules and the lysosome-associated membrane proteins and provide additional evidence that CHS is a "lysosomal" disease. Further study will be necessary to delineate whether the function of these membrane proteins is altered in Chediak-Higashi syndrome.

Antigens, CD↗
PubMed1992

Interleukin-2-induced cytotoxicity of Chediak-Higashi lymphocytes.

Peripheral blood mononuclear cells (PBMCs) from patients with Chediak-Higashi syndrome (CHS) exhibit minimal natural-killer-like cytotoxicity by standard 51Cr-release assays in vitro. However, a CHS-derived gamma delta-T-cell clone maintained in long-term culture with low-dose interleukin-2 (IL-2) does exhibit cytotoxic activity. PBMCs from 2 patients with CHS were stimulated with low-dose IL-2 in short-term culture and compared with a control for induction of cytotoxicity against a panel of target cell lines. The CHS-derived PBMCs exhibited IL-2-induced cytotoxicity, though the magnitude of induction was uniformly less than in controls. This was accompanied by no significant change in the proportion of PBMCs bearing the gamma delta-T-cell receptor antigens. The inducibility of cytotoxicity with low-dose IL-2 in vitro suggests a possible in vivo therapy for patients with CHS.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

Linkage of loci associated with two pigment mutations on mouse chromosome 13.

Progeny from one intra- and two inter-specific backcrosses between divergent strains of mice were typed to map multiple markers in relation to two pigment mutations on mouse chromosome 13, beige (bg) and pearl (pe). Both recessive mutants on a C57BL/6J background were crossed separately with laboratory strain PAC (M. domesticus) and the partially inbred M. musculus stock PWK. The intra- and inter-specific F1 hybrids were backcrossed to the C57BL/6J parental strain and DNA was prepared from progeny. Restriction fragment length polymorphisms were used to follow the segregation of alleles in the backcross offspring at loci identified with molecular probes. The linkage analysis defines the association between the bg and pe loci and the loci for the T-cell receptor gamma-chain gene (Tcrg), the spermatocyte specific histone gene (Hist1), the prolactin gene (Prl), the Friend murine leukaemia virus integration site 1 (Fim-1), the murine Hanukuh Factor gene (Muhf/Ctla-3) and the dihydrofolate reductase gene (Dhfr). This data confirms results of prior chromosomal mapping studies utilizing bg as an anchor locus, and provides previously unreported information defining the localization of the prolactin gene on mouse chromosome 13. The relationship of multiple loci in relation to pe is similarly defined. These results may help facilitate localization of the genes responsible for two human syndromes homologous with bg and pe, Chediak-Higashi syndrome and Hermansky-Pudlak syndrome.

Animals↗
PubMed1991

A human gene homologous to the formin gene residing at the murine limb deformity locus: chromosomal location and RFLPs.

The murine limb deformity (ld) locus resides on mouse chromosome 2 and gives rise to a recessively inherited, characteristic limb deformity/renal aplasia phenotype. In this locus in the mouse, a gene, termed the "formin" gene, has been identified which encodes an array of differentially processed transcripts in both adult and embryonic tissues. A set of these transcripts are disrupted in independent mutant mouse ld alleles. We wish to report the isolation of a human genomic clone which is homologous to the mouse formin gene by virtue of sequence comparison and expression of conserved exons. Among human fetal tissues analyzed, the kidney appears to be a major site of expression. This human gene, LD, maps to chromosome 15q11----qter in mouse human somatic cell hybrids and, specifically, to 15q13----q14 by chromosomal in situ hybridization. This localization establishes both LD and beta 2-microglobulin as syntenic genes on mouse chromosome 2 and human chromosome 15 and implies the interspecies conservation of the region between them. In addition, we identify in the human locus two frequently occurring DNA polymorphisms which can be used to test the linkage of LD to known human dysmorphoses.

Alleles↗
PubMed1991

Chronic myelomonocytic leukemia transformation in polycythemia vera.

Myelodysplasia is an increasingly recognized complication of polycythemia vera (PCV) which often precedes leukemic transformation. This paper describes two patients with aggressive chronic myelomonocytic leukemia, previously undescribed as a complication of PCV. Both patients presented with rapidly increasing splenomegaly which was resistant to treatment with hydroxyurea and external beam irradiation. Splenectomy precipitated fatal hepatic failure in one patient. The other died shortly after transformation to acute myelomonocytic leukemia (FAB M4 classification). Pathology of the bone marrow, spleen, and liver was remarkable for extensive infiltration by dysplastic myeloid elements. Survival was short, only 4-6 months from diagnosis. The unique characteristics in these patients were: (i) prior history of PCV; (ii) rapidly increasing splenomegaly resistant to standard therapy; (iii) absence of overt marrow fibrosis; (iv) hypercellularity (greater than or equal to 90% cellular) of the bone marrow with dysplasia in the myeloid, erythroid, and megakaryocytic cell lines; (v) peripheral monocytosis greater than 1 x 10(9); and (vi) extensive infiltration of the spleen and liver by dysplastic myeloid cells. In addition, the patient who subsequently developed acute leukemia had been treated with hydroxyurea under the PVSG-08 protocol, providing further evidence of the potential leukemogenic effects of this agent.

Aged↗
PubMed1990

Drug-induced granulocytopenia with natural killer lymphocytosis after renal transplantation.

Following renal transplantation, a patient developed life-threatening granulocytopenia secondary to a specific combination of drugs which are commonly utilized in this setting. Coincident with the depression of granulocytes, an expansion of natural killer cells was seen, which may have been a consequence of immunosuppressive therapy required for allograft retention. Infection with cytomegalovirus may have contributed to both phenomena.

Adult↗
PubMed1990

Gamma-delta T cells in Chediak-Higashi syndrome.

Lymphocytes from children with Chediak-Higashi syndrome (CHS) have impaired natural killer (NK) activity and lack antibody-dependent cell-mediated cytotoxicity. Study of T cells bearing an alternate T cell receptor comprised of gamma- and delta-chains, which typically demonstrate NK activity in vitro, was undertaken in CHS patients. We demonstrate that the cellular machinery for lysis of target cells in vitro is present in CHS-derived gamma delta T cell clones. We also show that the proportion of gamma delta T cells among peripheral blood mononuclear cells is significantly increased in CHS, the first example of a specific immunodeficiency disorder with a relative expansion of these T cells.

Cell Line↗
PubMed1989

Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1.

To identify the chromosomal location of a gene responsible for familial hypertrophic cardiomyopathy, we used clinical and molecular genetic techniques to evaluate the members of a large kindred. Twenty surviving and 24 deceased family members had hypertrophic cardiomyopathy; 58 surviving members were unaffected. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the entire genome, to identify a locus that was inherited with hypertrophic cardiomyopathy in family members. The significance of the linkage detected between the disease locus and polymorphic loci was assessed by calculating a lod score (the logarithm of the probability of observing coinheritance of two loci, assuming that they are genetically linked, divided by the probability of detecting coinheritance if they are unlinked). A DNA locus (D14S26), previously mapped to chromosome 14 and of unknown function, was found to be coinherited with the disease in this family. No instances of recombination were observed between the locus for familial hypertrophic cardiomyopathy and D14S26, yielding a lod score of +9.37 (theta = 0). These data indicate that in this kindred, the odds are greater than 2,000,000,000:1 that the gene responsible for familial hypertrophic cardiomyopathy is located on chromosome 14 (band q1).

Adolescent↗
PubMed1989

The gene for the human mast cell high-affinity IgE receptor alpha chain: chromosomal localization to Iq21-q23 and RFLP analysis.

We have used a cDNA probe for the human IgE receptor alpha chain to determine the chromosomal location for the human gene. A combination of Southern blot analysis of panels of somatic-cell hybrid DNAs and chromosomal in situ hybridization has localized the gene to the long arm of chromosome 1 at q21-q23. With this cDNA probe, we have also identified an RsaI RFLP which is inherited in a Mendelian fashion. This polymorphic marker on chromosome 1 should be valuable for studies directed at the identification both of diseases involving the IgE receptor alpha chain and of genetic factors affecting the allergic response.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1987

Relationship of the genes for Chediak-Higashi syndrome (beige) and the T-cell receptor gamma chain in mouse and man.

The genetic linkage of Chediak-Higashi syndrome and its murine analog, beige (bg), to the T-cell receptor (TCR-gamma) gamma chain gene is further defined. Previous studies using recombinant inbred strains of mice demonstrated that the murine bg gene is genetically linked to a murine TCR-gamma gene. We report that in the mouse the frequency of recombination between these two markers is 0.025. Further, we tested the hypothesis that these two genes are linked in the human genome by analyzing restriction fragment length polymorphisms (RFLPs) in five families with children afflicted with Chediak-Higashi syndrome. In three families, RFLPs in TCR-gamma genes were inherited discordantly from Chediak-Higashi syndrome, demonstrating nonlinkage. We postulate that there is an evolutionary chromosomal breakpoint between the bg gene and the TCR-gamma gene.

Animals↗
PubMed1982

Effect of angiotensin II on vascular resistance in whole-body perfused dogfish.

1. The effect of angiotensin II (AII), norepinephrine (NE), epinephrine (E) and isoproterenol (ISO) was observed on the branchial and systemic circulations in a whole-body-pump perfused dogfish preparation. 2. NE and E increased systemic blood flow resistance, but decreased branchial resistance. 3. ISO decreased both systematic and branchial blood flow resistance. 4. AII had no significant effect on either branchial or systemic resistance.

Angiotensin II↗