Biomedical subjects
Publications and source records attributed to S Mathew.
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We report the clinical, hematologic, and cytogenetic findings for a child with secondary myelodysplastic syndrome (MDS) after treatment for a primitive neuroectodermal tumor. At the time of conversion to MDS, conventional cytogenetics revealed an unbalanced der(6)t(1;6) that resulted in trisomy of the long arm of chromosome 1 and partial monosomy and duplication of 6p. Using alpha satellite probes, fluorescence in situ hybridization of bone marrow cells showed that the rearranged chromosome contained the centromeres of both chromosomes 1 and 6, thus forming a dic(1;6) resulting in trisomy 1q. This report is the first to describe a case of childhood secondary myelodysplastic syndrome associated with a trisomy 1q involving chromosome 6.
OBJECTIVE: To develop a simple, inexpensive method for testing direct drug susceptibility of tubercle bacilli to isoniazid (INH) and streptomycin (SM) which can be adopted for use even in remote parts of the world. DESIGN: Using 239 smear-positive sputum specimens obtained from an equal number of patients, a comparison was made between the direct swab susceptibility test and the standard indirect method for INH and SM using Löwenstein-Jensen (L-J) medium. RESULTS: There was 95% agreement of results for INH by 6 weeks and 90% for SM by 8 weeks; 96% of INH-resistant cultures could be detected in 5 weeks and 91% of SM-resistant cultures by 8 weeks. The discrepancies in the two tests were virtually symmetrically distributed at 6 and 8 weeks. The speed and efficiency of detection of resistance by the swab method was also assessed in relation to the standard indirect method. For INH, 96% of the cultures were detected by the fifth week, while 66% were detected as early as 2 weeks and 93% by 4 weeks. With SM, 84% were detected by 4 weeks, 89% by 5 weeks and 91% by 8 weeks. CONCLUSION: This study has indicated the usefulness of the swab method for testing the drug susceptibility of tubercle bacilli. As this method is simple and easy, and does not even require a centrifuge, it has the potential of application even in the remote parts of the world. The material used, Cetavlon (Cetrimide), is inexpensive and easily water soluble, and more importantly, aqueous solutions are self-sterilizing. It should be stressed, however, that the results obtained with this test take the same time as conventional methods, and it can therefore not be considered as a rapid test.
The MLL gene at 11q23 is frequently disrupted by chromosomal translocations in de novo acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), and in secondary leukemia induced by treatment with inhibitors of topoisomerase II, including the epipodophylotoxins. The CBFA2 gene at 21q22 is also frequently disrupted in de novo ALL and AML and less commonly in secondary AML. Rearrangements of MLL and CBFA2 have been described in de novo and secondary myelodysplastic syndrome (MDS). There have been no previous descriptions of coexisting abnormalities of MLL and CBFA2 in cases of MDS or acute leukemia. We describe a patient who developed secondary MDS after chemotherapy for hyperdiploid ALL. At the time of conversion to MDS, the patient had 46 chromosomes, with an 11q23/MLL translocation involving a new partner breakpoint at 2p23 and a 21q22/CBFA2 translocation involving a new partner breakpoint at 6p22. This report is the first to describe new partner breakpoints at 2p23 and 6p22 for MLL and CBFA2 genes, respectively, and concurrent rearrangements of these genes in a patient with secondary MDS.
We describe the isolation and characterization of a cDNA clone, called cCLP-1, that is a candidate for the previously described early cardiac-specific transcription factor BBF-1. BBF-1 binds the MEF2 (or element B) binding site within the cardiac myosin light chain 2 (MLC2) gene promoter. We used the element B sequence as a probe to screen an expression library constructed from mRNA obtained from the presumptive heart-forming regions of stage 6 chicken embryos. This yielded the cCLP-1 cDNA clone. Gel-shift analysis of stage 6 embryonic chicken protein extracts suggests that a protein that is recognized by the anti-cCLP-1 antibody binds to the same element B binding site to which BBF-1 binds. cCLP-1 mRNA was detected early in chicken development, prior to cardiac fate assignment at stage 4. The expression pattern of cCLP-1, based on whole mount in situ hybridization, coincides remarkably well with the established morphogenetic field of early heart formation. The nuclear localization of cCLP-1 is phosphorylation-dependent, suggesting that cCLP-1 may be a member of that class of transcription factors whose activity is regulated by cytoplasm to nucleus transport. Taken together, these data suggest that cCLP-1 may encode a novel transcription factor whose expression pattern is in agreement with that of the cardiogenic precursor cells of the early chicken embryo.
Methotrexate (MTX) is one of the most active and widely used agents for the treatment of acute lymphoblastic leukemia (ALL). To elucidate the mechanism for higher accumulation of MTX polyglutamates (MTX-PG) in hyperdiploid ALL and lower accumulation in T-lineage ALL, expression of the reduced folate carrier (RFC) was assessed by reverse transcription-polymerase chain reaction in ALL blasts isolated from newly diagnosed patients. RFC expression exhibited a 60-fold range among 29 children, with significantly higher expression in hyperdiploid B-lineage ALL (median, 11.3) compared with nonhyperdiploid ALL (median, 2.1; P <.0006), but no significant difference between nonhyperdiploid B-lineage and T-lineage ALL. Furthermore, mRNA levels of RFC (mapped by FISH to chromosome 21) were significantly related to chromosome 21 copy number (P =.0013), with the highest expression in hyperdiploid ALL blasts with 4 copies of chromosome 21. To assess the functional significance of gene copy number, MTX-PG accumulation was compared in ALL blasts isolated from 121 patients treated with either low-dose MTX (LDMTX; n = 60) or high-dose MTX (HDMTX; n = 61). After LDMTX, MTX-PG accumulation was highest in hyperdiploid B-lineage ALL with 4 copies of chromosome 21 (P =.011), but MTX-PG accumulation was not significantly related to chromosome 21 copy number after HDMTX (P =.24). These data show higher RFC expression as a mechanism for greater MTX accumulation in hyperdiploid B-lineage ALL and indicate that lineage differences in MTX-PG accumulation are not due to lower RFC expression in T-lineage ALL.
Lymphoid lesions of the parotid gland are much less common than their epithelial counterparts, and thus cytologic experience on fine-needle aspiration (FNA) is limited. FNA of lymphoid lesions with ancillary aids (flow cytometry and immunophenotypic studies) can make a definitive diagnosis. All FNAs of the parotid gland performed at the Johns Hopkins Hospital in an 8-yr span (1990-1998) were reviewed retrospectively. In all, 391 cases were done, of which 76 cases of lymphoid lesions were identified. The relevant cytology, histology, and flow cytometry were analyzed. Of the 76 lymphoid lesions, results included reactive lesions (n = 35), lymphoepithelial cysts (n = 27), malignant lymphomas (n = 12), an atypical lymphoid population (n = 1), and Sjogren's disease (n = 1). We conclude that both reactive and malignant lymphoid lesions of the parotid can be diagnosed on FNA with adjunctive tests such as flow cytometry and immunophenotyping, obviating the need for surgery. Diagn. Cytopathol. 1999;21:170-173.
The t(12;21)(p13;q22) is a cryptic abnormality observed in 25% of children with B-lineage acute lymphoblastic leukemia (ALL), associated with a favorable prognosis. To determine whether specific cytogenetic abnormalities accompany the t(12;21), we analyzed the cytogenetic profiles of blast cells from 169 ALL cases positive for the t(12;21), previously identified by molecular methods. Only 13.6% of samples had normal karyotypes. Structural changes were detected in 89.7% of abnormal karyotypes, and numerical abnormalities in 47%. Rearrangements of 12p were the most frequent structural aberration (57 out of 146 patients with chromosomal abnormalities). Nonspecific deletions of chromosomes 6 and 9 were also found. The most frequent numerical abnormalities was trisomy for chromosomes 21. Blast cells were pseudodiploid (45.6%), hyperdiploid with 47 to 51 chromosomes (24.3%), hypodiploid with 44 to 45 chromosomes (10%), near-triploid (0.6%), or near-tetraploid (5.9%). Our results show that the t(12;21) is not associated with hyperdiploidy of 52 to 68 chromosomes or with the prognostic t(1;19), t(4;11) or t(9;22). Only children with B-lineage ALL who lack these abnormalities detected by conventional cytogenetics will probably benefit from additional testing by molecular methods to detect the t(12;21).
Bone marrow samples from 67 children with acute leukemia and with cytogenetic evidence of chromosome 11 band q23 (11q23) abnormalities were characterized by fluorescence in situ hybridization (FISH) and Southern blot analysis to determine whether FISH could reliably detect MLL gene rearrangements in this population. Among the 42 patients with acute lymphoblastic leukemia (ALL), MLL gene rearrangements were detected in cells from 23 patients (54.8%) by both FISH and Southern blot analysis. FISH identified allelic deletions of MLL gene in five of 12 patients (42%) with ALL and with deletion of 11q23. In 22 of 25 children (88%) with AML, FISH detected MLL gene rearrangements, whereas Southern blot analysis identified rearrangements in 24 of 25 patients (96%). For children with acute leukemia and with 11q23 abnormalities, we recommend that FISH be used for the rapid screening of MLL gene rearrangements and that Southern blot analysis be used for the definitive assessment of the MLL gene status.
BACKGROUND: Phaeochromocytoma has been traditionally called the 'Tumour of Tens'. Many investigators have reported the prevalence of extra-adrenal phaeochromocytoma to be more than 10%. METHODS: All consecutive adult patients diagnosed to have phaeochromocytoma by the departments of endocrinology and surgical endocrinology of the Christian Medical Hospital, India, over a period of 10 years from 1988 to 1998, were included in the study. RESULTS: A total of 30 patients were diagnosed to have phaeochromocytoma. Extra-adrenal phaeochromocytoma accounted for 26.6% of cases, Ten per cent of cases were bilateral, 6.6% were malignant and one patient had a familial tumour (multiple endocrine neoplasia IIB). The tumours were localized pre-operatively in all patients. Multicentric extra-adrenal tumours were not found in this series. All patients except one were explored by the anterior transperitoneal approach. Persistent hypertension was noted in 30% of patients. CONCLUSIONS: Our series shows a higher prevalence (26.6%) of extra-adrenal tumours than the traditionally described 10%. With accurate pre-operative localization, a transperitoneal approach may not be necessary. The laparoscopic approach needs to be evaluated in light of these findings.
Four experiments were conducted investigating the role of phonology in repetition priming. Experiment 1 used a cross-modal priming paradigm in which participants made semantic judgments about spoken words and then performed a visual stem completion task. In Experiments 2-4, both the primes and the test stems were presented visually. The results of the first three experiments revealed that priming transfers across interpretations of a homophone. That is, seeing or hearing week primes both week and weak. The results of Experiment 4 showed that homophone priming cannot be attributed to the orthographic similarity of homophonic words. Together, these results indicate that repetition priming on a visual word completion task includes a phonological component.
The indirect susceptibility test results on L-J medium for tubercle bacilli against streptomycin, isoniazid and rifampicin were read at the end of 2 wk and compared with the results at 4 wk. It was found that drug resistance could be correctly predicted in over 70 per cent of cultures including multi-drug resistant tuberculosis (MDR TB) strains at the end of 2 wk. The susceptibility to para-nitrobenzoic acid (PNB) read at 2 wk was able to distinguish non-tuberculous mycobacteria from Mycobacterium tuberculosis cultures. The early detection of resistance by this procedure requires only minimum inputs, and can benefit the majority of patients harbouring drug resistant tubercle bacilli.
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Large deletions of exons 2 and 3 of the hprt gene are the most common type of hprt mutation in lymphocytes of newborn infants, and their frequency increases in cultured human T-lymphoid cells as a result of exposure to etoposide. Sequenced PCR products for these deletions are consistent with a V(D)J recombinase-mediated mechanism underlying their genesis. Herein, we describe the isolation and characterization of an etoposide-induced mutant CEM cell line that is clonal for a V(D)J recombinase-mediated exon 2 + 3 deletion. Human CCRF-CEM cells were exposed to 5 muM etoposide for 4 h, selected in 6-thioguanine, and an exon 2 + 3 deletion mutant was isolated through serial limiting dilution, using a PCR-based assay for detection of the exon 2 + 3 deletion. Untreated CEM cells and cells treated with 6-thioguanine alone were similarly subcultured. The exon 2 + 3 deletion-containing line was termed SJCEM808 and had a slightly longer doubling time than the control lines, tended to clump in suspension, and was characterized by cell membrane blebbing. Compared to the parent line, SJCEM808 had similar cytogenetic abnormalities, lower CD2, CD1, and CD10 expression, and negligible RAG-1 expression. However, RAG-1 expression was down-regulated in some untreated parental subclones following similar subculturing. The sequence of the exon 2 + 3 deletion mutation exhibited nucleotide insertions, and the breakpoints were adjacent to heptamer signal recognition sequences in intact hprt, consistent with a V(D)J recombinase-mediated mechanism underlying its genesis. There were no MLL gene or interlocus T-cell receptor (TCR) rearrangements. These results indicate that non-homologous recombination following etoposide treatment is neither necessarily accompanied by other large DNA rearrangements nor simply a pre-lethal event, and this cell line may serve as a useful tool for studying illegitimate V(D)J recombinase-mediated deletions.
Pentoxifylline, which has immunomodulatory effects in addition to its better known rheologic effects, might potentiate the effectiveness of traditional immunosuppressive drugs. We therefore studied the suppressive effect of pentoxifylline in combination with clinically relevant concentrations of prednisolone, methylprednisolone, cyclosporine, tacrolimus, rapamycin, and mycophenolic acid on mitogen-stimulated lymphocytes from 29 patients with glomerular diseases. Inhibition of lymphocyte proliferation obtained with 10(-7) and 10(-8) mol/L concentrations of the glucocorticoids and with 300 ng/mL cyclosporine was significantly increased when each was combined with 5, 25, or 50 microg/mL of pentoxifylline. The additive inhibitory effect of pentoxifylline in combination with 10(-7) mol/L glucocorticoids was inversely proportional to the inhibitory effect of the 10(-7) mol/L concentration of glucocorticoid alone, suggesting that the less sensitive the patient's cells, the greater the potentiation by pentoxifylline. The greatest degree of potentiation by pentoxifylline occurred when combined with the lower (10(-8) mol/L) concentration of glucocorticoids. Pentoxifylline also significantly increased lymphocyte suppression in combination with 150 and 300 ng/mL concentrations of cyclosporine, 5 ng/mL of tacrolimus, 2.5 x 10(-7) mol/L mycophenolic acid, and 10 ng/mL of rapamycin. These in vitro results suggest that pentoxifylline might have steroid-sparing effects and contribute to improved clinical outcomes from immunosuppressive treatment of renal diseases.
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BACKGROUND: In children with lower respiratory tract symptoms, the elicited signs are not enough to distinguish common diagnosis like pneumonic consolidation, foreign body aspiration and atelectasis. Radiology and bronchoscopy would identify the true nature of the etiology. DESIGN: Prospective study. SUBJECTS: Thirty five children with both acute and chronic lower respiratory tract symptomatology, were analyzed for clinical and radiological signs of atelectasis. RESULTS: There were 23 cases in the acute group and 12 in chronic group. Acute group included cases of pneumonia, foreign body aspiration and mucus plug syndrome. Chronic group included cases of congenital heart disease, endobronchial tuberculosis and bronchial stenosis. Clinical recognition of atelectasis on the basis of localized loss of breath sounds and mediastinal shift was seen only in a minority of cases (8/35). The presence of atelectasis in children with pneumonia, missed clinically were diagnosed by the presence of tracheal shift, elevated hemidiaphragm and silhouette sign. In 21 cases, silhouette sign was positive making it an important radiological sign. Twenty one children underwent either diagnostic or/and therapeutic bronchoscopy. Findings included foreign bodies (n = 5), mucus plugs (n = 4), narrowing of main bronchus (n = 4) and inflammatory mucoid secretions and narrowing of lumen (n = 8). There were no major complications. CONCLUSION: The diagnosis of atelectasis in children may pose difficulties and there is a need to have a high index of suspicion to exclude atelectasis in children with either acute or chronic respiratory tract symptomatology.
Consumption of ochratoxin-contaminated feed (10 mg/kg) by young rabbits for 90 days altered total and differential counts of WBC. Time dependent decline in WBC count indicates occurrence of cumulative toxicity.