Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A multicenter, immunohistochemical and morphometric study was performed on diagnostic pretreatment bone marrow biopsies in 614 adult patients with Ph1+ chronic myeloid leukemia (CML) to compare histological features with clinical findings. For identification of megakaryopoiesis we used the monoclonal antibody CD61 and additionally the PAS reaction to determine the subfraction of atypical micromegakaryocytes and precursors. Labelling of erythroid precursors was carried out by a monoclonal antibody directed against glycophorin C. In order to selectively stain macrophages and their activated subset we applied CD68 and the GSA-I lectin. Density of argyrophilic fibers (reticulin plus collagen) was measured following Gomori's silver impregnation method. In accordance with laboratory data morphological variables revealed a comparable amount of congruence in the various groups of CML patients derived from different sources. In about 26% of patients early (reticulin) to advanced (collagen) fibrosis was detectable. Significant correlations were calculated between the extent of myelofibrosis with splenomegaly, anemia and increasing numbers of erythroblasts and myeloblasts in the peripheral blood count. These features were assumed to indicate more advanced stages of the disease process with ensuing transition into myeloid metaplasia and consequently were associated with an unfavorable prognosis. Significant relationships were revealed between the number of CD61+ megakaryocytes and more important, also their precursor fraction with the degree of fibrosis. This result extends previous experimental findings regarding the impact of immature elements of this cell lineage for the generation of myelofibrosis. The significant association of erythroid precursors with the number of mature (resident) macrophages including their activated GSA-I subset may shed some light on their functional involvement in iron turnover and hemoglobin synthesis. A modified histological classification of predominant bone marrow features is introduced. This simplified synthesis staging system (Cologne Classification) is not only associated with certain sets of laboratory data, but also with different survival patterns.
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PMID:Bone marrow features and clinical findings in chronic myeloid leukemia--a comparative, multicenter, immunohistological and morphometric study on 614 patients. 1067 1

A cohort of 250 Ghanaian schoolchildren aged 5-15 years was followed clinically and parasitologically for 4 months in 1997/98 in order to study the effect of asymptomatic Plasmodium falciparum infections on haematological indices and bone-marrow responses. Of the 250 children 65 met the predefined study criteria. Thus, 14 children were parasite-free throughout (group 1), 44 had P. falciparum in all blood samples collected but no symptoms of malaria (group 2), and 7 had 1 malaria attack during the study period (group 3). At the end of the study the mean haemoglobin (Hb) level in group 1 was 123 g/L, significantly higher than the value of 114 g/L in groups 2 and 3 (P < 0.02, adjusted for age and splenomegaly). The low Hb in group 2 was associated with subnormal plasma iron. Low Hb was associated with elevated erythropoietin (EPO) levels, and there was a positive correlation between EPO and reticulocyte counts. However, the reticulocyte response to EPO was more pronounced in uninfected than in infected children, suggesting a partial interference with erythropoiesis in asymptomatic infections. Children with asymptomatic infections had significantly higher plasma levels of tumour necrosis factor than uninfected children (geometric means 50 ng/L and 27 ng/L, respectively, P < 0.001) and this cytokine may contribute to bone-marrow suppression and disturbed iron metabolism. We suggest that asymptomatic malaria leads to a homeostatic imbalance in which erythrocyte loss due to parasite replication is only partially compensated for by increased erythropoiesis. The consequences of the reduced Hb levels on the development and cognitive abilities of children with asymptomatic infections, and the risk of precipitation of iron deficiency, deserve further study and should be considered in malaria control programmes that aim at reducing morbidity rather than transmission.
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PMID:Anaemia caused by asymptomatic Plasmodium falciparum infection in semi-immune African schoolchildren. 1071 50

Females of OFI mice were given single repeated intravenous injections of magnetite-dextran nanoparticles (MD3), the total partical diameter being 49 nm, with the magnetic core diameter equal to 10-15 nm. MD3 is a superparamagnetic preparation commonly used for magnetic resonance imaging (MRI). The liver, spleen, heart, kidney, and lung microstructures of these mice were determined after MD3 administration. Both dose- and time-dependent changes in the examined organs were compared after single and repeated MD3 doses. MD3 induces an increse in ferritine and iron levels in all the organs, the appearance of small aggregates of lymphoid cells in the liver, the appearance of iron-containing cell formations in hepatic sinusoids, presumably composed of the Kupffer cells and portal macrophages, splenomegaly, and hemostasis of spleen blood vessels. The pronounced morphological alterations have been revealed primarily in the liver and spleen after a single administration of high MD3 doses and after repeated MD3 injections. The results of The present investigation seem to narrow somewhat the safety limits of superparamagnetic iron oxide particles. Nevertheless, the degree of morphological changes in the liver and spleen in our experiments appeared to be rather low even after a single MD3 dose that exceeds approximately by 200 times a dose necessary for diagnostics in MRI.
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PMID:[Toxicity of magnetite-dextran particles: morphological study]. 1084 30

The congenital dyserythropoietic anemias (CDA) are hereditary diseases characterized by a lifelong, mostly moderate anemia. CDA can be diagnosed already in early childhood. However, diagnosis is complicated due to poor knowledge of morphological criteria and the large number of differential diagnoses that have to be excluded. CDA type I is characterized by macrocytic anemia with megaloblastic changes in erythropoiesis and chromatin bridges between isolated erythroblasts. Type II shows a normocytic anemia with a positive acidified serum test and increased agglutination with anti-i. Erythroblasts can present with 2 or more nuclei. CDA type III presents with a macrocytic anemia and erythroblasts with up to 12 nuclei, the so called gigantoblasts. Some patients lack the typical morphological abnormalities of type I-III (variants or type IV). Besides light microscopic abnormalities, CDA type-specific changes in electron microscopy are described. The clinical picture of the patients vary between the different forms: signs of hemolysis and ineffective erythropoiesis such as icterus, splenomegaly and gall stones can be present. Most important is the tendency of a part of patients to have an increased iron absorption and iron storage. Patients with and without transfusion dependency are described. Supportive care such as iron chelation can be necessary in some patients. The CDA are inherited in an autosomal recessive manner; in type III an additional autosomal dominant variant exists. Recently, the determination of gene loci for type I, II and III was enabled by linkage analysis on different regions of chromosome 15 and 22. It is considered that CDA I and II are genetically heterogenic. Until now no gene has been identified in either type of CDA. In CDA type II, a glycosylation defect of erythrocyte membrane proteins is present. An international group plans to do further research. Therefore, identification and registration of patients in a registry is necessary. Patients' data and material would enable gene characterization. The results would allow an extended classification according to genotype and prediction of the course of the disease. Additionally, information on the regulation and control of normal and abnormal erythropoiesis could be obtained.
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PMID:[Diagnosis and genetics of congenital dyserythropoietic anemias (CDA)]. 1099 42

Type II congenital dyserythropoietic anaemia (CDA-II or HEMPAS) is an autosomal recessive disorder, representing the most frequent form of congenital dyserythropoiesis. It is characterised by normocytic anaemia, variable jaundice and hepato-splenomegaly. Gallbladder disease and secondary haemochromatosis are frequent complications. We report a case characterised by severe transfusion-dependent anaemia. The proband inherited CDA-II in association with beta-thalassaemia trait. Splenectomy did not abolish the transfusion dependence and this, in association with poor compliance to iron-chelation therapy, prompted us to consider bone marrow transplantation (BMT) from his HLA-identical sibling. The preparative regimen included busulfan, thiotepa and fludarabine, and graft-versus-host disease prophylaxis consisted of cyclosporin A and short-term methotrexate. Engraftment of donor cells was prompt and the post-transplant course uncomplicated. The patient is alive and transfusion-independent 36 months after allograft. This is the first case of severe CDA-II to undergo BMT. Analysis of this pedigree suggests that interaction with beta-thalassaemia enhanced the clinical severity of CDA-II, making BMT an attractive therapy for patients with transfusion dependence.
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PMID:Bone marrow transplantation in a case of severe, type II congenital dyserythropoietic anaemia (CDA II). 1128 93

Thirty three B-chronic lymphoproliferative disorder (B-CLD) patients [22 with B-chronic lymphocytic leukemia (B-CLL), 5 with small lymphocytic lymphoma (SLL) and 6 with lymphoplasmacytic lymphoma (LPL)] with anaemia (Ht <32%) of no other cause but their disease, received recombinant human erythropoietin (r-HuEPO). The treatment protocol provided r-HuEPO in a dose of 150 U/kg s.c. thrice weekly for 3 mo. After 1.5 mo of r-HuEPO administration, if response was not satisfactory, r-HuEPO dose escalation was utilised by giving incremental doses of 50 U/kg more than the previous dose up to a maximum dose of 300 U/kg tiw. After maximal response, half of the responding patients discontinued therapy, while the other half received maintenance therapy at a dose of 150 U/kg s.c./w. Oral iron was given throughout the study. Pretreatment EPO levels were determined in all patients. A complete response (CR) was defined when Ht was >38% and a partial response (PR) when there was an increase of the Ht >6% from the initial value was achieved. Sixteen of the 22 B-CLL patients had Rai stage III disease and 6 stage IV, with a median duration of anaemia 27 months (6-38); twelve of them were receiving chlorambucil while the rest were on no treatment. Of the SLL and LPL group, 4 patients had Ann Arbor stage III disease and 7 stage IV with a median duration of anaemia 24 months (5-36); 8 patients were on chlorambucil. Complete response was achieved in 50% of the B-CLL group and 54% of the SLL and LPL group, with an overall response rate of 77% and 81% respectively. All patients on maintenance therapy had a continuous response, while all patients, in whom rHuEPO was discontinued, relapsed. No correlation was found between patients: with low or high pretreatment serum EPO levels; those receiving concomitant therapy or not; those with B-symptoms or not; those with a non-diffuse or diffuse bone marrow infiltration pattern; and with splenomegaly or not. Life quality was significantly improved and no major side effects were encountered. We conclude from our study that r-HuEPO is very effective in correcting disease-related anaemia in B-CLD, resulting in down-staging of Rai stage III patients and that maintenance therapy is necessary. Whether the correction of anaemia improves patients' overall survival, still remains to be seen.
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PMID:Correction of disease related anaemia of B-chronic lymphoproliferative disorders by recombinant human erythropoietin: maintenance is necessary to sustain response. 1142 15

Gaucher's disease is an autosomal recessive lysosomal storage disease resulting from glucocerebrosidase deficiency. In this report, five patients with adult Gaucher's disease are described. The clinical course of these patients was characterized by progressive diffuse aseptic necrosis in the large bones, so-called Erlenmeyer's flask deformity, and hepatosplenomegaly. Splenomegaly was accompanied by hypersplenism with anemia and thrombocytopenia, therefore splenectomy was performed. The diagnosis of Gaucher's disease was based on the finding of Gaucher's cells on bone marrow biopsy. Tissue blocks were cut and routinely processed. Slides staining for iron (Peris' blue) and PAS (periodic acid--Schiff) including immunohistochemical staining for CD68 and HLA-DR was performed in all five cases. Gaucher's cells were seen as large cells with granular or fibrillar distended cytoplasm, with the characteristic 'wrinkled tissue paper' appearance, and eccentric nuclei. PAS staining showed strongly positive granular or fibrillar material in the cytoplasm. Immunohistochemical stain for CD68 and HLA-DR helped identify isolated Gaucher's cells, which are hystiocytic in nature. This stain accentuates their fine linear striations. Small pieces were ultrastructurally analyzed.
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PMID:Immunohistochemical and ultrastructural features of Gaucher's cells--five case reports. 1185 32

We describe data on a 7-year-old girl with congenital dyserythropoietic anemia (CDA), who also had familial Mediterranean fever (FMF). Repeated transfusions required since the age of 6 months to treat her CDA led to iron overload and a persistently high ferritin level. Her relapsing FMF made effective iron chelation therapy very difficult. Consequently, at the age of 4 years, she underwent allogeneic, sibling bone marrow transplantation (BMT). During conditioning for her BMT, symptoms of FMF, including splenomegaly, arthritis, and recurrent abdominal pain, began to resolve and she was gradually weaned off colchicine. Now, 2 years after the transplantation, she remains free from FMF symptomatology and is off all immunosuppressants. This case demonstrates that symptoms of FMF can be alleviated by the therapy used during allogeneic BMT. In this patient it is likely that the missing factor in FMF is now being provided by granulocytes derived from the stem cells within transplanted bone marrow.
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PMID:Allogeneic bone marrow transplantation: cure for familial Mediterranean fever. 1281 18

Achieving long-term pancellular expression of a transferred gene at therapeutic level in a given hematopoietic lineage remains an important goal of gene therapy. Advances have recently been made in the genetic correction of the hemoglobinopathies by means of lentiviral vectors and large locus control region (LCR) derivatives. However, panerythroid beta globin gene expression has not yet been achieved in beta thalassemic mice because of incomplete transduction of the hematopoietic stem cell compartment and position effect variegation of proviruses integrated at a single copy per genome. Here, we report the permanent, panerythroid correction of severe beta thalassemia in mice, resulting from a homozygous deletion of the beta major globin gene, by transplantation of syngeneic bone marrow transduced with an HIV-1-derived [beta globin gene/LCR] lentiviral vector also containing the Rev responsive element and the central polypurine tract/DNA flap. The viral titers produced were high enough to achieve transduction of virtually all of the hematopoietic stem cells in the graft with an average of three integrated proviral copies per genome in all transplanted mice; the transduction was sustained for >7 months in both primary and secondary transplants, at which time approximately 95% of the red blood cells in all mice contained human beta globin contributing to 32 +/- 4% of all beta-like globin chains. Hematological parameters approached complete phenotypic correction, as assessed by hemoglobin levels and reticulocyte and red blood cell counts. All circulating red blood cells became and remained normocytic and normochromic, and their density was normalized. Free alpha globin chains were completely cleared from red blood cell membranes, splenomegaly abated, and iron deposit was almost eliminated in liver sections. These findings indicate that virtually complete transduction of the hematopoietic stem cell compartment can be achieved by high-titer lentiviral vectors and that position effect variegation can be mitigated by multiple events of proviral integration to yield balanced, panerythroid expression. These results provide a solid foundation for the initiation of human clinical trials in beta thalassemia patients.
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PMID:Permanent and panerythroid correction of murine beta thalassemia by multiple lentiviral integration in hematopoietic stem cells. 1239 30

Intravascular hemolysis is associated with several pathologic conditions that include hemoglobinopathies, trauma, malaria, and bacterial infections. Among plasma-protective proteins against oxidative damage caused by red blood cell rupture, haptoglobin and hemopexin are thought to play a crucial role. Haptoglobin and hemopexin, by binding with high-affinity hemoglobin and heme, respectively, exert an antioxidant action by preventing heme-catalyzed free radical production. Moreover, these proteins prevent iron loss by inhibiting glomerular filtration of hemoglobin and heme diffusion through plasma membranes. Analysis of single-null mice demonstrated the antioxidant action of haptoglobin and hemopexin in vivo and suggests that the 2 proteins cooperate in the resolution of hemolytic stress. To evaluate the physiological relevance of the haptoglobin-hemopexin system and the principal targets of its action, we generated haptoglobin-hemopexin double-knockout mice and analyzed them under basal conditions and after acute hemolysis. Whereas haptoglobin-hemopexin double-null mice displayed no obvious alteration in phenotype under basal conditions, nonlethal hemolytic stress in these animals led to pronounced splenomegaly as well as liver inflammation and fibrosis. These data demonstrate that haptoglobin and hemopexin together are essential for protection from splenomegaly and liver fibrosis resulting from intravascular hemolysis.
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PMID:Enhanced splenomegaly and severe liver inflammation in haptoglobin/hemopexin double-null mice after acute hemolysis. 1239 71


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