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Biomedical subjects

U Ramenghi

Publications and source records attributed to U Ramenghi.

At least 55 records · Page 3Linked to original sources
PubMed1991

Inhibition of hexose monophosphate shunt in young erythrocytes by pyrimidine nucleotides in hereditary pyrimidine 5' nucleotidase deficiency.

Recent reports have suggested that haemolytic anaemia in pyrimidine 5' nucleotidase (P5'N) deficiency might be due to impaired erythrocyte hexose monophosphate shunt (HMS). To investigate the relationship between pyrimidine accumulation, HMS impairment and shortened red-cell survival, we tested glucose 6-phosphate dehydrogenase (G-6PD), HMS, P5'N activities and the UV spectrum in whole red cells and in red cells of different age from 2 P5'N-deficient patients with different degrees of haemolytic anaemia. In whole red cells we found a reduction of both G-6PD and stimulated HMS activity in the presence of a variable amount of pyrimidine nucleotides (37.79 and 17.88 mumol/gHb respectively). A drastic inhibition of stimulated HMS activity was already present in the lightest red-cell fractions from patient 1, who presented a more severe haemolytic anaemia. The variable degree of pyrimidines found among red cell fractions, with a minor accumulation in the older red cells, supports the hypothesis that pyrimidine accumulation and HMS impairment occur in the younger erythrocytes of P5'N-deficient patients.

5'-Nucleotidase↗
PubMed1989

Pyrimidine 5'-nucleotidase acquired deficiency in beta-thalassemia: involvement of enzyme-SH groups in the inactivation process.

Pyrimidine 5'-nucleotidase (P5'N) partial deficiency has been described in several hematological disorders and also in the beta-thalassemic trait. To check if the P5'N deficiency in thalassemia was acquired we used thalassemic red cells (from either homo- or heterozygous subjects), whose P5'N activity was lower than in control cells. After separation on a density gradient, activity in lighter cells was similar to controls and less than 50% in denser cells. The most probable mechanism for this faster inactivation involves enzyme -SH groups modification by oxidation and reaction with monofunctional aldehydes produced by membrane lipid peroxidation. In vitro challenge of thiol enzymes as pyruvate kinase (PK), adenylate kinase (AK) and P5'N with increasing concentrations of GSSG, hexanal (HEX) and 4-hydroxynonenal (HNE), showed that HNE is the most powerful among the enzyme inhibitors tested and that P5'N activity is a more sensitive index of -SH groups damage, when compared to PK and AK.

5'-Nucleotidase↗
PubMed1987

Pro-hemolytic effect of aldehydic products of lipid peroxidation.

In order to evaluate the pro-hemolytic action exerted by different classes of biogenic aldehydes, normal red cells obtained from human beings of both sexes were incubated at 37 degrees C under iso or hypo-osmotic conditions in the presence of hydroxyalkenals or alkanals, in a concentration compatible with those actually recovered during red cell lipid peroxidation. None of the tested aldehydes showed a direct hemolytic effect, i.e. red cell lysis in iso-osmotic conditions. Conversely, almost all assayed alkanals and hydroxyalkenals exhibited a pre-lytic damage of human erythrocytes, as detected in the red cells suspended in hypo-osmotic medium. The highest pro-hemolytic effect was displayed by hexanal, nonanal, 2-nonenal and 4-hydroxynonenal.

Aldehydes↗
PubMed1985

Membrane events leading to interferon-gamma induction by antigens.

Mitogenic induction of interferon-gamma in human peripheral blood mononuclear cells (PBMC) is prevented by enzymatic cleavage of galactose residues on the cell membrane, and by calcium depletion, suggesting that oxidation of galactose on the membrane glycoproteins and activation of a calcium flux across the membrane are critical events for interferon-gamma induction in nonspecifically stimulated human PBMC. The same experimental design has been applied to human PBMC cultures enriched of specifically sensitized lymphocytes and stimulated with the respective antigens. The results of these experiments show that also antigenic induction of interferon-gamma by purified protein derivative, tetanus toxoid, and MLR requires integrity of galactose residues and calcium intake suggesting that alteration of membrane-bound galactose and activation of a calcium flow are critical triggering events for both specific and nonspecific lymphocyte activation.

Adult↗
PubMedDate not supplied

Increased plasma corticosteroid-binding globulin in insulin-dependent pubertal diabetics: relationships with other glycoproteins, growth hormone and prolactin.

A selected group of 13 juvenile-onset insulin-dependent diabetics in mid-late puberty (stages 3-4) and under comparable conditions of metabolic control was studied in order to evaluate the plasma levels of corticosteroid-binding globulin (CBG, transcortin: expressed as the binding capacity for cortisol) in relation to the levels of other glycoproteins and to growth hormone (GH) and prolactin (PRL) responsiveness to provocative tests (arginine infusion and TRH injection, respectively). Further evidence was provided that juvenile-onset diabetics show most frequently enhanced plasma CBG binding capacity; statistical significance with p-values less than 0.01 was attained in comparison to 25 age-matched controls. Among other variables examined, only hemoglobin A1c amd alpha 2-macroglobulin were significantly raised in the diabetic group (p less than 0.01 and less than 0.02, respectively). In our patients growth hormone response to arginine infusion was in the normal range, whereas PRL response to TRH was slightly but significantly supranormal in terms of maximum value and maximum increment above baseline value. No correlation was found between CBG binding capacity and other variables examined. We conclude that raised levels of CBG may occur as an additional alteration of the plasma glycoprotein pattern in juvenile-onset insulin-dependent diabetics. Specific regulatory factors conceivably subserve plasma concentrations of different glycoproteins.

Adolescent↗
PubMedDate not supplied

Diamond-Blackfan Anaemia: an overview.

Diamond Blackfan Anaemia (DBA) is a congenital disease characterised by defective erythroid progenitor maturation. It is usually diagnosed during the first year of life. The main clinical sign is profound isolated normochromic or macrocytic anaemia, with normal numbers and function of the other haemopoietic cells. Reticulocyte counts in patients with DBA are very low. Bone marrow reflects the defective erythropoiesis, showing a very low number of erythropoietic precursors and a reduction of erythroid burst-forming unit progenitor cells. The proliferation and differentiation of the other lineages are normal. More than one-third of patients have malformations, most often involving the upper limbs and head, and the urogenital or cardiovascular systems. However, the link between these malformations and defective erythropoiesis is unclear and a defect in a molecule acting on both early embryonic development and haematopoiesis has been proposed. Whereas most cases are sporadic, inheritance is observed in 10% of patients, with a dominant or, more rarely, recessive pattern. One locus on chromosome 19q13.2 encoding ribosomal protein S19 accounts for a quarter of patients with either the dominant or the sporadic form. Families not linked with this locus have also been described. The diagnosis of DBA may be difficult and differential diagnoses include Fanconi's anaemia and acquired erythroid aplasias. Erythrocyte adenosine deaminase levels are generally high in DBA patients, which may help in the diagnosis, but they are not pathognomic. Corticosteroids are the main treatment option in DBA and these agents induce erythropoiesis in over 60% of patients. Some patients achieve complete remission, which may be either corticosteroid-induced or spontaneous. The increased in vitro erythropoiesis occasionally induced by the addition of specific cytokines, namely interleukin (IL)-3 and stem cell factor (SCF), has suggested their use in vivo. However, few patients have responded to IL-3, whereas SCF administration, though interesting in theory, has not yet been attempted. Patients who do not respond to corticosteroids and those who have to discontinue treatment because of adverse events must rely on long term transfusions, and are thus exposed to all of the associated complications. Bone marrow or cord blood transplantation has been performed in some patients. The former approach is burdened with severe complications and high mortality.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Effect of different exposures to desferrioxamine on neuroblastoma cell lines.

Desferrioxamine (DFO) has shown anti-proliferative and cytotoxic effects on several tumor cells. DFO is used at present in the treatment of neuroblastoma in combination with chemotherapy (D-CECaT regimen: cyclophosphamide, etoposide, carboplatin, and thiotepa). We compared the effect of continuous or intermittent exposures to DFO on 3H-thymidine uptake, viability, and cell cycle of human neuroblastoma (NB) cell lines. Our results show that continuous exposures to DFO cause dose- and time-dependent cytotoxicity of NB cells, while intermittent exposures result in significant NB cell toxicity only when using high DFO concentrations. By 3H-thymidine uptake, a significant inhibition of proliferation was observed only in continuous exposures. In addition, a consistent arrest in G1 phase was detected only in cultures treated continuously with high DFO concentrations. Our data indicate that 3H-thymidine uptake, viability, and cell cycle changes are proportional to the extent of exposure and concentration of DFO, suggesting that in vivo DFO continuous infusion may improve anti-neuroblastoma activity.

Antineoplastic Agents↗
PubMedDate not supplied

Hematological studies in children with Down syndrome.

Previous studies have reported erythrocyte macrocytosis in adults and children with Down syndrome (DS), the significance of which remains unclear. We compared hematological parameters of 50 DS children aged 2 to 15 years, divided into three age groups, with those of 68 aged-matched healthy children. Patients with DS had a significantly increased mean corpuscular volume (MCV) and hemoglobin in all groups when compared with the controls. Erythrocyte creatine content, hexokinase (Hk) activity, erythrocyte and serum folates, vitamin B12, haptoglobin, serum iron, and ferritin were tested. All of these parameters were not significantly different from those of the control group. We conclude that macrocytosis may not be an expression of reduced red cell survival but rather of an altered folate remethylation pathway, secondary to enhanced cystathionine beta-synthase (CBS) activity, the gene for which is present on chromosome 21.

Adolescent↗
PubMedDate not supplied

Specificity of antinuclear and antiphospholipid antibodies in sera of patients with autoimmune lymphoproliferative disease (ALD).

OBJECTIVE: A human lymphoproliferative syndrome characterized by a defect of the Fas-mediated apoptosis pathway in the absence of a fas gene mutation (Autoimmune Lymphoproliferative Disease) has recently been described and characterized by autoimmune phenomena. The aim of this study was to investigate the presence of antinuclear and antiphospholipid antibodies and to define their specificity in 5 pediatric patients with this syndrome. METHODS: Antinuclear antibodies were investigated by Western Blot and IIF performed under standard as well as apoptotic conditions. The fine specificity of antiphospholipid antibodies was dissected by an ELISA for anti-beta 2-glycoprotein I, anti-prothrombin, anti-annexin V and anti-protein S antibodies, and by immunostaining on thin layer chromatography plates for antiphospholipid molecule antibodies. RESULTS: This study showed that the autoantibodies found in these patients targeted a broad spectrum of nuclear antigens which undergo redistribution from the nucleus to the cytoplasm and plasma membrane during the course of the apoptotic process. This reactivity does not comprise known specificities such as anti-extractable nuclear antigens or anti-dsDNA. Antiphospholipid antibodies were also found in these sera. A further characterization of the antiphospholipid antibodies showed the presence of a heterogeneous response with antibodies directed to negatively-charged phospholipids and antibodies targeting coagulation-related proteins (beta 2-GPI, prothrombin, annexin V) which are considered relevant antigens in the antiphospholipid syndrome. CONCLUSIONS: These results suggest that lack of tolerance due to a defect of Fas-mediated apoptosis allows the survival of B and T clones involved in the antinuclear and antiphospholipid immune responses.

Adolescent↗
PubMedDate not supplied

Analysis of the carbonyl compounds produced in beta thalassaemic erythrocytes by oxidative stress.

Several carbonyls more toxic than malonaldehyde (MDA) are also generated during the propagation of lipid peroxidation stimulated "in vitro" in human erythrocytes. As regards thalassaemia, after "in vitro" treatment with tert-butyl hydroperoxide (TBHP), the total amount of aldehydes formed (MDA plus the other carbonyls) is significantly increased in the red cells from homozygous as compared to heterozygous and normal subjects. These findings lead to the conclusion that the extent of lipid peroxidation in erythrocytes is actually wider than that measurable in terms of malonaldehyde only, and that aldehydes of the hydroxyalkenal class in particular may play a role in the pathogenesis of reduced red cell survival in haemolytic anaemias.

Aldehydes↗
PubMedDate not supplied

[Bone marrow aplasia].

Aplastic anaemia is a haematological syndrome in which pancytopenia is due to a depletion, damage of inhibition of hemopoietic stem cells. The pathogenetic factors are still unclear: damage or inhibition of hemopoietic stem cells may be direct or indirect mediated through changes in the cellular humoral environment; evidence is accumulating that in some cases these processes are of autoimmune nature. The prognostic evaluation is based on hematological parameters at diagnosis: severe aplastic anemia (SAA) is defined by the following criteria: neutrophils less than 0.5 X 10(9)/l; reticulocytes less than 0.5 X 10(9)/l and platelets less than 20 X 10(9)/l. Survival rates in children with SAA are poor; the probability of survival at 1 year from diagnosis being 10%. In this form treatment is based on supportive therapy (transfusion and prevention of infections) and on a specific therapy: immunosuppression and/or BMT. BMT is reserved to patient with an HLA identical sibling donor and may be curative in 70-80% of cases. To date the use of antilymphocytoglobulin in SAA has also given satisfactory results with a favorable response in 50-60% of cases.

Anemia, Aplastic↗