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Biomedical subjects

C M Roifman

Publications and source records attributed to C M Roifman.

At least 73 records · Page 4Linked to original sources
PubMed1991

Activation of calcium oscillations by thapsigargin in parotid acinar cells.

The tumor promoter thapsigargin releases Ca2+ from intracellular stores by specific inhibition of microsomal Ca-ATPase activity without inositol phosphate formation. Recent studies of the actions of thapsigargin support the concept that the level of Ca2+ within the inositol (1,4,5)-trisphosphate (IP3)-sensitive intracellular pool regulates the Ca2+ permeability of the plasma membrane. We examined the effects of thapsigargin on intracellular Ca2+ concentration ([Ca2+]i) in single rat parotid cells using digital fluorescence microscopy. In the absence of extracellular Ca2+ (Ca2+o), thapsigargin transiently increased [Ca2+]i. Following the thapsigargin-induced [Ca2+]i transient, carbachol in the continued absence of Ca2+o was unable to raise [Ca2+]i, indicating that thapsigargin mobilizes Ca2+ from the IP3-sensitive store. In the converse experiment, carbachol prevented a rise of [Ca2+]i by thapsigargin, suggesting that the IP3- and thapsigargin-sensitive Ca2+ pools are the same. Depletion of Ca2+ from the IP3-sensitive pool by thapsigargin enhanced plasma membrane Ca2+ permeability. Thapsigargin triggered sustained Ca2+ oscillations in Ca2(+)-containing medium which are highly reminiscent of agonist-induced oscillations in these cells. Carbachol addition rapidly raised IP3 levels during oscillations triggered by thapsigargin but did not elevate [Ca2+]i, indicating that the IP3-sensitive pool remains continuously depleted during [Ca2+]i fluctuations. The results from this study rule out the involvement of the IP3-sensitive pool in the mechanisms involved in thapsigargin-induced (and by analogy, agonist-induced) oscillations in parotid cells.

Animals↗
PubMed1991

Treatment of dermatomyositis with intravenous gammaglobulin.

PURPOSE: The mainstay of pharmacologic therapy in patients with dermatomyositis is corticosteroids. However, because patients sometimes become refractory to these drugs and because these drugs have potential short- and long-term toxicities, alternate therapy is highly desirable. Therefore, a pilot study was initiated using high-dose intravenous gammaglobulin (IVGG) in the treatment of dermatomyositis. PATIENTS AND METHODS: IVGG was administered to five patients with juvenile dermatomyositis. Prior to IVGG treatment, all patients had persistent muscle weakness despite daily corticosteroids and three patients had developed unacceptable steroid toxicity. Two of the patients had previously developed toxicity while receiving immunosuppressive therapy. RESULTS: IVGG therapy resulted in improved muscle strength and ameliorated skin rash in all patients. The percentage increase in muscle strength as measured by sphygmomanometry following the 9-month course of IVGG ranged from 56% to 606% in the proximal lower extremities and from 30% to 186% in the proximal upper extremities. Following IVGG therapy, prednisone could be discontinued or the dose reduced in all patients. CONCLUSION: This study suggests that IVGG may allow steroid sparing in dermatomyositis and may provide a safe alternative to cytotoxic therapy.

Adrenal Cortex Hormones↗
PubMed1991

Expression of the human T cell receptor V beta repertoire.

We have used a sensitive assay, based on amplification of cDNA by the polymerase chain reaction, to determine in a variety of human tissues the relative levels of expression of the genes coding for each of the twenty families of human TcR V beta. We have determined the diversity of the expressed TcR V beta repertoire early in the development of the immune system. We have shown that the full TcR V beta repertoire is expressed early into the second trimester; the expressed repertoire is as diverse at this point, in both fetal thymus and spleen, as it is in mature thymus and peripheral blood lymphocytes. In addition the relative expression in the fetal thymus of each V beta gene is conserved to a large extent in the fetal spleen.

Adult↗
PubMed1991

Adenosine deaminase and thymocyte maturation.

The congenital absence of adenosine deaminase in humans results in severe combined immunodeficiency. To clarify the process whereby thymocytes are destroyed in the absence of adenosine deaminase activity, we induced a parallel condition in mice through the injection of an inhibitor of adenosine deaminase, deoxycoformycin. We have observed that deoxycoformycin, in addition to maintaining high levels of dATP in thymocytes, blocks the progression of thymocyte differentiation at two points. As a result of the first block, the cortex is depleted of immature cortical thymocytes while CD4+CD8+ thymocytes with functionally rearranged T-cell receptors survive. As a result of the second block, the CD4+CD8+ thymocytes are prevented from further differentiation to mature CD4+CD8- or CD4-CD8+ T lymphocytes and accumulate at the corticomedullar junction and in the medulla. These observations suggest that the maintenance of dNTP pools by adenosine deaminase is critical to at least two stages of thymocyte differentiation.

Adenosine Deaminase↗
PubMed1991

Lymphocytic pneumonitis following bone marrow transplantation in severe combined immunodeficiency.

Lung disease in patients with severe combined immune deficiency (SCID) undergoing bone marrow transplantation (BMT) is most commonly caused by infection. Noninfectious episodes of pulmonary disease following BMT are more frequently encountered in patients with hematologic disorders or malignancy and are probably related to ablation therapy or graft-versus-host disease (GVHD). In contrast, patients with SCID do not receive chemotherapy before an HLA-identical allogeneic BMT and they do not suffer significant GVHD. We report a patient who developed severe lung disease during the period of rapid engraftment following an HLA-identical allogeneic bone marrow transplantation. Lung biopsy showed dense lymphocytic infiltrates in the alveolar septae and no evidence of infection. Following the idea that the acute recruitment of engrafted lymphocytes may have contributed to or caused the pulmonary disease, we have attempted to suppress cellular immunity by administering high-dose methylprednisolone. The patient's lung disease rapidly improved and eventually completely resolved.

Bone Marrow↗
PubMed1991

Activation of phospholipase C in human B cells is dependent on tyrosine phosphorylation.

Cross-linking of the surface antigen receptor on B lymphocytes has been demonstrated to lead to activation of phospholipase C (PLC) with subsequent increases in production of inositol phosphates and diacylglycerol. In turn, these second messengers increase cytosolic free calcium [( Ca2+]i) and activate the serine threonine phosphotransferase protein kinase C (PKC). These processes are thought to play a major role in B cell activation and proliferation. However, the mechanism linking the B lymphocyte antigen receptor to phospholipase C remains to be identified. We demonstrate herein that activation of the antigen receptor on human lymphocytes, in addition to activation of PLC, increases tyrosine phosphorylation of specific substrates. Tyrphostins, a new class of tyrosine kinase inhibitors which compete for substrate binding site of specific tyrosine kinases have recently been synthesized. Preincubation of B lymphocytes with two different tyrphostins blocked anti-IgM-induced proliferation, oncogene expression, tyrosine phosphorylation, increases in [Ca2+]i, and production of inositol phosphates. The same inhibitors were without effect on B cell proliferation induced by phorbol esters and cation ionophores which directly activate PKC and increase [Ca2+]i thus bypassing PLC. These findings strongly indicate that tyrphostins do not exhibit significant nonspecific toxicity and suggest that they act proximal to PLC. The ability of the tyrphostins to block increases in [Ca2+]i and inositol phosphate production, after activation of the B cell antigen receptor, indicates that a tyrosine kinase acts as an essential link between the B cell antigen receptor and PLC.

B-Lymphocytes↗
PubMed1991

Benefit of ketotifen in patients with eosinophilic gastroenteritis.

PURPOSE: Eosinophilic gastroenteritis (EG) is a rare condition of unknown etiology characterized by vomiting, diarrhea, protein-losing enteropathy, and eosinophilic infiltration of the gastrointestinal mucosa. The potential association of EG with allergy and related mast-cell release of mediators led us to evaluate the ability of an antihistamine drug to modify the course of the disease. PATIENTS AND METHODS: Six patients with protracted gastrointestinal symptoms were diagnosed with EG because of histologic evidence of predominantly eosinophilic infiltrates in the gastrointestinal mucosa. Each patient was treated in an open trial for 12 months with ketotifen (Zaditen), an antihistamine of the H1 class that is known to stabilize mast cells. RESULTS: All six patients improved clinically; four also gained weight. Total serum IgE levels decreased after 4 to 6 months of therapy. Clearing of eosinophilic infiltrates was documented in the four patients who underwent follow-up mucosal biopsies. CONCLUSION: We conclude that ketotifen treatment represents a safe and effective alternative to traditional systemic corticosteroid therapy for treatment of EG.

Adolescent↗
PubMed1991

Acquired Brown's syndrome associated with hypogammaglobulinemia.

We describe a 10-year-old girl with hypogammaglobulinemia who presented initially with painless progressive diplopia on right upward gaze and associated tenderness in the area of the superior oblique tendon (Brown's syndrome). She was given prednisone (40 mg/day) with gradual improvement of her symptoms. Prednisone was tapered and her symptoms remained unchanged for 10 months. She then experienced rapid deterioration. Prednisone was reinstituted with similar improvement and then therapy was switched to naproxen. She remains with only slight diplopia on extreme upward gaze.

Agammaglobulinemia↗
PubMed1990

Intravenous gamma globulin therapy in systemic juvenile rheumatoid arthritis.

Intravenous (IV) gamma globulin has been successfully used as replacement therapy for antibody-deficient patients and, more recently, in the treatment of autoimmune diseases such as idiopathic thrombocytopenic purpura, myasthenia gravis, and Kawasaki disease. In view of the successful treatment of these diseases, we initiated a pilot study of the effect of IV gamma globulin in systemic juvenile rheumatoid arthritis (JRA). Eight patients with active systemic JRA that was unresponsive to first-line agents, second-line agents, and/or corticosteroids received this therapy monthly for 6 months. Outcome measures included changes in articular and extraarticular features, steroid dosage, and laboratory parameters. Following IV gamma globulin therapy, there was significant improvement in arthritis and/or morning stiffness in 5 of 8 patients, while extraarticular features significantly improved in 7 of 8 patients. At study entry, 6 of 8 patients were receiving prednisone; at study end, prednisone was discontinued in 3 patients and decreased by more than 50% in the other 3. Overall, there was an 80% reduction in the prednisone dosage. Initially, all patients had anemia, low levels of serum albumin, and an elevated erythrocyte sedimentation rate, while a thrombocytosis was seen in 7 of 8 patients. Serum IgG was initially elevated in 6 patients. IV gamma globulin therapy resulted in a significant increase in hemoglobin and albumin levels and a significant decrease in the mean serum IgG level, platelet count, and erythrocyte sedimentation rate. In only 1 patient did IV gamma globulin fail to significantly improve the clinical or laboratory features of the disease. We suggest that this therapy may be beneficial in the treatment of systemic JRA.

Arthritis, Rheumatoid↗
PubMed1990

Cutaneous lymphohistiocytic infiltrates in patients with hypogammaglobulinemia.

Six patients (5 to 15 years of age) with hypogammaglobulinemia had scattered papular lesions in association with widespread dermatitis. These disfiguring lesions were a portal of entry for secondary infections and led to social withdrawal. Biopsy specimens from the papules demonstrated dense lymphohistiocytic infiltrate limited to the dermis. Infectious causes (bacterial, fungal, and viral) were excluded. The skin lesions failed to respond to conventional treatment, including topical corticosteroids. Replacement therapy with monthly infusions of high doses of immune serum globulin resulted in gradual improvement and ultimate clearing of the lesions. This unusual skin abnormality, which is unresponsive to traditional treatment, may provide the earliest clue to the presence of hypogammaglobulinemia.

Adolescent↗
PubMed1990

X-linked severe combined immunodeficiency. Diagnosis in males with sporadic severe combined immunodeficiency and clarification of clinical findings.

Over 80% of infants with severe combined immunodeficiency (SCID) of unknown genetic etiology are males, yet less than a third of these affected males have a family history of X-linked disease. To help identify new mutations of the X-linked SCID gene and to provide genetic counseling, X chromosome inactivation patterns in T cells from 16 women who had sons with sporadic SCID were examined. Between 9 and 35 human/hamster hybrids that selectively retained the active human X chromosome were produced from the T cells of each woman and analyzed with an X-linked restriction fragment length polymorphism for which the woman in question was heterozygous. Exclusive use of a single X as the active X was seen in the T cell hybrids from 7 of the 16 women, identifying these women as carriers of X-linked SCID. Studies on additional family members confirmed the mutant nature of the inactive X and revealed the source of the new mutation in three families. To determine whether there were any laboratory characteristics that might differentiate the boys whose mothers were identified as carriers of X-linked SCID from those whose mothers were not, the clinical records of both groups were compared to each other and to a group of 14 boys with a family history of X-linked SCID. The most consistent finding in the 21 patients with X-linked SCID was an elevated proportion of B cells. These data demonstrate the high incidence of spontaneous mutation for the X-linked SCID gene and help clarify the characteristic presenting features of this disorder.

B-Lymphocytes↗
PubMed1989

Depletion of CD8+ cells in human thymic medulla results in selective immune deficiency.

CD8 molecules expressed on the surface of a subset of T cells participate in the selection of class I MHC antigen-restricted T cells in the thymus, and in MHC-restricted immune responses of mature class I MHC antigen-restricted T cells. Here we describe an immune-deficient patient with lack of CD8+ peripheral blood cells. The patient presented with Pneumocystis carinii pneumonia and was unable to reject an allogeneic skin graft, but had normal primary and secondary antibody responses. Examination of the patient's thymus revealed that the loss of CD8+ cells occurred during intrathymic differentiation: the patient's immature cortical thymocytes included both CD4+ and CD8+ cells while the mature medullary cells expressed the CD4 but not the CD8 protein on their surface. Northern blot and polymerase chain reaction analyses revealed the presence of CD8 alpha and beta mRNA in the patient's thymus but not in the peripheral blood. Both class I MHC antigen expression and the expressed TCR V beta repertoire are normal in this patient. These data are consistent with an impaired selection of CD8+ cells in the patient's thymus and support the role of the CD8 surface protein in thymic selection previously characterized in genetically manipulated and inbred mice.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

A putative new growth factor in ascitic fluid from ovarian cancer patients: identification, characterization, and mechanism of action.

Ascitic fluid form ovarian cancer patients (n = 16), but not from patients with other cancers or with benign diseases, contains a growth-promoting activity which induces the proliferation of both fresh ovarian cancer cells (n = 5) and the ovarian cancer cell line HEY. The ascitic fluid growth factor(s) appears to signal cells through binding and activation of specific, saturable, high-affinity cell surface receptors. Incubation of fresh or cultured ovarian cancer cells with a partially purified preparation of ascitic fluid stimulates phosphatidylinositol turnover and increases cytosolic-free calcium. Each of these biochemical events has been implicated in the action of growth factors. Purified preparations of previously identified growth factors including epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, platelet-derived growth factor, thrombin, insulin, interleukin-1, interleukin-2, vasopressin, angiotensin, alpha- and gamma-interferons, and fibroblast growth factor did not increase cytosolic-free calcium in either fresh ovarian cancer cells or HEY cells. Therefore, ascitic fluid appears to contain one or more previously unidentified growth factors which activate ovarian cancer cells through phosphatidylinositol hydrolysis and resultant changes in cytosolic-free calcium.

Ascitic Fluid↗