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Biomedical subjects

R Hoffman

Publications and source records attributed to R Hoffman.

At least 73 records · Page 4Linked to original sources
PubMed1999

The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer.

PURPOSE: To assess the outcome and tolerance of HIV-positive patients with anal cancer to standard therapy based on their pretreatment CD4 count. METHODS AND MATERIALS: Between 1991 and 1997, 17 HIV-positive patients with anal cancer and documented pretreatment CD4 counts were treated at the University of California, San Francisco or its affiliated hospitals with either concurrent chemotherapy and radiation or radiation alone. The outcome and complications of treatment were correlated with the patients' pretreatment CD4 count. RESULTS: Disease for all 9 patients with pretreatment CD4 counts > or = 200 was controlled with chemoradiation. Although four required a treatment break of 2 weeks because of toxicity, none required hospitalization. Of the 8 patients with pretreatment CD4 counts < 200, 4 experienced decreased counts, intractable diarrhea, or moist desquamation requiring hospitalization. Additionally, 4 of these 8 ultimately required a colostomy either for a therapy-related complication or for salvage. Nevertheless, 6/7 in this group who received concurrent chemotherapy and radiation had their disease controlled, whereas the patient treated with radiation alone failed and required a colostomy for salvage. CONCLUSION: Patients with CD4 > or = 200 had excellent disease control with acceptable morbidity. Patients with CD4 < 200 had markedly increased morbidity; however, disease was ultimately controlled in 7/8 patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

An outbreak of Escherichia coli O157:H7 infection from unpasteurized commercial apple juice.

BACKGROUND: Escherichia coli O157:H7 infections have traditionally been associated with animal products, but outbreaks associated with produce have been reported with increasing frequency. In fall 1996, a small cluster of E. coli O157:H7 infections was epidemiologically linked to a particular brand (brand A) of unpasteurized apple juice. OBJECTIVE: To define the extent of the outbreak, confirm the source, and determine how the apple juice became contaminated. DESIGN: Descriptive epidemiologic study and traceback investigation. SETTING: Western United States and British Columbia, Canada. PATIENTS: Patients with E. coli O157:H7 infection who were exposed to brand A apple juice. MEASUREMENTS: Clinical outcome and juice exposure histories of case-patients, pulsed-field gel electrophoresis of case and juice isolates, and juice production practices. RESULTS: Seventy persons with E. coli O157:H7 infection and exposure to brand A unpasteurized apple juice were identified. Of these persons, 25 (36%) were hospitalized, 14 (20%) developed the hemolytic uremic syndrome, and 1 (1%) died. Recalled apple juice that was produced on 7 October 1996 grew E. coli O157:H7 with a pulsed-field gel electrophoresis pattern indistinguishable from that of case isolates. Apple juice produced on 7 October 1996 accounted for almost all of the cases, and the source of contamination was suspected to be incoming apples. Three lots of apples could explain contamination of the juice: Two lots originated from an orchard frequented by deer that were subsequently shown to carry E. coli O157:H7, and one lot contained decayed apples that had been waxed. CONCLUSIONS: Standard procedures at a state-of-the-art plant that produced unpasteurized juices were inadequate to eliminate contamination with E. coli O157:H7. This outbreak demonstrated that unpasteurized juices must be considered a potentially hazardous food and led to widespread changes in the fresh juice industry.

Adolescent↗
PubMed1999

Budd-Chiari syndrome associated with factor V leiden mutation: a report of 6 patients.

Budd-Chiari syndrome is characterized by hepatic venous outflow obstruction. Although myeloproliferative disorders are usually responsible for this severe thrombotic disorder, deficiency or dysfunction of the natural anticoagulants can be involved. Resistance to activated protein C caused by factor V Leiden mutation has been recently identified as a major cause of thrombophilia. We report 6 patients with Budd-Chiari syndrome associated with factor V Leiden mutation combined with another acquired thrombophilic state (myeloproliferative disorder and lupus anticoagulant in 3 cases) and without another thrombophilic disorder in the other 3 cases. We conclude that factor V Leiden mutation should be evaluated in any case of hepatic vein occlusion because the prevalence of this mutation in the general population is high.

Adolescent↗
PubMed1999

Integrating Physical and Chemical Characteristics of Lakes into the Glacially Influenced Landscape of the Northern Cascade Mountains, Washington State, USA.

/ A basic knowledge of the physical and chemical characteristics of lakes is needed by management to make informed decisions to protect water resources. In this study we investigated some of the physical and chemical characteristics of 58 lakes in alpine, subalpine, and forest vegetation zones in a natural area (North Cascades National Park Service Complex) between 1989 and 1993. The objectives of the study were to: (1) document the time of ice-out relative to lake elevation; (2) determine how a sharp climate gradient west and east of the hydrologic divide affected the time of ice-out for subalpine lakes; and (3) assess how lake water quality was associated with lake elevation, lake depth, and basin geology. As expected, lake ice-out times occurred earlier with decreasing elevation. East-slope subalpine lakes iced-out earlier than did west-slope subalpine lakes because the east slope of the study area was drier and warmer than the west slope. On average, the lakes were relatively cold, neutral in pH, and low in dissolved substances and concentrations of nitrogen and phosphorus. Although some shallow lakes (depth <10 m) exhibited the highest alkalinities, conductivities, and concentrations of phosphorus and nitrogen, most shallow lakes exhibited low values for these variables that were comparable to values observed in deep lakes. Geology did not play a major role in segregating the lakes based on water quality. Overall, lake temperature, pH, alkalinity, conductivity, and concentrations of total phosphorus and total Kjeldahl N increased with decreasing elevation. These changes in water quality with decreasing elevation in this temperate mountainous region corresponded with warmer air temperatures and increased vegetation biomass, soil depth and maturity, and dissolved substances and nutrients.KEY WORDS: Limnology; Mountain lakes; Water quality; North Cascades National Park Service Complex; National Park Servicehttp://link.springer-ny.com/link/service/journals/00267/bibs/24n2p219.html

Journal Article↗
PubMed1999

Primitive human hematopoietic progenitor cells express receptors for granulocyte-macrophage colony-stimulating factor.

Most cytokines act only synergistically in assays of primitive progenitor cell proliferation, and effects have usually been observed first after prolonged cell culture. Studies reporting that primitive progenitors lack receptors for a number of cytokines, including granulocyte-macrophage colony stimulating factor (GM-CSF), could indicate that several "synergistic" cytokines primarily affect cells that have differentiated in vitro. Here, however, we show that freshly isolated primitive progenitor cells (CD34hi CD38-) express receptors for GM-CSF at levels 20%-30% of granulo-monocytic progenitors. Although GM-CSF had minimal effects on the survival or proliferation of primitive progenitors when added alone, the cytokine enhanced stem cell factor (SCF) induced cell cycle entry in the first generation. The effect was not observed when cells were incubated sequentially with SCF and GM-CSF. The results suggest that the synergistic effects of GM-CSF are mediated directly on primitive progenitor cells and that the cytokine may be useful to enhance cell cycle entry of hematopoietic stem cells.

Antigens, CD↗
PubMed1999

Defective expression of the SHP-1 phosphatase in polycythemia vera.

The SHP-1 phosphatase associates with the receptors for erythropoietin, stem cell factor, and interleukin-3, and negatively regulates the mitogenic signals generated during engagement by their respective ligands. The erythroid progenitors of patients with polycythemia vera are hypersensitive to the mitogenic effects of these growth factors despite the fact that the numbers and binding affinities for their receptors are not increased. To determine whether post-receptor signaling defects may account for growth factor-hypersensitivity in polycythemia vera, we determined the expression of SHP-1 in highly purified erythroid progenitors from polycythemia vera patients. Our data demonstrate that in approximately 60% of the patients, expression of SHP-1 in the colony forming unit-erythroid population is diminished. The decreased expression of the protein may result from a transcriptional defect, as suggested by the diminished SHP-1 mRNA expression in the erythroid progenitors of these patients. Studies to determine the level of maturation of polycythemia vera and normal cells indicated that there was no difference between the two at early colony forming unit-erythroid stage of differentiation although polycythemia vera cells showed retarded differentiation kinetics at late colony forming unit-erythroid stage of differentiation. Furthermore, SHP-1 expression in normal colony forming unit-erythroid demonstrated downregulation of mRNA and protein levels during terminal differentiation, suggesting that its function is required for growth control during the early stages of erythropoiesis. These results indicate an important role for SHP-1 in the regulation of normal human erythroid progenitors and suggest that defective expression of the protein may contribute to the pathogenesis of polycythemia vera.

Cell Differentiation↗
PubMed1999

CrkL and CrkII participate in the generation of the growth inhibitory effects of interferons on primary hematopoietic progenitors.

Interferons are potent regulators of normal and malignant hematopoietic cell proliferation in vitro and in vivo, but the signaling mechanisms by which they exhibit their growth inhibitory effects are unknown. We have recently shown that CrkL is engaged in Type I IFN signaling, as shown by its rapid tyrosine phosphorylation during engagement of the Type I IFN receptor. In the present study, we provide evidence that the related CrkII protein is also rapidly phosphorylated on tyrosine during treatment of U-266 and Daudi cells with IFNalpha or IFNbeta. We also show that both members of the Crk-family, CrkL and CrkII, are phosphorylated in an interferon-dependent manner in primary hematopoietic progenitors. Furthermore, inhibition of CrkL or CrkII protein expression by antisense oligonucleotides, reverses the inhibitory effects of IFNalpha or IFNgamma on the proliferation of normal bone marrow progenitor cells (colony forming units-granulocytic/monocytic [CFU-GM] and burst-forming units-erythroid [BFU-E]). Thus, both CrkL and CrkII are engaged in a signaling pathway (s) that mediates interferon-regulated inhibition of hematopoietic cell proliferation.

Adaptor Proteins, Signal Transducing↗
PubMed1999

CD109 is expressed on a subpopulation of CD34+ cells enriched in hematopoietic stem and progenitor cells.

CD109 is a monomeric cell surface glycoprotein of 170 kD that is expressed on endothelial cells, activated but not resting T-lymphocytes, activated but not resting platelets, leukemic megakaryoblasts, and a subpopulation of bone marrow CD34+ cells. Observing an apparent association between CD109 expression and the megakaryocyte lineage (MK), we sought to determine whether CD109 was expressed on MK progenitors. In fetal bone marrow (FBM), a rich source of MK progenitors, CD109 is expressed on a mean of 11% of CD34- cells. Fluorescence activated cell sorting (FACS) of FBM CD34+ cells into CD109+ and CD109- fractions revealed that the CD34+CD109+ subset contained virtually all assayable MK progenitors, including the colony-forming unit-MK (CFU-MK) and the more primitive burst-forming unit-MK (BFU-MK). The CD34+CD109+ subset also contained all the assayable burst-forming units-erythroid (BFU-E), 90% of the colony-forming units-granulocyte/macrophage (CFU-GM), and all of the more primitive mixed lineage colony-forming units (CFU-mix). In contrast, phenotypic analysis of the CD34+CD109- cells in FBM, adult bone marrow (ABM) and cytokine-mobilized peripheral blood (MPB) demonstrated that this subset comprises lymphoid-committed progenitors, predominantly of the B-cell lineage. CD109 was expressed on the brightest CD34 cells identifiable not only in FBM, but also in ABM and MPB indicating that the most primitive, candidate hematopoietic stem cells (HSC) might also be contained in the CD109+ subset. In long-term marrow cultures of FBM CD34+ cells, all assayable cobblestone area forming cell (CAFC) activity was contained within the CD109+ cell subset. Further phenotypic analysis of the CD34+CD109+ fraction in ABM indicated that this subset included candidate HSCs that stain poorly with CD38, but express Thy-1 (CD90) and AC133 antigens, and efflux the mitochondrial dye Rhodamine 123 (Rho123). When selected CD34+ cells were sorted for CD109 expression and Rho123 staining, virtually all CAFC activity was found in the CD109+ fraction that stained most poorly with Rho123. CD34+ cells were also sorted into Thy-1 CD109+ and Thy-1 CD109+ fractions and virtually all the CAFC activity was found in the Thy-1+CD109+ subset. In contrast, the Thy-1-CD109+ fraction contained most of the short-term colony-forming cell (CFC) activity. CD109, therefore, is an antigen expressed on a subset of CD34+ cells that includes pluripotent HSCs as well as all classes of MK and myelo-erythroid progenitors. In combination with Thy-1, CD109 can be used to identify and separate myelo-erythroid and all classes of MK progenitors from candidate HSCs.

Adult↗
PubMed1999

Symptom assessment in schizophrenic prodromal states.

Individuals who develop schizophrenia often suffer long standing deficits. All too often available treatments remain palliative and do not improve the long-term course of illness. The neurobiological deficits associated with the onset of schizophrenia may be most active and damaging in the early stages of this life long illness, a fact which has shifted the focus of research and clinical work toward the early or prodromal stages of this disorder. Results from limited studies suggest that early intervention may lead to a better prognosis. Early interventions that could delay or prevent the onset of psychotic illnesses have obvious public health implications and rely on being able to identify true prodromal patients. The Structured Interview for Prodromal Symptoms and the Scale of Prodromal Symptoms are assessment instruments developed for operationally defining diagnosis and for quantitatively rating symptom severity for patients prodromal for psychosis.

Antipsychotic Agents↗
PubMed1999

Progress in the development of systems for in vitro expansion of human hematopoietic stem cells.

Hematopoietic stem cells are the cells primarily responsible for short term and long term hematological reconstitution when a graft is infused into a myeloablated host. The number and quality of hematopoietic stem cells within a graft are the major determinants of the time to and durability of hematological reconstitution of a transplant recipient. Ex vivo hematopoietic stem cell expansion is, therefore, a critical component of several potentially important clinical strategies including gene therapy, tumor purging and graft engineering. Recent clinical trials using a variety of ex vivo hematopoietic stem cells expansion systems have, to date, met with limited success. Recognition of the consequences of hematopoietic stem cell self-replication will assist in the development of new approaches to hematopoietic stem cell expansion. The use of suitable in vivo models to assay the marrow repopulating potential of expanded hematopoietic stem cell products is a vital step prior to entry again into clinical trials.

Animals↗
PubMed1999

EGF activates ErbB-2 and stimulates phosphatidylinositol 3-kinase in human airway smooth muscle cells.

The epidermal growth factor (EGF)-receptor (EGFR) family includes four homologous transmembrane receptor protein tyrosine kinases, EGFR, ErbB-2, ErbB-3, and ErbB-4. This receptor family plays a pivotal role in regulating cell proliferation, differentiation, and transformation. Ligand-induced activation of these receptors results in formation of homo- and heterodimers, which undergo transphosphorylation and transactivation. The aim of this study was to characterize the role of EGFR family members in signaling EGF-induced human airway smooth muscle (HASM) cell proliferation. Here, we show that EGF stimulates activation of EGFR and transactivation of ErbB-2 in quiescent HASM cells. Phosphatidylinositol (PI) 3-kinase, a critical signaling enzyme that modulates HASM cell growth, is preferentially associated with ErbB-2, and EGF-stimulated transactivation of ErbB-2 induces PI 3-kinase activation. ErbB-3 and ErbB-4 are present in HASM cells; however, EGF has no effect on their activation. Betacellulin, a ligand for EGFR, ErbB-3, and ErbB-4, induced DNA synthesis of HASM cells and stimulated signaling through the activation of EGFR and ErbB-2 but not of ErbB-3 and ErbB-4. Heregulin, a specific ligand for ErbB-3 and ErbB-4, did not effect DNA synthesis and did not activate its specific receptors. These data suggest that EGF imparts signals that involve activation of ErbB-2 and are associated with ErbB-2 PI 3-kinase activation. Despite the mRNA and protein expression of all members of the EGFR family, ligand-stimulated signaling induced activation of EGFR and ErbB-2 but not of ErbB-3 and ErbB-4.

Cells, Cultured↗
PubMed1999

The use of proteases as prognostic markers for the healing of venous leg ulcers.

Abnormally high levels of some proteases are associated with pathological changes in the wound bed of venous leg ulcers. This study involved two experiments which measured proteases in wound fluid harvested from leg ulcers in order to predict healing. In the first experiment, neutrophil elastase, a protease, was harvested from wound fluid extracted from the bandages of seven patients with leg ulcers. This was undertaken once a week over a period of up to six weeks. The amount of elastase recovered from the bandages showed wide variation between patients and there was no consistent correlation between the activity of elastase and healing of the ulcers, as determined nine months after sampling for the enzyme. The second experiment determined the stability of neutrophil elastase that was added to bandages for one week. The stability was found to vary from approximately 50% to 100%, depending on the type of bandage used. In addition to the possibility of using protease measurements to predict healing, the procedure was found to be simple, non-invasive and relatively inexpensive, and could be performed routinely in the clinic.

Bandages↗
PubMed1999

Current management of unusual genitourinary cancers. Part 1: Penile cancer.

Often overshadowed by more common genitourinary cancers, such as prostate, testicular, and kidney cancers, penile and urethral cancers nonetheless represent difficult treatment challenges for the clinician. The management of these cancers is slowly evolving. In the past, surgery, often extensive, was the treatment of choice. Recently, however, radiation and chemotherapy have begun to play larger roles as initial therapies, with surgery being reserved for salvage. With these modalities in their treatment armamentarium, oncologists may now be able to spare patients some of the physical and psychological sequelae that often follow surgical intervention without compromising local control and survival. Part 1 of this two-part article focuses on cancer of the penis. Part 2, which will appear in next month's issue, discusses cancer of the urethra in both females and males.

Antineoplastic Agents↗
PubMed1999

Current management of unusual genitourinary cancers. Part 2: Urethral cancer.

Often overshadowed by more common genitourinary cancers, such as prostate, testicular, and kidney cancers, penile and urethral cancers nonetheless represent difficult treatment challenges for the clinician. The management of these cancers is slowly evolving. In the past, surgery, often extensive, was the treatment of choice. Recently, however, radiation and chemotherapy have begun to play larger roles as initial therapies, with surgery being reserved for salvage. With these modalities in their treatment armamentarium, oncologists may now be able to spare patients some of the physical and psychological sequelae that often follow surgical intervention without compromising local control and survival. Part 1 of this two-part article, published in last month's issue, dealt with cancer of the penis. This second part focuses on cancer of the urethra in both females and males.

Female↗
PubMed1998

Role of members of the Wnt gene family in human hematopoiesis.

The hematopoietic system is derived from ventral mesoderm. A number of genes that are important in mesoderm development have been identified including members of the transforming growth factor-beta (TGF-beta) superfamily, the fibroblast growth factor (FGF) family, and the Wnt gene family. Because TGF-beta plays a pleiotropic role in hematopoiesis, we wished to determine if other genes that are important in mesoderm development, specifically members of the Wnt gene family, may play a role in hematopoiesis. Three members of the Wnt gene family (Wnt-5A, Wnt-2B, and Wnt-10B) were identified and cloned from human fetal bone stromal cells. These genes are expressed to varying levels in hematopoietic cell lines derived from T cells, B cells, myeloid cells, and erythroid cells; however, only Wnt-5A was expressed in CD34(+)Lin- primitive progenitor cells. The in vitro biological activity of these Wnt genes on CD34(+)Lin- hematopoietic progenitors was determined in a feeder cell coculture system and assayed by quantitating progenitor cell numbers, CD34(+) cell numbers, and numbers of differentiated cell types. The number of hematopoietic progenitor cells was markedly affected by exposure to stromal cell layers expressing Wnt genes with 10- to 20-fold higher numbers of mixed colony-forming units (CFU-MIX), 1.5- to 2. 6-fold higher numbers of CFU-granulocyte macrophage (CFU-GM), and greater than 10-fold higher numbers of burst-forming units-erythroid (BFU-E) in the Wnt-expressing cocultures compared with the controls. Colony formation by cells expanded on the Wnt-expressing cocultures was similar for each of the three genes, indicating similar action on primitive progenitor cells; however, Wnt-10B showed differential activity on erythroid progenitors (BFU-E) compared with Wnt-5A and Wnt-2B. Cocultures containing Wnt-10B alone or in combination with all three Wnt genes had threefold to fourfold lower BFU-E colony numbers than the Wnt-5A- or Wnt-2B-expressing cocultures. The frequency of CD34(+) cells was higher in Wnt-expressing cocultures and cellular morphology indicated that coculture in the presence of Wnt genes resulted in higher numbers of less differentiated hematopoietic cells and fewer mature cells than controls. These data indicate that the gene products of the Wnt family function as hematopoietic growth factors, and that they may exhibit higher specificity for earlier progenitor cells.

Adult↗