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Biomedical subjects

I Brodsky

Publications and source records attributed to I Brodsky.

At least 73 records · Page 4Linked to original sources
PubMed1990

Prophylactic tranexamic acid decreases bleeding after cardiac operations.

Thirty-eight patients undergoing a cardiac operation randomly received either tranexamic acid, a potent inhibitor of plasminogen, or placebo in an effort to determine whether prophylactic antifibrinolytic therapy reduces chest tube drainage. Twelve-hour blood loss was 750 +/- 314 (standard deviation) ml in the placebo group and 496 +/- 228 ml in the drug group (p = 0.0057). Fibrin split products were present more frequently in patients in the placebo group (17 of 20 compared with four of 18 in the drug group; p = 0.0002). Tranexamic acid markedly decreased plasminogen availability (112 +/- 104 units in the placebo group versus 36 +/- 18 units in the drug group, p = 0.0058). Plasma fibrinogen concentrations were similar in the placebo and drug groups. Patients in the placebo group received more fresh-frozen plasma and more mediastinal shed blood than those in the drug group. No coagulation-related complication occurred in the group receiving tranexamic acid. We conclude that prophylactic tranexamic acid can be administered safely to inhibit fibrinolysis during cardiac operations, decrease postoperative bleeding, and possibly decrease the frequency of blood product transfusion.

Adult↗
PubMed1989

Hereditary sideroblastic anemia with associated platelet abnormalities.

A 62 year old male (R.H.) presented with a mild anemia (Hb 11-12 gm%) and a history of multiple hemorrhagic episodes. The marrow had 40-50% sideroblasts. Marrow chromosomes were normal. His wife was hematologically normal, while one daughter, age 30 years, had a sideroblastic anemia (Hb 11-12 gm%) with 40-50% sideroblasts in the marrow. Her anemia was first noted at age 15 years. Administration of vitamin B6 did not correct the anemia in either the father or daughter. Platelet abnormalities inherited jointly with this disorder are described for the first time. Both R.H. and his daughter had prolonged bleeding times, with normal PTT, PT times, fVIII:C, fVIII:Ag levels, and vWF multimers, which may rule out a von Willebrand's disease. They have normal platelet numbers but abnormally low platelet adhesiveness and greatly depressed ADP, collagen, and epinephrine responsiveness. Response to ristocetin was in the low normal range, and aggregation with thrombin was normal. While desmopressin completely normalized R.H.'s bleeding time, none of these platelet parameters were improved. No differences in the SDS PAGE protein patterns of RH platelets could be detected in comparison to normal samples. His platelets took up and released serotonin (5HT) normally, and electron micrographs defined no morphological abnormalities. However, no ATP was released from platelets activated with collagen, and when followed by thrombin about fourfold greater ATP was released by control platelets as compared to RH platelets. The dense granule fraction derived from RH platelets contained about 20% the level of ATP, 40% the level of ADP, and 50% the level of 5HT detected in a normal sample. The results indicate that the bleeding disorder is related to a non-classical heritable storage pool defect. The connection between the inherited sideroblastic anemia and platelet defects is obscure.

Adenosine Triphosphate↗
PubMed1987

Clinical, immunological, and virological effects of ampligen, a mismatched double-stranded RNA, in patients with AIDS or AIDS-related complex.

10 patients with the acquired immunodeficiency syndrome (AIDS), AIDS-related complex (ARC), or lymphadenopathy syndrome (LAS) were given 200-250 mg ampligen, a mismatched double-stranded (ds) RNA with in-vitro antiviral activity against human immunodeficiency virus (HIV), twice a week for up to 18 weeks, without side-effects or toxicity. In all 9 patients who were positive for HIV RNA in peripheral blood mononuclear cells before therapy, levels became undetectable between days 10 and 40 of the start of therapy. 6 of the 7 patients with ARC or LAS also showed a progressive reduction in HIV load as measured by co-culture assays. All 10 patients had augmentation of delayed-type hypersensitivity skin reactions. Other changes noted during ampligen therapy included an increase in or maintenance of numbers of helper-inducer T lymphocytes, improvements in HIV-related symptoms, rises in titre of neutralising antibodies against HIV, and restoration of proper functioning of the natural lymphocyte antiviral dsRNA-dependent (2'-5'-oligoadenylate/RNA-ase L) pathway. Thus, in the short term, ampligen seems to have the dual ability to restore immunological function and to control HIV replication.

AIDS-Related Complex↗
PubMed1987

Implications of retroviral and oncogene activity in chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a stem cell disease which, on a clinical level, progresses from the release from growth control of normally differentiated cells (a preleukemic state) to an acute leukemia. On a molecular level, the evolution of CML to acute leukemia is a multistep process. We propose that an early step, at the stem cell level, is acquisition of the ability for gene movement, which allows subsequent submicroscopic and chromosomal rearrangements that cause changes in the growth characteristics and regulation of the stem cell. A specific platelet DNA polymerase (PDP - reverse transcriptase) may play a role in gene movement. The characteristic reciprocal translocation of chromosomes #9 and #22, causing the activation of the c-abl oncogene, appears to be responsible for the uncontrolled cellular growth. Yet, other growth factors (e.g., platelet derived growth factor) and activated oncogenes (e.g., c-sis) must be responsible for the stimulation, progression, and variability seen during the course of the disease. Because CML is a progressive disease with clinically definable stages, CML appears to be a model system for the study of the molecular basis of the progression of preleukemia to leukemia specifically, and preneoplasia to aggressive neoplasia in general.

Blood Platelets↗
PubMed1987

Cytogenetics and cell surface marker analysis in chronic myelocytic leukemia. II. Implications for patient management.

Chronic myelocytic leukemia (CML) is a model system for the study of many aspects of malignant disease. One aspect that correlates with decreasing therapeutic response is tumor progression. This progression is often accompanied by clonal evolution. In those cases where aggressive therapy does not prevent this evolution, the clinical response to therapy usually proves to be poor and of short duration. Investigators are concentrating their efforts in three primary, but not mutually exclusive, areas with respect to the clinical management of CML. These include: an attempt to distinguish patients at risk for early transformation from those who will have a prolonged chronic phase; the cryopreservation of autologous bone marrow or buffy coat early in chronic phase for subsequent use in the accelerated phase and; endeavors to identify early markers for disease progression allowing intervention before an irreversible blast crisis occurs. This report deals with two types of potential prognostic markers of transformation: chromosomal and cell surface characteristics. The appearance of nonrandom abnormal chromosomal patterns has been correlated with myeloblastic transformation by many investigators. However, there has always been a subset of CML patients who do not undergo clonal evolution. Additionally, the type(s) of transformation in CML may vary depending on the cell lineages involved. Unlike myeloblastic transformants, many of our patients who do not exhibit clonal evolution as a concomitance of disease progression develop a lymphoblastic transformation. Cytofluorometric analysis can distinguish small populations of abnormal cells with lymphoblastic characteristics (HLA DR+). Initial data suggests that patients expressing the HLA DR+ in their "normal" peripheral blood cells are at risk of undergoing lymphoblastic transformation. The combined use of clinical, cytogenetic, and cytofluorometric data to predict an impending transformation and to discriminate between myeloblastic and lymphoblastic populations allows clinicians to manage their patients more effectively.

Adolescent↗
PubMed1987

Herpes simplex virus replication and protein synthesis in a human blood-derived cell line.

Herpes simplex virus (HSV) types 1 and 2 were shown to replicate in a newly described human cell line (Meg) derived from the peripheral blood of a healthy volunteer. The cell line has both megakaryocyte-like and B cell-like properties. Upon infection with HSV-1 or -2, at a m.o.i. between 0.5 and 5, unlike B and T cells, the Meg cells were growth-arrested and this was accompanied by cytopathic effects and virus replication. The HSV proteins and glycoproteins B and D (gB and gD) made in the blood-derived Meg cells were compared to the corresponding proteins made in the non-blood-derived cell lines, Vero (African green monkey kidney cell) and HEp-2 (human epidermoid carcinoma cell). The maximum level of HSV protein synthesis occurred earlier in the Meg cells than in the Vero and HEp-2 cells. The electrophoretic pattern of HSV-1 and -2 proteins made in the Meg cell line was similar to the corresponding proteins made in the Vero and HEp-2 cell lines; however, some qualitative and quantitative differences were evident. There were no apparent differences detected in the migration pattern of gB made in all three cell lines while significant differences were observed with the gD species. However, upon hydrolysis with Staphylococcus aureus V-8 protease of the monoclonal antibody-purified gB and gD, distinct differences were observed in the electrophoretic pattern of the generated peptide fragments of both gB and gD made in the three cell lines. The results demonstrate that a human blood cell can support HSV replication and that species-specific post-translational modification of gB and gD occurs in HSV-infected Vero cells as compared to HSV-infected human cells.

Animals↗
PubMed1986

Familial occurrence of breast cancer is associated with reduced natural killer cytotoxicity.

A factor in the incidence of spontaneous neoplasms in mice is the endogenous level of natural cell-mediated cytotoxicity. These immunosurveillant or host defense mechanisms are probably under the control of multiple gene products including interferons. We studied natural killer (NK) cytotoxicity using peripheral blood mononuclear cells from 59 normal individuals with either a high (17) or low (42) familial incidence of breast cancer. The K562 cell line was used as target in 51Cr release assays. Three effector: target ratios (6.2:1, 25:1, and 50:1) were studied in quadruplicate using 3, 4 and 5-h incubations. Significantly lower natural killer activity (p less than 0.002) was detected in normal individuals with high familial incidences of breast cancer compared to individuals with low incidences in each of the three separate assays (50:1). The same conclusion was reached whether the data were expressed in terms of lytic units per 10(7) blood mononuclear cells or as % specific 51Cr released. Thus, a relationship was observed between the occurrence of breast cancer in closely related family members and low natural cell-mediated cytotoxicity. This result suggests that defects in NK activity may play a role in the initiation of human breast tumors. However, prospective studies will be necessary to establish whether low NK cell activity is a risk factor for breast cancer.

Adult↗
PubMed1986

Antiproliferative effect of mismatched double-stranded RNA on fresh human tumor cells analyzed in a clonogenic assay.

Colony growth in soft agar was used to identify human tumors that were sensitive to the direct antiproliferative effects of mismatched dsRNA (Ampligen). The results suggest that different human solid malignancies vary significantly in their sensitivity to Ampligen. Tumors with 50% or more of their surgical specimens showing sensitivity included carcinoid, glioblastoma, and carcinomas of the kidney, and lung. Resistant tumors (less than 15% sensitivity) included sarcomas and colo-rectal carcinomas. Overall, 42% of the tumor specimens studied showed a 50% or greater reduction in tumor cell colony formation after a single initial treatment with Ampligen (250 micrograms/ml). Interestingly, one patient's tumor which was de novo sensitive to interferon (IFN), but emerged as IFN-resistant following IFN therapy, remained sensitive to Ampligen. Thus, a clonogenic assay may prove useful in identifying human tumors and individuals for clinical trials with Ampligen, including patients resistant to IFN.

Base Composition↗
PubMed1985

Cytogenetics and cell surface marker analysis in CML--1. Prediction of phenotype of acute phase transformation.

Thirty-nine patients with Philadelphia chromosome-positive (Ph1) chronic myelocytic leukemia (CML) were monitored using cytofluorometry and cytogenetics. During chronic phase, abnormal populations could be detected using commercially available monoclonal antibodies. Most of these abnormal populations had either an HLA.DR+ or an OKM1+ HLA.DR- phenotype. Thirteen patients progressed to acute phase disease. Five patients with HLA-DR+ abnormal cells during chronic phase showed no clonal evolution detectable using standard cytogenetic techniques and underwent lymphoid transformation. Seven patients with OKM1+-HLA.DR- abnormal cells exhibited chromosomal abnormalities in addition to the Ph1 and progressed to a myeloblastic acute phase. One patient with HLA.DR+ OKM1+ 63D3+ abnormal cells in chronic phase showed clonal evolution and progressed to a myelomonocytic acute phase. These results suggest that cell surface markers on chronic phase cells can be used in conjunction with cytogenetic monitoring to predict the phenotype of cells involved in the acute transformation of CML. B cells (6, 13), but not T cells (18), bearing the Ph1 have been isolated from chronic phase CML patients. Thus cells other than those of myeloid lineage may be involved. Periodic cytogenetic monitoring has been shown to detect clonal evolution (i.e. genetic changes in addition to the PH1) in as many as 75% of patients prior to the acute phase (14, 37). However, neither cytogenetic changes nor morphologic analysis appear to predict the lymphoblastic type of transformation (14). Since fluorescence analysis of cell surface markers has shown reduced numbers of normal cells (28), the identity of the 'abnormal' cells was probed with antibodies recognizing a variety of markers on immature and mature lymphoid and myeloid cells. Not only were significant numbers of abnormal cells detected in the peripheral blood of chronic phase patients, but the phenotype of the abnormal population, in combination with cytogenetic analyses, predicted the type of blasts involved in acute phase disease.

Adult↗
PubMed1985

Novel peripheral blood-derived human cell lines with properties of megakaryocytes.

For 18 mo, we derived 18 cell lines from 11 donors with various clinical profiles ranging from normal to leukemic. Suspension cultures were initiated with 1 X 10(6) mononuclear blood cells/ml of nutrient medium containing 10% human serum and 10% lectin-stimulated human lymphocyte conditioned medium. The cultures were monitored weekly by morphological analyses of Wright-Giemsa-stained cell preparations. All successful cultures showed a significant decline in viability during the first 3-4 wk with rate "lymphoid" cells observed in mitosis. Within the next 2 wk, the proliferating cells gave rise to a rapidly expanding population of mononuclear cells. As the cultures expanded, cell morphology became heterogeneous with respect to cell size and nuclear ploidy, with an accumulation of giant multinuclear cells that were suggestive of megakarocytes. Even though the cells did not have the classical morphology of mature platelet-forming megakaryocytes, 90% of the cells within a cell line were positive by direct or indirect immunofluorescence for the platelet membrane glycoproteins IIb and IIIa; for surface markers HLA-Dr and B2-microglobulin; for intracellular platelet-derived growth factor and platelet factor IV; and for membrane affinity or binding with serum platelet-derived growth factor and platelet factor IV. These results suggest that a blood precursor cell, most likely a primitive megakaryoblast, was isolated from the peripheral blood and was provided with an optimal culture environment for sustained growth. These cells did not mature to a more differentiated stage, perhaps owing to regulatory factor deficiencies in this in vitro system. The remarkable frequency of obtaining cell lines with megakaryocyte properties from normal peripheral blood and the capacity of some normal donors to repeatedly yield these cell lines make this cell culture system indeed unique by being selective for putative megakaryocyte precursors.

Antigens, Viral↗
PubMed1985

Cytogenetics and flow cytometry may predict phenotype of CML blast crisis.

Twenty-eight patients with chronic myelocytic leukemia (CML) and the Philadelphia chromosome (Ph1) were monitored using cytofluorometry and cytogenetics. During chronic phase, abnormal populations could be detected using commercially available monoclonal antibodies. These abnormal populations fell into two categories based on the presence or absence of HLA.DR. Patients with HLA.DR+ abnormal cells showed no clonal evolution and progressed to lymphoid blast crisis. Patients with HLA.DR- abnormal cells exhibited chromosomal abnormalities in addition to the Ph1 and progressed to a myeloblastic acute phase.

Adult↗
PubMed1985

Preclinical studies with Ampligen (mismatched double-stranded RNA).

Historically, double-stranded (ds) RNAs have been largely over-looked as potentially valuable anticancer/antiviral drugs, primarily because of the many clinical toxicities and lack of efficacy associated with the first clinically tested dsRNA--polyinosinic-polycytidylic acid (rIn X rCn). However, studies summarized herein demonstrate that the therapeutic ratio of dsRNAs can be greatly enhanced by purposeful mispairing of bases. For example, a mispaired dsRNA, termed Ampligen (rIn X r(C12,U)n), shows strong antitumor activity in a variety of relevant test systems with little or none of the toxicities associated with rIn X rCn. Furthermore, Ampligen demonstrates a much wider therapeutic spectrum than that displayed to date by any single type of interferon (natural or recombinant DNA-derived). Importantly, Ampligen, the product of a straight-forward enzymatic synthesis, shows excellent lot-to-lot biological and biophysical specifications, which is often not the case with biologically derived new compounds. Furthermore, a significant fraction of human solid tumors, which are largely unresponsive to conventional chemotherapy or interferon (IFN), is sensitive to Ampligen in a fresh human tumor clonogenic assay. Indeed, whereas 50% of untreated and IFN-treated athymic mice engrafted with human renal cancer cells die within 20-22 weeks, mice treated with Ampligen survive a minimum of 32 weeks (p less than 0.0003). A summary of all animal models tested and human clinical trials to date demonstrates that Ampligen exerts a greater antitumor activity than IFN and has a superior therapeutic ratio compared to rIn X rCn.

Animals↗
PubMed1985

Clinical studies with ampligen (mismatched double-stranded RNA).

Results of an ongoing clinical study of a mismatched double-stranded (ds) RNA, termed Ampligen, in patients with metastatic cancer are described. In a pilot study of Ampligen (lot 1) involving mostly hematologic malignancies, patients received cumulative doses up to approximately 450 mg without untoward effects. Evidence of biologic/antitumor effects was observed (3/5 patients) by monitoring tumor-specific markers or tumor cell morphology. In patients with solid tumors receiving lot 2, Ampligen cumulative doses over 4 g were well tolerated. The drug was given by intravenous infusion (10-80 mg/infusion, twice weekly), in some instances for more than 1 year, without clinically significant side effects. Specifically, no evidence of hematologic, liver, or renal toxicity, which was previously noted with other dsRNAs, was observed. Side effects consisted of occasional mild fatigue or flu-like symptoms. Fever, when encountered, was transient and low grade (less than 100.5 degrees F). Importantly, an analysis of patient sera for dsRNA antibodies revealed that no patient had evidence of specific antibodies directed against Ampligen. Other dsRNAs cause up to a 60% incidence of antibody formation. Additionally, a novel method was developed to monitor Ampligen blood levels. In a survey of seven patients, Ampligen had a mean plasma half-life of 23 min. Ampligen administration can also result in activation of both natural killer (NK) cells and a lymphocyte, interferon-associated, intracellular enzyme. Dose-dependent antitumor effects were seen in several solid tumors; in doses of 10-40 mg, 3/9 patients showed stable disease for up to 1 year. At the 80-mg dose level, 2/5 patients showed tumor regressions (mixed and partial responses).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody Formation↗