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Biomedical subjects

J P Halper

Publications and source records attributed to J P Halper.

At least 19 recordsLinked to original sources
PubMed1997

Subsensitivity of adenylyl cyclase-coupled receptors on mononuclear leukocytes from drug-free inpatients with a major depressive episode.

Previous studies have demonstrated blunted beta-adrenergic responsivity in leukocytes from depressed patients. We sought to determine if this blunted cyclic adenosine monophosphate (AMP) response is specific for beta-adrenergic receptors (homologous), or whether other adenylyl cyclase-coupled receptors are also involved (heterologous), in order to localize this effect at the level of the receptor versus the coupling protein or the transducer, adenylyl cyclase. We studied adenylyl cyclase-mediated responses in peripheral blood mononuclear cells from 95 drug-free patients with a major depressive episode and 69 healthy controls. We found a similar degree of decrease in the peak cyclic AMP response to activation of the beta-adrenergic receptor (28%) and the prostaglandin receptor (34%) in the depressed patients, which indicated heterologous desensitization. Forskolin cyclic AMP responses were not blunted. Blunting of cyclic AMP responses to isoproterenol did not appear to correlate with levels of plasma norepinephrine and epinephrine or hypothalamic-pituitary-adrenocortical function. The absence of a decrease in the peak forskolin-generated cyclic AMP response, which involves direct activation of adenylyl cyclase, suggests an abnormality at the level of the coupling protein in these adenylyl-coupled receptors in depressed patients. Future studies need to determine whether this leukocyte signal transduction defect in depression also involves brain adenylyl cyclase-coupled receptors.

Adenylyl Cyclases↗
PubMed1992

Pursuit eye movement dysfunction in obsessive-compulsive disorder.

Disturbances in neural circuitry including the basal ganglia and prefrontal cortex have been hypothesized to be a cause of obsessive-compulsive disorder (OCD). Because eye movements are often impaired in neurologic diseases affecting these brain areas, oculomotor functioning was assessed in 17 unmedicated patients with OCD and in 25 normal controls. As compared with control subjects, patients with OCD demonstrated low-gain (slow) pursuit eye movements and an increased frequency of square wave jerk intrusions, but no increase in anticipatory saccades. In addition, several OCD patients showed an unusual pattern of intrusive, brief epochs of high-gain (fast) pursuit lasting on the order of 50 to 130 msec. These epochs of fast pursuit moved the eyes ahead of the target being tracked, and were terminated by corrective reversal saccades. Studies of eye movement abnormalities may provide an informative neurophysiologic approach for studying disturbances in basal ganglia and frontal cortical function that have been observed in functional neuroimaging and neuropsychological studies of OCD.

Adult↗
PubMed1991

Biochemical mechanisms of stress-induced impairment of rat T cell mitogenesis.

Splenic mononuclear cells isolated from rats exposed to two brief stressors (5 min of restraint or 2 min of footshock) showed a diminished response to the T cell mitogens, concanavalin A and phytohemagglutinin. Cells from these stressed animals also exhibited a diminished response to stimulation with the phorbol ester, tetradecanoylphorbol acetate (TPA), and/or the calcium ionophore, ionomycin. Since stimulation with these latter two agents mimics early signals generated by mitogen surface receptor binding including increased intracellular calcium and protein kinase C activation, the data indicate that stress-related defects in T cell proliferation occur at sites other than or in addition to these early events in cellular activation.

Analysis of Variance↗
PubMed1990

Normalization of blunted lymphocyte beta-adrenergic responsivity in melancholic inpatients by a course of electroconvulsive therapy.

Electroconvulsive therapy has been reported to desensitize brain beta-adrenergic receptors in rodents, but this effect has not been studied in man. We examined the effect of a course of electroconvulsive therapy on lymphocyte beta-adrenergic responsivity in 19 inpatients with melancholia. Before treatment, beta-adrenergic cyclic adenosine monophosphate response to isoproterenol was significantly blunted in the patients compared with controls. Following a course of electroconvulsive therapy, beta-adrenergic responsivity increased such that patients no longer differed from controls. Thus, blunted lymphocyte beta-adrenergic responsivity is a state-dependent effect of melancholia that can be corrected by a therapeutic course of electroconvulsive therapy. The effect of electroconvulsive therapy on this beta-adrenergic system is in the opposite direction to that reported for rodent forebrain, where electroconvulsive therapy causes desensitization, and may reflect differences between peripheral and central effects, species differences, or disease effects.

Cyclic AMP↗
PubMed1988

Blunted beta-adrenergic responsivity of peripheral blood mononuclear cells in endogenous depression. Isoproterenol dose-response studies.

Previous studies of peripheral blood mononuclear cells isolated from drug-free, hospitalized patients with endogenous major depression have demonstrated a diminished adenosine 3',5'-monophosphate (cyclic AMP) response to single concentrations of isoproterenol as compared with that obtained from normal control subjects. We now report results of isoproterenol dose-response studies that indicate lower basal levels of cyclic AMP as well as diminished cyclic AMP levels in response to isoproterenol stimulation at concentrations ranging from 10(-10) to 10(-5) mol/L in drug-free, hospitalized patients with endogenous depression. The major factor responsible for the diminished cyclic AMP production in the depressed patients was a loss of receptor sites capable of cyclic AMP production. Taken together with our previously reported finding that beta-adrenergic antagonist binding was normal in peripheral blood mononuclear cells obtained from depressed patients, the results of the dose-response studies suggest a loss of receptor function (desensitization) rather than a diminished number of receptor binding sites (down-regulation) as the underlying mechanism. Potential explanations for beta-adrenergic desensitization and its implications for the catecholamine hypothesis of depressive disorders are discussed.

Adult↗
PubMed1985

Reduced sensitivity of lymphocyte beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation.

It has been suggested that there are altered levels of norepinephrine or other neurotransmitters at functionally important receptors in patients with depressive disorders. This hypothesis is difficult to study in the human central nervous system. However, noradrenergic function can be assessed indirectly with peripheral-blood lymphocytes used as a model of the beta-adrenergic receptor complex. We found that drug-free inpatients with endogenous depression had lower isoproterenol-stimulated cyclic AMP levels in intact lymphocytes than did healthy control subjects (3.9 +/- 0.5 vs. 7.4 +/- 1.0 pmol per 10(6) cells, P less than 0.01). The density and affinity of beta-adrenergic receptors were similar in controls and depressed subjects (beta-receptor number, 5.4 +/- 0.7 and 5.3 +/- 0.8 fmol per 10(6) cells; binding affinity, 106 +/- 7.6 vs. 99.2 +/- 11.4 pM, respectively). When the depressed patients were subdivided by psychomotor manifestations, binding characteristics were indistinguishable among the subgroups. However, a significant reduction in beta-adrenergic responsiveness was observed in patients with psychomotor agitation, as compared with controls (2.6 +/- 0.5 vs. 7.4 +/- 1.0 pmol per 10(6) cells, P less than 0.01), but not in patients with psychomotor retardation (5.8 +/- 1.1 pmol per 10(6) cells, P less than 0.05). Thus, the desensitization of beta-adrenergic receptors was correlated more closely with the severity of psychomotor agitation than with the overall severity of depression.

Cyclic AMP↗
PubMed1985

Alterations in the activity and isozymic profile of human phosphofructokinase during malignant transformation in vivo and in vitro: transformation- and progression-linked discriminants of malignancy.

6-Phosphofructokinase (PFK) plays a central role in the regulation of glycolysis in both normal and neoplastic cells. Since PFK also mediates the Pasteur effect, it coordinates the two modes of energy production in most cell systems, i.e., glycolysis and respiration. The energy production in the cancer cell is characterized by a predominance of aerobic glycolysis (the Warburg effect) and a diminution or lack of the Pasteur effect. Previous studies from this laboratory have demonstrated that PFK in humans and in the rat exists in multiple tetrameric isozymic forms consisting of three unique subunits under separate genetic controls, M, L, and P types. These isozymes are distinguishable from one another by ion-exchange chromatography and subunit-specific antibodies. Various organs exhibit unique isozyme distribution patterns which essentially reflect the preferred mode of carbohydrate metabolism utilized, i.e., glycolysis or gluconeogenesis or both. In order to investigate whether the high aerobic glycolysis of the cancer cell can be explained on the basis of a lack of the regulatory function of PFK due to an altered isozyme distribution pattern, we compared the activity and isozymic profile of the enzyme from malignant cells of human leukemias, lymphomas, virus-transformed cell lines, and established malignant cell lines of lymphoid, myeloid, erythroid, and fibroblastic origin and their normal counterparts. The myeloid and erythroid cell lines were also investigated after in vitro differentiation induced by dimethyl sulfoxide, sodium butyrate, hemin, etc. Our results show that, as is the case with hexokinase and pyruvate kinase, the other two rate-limiting enzymes of glycolysis, PFK shows both quantitative increases and isozymic alterations secondary to altered gene expression during neoplastic transformation, both in vivo and in vitro. In contradistinction to the isozymic alteration in hexokinase and pyruvate kinase, where highly regulated liver-type isozymes decrease or disappear and are replaced by the nonregulated ones, in the case of PFK, the highly regulated liver-type isozyme not only persists but actually increases, followed by an increase in the platelet-type isozyme. These isozymic alterations closely parallel the quantitative increases in total PFK activity, which in turn is closely related to the rate of replication of cancer cells and hence an increase in metabolism. Thus, human PFK is both a transformation- and a progression-linked discriminant of malignancy (For definitions of these terms, see Weber et al., N. Engl. J. Med., 296: 486-493, 1977.).(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1984

Beta adrenergic receptors and cyclic AMP levels in intact human lymphocytes: effects of age and gender.

A saturable, stereospecific high affinity beta 2 adrenergic receptor was demonstrated on intact human peripheral blood lymphocytes using the ligand [125I]-iodocyanopindolol ([125I]ICYP). A method is described for parallel measurements of saturation binding isotherms and isoproterenol-cAMP responsiveness in split samples of intact lymphocytes isolated from 40 ml. of whole blood. A significant positive correlation between beta receptor density (Bmax) and the ratio of maximal isoproterenol-generated cAMP to basal levels was found in healthy subjects (r = 0.65, p less than 0.001). A significant positive correlation was found between age and the fold increase over basal cAMP levels induced by isoproterenol. Older females had a significantly higher fold increase in cAMP levels after isoproterenol than older males. These effects were largely accounted for by the lower basal levels of cAMP in older subjects. Beta receptor binding indices (Bmax and KD) did not differ between males and females, or change with aging. The effects of age and sex upon cAMP levels appear to be at least partly mediated by mechanisms independent of the beta receptor. The method, which describes a convenient assay for parallel measurement of beta receptor binding and cAMP levels in small blood samples, represents a useful model for studying human beta receptor function.

Adult↗
PubMed1984

T-lymphocyte subpopulations in B-cell-derived non-Hodgkin's lymphomas and Hodgkin's disease.

The authors used E-rosette formation and OKT3 reactivity to determine the percent of T-cells in lymph nodes involved by B-cell non-Hodgkin's lymphomas (B-NHL) and by Hodgkin's disease (HD). The percent of helper and suppressor/cytotoxic T-cells was determined by reactivity with OKT4 and OKT8, respectively. T-cells were also analyzed for two signs of activation: acquisition of Ia antigens and loss of acid a-naphthyl acetate esterase (ANAE) activity. The results were compared with those of lymph nodes exhibiting benign lymphoid hyperplasia (BLH). The percentage of T-cells ranged from 50% to 82%, mean 63 +/- 13%, in 25 cases of BLH, and from 6% to 62%, mean 23 +/- 11%, in 51 cases of B-NHL. The OKT4/T8 ratio was 1.0 to 6.2, mean 3.4 +/- 2.2, in the cases of BLH, and 0.5 to 5.1, mean 2.4 +/- 1.3, in the cases of B-NHL. There was no obvious or significant correlation between the percent of T-cells or the OKT4/T8 ratio and the surface immunoglobulin isotype expressed by the neoplastic B-cells, the morphologic category of B-NHL, or the clinical stage of disease. Activated T-cells were less than or equal to 3% in the cases of BLH and B-NHL. Fifteen lymph nodes involved by HD contained 44% to 96%, mean 74%, E+ (T) cells. Five of these 15 cases contained a significant number of E-OKT3+ cells suggesting that E-rosette formation is not always a reliable T-cell marker in HD. Three other cases contained a large number of E+OKT3- cells. The OKT4/T8 ratio ranged from 0.4 to 21.7, mean 6.7 +/- 5.3, in these cases, representing the most significant T-cell subset imbalances in this series. Large numbers of Ia+E+ and/or E+ANAE- cells, presumably activated T-cells, were present in 7 of these 15 cases of HD. These studies demonstrate the wide variation in the percent of T-cells and in the T-cell subset distribution in lymph nodes exhibiting benign lymphoid hyperplasia and in lymph nodes involved by B-cell-derived non-Hodgkin's lymphomas and Hodgkin's disease.

Antibodies, Monoclonal↗
PubMed1983

Reactivity of monoclonal antibodies Leu 1 and OKT1 with malignant human lymphoid cells. Correlation with conventional cell markers.

This study delineated the distribution of reactivity of malignant human lymphoid cells with monoclonal antibodies Leu 1 and OKT1, and correlated this expression with that of conventional lymphoid cell markers. The presence of Leu 1 on benign lymph nodal T-cells and its absence from benign lymph nodal B-cells was confirmed. Twenty-two T-cell neoplasms, expressing a variety of intrathymic and mature peripheral phenotypes, expressed Leu 1, but this expression was heterogeneous with respect to percent-positive cells and antigenic density, and appeared to correlate with stages of T-cell differentiation. This study demonstrated the expression of Leu 1 by 33 of 36 cases of B-CLL, by 10 of 15 cases of the closely allied small lymphocytic cell lymphoma, and by 9 of 29 follicular center-cell lymphomas. This included B-cell malignancies of each surface immunoglobulin isotype, and some cases associated with a monoclonal protein spike. Leu 1 was not expressed by myeloma plasma cells, and was absent from non-B, non-T acute lymphoblastic leukemia cells in each of 15 cases studied. Finally, Leu 1 and OKT1 were expressed in parallel, with respect to percent-positive cells and staining intensity, on benign and malignant T-cells, and on malignant B-cells, wherever studied. Possible explanations for this shared antigen are the existence of a minor Leu 1+ B-cell subset, a transformation-associated event, or glycosylation.

Antibodies, Monoclonal↗
PubMed1983

A new human B-lymphocyte surface antigen (BL 2) detectable by a hybridoma monoclonal antibody: distribution on benign and malignant lymphoid cells.

A hybridoma-derived monoclonal antibody, produced by immunization with the Burkitt's tumor-derived B-lymphoblastoid cell line, B35M, was previously shown to detect a 68,000 dalton surface membrane protein, BL2, on the surface of peripheral blood B cells, which is absent from thymocytes, T cells, and granulocytes. In this study, we investigated the expression and distribution of BL2 on benign and malignant human lymphoid cells. Indirect immunofluorescent assay with this monoclonal antibody demonstrated that BL2 is expressed by cells within the fetal liver and by a variable proportion of lymph node, tonsil, and spleen B cells, but not by T cells. The neoplastic cells isolated from 18 T-cell malignancies were BL2- . BL2 was was heterogeneously expressed by a variable proportion of the malignant cells in 29/32 cases of B-chronic lymphocytic leukemia and 33/38 cases of B-cell lymphomas, but appeared to be lost in the terminal stages of B-cell differentiation, as myeloma plasma cells were BL2- . BL2 expression was not limited to B cells of a particular surface immunoglobulin isotype. Immunofluorescent staining for BL2 in cryostat tissue sections demonstrated that the majority, but not all, germinal center and interfollicular Ia+ (non-T) cells are BL2+. These findings suggest that BL2 is a B-cell lineage-specific differentiation marker that may be useful in the study of B-cell ontogeny and in defining subgroups of the B-cell malignancies.

Antibodies, Monoclonal↗
PubMed1982

The immunologic characterization of 40 extranodal lymphoid infiltrates: usefulness in distinguishing between benign pseudolymphoma and malignant lymphoma.

In the studies described here, 40 extranodal lymphoid tumors obtained from 38 patients were evaluated by cell-marker analysis and the results correlated with the light microscopic features. These infiltrates were investigated for the present composition of cells expressing Ia antigens, surface immunoglobulin (SIg), including kappa and lambda light chains, sheep erythrocyte (E) rosette formation, and acid a-naphthyl acetate esterase (ANAE) activity. Fifteen biopsy specimens consisted of variable proportions of benign T and polyclonal B cells; these 15 lesions had the histopathologic features of benign pseudolymphomas. The remaining biopsy specimens consisted almost entirely of B cells bearing monoclonal SIg (18 cases) or a great preponderance of T cells (five cases) or non-B, non-T (null) cells (two cases); these 25 lesions were classified histopathologically as malignant lymphomas. Thus, the extranodal lymphoid infiltrates were divisible, according to their cell-marker characteristics, into two categories: lesions that are immunologically polyclonal and lesions that are immunologically monoclonal B-cell proliferations or consist of a great preponderance of T or null cells. In each case, polyclonality correlated with benign cytomorphologic features and monoclonality correlated with malignant histopathology. Cell-marker analysis appears to represent an important adjunct to light microscopy in distinguishing histologically problematic benign pseudolymphomas from malignant lymphomas that arise in the extranodal tissues. Cell marker analysis will undoubtedly provide insights into the histogenesis, natural history, and biologic behavior of the extranodal lymphoid neoplasms not attainable using light microscopy alone.

Adult↗
PubMed1982

Phenotypic heterogeneity of human T-cell malignancies: demonstration by monoclonal antibodies and cytochemical markers.

The present study sought to delineate the phenotypic heterogeneity of the human T-cell malignancies. Twenty T-cell neoplasms were investigated for reactivity with the OKT hybridoma monoclonal antibodies and expression of acid alpha-naphthyl acetate esterase (ANAE), beta-glucuronidase (BG), and acid phosphatase (AP) activity. Twelve cases (Mycosis fungoides, Sezary syndrome, cutaneous T-cell lymphoma, chronic lymphocytic leukemia) were OKT3'T4', ie, expressed the phenotype commonly associated with mature T-helper cells. These cases were further divisible into ANAE+BG+ (6 cases), ANAE-BG+ (5 cases), and ANAE-BG- (1 case) phenotypes. In contrast to the 12 OKT3+T4+ cases, the remaining 8 cases showed considerable inter- and intratumor heterogeneity with respect to reactivity with the OKT antibodies. Six of these cases (acute lymphoblastic leukemia, lymphoblastic lymphoma) expressed phenotypes consistent with various intrathymic stages of T-cell differentiation. Five of the latter 6 cases were AP+BG+ANAE-, analogous to the majority of normal cortical thymocytes; an OKT3+T4-T8+T10+ neoplasm was ANAE+, analogous to normal medullary thymocytes. Two cases expressed the previously undescribed OKT3+T4-T8-T10+ phenotype. These studies demonstrate that the T-cell malignancies are divisible into phenotypes which correspond to normal maturational stages of T-cell differentiation and functionally distinct T-cell subsets. Phenotypic analysis of the human T-cell malignancies may provide a basis for understanding their biological heterogeneity and may aid in the identification of transitional stages of T-cell differentiation and minor T-cell subsets.

Adolescent↗
PubMed1982

OT-CLL: a human T cell chronic lymphocytic leukemia that produces IL 2 in high titer.

This report identifies and describes a human T cell chronic lymphocytic leukemia, OT-CLL, which can be triggered by selected mitogens (either PHA or Con A) to produce IL 2 in high titer. Optimal IL 2 production requires culturing OT-CLL cells at 2 to 5 X 10(6)/ml for 24 hr in the presence of 1 to 2% PHA-M. Under these conditions, the titer of IL 2 generated is greater than 20-fold that obtained from conventional sources, e.g., from mitogen-activated tonsillar lymphocytes. Two lines of experimental evidence suggest that the tumor cell product(s) is IL 2. First, in functional assays, suprenatants derived from cultures of PHA-activated OT-CLL cells trigger the proliferation and long-term growth of IL 2-dependent human TCL cells. Second, a partial biochemical purification of the active moiety(ies) derived from OT-CLL demonstrates marked similarity to conventional human IL 2. Thus, the biologically active material(s) precipitates in 50 to 70% saturated (NH4)2 SO4 solutions; elutes from DEAE-Sepharose in the presence of 0.04-0.08 M NaCl; and has an apparent m.w. of approximately 14,000, as determined by Sephadex G-100 gel filtration. In addition, analysis of OT-CLL cells by indirect immunofluorescence, utilizing a panel of monoclonal antibodies, confirms not only that these tumor cells are of T cell lineage but that they display surface antigens that define the normal human peripheral T cell subset subserving helper or inducer function: OKT3+, OKT4+ , OKT8-.

Cell Count↗
PubMed1982

Human T-cell malignancies: Correlative clinical, histopathologic, immunologic, and cytochemical analysis of 23 cases.

Twenty-three T-cell neoplasms were investigated for their reactivity with the OKT monoclonal antibodies and expression of certain cytochemical markers. Fourteen neoplasms with diverse histopathologic features, T-cell chronic lymphocytic leukemia, mycosis fungoides, the Sézary syndrome, T-immunoblastic sarcoma, and a pleomorphic large-cell lymphoma, expressed the T helper cell phenotype, OKT3+T4+. Nine other neoplasms displayed marked inter- and intra- tumor heterogeneity. Seven of these cases, lymphoblastic lymphoma, T-cell acute lymphoblastic leukemia, and tumors with feature of T-immunoblastic sarcoma or the multilobated lymphoma of Pinkus, expressed intrathymic phenotypes. The other 2 cases, a lymphoblastic lymphoma and a so-called Lennert's lymphoma, expressed the previously undescribed OKT3+T10+ phenotype. These studies demonstrate that the T-cell malignancies are divisible into phenotypes corresponding to normal maturational stages of T-cell differentiation and functionally distinct T-cell subsets. Such studies should provide a basis for understanding the biologic heterogeneity, clinical diversity, and significance of the variable cytomorphologic characteristics of T-cell malignant tumors and assist in the further delineation of normal human T-cell heterogeneity.

Aged↗
PubMed1982

A phorbol ester tumor promoter induces changes in the expression of immunoglobulins and DR antigens in human lymphoblastoid cells.

The present study indicates that 12-O-tetradecanoyl phorbol 13-acetate (TPA) can induce either increases or decreases in the relative expression of membrane-associated IgM and IgD as well as the expression of other markers of lymphocyte differentiation on human B lymphoblasts, depending on the clone studied. The changes in membrane Ig expression are apparent within 24 hr and are maximal at about 48 hr after the addition of the compound. In clone BL, TPA decreases the membrane IgM/IgD ratio as determined by the percentage of cells bearing these isotypes and by their densities on single cells. In clone MW-E, TPA has the opposite effect. Although these changes are followed by an increase in Ig secretion by MW-E cells, measured by immunofluorescence and the protein A plaque assay, there is no induction of Ig secretion in BL cells. In addition, TPA increases the expression in BL of an additional B lymphocyte marker, the D region-related (DR) antigens, while having the opposite effect in MW-E. In two sublines of Daudi, a membrane IgM-positive, IgD-negative, nonsecreting cell line, TPA treatment resulted in the expression of membrane IgD without the induction of Ig secretion. Thus, the TPA-induced changes in the IgM/IgD ratio and DR antigen expression are inversely related and are not due to differential proliferation of subpopulations. Taken together, it appears that, depending on the particular clone of B lymphoblasts studied, TPA can induce or inhibit a coherent program of B lymphocyte maturation.

Antibody-Producing Cells↗