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Biomedical subjects

R Hoffman

Publications and source records attributed to R Hoffman.

At least 163 records · Page 9Linked to original sources
PubMed1995

Slight renal effect of mercury from amalgam fillings.

The current study was to answer the question: Is enough mercury absorbed from dental amalgam fillings to produce renal damage? One hundred healthy adults (18-44 years old) filled out health questionnaires and voided urine samples. Urine mercury concentration and N-acetyl-beta-glucosaminidase (NAG) were measured. Subjects were grouped into those having amalgam fillings (N = 66) and those without (N = 34). Median (95% Confidence Interval) urine mercury was 1 (1-2) and 0 (0-0.6) ng/ml (P < 0.01) and median urine NAG was 23 (18-27) and 16 (11-18) units (P < 0.05) in the two groups respectively. People with mercury amalgam fillings excreted slightly more mercury than people without them, and have a very small increase in urinary NAG excretion that is probably of no clinical significance. This dose of mercury absorbed from amalgam appears to be too little to be a public health hazard for renal injury.

Acetylglucosaminidase↗
PubMed1995

Characterisation of a laminarin sulphate which inhibits basic fibroblast growth factor binding and endothelial cell proliferation.

We have evaluated a series of laminarin sulphates with different degrees of sulphation (0.3-2.3) as antagonists of basic fibroblast growth factor (bFGF) and as inhibitors of the bFGF-dependent endothelial cell line FBHE. Inhibition of binding of bFGF by the laminarin sulphates increased with increasing degree of sulphation. Binding of bFGF to low affinity sites on BHK cells was inhibited more strongly than binding to high affinity sites. IC50 values for inhibition of binding to low and high affinity sites by the most highly sulphated laminarin sulphate (LAM S5; degree of sulphation 2.31) were 12 +/- 8 micrograms/ml and 69 +/- 66 micrograms/ml, respectively. LAM S5 dissociated bFGF from low affinity sites on BHK cells but not from high affinity sites. LAM S5 increased the electrophoretic mobility of bFGF indicating that LAM S5 binds directly to bFGF. LAM S5 reduced uptake of bFGF by FBHE cells by 67%. Increasing the degree of sulphation of laminarin sulphates increased the inhibition of bFGF-stimulated DNA synthesis of the endothelial cell line FBHE (IC50 for LAM S5 approx. 1 microgram/ml). There was no inhibition of DNA synthesis of FBHE cells by LAM S5 in the presence of 1 microgram/ml bFGF indicating that bFGF antagonism is involved in the anti-proliferative activity of this compound. LAM S5 may be of value against diseases associated with bFGF-dependent cell proliferation.

Animals↗
PubMed1995

Aplastic anemia induced by an adulterated herbal medication.

Herbal medication use is common in many cultural groups. Because these products are unregulated, the potential for significant toxicity exists. We report a case of aplastic anemia associated with the use of an herbal medication by a 12-year-old boy. On analysis, the herbal medication was found to contain phenylbutazone, which has been strongly associated with the production of similar hematologic abnormalities. The medication was not listed as an ingredient and no warning was present on the box.

Anemia, Aplastic↗
PubMed1995

pIXY321 protects against Ara-C or taxol-induced apoptosis and loss of clonogenic survival of normal human bone marrow progenitor cells.

By suppressing apoptosis, hemopoietic growth factors (HGFs) promote the survival of CD34+, HLA-DR+ marrow cells that are enriched for hemopoietic progenitor cells (HPC). In the present studies, we have examined the effects of pIXY321, a genetically engineered fusion protein of GM-CSF and IL-3 (GM-CSF/IL-3), on high-dose Ara-C (HIDAC) and taxol-induced apoptosis and survival of a multilineage HPC, the CFU-GEMM. Exposure to 1.0 mumol/l taxol for 24 h or HIDAC > or = 10 mumol/l for 4 h induced internucleosomal DNA fragmentation and the morphologic features of apoptosis in CD34+, HLA-DR+ cells. These treatments were associated with > or = 50% inhibition of the assayable CFU-GEMM colony numbers. Incubation in serum-free medium (SFM) alone for 24 h also induced apoptosis of CD34+, HLA-DR+ cells, which was associated with reduced intracellular levels of the bcl-2 gene product p26BCL-2. Co-treatment with pIXY321 (10 ng/ml) inhibited apoptosis of CD34+, HLA-DR+ cells incubated in SFM, without significantly increasing the intracellular p26BCL-2 levels. Furthermore, co-treatment with pIXY321 significantly reduced taxol- and Ara-C-induced apoptosis and promoted the survival of CFU-GEMM (P < 0.05). Taxol and Ara-C mediated apoptosis of CD34+, HLA-DR+ cells, and its inhibition by pIXY321, was not accompanied by any significant alteration in the intracellular p26BCL-2 levels. By demonstrating that co-treatment with pIXY321 confers significant protection against apoptosis of CD34+, HLA-DR+ cells as well as promotes survival of normal HPC exposed to clinically relevant schedules and concentrations of taxol of Ara-C, these results support the design of chemotherapy regimens incorporating pIXY321 plus taxol and/or high-dose Ara-C for solid tumors and/or acute leukemias. It is hoped that the use of such a cytokine might maintain normal HPC numbers following chemotherapy, therefore avoiding prolonged suppression.

Antigens, CD34↗
PubMed1995

Retention of long-term repopulating ability of xenogeneic transplanted purified adult human bone marrow hematopoietic stem cells in sheep.

We have previously reported on the successful engraftment and long-term multilineage expression (erythroid, myeloid, lymphoid) of human adult marrow CD34+ HLA-DR- cells in sheep after transplantation in utero. The persistence in these animals of CD34+ HLA-DR- cells, the phenotype of the original graft, and the presence of assayable high proliferative potential colony-forming cells (HPP-CFCs), a primitive progenitor cell that has self-renewal capacity and multilineage differentiative capacity, suggested that these chimeric animals continued to contain human pluripotent hematopoietic stem cells (HSCs). To test this hypothesis, CD45+ cells from the bone marrow of such an animal were isolated by panning at 19 and 24 months after birth, were pooled, and were transplanted into 4 preimmune sheep fetuses (0.6 x 10(6) viable cells per fetus). Three of the sheep were born alive. Bone marrow from one of these secondary recipients (lamb 58) exhibited significant donor (human) cell presence at 3, 9, 12, and 15 months (last evaluation period) after transplant. The engraftment was sustained along with multilineage expression involving lymphoid, erythroid, and myeloid cells of human origin. These results indicated that human CD34+ HLA-DR- cells are capable of long-term marrow repopulation and that this cell population is enriched for human long-term repopulating HSCs.

Antigens, CD↗
PubMed1995

Marrow-derived heparan sulfate proteoglycan mediates the adhesion of hematopoietic progenitor cells to cytokines.

Heparan sulfate proteoglycan (HS-PG), an important component of the human bone marrow extracellular matrix (ECM), is believed to influence hematopoietic progenitor cell development by binding and localizing growth factors to specific niches within the hematopoietic microenvironment. We utilized a model ECM system, which uses immobilized ECM proteins and/or cytokines and bone marrow populations enriched for human hematopoietic stem cell (HSC), to assess the effects of HS-PG on the development of primitive hematopoietic progenitor cells. HS-PG alone failed to bind hematopoietic progenitor cells cloned from bone marrow CD34+CD15-HLA-DR- cells, which are enriched for HSC. HS-PG alone failed to function as a mitogen. In sharp contrast, the interaction of HS-PG with either growth factors (interleukin-3 [IL-3] or stem cell factor/Kit ligand [KL] or an ECM protein (thrombospondin [TSP]) markedly influenced progenitor cell adherence. The binding of either IL-3 or KL to HS-PG resulted in a two-fold increase in attachment of the colony-forming unit-granulocyte/macrophage (CFU-GM), a 1.5-fold increase in attachment of the burst-forming unit-erythroid (BFU-E) and the high-proliferative-potential colony-forming cell (HPP-CFC), and a two- to three-fold increase in attachment of the colony-forming unit-granulocyte/erythroid/macrophage/megakaryocyte (CFU-GEMM) compared to localized growth factor alone. Attachment of the BFU-megakaryocyte (BFU-MK), however, was slightly reduced by the interaction of either IL-3 or KL with HS-PG. The interaction of HS-PG with TSP resulted in a two-fold increase in CFU-GM and CFU-GEMM attachment, while the attachment of BFU-E, HPP-CFC, and BFU-MK was unaltered. We conclude that HS-PG cooperatively interacts with both growth factors and ECM proteins to augment progenitor cell localization within the hematopoietic microenvironment.

Bone Marrow↗
PubMed1994

Designing studies of diagnostic tests for low back pain or radiculopathy.

New diagnostic tests for the evaluation of patients with low back pain are constantly emerging, but are often not completely evaluated before they become used. Many published studies have a number of biases that tend to exaggerate the estimated accuracy of a diagnostic test. Several key study design features should be considered in such studies: independent comparison of the diagnostic test results with an appropriate "gold standard"; blinded assessment of the new test and the gold standard or competing tests; the reproducibility of interpretation of the test being examined; and the sensitivity and specificity of the test for the final gold standard diagnosis. In addition, evaluations of test accuracy should include patients with a wide spectrum of illness from mild to severe, and the study setting and patient characteristics should be described in detail. Finally, the contribution of a diagnostic test to the overall validity of a full group or sequence of tests should be considered, and, ideally, the effect of the test on actual patient outcomes should be determined.

Evaluation Studies as Topic↗
PubMed1994

Generation of human natural killer cells from immature progenitors does not require marrow stromal cells.

Human natural killer (NK) cells comprise 10% to 15% of peripheral blood mononuclear cells and have an important role in immune responses against tumors, viral infections, and graft rejection. NK cells originate in bone marrow (BM), but their progenitors and lineage development have not been completely characterized. We studied the generation of NK cells from purified CD34+HLADR- and CD34+HLADR+ BM progenitors and the influence of various cytokines on their production. We show that CD3-CD56+ cytotoxic NK cells can develop from both progenitors populations when interleukin-2 (IL-2) is present in an in vitro suspension culture system containing IL-1 alpha and stem cell factor. Up to 83.8% and 98.6% CD3-CD56+ cells were detected in CD34+HLADR- and CD34+DR+ cultures, respectively, after 5 weeks of culture; significant numbers of NK cells were first detected after 2 weeks. Cytotoxic activity paralleled NK cell numbers; up to 70% specific lysis at an effector:target ratio of 10:1 was observed at 5 weeks. IL-7 also triggered development of CD3-CD56+ cells from these immature progenitors (up to 24% and 55% appeared in CD34+HLADR- and CD34+HLADR+ cultures, respectively). Our data suggest that BM stromas are not necessary for NK cell development and that IL-2 remains essential for this lineage development and differentiation.

Adult↗
PubMed1994

PE-1, a novel ETS oncogene family member, localizes to chromosome 1q21-q23.

The v-ets oncogene family shares a conserved peptide motif called the ETS domain that mediates sequence-specific DNA binding. This motif is unique among transcription factor families. Using partially degenerate oligonucleotides from conserved regions of the ETS domain and the polymerase chain reaction, we isolated a new member of the v-ets family designated PE-1 from HL60 cells. PE-1 was expressed as an approximately 7.5-kb transcript in most cell lines tested. In the hairy cell leukemia line Eskol, there was an additional 1.8-kb transcript observed. PE-1 was the most common ETS domain gene found in CD34+HLA-DR- hematopoietic progenitors. PE-1 was localized to human chromosome 1q21-q23 using both in situ chromosomal hybridization and human-hamster hybrids.

Amino Acid Sequence↗
PubMed1994

Effects of interleukin-3 and c-kit ligand on the survival of various classes of human hematopoietic progenitor cells.

We examined the effects of interleukin-3 (IL-3) and c-kit ligand (KL) on the survival of differentiated hematopoietic progenitor cells (HPC), the burst-forming unit-erythroid (BFU-E); colony-forming unit-granulocyte, erythroid, monocyte, megakaryocyte (CFU-GEMM); and CFU-granulocyte-monocyte (CFU-GM) and more primitive hematopoietic cells that give rise to these progenitor cells (pre-colony-forming cells [pre-CFC]). CD34+ HLA-DR+ cells, which are highly enriched for committed HPC, and CD34+ HLA-DR- c-kit+ cells, which contain the most primitive assayable hematopoietic cells, including long-term bone marrow culture-initiating cells, high proliferative potential-CFC, the CFU-blast, and the BFU-megakaryocyte, were suspended in serum-free medium in the presence or absence of IL-3 or KL. CD34+ HLA-DR+ cells incubated under serum-free conditions or in the presence of KL for 96 hours lost greater than 90% of assayable unilineage or multilineage HPC, whereas those cells incubated in the presence of IL-3 retained 40% of the number of HPC present at time 0. The effect of IL-3 on HPC survival was most pronounced on the BFU-E and CFU-GEMM present within CD34+ HLA-DR+ cells. Addition of IL-3, but not of KL, to CD34+ HLA-DR+ cells delayed the appearance of morphologic changes and DNA fragmentation patterns associated with cell death occurring by apoptosis. CD34+ HLA-DR-c-kit+ cells were incubated under similar serum-free conditions in the presence or absence of IL-3 or KL, and the frequency of pre-CFC was determined by limiting dilution analysis. The frequency of pre-CFC in cells incubated for 48 hours in the absence of serum was similar to that of cells incubated in the presence of IL-3 and approximately doubled when CD34+ HLA-DR- c-kit+ cells were incubated in the presence of KL. Addition of KL to serum-free suspension cultures of CD34+ HLA-DR- c-kit+ cells delayed the appearance of DNA fragmentation patterns associated with apoptosis to a greater extent than did the addition of IL-3. These studies suggests that IL-3, but not KL, promotes HPC survival, whereas KL plays a greater role than IL-3 in sustaining more primitive HPC, such as pre-CFC. The effects of both cytokines in mediating HPC and primitive hematopoietic cell survival appear to be related, in part, to their ability to suppress apoptosis.

Antigens, CD↗
PubMed1994

A suppressor of a mating-type limited zygotic lethal allele also suppresses uniparental chloroplast gene transmission in Chlamydomonas monoica.

Uniparental inheritance of Chlamydomonas chloroplast genes is thought to involve modification of maternal (mt+) chloroplast genomes to protect against a nuclease that is activated after gamete fusion. The mating-type limited mtl-1 mutant strain of Chlamydomonas monoica is unable to protect mt(+)-derived chloroplast DNA. Zygotes homozygous for mtl-1 lose all chloroplast DNA and fail to germinate. We have selected for suppression of this zygote-specific lethality, and have obtained 20 mutant strains that produce viable homozygotes despite the continued presence of the mtl-1 allele. Genetic analysis indicates that the suppressor mutations are all recessive alleles at a single locus (sup-1) which is unlinked to mtl-1. Crosses between sup-1 strains carrying distinctive chloroplast antibiotic resistance markers also show predominantly biparental chloroplast gene transmission. Chloroplast nucleoids of both parental origins (stained with the DNA-specific fluorochrome, DAPI) are retained in the zygotes homozygous for sup-1. The data are compatible with the idea that the sup-1 (suppressor of uniparental inheritance) locus may encode a chloroplast DNA nuclease that is expressed from both parental genomes.

Alleles↗
PubMed1994

Rapid appearance of severe mitral regurgitation under high-dosage corticosteroid therapy in a patient with systemic lupus erythematosus.

Survival of patients with systemic lupus erythematosus has increased with corticosteroid therapy. However, adverse effects of corticosteroid therapy on cardiovascular structures, such as scarring and shrinking of affected valves, are not well known. We report the case of a 19-year-old patient who developed severe mitral insufficiency within a few weeks after high-dosage corticosteroid therapy had been instituted for an acute relapse of systemic lupus erythematosus. The rapid development of severe mitral regurgitation was documented by sequential colour Doppler echocardiography.

Adult↗
PubMed1994

Retroviral mediated gene transfer in chronic myelogenous leukaemia.

Gene therapy for chronic myelogenous leukaemia (CML) may provide a therapeutic option for patients who are ineligible for bone marrow transplantation. To determine the feasibility of such an approach we evaluated the transduction efficiency of CML progenitor colonies from seven patients in chronic phase. Vector transduction was optimized using the CML-derived K562 cell line and applied to CML mononuclear cells. After vector exposure, optimal gene transfer was noted when CML mononuclear cell cultures contained stem cell factor, IL-3, GM-CSF and erythropoietin. The addition of IL-6 to this combination decreased transduction efficiency. Using these conditions, 20.4% +/- 2.4 (SE) of erythroid colonies (CFU-GEMM and BFU-E) and 20.2% +/- 4.7 of CFU-GM colonies were G418 resistant. This compares with a transduction efficiency of 5.9% +/- 1.1 and 6.4% +/- 1.5, respectively, for erythroid and CFU-GM colonies using marrow obtained from normal donors. Only a modest increase in gene transfer was noted when CML cells were stimulated with cytokines for the 24 h preceding vector exposure. Vector DNA in colonies expressing the BCR/ABL transcript was documented by performing PCR analysis on individual colonies. The relatively high gene transfer rate in CML suggests that this disease might be very suitable for gene therapy.

Base Sequence↗