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Biomedical subjects

Y Ravindranath

Publications and source records attributed to Y Ravindranath.

At least 55 records · Page 3Linked to original sources
PubMed1997

Increased frequency of expression of elevated dihydrofolate reductase in T-cell versus B-precursor acute lymphoblastic leukemia in children.

The relationships between dihydrofolate reductase (DHFR) levels or methotrexate membrane transport and acute lymphoblastic leukemia (ALL) immunophenotype were evaluated on 51 T-cell and 44 B-precursor ALL specimens from 90 pediatric ALL patients at diagnosis and relapse, using a fluorescent methotrexate analog (PT430) and flow cytometry assay (Matherly et al, Blood 85:500, 1995). For T-cell ALL, 35 of 45 (78%) of newly diagnosed patients' specimens exhibited elevated DHFR relative to DHFR levels in ALL blasts from methotrexate-responsive patients. For 30 of 45 diagnostic T-ALL specimens, DHFR expression was heterogeneous, with up to 3 separate subpopulations covering a 44-fold range; the DHFR-overproducing fractions comprised 10% to 88% of the total blasts. Elevated DHFR was less common in B-precursor ALL at diagnosis, being detected in only 17 of 36 specimens (47%); 11 of these samples exhibited DHFR heterogeneity. Median maximal DHFR levels were fourfold higher in T-cell than B-precursor ALL at diagnosis. Within a particular phenotypic group, there were no correlations between DHFR levels and patient prognostic features, including age, sex, chromosomal abnormalities, white blood cell counts (WBCs), and percentage of S-phase. However, for B-precursor ALL, there was a notably higher fraction of African-American than white patients with elevated DHFR. For patients (both phenotypes) with low WBCs (<50,000/ microL), event-free survival times were significantly shorter for those expressing DHFR above a threshold level than for patients expressing DHFR below this level (P < .016); this relationship was not seen for patients with high WBCs (>50,000/microL). Elevated DHFR was detected in 11 of 14 relapse specimens (5 of 6 T-cell and 6 of 8 B-precursor). Two of five paired relapse specimens (both T-cell) from patients treated with methotrexate exhibited increased DHFR levels over those at diagnosis (2.5- to 5-fold); the fraction of DHFR-overproducing blasts was also increased in 4 of 5 paired relapse specimens (2 B-precursor and 2 T-cell). In contrast to the variations in DHFR, highly impaired methotrexate transport was detected in only 6 of 95 ALL specimens, including both diagnosis and relapse. There was no correlation between phenotype and impaired transport. These data provide further rationale for the use of mechanistically based prognostic factors to complement known biologic or disease-based prognostic indicators in the design of ALL therapy including methotrexate, particularly with patients presenting with low WBCs. The finding of a markedly increased frequency of DHFR overexpression in T-cell over B-precursor ALL suggests that this difference is associated with the poorer prognosis of patients with T-cell ALL treated with standard-dose antimetabolite therapy and implies that higher-dose methotrexate (> or = 1 g/m2) during consolidation therapy may be useful in the treatment of this disease.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed1997

Treatment of familial erythrophagocytic lymphohistiocytosis with cyclosporine A.

Familial erythrophagocytic lymphocytosis (FEL) is a rare, nonmalignant class II histiocytosis characterized by fever, irritability, hepatosplenomegaly, pancytopenia, and hemophagocytosis. Various chemotherapeutic regimens have had mixed success, with the only curative therapy being bone marrow transplantation. We report our experience with two children whose therapy with etoposide and steroids failed. They were successfully treated and had durable remissions with cyclosporine A (CSA). We propose that in FEL there may exist abnormal interactions between antigen-presenting cells and T-lymphocyte subsets, and that CSA may down-modulate this aberrant response. The use of a low-dose CSA regimen may represent a treatment option that should be further explored.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

The spectrum of Evans' syndrome.

Eleven patients (10 boys, one girl) with Evans' syndrome with a median follow up time of 8.0 years were evaluated retrospectively. Six patients had either persistent hepatosplenomegaly or generalised lymphadenopathy, or both. In five patients, an increase in lymph node and/or spleen size was observed during the exacerbations of cytopenias. Seven patients had quantitative serum immunoglobulin abnormalities at the time of presentation. There were associated systemic manifestations in nine patients. Various forms of treatment were used with mixed results. Four patients died from sepsis and haemorrhage; four had complete recovery--two after splenectomy. These findings show that Evans' syndrome is a heterogeneous disorder with significant morbidity and mortality. High incidence of quantitative serum immunoglobulin abnormalities, lymphoid hyperplasia, and associated systemic manifestations suggest that Evans' syndrome may represent a stage of a more broad spectrum, generalised immune dysregulation.

Adolescent↗
PubMed1996

Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group.

BACKGROUND: The value of autologous bone marrow transplantation in the treatment of children with acute myeloid leukemia (AML) is unknown. We compared autologous bone marrow transplantation with intensive consolidation chemotherapy as treatments for children with AML in first remission. METHODS: We induced remission with one course of daunorubicin, cytarabine, and thioguanine, followed by one course of high-dose cytarabine (3 g per square meter of body-surface area for six doses). Patients in remission after the second course of induction therapy were eligible for randomization. Between June 1988 and March 1993, 552 of 649 enrolled patients who could be evaluated (85 percent) entered remission. A total of 209 patients were not eligible for randomization; of the remaining 343 patients, 232 were randomly assigned to receive six courses of intensive chemotherapy (117 patients) or autologous transplantation (115 patients). Of the original 649 patients, 189, including 21 with Down's syndrome, were nonrandomly assigned to receive intensive chemotherapy. RESULTS: The rates of event-free survival and overall survival for the entire group at three years were 34 +/- 2.5 percent and 42 +/- 2.6 percent, respectively. For patients who were randomly assigned to one of the two treatment groups, the mean (+/- SE) rates of event-free survival three years after randomization were not significantly different in the two groups when examined by intention-to-treat analysis: 36 +/- 5.8 percent for the intensive-chemotherapy group as compared with 38 +/- 6.4 percent for the autologous-transplantation group; and the relative risk of treatment failure for the chemotherapy group as compared with the autologous-transplantation group was 0.81 (P = 0.20 by the log rank test; 95 percent confidence interval, 0.58 to 1.12). Overall survival at three years followed a similar pattern. There was a lower relapse rate (31 percent vs. 58 percent, P < 0.001) but a higher rate of treatment-related mortality (15 percent vs. 2.7 percent, P = 0.005) in the group treated with autologous transplantation than in the intensive-chemotherapy group. The event-free survival at three years for the nonrandomized intensive-chemotherapy group was 39 +/- 5.1 percent, and for a contemporaneous group of patients each of whom received a histocompatible bone marrow transplant from a sibling, it was 52 +/- 8.0 percent. CONCLUSIONS: Treatment of children with AML in first remission with either autologous bone marrow transplantation or intensive chemotherapy prolongs event-free survival equally.

Acute Disease↗
PubMed1996

Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia.

Down syndrome (DS) children with acute myeloid leukemia (AML) have significantly higher event-free survival (EFS) rates compared with non-DS children when treated with protocols containing 1-beta-D-arabinofuranosylcytosine (ara-C). Sensitivity and metabolism of ara-C was examined in myeloblasts from DS and non-DS patients with AML, DS infants with the transient myeloproliferative disorder, and Epstein-Barr Virus (EBV) transformed lymphoblastoid cell lines with and without trisomy 21. DS myeloblasts were approximately 10-fold more sensitive to ara-C (measured by the 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) colorimetric sensitivity assay), compared with non-DS myeloblasts, following exposure to ara-C for 72 hours. Mean levels of l-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) were significantly higher in DS myeloblasts compared with non-DS myeloblasts after incubation with 5 micromol/L ara-C (621.4 v 228.4 pmol/mg protein). DS cell lines also generated higher levels of ara-CTP compared with cell lines with diploid chromosome numbers (66.5 v 13.6 pmol/mg protein and 137.6 v 41.7 pmol/mg protein at 1 and 5 micromol/L ara-C, respectively). Elevated ara-CTP levels in the DS cells were accompanied by slightly lower levels of endogenous deoxycytidine triphosphate (dCTP) pools, slightly greater extent of ara-C incorporation into DNA, and increased relative numbers of double strand DNA strand breaks. There were no significant differences in the cell cycle distributions of DS and non-DS cells. These in vitro studies support our hypothesis that enhanced metabolism of ara-C in DS cells may be a contributing factor to the superior survival rate of DS children with AML and is possibly based on a gene dosage effect of genes localized to chromosome 21 including cystathionine-beta-synthase. Further study of the mechanisms (ie, alterations in dCTP pools and DNA methylation) involved may lead to improvements in the treatment of all AML patients.

Acute Disease↗
PubMed1996

Acute myeloid leukaemia with t(8;16)(p11;p13) in a child after intrauterine X-ray exposure.

We describe t(8;16)(p11;p13) acute myeloid leukaemia (AML-M4) in a 12-year-old white male with a history of prenatal X-ray exposure. He had skin and bone involvement and some of the leukaemic blasts showed haemophagocytosis, characteristic features seen in t(8;16) AML. 20% of the reported cases of t(8;16)(p11;p13) AML are therapy-related and this case further supports the possible role of the ionizing radiation in the development of this disorder.

Adult↗
PubMed1996

Primary embryonal rhabdomyosarcoma of long bone. Case report and review of the literature.

We report a case of primary embryonal rhabdomyosarcoma of long bone, presenting as a lytic destructive bone tumor in the right femoral diaphysis of a 7-year-old girl. To our knowledge, this is only the third report of this entity. The neoplasm was a pure embryonal rhabdomyosarcoma with numerous rhabdomyoblasts. Immunohistochemistry confirmed the diagnosis: The cells were reactive with antibodies directed against desmin, muscle-specific actin, and myoglobin. No other neoplastic mesenchymal component was present within the tumor. Although rare, primary rhabdomyosarcoma, along with Ewing's tumor and osteosarcoma, should be considered in the differential diagnosis of malignant bone tumors in childhood.

Actins↗
PubMed1996

Osmotic scan ektacytometry in clinical diagnosis.

PURPOSE: The use of red blood cell deformability measurements in the diagnosis of hemolytic anemia is reviewed. PATIENTS AND METHODS: Results from 500 individuals are discussed. Erythrocytes were characterized by the automated measurement of cell deformability as the tonicity of the medium is varied (osmotic scan ektacytometry). RESULTS: The measurement yields a reliable identification of hemolytic anemias caused by deficiencies or abnormalities in erythrocyte structural proteins. In addition, it can, with good reliability, signal the presence of a glycolytic enzyme deficiency. The scan is complete in 15 min, and can therefore give a rapid indication of the type of hemolytic anemia. The osmotic scans of other hemolytic anemias are also discussed. CONCLUSION: The analysis of red blood cell deformability can offer a valuable addition to diagnostic methods in hemolytic anemia.

Anemia, Hemolytic↗
PubMed1995

Alkylsulphonic acid ion pairing with radial compression columns for determining plasma or cerebrospinal fluid 1-beta-D-arabinofuranosylcytosine in pediatric pharmacokinetic analysis.

In order to accurately and precisely measure plasma and cerebrospinal fluid (CSF) 1-beta-D-arabinofuranosylcytosine (Ara-C) in pediatric samples with adequate sensitivity and without interference, we have developed a reversed-phase ion-pairing technique utilizing the free amino group of the pyrimidine ring of Ara-C. Optimum resolution and separation was achieved utilizing a 4 microns C18 radial compression column. Ara-C and the internal standard 8-bromo-cyclic-AMP eluted at 6.5 and 4.6 min, respectively, with complete resolution. The minimum detectable amount is 2.5 pmol in a 50-microliters volume. The assay was linear in both plasma and CSF. Intra- and inter-day assay precision were less than 4% and 9%, respectively, for plasma with similar results obtained for CSF. Neither endogenous compounds nor commonly co-administered drugs interfere. Validity for our method was supported by the successful assay of over 400 pediatric plasma and 50 CSF samples for pharmacokinetic analysis. The method offers accuracy, precision, sensitivity and efficiency for plasma or CSF Ara-C determination.

Artifacts↗
PubMed1995

Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphoblastic leukemia.

A retrospective study of clinical resistance to methotrexate (MTX) was performed on 29 archival specimens of frozen lymphoblasts obtained from children with acute lymphoblastic leukemia (ALL), including 19 at initial presentation and 10 at first relapse. Blasts were assayed for dihydrofolate reductase and MTX transport by flow cytometry using the fluorescent methotrexate analog, PT430 (Rosowsky et al, J Biol Chem 257:14162, 1982). In contrast to tissue culture cells, patient blasts were often heterogeneous for dihydrofolate reductase content. Of the 19 specimens at initial diagnosis, 7 exhibited dual blast populations, characterized by threefold to 10-fold differences in relative dihydrofolate reductase; the dihydrofolate reductase-overproducing populations comprised 12% to 68% of the total blasts for these specimens. Remission duration intervals for patients exhibiting dual blast populations were notably shorter than for patients expressing a single blast population with lower dihydrofolate reductase ( < or = 9 months v > or = 15 months, respectively), a difference that was statistically significant (P = .045). There was no apparent correlation between expression of increased dihydrofolate reductase at diagnosis and known patient and disease prognostic features (immunophenotype, age, sex, and white blood count). For the relapsed patients, 4 of 10 exhibited dual lymphoblast populations with elevated dihydrofolate reductase. The majority of the patient lymphoblast specimens were entirely competent for MTX transport and, likewise, expressed immunoreactive reduced folate carriers by indirect immunofluorescence staining with specific antiserum to the transporter. Three patients (2 at relapse and 1 at diagnosis) exhibited heterogeneous expression of imparied MTX transport (14% to 73% of blasts). In only 1 of these patients did the majority of the lymphoblasts (73%) show impaired MTX transport and for this specimen, immunoreactive carrier proteins were virtually undetectable. These results suggest that heterogeneous expression of elevated dihydrofolate reductase and impaired MTX transport are important modes of resistance in childhood ALL patients undergoing chemotherapy with MTX and that these parameters may serve as predictive indices of clinical response to MTX.

Adolescent↗
PubMed1994

Variant t(8;21) rearrangements in acute myeloblastic leukemia of childhood.

In a collaborative cytogenetic analysis of blast cells from 638 children with acute myeloid leukemia, 74 (11.6%) of the patients had the typical t(8;21)(q22;q22), while seven (1.1%) had complex variant translocations also involving 8q22 and 21q22 as well as a variable chromosome. In each case with a complex rearrangement, the myeloid leukemic cells contained Auer rods and were classified as M2 in the French-American-British (FAB) system. These seven children had a median age of 14 years (range, 7.3-18.9 years), a median initial leukocyte count of 9.1 x 10(9)/L (range, 2.5-142.2 x 10(9)/L), and have survived leukemia free for a median of 23 months (1-41 months) after attaining complete remission. The variable chromosomes in these seven cases--1, 2, 7, 12, 13, 15, and 17--appeared to be randomly involved. The clinico-biologic features of our cases with a variant t(8;21) are consistent with those of the published cases with the standard t(8;21), and support the hypothesis that the critical genetic alteration produced by the t(8;21) is located on the derivative 8.

Adolescent↗
PubMed1994

Oxidant damage to erythrocyte membrane in glucose-6-phosphate dehydrogenase deficiency: correlation with in vivo reduced glutathione concentration and membrane protein oxidation.

Chronic nonspherocytic hemolytic anemia has been observed in a recently described glucose-6-phosphate dehydrogenase (G6PD) variant, G6PDWayne. The mechanical properties of these erythrocytes and other G6PD variants were examined. The deformability of G6PD-deficient erythrocytes was normal, as determined by osmotic scan ektacytometry, and was not significantly affected by hemolytic crisis. In the common varieties of G6PD deficiency, the mechanical stability of the red blood cell (RBC) membrane was greater than normal, but G6PDWayne membranes were abnormally susceptible to shear-induced fragmentation. There was no evidence for a concurrent genetic defect in spectrin, because self-association constants and tryptic digests were normal. The fragility of G6PDWayne membranes appeared to be a consequence of oxidative damage to membrane thiol groups associated with a low glutathione (GSH) level in these RBCs. Associations among GSH level, thiol oxidation, and membrane instability were also found when a larger group of G6PD-deficient RBCs were examined. In normal erythrocytes, 1-chloro-2,4-dinitrobenzene was used to reduce GSH levels by 50%. Membrane thiol oxidation and membrane fragility both increased when these cells were kept at 4 degrees C for 3 to 5 days. Our findings suggest that chronic depletion of GSH leads to the destabilization of membrane skeleton through oxidation of membrane protein thiols.

Child↗