Cardiovascular effects of intracerebral injections of glutamate and kainate in rats.
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Animals↗
Biomedical subjects
M Cazzola
Publications and source records attributed to M Cazzola.
Iron metabolism in thalassemia.
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Bone Marrow↗
Natural history of idiopathic refractory sideroblastic anemia.
We analyzed the natural history of idiopathic refractory sideroblastic anemia (IRSA) in 37 patients studied between 1969 and 1986. Although erythroid abnormalities were prominent in all, 12 patients also showed involvement of the granulocytic and/or megakaryocytic cell lines, and nonrandom chromosomal aberrations were observed in five of 23 patients studied for such defects. Measurements of erythroid marrow function showed in most cases erythroid expansion with ineffective erythropoiesis. In seven patients, however, the erythroid activity was found to be inappropriately low for the degree of anemia. Transfusion dependence occurred in 26 of 37 cases. Iron overload was a common feature at presentation but produced clinical manifestations of hemochromatosis only in those patients who subsequently had a regular need for blood transfusions. Five patients progressed to bone marrow failure, and another five patients (two of whom had monosomy 7) evolved into acute nonlymphocytic leukemia (ANLL). The median survival was 72 months, with a high transfusion requirement, multilineage defects, and inappropriately low erythroid proliferation being associated with a poor prognosis. The most common causes of death were complications of iron overload and evolution into ANLL. We conclude that (a) the natural history of IRSA is characterized by an initial phase of erythroid hyperplasia and ineffective erythropoiesis, which is usually stable for many years but in a subset of patients may be followed by a phase of marrow failure with or without the later emergence of leukemic blasts; (b) peripheral blood counts, measurement of erythroid marrow function, and chromosomal analysis are useful for identifying subjects at risk of evolution into marrow failure or ANLL; and (c) IRSA patients with no need for blood transfusions are very likely to be long survivors, whereas those who become transfusion dependent are at risk of death from the complications of secondary hemochromatosis.
Adult↗
Lymphoproliferative disorder of large granular lymphocytes: reversal of lymphocyte proliferation, anemia and neutropenia with chlorambucil.
A 54-year-old woman presented with hepatosplenomegaly, anemia, neutropenia and lymphocytosis. Most peripheral blood lymphocytes had the surface antigens T3+, Leu11+ and were morphologically large granular lymphocytes. Bone marrow presented 60% lymphoid infiltration. Treatment with chlorambucil produced complete reversal of hepatosplenomegaly, anemia, neutropenia and lymphocytosis, and reduction of marrow infiltration. The patient is well 12 months after discontinuation of therapy.
Anemia↗
Measurement of ferritin-bearing lymphocytes in man. Preliminary studies on the use of monoclonal antibodies specific for the L and H subunits of ferritin.
We used the monoclonal antibodies LFO3 (specific for the L subunit of ferritin) and 2A4 (specific for the H subunit) in an indirect immunofluorescence test for enumerating ferritin-bearing lymphocytes (FBL). In 13 normal subjects, the geometric mean value of FBL was 4% (range 0-13%) with the monoclonal antibody LFO3, and 3% (range 0-8%) with the monoclonal antibody 2A4. Values in 5 subjects with transfusional iron overload and increased plasma L-type ferritin concentration were 5% (4-7%) and 3% (2-4%), respectively, which is similar to those in normal subjects. Thirteen patients with malignant disease had normal to increased values for plasma ferritin; the circulating protein was largely of L-type with undetectable or very low concentrations of H-type ferritin. In the same patients, the percentage of FBL was greater with the monoclonal antibody 2A4 (geometric mean value 8%; range 3-12%) than with the monoclonal antibody LFO3 (geometric mean value 3%; range, 1-7%). It is concluded that acidic and basic isoferritins can be differently expressed on the surface of peripheral blood lymphocytes, and that the monoclonal 2A4 could be particularly useful in the measurement of FBL in patients with malignancy.
Antibodies, Monoclonal↗
Refractory cytopenias: clinical course according to bone marrow cytology and cellularity.
One hundred and one patients with refractory cytopenia were reviewed for morphological classification (using bone marrow, BM, imprints for cytology and Jamshidi biopsies for BM cellularity) and clinical course. Final diagnoses were: moderate aplastic anemia (MAA), myelodysplastic syndromes (MDS) and hypoplastic acute leukemia (HAL). Ninety-two patients received high dose testosterone enanthate (TE) as first treatment (starting dose = 7-10 mg/week i.m. for at least three months). Median survival was significantly longer in MAA than in MDS and in HAL. Among MDS patients, those with primary acquired sideroblastic (AISA) and refractory (RA) anemia had median survival similar to those with MAA, but distinctly longer (p = 0.01) than patients with RA with an excess of blasts (RAEB), RAEB in transformation (RAEBtr) and chronic myelomonocytic leukemia (CMMoL). Acute leukemia (AL) developed more rarely (p less than 0.02) in MAA, AISA and RA than in RAEB, RAEBtr and CMMoL. Response to TE was seen in about two thirds of MAA and in a half of MDS and HAL patients. Among MDS patients, those with hypocellular BM developed leukemia less frequently, responded to androgens more often and survived longer than those with normocellular and, especially, with hypercellular BM. These data indicate that the cytohistological classification of refractory cytopenias identifies essentially two groups with different clinical behaviour, one (MAA, AISA and RA) having long life expectancy and a low probability of developing AL and the other (RAEB, RAEBtr, CMMoL) with a short survival and relatively frequent leukemic complication. Bone marrow hypocellularity seems to be a favourable prognostic factor in MDS. Patients with refractory cytopenias, especially those with a hypocellular BM, can be advantageously treated with androgens.
Acute Disease↗
[Infections of the lower respiratory tract in general practice].
Haemophilus influenzae and Streptococcus pneumoniae are found in 87% of all cases of exacerbated chronic obstructive bronchopulmonary disease. Complications of viral respiratory tract disease are most frequently caused by H. influenzae. Not only encapsulated forms of H. influenzae, but also non-encapsulated strains may be responsible for the onset of pneumonia and acute exacerbations of chronic bronchitis in adults. The most common symptoms of infections with H. influenzae are cough, dyspnoea, increase in purulent sputum and wheezing. A quantitative sputum culture is recommended for diagnosing chronic obstructive bronchopulmonary disease. Acute exacerbations of chronic bronchitis are always treated with antibiotics effective against H. influenzae and pneumococci. As a rule, empirical treatment should suffice in general practice. In the comparison between ampicillin, co-trimoxazole and cefaclor included in the study protocol appended to this report, the latter produced the most favourable results both in the empirical and specific forms of treatment. We would recommend cefaclor as the antibiotic of choice for this disease.
Anti-Bacterial Agents↗
Participation of GABAergic mechanisms in the hypotensive and bradycardic effects of clonidine: experimental study in conscious normotensive and hypertensive rats.
In conscious rats with normal arterial blood pressure or with spontaneous or DOC induced hypertension, effects of drugs increasing (cycloserine, ethanolamine-o-sulphate, piracetam, chlordesmethyldiazepam) or depressing (bicuculline, Ro 15-1788, PK 11195) GABAergic reactivity were evaluated on the arterial hypotension and sinus bradycardia induced by clonidine. Clonidine was administered orally by gastric gavage (0.1-1 mg/kg). Pretreatment with cycloserine, ethanolamine-o-sulphate, piracetam or chlordesmethyldiazepam increased the hypotension and sinus bradycardia induced by clonidine. On the contrary, pretreatment with bicuculline or Ro 15-1788 reduced the cardiovascular effects of clonidine. These results suggest that the GABAergic system is involved in cardiovascular effects of clonidine in normotensive and hypertensive rats.
Animals↗
Characteristics of a ferritin-binding protein present in human serum.
The ferritin present in human serum differs from the ferritins found in tissues and other body fluids in having negligible proportions of H subunits. This has been related to the possible presence of binding factors which would form complexes with H-subunit containing ferritins and thereby determine their rapid clearance and/or interference with immunoassays ('serum inhibition'). In this work we have tried to identify and characterize these binding factors. Dotting and blotting experiments demonstrated an interaction between tissue ferritins and human serum. This was stronger with human heart and recombinant H-type ferritin obtained from E. coli than with human liver ferritin. The serum binder appeared to be a glycoprotein migrating in the beta-2 region and with a molecular weight of about 200,000 and pI between 4 and 5. Two different approaches to purification of the ferritin-binding protein yielded enriched fractions containing also the complement proteins C3 and C4, the plasma protease inhibitor alpha-2-macroglobulin, and immunoglobulins. These in vitro findings may have physiological relevance.
Blood Proteins↗
Pathophysiological classification of acquired bone marrow failure based on quantitative assessment of erythroid function.
Bone marrow failure encompasses a broad spectrum of disorders including aplastic, dysmyelopoietic and myelophtisic anemias. In the present study, these anemias were characterized according to the degree of erythroid proliferation and efficiency of erythropoiesis. Total erythropoietic activity was evaluated in 43 patients by measuring the erythron transferrin uptake (ETU). It averaged 20% of basal (range 3-43%) in 13 patients with severe aplastic anemia, 75% of basal (range 60-103%) in 3 patients with extensive bone marrow infiltration by neoplastic cells, 131% of basal (range 50-217%) in 16 patients with refractory anemia, and 452% of basal (range 63-720) in 11 patients with idiopathic refractory siderobastic anemia. Respective efficiencies of erythropoiesis were 74% in aplastic anemia, 70% with bone marrow infiltration, 46% in refractory anemia, and 14% in sideroblastic anemia. Based on the ETU, patients could be categorized into absolute marrow failure, relative marrow failure, and adequate erythropoietic response to anemia. This simple determination of proliferating activity of the erythroid marrow can provide useful information on the pathophysiology of marrow failure and a basis for the selection of therapeutic approaches.
Adolescent↗
Ketanserin, a new blocking agent of serotonin S2-receptors. Respiratory functional effects in chronic obstruction of the airways.
The role played by serotonin (5-HT) in the regulation of bronchomotor tone has up to now been a much debated question, although there is good evidence that it induces intense bronchoconstriction after inhalation in asthmatic patients. Serotonin has been found to contract the tracheobronchial smooth muscle of different animals. Some data suggest that tracheobronchial contraction due to serotonin is mediated by its interaction with the S2-receptor. The blockade of this receptor by ketanserin, a serotoninergic antagonist which primarily binds to S2-serotoninergic receptors, produces bronchodilation. The respiratory effects of intravenously administered ketanserin (10 mg) or placebo were compared in a double-blind crossover study in 14 patients with chronic obstruction of the airways. The forced expiratory volume in one second (FEV1) and the instantaneous forced expiratory flow after 50 percent of the forced vital capacity has been exhaled (FEF50%) did not change after placebo, but they increased significantly after administration of ketanserin. The results suggest that in patients with chronic obstructive pulmonary disease, serotonin may play a role in the development of obstruction of the airways, even if the mechanism remains undefined.
Adult↗
Erythroid marrow function in anemic patients.
Erythropoietic activity is known to be closely associated with marrow iron uptake. A modification of the standard measure of plasma iron turnover has been developed in which erythron transferrin uptake (ETU) rather than iron uptake has been calculated. The ETU has the advantage of providing a parameter of erythroid marrow activity independent of change produced by plasma iron and transferrin saturation. Measurements in 80 patients with anemia were compared to the normal value of 60 +/- 12 mumol/L whole blood/d. The mean ETU for ten patients with severe aplastic anemia and for six patients with pure red-cell aplasia were 12 +/- 8 and 12 +/- 11 mumol/L whole blood/d, respectively. In ten transfusion-dependent patients with renal failure under dialysis therapy, the mean value was 35 +/- 11, while ten other dialyzed patients who were transfusion independent had a mean ETU of 73 +/- 21 mumol/L whole blood/d. Sixteen patients with hemolytic anemia had an average ETU of 400 +/- 130, while 28 patients with ineffective erythropoiesis had a mean value of 474 +/- 147 mumol/L whole blood/d. While patients with hypoproliferative anemia showed no relation between the severity of anemia and ETU, those with hyperproliferative erythroid marrow showed increasing values as the anemia became more severe. Sequential measurements in patients with aplastic anemia under treatment and in thalassemic patients under transfusion therapy showed the value of this measurement in monitoring the effects of treatment on erythroid marrow activity. It is concluded that the measurement of ETU provides a more direct ferrokinetic evaluation of erythroid activity in anemic states.
Acute Kidney Injury↗
Effects of recombinant alpha and gamma interferons on the in vitro growth of circulating hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM) from patients with myelofibrosis with myeloid metaplasia.
Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder due to clonal expansion of a pluripotent hematopoietic progenitor cell with secondary marrow fibrosis. No definitive treatment has as yet been devised for this condition, which shows a marked variability in clinical course. To evaluate whether excessive hematopoietic progenitor cell proliferation could be controlled by recombinant human interferon alpha (rIFN-alpha) and gamma (rIFN-gamma), we studied the effects of these agents on the in vitro growth of pluripotent and lineage-restricted circulating hematopoietic progenitor cells in 18 patients with MMM. A significant increase in the growth (mean +/- 1 SEM) per milliliter of peripheral blood of CFU-GEMM (594 +/- 253), CFU-Mk (1,033 +/- 410), BFU-E (4,799 +/- 2,020) and CFU-GM (5,438 +/- 2,505) was found in patients as compared with normal controls. Both rIFN-alpha and rIFN-gamma (10 to 10(4) U/mL) produced a significant dose-dependent suppression of CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM growth. Concentrations of rIFN-alpha and rIFN-gamma causing 50% inhibition of colony formation were 37 and 163 U/mL for CFU-GEMM, 16 and 69 U/mL for CFU-Mk, 53 and 146 U/mL for BFU-E, and 36 and 187 U/mL for CFU-GM, respectively. A marked synergistic effect was found between rIFN-alpha and rIFN-gamma: combination of the two agents produced inhibitory effects greater than or equivalent to those of 10- to 100-fold higher concentrations of single agents. These studies (a) confirm that circulating hematopoietic progenitors are markedly increased in MMM, (b) indicate that these presumably abnormal progenitors are normally responsive to rIFNs in vitro, and (c) show that IFNs act in a synergistic manner when used in combination. Because rIFN-gamma can downregulate collagen synthesis in vivo, this lymphokine could be particularly useful in the treatment of patients with MMM.
Antibodies, Monoclonal↗
Respiratory responses to pirenzepine in healthy subjects.
Since no information is available concerning the action of pirenzepine in vivo on human tracheobronchial tree, we evaluated the respiratory responses to pirenzepine in a group of healthy subjects. This clinical study suggests that pirenzepine exerts its bronchodilatory action on small airways (from 9th generation to distal airways), but not on larger airways, in normal subjects. These results are consistent with a probable presence of muscarinic high affinity receptors (M1 subtype) only in peripheral airways.
Adolescent↗
Adequacy of iron supply for erythropoiesis: in vivo observations in humans.
The adequacy of tissue iron supply was examined with ferrokinetic techniques in subjects with decreased plasma iron concentration and in subjects with a normal plasma iron concentration but with increased tissue iron requirements. The competition by transferrin receptors for diferric vs monoferric transferrin was measured in eight normal persons and eight with iron deficiency. There was a highly significant (P less than 0.001) decrease in receptor preference for diferric transferrin in subjects with iron deficiency, indicating an insufficient amount of iron-bearing transferrin to saturate tissue receptors. The adequacy of the plasma iron supply was also examined by determining the number of iron-bearing transferrin molecules with receptors at normal and elevated plasma iron concentrations. Significant increases were found at the higher plasma iron concentration, not only in patients with iron deficiency, but also in patients with sickle cell anemia and thalassemia. Furthermore, the increase in the latter two groups was shown to be proportional to the degree of erythroid hyperplasia. These data indicate that tissue iron supply must be evaluated in terms of both plasma iron supply and erythropoietic requirements and that a relative iron deficiency is frequent in patients with erythroid hyperplasia.
Anemia, Hypochromic↗
Red cell ferritin as a diagnostic tool.
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Erythrocytes↗
Effect of acidic and basic isoferritins on in vitro growth of human granulocyte-monocyte progenitors.
Acidic isoferritins have been previously found to be highly potent inhibitors of hematopoietic progenitors at concentrations of 10(-16) to 10(-18) mol/L, and it has been suggested that acidic isoferritin inhibitory activity plays a role in the regulation of normal hematopoiesis and also in the pathogenesis of leukemia. To characterize the ferritin species that affect the in vitro growth of human colony-forming unit-granulocyte-macrophage (CFU-GM), we tested different preparations of basic (L-subunit-rich) and acidic (H-subunit-rich) isoferritins. Three preparations of human liver (basic) ferritin did not show any effects on CFU-GM growth at concentrations up to 10(-9) mol/L, irrespective of the degree of glycosylation. Acidic isoferritins were purified both from HeLa cells and human heart. HeLa cell ferritin did not affect in vitro colony formation. One of two preparations of human heart ferritin, containing 5% glycosylated ferritin, showed a mean inhibition of 26% +/- 8% of the control at 10(-9) mol/L (P less than .02), whereas the other preparation, which contained no glycosylated ferritin, did not show any effect of CFU-GM growth. A preparation enriched for glycosylated acidic isoferritins from human heart was found to produce a mean inhibition of 32% +/- 11% of the control at 10(-9) mol/L (P less than .01), whereas another one was ineffective. A significant part of the inhibitory activity was removed by preincubation with the monoclonal antibody 2A4 directed against human heart ferritin. The present findings indicate that basic isoferritins, ie, the predominant ferritin type in human blood, have no effect on the growth of human CFU-GM, and this is in keeping with indirect clinical evidence. Inhibition of colony formation may be obtained by some preparations of acidic isoferritins that are rich in H subunits and bind to concanavalin A. The mechanism(s) responsible for this are not clear, but the effective concentrations are higher than those found in human blood both under normal conditions and in leukemia. At present, the physiologic significance of the observed inhibitory activity is uncertain.
Ferritins↗
Immunological reactivity of serum ferritin in patients with malignancy.
Serum ferritin has been suggested as a tumor marker in the diagnosis of certain malignancies and for following the activity or dissemination of the malignant process. Since neoplastic tissues generally contain more acidic isoferritins than their normal tissue counterparts, it has also been suggested that the specific assay of such isoferritins in serum may be of particular value in the diagnosis of malignancy. In this work, we have evaluated ferritin concentration in the serum of normal subjects and patients with acute nonlymphocytic leukemia, Hodgkin's disease, breast cancer and lung cancer by simultaneously using three different immunoassays: an immunoradiometric assay based on polyclonal antibodies against human liver (basic, L-subunit rich) ferritin, a radioimmunoassay based on polyclonad antibodies against HeLa cell (acidic, H-subunit rich) ferritin, and an immunoradiometric assay based on the monoclonal antibody 2A4 raised against human heart (acidic, H-subunit rich) ferritin. Most of the patients studied had increased values for liver-type ferritin in the absence of increased iron stores. Binding of serum ferritin to concanavalin A did not prove to be useful in distinguishing a tumor-specific basic isoferritin. The HeLa ferritin assay was found to be less specific than the heart ferritin assay in the detection of acidic isoferritins, and did not provide any advantage over the liver assay in detecting the increased levels of serum ferritin associated with malignant disease. Heart-type ferritin was found in one-fifth of normal sera and 64% of sera from patients with malignancy. Values were very low compared with those for basic ferritin, ranging from less than 0.1 to 17% of total serum ferritin (geometric mean value 1.3%) in patients with malignancy. These findings indicate that at present there is little application for serum ferritin immunoassays based on antibodies to HeLa cell or heart ferritin in the diagnosis or monitoring of malignant disease. This seems to be due to the presence in human serum of biding factors which are responsible for the rapid clearance of acidic isoferritins from the circulation. The serum concentration of basic ferritin, however, can be useful in the diagnosis and management of some malignancies, and it is possible that studies on cell isoferritins can be important in biologic monitoring of neoplastic disorders. It should also be noted that the increased levels of serum ferritin found in patients with malignancy can exert adverse effects on the host immune response and perhaps an inhibitory effect on hematopoiesis.
Antibodies, Monoclonal↗