Search PubMed⌕ Search

Biomedical subjects

M H Steinberg

Publications and source records attributed to M H Steinberg.

At least 19 recordsLinked to original sources
PubMed2001

Pathophysiology of sickle cell disease: role of cellular and genetic modifiers.

Sickle hemoglobin (HbS), caused by a point mutation in the beta-globin gene of hemoglobin, polymerizes when deoxygenated. The pathophysiology of sickle cell disease results from cellular defects caused directly by the hemoglobin mutation interacting with the environment and many other gene products--a few known, but most yet unidentified--a typical example of epistasis. How normal tissue perfusion is interrupted is complex and why the phenotype of sickle cell disease differs from patient to patient is poorly understood. We review the "classic" aspects of the pathophysiology of sickle cell disease and focus on known and potential modulators of the phenotype of this disorder.

Anemia, Sickle Cell↗
PubMed2001

Modulation of fetal hemoglobin in sickle cell anemia.

A partial understanding of the pathophysiology of sickle cell disease has suggested one means of treatment-increasing the distribution and concentration of fetal hemoglobin in sickle erythrocytes. Although this can be accomplished clinically with drugs like hydroxyurea, a complete understanding of the molecular and cellular basis of fetal hemoglobin regulation may suggest new and better ways of attaining this goal.

Anemia, Sickle Cell↗
PubMed2000

Maximum urine concentrating ability in children with Hb SC disease: effects of hydroxyurea.

Studies in adults with Hb SC disease suggested that hydroxyurea reduced hemolysis and increased red cell hydration. Because increased hydration should diminish the polymerization tendency of Hb S we hypothesized that hydroxyurea might repair the urine concentration defect of HbSC disease. Eight Hb SC disease patients, aged 10 to 17 years, were given hydroxyurea daily. Maximal urine concentrating ability following overnight fasting and after subcutaneous arginine vasopressin (dDAVP), blood counts, and cell volumes were observed for 12-15 months. All patients had impaired urine concentrating ability prior to hydroxyurea treatment and failed to increase their ability to concentrate urine following treatment (maximum urine concentration after an overnight fast and dDAVP, 520-530 mOsm). Mean corpuscular volume (MCV) and reticulocyte MCV increased after administration of hydroxyurea, and the reticulocyte count and ratio of red cell hemoglobin to reticulocyte hemoglobin fell but there was little change in PCV. Hb F increased substantially in 2 patients but showed little change in the remaining patients. There was no evidence that hydroxyurea was associated with increased urine concentrating ability in children with Hb SC disease. These results may reflect irreversible renal medullary damage prior to beginning treatment or insufficient intensity or duration of treatment.

Adolescent↗
PubMed1999

Sickle cell anemia as a possible state of enhanced anti-apoptotic tone: survival effect of vascular endothelial growth factor on circulating and unanchored endothelial cells.

The biologic processes of apoptosis and angiogenesis are linked in endothelial biology because some endothelial cell growth factors also exert anti-apoptotic effects. We studied whether apoptosis is occurring in circulating endothelial cells (CEC) that have lost the survival signals derived from anchorage to extracellular matrix. Consistent with this expectation, 64% +/- 16% of CEC from normal donors showed evidence of apoptosis (by morphology and TdT-mediated dUTP nick end labeling [TUNEL] assay). However, only 30% +/- 15% (P <.001 v normal) of CEC from donors with sickle cell anemia were apoptotic. Vascular endothelial growth factor (VEGF) levels were significantly (P =.001) higher in plasma of sickle donors (120.1 +/- 81.4 pg/mL) than that of normal donors (37.6 +/- 34.6 pg/mL), and there was an inverse correlation between VEGF and CEC apoptosis (r =. 612, P =.001). Consistent with stimulation by VEGF, CEC from sickle donors exhibited increased expression of alphavbeta3. In vitro experiments showed that VEGF inhibits apoptosis for cultured endothelial cells that are kept unanchored and not allowed to re-establish attachment to extracellular matrix, thus demonstrating that VEGF provides survival signals independent of its ability to promote matrix reattachment. These data suggest the hypothesis that sickle cell anemia is a state of enhanced anti-apoptotic tone for endothelial cells. If true, this has implications for disease pathobiology, particularly the development of neovascularizing retinopathy.

Adult↗
PubMed1999

Low-density lipoprotein susceptibility to oxidation and cytotoxicity to endothelium in sickle cell anemia.

Patients with sickle-cell anemia exhibit pro-oxidative metabolic perturbations. We hypothesize that because of chronic oxidative stress, plasma low-density lipoprotein (LDL) from patients with sickle-cell anemia is more susceptible to oxidation. To test this hypothesis, LDL susceptibility to copper-mediated oxidation was measured in 24 patients with sickle-cell anemia and 48 control subjects. Sickle-cell LDL was more susceptible to oxidation than control LDL, measured by a 22% shorter mean lag time between LDL exposure to CuSO4 and conjugated diene formation (97 vs 124 minutes; P = .023). LDL vitamin E, iron, heme, and cholesterol ester hydroperoxide (CEOOH) levels were also measured. LDL vitamin E levels were significantly lower in patients with sickle-cell anemia compared with control subjects (1.8 vs 2.9 mol/mol LDL; P = .025), but there was no correlation with lag time. Pro-oxidant heme and iron levels were the same in sickle-cell and control LDL. LDL CEOOHs were not significantly different in sickle and control LDL (3.1 vs 1.2 mmol/mol of LDL unesterified cholesterol, P = .15), but LDL CEOOH levels were inversely correlated with lag times in patients with sickle-cell anemia (r2 = 0.38; P = .018). The cytotoxicity of partially oxidized LDL to porcine aortic endothelial cells was inversely correlated with lag times (r2 = 0.48; P = .001). These preliminary data suggest that increased LDL susceptibility to oxidation could be a marker of oxidant stress and vasculopathy in patients with sickle-cell anemia.

Adolescent↗
PubMed1999

Double heterozygosity for the codon beta 39 C-to-T nonsense mutation and a triplicate alpha-globin gene locus can cause "dominantly" inherited beta-thalassemia intermedia.

BACKGROUND: A beta-thalassemia intermedia phenotype can be caused by multiple genotypes. METHODS: We studied a family where the mother was hematologically normal and both father and daughter had beta-thalassemia intermedia. RESULTS: Both affected individuals were heterozygous for a codon 39 CAG-to-TAG mutation. They also were heterozygous for a triplicate alpha-globin gene locus (alphaalphaalpha(anti 3.7)). CONCLUSIONS: This compound heterozygous condition of a beta39 C-to-T mutation and triplicate alpha-globin gene increases alpha:beta-globin chain imbalance and accounts for the presence of beta-thalassemia intermedia. The proband received both an abnormal beta-globin gene and a triplicate alpha-globin locus from her father. Although the phenotype seems to be dominantly inherited, because of independent segregation of the alpha- and beta-globin genes, it is more accurately an example of polygenic inheritance.

Codon↗
PubMed1999

Genetic studies suggest a multicentric origin for Hb G-Coushatta [beta22(B4)Glu-->Ala].

Hb G-Coushatta [beta22(B4)Glu-->Ala] is found in geographically separated ethnic groups. Commonest along the Silk Road region of China but also present in the North American Coushatta, we sought to determine whether this variant had a unicentric or multicentric origin. We examined the haplotype of the beta-globin gene cluster in two Chinese families and in five Louisiana Coushatta heterozygous for this mutation. Chinese and Louisiana Coushatta had different haplotypes associated with the identical Hb G mutation. These haplotypes were defined by the presence of a HindIII restriction site in the Agamma-globin gene and AvaII restriction site in the beta-globin gene in Chinese subjects and their absence in the Louisiana Coushatta. We found a CAC at codon beta2 (beta-globin gene framework 1 or 2) linked to the Hb G-Coushatta gene in Chinese, and a CAT (framework 3) in Louisiana Coushatta, indicating different beta-globin gene frameworks. Both the Hb G-Coushatta mutation (GAA-->GCA) and the codon 2 CAC-->CAT polymorphism are normal delta-globin gene sequences, suggesting the possibility of gene conversion. We conclude that Hb G-Coushatta had at least two independent origins. This could be due to separate mutations at codon beta22 in Chinese and Louisiana Coushatta, a mutation at this codon and a beta-->delta conversion, or two beta-->delta gene conversion events.

China↗
PubMed1998

Hematological effects of atypical and Cameroon beta-globin gene haplotypes in adult sickle cell anemia.

To examine the effects of unusual or atypical beta-globin gene cluster haplotypes on the hematological features and Hb F levels of sickle cell anemia, we studied African Americans who had an atypical or Cameroon haplotype chromosome in association with a typical haplotype. We identified over 20 atypical haplotypes. The distribution of 5' sub-haplotypes of the atypical chromosomes mirrored the distribution of common haplotypes in African Americans with sickle cell anemia. Neither 5' nor 3' subhaplotypes of the atypical chromosomes affected Hb F levels, packed cell volume, or mean corpuscular volume in individuals with a Benin chromosome. That the 5' subhaplotype is unaffected might be a consequence of the small numbers of Senegal 5' subhaplotypes in our sample, the need for linkage of both 5' and 3' subhaplotypes of any haplotype for an effect on Hb F to be present, or the likelihood that a normal beta-globin gene contributed the 5' subhaplotypes of some atypical haplotypes.

Adult↗
PubMed1998

Pathophysiology of sickle cell disease.

Sickle cell disease is caused by a mutation in the beta-globin chain of the haemoglobin molecule. Sickle haemoglobin, the result of this mutation, has the singular property of polymerizing when deoxygenated. Exactly how normal tissue perfusion is interrupted by abnormal sickle cells is complex and poorly understood. Despite genetic identity at the site of the sickle haemoglobin mutation, all patients with sickle cell anaemia are not affected equally by this disease. Secondary genetic determinants and acquired erythrocyte and vascular damage are likely to be central components of the pathophysiology of sickle cell anaemia.

Anemia, Sickle Cell↗
PubMed1997

Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea.

Hydroxyurea (HU) can increase fetal hemoglobin (HbF) in sickle cell anemia (HbSS). To identify determinants of the HbF response, we studied 150 HU-treated patients grouped by quartiles of change in HbF from baseline to 2 years. Half of the HU-assigned patients had long-term increments in HbF. In the top two quartiles, HbF increased to 18.1% and 8.8%. These patients had the highest baseline neutrophil and reticulocyte counts, and largest treatment-associated decrements in these counts. In the lower two quartiles, 2-year HbF levels (4.2% and 3.9%) and blood counts changed little from baseline. In the highest HbF response quartile, myelosuppression developed in less than 6 months, compliance was best, and final doses of HU were 15 to 22.5 mg/kg. All four quartiles had substantial increases of F cells in the first year. This was maintained for 2 years only in the top three quartiles. Leukocyte and reticulocyte counts decreased initially in all quartiles, but drifted back toward baseline levels in the lowest HbF response quartile. Initial HbF level and phenotype of the F-cell production (FCP) locus were not associated with HbF response, but absence of a Central African Republic (CAR) haplotype was. Bone marrow ability to withstand HU treatment may be important for sustained HbF increases during HU treatment of HbSS.

Adult↗
PubMed1997

Fetal hemoglobin in sickle cell anemia: examination of phylogenetically conserved sequences within the locus control region but outside the cores of hypersensitive sites 2 and 3.

Regulatory elements linked to the beta-globin gene cluster modulates gamma-globin gene expression. The location of all of these elements and their mechanisms of action are still incompletely defined. Phylogenetically conserved DNA within the beta-globin gene cluster locus control region (LCR), but outside the core sequences of its hypersensitive sites (HS), were identified and we searched for any differences between HS 3 and HS 2, and HS 2 and HS 1, among patients with sickle cell anemia with different levels of Hb F who were homozygous for the common haplotypes. DNA was amplified with and without GC clamps, digested with restriction endonucleases, and examined by denaturing gradient gel electrophoresis (DGGE). We found limited fragment size diversity. However, the type of differences found and their distribution among haplotypes did not suggest that they represented distinctive changes that might explain the differential expression of the gamma-globin genes in sickle cell anemia.

Anemia, Sickle Cell↗
PubMed1997

Cellular effects of hydroxyurea in Hb SC disease.

Hb S polymerizes in high-density Hb SC disease erythrocytes. We hypothesized that hydroxyurea -- perhaps independent of increasing Hb F -- might reduce the density of these cells. Six Hb SC disease patients were given 1000mg of hydroxyurea daily and blood counts, cell volumes, and cell density were followed for 12 months. There was an increase in MCV and reticulocyte MCV. A fall in absolute reticulocyte counts, high-staining ('stress') reticulocytes, serum bilirubin, and an increase in the ratio of mature red cell haemoglobin to reticulocyte haemoglobin, coupled with a rise in the haematocrit inferred a decrease in haemolysis and 'stress erythropoiesis'. An improvement in cell hydration was suggested by a reduction in reticulocyte mean cell haemoglobin concentration (CHCMr), red cells and reticulocytes with CHCM > 38, and decreased dense cell counts estimated by phthalate ester and Percoll-Larex gradients. After 4-5 months treatment, Hb F rose in a few patients but the overall difference in pre- and post-treatment Hb F was not significant. A decline in cell density should diminish the polymerization tendency of Hb S in Hb SC disease.

Anemia, Sickle Cell↗