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Biomedical subjects

J Mladenovic

Publications and source records attributed to J Mladenovic.

At least 19 recordsLinked to original sources
PubMed2006

Survival and mortality of myotonic dystrophy type 1 (Steinert's disease) in the population of Belgrade.

The purpose of this investigation was to determine survival and mortality in patients with myotonic dystrophy type 1 (DM1) in the Belgrade population within the period from 1983 to 2002. Data of a number of diagnosed DM1 patients with their demographic, clinical and genetic characteristics were gathered from hospital records in all neurologic institutions in Belgrade for the period 1983-2002. Death certificates were reviewed to determine the cause of death. Survival analysis by life table method and Cox proportional hazard model was performed. Within the observed period, in the population of Belgrade, 15 fatal outcomes among 101 patients with DM1 were registered. Average DM1 mortality rate was 0.5/1,000,000 (95% CI 0.3-0.8), and standardized mortality ratio (SMR) was 5.3. A significant inverse correlation was found between age at onset of DM1 and CTG repeats (P=0.023). The cumulative probability of 15-year survival for DM1 patients in Belgrade was 49+/-5% (48+/-2% for males and 50+/-7% for females). Younger age at onset was a significant unfavorable prognostic factor (hazard ratio=4.2; P=0.012).

Adolescent↗
PubMed2001

Lack of clinical utility of folate levels in the evaluation of macrocytosis or anemia.

PURPOSE: Folate levels are routinely ordered in the evaluation of macrocytosis with or without frank anemia, yet the value of these tests is questionable. We evaluated the clinical utility of folate testing in routine clinical practice. SUBJECTS AND METHODS: We conducted a retrospective review of all serum and erythrocyte folate assays performed over a one-year period at three hospitals. We determined the frequency of low values, then reviewed the medical records of all patients with low values to determine whether low folate levels changed clinician behavior. We also performed a cost analysis to determine the cost of testing per case in which behavior changed. RESULTS: Only 2.3% of the 2,998 folate levels obtained during the study period were low. The low levels were noted in the record in 53% of cases, and folic acid was prescribed or continued at discharge in only 24%. The cost analysis showed that nearly $10,000 was spent in folate testing per patient in which behavior changed. CONCLUSIONS: Folate values were rarely low in the population tested, and low values infrequently led to a change in clinician behavior. Given the limited clinical value of folate tests, we propose that, in cases of macrocytosis with or without anemia, to minimize cost and prevent missed cases of true folate deficiency, empirical supplementation with folic acid should be used in place of testing for deficiency.

Anemia↗
PubMed2000

Changes in human immunodeficiency virus type 1 virus load during mobilization and harvesting of hemopoietic progenitor cells. Adult AIDS Clinical Trials Group 285 Study Team.

Genetic modification of hemopoietic progenitor cells ex vivo, followed by the infusion of the genetically modified cells into the human immunodeficiency virus-1 (HIV-1) infected donor, has been proposed as a treatment for HIV-1 infection. The current study was undertaken to evaluate the effect of hemopoietic stem cell mobilization and harvesting on HIV-1 replication in persons with HIV-1 infection. Eighteen HIV-1-infected persons received recombinant granulocyte colony-stimulating factor (G-CSF; Filgrastim) 10 microg/kg per day, for 7 days. On days 4 and 5, peripheral blood mononuclear cells were harvested by leukapheresis. The CD4+ lymphocyte count at entry was >500/microL for 6 subjects, 200 to 500/microL for 6 subjects, and <200/microL for 6 subjects. For 9 of 18 subjects, plasma HIV-1 RNA levels increased 4- to 100-fold (>0.6 log(10)) above baseline between days 4 and 7 and returned to baseline by day 27. Significant increases of plasma HIV-1 RNA levels occurred in 5 subjects despite 3-drug antiretroviral therapy. Changes in CD4+ and CD34+ cells during mobilization and harvesting were similar in all subjects whether they had or did not have increased plasma HIV-1 RNA levels. Thus, mobilization and harvesting of bone marrow progenitor cells from persons infected with HIV-1 induced a transient increase in viral replication in some patients but was not associated with adverse effects. (Blood. 2000;95: 48-55)

Adult↗
PubMed2000

Reduced mobilization of CD34+ stem cells in advanced human immunodeficiency virus type 1 disease.

Granulocyte colony-stimulating factor (r-met Hu G-CSF; filgrastim; 10 microgram/kg/day for 7 days) was used to mobilize CD34+stem cells into the peripheral blood of human immunodeficiency virus type 1 (HIV-1)-infected individuals and a group of HIV-1-uninfected donors as a measure of immunologic reserve in HIV-1-infected people. G-CSF mobilized CD34+ cells of HIV-1-infected individuals with cell counts >500 CD4+ cells/mm3, as well as in HIV-1-uninfected donors. In contrast, CD34 cell mobilization was significantly blunted in HIV-1-infected individuals with cell counts <500 CD4+ cells/mm3 (<200 cell days vs. >650 cell days, P<.0005, compared with the >500 CD4+ cell cohort). At least 1.75x10(7) CD34 cells were harvested by leukapheresis from patients in each study cohort. CD34+ cell viability and the ability to differentiate precursor cells into myeloid and erythroid progenitor cells were not affected by HIV-1 infection.

Adult↗
PubMed1996

HIV type 1 RNA expression in bone marrows of patients with a spectrum of disease.

HIV-1-infected individuals at various stages of disease harbor virus in their lymphoid organs, which serve as reservoirs of viral replication throughout the course of infection. Hematologic abnormalities are extremely common in HIV-1-infected individuals and occur at all stages of disease. To determine if the bone marrow is a reservoir of HIV-1 in vivo and if active HIV-1 RNA expression in that site is related to hematologic disease in infected individuals, we examined HIV-1 RNA expression in bone marrow biopsies from 37 patients with a broad spectrum of hematologic and HIV-1-related disease. To detect HIV-1 RNA expression, we performed in situ hybridization. Double-label in situ hybridization-immunohistochemistry was used for precise identification of the type of cell expressing viral RNA. Six of 37 (16%) patients demonstrated HIV-1 RNA expression in the bone marrow. Double-label analysis performed on two marrows localized HIV-1 RNA to cells of the macrophage lineage. Active HIV-1 expression correlated with advanced HIV-1-related disease and CD4 cell depletion rather than a specific hematologic or clinical diagnosis. These data suggest that although the bone marrow does not serve as a reservoir of viral expression throughout the course of infection as do the lymphoid organs, HIV-1-expressing cells are present in the bone marrow during late stages of disease. These data also suggest that hematologic abnormalities in the majority of infected individuals may result from indirect effects of HIV-1 such as cytokine dysregulation rather than HIV-1 expression in the bone marrow itself.

Adult↗
PubMed1996

The BCR-ABL oncogene requires both kinase activity and src-homology 2 domain to induce cytokine secretion.

Expression of either the BCR-ABL or the v-abl oncogene in the factor-dependent murine myeloid cell line FDCP-1 results in growth factor independence. Studies with temperature-sensitive mutants of v-abl show that this growth factor independence is oncogene dependent. Likewise, cells expressing a kinase inactive mutant of BCR-ABL did not grow in the absence of interleukin-3 (IL-3). Conditioned media from cells expressing either v-abl or BCR-ABL contained growth factor(s) capable of stimulating the proliferation of uninfected FDCP-1 cells. Based on enzyme-linked immunosorbent assay studies and antibody neutralization studies, the major growth factor present in these conditioned media is IL-3. Because of the importance of SH2 domains in regulating substrate interactions, we examined the ability of SH2 deletion mutants in BCR-ABL to induce growth factor independence. Cells expressing a mutant of BCR-ABL lacking the SH2 domain were growth factor independent; however, they did not secrete growth factors. This finding suggests that while IL-3 produced by cells infected with BCR-ABL may contribute to autocrine or paracrine growth factor independence, expression of an activated tyrosine kinase alone may be able to induce growth factor independence. Furthermore, the secretion of cytokines maybe correlated with a specific region of the BCR-ABL oncogene, suggesting that activation (phosphorylation) of specific substrates may be critical for transcriptional activation of cytokine genes.

Animals↗
PubMed1992

Over-expression of c-src or v-src in bone marrow stromal cells stimulates hematopoiesis in long-term bone marrow culture.

The S17 murine stromal cell line was infected with retroviral vectors encoding the v-src and c-src oncogenes and cells expressing high levels of either pp60v-src or pp60c-src were isolated. Long-term bone marrow cultures (LTBMCs) established with these different stromal cell lines showed that progenitor cells proliferated to a greater extent in cultures with stromal cells that over-expressed either c-src or v-src. An increase in the number of granulocytes, monocytes, and colony-forming units granulocyte-macrophage (CFU-GM) in the nonadherent cell population of LTBMCs prepared with S17/v-src or S17/c-src stromal cells was observed. Conditioned media from the S17/v-src and S17/src stromal cell lines stimulated the formation of CFU-GM in the absence of additional hematopoietic cell growth factors. Conditioned media from S17/v-src and S17/c-src stimulated proliferation of the granulocyte-macrophage colony-stimulating factor (GM-CSF)-responsive cell line FDCP-1 and this stimulation was inhibited by neutralizing antisera to murine GM-CSF. An increase in the concentration of GM-CSF was confirmed by enzyme-linked immunosorbent assay. No secretion of interleukin-1 alpha (IL-1 alpha) or tumor necrosis factor-alpha was detected by any of the stromal cell lines. There was no increase in the secretion of either CSF-1 or IL-6 by either S17/v-src or S17/c-src. The addition of 1 micrograms/mL monoclonal anti-GM-CSF antibody to LTBMCs caused a decrease in the number of nonadherent cells in cultures established with each of the different stromal cell lines. Northern blot analysis showed no difference in the level of GM-CSF RNA among the different stromal cell lines. These studies suggest that the increased proliferation of hematopoietic progenitor cells in LTBMCs with S17/v-src or S17/c-src cells may result from a posttranscriptional event that elevates production of GM-CSF by the S17/c-src and S17/v-src stromal cells.

3T3 Cells↗
PubMed1990

How reorganizing a general medicine clinic affected residents' and patients' satisfaction.

The authors examined how satisfied patients and residents were before and after the restructuring of the general medicine clinic at a large urban teaching hospital in 1985; the change to a longitudinal care clinic was made to provide greater continuity of care, more consistent access of residents to attending physicians, and a more structured educational curriculum. Questionnaires to assess satisfaction were administered three weeks before and ten months after the change to all 80 of the second- and third-year residents. A convenience sample of 310 patients seen during a two-week period before the change and another such sample of 267 patients seen during a two-week period ten months after the change comprised the patients who completed a patients' satisfaction questionnaire. The residents were significantly more satisfied with the quality of care, functioning, and educational value of the new longitudinal care clinic. Their average overall rating of satisfaction (on a scale where 1 = completely dissatisfied and 5 = completely satisfied) increased from 2.3 to 3.7 (p less than .001). Unexpectedly, the patients were "very satisfied" with both clinic models and their overall ratings changed little (4.5 before, 4.4 after). In addition, the patients' and residents' before-and-after perceptions of the quality of care delivered in the clinic differed substantially. These findings show that the longitudinal care clinic significantly enhanced the satisfaction of the residents but not of the patients. Furthermore, the data suggest that results from standardized patients' satisfaction surveys may not accurately assess the quality of care being delivered.

Consumer Behavior↗
PubMed1988

Aluminum inhibits erythropoiesis in vitro.

Anemia has been associated with aluminum intoxication in patients on chronic dialysis and in animals. In studies presented here, in vitro human erythroid culture was used to delineate the effects of aluminum on normal hematopoiesis. Aluminum by itself in routine culture, even at very high levels (1,035 ng/ml), did not significantly affect erythroid colony growth. The addition of human transferrin to the culture, however, resulted in a marked dose-dependent inhibition of erythroid, but not myeloid colony growth. At all doses, CFU-E progenitors showed greater inhibition than burst-forming units (BFU-E). Aluminum inhibition was not overcome by increasing the dose of erythropoietin or adding additional burst-promoting activity to the culture. Inhibition by aluminum was directly related to the number of binding sites on transferrin in the culture, and was not observed in the presence of fully iron-saturated transferrin.

Aluminum↗
PubMed1988

Erythropoietin induces rapid increases in intracellular free calcium in human bone marrow cells.

Elevation of intracellular free calcium (Ca++) is an early activation event that occurs as a result of ligand binding in several human cell systems. In this report, erythropoietin, the major hormone governing erythroid differentiation, was found to elicit an increase in Ca++ in human bone marrow mononuclear cells. Two chelators of intracellular calcium, quin 2 and the more specific and sensitive analogue, fura-2, were used to characterize the response evoked by both recombinant and native hormone. Erythropoietin caused a rapid, dose-dependent rise (within seconds) in Ca++ in bone marrow mononuclear cells, which could be prevented by preincubation of hormone with a rabbit erythropoietin antiserum. The erythropoietin response did not occur in purified populations of T- or B-lymphocytes. These studies suggested that increased Ca++ on erythropoietin binding may be an early transmembrane signal in hormone action.

Aminoquinolines↗
PubMed1986

Application of the immunoperoxidase technic to bone marrow trephine biopsies in the classification of patients with monoclonal gammopathies.

This study evaluated the utility of the immunoperoxidase method as applied to bone marrow sections in the diagnosis of patients with monoclonal gammopathies. Intracellular immunoglobulin light chains were identified in fixed, decalcified bone marrow biopsy sections from 66 patients with monoclonal proteins, using an avidin-biotin-peroxidase complex immunoperoxidase method. In all cases the predominant light chain identified in the bone marrow biopsy correlated with the monoclonal light chain identified in the serum. In addition, a light chain ratio was defined that correlated with the clinical diagnoses. The light chain ratios were highest in patients with multiple myeloma and were significantly different from those with monoclonal gammopathy of undetermined significance. There was no correlation between level of serum monoclonal protein and light chain ratios. The ratios were also high in patients with macroglobulinemia, primary amyloidosis, and renal disease secondary to monoclonal proteins but without overt myeloma. Determination of light chain ratios differentiated patients with multiple myeloma from those with monoclonal gammopathy of undetermined significance and helped identify patients with end organ damage secondary to monoclonal proteins but without overt myeloma.

Biopsy↗
PubMed1986

Erythropoietin kinetics in rats: generation and clearance.

Detailed studies to analyze the early events of erythropoietin (Ep) secretion and clearance were performed in a rat model using a double antibody radioimmunoassay. Ep clearance was determined following intravenous injection of 1 mL of Ep-rich plasma, 1,080 mU/mL, obtained from phlebotomized rats. Analysis revealed a disappearance curve that conformed to a two-compartment model with an alpha half-life t1/2 of 3.6 minutes and a beta t1/2 of 86 minutes. The volume of distribution was similar to the calculated plasma volume. In anephric animals, there was no change in the plasma clearance rate or the volume of distribution. Rapid Ep secretion was elicited by a single 15 mL/kg phlebotomy (hematocrit decrement 45% to 30%), so that levels reached 20 to 30 times baseline (524 +/- 76 v 24 +/- 7 mU/mL) at five hours, whereas they plateaued for at least 33 hours. The increase in the rate of secretion was geometric, from 9.9 mU/h baseline secretion to 429 mU/h. These data identify a very sensitive and rapidly responsive system for Ep modulation in the rat.

Animals↗
PubMed1985

Erythropoietin kinetics in normal and uremic sheep.

Homologous erythropoietin (Ep)-rich plasma was infused into sheep to determine the kinetics of this hormone in a large animal model. Ep levels after infusion were measured by radioimmunoassay using a sheep standard. Twenty-seven infusions into normal (14), subtotally nephrectomized (11), and anephric (two) animals were analyzed according to a single-compartment model. The volume of distribution was also calculated, and compared with values obtained indirectly from measurement of chromium 51-labeled red blood cells. The data showed that the t1/2 of the infused hormone was approximately 9 hours and was independent of renal function. After multiple infusions, the t1/2 appeared to shorten. The volume of distribution for this hormone corresponded to the plasma volume of the animals. These studies suggest that Ep, if administered to patients with chronic renal failure, could be given infrequently with little dependence on renal function.

Anemia↗
PubMed1984

Adrenergic modulation of erythropoiesis: in vitro studies of colony-forming cells in normal and polycythaemic man.

The effect of hormonal interactions on human erythroid colony growth has been studied using the beta adrenergic agonist, isoproterenol. The growth of colonies derived from both erythroid burst-forming cells (BFU-E) and erythroid colony-forming cells (CFU-E) was enhanced in the presence of isoproterenol. While isoproterenol was effective at all concentrations of erythropoietin (Ep) in cultures of marrow cells, an increase in BFU-E-derived colonies in peripheral blood cultures could be detected only at suboptimal levels of Ep concentrations. The isoproterenol effect was blocked by an agent with beta 2 receptor specificity (butoxamine), and L-isomeric configuration (L-propranolol). The stimulatory effect appeared to be mediated by a receptor different from that for Ep or for phytohaemagglutinin-stimulated leucocyte conditioned medium. Circulating BFU-E from eight patients with polycythaemia vera were also studied. Those colonies which grew in the absence of added Ep increased with isoproterenol; in cultures from normal subjects and in patients with secondary erythrocytosis, agonist stimulation was seen only in the presence of Ep. These studies provide evidence that the growth of both normal and neoplastic erythroid progenitors may be modulated by hormonal interactions.

Butoxamine↗
PubMed1984

The anaemia of chronic renal failure in sheep: studies in vitro.

The presence of inhibitors which accumulate during uraemia has been postulated as a significant factor in the development of anaemia in chronic renal failure (CRF). To determine whether factors in uraemic serum depress erythropoiesis, samples were obtained from sheep prior to and after surgical induction of CRF. The sera were tested in vitro for their effect on erythroid colony growth. The sheep sera were substituted for fetal calf serum (30% concentration) in cultures of serotype-matched or autologous sheep marrow cells at optimal doses of erythropoietin (Ep). Forty-two paired sera from five animals were tested against normal (22) and uraemic marrow (20). In 7/42 random pairs, erythroid colony growth was decreased by 20% in the presence of uraemic serum when compared to a normal sample from the same animal. In the remainder of the cultures, uraemic sera stimulated or supported erythroid colony growth as well as normal sera. When the results were analysed individually, serum from only one of five animals showed minimal (10%) in vitro inhibition of erythroid colony growth. This study, performed in a prospective manner utilizing compatible target cells, disputes the hypothesis that uraemic toxins significantly inhibit in vitro erythropoiesis. These data correlate with the in vivo response to Ep in this sheep model, and suggest Ep would be effective in treating the anaemia of CRF.

Anemia↗