Diabetes and retinal function.
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Blood-Retinal Barrier↗
Biomedical subjects
J Lipton
Publications and source records attributed to J Lipton.
Cytosine arabinoside (ara-C) and cis-dichlorodiammineplatinum II (cisplatin) alone and in combination: effects on acute myeloblastic leukemia blast cells in culture and in vivo.
Cytosine arabinoside (ara-C) and cis-dichlorodiammineplatinum II (cisplatin) are lethal to mammalian cells by very different mechanisms; however, they share interactions with the biology of blast cells in acute myelogeneous leukemia (AML). Both agents are more toxic to AML blasts in suspension than when a clonogenic assay in methyl cellulose is used; both agents are more toxic in suspension in the presence of rG-CSF than with rGM-CSF. Accordingly, preclinical tests were undertaken of cisplatin and ara-C in combination. At the same time, a phase I/II clinical trial of the combination was conducted, using AML patients refractory to treatment or in relapse. In the laboratory, blasts from eight AML patients were tested against each agent singly and in combination. The observed survival values for the mixture were compared with those predicted by assuming either an additive effect or a more general effect that allows synergism or antagonism. Blasts from two patients were tested with this design in the presence of rG-CSF or rGM-CSF. In most instances the toxic effects of ara-C and cisplatin were additive. Evidence of synergism was seen in blasts from three patients.
Adolescent↗
Long-term results of bone marrow transplantation for patients with AML, ALL and CML prepared with single dose total body irradiation of 500 cGy delivered with a high dose rate.
One hundred and sixty-six patients between the ages of 12 and 48 years with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation following single fraction total body irradiation (TBI) of 500 cGy from a cobalt source. Patients also received one of three chemotherapeutic regimens according to their diagnosis or disease status at time of transplant. The median follow-up was 67 months with a range of 33-120 months. The actuarial 5-year event-free survival (EFS) for the subgroup of patients with good risk disease (first complete remission AML and ALL or first chronic phase CML) was 43% with an actuarial relapse rate at 5 years of 26%. Patients with poor risk disease (other than first remission AML and ALL or other than first chronic phase CML) had an EFS at 5 years of 15% with a relapse rate of 62%. Disease status at the time of transplantation was the most important factor predicting outcome in this patient population. We conclude that preparation of good risk patients with chemotherapy and single fraction TBI of 500 cGy at a dose rate of 42-91 cGy/min resulted in EFS and relapse rates similar to those observed by centers using fractionated radiotherapy schedules, without a concomitant increase in toxicity, in particular interstitial pneumonitis and cataracts.
Adolescent↗
Problems in access to benefits and services among persons with rheumatoid arthritis.
This exploratory survey of 100 patients with rheumatoid arthritis (RA) was conducted (1) to learn about the types and frequencies of disability law-related problems encountered as a result of having RA, and (2) to assess the respective relationships between the number of disability law-related problems reported and the patients' sociodemographic and RA disease characteristics. The underlying concern of health care and legal professionals was that the often protracted exclusionary RA diagnostic process and the episodic nature of RA could make it more difficult to establish a precise clinical diagnosis and level of disability. Therefore, patients with RA would encounter difficulties in accessing entitlements and benefits provided under disability laws. The findings from this survey were used to develop a legal manual to empower health care professionals and people with arthritis to take litigative, legislative, social action, and self-help measures to redress the disability-law related problems.
Adolescent↗
Direct inhibitory effect of atriopeptin III on renin release in primate kidney.
Patterns of in vitro renal renin release and the ability of atriopeptin to directly inhibit renin release have been examined in the rat, rabbit, and dog, but have been unstudied in the primate kidney. Accordingly, we examined renin release from superficial renal cortical slices of the squirrel monkey (Samiri sciuresus). The average age of the 5 animals was 10.2 +/- 2.5 yr at the time of study. Renin release was stimulated significantly by the beta-adrenergic agonist isoproterenol in concentrations of 10(-5) M (1.67-fold) and 10(-4) M (1.84-fold). Isoproterenol-induced renin release was inhibited by atriopeptin III (ANP, 2 X 10(-8) M) and the adenylate cyclase inhibitor dideoxadenosine (DDA, 10(-5) M). Similarly, the incubation of the superficial cortical slices with arachidonic acid (10(-3) M) resulted in a 4-fold increase in tissue renin release which was blocked by the calcium ionophore A23187 (17 X 10(-6) M) and ANP; interestingly, DDA did not block arachidonic acid-induced renin release. These results suggest that ANP exerts a direct inhibitory effect on B-adrenergic and arachidonic acid-induced renin release in the primate kidney. Further, the inhibitory action of A23187 on renin release suggests, as in other species, an integral role for intracellular calcium in the renin release process. These patterns of renin release in primate kidney are similar to those observed in the rodent kidney in vitro.
Animals↗
Assessment of the reliability and validity of the arthritis impact measurement scales for children with juvenile arthritis.
There are few multidimensional measures of functional status in children, and none have been developed for children with juvenile arthritis (JA). This report describes an attempt to apply selected components of the Arthritis Impact Measurement Scales (AIMS), which were developed and validated for adults, to a sample of children with active JA (n = 60) or inactive JA (n = 17). Our results suggest that the Pain scale and the Physical Activity scale are the most reliable measures for children with JA; the correlations of the Pain scale, Physical Activity scale, and Dexterity scale results with the clinical measures of JA diagnostic category and joint count support the convergent validity of these scales for the active JA group; and the AIMS revised Physical Disability dimension and the Pain dimension, used to predict the children's classification in the active or inactive JA group, evidence discriminant validity. Additional studies of children with a wider range of impairments are needed to further assess the usefulness of the AIMS for children with JA.
Arthritis, Juvenile↗
Engraftment following T-cell-depleted marrow transplantation. I. The role of major and minor histocompatibility barriers.
These experiments describe a murine model for survival and engraftment of bone marrow transplantation across differing histocompatibility barriers. Anti-Thy-1.2 antibody and complement-treated C57BL/6 (B6) marrow was transplanted at varying cell dose levels into syngeneic (B6), major histocompatibility complex congenic (A.BY), semiallogeneic (B6AF1), and fully allogeneic (A/J) recipients. Survival was monitored and engraftment determined by hemoglobin and lymphocyte phenotype. Survival was cell-dose dependent and was equivalent in B6, A.BY, and B6AF1 recipients. Survival was poor in allogeneic A/J recipients due to bone marrow failure even at high marrow dose levels. Survival posttransplant did not always correlate with stable donor engraftment, and competitive host marrow repopulation was frequently seen in B6AF1 recipients but rarely in A.BY recipients. This repopulation could be prevented by transplanting a larger marrow dose.
Animals↗
Bilateral acute dacryocystitis in an infant.
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Acute Disease↗
Antigenic heterogeneity among Burkitt's lymphoma cells surviving treatment with monoclonal antibody and complement.
Selective removal of malignant cells from human bone marrow is one requirement for autologous bone marrow transplantation. In earlier studies treatment with multiple monoclonal antibodies and C' was more effective than treatment with individual reagents in eliminating clonogenic Burkitt's lymphoma cells from a twenty-fold excess of human bone marrow. To explore possible mechanisms underlying the additive or synergistic effects observed with multiple reagents, clones of malignant cells that have survived treatment with antibody and C' have now been isolated at limiting dilution. Marked heterogeneity has been observed in binding of different monoclonal antibodies and in resistance to C'-dependent lysis among these different clones. Phenotypic traits were stable for at least two weeks in culture. Clones that survived treatment with the J5 anti-CALLA antibody and C' exhibited a relative decrease in CALLA expression but did not exhibit an increased susceptibility to lysis by anti-CALLA and C'. No selective decrease in gp-26 or B1 was observed in clones treated with J2 or anti-B1. A correlation between CALLA and gp-26 expression was observed in clones treated with J2 and anti-B1, but no clear correlation was observed between antigen expression and susceptibility to C'-dependent lysis. In this model system, escape from C' dependent cytotoxicity does not appear related to the existence of phenotypically stable C' resistant variants within the tumor cell population.
Animals↗
Elimination of clonogenic tumor cells from human bone marrow using a combination of monoclonal antibody:ricin A chain conjugates.
Effective autologous bone marrow transplantation for leukemia and lymphoma is likely to depend upon the selective removal in vitro of malignant cells from normal human bone marrow precursors. Highly specific cytotoxic conjugates formed by coupling ricin A chain to monoclonal antibodies might prove useful for the selective elimination of malignant cells. Consequently, ricin A chain conjugates have been prepared with several different murine monoclonal antibodies and tested for their ability to eliminate clonogenic Burkitt's lymphoma cells from an excess of human bone marrow. The most active reagents included an antibody:A chain conjugate which bound to the nonpolymorphic chain of the la molecule and another which reacted with the mu heavy chain of cell surface immunoglobulin. Conjugates formed with anti-common acute lymphoblastic leukemia antigen, anti-Mr 26,000 glycoprotein, and anti-B1 were much less active on these Burkitt's cells, contrasting with results of complement-dependent tumor cell lysis. Tumor cell kill was partially inhibited by the addition of greater than 2 X 10(6) human bone marrow cells/ml but could be potentiated by increasing the concentration of conjugate or by the addition of 10 mM ammonium chloride. In the presence of ammonium chloride, at least 4 logs of clonogenic tumor cells could be eliminated within 24 h from a 20-fold excess of bone marrow using 10(-7) M ricin A chain linked to one or two different antibodies. Similar treatment of normal human bone marrow temporarily inhibited granulocyte-macrophage colony-forming units (cell) formation but did not compromise establishment of continuous bone marrow cultures. The degree of selective elimination of tumor cells with A chain antibody conjugates was comparable to that achieved with 4-hydroperoxycyclophosphamide or with multiple monoclonal antibodies and complement.
Ammonium Chloride↗
Efficacy of a short course (four doses) of methotrexate following bone marrow transplantation for prevention of graft-versus-host disease.
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Actuarial Analysis↗
Isolated thrombocytopenia after allogeneic bone marrow transplantation: existence of transient and chronic thrombocytopenic syndromes.
Isolated thrombocytopenia after bone marrow transplantation was investigated in 65 fully engrafted patients surviving at least 60 days posttransplant. Twenty-four patients (37%) developed this complication, which occurred most frequently in patients receiving pretransplant preparation with total body irradiation or busulfan. Two distinct thrombocytopenic syndromes were identified: (1) transient thrombocytopenia (nine patients), in which a normal platelet count (greater than 100,000/microL) was initially established by day +40 but then diminished to less than 10,000 to 45,000/microL on day +40 to +70, with subsequent resolution of the thrombocytopenia by day +90; (2) chronic thrombocytopenia (15 patients), in which a platelet count greater than 100,000/microL was not achieved at any time during the first four months posttransplant, despite the simultaneous presence of normal granulocyte and reticulocyte counts. Although the transient syndrome did not adversely affect prognosis, the chronic syndrome carried a high mortality (21% actuarial survival at 1,000 days posttransplant compared with 67% survival for all patients, P less than .01) and had a high association with both severe (grades 3 to 4) acute graft-versus-host disease (GVHD) and chronic GVHD. In three of nine patients with transient thrombocytopenia, a temporal association with trimethoprim-sulfamethoxazole administration was observed, whereas in all other patients, no drug association could be found. Bone marrow biopsies in those patients with drug-associated thrombocytopenia showed decreased numbers of megakaryocytes, whereas biopsies in the remainder of the transiently thrombocytopenic patients demonstrated adequate numbers of platelet precursors, suggesting peripheral platelet destruction or ineffective thrombopoiesis. Biopsies in the chronic thrombocytopenic patients included those with and without adequate numbers of platelet precursors, although the association with chronic GVHD was strongest in patients demonstrating normal numbers of megakaryocytes. We conclude that isolated thrombocytopenia represents a significant complication of bone marrow transplantation, particularly in patients receiving hematopoietic ablative preparatory regimens, and that it is the chronic, not the transient, thrombocytopenic syndrome that is associated with an adverse patient prognosis.
Actuarial Analysis↗
Elimination of malignant clonogenic cells from human bone marrow using multiple monoclonal antibodies and complement.
A clonogenic assay has been developed that utilizes Burkitt's lymphoma tumor cell lines to detect elimination of up to 5 logs of tumor cell contamination within human bone marrow. Different Burkitt's lymphoma lines bear one or more of a group of markers, including common acute lymphoblastic leukemia antigen gp26 (glycoprotein with a molecular weight of 26,000), B1, surface membrane immunoglobulin, HLA, beta 2-microglobulin, and Ia. Burkitt's tumor cells of the Namalwa line have been mixed with a 20-fold excess of irradiated human bone marrow cells. After treatment with one or more monoclonal antibodies and rabbit complement (RC), mixtures have been grown on a monolayer of irradiated human bone marrow cells and tumor cells enumerated by limiting dilution. Multiple treatments with antibody and RC were more effective than a single treatment in destroying clonogenic tumor cells which bore relevant determinants. Human serum components inhibited the lytic activity of RC in the presence of murine monoclonal antibodies. The total concentration of bone marrow cells proved critical in determining the complete elimination of tumor. Incubation of the Namalwa tumor cell line with RC and the J2 anti-gp26 eliminated more than 3 logs of malignant cells from a 20-fold excess of human bone marrow. Combinations of two monoclonal antibodies were more effective than any single antibody in eliminating Namalwa cells. A combination of three monoclonal reagents was no more effective than a combination of J2 and B1 or J2 and J5 in eliminating Namalwa cells. Treatment of human bone marrow with three antibodies and RC did not, however, produce a selective loss of nonmalignant GM-CFU-C, CFU-E, or BFU-E.
Antibodies, Monoclonal↗
Elimination of clonogenic Burkitt's lymphoma cells from human bone marrow using 4-hydroperoxycyclophosphamide in combination with monoclonal antibodies and complement.
One requirement for autologous bone marrow transplantation is the selective removal of malignant cells from normal marrow precursors. Development of a clonogenic assay that detects elimination of up to 5 logs of Burkitt's lymphoma cells in the presence of a 20-fold excess of human bone marrow has permitted the evaluation of two different methods for the selective removal of malignant cells. Treatment with 4-hydroperoxycyclophosphamide (4-HC) (60 to 100 micrograms/mL) eliminated 2.0 to 3.5 logs of clonogenic cells. Antitumor activity depended upon the concentration of 4-HC and the length of incubation, but not upon the concentration of normal bone marrow cells. Comparable removal of clonogenic Burkitt's cells was achieved by treatment with rabbit complement (C') and a combination of J5 anti-common acute lymphoblastic leukemia antigen (J5 anti-CALLA), J2 anti-gp 26, and the B1 anti-B1 murine monoclonal antibodies. A combination of 4-HC and monoclonal antibodies proved slightly but significantly more effective than either single agent in eliminating clonogenic tumor cells. Although treatment with 4-HC markedly reduced granulocyte-macrophage colony-forming units-C (GM-CFU-C) content of human bone marrow, neither treatment with 4-HC nor treatment with monoclonal antibodies and C' eliminated precursor cells that could generate new GM-CFU-C after growth in continuous bone marrow cultures. Our data suggest that treatment with 4-HC in combination with multiple monoclonal antibody reagents could be a safe and effective method of eliminating clonogenic tumor cells from human bone marrow.
Antibodies, Monoclonal↗
Busulfan and total body irradiation as antihematopoietic stem cell agents in the preparation of patients with congenital bone marrow disorders for allogenic bone marrow transplantation.
The capacity of busulfan and total body irradiation to ablate hematopoietic stem cells as preparation for the allogeneic bone marrow transplantation of patients with congenital bone marrow disorders was studied. Fourteen patients received 18 transplants; busulfan was used in the preparatory regimen of eight transplants and total body irradiation in the regimens of six transplants. Sustained hematopoietic ablation was achieved in six of eight patients prepared with busulfan and in all six patients prepared with total body irradiation. Three patients prepared with total body irradiation died with idiopathic interstitial pneumonitis, whereas no patients receiving busulfan developed interstitial pneumonitis. The optimal antihematopoietic stem cell agent to be used for the preparation of patients with congenital bone marrow disorder for bone marrow transplantation is not certain.
Adolescent↗
Epidemic keratoconjunctivitis in Liverpool.
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Disease Outbreaks↗
Molecular and transport effects of 1,25-dihydroxyvitamin D3 in rat duodenum.
The saturable component of transmural calcium transport in rat duodenum is transcellular, dependent on vitamin D, and can be evaluated by in situ gut loops or everted sacs. Vitamin D action at the molecular level can be studied by analyzing the response in terms of calcium-binding protein (CaBP; Mr congruent to 9000) biosynthesis to exogenous 1,25-dihydroxyvitamin D3 (1,25-(OH)2-D3). In vitamin D-replete animals, the CaBP response occurs within 1 h of intraperitoneal injection when the animals have been fed a high-calcium diet (III), but in 7 h if the animals have been fed a low-calcium diet(I). The latter response appears to be transcriptional, whereas the former seems posttranscriptional. In vitamin D-deficient animals, exogenous 1,25-(OH)2-D3 evokes a CaBP response that occurs 7-8 h after treatment and is transcriptional in nature. Calcium uptake by isolated duodenal cells can be stimulated by prior in vivo treatment with 1,25-(OH)2-D3. Peak response times parallel those found with CaBP biosynthesis, i.e., 3 h in cells from vitamin D-replete animals fed diet III, 7 h in cells from vitamin D-replete animals fed diet I, and 12 h in cells from vitamin D-deficient animal. Cycloheximide treatment appears to inhibit these responses. Moreover, everted sacs from vitamin D-replete animals fed diets III and I show an early and a delayed transport response, respectively. Studies with brush border membrane vesicles prepared from rat duodenum have shown calcium uptake to be vitamin D-dependent. Part of this uptake involves binding to the inner aspect of the membrane and may involve a high-affinity CaBP. Thus a major component of the action of vitamin D in stimulating calcium transport appears to involve protein synthesis. The time and molecular nature of these responses depend on the calcium intake and vitamin D status of the animals. A model of calcium movement through the intestinal cell is included.
Animals↗
Levels of 2'-deoxycoformycin, adenosine, and deoxyadenosine in patients with acute lymphoblastic leukemia.
2'-Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase, has recently undergone Phase I clinical trials and has been found to be therapeutically active in acute lymphoblastic leukemia. In this report, levels of dCF in plasma, plasma concentrations of adenosine and deoxyadenosine, and urine levels of deoxyadenosine were measured in leukemic patients undergoing treatment with dCF during a Phase I clinical trial. dCF was administered i.v. at a dose of 0.25 to 1.0 mg/kg (7.5 to 30 mg/sq m) for 3 consecutive days. Plasma drug levels of 2 to 6 microM were observed following the third dose of dCF, and drug accumulation occurred only at the 1-mg/kg dosage. In this limited series of patients, the plasma concentrations of adenosine and deoxyadenosine and the urine concentrations of deoxyadenosine did not show an obvious correlation with dCF dose, therapeutic response, or toxicity.
Adenosine↗