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B P Alter

Publications and source records attributed to B P Alter.

At least 19 recordsLinked to original sources
PubMed2001

Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the alpha globin cluster.

We have cloned, sequenced and annotated segments of DNA spanning the mouse, chicken and pufferfish alpha globin gene clusters and compared them with the corresponding region in man. This has defined a small segment ( approximately 135-155 kb) of synteny and conserved gene order, which may contain all of the elements required to fully regulate alpha globin gene expression from its natural chromosomal environment. Comparing human and mouse sequences using previously described methods failed to identify the known regulatory elements. However, refining these methods by ranking identity scores of non-coding sequences, we found conserved sequences including the previously characterized alpha globin major regulatory element. In chicken and pufferfish, regions that may correspond to this element were found by analysing the distribution of transcription factor binding sites. Regions identified in this way act as strong enhancer elements in expression assays. In addition to delimiting the alpha globin chromosomal domain, this study has enabled us to develop a more sensitive and accurate routine for identifying regulatory elements in the human genome.

Animals↗
PubMed2001

Griscelli syndrome: rare neonatal syndrome of recurrent hemophagocytosis.

Griscelli syndrome (GS) is a rare inherited disease characterized by immunodeficiency and partial albinism. The microscopic findings of the skin and hair are highly suggestive of the disease. The GS locus colocalizes on chromosome 15q21 with the myosin-Va gene (MYO5a), and mutations have been identified in few patients. We describe a 2-month-old Hispanic girl with severe pancytopenia secondary to hemophagocytosis. Even though a mutation at the Griscelli locus had not been identified, her clinical features and outcome were typical of GS. The purpose of this article is to alert physicians to the association between GS and hemophagocytosis. We suggest that GS should be considered in infants with hemophagocytosis because the features of partial albinism can be subtle. The relevant literature is summarized.

Albinism↗
PubMed2000

Fanconi anemia: myelodysplasia as a predictor of outcome.

The adverse potential of the development of myelodysplastic syndrome (MDS) in Fanconi anemia (FA) was examined in a retrospective study of 41 FA patients who had bone marrow morphology and chromosomes reviewed by a single group. Thirty-three patients had adequate cytogenetic studies, and 16 (48%) had one or more abnormal studies: nine initially, and seven more on follow-up. Cytogenetic clonal variation was frequent, including disappearance of clones, clonal evolution, and appearance of new clones. The estimated five-year survival with a cytogenetic clone is 0.40, compared to 0.94 without a clone. Morphologic myelodysplasia (MDS), independent of a cytogenetic clone, was found in 13/41 patients (32%). The estimated five-year survival with MDS is 0.09, versus 0.92 without MDS. Leukemia developed in three patients whose initial cytogenetic clones prior to leukemia were t(1;18), t(5;22) and monosomy 7; the one with t(1;18) also had MDS. Our results focus on marrow morphology, and suggest that morphologic MDS may be more important than classical cytogenetics in prediction of an adverse outcome.

Adolescent↗
PubMed2000

Successful bone marrow transplantation in a patient with Schimke immuno-osseous dysplasia.

Early death in Schimke immuno-osseous dysplasia often results from renal failure and/or cell-mediated immunodeficiency. Kidney transplants have improved renal function, but effective therapy for the immunodeficiency has not yet been reported. We describe markedly improved marrow function 2 years after bone marrow transplantation in a boy with Schimke immunoosseous dysplasia.

Antigens, CD↗
PubMed1999

Embryonic hemoglobins are expressed in definitive cells.

Human embryonic zeta and epsilon globin chains are synthesized in yolk sac-derived primitive erythroid cells, and decrease rapidly during definitive erythropoiesis. Examination of zeta and epsilon globin expression at the cellular level using dual-color immunofluorescence staining with specific monoclonal antibodies showed that embryonic globin proteins are present in definitive erythroid cells. More than half of fetal erythrocytes were positive for zeta and approximately 5% for epsilon globin. Approximately one third of newborn red blood cells were zeta-positive and less than 1% epsilon-positive. Adult erythrocytes did not have embryonic globins. Erythroblasts that developed in liquid cultures also contained embryonic globin in amounts which declined with ontogenic age, and the proportion of positive cells in vitro was less than in the comparable erythrocytes that developed in vivo. Thus, embryonic globin chains are synthesized in definitive erythroid cells and decrease with ontogeny. Modulation of embryonic globin gene expression is not solely due to a switch from primitive to definitive erythropoiesis.

Adult↗
PubMed1999

Pregnancy in bone marrow failure syndromes: Diamond-Blackfan anaemia and Shwachman-Diamond syndrome.

Pregnancy in bone marrow failure syndromes has risk to mother and fetus. There are fewer than 30 reports of cases with Diamond-Blackfan anaemia (DBA), and none with Shwachman-Diamond syndrome (SD). We report two DBA and one SD cases. One DBA mother received transfusions intra-partum, and the other only post-partum. Both required caesarean sections (C-sections) for failure of labour to progress and severe pre-eclampsia respectively. Both subsequently resumed pre-pregnancy steroid-induced control of anaemia. approximately 40% of DBA pregnancies required maternal transfusions; 25% delivered by C-section. The SD patient also had Ehlers-Danlos (ED) syndrome and urticaria pigmentosa (UP). Her blood counts were adequate until week 38, when the platelet count dropped and a C-section was performed. Pregnancy management in marrow failure disorders requires obstetricians with expertise in high-risk pregnancies, and haematologists with experience with marrow failure syndromes.

Adult↗
PubMed1999

Bone marrow failure syndromes.

Laboratory diagnosis of inherited bone marrow failure syndromes includes general evaluations, such as blood counts, examination of the peripheral blood smear for morphology, and bone marrow aspirates and biopsies, which may help the clinician classify the patient, particularly if there are no characteristic physical anomalies. Specific diagnoses require unique tests that are only available for a few of the diagnoses. The most useful is chromosome breakage in the diagnosis of FA, with gene mutation analysis or mapping about to become the gold standard when all of the FA genes have been cloned. The diagnosis of DC remains clinical at this time, although linkage to Xq28 and skewed maternal X inactivation may be helpful in some families. Laboratory proof of SD may be provided by decreased serum trypsinogen or other evidence of exocrine pancreatic insufficiency. CHH is substantiated when absent central pigment in hair is found and when it is mapped to 9p21-p13. The only mitochondrial syndrome, PS, is proved with demonstration of deleted mitochondrial DNA. RD is diagnosed from blood and marrow studies that demonstrate lack of lymphoid as well as myeloid activity. Amega requires absent or abnormal marrow megakaryocytes; if radii are also absent, the diagnosis is TAR. DBA usually has elevated red-cell ADA, and the DBA locus may map to 19q13. KS is diagnosed in patients who have congenital nonimmune severe neutropenia. Clinical suspicion of particular diagnoses can often be substantiated by laboratory tests of varying specificity.

Bone Marrow Diseases↗
PubMed1998

Hematopoietic growth factors for the treatment of aplastic anemia.

The use of hematopoietic growth factors, although well established for the management of chemotherapy-induced neutropenia, remains controversial for the treatment of aplastic anemia and inherited bone marrow failure syndromes. The most commonly used factors are granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, and erythropoietin. Newer growth factors such as stem cell factor, thrombopoietin, Flt3 ligand, and interleukins have shown promising results in the laboratory, and some have been used in clinical trials. This article reviews the clinical use of old and new hematopoietic growth factors in acquired and inherited bone marrow failure, and discusses emerging concerns about long term toxicity of these factors.

Anemia, Aplastic↗
PubMed1997

Treatment of dyskeratosis congenita with granulocyte colony-stimulating factor and erythropoietin.

Aplastic anaemia is both frequent and difficult to manage in patients with dyskeratosis congenita (DC). We recently treated a 23-year-old male for a year with granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Ep), with an excellent neutrophil response, and a transient effect on haemoglobin levels. G-CSF alone or combined with other cytokines may provide at least a partial effect in pancytopenic patients with DC.

Adult↗
PubMed1997

Pure red cell aplasia associated with hepatitis C infection.

We report the case of a 34-year-old woman with recurrent pure red cell aplasia and evidence of hepatitis B and C infection. Review of the English literature identified 19 prior cases in which pure red cell aplasia was associated with hepatitis. This case is the first in which serologic evidence of hepatitis C infection was documented. This patient also had porphyria cutanea tarda and marked hepatic siderosis but no active hepatitis or cirrhosis. Treatment with cyclophosphamide and prednisone produced complete remission of the pure red cell aplasia. Erythroid colony formation (colony-forming unit-erythroid and erythroid burst-forming unit) was reduced in cultures of bone marrow obtained during relapse but was normal in remission marrow. However, addition of the patient serum, whether collected during relapse or remission, inhibited erythroid colony formation by her bone marrow. These observations, and the known extrahepatic immunologic manifestations of hepatitis C infection, suggest that the pure red cell aplasia occurred because of autoimmune mechanism provoked by the infection.

Adult↗
PubMed1997

A new syndrome of familial aplastic anemia and chronic liver disease.

This report describes a new familial syndrome characterized by a combination of bone marrow failure and chronic liver disease. This disorder appears to be genetic in origin with an autosomal dominant inheritance and was characterized by hyperactivity of the immune system with increased activated cytotoxic T lymphocytes in peripheral blood and bone marrow and the presence of gamma-interferon messenger RNA in bone marrow of several cases.

Adolescent↗
PubMed1996

Prolonged administration of granulocyte colony-stimulating factor (filgrastim) to patients with Fanconi anemia: a pilot study.

This report examines the effect of filgrastim (granulocyte colony-stimulating factor, [G-CSF] in 12 patients with neutropenia [absolute neutrophil count [ANC] < 1,000/mm3]) caused by Fanconi anemia (FA). Two of 14 patients who were evaluated for study entry were ineligible because of unsuspected cytogenetic abnormalities in their bone marrow (BM). G-CSF was started at 5 micrograms/kg/d. All patients had an increase in their ANC at week 8 (mean increase = 15,664/mm3). The median ANC during therapy was 5,030/mm3. Eight of 10 patients who completed 40 weeks on study maintained an ANC > 1,500/mm3 on G-CSF given every-otherday. Four patients had an increase in their platelet count by week 8 without transfusion (maximum increase = 23,000 to 45,000/mm3); however, platelet counts fell toward baseline levels as the G-CSF dose was reduced. BM CFU-MK were increased at week 8 in three of four evaluable patients. Four patients who did not receive red blood cell transfusions had an increase in their hemoglobin level of at least 2.0 g/dL. A fifth patient had a red blood cell transfusion in week 2 and then had a similar increase in hemoglobin level without subsequent transfusion. Eight of 10 patients who completed 40 weeks of treatment showed increases in the percentage of BM CD34+ cells measured by flow cytometry. The same proportion showed increases in peripheral blood CD34+ cells. Increased BM cellularity and myeloid hyperplasia were constant findings and were associated with increased expression of the proliferating cell nuclear antigen. Adverse experiences were mild fever (1 patient) and a new BM cytogenetic abnormality at week 40 (1 patient). This study shows that prolonged administration of G-CSF exerts a stimulatory effect on the BM of FA patients and may be used to maintain a clinically adequate ANC in these patients. G-CSF has beneficial effects on multiple hematopoietic lineages in some patients and may be a good candidate for use in combination cytokine protocols for FA patients with progressive aplastic anemia. G-CSF use results in an increase in circulating CD34+ cells, a finding with important implications for future gene transfer protocols.

Adolescent↗
PubMed1996

Fanconi's anemia and malignancies.

Patients with Fanconi's anemia (FA) are at a high risk for development of malignancies. It is well-known that leukemia occurs in approximately 10% of cases, with increasing risk with age. Less commonly recognized is the risk for myelodysplastic syndromes (approximately 5%); the relationship between myelodysplasia and evolution to leukemia remains speculative. What also needs to be emphasized is that older patients have an ever-increasing risk for development of solid tumors, with at least 5% reported to have liver tumors (male:female ratio, 2:1) and an equal number of other cancers (female:male ratio, 3:1, even after exclusion of gynecologic malignancies). Hematologists have tended to focus on aplastic anemia and leukemia. As FA patients live longer, more of the other malignancies will occur, perhaps related to cord blood or bone marrow transplant, or treatment with cytokines. This review identifies the types of tumors for which patients with Fanconi's anemia are at risk.

Fanconi Anemia↗