'TUNEL' evidence of reduced bone marrow cells apoptosis in a refractory anaemia patient treated with amifostine.
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Amifostine↗
Biomedical subjects
R Invernizzi
Publications and source records attributed to R Invernizzi.
Fluoxetine increases extracellular dopamine in the prefrontal cortex by a mechanism not dependent on serotonin: a comparison with citalopram.
Fluoxetine at 10 and 25 mg/kg increased (167 and 205%, respectively) the extracellular dopamine concentration in the prefrontal cortex, whereas 25 (but not 10) mg/kg citalopram raised (216%) dialysate dopamine. No compound modified dialysate dopamine in the nucleus accumbens. The effect of 25 mg/kg of both compounds on cortical extracellular dopamine was not significantly affected by 300 mg/kg p-chlorophenylalanine (PCPA) (fluoxetine, saline, 235%; PCPA, 230%; citalopram, saline, 179%; PCPA, 181%). PCPA depleted tissue and dialysate serotonin by approximately 90 and 50%, respectively, and prevented the effect of fluoxetine and citalopram on dialysate serotonin (fluoxetine, saline, 246%; PCPA, 110%; citalopram, saline, 155%; PCPA, 96%). Citalopram significantly raised extracellular serotonin from 0.1 to 100 microM (251-520%), whereas only 10 and 100 microM increased dialysate dopamine (143-231%). Fluoxetine similarly increased extracellular serotonin (98-336%) and dopamine (117-318%). PCPA significantly reduced basal serotonin and the effects of 100 microM fluoxetine (saline, 272%; PCPA, 203%) and citalopram (saline, 345%; PCPA, 258%) on dialysate serotonin but did not modify their effect on dopamine (fluoxetine, saline, 220%; PCPA, 202%; citalopram, saline, 191%; PCPA, 211%). The results clearly show that the effects of fluoxetine and of high concentrations of citalopram on extracellular dopamine do not depend on their effects on serotonin.
Aminopyridines↗
The myelodysplastic syndromes: predictive value of eight prognostic systems in 143 cases from a single institution.
BACKGROUND AND OBJECTIVE: Despite the fact that several prognostic systems for myelodysplastic syndromes (MDS) have been proposed, few studies have been designed to test their effectiveness in independent patient populations. The aim of this study was to compare the prognostic value of 8 previously described prognostic systems in a series of consecutive MDS patients observed at a single institution over a 10-year period. DESIGN AND METHODS: One hundred and forty-three patients were diagnosed as having myelodysplastic syndrome (MDS) according to the French-American-British (FAB) criteria. They were studied retrospectively in order to assess the prognostic value of the FAB classification and 7 other prognostic systems. RESULTS: On the basis of data at diagnosis, all investigated systems effectively stratified patients into groups with different life expectancies and identified a subset of patients with poor clinical outcome. However, the systems had different outcomes concerning median survival of patients classified as low-risk, ranging from less than 3 years for the Mufti scoring system to more than 8 years for the FAB classification modified according to Rosati et al. Moreover, patient distribution into different risk categories was quite different with the different prognostic systems. INTERPRETATION AND CONCLUSIONS: When applied to our case series, some of the prognostic systems had a much lower prognostic value than in the patient population from which they derived. This evidence suggests that testing of prognostic systems in independent case series is necessary before using the systems in clinical practice.
Adult↗
Expression of dipeptidylaminopeptidase IV/CD26 in peripheral blood lymphocytes of hemophilic subjects.
CD26 antigen, a 110 kDa membrane glycoprotein with exopeptidase activity (DAP IV), is an activation marker of T lymphocytes preferentially expressed on CD4+ memory cells and involved in T cell proliferation and IL-2 production after antigenic stimulation. We employed cytochemical and immunocytochemical techniques to study DAP IV/CD26 expression in circulating lymphocytes from 40 hemophilic patients, chronically treated with coagulation factors, in order to verify the possible involvement of this molecule in the immunological alterations of hemophilia. In all the hemophiliacs DAP IV activity was significantly lower than in the controls, independently of the quantity of blood transfused and previous exposure to viruses. This reduction may be responsible for the impaired proliferative response of lymphocytes to antigens and mitogens, notoriously observed in hemophilia. Whereas in the group of HIV- patients CD26 expression was similar to that of normal controls, in the 8 HIV+ hemophilic patients both percentages of positive lymphocytes and intensity of staining were significantly lower. In only 4 of the 8 cases was this deficit associated with CD4+ cell depletion. The significant selective loss of CD26 expression observed in HIV+ patients is probably an early event after HIV infection and seems to occur even before CD4 cell depletion. In conclusion, evaluation of DAP IV/CD26 might be a useful option for monitoring the immunological alterations of all hemophilic patients, HIV positive or not, chronically treated with coagulation factors.
Adolescent↗
A case of microcytic anemia.
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Anemia, Sideroblastic↗
A case of multiple myeloma with multilobated plasma cell nuclei.
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Aged↗
Interleukin-2 therapy in relapsed acute myelogenous leukemia.
PURPOSE: Several studies have been conducted in Italy to assess the activity of recombinant interleukin-2 (rIL-2) in patients with relapsed-refractory acute myelogenous leukemia (AML) and in AML patients in second complete remission (CR) who are not eligible for standard therapy. We report here the updated results of those studies. PATIENTS AND METHODS: Since 1988, a total of 24 patients with relapsed-refractory AML and < or = 30% bone marrow blasts (median blastosis, 15%), who were not suitable for further chemotherapy, were treated with a daily dose-escalating protocol of rIL-2 (8-18 x 10(6) IU/m2 x 5 days) by continuous intravenous infusion with a 72-hour rest period between each cycle. Patients achieving a response to induction therapy received subcutaneous maintenance rIL-2 therapy at lower doses for 5 days/month. Based on these encouraging results, a prospective randomized trial was initiated by the Italian cooperative groups GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto) and AIEOP (Associazione Italiana Ematologie e Oncologia Pedietrica) to assess the efficacy of this rIL-2 regimen in AML patients in second CR. Of 264 AML patients enrolled, 146 patients (55%) achieved a second CR in response to mitoxantrone, etoposide, and cytarabine; 32 patients who were not eligible for transplantation were randomized to rIL-2 (15 patients) or no treatment (17 control patients). Accural goals were never reached, however, due to low recruitment. RESULTS: In the pilot study, 13 patients (54%) obtained a CR, which persists in eight patients with a median follow-up of 64 months (range, 1-110 months) on maintenance rIL-2. In the randomized study, a trend in favor of improved disease-free survival was observed in the rIL-2 arm. CONCLUSIONS: Encouraging results have been obtained with rIL-2 therapy in AML patients with relapsed-refractory disease and limited blastosis and in patients in second CR. These results have prompted a large, multicenter, randomized study to evaluate the efficacy of high-dose rIL-2 therapy in AML patients with advanced disease but limited blastosis in relapse following cytoreductive chemotherapy or autologous transplantation.
Adolescent↗
Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis.
Systemic-onset juvenile chronic arthritis (SoJCA) is associated with high levels of circulating interleukin-6 (IL-6) and is frequently complicated by severe microcytic anemia whose pathogenesis is unclear. Therefore, we studied 20 consecutive SoJCA patients with hemoglobin (Hb) levels <12 g/dL, evaluating erythroid progenitor proliferation, endogenous erythropoietin production, body iron status, and iron supply for erythropoiesis. Hb concentrations ranged from 6.5 to 11.9 g/dL. Hb level was directly related to mean corpuscular volume (r = .82, P < .001) and inversely related to circulating transferrin receptor (r = -.81, P < .001) suggesting that the severity of anemia was directly proportional to the degree of iron-deficient erythropoiesis. Serum ferritin ranged from 18 to 1,660 microgram/L and was unrelated to Hb level. Bone marrow iron stores wore markedly reduced in the three children investigated, and they also showed increased serum transferrin receptor and normal-to-high serum ferritin. All 20 patients had elevated IL-6 levels and normal in vitro growth of erythroid progenitors. Endogenous erythropoietin (epo) production was appropriate for the degree of anemia as judged by both the observed to predicted log (serum epo) ratio 10.95 +/- 0.12) and a comparison of the serum epo-Hb regression found in these subjects with that of thalassemia patients. Multiple regression analysis showed that serum transferrin receptor was the parameter most closely related to hemoglobin concentration: variation in circulating transferrin receptor explained 61% of the variation in Hb level (P < .001). In 10 severely anemic patients, amelioration of anemia following intravenous iron administration resulted in normalization of serum transferrin receptor. Defective iron supply to the erythron rather than blunted epo production is the major cause of the microcytic anemia associated with SoJCA. A true body-iron deficiency caused by decreased iron absorption likely complicates long-lasting inflammation in the most anemic children, and this can be recognized by high serum transferrin receptor levels. Although oral iron is of no benefit, intravenous iron saccharate is a safe and effective means for improving iron availability for erythropoiesis and correcting this anemia. Thus, while chronically high endogenous IL-6 levels do not appear to blunt epo production, they are probably responsible for the observed abnormalities in iron metabolism. Anemia of chronic disease encompasses a variety of anemic conditions whose peculiar features may specifically correlate with the type of cytokine(s) predominantly released.
Administration, Oral↗
Role of 5-HT1A receptors in the effects of acute chronic fluoxetine on extracellular serotonin in the frontal cortex.
Fluoxetine 10 mg/kg i.p. significantly increased the extracellular concentrations of serotonin (5-HT) in the frontal cortex as assessed by in vivo microdialysis. This effect was significantly potentiated when 0.3 mg/kg s.c. WAY-100635, a 5-HT1A receptor antagonist, was administered 30 min before. WAY-100635 by itself had no effect on extracellular 5-HT. Twenty-four hours after chronic fluoxetine schedule (10 mg/kg/day i.p. x 14 days), basal extracellular 5-HT concentrations in the frontal cortex were higher than those of animals that had received the vehicle chronically. At 24 h after the last dose, a challenge dose of fluoxetine (10 mg/kg i.p.) raised extracellular 5-HT similarly in chronically vehicle or fluoxetine treated rats. At this same interval 25 micrograms/kg s.c. 8-OH-DPAT, a 5-HT1A receptor agonist, significantly reduced extracellular 5-HT only in the frontal cortex of rats treated chronically with the vehicle. Examining basal extracellular 5-HT, the effect of a challenge dose of fluoxetine and the effect of 25 micrograms/kg 8-OH-DPAT after 96 h washout, no differences were found between chronically fluoxetine and vehicle-treated rats. The results confirm that the ability of fluoxetine to stimulate 5-HT1A autoreceptors through an increase of endogenous 5-HT attenuates its effect on cortical dialysate 5-HT. Chronic fluoxetine increased the basal concentrations of extracellular 5-HT only when a substantial amount of its metabolite was present in the brain and during the desensitization of presynaptic 5-HT1A autoreceptors (24 h after the last dose). These effects, in fact, disappeared after 96 h washout. The continuous presence of the drug may, therefore, be necessary to maintain extracellular 5-HT at concentrations high enough to produce a therapeutic effect.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Extracellular concentrations of serotonin in the dorsal hippocampus after acute and chronic treatment with citalopram.
Citalopram, 1 and 10 mg/kg i.p., that in a previous study using identical treatment and dialysis conditions had little or no effect on dialysate serotonin (5-HT) in the frontal cortex, dose-dependently raised the extracellular concentrations of 5-HT in the dorsal hippocampus, by 70% and 205% respectively at the peak. In animals given 10 mg/kg citalopram twice daily for 14 days, intraperitoneal doses of 1 and 10 mg/kg or infusion of 10(-8) - 10(-6) M through the hippocampal probe raised dialysate 5-HT in the dorsal hippocampus similarly in animals treated chronically with citalopram or saline. A dose of 100 micrograms/kg 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), an agonist at 5-HT1A receptors, reduced hippocampal extracellular 5-HT concentrations to the same extent in rats repeatedly given saline or citalopram. Half this dose had no such effect in either group. The effect of citalopram and the sensitivity of autoreceptors controlling 5-HT release in the dorsal hippocampus were unaffected by a chronic treatment known to facilitate the drug's effect on dialysate 5-HT and to reduce the sensitivity of 5-HT1A receptors controlling 5-HT release in the frontal cortex. The effects of acute and chronic treatment with citalopram on dialysate 5-HT in the rat brain thus appear to differ in at least two brain regions: the frontal cortex and the dorsal hippocampus.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Intranigral GR-113808, a selective 5-HT4 receptor antagonist, attenuates morphine-stimulated dopamine release in the rat striatum.
GR-113808, a potent and selective 5-HT4 receptor antagonist, was infused through a microdialysis probe into the striatum and nucleus accumbens of awake rats, and basal and morphine-stimulated extracellular concentrations of dopamine (DA) were measured in these regions. At 1 and 10 microM GR-113808 did not affect the extracellular concentrations of DA in either region and 100 microM significantly reduced dialysate DA only in the striatum. A subcutaneous dose of 5 mg/kg morphine significantly raised extracellular concentrations of DA in the striatum and nucleus accumbens from 60 to 120 min after injection and the effect was not modified by 10 microM GR-113808 infused through the probe 20 min before and for 60 min after morphine. Bilateral injections of GR-113808 (1, 2.5 and 10 micrograms/0.5 microliter) in the substantia nigra pars compacta did not affect dialysate DA in the striatum, except for a significant increase 120 min after the injection of 10 micrograms but the highest dose of GR-113808 prevented the increase of striatal DA caused by 5 mg/kg morphine s.c. The results suggest that 5-HT4 receptors in the substantia nigra modulate the activity of the dopaminergic nigrostriatal system only when the neurons are activated.
Animals↗
Further studies on the effects of chronic clozapine on regional extracellular dopamine levels in the brain of conscious rats.
The effect of chronic oral treatment with clozapine (20 mg/kg daily for 21 days) on the extracellular concentrations of dopamine, dihydroxyphenylacetic acid and homovanillic acid in the dorsolateral anterior striatum, nucleus accumbens and frontal cortex was studied by microdialysis in conscious rats. Basal levels of dopamine and its metabolites in the three brain regions of rats treated chronically with clozapine were not significantly different from those of vehicle-treated rats. A subcutaneous challenge dose of clozapine (20 mg/kg) significantly increased the extracellular concentrations of dopamine and its metabolites in the three brain regions, with no differences between chronic vehicle- and clozapine-treated rats.
3,4-Dihydroxyphenylacetic Acid↗
Selective reduction of extracellular dopamine in the rat nucleus accumbens following chronic treatment with DAU 6215, a 5-HT3 receptor antagonist.
The effect of chronic treatment with (3-alpha-tropanyl)1H-benzimidazolone-3-carboxamide chloride (DAU 6215; 15 micrograms/kg s.c. twice daily for 21 days), a serotonin3 receptor antagonist, on the extracellular concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was studied by intracerebral dialysis in the striatum, nucleus accumbens and frontal cortex of conscious rats. Twenty-four hours after the last injection, the basal extracellular concentrations of DA in the nucleus accumbens of rats given DAU 6215 were significantly lower than in saline-treated rats. DA output in the dorsolateral striatum or frontal cortex was not significantly different between the DAU 6215 and saline-treated rats. Chronic DAU 6215 significantly reduced the extracellular concentrations of DOPAC and HVA in the frontal cortex but had no effect in the other brain regions. A subcutaneous challenge dose of DAU 6215 (15 micrograms/kg) did not significantly modify the extracellular concentrations of DA and its metabolites in either DAU 6215 or saline treated rats in any of the brain regions examined. The present investigation is the first on the effect of chronic administration of a 5-HT3 receptor antagonist on basal extracellular DA in the rat brain. The results provide evidence of an association between the electrophysiological and biochemical effects of chronic treatment with a serotonin3 receptor antagonist on the activity of the mesolimbic DA system. In line with the theory that hyperactivity of the mesolimbic dopaminergic system is involved in psychosis, the results suggest that DAU 6215 may be useful in the treatment of psychotic disorders, possibly with limited extrapyramidal effects.
3,4-Dihydroxyphenylacetic Acid↗
Jumping translocations in acute lymphoblastic leukemia.
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Aged↗
Acute promyelocytic leukemia toluidine blue subtype.
In the hypergranular group of acute promyelocytic leukemia (APL) a rare subvariant with basophilic granules, metachromatic for toluidine blue, is recognizable. To evaluate the incidence as well as the biological and clinical significance of this subtype, we studied 53 consecutive untreated patients with APL with morphological, cytochemical, immunological and cytogenetic methods. In 10 cases (19% of the total) granules stained metachromatically in percentages of promyelocytes ranging from 16 to 60. In these cases peroxidase positivity was weaker than in the classic hypergranular and microgranular M3 and activities of esterases were usually present; at the ultrastructural level granules contained particulate material. Immunophenotypic and cytogenetic characteristics seemed not to differ from those of other M3 cases. Coagulopathy was usually life-threatening, notwithstanding the low white cell count, and the median survival was short. Hyperhistaminemia-related symptoms were not observed. Cytochemical, immunologic and cytogenetic findings are useful to differentiate this form from M2 with basophilic differentiation and from mast cell leukemia.
Cytoplasmic Granules↗
Chronic treatment with citalopram facilitates the effect of a challenge dose on cortical serotonin output: role of presynaptic 5-HT1A receptors.
In animals given citalopram (10 mg/kg) twice daily for 14 days a further dose of 1 mg/kg, administered 24 h after the last dose, markedly increased cortical dialysate serotonin (5-hydroxytryptamine, 5-HT), but had no effect in control animals. The effect on dialysate 5-HT in the dorsal raphe was not increased by the chronic treatment. At 25 micrograms/kg, 8-hydroxy-2-(di-n-propylamino)tetralin, an agonist at 5-HT1A receptors, reduced cortical 5-HT output in controls but not in animals treated chronically with citalopram whereas 50 micrograms/kg reduced 5-HT output in both groups. These findings suggest that somatodendritic 5-HT1A receptors are desensitized after chronic treatment with citalopram and this results in facilitation of its effect on cortical dialysate 5-HT. These results also agree with the concept that the effect of 5-HT re-uptake inhibitors on increasing 5-HT output in the frontal cortex is attenuated by their simultaneous ability to activate somatodendritic 5-HT1A receptors via an increase of endogenous 5-HT in the raphe region.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Evidence that extracellular concentrations of dopamine are regulated by noradrenergic neurons in the frontal cortex of rats.
Experiments were performed to confirm that noradrenergic terminals regulate extracellular concentrations of dopamine (DA) in the frontal cortex of rats. The effects of 20 mg/kg 1-[2-[bis(4-fluorphenyl)methoxy]-ethyl]-4-(3- phenylpropyl)piperazine (GBR 12909), a selective inhibitor of DA uptake, and 2.5 mg/kg desipramine (DMI) on the extracellular concentrations of DA in the frontal cortex and striatum were studied in rats given 6-hydroxydopamine (6 micrograms/microliters) bilaterally into the locus coeruleus to destroy noradrenergic terminals. GBR 12909 increased dialysate DA similarly in the striatum of vehicle and 6-hydroxydopamine-treated rats, whereas in the frontal cortex it raised DA concentrations only in lesioned animals. DMI raised extracellular DA concentrations in the frontal cortex but not in the striatum of controls. The effect of DMI on cortical DA was abolished by the 6-hydroxydopamine lesion. GBR 12909, at a subcutaneous dose of 20 mg/kg, further increased cortical dialysate DA in rats given DMI intraperitoneally at 20 mg/kg or through the probe at 10(-5) mol/L. The data support the hypothesis of an important regulation of the extracellular concentrations of DA in the frontal cortex by noradrenergic terminals.
Animals↗