Biomedical subjects

E Garelli

Publications and source records attributed to E Garelli.

23 records · Page 2Linked to original sources

PubMed1996

Mutations in the erythropoietin receptor gene are not a common cause of Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is an inherited pure red blood cell aplasia that often requires lifelong transfusional support. The origin of the imperfect erythrogenesis is not known. The existence of more than one molecular basis for DBA is indicated by its different modes of inheritance and widely variable clinical phenotypes. Several erythroid growth factors have been thought to have a role in the pathogenesis of DBA. However, there is neither molecular nor clinical evidence for the involvement of stem cell factor or interleukin-3. The observation of elevated erythropoietin (EPO) concentrations and an impaired in vivo and in vitro response to pharmacologic doses of recombinant human EPO has suggested a defective EPO function in the pathogenesis of DBA. We have investigated the possible involvement of the EPO receptor (EPO-R) gene in 23 patients by screening its coding sequence for mutations using single-strand conformation polymorphism (SSCP). A Southern blot and hybridization with an EPO-R probe was also performed on DNA from seven patients. No causal mutations were identified. The absence of concordant segregation of the disease with the EPO-R gene in two informative families ruled out its role in their DBA children. These findings demonstrate that DBA is not commonly associated with EPO-R gene mutations.

Base Sequence↗

PubMed1993

Reversal of excessive effect of regular anticoagulation: low oral dose of phytonadione (vitamin K1) compared with warfarin discontinuation.

To determine the best way to reverse the excessive effect of regular anticoagulation in patients with INR > 5 and no bleeding complications, 23 patients with INR > 5 were randomly subdivided into two groups: group A (n = 12) discontinued warfarin for one day and group B (n = 11) received 2 mg of vitamin K1 orally in addition to the usual warfarin dose. INR was determined after 24 h (day 1), after which both groups continued with their usual dose of warfarin. After 48 h (day 2), warfarin dosage was changed according to the INR value. On day 9, INR values were determined again. Five out of twelve patients in group A had INR values > 5 on day 1. One patient in group A had an INR value < 5 both on days 1 and 2. All eleven patients in group B had INR values < 5 on day 1, and all but one on day 2. On day 9, INR values were acceptable (INR 2.0-4.5) in ten group A patients and eight group B patients. These findings suggest that a low oral dose of vitamin K1 is a convenient treatment for excessive anticoagulation in patients with no bleeding complications.

Adult↗

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

Diamond-Blackfan anemia: a congenital defect in erythropoiesis.

Diamond-Blackfan anemia (DBA) is a congenital pure red blood cell aplasia diagnosed in the first year of life. Familiarity is apparent in 10% of patients, with all other cases being sporadic. Physical abnormalities are present in at least one third of patients, pointing to a defect in early embryo development. The main clinical sign is profound isolated anemia, with normal numbers and functioning of the other hemopoietic cells. Reticulocyte counts are very low. Bone marrow reflects defective erythropoiesis, showing a very low number of erythropoietic precursors and a reduction of BFU-E progenitor cells. Proliferation and differentiation of the other lineages are normal. The very high erythropoietin (EPO) levels are usually not proportionate to the level of anemia and reflect relative EPO insensitivity, which is also apparent in vitro. Conversely, erythroid progenitors from DBA patients also show a defective or incomplete response to other erythropoietic growth factors, such as IL-3 or IL-6. A significant response has been observed in vitro to stem cell factor in many, but not all patients. Many patients respond clinically to corticosteroids and some develop hematologic remissions, both after corticosteroids and spontaneously. Patients who do not respond to corticosteroids and those who have to discontinue treatment because of side effects must rely on chronic transfusion and are thus exposed to all its complications. Bone marrow transplantation has been performed in some individuals, usually with a successful outcome. This suggests a normal marrow microenvironment and rules out the hypothesis of defective stromal cell function. The variable clinical and biological patterns may be the expression of multiple etiologies or represent variable expressivity of a single genetic defect. Only identification of the responsible gene(s) will solve this question. Growth factors exerting an effect on erythropoiesis (and relative receptors) or transacting proteins which regulate their expression are likely candidates in the hunt for a causal gene.

Animals↗

PubMedDate not supplied

Low intensity warfarin therapy.

BACKGROUND AND OBJECTIVE: Several studies comparing different intensities of oral anticoagulant treatment have clearly shown a relationship between bleeding complications and prolongation of prothrombin time. In the early '50s, de Takats suggested that low-dose oral anticoagulants might be as effective as higher doses in preventing thrombosis, at a lower risk of bleeding. This review article examines the potential of low dose warfarin therapy. INFORMATION SOURCES: The authors have been working in this field, contributing original papers. In addition, the material examined in this article includes articles published in the journals covered by the Science Citation Index and MedLine. STATE OF ART AND PERSPECTIVES: The hypothesis that low-dose oral anticoagulants can be effective in preventing thrombosis was first proven by experiments in animal models, and showed that a prothrombin time ratio as low as 1.14 using rabbit brain thromboplastin was still able to confer some inhibition of experimental thrombosis. Low-dose or very low-dose warfarin were subsequently demonstrated to be effective in patients with morbid obesity and decreased antithrombin III functional and antigenic levels, in patients with indwelling catheters, in patients undergoing gynecological surgery, as well as in patients with stage IV breast cancer. Low-dose warfarin is also effective in the prevention of embolic strokes in patients with non-rheumatic atrial fibrillation. However, older patients (> 75 years), who have a very high risk of bleeding, might be safer taking a very low dose of warfarin (i.e., a daily dose of 1-1.25 mg). Moreover, after a period of run-in, a fixed, very low-dose warfarin schedule does not need further laboratory control, which is a factor that could contribute to the full acceptance of treatment by patients and could stimulate a broader prescription of warfarin for the primary prevention of stroke in older patients with nonrheumatic atrial fibrillation. Therefore, we have organized a multicenter clinical trial in which 1000 patients with non-rheumatic atrial fibrillation will be randomized to receive either a fixed mini-dose of warfarin or a standard dose. Positive results might permit the treatment of most older patients with non-rheumatic atrial fibrillation, creating a benefit for the community as a consequence of its effective prevention of disabling strokes.

Animals↗