Biomedical subjects

B V Mendelow

Publications and source records attributed to B V Mendelow.

31 records · Page 2Linked to original sources

PubMed1989

Clinical relevance of immunophenotypic and immunogenotypic analysis in acute non-lymphoblastic leukaemia.

Molecular biology is playing an increasing role in defining pathology today, and has clinical relevance in the routine work-up of patients with malignant diseases, especially those of the blood and lymphatic system. The majority of acute non-lymphoblastic leukaemias (ANLL) express specific myeloid differentiation markers and are terminal deoxynucleotidyl transferase (Tdt) negative. Rarely, some cases are Tdt+ and express the T-cell marker CD7. Although uncommon in Tdt-ANLL, there appears to be a significant incidence of T-cell receptor beta chain (TCR beta) and/or immunoglobulin heavy chain (IgH) gene rearrangements in Tdt+ ANLLs. We have investigated the immunogenotype of 39 patients with ANLL, including 28 from whom immunophenotypic data were available. Thirty-seven of 39 cases had germline IgH and TCR beta genes. Two cases, one with a myeloid/CD7+ CD2+ immunophenotype, had non-germline IgH gene arrangements detectable on Hind III digests only. The possibility of Hind III polymorphisms, or of true somatic gene rearrangement of the IgH gene in these patients, is discussed. Two additional cases had a Tdt+ CD7+ immunophenotype with germline IgH and TCR beta chain genes. Our results confirm the infrequent occurrence of IgH and TCR beta gene rearrangements in ANLL. Expression of Tdt and/or CD7, often in association with IgH gene rearrangements, would appear to identify a subgroup of ANLL patients that respond poorly to standard ANLL therapy and have a poorer prognosis. The diagnostic and prognostic importance of multiparametric analysis in ANLL is emphasised.

Adolescent↗

PubMed1989

The routine diagnostic utility of immunoglobulin and T-cell receptor gene rearrangements in lymphoproliferative disorders.

Immunophenotypic studies have a well-documented role in the assignment of lineage in the lymphoproliferative disorders. With the exception of mature B-cell disorders, it is difficult to demonstrate clonality by immunophenotypic studies. The advent of specific DNA probes for immunoglobulin and T-cell receptor genes has greatly facilitated the detection of clonality and, to a lesser degree, lineage, in these cases. The authors have evaluated the diagnostic utility of these probes and compared them with standard immunophenotyping in 65 patients with a variety of lymphoproliferative disorders. Their results show a significant correlation (P less than 0.01) between lineage assignment as determined by phenotyping and gene rearrangement studies, with the latter far superior in determining clonality. Furthermore, analysis of gene rearrangements facilitated the documentation of lineage and/or clonality in six cases in which standard techniques had failed. Although the scientific basis of the study of gene rearrangements has been well established, the authors wish to emphasize the role that these techniques have in evaluating problem cases in the routine diagnostic laboratory.

DNA Probes↗

PubMed1989

Selective culture of primate marrow-derived macrophages in medium devoid of protein additives.

Viable cultures of bone marrow-derived macrophages (BMM phi) from a primate source, the baboon, were maintained for up to 4 weeks in culture in the absence of any exogenous protein in the medium. Baboon peripheral blood monocytes, spleen, lung, and liver M phi s or human BMM phi failed to survive for greater than 4 days. The protein-free BMM phi cultures were morphologically distinctive by virtue of the extremely dendritic appearance of the M phi s. In contrast baboon marrow cultured in the presence of fetal calf serum led to the overgrowth of fibroblastoid cells and in the presence of horse serum produced numbers of giant cells or polykaryocytes in addition to M phi s. The BMM phi were capable of nonimmune phagocytosis of yeast particles, expressed Ia antigen on their surfaces (59%), and were positive cytochemically for nonspecific (alpha-naphthyl acetate) esterase, oil red O, and tartrate resistant acid phosphatase. The addition of sera to established protein-free BMM phi cultures induced a rapid change of shape, viz., retraction of the dendritic processes and rounding up of the M phi s apparent within 10 min. This shape change was not induced by the addition of hemopoietic growth factors granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), macrophage CSF (M-CSF), or interleukin 3 (IL-3), nor could it be inhibited by the calcium channel blocking agent Nifedipine. Low levels of M-CSF activity, assayed by the murine bone marrow proliferation assay, were detected in the supernatant.

Animals↗

PubMed1988

Platelet parameters. Part I. Platelet counts and mean platelet volume in normal and pregnant subjects.

Platelet counts and mean platelet volume (MPV) were studied in 564 normal subjects and 297 pregnant women using a Coulter Model S-Plus electronic counter. The reproducibility of these measurements both intra- and inter-sample was documented. The mean platelet count in the normal group was 283 x 10(9)/l while the mean MPV was 9.32 fl. An inverse correlation between platelet volume and platelet number was documented (r = -0.38; P less than 0.0001). By interval analysis, this inverse relationship was shown to be non-linear. In the pregnant subjects there appeared to be a progressive decrease in platelet count with advancing gestation; this reached a significant level when the first and third trimesters were compared with each other (P less than 0.05). The MPV was unchanged. The fact that the platelet count decreased in proportion to the red cell count suggested that a common factor, such as haemodilution, was in part responsible. There was again an inverse relationship between MPV and platelet number (r = -0.39; P less than 0.0001) shown to be non-linear by interval analysis.

Blood Platelets↗

PubMed1988

Daily exposure to forty percent oxygen causes a decrease in platelet count.

A study was undertaken to evaluate a previous observation made in this laboratory that hyperoxic treadmill training is associated with a decrease in the circulating platelet count (PLT). The subjects studied breathed air containing 40% oxygen for 30 min/day, 5 days/week, for 6 weeks, while at rest in the seated position. Such exposure resulted in a consistent fall in PLT between day 1 and day 5 of each week (P less than .01). In addition, there was a progressive decline in PLT over the 6 weeks of exposure to the hyperoxic air, PLT being inversely correlated with the duration of hyperoxic exposure (rs = -0.886, P less than .02). The total decrease in PLT over the 6 weeks was 56 +/- 46 x 10(9) l(-1) (P less than .025). Not surprisingly, these changes were mirrored in the plateletcrit (Pct). The decrease in PLT did not appear to be secondary to either hemodilution or reduced erythropoietic stimulation. The mechanism of production and the biological significance of these changes remain to be elucidated.

Administration, Inhalation↗

PubMed1987

Unusual presentation of malaria as a leukaemoid reaction. A case report.

In a 4-year-old black patient with Plasmodium falciparum malaria the diagnosis was established by observing plentiful gametocytes in the peripheral blood, although ring forms were very scanty. The blood picture was that of a leukaemoid reaction with severe anaemia, high total leucocyte count and thrombocytosis. Treatment with chloroquine and primaquine, together with packed red cell transfusions, was successful in eliminating both the malaria parasites and the leukaemoid blood picture. The rarity of malaria presenting as a leukaemoid blood picture is discussed.

Child, Preschool↗

PubMed1987

Acute mixed-lineage leukaemia involving myeloid and T-cell phenotypes. A case report.

Among the rare acute mixed-lineage leukaemias, a myeloid T-cell phenotype has recently been recognised. An additional case characterised by myeloid cytochemistry, development of Auer rods in culture and Tdt, WT1 and T11 phenotypes on cell-marker analysis is reported. The patient died from disseminated non-reactive tuberculosis after chemotherapy.

Adolescent↗

PubMed1987

Reactive thrombocytosis in pulmonary tuberculosis.

The incidence of reactive thrombocytosis in active pulmonary tuberculosis was studied in 122 patients. Thrombocytosis was common, platelet counts often exceeding 1 X 10(12)/1. A significant inverse correlation was noted between the mean platelet volume and the platelet count (r = -0.54, p less than 0.0001). Interval estimation suggested that this relation was non-linear. Further studies were done in a small group of six patients. Platelet survival was considerably shortened, the platelets aggregated excessively in vitro, serum concentrations of thrombopoiesis stimulating activity were raised, and serotonin uptake and release were within normal limits. The degree of thrombocytosis correlated significantly with the degree of inflammation measured by the erythrocyte sedimentation rate (r = 0.40, p less than 0.003) and serum C-reactive protein concentration (r = 0.35, p less than 0.008).

Arachidonic Acids↗

PubMedDate not supplied

Mechanism of thrombosis caused by sclerotherapy of esophageal varices using sodium tetradecyl sulphate.

The mechanism of thrombosis following intravariceal injection of sodium tetradecyl sulphate (S.T.D.) was investigated with respect to effects on the vascular endothelium, the coagulation cascade, and platelet function. Using an umbilical cord model designed to simulate blood flow over the endothelium, it was found that S.T.D. is a potent toxin for endothelial cells in that brief exposure to even low concentrations of the agent were effective in stripping endothelium over a considerable distance, exposing highly thrombogenic endothelium in the process. Effects on coagulation and platelet function were found to be dependent on concentration. Diluted S.T.D. induced a hypercoagulable state, possibly in consequence of a selective inhibition of the physiological anticoagulant, protein C, and promoted platelet aggregation. Higher concentrations inactivated the coagulation cascade and lysed platelets completely. These results suggest that intravariceal infusion of S.T.D. at considerable dilution may be at least as effective in inducing thrombosis as standard dosage, and possibly more so.

Blood Coagulation↗

PubMedDate not supplied

Puromycin is a potent and specific inhibitor of tyrosine kinase activity in HL-60 cells.

The search for specific tyrosine kinase inhibitors constitutes a novel approach to the development of anticancer agents. Puromycin (PM) inhibits protein synthesis by causing the premature release of truncated PM-peptide complexes (PMPs), the structure of which predicts an inhibitory effect on tyrosine kinase activity (21). The present study was undertaken to investigate the effects of a low dose of PM (0.9 microM) on tyrosine kinase activity in HL-60 leukaemic cells. Experiments were specifically controlled to exclude inhibitory effects consequent on protein synthesis blockade. Soluble enzyme extracts derived from PM-treated cells showed attenuated phosphorylation of two independent synthetic tyrosine kinase-specific substrates, the polymer Poly(Glu:Tyr; 4:1) and the peptide substrate Raytide. In contrast, Protein Kinase C-specific activity was unaffected by PM-exposure. It is possible that inhibition was due to metabolites of PM, perhaps PMPs, rather than to PM itself. Whether the inhibition of tyrosine kinase activity observed with the substrates used in this study is equally applicable to all tyrosine kinases, is not yet clear. Nevertheless, low-dose PM could provide a useful tool for dissecting out the role of tyrosine phosphorylation in the regulation and dysregulation of cell growth, and could conceivably prove beneficial in the treatment of tumours in which tyrosine kinase overactivity is linked to oncogenesis.

Cycloheximide↗

PubMedDate not supplied

Protein synthesis inhibition is not a requisite for puromycin- and cycloheximide-induced c-myc mRNA superinduction.

The phenomenon of superinduction refers to the process by which high doses (30-180 microM) of the protein synthesis inhibitors Puromycin (PM) or Cycloheximide (CHX) augment and stabilize mRNA transcript levels through mechanisms which are dependent on the complete inhibition of protein synthesis. The current study undertaken in HL-60 leukaemic cells has dissociated the protein synthesis-inhibitory effects of PM and CHX from their c-myc mRNA superinducing effects. When employed at concentrations which were sub-inhibitory with respect to protein synthesis (0.2 microM), PM and CHX nevertheless elicited the phenomenon of superinduction, possibly through mechanisms related to intracellular signalling.

Cycloheximide↗

PubMedDate not supplied

Puromycin-elicited c-myc mRNA superinduction precedes apoptosis in HL-60 leukaemic cells.

The phenomenon of superinduction refers to the process by which high concentrations of protein synthesis inhibitors augment and stabilize mRNA transcript levels, e.g. 36-180 microM of Puromycin (PM) has been found to elicit c-myc mRNA superinduction. The expression of the proto-oncogene c-myc has been strongly variously implicated in the regulation of the apoptotic cascade. Since we recently found that a low dose of the protein synthesis inhibitor PM activated the apoptotic cascade in HL-60 leukaemic cells, the current study was undertaken to examine c-myc mRNA transcript levels in such cells, and to assess the relationship, if any, between PM-elicited c-myc mRNA superinduction and subsequent activation of the apoptotic cascade. PM was employed in vitro at doses of 0.9 microM and 2 microM. Dose-dependent c-myc mRNA superinduction was present at 1 hour of PM-exposure, and was associated with subsequent activation of the apoptotic cascade at 24 hours of exposure. Apoptosis was confirmed morphologically as evidenced by chromatin condensation, nuclear fragmentation and the formation of apoptotic bodies, and by DNA agarose gel electrophoresis which showed the pattern of double-stranded DNA fragments that result from the activation of an endogenous endonuclease. [C14]Leucine incorporation studies at 1 hour demonstrated minimal protein synthesis inhibition at doses used, suggesting that c-myc mRNA superinduction in this context may have been the result of mechanisms which were independent of the inhibition of synthesis of new proteins, such as interruptions in signal transduction.

Apoptosis↗

PubMedDate not supplied

C-myc expression is down-regulated in mafosfamide-treated HL-60 cells undergoing apoptosis.

The expression of the proto-oncogene c-myc has been strongly implicated in the regulation of apoptosis. Since we have previously shown apoptosis to occur in HL-60 leukemic cells exposed to the prodrug Mafosfamide (ASTA Z 7557), the present study was undertaken to examine the levels of c-myc mRNA transcripts in such cells. Mafosfamide, which is a cyclophosphamide derivative that rapidly generates 4-Hydroperoxycyclophosphamide after aqueous dissolution, was employed in doses ranging from 0.1 to 20 micrograms/ml. No changes in c-myc mRNA levels were evident after 1 hour of exposure to Mafosfamide. After 6 and 24 hours of Mafosfamide-exposure, however, there was a dose- and time-dependent decrease in c-myc transcripts. c-myc mRNA expression was reduced to a greater extent than was either beta-actin of GAPDH expression. Morphological, biochemical and ultrastructural evidence of apoptosis accompanied the Mafosfamide-induced c-myc mRNA down-regulation at 24 hours. We conclude that, in the context of Mafosfamide-treated HL-60 cells, upregulation of c-myc mRNA transcription was not fundamental for the activation of the apoptotic cascade.

Actins↗