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Biomedical subjects

I Sklenar

Publications and source records attributed to I Sklenar.

13 recordsLinked to original sources
PubMed1995

Mobilization of peripheral blood stem cells with chemotherapy and cytokines in multiple myeloma.

In an attempt to offset the impaired hematopoietic progenitors' mobilization and collection which are frequently encountered in multiple myeloma (MM), we have started a pilot study to evaluate the ability of a combination of high-dose melphalan (HDM) and sequential s.c. administration of recombinant human interleukin 3 (rhIL-3) and rh-granulocyte colony-stimulating factor (G-CSF) to mobilize blood cells (BC) in MM patients. Two different schedules for administration were successively tested. Schedule A consisted of IL-3 (5 micrograms/kg/d) from day 7 to day 11 after HDM followed by G-CSF (5 micrograms/kg/d) from day 12 to day 20. Under schedule B, HDM was followed by IL-3 alone at the same dosage from day 1 to day 3, IL-3 and G-CSF (idem) from day 4 to day 7 and G-CSF alone from day 8 until completion of apheresis. Two patients (one previously untreated, one having received prior chemotherapy for one year) underwent schedule A; three patients (one previously untreated, two pretreated) underwent schedule B. The post-HDM aplasia was not shortened in schedule A patients in comparison to what we usually observed following HDM alone (25 days) correlated with a very moderate two- to three-fold CD34+ cell increase. Only one patient was further transplanted with apheresis products: the post-transplant granulocyte recovery was slower than usual (16 days versus 12 days) while platelet count never recovered over 20 x 10(9)/l. In contrast, the post-HDM aplasia was significantly shortened in two of the schedule B patients (3 to 10 days) and was followed by a 25- to 165-fold increase in CD34+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Recombinant human interleukin-3 hastens trilineage hematopoietic recovery following high-dose (7 g/m2) cyclophosphamide cancer therapy.

BACKGROUND: Interleukin-3, a recombinant cytokine with multilineage stimulatory effect on hematopoietic cells, was administered to 22 previously untreated breast cancer patients following high-dose therapy with cyclophosphamide (7 g/m2). PATIENTS AND METHODS: The growth factor, administered through continuous intravenous infusion at 1 (3 patients), 2.5 (3 patients), 5 (10 patients) and 10 micrograms/kg/day (6 patients), was well tolerated up to 5 micrograms/kg/day. RESULTS: Nausea, vomiting, fever and headache prevented administration of the intended dose to all 6 patients in the 10 micrograms/kg/day cohort. At the maximal tolerable dose (5 micrograms/kg/day) the growth factor significantly accelerated granulocyte, platelet and reticulocyte recovery as compared to matched historical controls who received high-dose cyclophosphamide without cytokine infusion. Moreover, no platelet transfusions and fewer erythrocyte transfusions were required in interleukin 3-treated patients. In contrast to GM-CSF and G-CSF, interleukin 3 showed no effect on the mobilization of hematopoietic progenitor cells in the peripheral blood. CONCLUSIONS: Interleukin-3 represents a well-tolerated cytokine, clinically useful for accelerating trilineage hematopoietic recovery following severely myelotoxic treatments such as high-dose cyclophosphamide.

Adolescent↗
PubMed1993

Increase in peripheral blood megakaryocyte progenitors following cancer therapy with high-dose cyclophosphamide and hematopoietic growth factors.

Seven patients received cancer chemotherapy with high-dose cyclophosphamide (HD-CTX) associated with either recombinant human granulocyte colony-stimulating factor (rhG-CSF), rh interleukin-3 (rhIL-3), rh granulocyte-macrophage CSF (rhGM-CSF) plus rh erythropoietin (rhEpo), rhIL-3 plus rhGM-CSF, or rhIL-3 plus rhG-CSF. In the steady-state blood samples (before HD-CTX), megakaryocyte burst-forming units (BFU-Meg) and megakaryocyte colony-forming units (CFU-Meg) were virtually undetectable (< or = 1/mL BFU-Meg and CFU-Meg, range 0 to 1) by assaying unfractionated leukocytes. In contrast, in the recovery-phase blood samples (after HD-CTX), BFU-Meg and CFU-Meg increased several hundred-fold over steady-state values. This occurred regardless of the in vivo growth factors used and in parallel with increases in mixed, erythroid, and myeloid progenitors. In vitro, recovery-phase BFU-Meg and CFU-Meg responded to the novel GM-CSF/IL-3 fusion protein PIXY321 similarly as to optimal concentrations of rhIL-3 and rhGM-CSF. However, these progenitors differed from those in the steady state because BFU-Meg had faster duplication time and CFU-Meg prevailed numerically (CFU-Meg to BFU-Meg ratio 3.4 [recovery] vs. 0.52 [steady state]). Furthermore, soluble c-kit ligand/rh stem cell factor (rhSCF), in vitro in combination with rhIL-3 and rhGM-CSF or PIXY321, increased the size but not the number of colonies derived from recovery-phase BFU-Meg and CFU-Meg. These quantitative and qualitative changes occurring in circulating megakaryocyte progenitors contribute to the understanding of the rapid platelet recovery that occurs when peripheral blood hematopoietic progenitors elicited by HD-CTX and growth factor(s) are transplanted into patients treated with myeloablative chemoradiotherapy.

Adult↗
PubMed1986

Association of symptomatic human infection with Toxoplasma gondii with imbalance of monocytes and antigen-specific T cell subsets.

During recent symptomatic toxoplasmosis, alterations in quantity and function of mononuclear cells in peripheral blood were observed. Flow cytofluorometric analysis and differential leukocyte counts revealed increased absolute numbers of T8+ cells, Leu 7+ (natural killer/killer) cells, and monocytes. T4+ cells and HLA-DR+ cells were not significantly changed. T4/T8 cell ratios were reversed in symptomatic toxoplasmosis (0.7 +/- 0.3) and normal in chronic infection (1.7 +/- 0.5). Toxoplasma antigen induced higher numbers of T8+ and TQ1+ cells in four T cell lines from two individuals with symptomatic infection than in five T cell lines from three individuals with asymptomatic infection. Eight cloned T cell lines produced gamma interferon in an antigen-specific fashion and in higher amounts when they originated from an asymptomatic subject than from a symptomatic subject. These results indicate that marked alterations in properties of immunoregulatory cells are characteristic of recent symptomatic toxoplasmosis. The transient immune dysfunction may be a major part of the observed disease and/or a feature of successful parasitism.

Acute Disease↗
PubMed1985

Evaluation of accessory cell heterogeneity. I. Differential accessory cell requirement for T helper cell activation and for T-B cooperation.

Several Ia+ tumor cell lines and peritoneal exudate macrophages were tested as accessory cells (AC) for the activation of antigen-specific T cells and for T-B cooperation. The macrophages and all the Ia+ tumor lines tested induced the release of lymphokines from T cells in a major histocompatibility complex (MHC)-restricted fashion and reconstituted the antibody responses of AC-depleted spleen cells or of purified T and B cells. However, only the normal macrophages but none of the tumor lines induced carrier-specific T helper (Th) cells which help B cells for specific antihapten antibody responses by linked recognition. For T-B cooperation accessory cells were also required, but in contrast to Th cell activation any type of Ia+ AC (e.g. macrophage or tumor line) was effective. Strong MHC-restriction between the lymphocytes and the AC was seen if antigen-pulsed AC were added into the AC-depleted T-B cooperation cultures. If the AC and antigen were concomitantly added to the AC-depleted T-B cultures, MHC-restriction was less obvious. Concanavalin A supernatant reconstituted the response of AC-depleted T-B cultures provided antigen-specific Th cells and the hapten-carrier conjugate were present. If, however, tumor line-activated T cells were added instead of macrophage-induced Th cells, no cooperation with B cells took place even in the presence of Con A supernatant. The results obtained demonstrate a differential AC requirement for the induction of Th cells depending on the differentiation stage of the Th cells.

Animals↗
PubMed1985

Evaluation of accessory cell heterogeneity. II. Failure of dendritic cells to activate antigen-specific T helper cells to soluble antigens.

The activation of antigen-specific T cells requires Ia+, antigen-presenting accessory cells (AC). Dendritic cells (DC) and macrophages (M phi) isolated from spleen an peritoneal exudate were tested as AC for the activation of the activation of T helper cells and the induction of T cell proliferation. The cell separations to obtain DC and splenic M phi were performed by discontinuous bovine serum albumin gradients, adherence on petri dishes and rosetting with opsonized sheep erythrocytes. DC as well as the M phi were able to induce antigen-specific T cell proliferation, but only the M phi and not the DC activated antigen-specific T helper cells which help B cells for antibody production to soluble antigens. Keyhole limpet hemocyanin-specific T cells repeatedly stimulated with DC and antigen also did not express helper activity. The failure of DC to induce T helper cells was not due to the activation of a suppressor pathway. Thus, dendritic cells, although very efficient as AC in the induction of various T cell functions, are not able to activate T helper cells required for carrier-specific T-B cooperation and therefore cannot be the sole accessory cells. Based on these results and on previous data using Ia+ tumor cell lines as AC, we confirm the existence of functional AC heterogeneity.

Animals↗
PubMed1985

Evaluation of accessory cell heterogeneity. III. Role of dendritic cells in the in vitro activation of the antibody response to soluble antigens.

Dendritic cells and macrophages obtained from spleen and peritoneal exudate were tested as accessory cells for the activation of lymphokine production by T cells, for supporting T-B cooperation and for the induction of antigen-specific T helper cells. Dendritic cells as well as macrophages were able to activate T cells for interleukin-2 secretion and functioned as accessory cells in T-B cooperation, but only macrophages induced T helper cells, which cooperate with B cells by a linked recognition interaction, to soluble antigens. Dendritic cell- and antigen-activated T cells also did not help B cells in the presence of Con A supernatants which contained various T cell- and B cell-stimulatory factors. The failure of dendritic cells to differentiate memory into functional T helper cells, but their efficient accessory cell function in T-B cooperation, where functional T helper cells are already present, can be best explained by a differential accessory cell requirement for T helper cell activation dependent on the differentiation stage of the T helper cell.

Animals↗
PubMed1982

Association of specific immune response to pork and beef insulin with certain HLA-DR antigens in type 1 diabetes.

To test the association of HLA-DR antigens with high-responder and low-responder status to either beef or pork insulin, insulin antibodies in diabetic sera were separated into those with average low and those with average high affinity and their insulin-binding capacities for each insulin determined. Significantly less binding of pork insulin by the high affinity antibodies occurred in the group of patients with DR3 antigens compared with those with DR4 antigens (p less than 0.01) and DR3/4 antigens (p less than 0.01). The difference in the binding capacity of beef insulin by the high affinity antibodies between the groups with DR3 and DR4 antigens was less pronounced but still significant. The high-responder status of DR3/4 antigens to pork insulin suggests that the gene or genes associated with HLA-DR4, and responsible for a high response to pork insulin, are dominant to genes associated with HLA-DR3 and a low response. If extended to human insulin and different HLA-DR and HLA-B antigen patterns, these finding should help in the therapeutic selection of the appropriate insulin and thus reduce the induction of an anti-insulin response in patients with diabetes.

Animals↗
PubMed1981

Acute cecitis.

Explore the source record for details and available documents.

Acute Disease↗
PubMed1977

One-dose and multiple-dose kinetics of minocycline in patients with renal disease.

Kinetic analysis of minocycline concentrations in plasma and urine resulted in the following findings: In normal subjects the biological half-life is about 17 hours after the first dose and 21 hours after repeated administration. The renal drug clearance is only about 8% of the overall plasma clearance which is independent of renal function with a mean value of 47 ml/min. The fraction of the absorbed dose eliminated unchanged in the urine is only 9--19%. As a consequence the elimination rate of the drug is practically independent of renal function and decreases only 9--19% in anuric patients. The renal drug clearance depends linearly on renal function. The gastro-intestinal bio-availability of minocycline from the coated tablet preparation is incomplete. The cumulative behaviour of the drug corresponds to the kinetic parameters determined after repeated administration. It is suggested that the usual dosage regimen should be used in patients with renal disease.

Adult↗
PubMedDate not supplied

Effect of various doses of intravenous polyclonal IgG on in vivo levels of 12 pneumococcal antibodies in patients with chronic lymphocytic leukaemia and multiple myeloma.

Polyclonal intravenous IgG (IVIG) was administered as an infusion 6 times every 3 weeks (week 0, 3, 6, 9, 12, 15) in doses of 0.1, 0.4 and 0.8 g/kg BW to determine the dose causing an increase in 12 pneumococcal antibody types above the protective level of 200 ng/ml of antibody N. The dose of 0.4 g/kg BW was found to be optimal in patients with chronic lymphocytic leukaemia (CLL). From the first infusion onwards at least 80% of CLL patients had increases in all 12 antibodies. Five weeks after the last infusion the antibody levels were still elevated in 80% of patients with CLL. The dose of 0.8 g/kg raised all 12 antibodies in 53-73% of CLL patients when assessments were made after each infusion. In multiple myeloma (MM) patients, 73-82% and 73-91% of patients had increased antibody levels, respectively, before and after the 4th-6th infusions at the 0.8 g/kg dose level. However, in only 45-50% of patients did the antibodies remain increased 2 weeks after the treatment at this dose. The dose of 0.4 g/kg caused antibody increases in only 30-50% of patients when measured before the 4th-6th infusion. Serum IgG increased significantly only in the CLL patients, whereas in the MM patients it was high from the beginning owing to the disease. Therefore, the pneumococcal antibody levels were a better marker for the purpose of dose finding. The dosage recommendation in CLL is 0.4 g/kg every 3 weeks until week 12, when steady state is reached. The maintenance dose is 0.4 g/kg every 5 weeks. In MM patients, who have a faster elimination rate of antibodies, the recommended loading dose is 0.8 g/kg, followed by 0.4 g/kg every week as a continuous treatment. Treatment with IVIG in CLL and MM was generally well tolerated. Only 25% of patients experienced minor side-effects, the most frequent being febrile reactions, shivering and headache.

Adult↗
PubMedDate not supplied

Spontaneous hypoglycemia associated with autoimmunity specific to human insulin.

A 55-yr-old woman with a history of Graves' disease experienced attacks of postprandial hypoglycemia for 6 yr. An insulinoma could not be confirmed by repeated fasting tests and by surgical pancreas revision. Extracted pancreatic insulin was chemically normal. Fasting plasma total insulin (1.22 nM = 183 microU/ml) and proinsulin (0.48 nM) were elevated and greatly increased after oral glucose. Glucose-clamp studies revealed delayed insulin clearance. Plasma free-insulin levels were normal. Insulin-binding antibodies were detected by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay with human insulin as ligand but not with pork or beef insulins. Analysis with a modified ELISA suggested a monotypic and monoclonal human insulin autoantibody, which showed a restriction to the lambda-light chain. T-lymphocytes (predominantly helper) demonstrated increased responsiveness to beef, pork, and human insulins by proliferation assay. A T-lymphocyte line showed exclusively human insulin specificity. All this indicated cellular and humoral anti-human insulin autoimmunities. Clinically, the cause of hypoglycemia associated with elevated total insulin and proinsulin was misdiagnosed as atypical insulinoma. The study of total and free plasma insulin levels and sensitive antibody assays specific to human insulin were necessary to correctly diagnose autoimmune hypoglycemia.

Autoimmune Diseases↗