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Biomedical subjects

Kenneth Weinberg

Publications and source records attributed to Kenneth Weinberg.

11 recordsLinked to original sources
PubMed2006

Renal dialysis as a risk factor for appropriate therapies and mortality in implantable cardioverter-defibrillator recipients.

BACKGROUND: Patients with end-stage renal disease are at increased risk for sudden cardiac death, although the utility of implantable cardioverter-defibrillators (ICDs) in these patients is unknown. OBJECTIVES: The purpose of this study was to evaluate whether end-stage renal disease is an independent risk factor for appropriate ICD therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) and to compare the long-term survival of ICD recipients with and without end-stage renal disease. METHODS: A retrospective cohort study was performed on ICD recipients at a single center. The primary endpoint was first appropriate ICD therapy for VT/VF. The secondary endpoint was survival. RESULTS: The study included 585 patients, 19 (3.2%) of whom had end-stage renal disease prior to device implantation. Average follow-up time was 2.2 +/- 2.4 years, during which time 156 patients (26.7%) received appropriate ICD therapy. End-stage renal disease was strongly associated with appropriate ICD therapy (hazard ratio 2.30, 95% confidence interval 1.17-4.54) and remained a significant predictor following adjustment for implant indication, ejection fraction, diabetes, hypertension, and beta-blocker use. Survival was significantly shorter in the end-stage renal disease patients, with a median survival time of 3.2 +/- 0.6 (SEM) years in the dialysis cohort and 7.4 +/- 0.5 (SEM) years in those without end-stage renal disease (log rank P = .009). The majority of deaths in the end-stage renal disease cohort were due to non-device-related infection. CONCLUSION: In this cohort, end-stage renal disease was the single greatest predictor of ICD therapies for VT/VF. The survival rate was significantly shorter than that of ICD recipients without end-stage renal disease, suggesting that comorbidities in end-stage renal disease patients meeting current implant indications may reduce the survival benefit of ICD placement in this population.

Adult↗
PubMed2005

The role of the hyaluronan receptor CD44 in mesenchymal stem cell migration in the extracellular matrix.

In a previous investigation, we demonstrated that mesenchymal stem cells (MSCs) actively migrated to cardiac allografts and contributed to graft fibrosis and, to a lesser extent, to myocardial regeneration. The cellular/molecular mechanism responsible for MSC migration, however, is poorly understood. This paper examines the role of CD44-hyaluronan interaction in MSC migration, using a rat MSC line Ap8c3 and mouse CD44-/- or CD44+/+ bone marrow stromal cells (BMSCs). Platelet-derived growth factor (PDGF) stimulation of MSC Ap8c3 cells significantly increased the levels of cell surface CD44 detected by flow cytometry. The CD44 standard isoform was predominantly expressed by Ap8c3 cells, accounting for 90% of the CD44 mRNA determined by quantitative real-time polymerase chain reaction. Mouse CD44-/- BMSCs bonded inefficiently to hyaluronic acid (HA), whereas CD44+/+ BMSC and MSC Ap8c3 adhered strongly to HA. Adhesions of MSC Ap8c3 cells to HA were suppressed by anti-CD44 antibody and by CD44 small interfering RNA (siRNA). HA coating of the migration chamber significantly promoted passage of CD44+/+ BMSC or Ap8c3 cells, but not CD44-/- BMSCs, through the insert membranes (p < .01). Migration of MSC Ap8c3 was significantly inhibited by anti-CD44 antibodies (p < .01) and to a lesser extent by CD44 siRNA (p = .05). The data indicate that MSC Ap8c3 cells, in response to PDGF stimulation, express high levels of CD44 standard (CD44s) isoform, which facilitates cell migration through interaction with extracellular HA. Such a migratory mechanism could be critical for recruitment of MSCs into wound sites for the proposition of tissue regeneration, as well as for migration of fibroblast progenitors to allografts in the development of graft fibrosis.

Animals↗
PubMed2005

Contribution of proliferation and DNA damage repair to alveolar epithelial type 2 cell recovery from hyperoxia.

In this study, C57BL/6J mice were exposed to hyperoxia and allowed to recover in room air. The sublethal dose of hyperoxia for C57BL/6J was 48 h. Distal lung cellular isolates from treated animals were characterized as 98% epithelial, with minor fibroblast and endothelial cell contaminants. Cells were then verified as 95% pure alveolar epithelial type II cells (AEC2) by surfactant protein C (SP-C) expression. After hyperoxia exposure in vivo, fresh, uncultured AEC2 were analyzed for proliferation by cell yield, cell cycle, PCNA expression, and telomerase activity. DNA damage was assessed by TdT-dUTP nick-end labeling, whereas induction of DNA repair was evaluated by GADD-153 expression. A baseline level for proliferation and damage was observed in cells from control animals that did not alter significantly during acute hyperoxia exposure. However, a rise in these markers was observed 24 h into recovery. Over 72 h of recovery, markers for proliferation remained elevated, whereas those for DNA damage and repair peaked at 48 h and then returned back to baseline. The expression of GADD-153 followed a distinct course, rising significantly during acute exposure and peaking at 48 h recovery. These data demonstrate that in healthy, adult male C57BL/6J mice, AEC2 proliferation, damage, and repair follow separate courses during hyperoxia recovery and that both proliferation and efficient repair may be required to ensure AEC2 survival.

Animals↗
PubMed2005

Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID).

Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (ADA-deficient SCID) is characterized by impaired lymphocyte development and function resulting from the adenosine metabolism defect. Enzyme replacement therapy with polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) minimizes infectious complications of ADA-deficient patients who have not received bone marrow transplantation. In PEG-ADA therapy, enzymatically active ADA continuously circulates to act as a metabolic sink, detoxifying the adenosine and deoxyadenosine metabolites that accumulate to high levels in the absence of ADA. Studies have shown that upon the initiation of PEG-ADA therapy, the absolute numbers of circulating T and B lymphocytes and NK cells increase and protective immune function develops. However, the long-term efficacy is unknown. This retrospective study was designed to assess the long-term effectiveness of PEG-ADA treatment, based on evaluation of the immune function of nine ADA-deficient SCID patients (age 5-15) treated over the past decade. The results showed that the lymphocyte counts of all of the PEG-ADA treated patients were below the normal range at all times, despite initial improvements. A gradual decline of mitogenic proliferative responses occurred after a few years of treatment and normal antigenic response occurred less than expected. To this date, these low numbers and functions of lymphocytes had been adequate to provide protective immunity. These patients should be followed closely to detect a premature decline in immune function with aging in future decades of PEG-ADA therapy.

Adenosine Deaminase↗
PubMed2004

Use of lentiviral vectors to induce long-term tolerance to gal(+) heart grafts.

BACKGROUND: Tolerance to organ grafts has been achieved by establishing a state of stable mixed-cell chimerism after bone marrow transplantation. Gene therapy has been applied to establish chimerism for cells expressing galactose alpha 1,3 galactose in alpha 1,3 galactosyltransferase deficient (gal knockout) mice using retroviral vectors. Limitations to the success of this methodology include short-term expression of the introduced gene and rejection of gal hearts transplanted into these animals within a month. METHODS: Autologous bone marrow from gal knockout mice was transduced with a lentiviral vector expressing porcine alpha 1,3 galactosyltransferase and transplanted into lethally irradiated gal knockout mice. Chimerism was monitored by flow cytometry. Hearts from wild type mice (gal/) were transplanted into these animals and palpated daily. Xenoantibodies directed at the gal carbohydrate or porcine xenoantigens were detected by enzyme-linked immunosorbent assay. RESULTS: Hearts from wild-type gal/ donors were permanently accepted in all mice receiving autologous, transduced bone marrow before heart transplantation. Control mice rejected gal hearts within 12 to 14 days. Histologic analysis demonstrated classical signs of rejection in controls and normal myocardium with no evidence of rejection in mice chimeric for the gal carbohydrate. Anti-gal xenoantibodies were not produced in gal chimeras, but normal antibody responses to other xenoantigens were detected. Specific tolerance for the gal carbohydrate was achieved by this procedure. CONCLUSIONS: These experiments report the first demonstration of permanent survival of gal hearts after transplantation with autologous, transduced bone marrow. Transduction with lentiviral vectors results in long-term, stable chimerism at levels sufficient to induce long-term tolerance to heart grafts in mice.

Animals↗
PubMed2004

Successful anti-CD20 monoclonal antibody treatment of severe autoimmune hemolytic anemia due to warm reactive IgM autoantibody in a child with common variable immunodeficiency.

Autoimmune hemolytic anemia due to warm reactive IgM autoantibodies is unusual, severe, and often fails to respond to standard immunosuppressive therapies in both adults and children. A 6-year-old girl with common variable immunodeficiency had longstanding steroid dependent, splenectomy-unresponsive, warm IgM autoantibody-mediated autoimmune hemolytic anemia. Rituximab, a monoclonal antibody directed against CD20 antigen, was used to deplete B lymphocytes and reduce autoantibody production. She received a total of six doses of rituximab (375 mg/m2). Therapy was well tolerated, and B-lymphocytes were effectively depleted from the peripheral blood. The patient was completely tapered off glucocorticoids. The patient has remained off immunosuppressive agents for 16 months despite the return of B lymphocytes to the peripheral circulation. She continues to require IVIG. Early treatment with rituximab might be an option for patients with warm reactive IgM autoantibody-mediated autoimmune hemolytic anemia not responding to other treatments or experiencing untoward side effects from those treatments.

Anemia, Hemolytic↗
PubMed2003

Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells.

Alveolar epithelial type 2 cells (AEC2) isolated from hyperoxia-treated animals exhibit increases in both proliferation and DNA damage in response to culture. AEC2 express the zonula adherens proteins E-cadherin, -, - and -catenin, desmoglein, and pp120, as demonstrated by Western blotting. Immunohistochemical analysis of cultured AEC2 showed expression of E-cadherin on cytoplasmic membranes varying from strongly to weakly staining. When cultured AEC2 placed in suspension were labeled with fluorescent-tagged antibodies to E-cadherin, cells could be sorted into at least two subpopulations, either dim or brightly staining for this marker. With the use of antibody to E-cadherin bound to magnetic beads, cells were physically separated into E-cadherin-positive and -negative subpopulations, which were then analyzed for differences in proliferation and DNA damage. The E-cadherin-positive subpopulation contained the majority of damaged cells, was quiescent, and expressed low levels of telomerase activity, whereas the E-cadherin-negative subpopulation was undamaged, proliferative, and expressed high levels of telomerase activity.

Adherens Junctions↗
PubMed2002

The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3.

The common cytokine receptor gamma chain (gamma c), an essential component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is critical for the development and function of lymphocytes. Recently, a novel lymphokine (IL-21) and its receptor (IL-21R alpha) were described which profoundly affect the growth and activation state of B, T, and NK cells in concert with other lymphokines or stimuli [Parrish-Novak, J., et al. (2000) Nature 408, 57-63]. In this report, we show that gamma c is also a required signaling component of the IL-21 receptor (IL-21R) using the gamma c-deficient X-linked severe combined immunodeficiency (XSCID) lymphoblastoid cell line JT, and JT cells reconstituted with gamma c (JT/gamma c). Moreover, we demonstrate a functional requirement for both gamma c and the gamma c-associated Janus family tyrosine kinase 3 (JAK3) in IL-21-induced proliferation of pro-B-lymphoid cells engineered to express human IL-21R alpha (BaF3/IL-21R alpha). Retroviral-mediated transduction of wild-type gamma c into XSCID JT cells restored function to the IL-21R, as shown by IL-21-induced tyrosine phosphorylation of JAK1 and JAK3, and downstream activation of STAT5, in JT/gamma c cells as well as BaF3/IL-21R alpha and primary splenic B cells. In contrast, IL-21 failed to activate the JAK-STAT pathway in nonreconstituted JT cells. Monoclonal antibodies specific for the gamma c chain effectively inhibited IL-21-induced growth of BaF3/IL-21R alpha cells, supporting a functional role for this molecule in the IL-21R complex. In addition, the specific JAK3 tyrosine kinase inhibitor WHI-P131 significantly reduced IL-21-induced proliferation of BaF3/IL-21R alpha cells. Taken together, these results definitively demonstrate that IL-21-mediated signaling requires the gamma c chain, and indicate that JAK3 is an essential transducer of gamma c-dependent survival and/or mitogenic signals induced by this cytokine.

Animals↗
PubMed2002

Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation.

Duchenne muscular dystrophy (DMD) is a severe progressive muscle-wasting disorder caused by mutations in the dystrophin gene. Studies have shown that bone marrow cells transplanted into lethally irradiated mdx mice, the mouse model of DMD, can become part of skeletal muscle myofibers. Whether human marrow cells also have this ability is unknown. Here we report the analysis of muscle biopsies from a DMD patient (DMD-BMT1) who received bone marrow transplantation at age 1 year for X-linked severe combined immune deficiency and who was diagnosed with DMD at age 12 years. Analysis of muscle biopsies from DMD-BMT1 revealed the presence of donor nuclei within a small number of muscle myofibers (0.5-0.9%). The majority of the myofibers produce a truncated, in-frame isoform of dystrophin lacking exons 44 and 45 (not wild-type). The presence of bone marrow-derived donor nuclei in the muscle of this patient documents the ability of exogenous human bone marrow cells to fuse into skeletal muscle and persist up to 13 years after transplantation.

Adolescent↗