Red Cell Hypoplasia Research Articles

Early Onset Colorectal Cancer: An Emerging Cancer Risk in Patients with Diamond Blackfan Anemia.

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome, the founding member of a class of disorders known as ribosomopathies. Most cases result from loss of function mutations or deletions in 1 of 23 genes encoding either a small or large subunit-associated ribosomal protein (RP), resulting in RP haploinsufficiency. DBA is characterized by red cell hypoplasia or aplasia, poor linear growth and congenital anomalies. Small case series and case reports demonstrate DBA to be a cancer predisposition syndrome. Recent analyses from the Diamond Blackfan Anemia Registry of North America (DBAR) have quantified the cancer risk in DBA. These studies reveal the most prevalent solid tumor, presenting in young adults and in children and adolescents, to be colorectal cancer (CRC) and osteogenic sarcoma, respectively. Of concern is that these cancers are typically detected at an advanced stage in patients who, because of their constitutional bone marrow failure, may not tolerate full-dose chemotherapy. Thus, the inability to provide optimal therapy contributes to poor outcomes. CRC screening in individuals over the age of 50 years, and now 45 years, has led to early detection and significant improvements in outcomes for non-DBA patients with CRC. These screening and surveillance strategies have been adapted to detect familial early onset CRC. With the recognition of DBA as a moderately penetrant cancer risk syndrome a rational screening and surveillance strategy will be implemented. The downstream molecular events, resulting from RP haploinsufficiency and leading to cancer, are the subject of significant scientific inquiry.

Importancia del manejo interdisciplinario de pacientes con Fisuras Labiopalatinas y Anemia de Blackfan Diamond. Reporte de caso: seguimiento a 2 años

Las fisuras labiopalatinas (FLP) son las malformaciones craneofaciales congénitas más comunes. La anemia de Diamond-Blackfan o anemia aneritroblástica es una hipoplasia congénita selectiva de la serie roja, asociada a alteraciones cardiacas, renales, malformaciones en manos, hipertelorismo y retraso en el crecimiento. La presentación de las FLP y pacientes con Anemia de Diamond-Blackfan es del 10.3%. Objetivo: Presentar un reporte de caso de un paciente de 12 años con anemia de Diamond-Blackfan y secuela de FLP de la Clínica Interdisciplinaria de LPH de la Pontificia Universidad Javeriana (Bogotá-Colombia) donde el abordaje interdisciplinario, el casomanejo del comportamiento y el apoyo psicológico brindado a la familia fueron fundamentales para lograr la adherencia, clarificar el diagnóstico y obtener los resultados terapéuticos esperados. Resultados: se logró la adherencia al tratamiento y el éxito de éste en apoyo con otras especialidades, permitiendo un seguimiento de 2 años. Conclusiones: El manejo multidisciplinario e interdisciplinario con especialidades odontológicas, médicas, y de la salud en general para el manejo de pacientes con FLP y síndromes asociados, resulta importante para el éxito en el tratamiento.

Lymphoblastoid cell lines from Diamond Blackfan anaemia patients exhibit a full ribosomal stress phenotype that is rescued by gene therapy

Diamond Blackfan anaemia (DBA) is a congenital bone marrow failure syndrome characterised by selective red cell hypoplasia. DBA is most often due to heterozygous mutations in ribosomal protein (RP) genes that lead to defects in ribosome biogenesis and function and result in ribosomal stress and p53 activation. The molecular mechanisms underlying this pathology are still poorly understood and studies on patient erythroid cells are hampered by their paucity. Here we report that RP-mutated lymphoblastoid cell lines (LCLs) established from DBA patients show defective rRNA processing and ribosomal stress features such as reduced proliferation, decreased protein synthesis, and activation of p53 and its target p21. These phenotypic alterations were corrected by gene complementation. Our data indicate that DBA LCLs could be a useful model for molecular and pharmacological investigations.

Primitive Erythropoiesis and Osteogenesis Are Differentially Impaired In Rpl5 and Rps19 Mutant Murine Embryonic Stem Cell Models Of Diamond Blackfan Anemia

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by red blood cell hypoplasia, congenital anomalies and cancer predisposition. In addition, short stature and poor skeletal growth are found in a subset of DBA patients, suggesting similar developmental abnormalities in erythropoiesis and osteogenesis in that subset. Furthermore it has been shown recently that osteoblasts secrete erythropoietin, linking the marrow niche to the modulation of erythropoiesis. DBA has been shown in the majority of cases to result from haploinsufficiency of large or small ribosomal subunit proteins. The p53 pathway, known to be activated by abortive ribosome assembly, contributes to the erythroid failure of DBA. We studied two DBA genotypes in vitro using murine embryonic stem (ES) cell lines harboring gene trap mutations in ribosomal proteins RPS19 and RPL5, respectively. Both mutants had decreased embryoid body (EB) formation, decreased definitive erythroid colony formation and similar p53-dependent primitive erythroid differentiation defects (see Figure A). Cell cycle analyses were normal in the Rps19 mutant ES cells, but there was a significant G2/M arrest in the Rpl5 mutant ES cells, which was unaffected by p53 knockdown. In addition, the Rpl5 mutant cells had a more pronounced growth defect in culture compared to the Rps19 mutant cells (Figure B). ES cells were differentiated, in vitro, to osteoblasts using established culture conditions, and confirmed both by morphology and molecular characterization (e.g. RUNX2 and Osteopontin). Following 14 days of osteogenic differentiation, bone mineralization was confirmed via Alizarin Red staining. A marked reduction in Alizarin Red staining was seen in the Rpl5 mutant cells while there was only a slight diminution of staining in the Rps19 mutant ES cultures (see Figure C). Therefore the erythroid differentiation defect appears similar in both the Rps19 and Rpl5 mutant ES cells. However the Rpl5 mutant appears to have a more severe phenotype at the ES stage, as evidenced by a pronounced p53-independent G2/M arrest and slower growth rate and subsequently during osteogenic differentiation. These data suggest an explanation for the more severe non-erythroid phenotype seen in a subset of DBA patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Knockdown of p53 Improves Hematopoietic and Erythroid Differentiation Defects in Mouse Embryonic Stem Cell Models of Diamond Blackfan Anemia

Abstract 728 Background:Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by red blood cell hypoplasia, congenital anomalies and cancer predisposition. The disease has been shown to result from haploinsufficiency of large or small ribosomal subunit proteins. The p53 pathway, known to be activated by abortive ribosome assembly, may play a role in the pathogenesis of DBA. Previously, we described murine embryonic stem (ES) cell models of DBA and reported hematopoietic and erythroid defects common to Rps19- and Rpl5-deficient cell lines, as well as a primitive erythropoiesis defect unique to an Rpl5-deficient cell line [Blood 116(21), 877, 2010]. Methods:We studied the effects of p53 knockdown on hematopoiesis in our Rps19- and Rpl5-mutant murine ES cell lines created by gene trap technology. Small interfering RNA (siRNA) targeting p53 was transfected into mutant cell lines at the ES cell stage. A non-targeting siRNA served as a negative control. After 24 hours, cells were plated into methylcellulose medium with fetal bovine serum and stem cell factor (SCF) to generate embryoid bodies (EBs). On day 7, EBs were fed with medium containing SCF, interleukin-3 (IL-3), IL-6 and erythropoietin (epo). EBs were scored on day 12 for total quantity and hematopoietic percentage. For secondary differentiation into primitive erythroid colonies, day 5 EBs were disrupted, and individual cells were suspended in a methylcellulose medium containing fetal bovine plasma-derived serum and epo. Primitive erythroid colonies were counted on day 7 of culture. Definitive hematopoiesis assays were performed by disruption of day 7 EBs, followed by suspension of cells in methylcellulose medium containing SCF, IL-3, IL-6 and epo. Definitive hematopoietic colonies were counted on day 10. In an independent set of experiments, we created an isogenic pair of wild-type and mutant DBA ES cells by electroporation of another Rps19- mutant line with a plasmid vector expressing wild-type Rps19 cDNA (wild-type) or an empty vector (mutant). Results:By immunoblot assays, we detected an increased amount of p53 protein in our Rps19-and Rpl5- mutant cell lines. Following p53 siRNA transfection, we confirmed 82–95% reduction in p53 expression by quantitative PCR, whereas ES cells transfected with non-targeting siRNA did not alter p53 expression. For both Rps19- and Rpl5- mutants, previously shown to have EB formation defects in comparison to parental controls, p53 knockdown significantly improved EB formation, especially hematopoietic-type EBs, compared to mutants treated with non-targeting siRNA. In addition, p53 knockdown in both mutants reversed the definitive hematopoiesis defect by increasing the ratio of erythroid colony to myeloid colony formation. Furthermore, p53 siRNA transfection of the Rpl5- mutant rescued the primitive erythropoiesis defect previously shown by us.To further explore the mechanistic basis of our findings, we additionally tested the effects of Rpl11 knockdown in our DBA models. The presence of free RPL11 secondary to abortive ribosome assembly has been hypothesized to be responsible for increased p53 in DBA by binding to and inhibiting the p53 inhibitor HDM2 (Mdm2 in mice). Transfection of Rpl11 siRNA into both Rps19- and Rpl5-mutant cell lines at the ES cell stage led to a marked reduction in EB formation, compared to cells transfected with non-targeting siRNA.Finally, we also extended our analysis to an isogenic pair of Rps19- wild-type and mutant cells. In the mutant line, we confirmed a 5–8 fold rescue of EB formation with siRNA targeting p53 when compared to the non-targeting siRNA. In order to clarify the role of two major downstream effectors of p53, siRNA targeting either Bax or p21 was transfected into the mutant cell line. Surprisingly, neither siRNA was able to rescue the EB formation defect of the mutant cells. Conclusions:(1) Knockdown of p53 markedly improves erythroid defects of Rps19- and Rpl5-deficient murine ES cell models of DBA, while inhibition of the upstream target Rpl11 causes significant toxicity to cells already haploinsufficient for Rps19 or Rpl5. (2) Knockdown of either Bax or p21 does not recapitulate knockdown of p53, suggesting that neither plays a significant individual role in downstream signaling from p53 in this model. (3) Further exploration of the p53 pathway may provide insights into the pathogenesis of DBA and identify new targets for therapy. Disclosures:No relevant conflicts of interest to declare.

Treatment of Red Cell Hypoplasia Following Fully Ablative Matched Related Allogeneic Transplant with Stem Cell Boost.

AbstractAbstract 4530We present the case of a 34 year old African American male with T-cell non-Hodgkin's Lymphoma who received a matched related allogeneic transplant using a preparative regimen of cyclophosphamide and TBI from his brother on 11/4/09. The patient's blood type was O+ and the donor's blood type was B+. The cell dose was 10.3 × 106 CD34/kg. His post transplant course was generally uncomplicated. Although he recovered his ANC on D+18 and he was platelet transfusion independent by D+28, he never became red cell transfusion independent. A bone marrow biopsy on day 33 showed no evidence of disease with minimal erythroid recovery. His engraftment studies were all 100% donor cells. His reticulocyte counts are detailed in the table below. On day 126 he had a positive qualitative PCR for parvovirus. He received IVIG (400 mg/kg) for 5 consecutive days beginning 3/15/10. Weekly surveillance for CMV by PCR remained non-detectable.Repeat bone marrow biopsies on day 63 and 88 continued to show neutrophil engraftment, hypoplastic megakaryocytes and aplasia of red cells. His immune suppression was discontinued on day 99. A fourth bone marrow biopsy on day 155 again showed erythroid hypoplasia with neutrophil and megakaryocyte hypoplasia.He received a second infusion of PBSC without a conditioning regimen. He received 2.5 × 106 G-CSF mobilized HPC-A from the original donor on day 205 post transplant. Tacrolimus was reinitiated on day 203. As noted in the table below, his reticulocyte count normalized three weeks post infusion. His last RBC transfusion was given two days prior to the stem cell infusion and he remains transfusion independent today. He continues on tapering doses of tacrolimus and has not experienced any graft versus disease.DateT+WBCHgbPLTANCreticParvo PCR12/7/09336.68.8632.412/9/09356.17.8692.50.68%negative2/25/101131.98.8691.10.10%3/10/101262.18.50.4positive3/25/101423.59.1732.20.10%negative4/1/101492.48.0491.2negative5/25/102032.77.0871.50.10%6/18/10227/233.18.31131.96.10%6/25/10234/303.68.41172.25.20% Disclosures:No relevant conflicts of interest to declare.

Mega-dose methylprednisolone in hematologic and non-hematological disorders.

The comprehensive, basic and stimulating review article entitled “A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation and apoptosis–inducing agent of myeloid leukemia cells” by Prof. Hicsonmez in the recent issue of the Journal gives me an opportunity to clarify this mode of treatment [1]. Although high-dose corticosteroid administration (up to 1000 mg) was used prior to our recommended method of methylprednisolone (MP) treatment, the drug was infused any time of the day intravenously over a 4-hour period, which is generally called “pulse MP treatment” although this term was not used before 1960. The term “high-dose methylprednisolone” (HDMP) was used for our method of MP administration initially [2-6], following the dose recommendation by Bacigalupo et al. [7], but we changed the term to mega-dose methylprednisolone (MDMP), since HDMP was also used in the literature for 4-10 mg/kg doses. I would also like to emphasize that MDMP treatment differs from conventional corticosteroid (2 mg/kg in divided doses) HDMP and pulse and bolus MP (1000 mg infused by Bacigalupo et al. in 4 hours) administration, not only by dose (which is increased up to 100 mg/ kg, if required for 3 days initially and then tapered gradually) but also the time of administration [8]. Each MDMP dose (in 10-15 iv or at once orally, covered by honey) is given around 6 am (originally stated as before 9 am) when the corticosteroid level is highest physiologically in the body, which seems to be important for adrenocorticotropic hormone (ACTH) and corticosteroid homeostasis (highest dose of 4950 mg was given to a patient with acquired aplastic anemia). We gave a short course of MP (30 mg/kg for 3 days followed by 20 mg/kg for 4 days) to patients with acute idiopathic thrombocytopenic purpura, in which the disease prognosis was good; the duration of treatment usually extended to months or even years, according to the severity of the disease. It seems that longer usage of MDMP treatment is better for the prevention of recurrences and relapses [9]. Thus far, more than 500 patients with different hematological (acquired aplastic anemia, DiamondBlackfan anemia, idiopathic myelofibrosis, idiopathic thrombocytopenic purpura, severe pure red cell hypoplasia, acquired thrombotic thrombocytopenic purpura, severe Coombs (+) hemolytic anemia, hypereosinophilic syndrome, paroxysmal nocturnal hemoglobinuria, Evans syndrome, idiopathic pulmonary hemosiderosis, Kasabach-Merritt syndrome, different acute leukemias, thalassemia intermedia) and non-hematological (steroid-resistant nephrotic syndrome, systemic lupus erythematosus, dermatomyositis, Kawasaki disease, mixed collagen disease, polyarteritis nodosa, rheumatic fever, rheumatoid arthritis, diaphyseal dysplasia, lymphocytic infiltration of the lung, alopecia universalis, sarcoidosis, osteopetrosis, hemangiomatosis) diseases have been treated with MDMP [10-13]. Corticosteroid side effects (hypertension, hyperglycemia, growth retardation, cushingoid appearance, etc.) were practically non-existent as reported by others [14], inasi Ozsoylu

Fibroblasts from patients with Diamond-Blackfan anaemia show abnormal expression of genes involved in protein synthesis, amino acid metabolism and cancer.

BackgroundDiamond-Blackfan anaemia (DBA) is a rare inherited red cell hypoplasia characterised by a defect in the maturation of erythroid progenitors and in some cases associated with malformations. Patients have an increased risk of solid tumors. Mutations have been found in several ribosomal protein (RP) genes, i.e RPS19, RPS24, RPS17, RPL5, RPL11, RPL35A. Studies in haematopoietic progenitors from patients show that haplo-insufficiency of an RP impairs rRNA processing and ribosome biogenesis. DBA lymphocytes show reduced protein synthesis and fibroblasts display abnormal rRNA processing and impaired proliferation.ResultsTo evaluate the involvement of non-haematopoietic tissues in DBA, we have analysed global gene expression in fibroblasts from DBA patients compared to healthy controls. Microarray expression profiling using Affymetrix GeneChip Human Genome U133A 2.0 Arrays revealed that 421 genes are differentially expressed in DBA patient fibroblasts. These genes include a large cluster of ribosomal proteins and factors involved in protein synthesis and amino acid metabolism, as well as genes associated to cell death, cancer and tissue development.ConclusionThis analysis reports for the first time an abnormal gene expression profile in a non-haematopoietic cell type in DBA. These data support the hypothesis that DBA may be due to a defect in general or specific protein synthesis.

Severe megaloblastic anaemia presenting as pancytopenia with red cell hypoplasia and elevated serum cobalamin and cobalamin binding proteins

In severe megaloblastic anaemia due to folate or cobalamin deficiency the bone marrow is usually hypercellular with megaloblastic change in erythropoiesis and giant metamyelocytes in the myeloid series. We report an unusual case of megaloblastic anaemia with marked erythroid hypoplasia and myeloid hyperplasia; the serum cobalamin and unsaturated cobalamin binding capacity were both grossly elevated.

Epoetin-induced pure red cell aplasia: diagnosis and treatment

Antibody-mediated pure red cell aplasia is now recognized as a rare complication of erythropoiesis-stimulating agent therapy. The incidence of this adverse effect peaked in 2002, but new cases still appear sporadically. The aim of this review is to discuss the latest opinions regarding the detection and management of this condition. The diagnosis of classical erythropoiesis-stimulating agent induced pure red cell aplasia is made by a constellation of clinical features, including severe transfusion-dependent anaemia, reticulocytopenia, low or absent erythroblasts in the bone marrow, and the presence of circulating antierythropoietin antibodies. Recently, some cases have been reported in which the bone marrow findings show red cell hypoplasia rather than aplasia; this may represent earlier presentations of the same condition. Management of pure red cell aplasia as a complication of erythropoiesis-stimulating agent therapy consists of stopping the drug and implementing an immunosuppressive regimen to reduce or abolish erythropoietin antibody production. A recent animal study suggested that a possible alternative strategy may be to administer a novel peptide-based erythropoietin receptor agonist called Hematide that does not cross react with antierythropoietin antibodies, and will allow ongoing stimulation of erythropoiesis; this is the subject of a current clinical trial.

The zebrafish udu gene encodes a novel nuclear factor and is essential for primitive erythroid cell development

Hematopoiesis is a complex process which gives rise to all blood lineages in the course of an organism's lifespan. However, the underlying molecular mechanism governing this process is not fully understood. Here we report the isolation and detailed study of a newly identified zebrafish ugly duckling (Udu) mutant allele, Udu(sq1). We show that loss-of-function mutation in the udu gene disrupts primitive erythroid cell proliferation and differentiation in a cell-autonomous manner, resulting in red blood cell (RBC) hypoplasia. Positional cloning reveals that the Udu gene encodes a novel factor that contains 2 paired amphipathic alpha-helix-like (PAH-L) repeats and a putative SANT-L (SW13, ADA2, N-Cor, and TFIIIB-like) domain. We further show that the Udu protein is predominantly localized in the nucleus and deletion of the putative SANT-L domain abolishes its function. Our study indicates that the Udu protein is very likely to function as a transcription modulator essential for the proliferation and differentiation of erythroid lineage.

A case of drug-induced hematotoxicity: from in vivo to in vitro assessment

As part of the early preclinical development of a new antipsychotic compound, Wistar rats of both sexes were dosed orally for upto 7 days. At high doses, expected changes in appearance and behavior, decreases in bodyweight gain and feed intake but also a fluid and pale bone marrow (BM) were observed. Blood cell counts were normal as were clinical chemical values. BM sections showed a red cell hypoplasia. Circulating reticulocytes and erythroblasts on BM smears were decreased suggesting that the compound might have a selective toxicity for the erythroid lineage. In a mechanistic experiment, rats were dosed for 9 days and phlebotomized after 7 days of exposure to stimulate erythroid regeneration. Red-blood cell mass, reticulocytes and erythropoietin (EPO) levels were monitored before and upto 48 h after bleeding. Results showed that an EPO-mediated pathogenesis could be excluded. The effect of the drug on the formation of Colony-forming units (CFU)-E and CFU-GM was then quantitatively measured in vitro after direct exposure to the compound. In two successive assays, rat or human BM cells were incubated with the drug dissolved in the collection medium at final concentrations of 0.3×10−7 –3×10−5 M. In the presence of adequate growth factors, CFU-E and CFU-GM were cultured and cell proliferation was compared between treated and control groups. Our results showed an expected inhibition by the drug of the growth of erythroid progenitors associated to a similar effect on myeloid progenitors. The CFU-E and CFU-GM of both human and rat sources were totally inhibited from the concentration of 3×10−5 M. The IC50 values were consistent with rat peak plasma levels reached in vivo by the drug. Therefore, the short-term cloning assays performed on rat BM cells were sensitive indicators of the hematotoxicity of the compound and were considered as predictive for human toxicity.

Value of In Vitro Models for the Assessment of Drug-Induced Haematotoxicity

BackgroundA new antipsychotic compound induced unexpected red cell hypoplasia (reticulocytopenia, red marrow hypoplasia) in rats dosed orally for 7days. Materials and methodsSince an erythropoietin-mediated pathogenesis was excluded, in vitro tests on rat and human bone marrow cells were performed with measurement of formation of late erythroid (CFU-E) and granulocyte-macrophage (CFU-GM) colony-forming units after incubation with the drug. CFU-E together with growth factors were cultured for 2days (rat) or 7days (human) and CFU-GM was cultured for 7days (rat) or 10days (human). ResultsThe drug induced inhibition of erythroid progenitors and myeloid progenitors for both species from 3×10−5 mol/L, with the concentration inhibiting the growth of 50% (IC50) consistent with drug plasma levels measured in rats. ConclusionThese cloning assays on rat bone-marrow cells were shown to be adequate models for determining the haematotoxicity of the agent and to be predictive of human toxicity. With only a small amount of compound required, they can be used as screening tools to detect haematotoxic potential of candidate drugs.

Ribosomal Protein S19 Gene Mutations in Patients with Diamond-Blackfan Anemia and Identification of Ribosomal Protein S19 Pseudogenes

ABSTRACTDiamond-Blackfan anemia (DBA) is a rare congenital pure red cell hypoplasia characterized by a selective defect of erythropoiesis with a normochromic macrocytic anemia and reticulocytopenia often accompanied by various congenital anomalies. The critical region responsible for the pathogenesis of DBA has been mapped in some patients to chromosome 19q13.2 (P Gustavsson, E Garelli, N Draptchinskaia, et al. Am. J. Hum. Genet. 63:1388–1395, 1998) and the gene encoding ribosomal protein S19 (RPS19) is believed to be the candidate gene. Here we present molecular analysis of the RPS19 gene in DBA patients from the Czech National DBA Registry. We found that the RPS19 gene was mutated in 25% (5/20) of DBA patients (insertion, deletion, and point mutations, but no nonsense or splice site mutations). Point mutations were localized to hot spots defined by Willig (TN Willig, N Draptchinskaia, I Dianzani, et al. Blood 94:4294–4306, 1999). Moreover, we describe two processed RPS19 pseudogenes, which were not expressed. Possible models of the DBA pathogenesis in the view of RPS19 mutations are discussed.

Chronic idiopathic pure red cell aplasia: successful treatment during pregnancy and durable response to intravenous immunoglobulin

A patient with chronic idiopathic pure red cell hypoplasia responded to intravenous immunoglobulin therapy. No other treatment was administered. During treatment, the patient was taken through two pregnancies without haematological problems. After 22 months of therapy, the intravenous immunoglobulin was discontinued; a durable remission was subsequently maintained. Intravenous immunoglobulin may be the treatment of choice for females of child-bearing potential.

Preoperative transfusion in sickle cell anemia

American Journal of HematologyVolume 38, Issue 2 p. 156-157 Letter to the EditorFree Access Preoperative transfusion in sickle cell anemia Samuel Charache, Samuel Charache Professor of Medicine and Laboratory Medicine Johns Hopkins University School of Medicine Baltimore, MarylandSearch for more papers by this author Samuel Charache, Samuel Charache Professor of Medicine and Laboratory Medicine Johns Hopkins University School of Medicine Baltimore, MarylandSearch for more papers by this author First published: October 1991 https://doi.org/10.1002/ajh.2830380220Citations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 National Institutes of Health: Perioperative red cell transfusion. Cons Dev Conf Statement 7: 1– 6, 1988. 2 National SCA Preoperative Transfusion Study Group: Preoperative transfusion in sickle cell anemia (abstract). Blood 74: 184a, 1989. 3 Lane PK, Embury SH, Toy PTCY: Oxygen-induced marrow red cell hypoplasia leading to transfusion in sickle painful crisis. Am J Hematol 27: 67– 68, 1988. 4 Taylor C, Rogers G, Goodman C, Baynes RD, Bothwell TH, Bezwoda WR, Kramer F, Hattingh J: Hematologic, iron-related, and acute-phase protein responses to sustained strenuous exercise. J Appl Physiol 62: 464– 469, 1987. 5 Schooley JC, Kullgren B, Allison AC: Inhibition by interleukin-1 of the action of erythropoietin on erythroid precursors and its possible role in the pathogenesis of hypoplastic anaemias. Br J Haematol 67: 11– 7, 1987. 6 Maury CPJ, Lahdevirta J: Correlation of serum cytokine levels with haematological abnormalities in human immunodeficiency virus infection. J Int Med 227: 253– 257, 1990. 7 Owren PA: Congenital hemolytic jaundice. The pathogenesis of the “hemolytic crisis”. Blood, 3: 231– 248, 1948. 8 Pattison JR, Jones SE, Hodgson J: Parvovirus infections and hypoplastic crisis in sickle cell anaemia. Lancer 1: 664– 665, 1981. Citing Literature Volume38, Issue2October 1991Pages 156-157 ReferencesRelatedInformation

Bone marrow transplantation in sickle cell anaemia.

Sickle cell anaemia is still responsible for severe crippling and death in young patients living in developing countries. Apart from prophylaxis and treatment of infections, no active treatment can be safely proposed in such areas of the world. Therefore a bone marrow transplantation was performed in 12 patients staying in Belgium and planning to return to Africa. Twelve patients, aged between 11 months and 23 years (median 4 years), underwent a HLA identical bone marrow transplantation. The conditioning regimen included oral busulphan for four consecutive days (4 mg/kg) followed by four days of intravenous cyclophosphamide (50 mg/kg). In 10 patients the engraftment was rapid and sustained. A further patient suffered transient red cell hypoplasia and another underwent a second bone marrow transplantation from the same donor at day 62 because of graft rejection. All patients are alive and well with a follow up ranging from 9-51 months (median 27 months). In all cases a complete cessation of vaso-occlusive episodes and haemolysis was observed as was a change in the haemoglobin pattern in accordance with the donor's electrophoretic pattern.

Red cell hypoplasia associated with myeloproliferative and myelodysplastic syndrome.

Although the biotransformation of ginsenosides in gastrointestinal tract has been extensively studied, very less is known about the hepatic cytochrome P450 catalyzed metabolism. The major aims of this study were to clarify the metabolic pathway and involved CYP isoforms,and to explore the structure metabolism relationship of, protopanaxatriol (PPT) type ginsenosides in hepatic microsomes. Efficient depletion of ginsenoside Rh1, Rg2, Rf, and PPT was found, whereas the elimination of Re and Rg1, characterized with a glucose substitution at C20 hydroxy group, was negligible, in microsomal incubation systems. Based on a LC/MS-IT-TOF analysis, the oxygenation metabolism on the C20 aliphatic branch chain was identified as the predominant metabolic pathway of PPT ginsenosides in both human and rat hepatic microsomes. By comparing with authentic standards, the C24-25 double bond was identified as one of the oxygenation site to produce the metabolites of C20-24 epoxide (ocotillol-type ginsenosides). Both chemical inhibition and human recombinant CYP isoforms assay indicated that CYP3A4 was the predominant isozyme responsible for the oxygenation metabolism of PPT ginsenosides. Enzyme kinetic evaluations in rat and human hepatic microsomes and human recombinant CYP3A4 isozyme incubation systems reached a generally consistent result in that the intrinsic clearance ranked as Rf≤Rg2<Rh1<PPT, closely correlating with their Log P values and the number of glycosyl substitutions. Results obtained from this study suggest that CYP3A4 catalyzed oxygenation metabolism plays an important role on the hepatic disposition of ginsenosides, and that the glycosyl substitution, especially at C20 hydroxy group, determines their intrinsic clearances by CYP3A4.

Red Cell Hypoplasia Following Autoimmune Hemolytic Anemia Associated with T-CLL: Report of a Case and Review of the Literature

Red Cell Hypoplasia Following Autoimmune Hemolytic Anemia Associated with T-CLL: Report of a Case and Review of the Literature

Disseminated Mycobacterium avium-intracellulare infection and red cell hypoplasia in patients with the acquired immune deficiency syndrome

During a period of 14 months in 1985 and 1986, infection with Mycobacterium avium-intracellulare (MAI) complex was diagnosed in 10 of 76 patients with Human Immunodeficiency Virus (HIV)-associated infection. In eight of the 10 patients, the infection was disseminated. All eight patients were anaemic. A bone marrow aspirate and/or trephine biopsy performed in six of them revealed evidence of red cell hypoplasia. MAI was cultured from all six samples of bone marrow. The strains of MAI isolated were resistant to conventional antituberculous drugs but were susceptible in vitro to ansamycin, ethionamide and cycloserine. None of the eight patients responded clinically to antituberculous therapy. The eight anaemic patients had pronounced constitutional symptoms. We suggest that severe anaemia and constitutional symptoms in patients with HIV-associated disease should prompt a search for evidence of disseminated MAI infection.