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Biomedical subjects

S J Rosenfeld

Publications and source records attributed to S J Rosenfeld.

13 recordsLinked to original sources
PubMed2000

High-dose cyclophosphamide in severe aplastic anaemia: a randomised trial.

BACKGROUND: High-dose cyclophosphamide has been proposed as an alternative immunosuppressive agent for treatment of severe aplastic anaemia, with a response rate similar to that with regimens containing antithymocyte globulin (ATG) but neither relapse nor clonal haematological complications. We undertook a phase III, prospective, randomised trial to compare response rates to immunosuppression with either high-dose cyclophosphamide plus cyclosporin or conventional immunosuppression with ATG plus cyclosporin in previously untreated patients. METHODS: Between June, 1997, and March, 2000, 31 patients were enrolled. 15 were assigned cyclophosphamide (1 h intravenous infusion of 50 mg/kg daily for 4 days) and 16 were assigned ATG (40 mg/kg daily for 4 days); both groups received cyclosporin, initially at 12 mg/kg daily with adjustment to maintain concentrations at 200-400 microg/L, for 6 months. The primary endpoint was haematological response (no longer meeting criteria for severe aplastic anaemia). The trial was terminated prematurely after three early deaths in the cyclophosphamide group. Analyses were by intention to treat. FINDINGS: Median follow-up was 21.9 months (range 1-33). There was excess morbidity in the cyclophosphamide group (invasive fungal infections, four cyclophosphamide vs no ATG patients; p=0.043) as well as excess early mortality (three deaths within the first 3 months cyclophosphamide vs no ATG patients; p=0.101). There was no significant difference at 6 months after treatment in the overall response rates among evaluable patients (six of 13 [46%] cyclophosphamide vs nine of 12 [75%] ATG). INTERPRETATION: A longer period of observation will be necessary to assess the secondary endpoints of relapse and late clonal complications as well as disease-free and overall survival. However, cyclophosphamide seems a dangerous choice for treatment of this disorder, given the good results achievable with standard therapy.

Adult↗
PubMed2000

Immunosuppressive treatment of aplastic anemia with antithymocyte globulin and cyclosporine.

Immunosuppression is the treatment modality for the majority of patients with aplastic anemia, most of whom are not candidates for allogeneic stem-cell transplantation. Antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) have proven to be essential components of all regimens. Initial response rates can be improved by the addition of cyclosporine A (CsA), and this combination has become the standard of care for appropriate patients. Several new approaches to immunosuppression are being studied, including the optimal timing of administration of these drugs, the use of novel immunosuppressive agents, and the addition of early- and late-acting hematopoietic growth factors.

Anemia, Aplastic↗
PubMed2000

Managing clinical research information: a case study in information access, presentation, and analysis.

Medical information systems at the NIH must meet the twin challenges of excellent patient care and innovative clinical research. This article describes the approach taken by the clinical center at the NIH to enhance its information systems to meet these challenges. The four key components of this strategy are the standard clinical desktop, the clinical data repository, the repository access package, and protocol mapping. Together, these tools provide significant new capabilities for patient care staff and clinical investigators.

Clinical Protocols↗
PubMed1998

Platelet von Willebrand factor in Hermansky-Pudlak syndrome.

The Hermansky-Pudlak Syndrome (HPS) is an autosomal recessive inherited disorder characterized by oculocutaneous albinism, tissue accumulation of ceroid pigment, and a mild to moderate bleeding diathesis attributed to storage-pool deficient (SPD) platlets. Patients have platelet aggregation and release abnormalities. In addition, low levels of plasma von Willebrand factor (vWF) antigen in some HPS patients have been associated with a greater bleeding tendency than would be predicted from either condition alone. Other HPS patients have severe bleeding despite normal levels of plasma vWF, suggesting that at least one additional factor is responsible for their bleeding diathesis. Because platelet vWF levels have been well correlated with clinical bleeding times in patients with von Willebrand's disease, we have measured the platelet vWF activity and antigen levels in 30 HPS patients and have attempted to correlate their clinical bleeding with these values. The platelet vWF activity levels in patients was significantly lower than that of normal subjects (P < 0.0001). The patients as a group also had slightly lower values of plasma vWF activity when compared with normals (P-0.03). In 11 of the HPS patients, the multimeric structure of plasma vWF showed a decrease in the high molecular weight multimers and an increase in the low molecular weight multimers. In correlating the platelet and plasma vWF values with the bleeding histories, we were not able to show a predictable relationship in the majority of the patients.

Adenosine Triphosphate↗
PubMed1997

Adhesive interactions in hemostasis.

Adhesion molecules and adhesive interactions play a critical role in the process of hemostasis. A vascular rent requires a patch, and this patch must be provided from constituents of the cellular and fluid phases of flowing blood, constituents that must not interfere with this flow under unperturbed conditions. Platelets, the cellular elements of the patch, are inert until they encounter conditions that trigger their activation. In response to injury they undergo a rapid and dramatic change both in shape and in their surface characteristics, a change that allows them to become both the nidus and the stimulus for the precipitation of a meshwork of fibrin. The interactions between platelets and exposed collagen in the damaged vessel wall, plasma and platelet von Willebrand factor, and plasma and platelet fibrinogen can all be considered 'adhesive interactions'.

Animals↗
PubMed1995

Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia.

Immunosuppressive therapy can produce hematologic improvement in a large proportion of patients with severe aplastic anemia. Antithymocyte globulin (ATG) is the current treatment of choice for patients who do not have histocompatible sibling donors or who are otherwise inegligible for allogeneic bone marrow transplantation. About 50% of patients respond to an initial course of ATG, and many nonresponders can be salvaged by subsequent treatment with cyclosporine (CsA). To determine whether simultaneous administration of these agents could further improve response rates, we enrolled 55 patients in a therapeutic trial of 4 days of ATG and 6 months of CsA. Among the 51 patients who had not received previous courses of ATG or CsA, 67% had responded by 3 months, and 78% had responded by 1 year (response was defined as an increase in peripheral blood counts sufficient that a patient no longer met the criteria for severe disease). There was a high incidence of relapse (36% actuarial risk at 2 years), but most relapsed patients responded to additional courses of immunosuppression, and relapse was not associated with a significant survival disadvantage. Evolution to myelodysplastic syndromes and acute leukemia was rare (1 of 51 patients), but the later appearance of paroxysmal nocturnal hemoglobinuria was more common (5 of 51 patients). Actuarial survival was 86% at 1 year and 72% at 2 years. These data support the use of a combination immunosuppressive regimen containing both ATG and CsA as first-line therapy for severe aplastic anemia.

Adolescent↗
PubMed1994

Subunit interaction in B19 parvovirus empty capsids.

B19 parvovirus is a small single-stranded DNA virus with a genome that encodes only two structural proteins, designated VP1 and VP2. 60 copies of the structural proteins assemble into the viral capsid, with approximately 95% VP2 and 5% VP1. Recombinant empty capsids composed of VP2 alone or of VP2 and VP1 self-assemble into particles that are morphologically indistinguishable from full virions. Empty capsids containing both VP2 and VP1 elicit a strong neutralizing antibody response when used to immunize rabbits. Capsids containing only VP2 are similarly antigenic but elicit only weak neutralizing activity. We performed fine structure epitope mapping by measuring the reactivity of antisera raised against capsids composed of VP2 and VP1 or VP2 alone against 85 overlapping peptides spanning the sequence of the two structural proteins. A profile of the antigenic difference between empty capsids with and without VP1 was produced from the resulting data. This profile divided the sequence of the structural proteins into four regions that correlated well with expected viral structures. Thus, the addition of a small number of VP1 residues altered the antigenicity of the entire capsid. The major area of enhanced antigenicity is homologous to the spike of canine parvovirus, an area known to contain both neutralizing and host-range determinants. Our data are consistent with a model in which the unique region of VP1 is necessary for the virus to assume its mature capsid conformation.

Amino Acid Sequence↗
PubMed1994

Increasing expression of the normal human CFTR cDNA in cystic fibrosis epithelial cells results in a progressive increase in the level of CFTR protein expression, but a limit on the level of cAMP-stimulated chloride secretion.

Cystic fibrosis (CF) results from mutations of the CF transmembrane conductance regulator (CFTR) gene and the consequent defective regulation of cAMP-stimulated Cl- permeability across epithelial cell apical membranes. Given that in vitro transfer of normal CFTR cDNA corrects this defect and that recombinant adenovirus (Ad) vectors can transfer the normal human CFTR cDNA in vivo, Ad vectors have significant potential in the development of effective strategies for CF gene therapy. One concern is whether CFTR overexpression achievable with Ad vectors may have untoward effects on cAMP-stimulated Cl- efflux. To address this, the CF pancreatic epithelial cell line CFPAC-1 was infected with increasing doses of AdCFTR, a recombinant Ad containing the normal CFTR cDNA, and analyzed for CFTR mRNA and protein levels and CFTR function. As the AdCFTR dose increased [multiplicity of infection (moi) 0-1,000], CFTR mRNA and protein levels increased. However, while CFTR function measured by cAMP-stimulated 36Cl- efflux was observed with low doses of the vector (moi 20), there was no further increase in CFTR function with increasing doses of AdCFTR (moi from 20 to 1,000). These data suggest that after AdCFTR-mediated gene transfer, epithelial cells limit the level of cAMP-stimulated Cl- secretion despite increasing levels of CFTR protein.

Adenocarcinoma↗
PubMed1992

Aplastic anemia and viral hepatitis. Non-A, Non-B, Non-C?

OBJECTIVE: To test the hypothesis that the rare, often fatal, syndrome of hepatitis-associated aplasia is associated with hepatitis C virus infection. DESIGN: Case series. SETTING: Tertiary referral centers in the United States, Japan, Italy, and Germany. PATIENTS: Twenty-eight patients with onset of aplastic anemia within 90 days after seeking medical attention for jaundice, or having serum transaminase levels 150% or more of normal (hepatitis-associated aplasia patients) and three patients who developed aplastic anemia following liver transplantation for non-A, non-B hepatitis. OUTCOME MEASURES: Presence of hepatitis C in serum, bone marrow, and liver samples, detected by the polymerase chain reaction; antibody testing; and percentage of activated peripheral cytotoxic T lymphocytes determined by immunophenotyping. RESULTS: Hepatitis ribonucleic acid was present in the serum samples of 10 (36%) patients with hepatitis-associated aplasia. However, hepatitis C virus viremia was associated with transfusions received after the onset of aplasia: seven (58%) of 12 patients with hepatitis-associated aplasia who had received 21 or more units of blood products at the time of serum sampling were viremic, compared with only three (19%) of 16 patients with hepatitis-associated aplasia who had received 20 or less units of blood products (P less than .05). Hepatitis C virus was not found in blood and bone marrow samples of three National Institutes of Health case patients tested at the time of diagnosis. None of three livers from non-A, non-B hepatitis patients who developed aplastic anemia after liver transplantation contained hepatitis C virus ribonucleic acid. Activated CD8+ T lymphocytes were elevated three- to 20-fold early in the course of hepatitis-associated aplasia. CONCLUSIONS: Our results implicate a novel, non-A, non-B, and non-C agent in both hepatitis-associated aplasia and fulminant hepatitis.

Adolescent↗
PubMed1992

Unique region of the minor capsid protein of human parvovirus B19 is exposed on the virion surface.

Capsids of the B19 parvovirus are composed of major (VP2; 58 kD) and minor (VP1; 83 kD) structural proteins. These proteins are identical except for a unique 226 amino acid region at the amino terminus of VP1. Previous immunization studies with recombinant empty capsids have demonstrated that the presence of VP1 was required to elicit virus-neutralizing antibody activity. However, to date, neutralizing epitopes have been identified only on VP2. Crystallographic studies of a related parvovirus (canine parvovirus) suggested the unique amino-terminal portion of VP1 assumed an internal position within the viral capsid. To determine the position of VP1 in both empty capsids and virions, we expressed a fusion protein containing the unique region of VP1. Antisera raised to this protein recognized recombinant empty capsids containing VP1 and VP2, but not those containing VP2 alone, in an enzyme-linked immunosorbent assay. The antisera immunoprecipitated both recombinant empty capsids and human plasma-derived virions, and agglutinated the latter as shown by immune electron microscopy. The sera contained potent neutralizing activity for virus infectivity in vitro. These data indicate that a portion of the amino terminus of VP1 is located on the virion surface, and that this region contains intrinsic neutralizing determinants. The external location of the VP1-specific tail may provide a site for engineered heterologous epitope presentation in novel recombinant vaccines.

Animals↗
PubMed1991

Viruses and bone marrow failure.

Many agents are associated with bone marrow failure, including toxins, inherited metabolic defects, ionizing radiation, and viral infection. In most cases, the etiologic agent is unknown. Many of these unclassified cases have symptomatic, immunologic, or epidemiologic similarities to viral infections. Viruses from different taxonomic families have been implicated in bone marrow failure syndromes, and they appear to cause hematosuppression by a variety of mechanisms. Some of the viruses involved in relatively well characterized suppressive interactions will be reviewed, including parovovirus B19, dengue, hepatitis viruses, Epstein-Barr virus, cytomegalovirus and the human immunodeficiency virus.

Bone Marrow Diseases↗
PubMed1985

Temporal profiles of proteins responsive to transient ischemia.

The responses of long and short half-lived proteins to ischemia were measured in rat brain during 6 days of recovery from 30 min of transient forebrain ischemia produced by four-vessel occlusion. At the end of the ischemic interval, the neocortical activities of four vulnerable enzymes [ornithine (ODC) and S-adenosylmethionine (SAMDC) decarboxylases, and RNA polymerases I and II] were unchanged, but within 30 min of reperfusion, their activities dropped by 25-50%. The loss of substance P in the striatum and substantia nigra was slower, reaching about 50% by 12 h. On the other hand, the activities of 5 long half-lived enzymes did not change in the neocortex at 5 and 15 h of reperfusion and regional protein concentrations were essentially unaffected over 6 days survival. The rate and extent of normalization of the amounts or activities of the vulnerable proteins varied. RNA polymerase II and ODC activities were restored within 4 h, and ODC showed a biphasic increase in activity, with peaks at 10 h and 2-3 days. RNA polymerase I and SAMDC activities were restored by 18 h and 5 days, respectively, whereas substance P concentrations did not completely recover, even at 6-15 days. The greater the regional reduction of blood flow during ischemia, the larger the net change (gain or loss) of SAMDC or ODC activity and the longer the time required to normalize the activities of these enzymes. The average rate of proteolysis, assessed by measuring the rate of clearance of 14C from protein prelabeled with [14C]bicarbonate, was abnormal during the first 2 days of reperfusion. Postischemic changes in both protein synthesis and degradation could affect the amounts of some of the proteins responsive to transient ischemia.

Adenosylmethionine Decarboxylase↗