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J Sklar

Publications and source records attributed to J Sklar.

At least 127 records · Page 7Linked to original sources
PubMed1985

Acute leukemias associated with the 4;11 chromosome translocation have rearranged immunoglobulin heavy chain genes.

Studies of acute leukemia with the 4;11 translocation have yielded conflicting results regarding the lineage of the cell of origin in this disease. To investigate this issue further, we have examined the state of immunoglobulin genes in tumor cells from two affected patients, immunophenotyped their leukemic cells using a number of monoclonal antibody reagents with specificities for lymphoid or myelomonocytic antigens, and examined the malignant cells by electron microscopy. DNA was extracted from leukemic bone marrow cells and hybridized with radiolabeled DNA fragment probes specific for the constant region of immunoglobulin heavy chain and kappa and lambda light chain genes. Autoradiographs revealed rearrangement of both allelic heavy chain genes, but a germline configuration of light chain genes in both cases. Surface marker analysis showed that blasts from both patients expressed HLA-DR and the myeloid antigens Leu-M1, 1C2, 2D1, and 4B3, but lacked common acute lymphocytic leukemia antigen or T antigens. Furthermore, they did not have sheep erythrocyte receptors nor did they express surface or cytoplasmic immunoglobulin or B cell precursor determinants. Electron microscopy analysis showed that blast cells from patient 1 exhibited numerous monoribosomes, polyribosomes, and isolated strands of rough endoplasmic reticulum in their cytoplasm. These ultrastructural features are characteristic for both common acute lymphocytic leukemia and pre-B-ALL cells, but not for T-ALL or acute myelogenous leukemia cells. Peroxidase was undetectable in cells from both patients. Our study suggests that this disorder represents a unique subtype of leukemia. The cell of origin may be an early B cell progenitor that shares certain surface antigens with myeloid cells or a stem cell with the potential for both lymphoid and myelomonocytic differentiation.

Antigens, Neoplasm↗
PubMed1985

DNA rearrangements in non-Hodgkin's lymphomas.

The configuration of DNA at genetic loci that undergo somatic recombination in lymphocytes provides genetic markers that are useful in the diagnosis and characterization of non-Hodgkin's lymphomas. The loci containing rearranged DNA fall into three groups: the immunoglobulin genes, the T cell receptor genes and sites of chromosomal rearrangements, such as chromosomal translocations. DNA fragments cloned from these loci can be used as hybridization probes to characterize the rearranged DNA sequences in biopsy tissues. Only probes for chromosomal rearrangements are capable of directly diagnosing neoplasia and histological subtypes; however, probes for rearrangements of immunoglobulin and T cell receptor genes are valuable for detecting clonal proliferations, determining B or T cell derivation of tumours and distinguishing individual clones of lymphocytes from each other. Applications of DNA rearrangements have already yielded a number of important findings concerning the biology of human lymphoma. These discoveries have included the existence of multiclonal B cell cancers, the widespread dissemination of occult tumour to lymph nodes in mycosis fungoides, the high incidence of circulating tumour cells in patients with low grade lymphomas and the molecular heterogeneity of chromosomal break-points in follicular lymphomas.

B-Lymphocytes↗
PubMed1985

Frequent immunoglobulin and T-cell receptor gene rearrangements in "histiocytic" neoplasms.

The authors have analyzed the DNA of immunoglobulin and T-cell receptor genes in a series of 6 malignancies which were judged to be of histiocytic derivation on the basis of morphologic criteria. They found that 4 of these cases showed rearrangements of the beta T-cell receptor genes in spite of the lack of any specific immunohistochemical markers for B or T cells. One case showed rearrangements of both heavy and light chain immunoglobulin genes and probably represents either a sinusoidal large cell lymphoma or a B-cell lymphoma with activation of histiocytes simulating malignant histiocytosis. A single case lacked both immunoglobulin and T-cell receptor rearrangements consistent with immunologic analyses that suggested its origin from an interdigitating reticulum cell. The result of this study in conjunction with the authors' previous immunologic observations suggests that many presumed histiocytic malignancies actually represent T-cell lymphomas. Alternatively, beta T-cell receptor rearrangement may be a common feature of tumors that show monocyte/histiocytic differentiation.

Antibodies, Monoclonal↗
PubMed1985

Detection of two distinct malignant B cell clones in a single patient using anti-idiotype monoclonal antibodies and immunoglobulin gene rearrangement.

Immunoglobulin gene rearrangement analysis and somatic cell hybridization techniques were used to examine the malignant cell population in an unusual patient with hairy cell leukemia and macroglobulinemia (N Engl J Med 296:92, 1977). Although previous investigations suggested that the IgM macroglobulin was secreted by the circulating leukemia cells, anti-idiotype monoclonal antibodies raised to the IgM macroglobulin failed to react with the malignant cells in the circulation and bone marrow. In contrast, approximately 50% of the mononuclear cells from an enlarged inguinal lymph node reacted strongly with the anti-idiotype antibodies. Subsequent reanalysis of all cell populations demonstrated that whereas the circulating and bone marrow cells were IgM kappa-bearing, the macroglobulin was IgM gamma-bearing and the lymph node cells were evenly divided among IgM kappa-bearing and IgM gamma-bearing. Immunofluorescence flow cytometry indicated that those lymph node cells that reacted strictly with the anti-idiotype antibody were IgM gamma-bearing, demonstrating that they were the source of macroglobulin. An analysis of immunoglobulin gene DNA confirmed the coexistence of two distinct malignant B cell populations in the lymph node and indicated that the IgM kappa-bearing lymph node cells were identical to the circulating and bone marrow leukemic cells.

Aged↗
PubMed1985

Most null large cell lymphomas are B lineage neoplasms.

DNA of immunoglobulin and the beta T cell receptor genes was analyzed for rearrangements in 34 diffuse large cell lymphomas that failed to express immunoglobulins or T cell antigens. Twenty-eight cases had both heavy and light chain immunoglobulin rearrangements, two cases had only heavy chain gene rearrangements, three cases had only light chain gene rearrangements, and one case failed to show rearrangements for any of the immunoglobulin genes. None of the cases showed rearrangements for the beta T cell receptor gene. These results indicate that the vast majority of diffuse large cell lymphomas that lack definitive B or T cell phenotypic markers are actually B cell in origin.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1984

Lymphoproliferative disorders in cardiac transplant recipients are multiclonal lymphomas.

Tissue specimens from 5 immunosuppressed cardiac transplant recipients with lymphoproliferative disorders were examined for rearrangements in immunoglobulin DNA. In each case DNA analysis of tissues obtained from several sites or at various times showed different clonal immunoglobulin gene rearrangements for each of the three immunoglobulin gene loci. These findings indicate that lymphoproliferative disorders in immunosuppressed cardiac transplant recipients represent multiclonal or oligoclonal B cell lymphomas.

Biopsy↗
PubMed1984

Biclonal B-cell lymphoma.

The cells of most tumors are considered to be genetically homogeneous because they are assumed to represent a single clone descended from one abnormal cell. We have discovered three cases of B-cell lymphoma for which this generalization is not true. In each case, the tumor was composed of two subpopulations of cells, each expressing a different immunoglobulin molecule. Antibodies directed against these immunoglobulins were used to separate the two cell subpopulations of each tumor on a fluorescence-activated cell sorter. DNA extracted from the original tumor and the two fractionated subpopulations was analyzed to determine the configuration of immunoglobulin genes. Differences were found in the arrangement of DNA in at least one immunoglobulin gene for each of the two subpopulations. Thus, biclonality of these tumors was revealed by examination of both protein markers (cell-surface immunoglobulin) and DNA markers (immunoglobulin-gene rearrangements). Our results indicate that the incidence of biclonal B-cell lymphoma may be higher than previously recognized, possibly as high as 10 per cent of all B-cell lymphomas. Furthermore, our findings may have important implications for the diagnosis and therapy of lymphoid cancers.

Adult↗
PubMed1984

Monoclonality of lymphoproliferative lesions in cardiac-transplant recipients. Clonal analysis based on immunoglobulin-gene rearrangements.

Whether lymphoproliferative disorders arising in immunosuppressed recipients of organ transplants are primarily neoplastic or hyperplastic in nature is a matter of controversy. Reports of polyclonal B-cell proliferations in these lesions suggest the presence of hyperplasia, but these disorders resemble lymphoma histologically and are clinically aggressive and often rapidly fatal, as expected of a malignant neoplastic disease. We examined tissue specimens from 10 cases of lymphoproliferative disease that occurred in immunosuppressed recipients of cardiac transplants. Specimens from nine of these patients lacked cellular immunoglobulin; however, analysis of DNA extracted from these tissues revealed that each lesion contained large numbers of cells possessing uniform, clonal rearrangements of immunoglobulin-gene DNA. Therefore, when first seen clinically these proliferations contained a notable monoclonal-cell population typical of conventional B-cell lymphomas that are not associated with immunosuppression. We therefore suggest that lymphoproliferative disorders in recipients of cardiac transplants are neoplastic at the earliest stages of detectable disease.

Adolescent↗
PubMed1984

Immunoglobulin gene rearrangement as a diagnostic criterion of B-cell lymphoma.

We describe the use of the Southern blot hybridization technique to diagnose B-cell lymphoma by detecting clonal immunoglobulin gene rearrangements in lymph node and other biopsy tissues. DNA was isolated from a wide variety of neoplastic and non-neoplastic specimens and analyzed for the presence of rearranged immunoglobulin genes using radiolabeled DNA probes specific for the heavy- and light-chain immunoglobulin constant region genes. Among the specimens examined, clonal immunoglobulin gene rearrangements were found only in biopsy samples of B-cell lymphoma and not in samples containing reactive lymphoid processes or non-B-cell cancers. In lymphomas, the presence of rearrangements for either the kappa or lambda light-chain gene correlated with expression of one or the other of these chains when cellular immunoglobulins could be detected by frozen-section immunophenotyping techniques. The analysis of immunoglobulin gene rearrangements offers several advantages over conventional diagnostic methods for lymphomas, including improved sensitivity in detecting minor populations of neoplastic lymphocytes composing as little as 1% of the total cell population. In addition, clonal immunoglobulin gene rearrangements are demonstrable in a subset of lymphomas that lack detectable surface or cytoplasmic immunoglobulin, thus offering positive evidence for both malignancy and the B-cell origin of these tumors. Our studies indicate that detection of immunoglobulin gene rearrangements is a valuable method for diagnosis and classification of various lymphoproliferative disorders that are difficult to evaluate histologically or that lack distinctive antigenic markers.

B-Lymphocytes↗
PubMed1984

Immunoglobulin gene rearrangements in hairy cell leukemia.

Studies of hairy cell leukemia have yielded conflicting data about the cell of origin in this disease. To investigate this issue, we have examined the state of immunoglobulin genes in the cells of 11 randomly selected spleens showing histologic involvement with hairy cell leukemia. DNA was extracted from splenic tissue samples and digested with restriction endonucleases. Following agarose gel electrophoresis and transfer to nitrocellulose filters or activated nylon membranes, splenic DNA was hybridized with radiolabeled DNA fragment probes specific for the constant regions of the immunoglobulin heavy chain and kappa and lambda light chain genes. Autoradiograms of the hybridized DNA in each case revealed rearrangements of a heavy chain gene and at least one light chain gene. In addition, immunophenotyping of cellular immunoglobulin polypeptides was carried out on frozen tissue sections from all but one case. In each case in which an immunoglobulin polypeptide could be detected, a rearrangement was present in the DNA of the corresponding immunoglobulin gene. These studies offer strong evidence for endogenous immunoglobulin synthesis in hairy cells and for the B lymphocytic character of this leukemia.

B-Lymphocytes↗
PubMed1983

Thallium-201 myocardial imaging during maximal and submaximal exercise: comparison of submaximal exercise with propranolol.

Propranolol is an effective drug for patients with angina and has been shown to favorably alter exercise ejection fraction and myocardial perfusion images in patients with coronary disease. A characteristic effect of propranolol is reduction in exercise heart rate (HR). Twenty men with coronary disease (10 with prior infarction), angina-limited exercise tests, abnormal myocardial blood flow distribution images (MBFDI) (201thallium) during exercise, and normal resting ejection fractions underwent treadmill exercise testing with imaging on three occasions. Control maximal exercise was performed initially with measurement of MBFDI. Propranolol, 40 mg by mouth four times a day, was administered for a week with exercise repeated to the same workload. A third study, with men off propranolol, was undertaken with exercise continued only to the HR obtained while the men were taking propranolol (submaximal exercise). All men had improvement in MBFDI while receiving propranolol (men without infarction +780 +/- 88 [average +/- SEM] normalized count rate difference between control and propranolol; men with infarction +724 +/- 73 normalized counts). Greater count differences were noted when control exercise and HR-controlled, submaximal exercise MBFDI were compared with a greater difference in men with infarction (+1094 +/- 89 normalized counts) than for men without infarction (+896 +/- 88 normalized counts). Results suggest that propranolol improves MBFDI during exercise in men with angina, but that submaximal exercise results in more normal MBFDI than does propranolol for exercise to the same HR.

Angina Pectoris↗
PubMed1982

The effects of a cardioselective (metoprolol) and a nonselective (propranolol) beta-adrenergic blocker on the response to dynamic exercise in normal men.

We compared the effects of a cardioselective beta-adrenergic blocking drug, metoprolol, with a nonselective beta-adrenergic blocker, propranolol, on the response of 10 normal men to dynamic treadmill exercise. The volunteers underwent a standard graded exercise test to exhaustion while receiving placebo; propranolol, 40 mg every 6 hours; propranolol, 80 mg every 6 hours; metoprolol, 50 mg every 6 hours; or metoprolol, 100 mg every 6 hours. The drugs were given in a double-blind fashion for 48 hours before exercise. Five days were allowed between successive drug administrations and the order of drug administration was randomized. Heart rate, arterial pressure, oxygen consumption, minute ventilation and CO2 production were monitored. Plasma drug concentrations were measured at the time of exercise. Judged by plasma levels, propranolol was about three times more potent than metoprolol in attenuating heart rate. Both drugs produced a wide variation in plasma levels after a given oral dose, and both drugs attenuated the systolic blood pressure response to exercise. Neither drug affected diastolic blood pressure or maximum oxygen consumption, maximum minute ventilation or the anaerobic threshold. We conclude that there is no evidence that the cardioselective drug metoprolol is superior to propranolol in terms of the ability to perform or respond to short-term maximal exercise. In addition, the fact that maximal oxygen consumption and the anaerobic threshold were unaffected implies that fatigue during exercise while on beta-adrenergic blocking drugs is not due to an effect of these drugs in limiting blood flow to the exercising extremities.

Adult↗
PubMed1982

Slow late myocardial clearance of thallium: a characteristic phenomenon in coronary artery disease.

We extended the quantitative seven-pinhole method to follow the dynamics of thallium redistribution after exercise. We observed a pattern of slow late thallium clearance that appears to be characteristic of myocardium supplied by obstructed coronary arteries. In 28 subjects, quantitative thallium scintigrams (seven-pinhole tomography, circumferential count profiles) and blood samples for thallium concentration were taken immediately, 2 hours and 4 hours after maximal treadmill exercise. Twenty subjects had coronary artery disease (CAD) and eight were normal. The rate of thallium clearance from the blood (TCB) was compared with the rate of thallium clearance from each segmental region of myocardium (TCM, derived by ratioing corresponding segments of the absolute circumferential count profiles) between the 2- and 4-hour images. In seven of the eight normal subjects, TCM exceeded TCB in all regions of all images (specificity 88%). Seventeen of the 20 CAD patients had at least one region where TCM was less than TCB (sensitivity 85%). Of the 13 patients with multivessel CAD, 11 had multiple regions with TCM less than TCB. Using this criterion, we detected 31 of 39 obstructed coronary arteries. Of the 37 regions that were abnormal by this analysis, 30 corresponded to obstructed coronary arteries. In contrast, while conventional circumferential count profile analysis also was abnormal in 17 of the 20 CAD patients, it diagnosed multivessel CAD in only five of the 13 patients that had it. These results show that slow late thallium clearance from myocardium is characteristic of regions of myocardium supplied by diseased coronary arteries and that observation of this phenomenon may improve diagnostic sensitivity for the presence of multivessel CAD.

Coronary Disease↗
PubMed1982

Single-photon emission tomography with a 12-pinhole collimator.

To assess the advantages of more complete angular sampling and of more views in the tomographic reconstruction process, tomographic imaging with a 12-pinhole (12PH) collimator has been compared with 7-pinhole tomography (7PH). The 12PH system gives a 50% increase in sensitivity but resolution degrades more rapidly with depth. The 7PH and 12PH systems provide similar accuracy of detection of lesions in a myocardial ring phantom. The 7PH images, however, demonstrated more noise and "ripple" artifacts. The 12PH system offers a larger reconstruction volume and generates fewer artifacts when the collimator is misaligned with the myocardial long-axis, thus making patient positioning less critical than with 7PH. A disadvantage is that individual views are minified by the 12PH collimator, and a 256 X 256 image matrix should be used during image acquisition to limit digital sampling errors.

Evaluation Studies as Topic↗
PubMed1977

Determination of the nucleotide sequence of part of the regulatory region for the galactose operon from Escherichia coli.

We have determined the sequence of 59 base pairs in the DNA preceding the site for initiation of transcription in the galactose operon. DNA from a lambdagal transducing phage was digested with restriction endonucleases to obtain a DNA fragment from the gal regulatory region. This fragment extends from 59 base pairs prior to the transcription initiation site through the 45 base pairs which specify the 5'-terminal sequence of gal mRNA. Analyses of RNA transcripts derived from this fragment and a variety of direct DNA sequence analyses allowed us to deduce the following sequence for the DNA in this fragment: (formula: see text) Position +1 corresponds to the site for initiation of gal mRNA synthesized in the presence of cyclic AMP and its receptor protein, CRP. Transcription experiments indicate, however, that this fragment lacks some element of the gal promoter required for the stimulation of transcription by CRP-cAMP. There are, nonetheless, some similarities between the gal sequence preceding the transcription start site and the sequences of other promoter regions. These include the heptamer sequence T-A-T-G-G-T-T (--12 to --8) and the sequence A-C-A-C-T-T-T (--36 to --30).

Alkylation↗
PubMed1977

Codeine-induced pulmonary edema.

We recently treated a patient with pulmonary edema and an oral overdose of codeine. Although overdoses of other opiate drugs are known to cause pulmonary edema, the association of an overdose of codeine with pulmonary edema has not been reported previously.

Adult↗