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E Rosner

Publications and source records attributed to E Rosner.

At least 19 recordsLinked to original sources
PubMed1998

Stereo- and regioselective conjugation of S-halovinyl mercapturic acid sulfoxides by glutathione S-transferases.

Hexachloro-1,3-butadiene (HCBD) is nephrotoxic in rats. Its toxicity is due to a multistep bioactivation pathway involving glutathione conjugation. N-Acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine resulting from further processing of the GSH conjugate of HCBD is oxidized in vitro and in vivo to the corresponding sulfoxide diastereomers by cytochromes P450 3A. N-Acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide diastereomers represent vinyl sulfoxides which are electrophiles. They are analogous to alpha,beta-unsaturated carbonyl compounds and may be conjugated with glutathione. This study presents experimental data for the different reactivity of the two diastereomers of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide with glutathione S-transferases in vitro. The structures of the individual diastereomers were assigned by stereoselective oxidation of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine with sodium periodate in the presence of chloroperoxidase. The two isolated diastereomers were incubated with rat liver and kidney cytosol in the presence of glutathione. In incubations with rat liver cytosol, the formation of a glutathione conjugate, which was identified as (R)-N-acetyl-S-(4-glutathion-S-yl-1,2,3,4-tetrachlorobutadienyl )-L-cysteine sulfoxide, was observed with the (R)-sulfoxide diastereomer. The enzymatic reaction of the (S)-sulfoxide diastereomer with glutathione resulted in two GSH conjugates identified as (S)-N-acetyl-S-(4-glutathion-S-yl-1,2,3,4-tetrachlorobutadienyl )-L-cysteine sulfoxide and (S)-N-acetyl-S-(2-glutathion-S-yl-1,3,4,4-tetrachlorobutadienyl )-L-cysteine sulfoxide. In rat kidney cytosol only the S-diastereomer of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide is transformed to (S)-N-acetyl-S-(2-glutathion-S-yl-1,3,4,4-tetrachlorobutadienyl )-L-cysteine sulfoxide, while transformation of the R-diastereomer to glutathione conjugates was not observed. In rat kidney cytosol, the rates of formation of (S)-N-acetyl-S-(2-glutathion-S-yl-1,3,4,4-tetrachlorobutadienyl )-L-cysteine sulfoxide from conjugation of the S-diastereomer were comparable to those in rat liver cytosol. Incubation of (S)-N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide with purified rat and human glutathione S-transferases indicates that both R- and S-diastereomers were conjugated to the corresponding 1,4-disubstituted compounds by mu-glutathione S-transferases. Formation of the 1,2-disubstituted conjugation product of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide was catalyzed exclusively by alpha-glutathione S-transferases. These results are one of the first examples for differences in regio- and stereospecificity in reactions catalyzed by different glutathione S-transferase enzymes.

Acetylcysteine↗
PubMed1998

Biotransformation, excretion, and nephrotoxicity of the hexachlorobutadiene metabolite (E)-N-acetyl-S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine sulfoxide.

Hexachlorobuta-1,3-diene (HCBD) is nephrotoxic in rodents. Its toxicity is based upon a multistep bioactivation pathway. Conjugation with glutathione by glutathione S-transferases to form (E)-S-(1,2,3,4,4-pentachlorobutadienyl)-L-glutathione (PCBG), further processing to the corresponding cysteine S-conjugate, and finally processing to a reactive thioketene are thought to be responsible for the observed nephrotoxic effects. A novel metabolite, identified as (E)-N-acetyl-S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine sulfoxide (N-AcPCBC-SO), was described after administration of [14C]HCBD to male Wistar rats. This metabolite is formed by sulfoxidation of N-acetyl-S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine (N-AcPCBC) mediated by cytochrome P450 3A and has been found to be cytotoxic to proximal tubular cells in vitro without activation by beta-lyase. In rats, given HCBD in vivo, only one diastereomer of the sulfoxide is excreted; however, in rat hepatic microsomes two diastereomers, (R)- and (S)-N-AcPCBC-SO, are formed. This study focuses on the mechanisms responsible for this discrepancy and on a possible contribution of N-AcPCBC-SO to the nephrotoxicity of HCBD in vivo. (R,S)-N-AcPCBC-SO (1:1 mixture of both diastereomers) and N-acetyl-alpha-methyl-S-(1,2,3,4,4-pentachlorobutadienyl)-d, L-cysteine sulfoxide (alpha-Me-N-AcPCBC-SO) were administered iv to male and female Wistar rats (20, 40, and 80 micromol/kg of body weight). alpha-Me-N-AcPCBC-SO cannot be cleaved by cysteine conjugate beta-lyase even if alpha-Me-N-AcPCBC-SO is deacetylated by acylases. Excretion of gamma-glutamyltranspeptidase, protein, and glucose in the urine, indicative for kidney damage, and histopathological examination of the kidneys showed marked differences in the renal damage in male and female rats after application of N-AcPCBC-SO and alpha-Me-N-AcPCBC-SO. Necroses of the kidney tubules were only found in male, but not female, rats. Major sex-specific differences were observed in the elimination of sulfoxides; the (R)-isomer was excreted in a 5-10-fold excess to the (S)-isomer after application of (R,S)-N-AcPCBC-SO. After purification, both isomers were administered to male rats resulting in the urinary excretion of (R)-N-AcPCBC-SO after giving the (R)-isomer; treatment with (S)-N-AcPCBC-SO, however, revealed the formation of (S)-N-acetyl-S-(2-glycinylcystein-S-yl-1,3,4, 4-tetrachlorobutadienyl)-L-cysteine. The results show major sex-specific differences in the nephrotoxic potency of N-AcPCBC-SO and alpha-Me-N-AcPCBC-SO. However, both N-AcPCBC-SO and alpha-Me-N-AcPCBC-SO are nephrotoxic in males, suggesting the formation of a vinyl sulfoxide as an additional, beta-lyase-independent mechanism in HCBD-caused nephrotoxicity.

Animals↗
PubMed1998

Assessment of the impact of a CD4+ T-cell testing laboratory improvement program.

OBJECTIVE: To evaluate the effectiveness of the Centers for Disease Control and Prevention's CD4+ T-cell laboratory testing improvement program and the influence of other laboratory improvement programs on CD4+ T-cell testing practices. DESIGN: Surveys asking for practice changes and factors that influenced the changes, a survey of clinicians' perceptions of laboratory quality in CD4 testing, and analysis of data from the Model Performance Evaluation Program. INTERVENTIONS: Centers for Disease Control and Prevention interventions included a series of 3-day workshops on flow cytometry, CD4+ T-cell testing guidelines published in the Morbidity and Mortality Weekly Report, the Clinical Laboratory Improvement Amendments of 1988, and the Model Performance Evaluation Program. PARTICIPANTS: All known laboratories in the United States that perform clinical CD4+ T-cell testing, workshop participants, and a sample of clinicians that treat patients infected with the human immunodeficiency virus. MAIN OUTCOME MEASURES: Changes in practices, factors most influential in effecting change, and performance on samples mailed to laboratories by the Model Performance Evaluation Program; knowledge before and after presentation of material in workshops; and practicing clinicians' observations of any effects of changes in laboratory practices. RESULTS: Many existing laboratories changed practices as a result of both governmental and nongovernmental CD4+ T-cell testing improvement programs. Sources of influence varied with each testing practice. Perceptions that test results were more reproducible seemed to offset presumed increases in the time and cost of testing. Clinicians who had ordered CD4+ T-cell testing for more than 10 years noted some improvements in results reported. CONCLUSIONS: As new complex testing methodologies are introduced into clinical and public health laboratories, the users seem to seek guidance in appropriate application of preanalytic, analytic, and postanalytic phases of the testing process. Testing improvement programs from a variety of sources were credited with changing practices and should continue to provide this guidance.

CD4 Lymphocyte Count↗
PubMed1997

CD4+ T-cell testing practices as implications for training.

As new diseases and new testing methods emerge, clinical laboratories are faced with updating the skills of their personnel. Complex techniques, such as flow cytometry, require both education and experience to achieve a high level of proficiency. One of the ways to determine areas in which training is needed is to assess laboratory practices and compare them with practices recommended in guidelines or by panels of experts. In this paper we describe practices reported in a written survey of 206 laboratories that perform CD4+ T-cell counts (CD4). We provided a list of alternate practices for each of the key steps in the testing process and asked participants to select the practices they use in their laboratories. Published guidelines and interviews with knowledgeable "key informants" and focus groups of people who perform CD4 testing were used to formulate the questions. We interpreted variations from recommended practices as indicators of training needs. Other factors that can affect performance, such as workload, supervision, and resources, were satisfactory to the respondents. A response rate of 73% (247 of 337 laboratories) revealed that laboratories followed most of the recommended practices. Notable exceptions included some areas of quality control and quality assurance and safety. This paper also describes flow cytometry testing as it was practiced in 1993 shortly after release of some of the testing guidelines and provides a baseline of practices for that time frame.

Antibodies, Monoclonal↗
PubMed1997

Central nervous system involvement at diagnosis in a case of pediatric CD30+ anaplastic large cell lymphoma.

Central nervous system (CNS) involvement in Ki-1/CD30 lymphoma is extremely rare, in contrast to the frequent involvement in other types of pediatric non-Hodgkin's lymphoma. No mechanism has yet been proposed to explain the sparing of the blood brain barrier in Ki-1/lymphoma. We present a 2-year-old boy who was admitted to the Department of Pediatric Hemato-Oncology due to lethargy, progressive breathing difficulties, massive diffuse lymphadenopathy, hepatosplenomegaly, and ichthyosis-like skin involvement with epidermolysis. A lymph node biopsy was compatible with Ki-1/CD30 anaplastic large cell lymphoma (ALCL). Bone marrow aspirate and biopsy demonstrated reactive hyperplasia. Cytogenetic analysis displayed hyperdiploid cells with 1p(-) in most cells. Cerebrospinal fluid examination showed pleocytosis with CD30+ cells. Possible mechanisms which could enable CNS involvement in this unusual case are discussed.

Central Nervous System Neoplasms↗
PubMed1997

Deletion of the long arm of chromosome 7 in myelomonocytic leukemia with bone marrow eosinophilia.

We report a 62-year-old man with acute myelomonocytic leukemia with bone marrow eosinophilia (M4Eo), and a deletion of the long arm of chromosome 7. The patient presented with pancytopenia, which shortly after evolved to overt leukemia. There was no response to the daunorubicin-cytosine arabinoside (Ara-C) regimen, and a remission achieved with amsacrine (AMSA)-Ara-C lasted only for a short time. On relapse, a peculiar skin rash accompanied the hematologic picture. While ANLL with chromosome 7 abnormalities usually carries adverse prognosis, patients with M4Eo (which is usually associated with chromosome 16 abnormalities) do better. The patient described here examplifies that M4Eo may be associated with del(7)(q22), and that it is the chromosomal abnormality rather than the type of leukemia that might determine the clinical outcome.

Bone Marrow↗
PubMed1996

Biotransformation of the fungicide chlorthalonil by glutathione conjugation.

The biotransformation of the nephrotoxic fungicide chlorthalonil (2,4,5,6-tetrachloroisophthalonitril) has been studied in the rat and in rat liver subcellular fractions. In rat liver cytosol, chlorthalonil was rapidly transformed to 4,6-bis(glutathion-S-yl)-2,5-dichloroisophthalonitril in the presence of glutathione in a reaction catalysed by glutathione S-transferases. 4-(Glutathion-S-yl)-2,5,6-trichloroisiphthalonitril was observed as an intermedite in the glutathione-dependent biotransformation of chlorthalonil. In the bile of rats dosed with chlorthalonil (0.18 mmol/kg, orally) 4,6-bis (glutathion-S-yl)-2,5-dichloroisophthalonitril was recovered as a minor metabolite. In rats, chlorthalonil was transformed to 4,6-bis (N-acetyl-cystein-S-yl)-2,5-dichloroisophthalonitril. This metabolite was excreted in small amounts in the urine of rats dosed orally with chlorthalonil (0.66 and 2.64 mmol/kg). In all experiments, a major part of the dose was recovered as unchanged chlorthalonil in feces. Oral administration of chlorthalonil (0.66 and 2.64 mmol/kg) resulted in a slight increase in the urinary excretion of gamma-glutamyltranspeptidase, indicative of nephrotoxicity. Other parameters indicative for renal proximal tubular damage (urinary glucose and protein excretion) were not changed by acute chlorthalonil administration. Very minor renal lesions were observed in chlorthalonil-dosed animals by histopathological examination.

Animals↗
PubMed1996

In vitro proliferative advantage of bone marrow cells with tetrasomy 8 in Ewing sarcoma.

We describe a case of a 14.5-year-old boy with a clinically aggressive pelvic Ewing sarcoma. The tumor cells showed the presence of a typical t(11;22)(q24;q12) aberration and gains of chromosomes 8, 10, 14, and 21. To determine the size of the trisomy and tetrasomy 8 clones an interphase analysis by fluorescence in situ hybridization with a centromere-specific chromosome 8 probe was performed. Significant quantitative differences between metaphase and interphase data were obtained. It was shown that culturing of bone marrow cells leads to enrichment of tetrasomy 8 population that may be explained by the proliferative advantage of the tetrasomy 8 cells.

Adolescent↗
PubMed1996

Translocation t(3;17)(q23;q21): a new translocation in acute lymphoblastic leukaemia.

We report on two adult patients with CD10+ positive acute lymphoblastic leukaemia (ALL) who presented with similar clinical and laboratory features and with a new chromosomal translocation: t(3;17)(q23;q21). This translocation may be involved in the formation of a new chimaeric transcription factor. Both patients shared several poor prognostic factors at presentation and an adverse clinical course. The t(3;17)(q23;q21) translocation may therefore predict a poor outcome in ALL.

Adult↗
PubMed1995

Translocation (2;14)(p13;q32) in CD10+ ;CD13+ acute lymphatic leukemia.

The rare t(2;14)(p13;q32) was previously described in the three pediatric patients with acute lymphatic leukemia. In these cases this abnormality was found at diagnosis, manifested the sole chromosomal abnormality, and was associated with a favorable prognosis. We here describe three cases of leukemia where such translocations were found at relapse, were associated in two of the cases with additional known characteristic chromosomal aberration, and were associated with a grave prognosis. Interestingly enough, the malignant cells of all three patients shared the same surface antigens: CD34, HLA DR, CD10, CD20, and the myeloid marker CD13. The leukemic clone exhibiting t(2;14) probably evolved from a t(1;19)6q- pre-B acute lymphatic leukemia in one of the cases, and from a chronic phase Ph1 chromosome in another. The significance of the translocation and the coexistence of CD10 and CD13 on the same cell are discussed.

Adolescent↗
PubMed1995

Hexasomy of chromosome 8 and trisomy of chromosome 11 characterize two karyotypically independent clones in a case of acute non-lymphocytic leukemia. Conventional cytogenetic and FISH investigation.

A case of ANLL following a myelodysplastic syndrome, probably resulting from occupational exposure to ionizing irradiation, with two cytogenetically unrelated clones, hexasomy 8 and trisomy 11, was investigated by conventional cytogenetics and FISH. Significant quantitative differences between data obtained by metaphase and interphase analysis of the hexasomy 8 clone were observed. A difference in the sensitivity to chemotherapy of the two clones was found: while the hexasomy 8 clone markedly decreased in response to treatment, the trisomy 11 clone remained unchanged.

Aneuploidy↗
PubMed1995

Preferred usage of specific immunoglobulin gene segments in chronic lymphocytic leukaemia cells of three HLA-identical sisters.

We report three family members, including a set of identical twins, who developed CD5 positive B-CLL. The patients are female Ashkenazi Jews sharing an identical HLA phenotype. Two of the HLA loci (B35 and Cw4) were common with those already described as being shared by Ashkenazi Jews with an increased incidence of CLL. The rearranged immunoglobulin genes of the malignant cells of all three patients were found to express genetically related VH regions belonging to the VH3 subgroup, and chromosomal studies suggest a process of clonal evolution in one of the twins.

Aged↗
PubMed1994

Lymphomatous T-cell leukemia in two Arab children. Is there a role for an environmental effect.

Two Arab children from the Gaza strip presented with fever, weakness, hepatosplenomegaly, lymphadenopathy and leukocytosis. The peripheral and bone marrow blasts had an immunophenotype compatable with T-cell acute lymphoblastic leukemia, and exhibited unusual markers (CD2+, CD3+, CD4-, CD8-). Cytogenetic studies revealed t(8;14)(q24;q11), possibly involving the alpha/delta locus of the T-cell receptor gene on chromosome 14 rather than the immunoglobulin heavy-chain locus usually involved in the t(8;14)(q24;q32), which is typical for Burkitt's leukemia/lymphoma. One of the children had a brother who died of T-cell acute lymphoblastic leukemia a few years later, however, his blasts showed deletion of chromosome 12. The possible role for environmental factors associated with low socioeconomic status, as well as of genetic factors in leukemogenesis are discussed.

Child, Preschool↗