PubMed Health⌕ Search

Biomedical subjects

R E Ware

Publications and source records attributed to R E Ware.

At least 37 records · Page 2Linked to original sources
PubMed2000

Prevalence and clinical correlates of glomerulopathy in children with sickle cell disease.

OBJECTIVES: Glomerular disease and renal failure cause substantial morbidity for patients with sickle cell disease (SCD). Proteinuria is an early manifestation of sickle nephropathy, but the prevalence of proteinuria and its clinical correlations in children with SCD are unknown. STUDY DESIGN: Data were collected prospectively on children with SCD for 10 years including physical measurements, laboratory test results, and clinical complications. Persistent proteinuria was defined as > or =1+ protein on urinalysis for at least 6 months. The glomerular filtration rate was estimated with serum creatinine concentration and height. Proteinuria was correlated with other variables by chi(2) analysis. RESULTS: Proteinuria occurred in 20 of 442 pediatric patients including 15 (6.2%) with sickle cell anemia. Proteinuria increased with age, affecting 12% of older teenagers with sickle cell anemia. Proteinuria was significantly associated with lower hemoglobin concentration, higher mean corpuscular volume, and higher leukocyte count. For children of some ages, proteinuria was associated with complications including stroke, acute chest syndrome, cholelithiasis, and hospitalizations. Glomerular filtration rate hyperfiltration occurred early in life, followed by normalization. CONCLUSIONS: Sickle nephropathy, manifested as persistent proteinuria, begins early in life, occurs in all forms of SCD, and is associated with severity of disease. Early detection of proteinuria may allow therapy to prevent progressive renal insufficiency.

Adolescent↗
PubMed1999

Positron emission tomography (PET): experience with a large-field-of-view three-dimensional PET scanner.

Positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) is an accurate technique for staging and therapeutic monitoring in oncology. We evaluated our use of FDG PET in an oncology centre after our first 2500 studies, and summarise our experience of PET for the major referral indications. Optimised for clinical service, PET offers lower scanning costs and therefore improved cost-effectiveness.

Cost-Benefit Analysis↗
PubMed1999

Hydroxyurea as an alternative to blood transfusions for the prevention of recurrent stroke in children with sickle cell disease.

Children with sickle cell disease (SCD) and stroke receive chronic transfusions to prevent stroke recurrence. Transfusion risks including infection, erythrocyte allosensitization, and iron overload suggest a need for alternative therapies. We previously used hydroxyurea (HU) and phlebotomy in two young adults with SCD and stroke as an alternative to transfusions. We have now prospectively discontinued transfusions in 16 pediatric patients with SCD and stroke. Reasons to discontinue transfusions included erythrocyte alloantibodies or autoantibodies, recurrent stroke on transfusions, iron overload, noncompliance, and deferoxamine allergy. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d based on hematologic toxicity. Patients with iron overload underwent phlebotomy. The children have been off transfusions 22 months, (range, 3 to 52 months). Their average HU dose is 24.9 +/- 4.2 mg/kg/d, hemoglobin concentration is 9.4 +/- 1.3 g/dL, and mean corpuscular volume (MCV) is 112 +/- 9 fL. Maximum percentage fetal hemoglobin (%HbF) is 20.6% +/- 8.0% and percentage HbF-containing erythrocytes (%F cells) is 79.3% +/- 14.7%. Fourteen patients underwent phlebotomy with an average of 8,993 mL (267 mL/kg) removed. Serum ferritin has decreased from 2,630 to 424 ng/mL, and 4 children have normal ferritin values. Three patients (19%) had neurological events considered recurrent stroke, each 3 to 4 months after discontinuing transfusions, but before maximal HU effects. These preliminary data suggest some children with SCD and stroke may discontinue chronic transfusions and use HU therapy to prevent stroke recurrence. Phlebotomy is well-tolerated and significantly reduces iron overload. Modifications in HU therapy to raise HbF more rapidly might increase protection against stroke recurrence.

Administration, Oral↗
PubMed1999

Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group.

Previous studies have determined the short-term toxicity profile, laboratory changes, and clinical efficacy associated with hydroxyurea (HU) therapy in adults with sickle cell anemia. The safety and efficacy of this agent in pediatric patients with sickle cell anemia has not been determined. Children with sickle cell anemia, age 5 to 15 years, were eligible for this multicenter Phase I/II trial. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d unless the patient experienced laboratory toxicity. Patients were monitored by 2-week visits to assess compliance, toxicity, clinical adverse events, growth parameters, and laboratory efficacy associated with HU treatment. Eighty-four children were enrolled between December 1994 and March 1996. Sixty-eight children reached maximum tolerated dose (MTD) and 52 were treated at MTD for 1 year. Significant hematologic changes included increases in hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and fetal hemoglobin parameters, and decreases in white blood cell, neutrophil, platelet, and reticulocyte counts. Laboratory toxicities typically were mild, transient, and were reversible upon temporary discontinuation of HU. No life-threatening clinical adverse events occurred and no child experienced growth failure. This Phase I/II trial shows that HU therapy is safe for children with sickle cell anemia when treatment was directed by a pediatric hematologist. HU in children induces similar laboratory changes as in adults. Phase III trials to determine if HU can prevent chronic organ damage in children with sickle cell anemia are warranted.

Adolescent↗
PubMed1999

Detection of hemoglobin variants in erythrocytes by flow cytometry.

BACKGROUND: With the emergence of fetal hemoglobin (Hb F)stimulating agents as potential treatments for sickle-cell disease and thalassemias, procedures to monitor the effect of these agents on Hb F levels in individuals will be needed. We developed a rapid procedure that detects fetal hemoglobin in erythrocytes (F cells) using a fluorescein isothiocyanate (FITC) conjugated monoclonal antibody against Hb F. METHODS: Ten microliters of washed blood was fixed in formaldehyde and glutaraldehyde, then permeabilized in a Triton X-100/PBS solution containing a FITC-labeled monoclonal antibody to Hb F. The blood was analyzed by flow cytometry to determine the percentage of F cells. RESULTS: Nearly 200 Hb F-containing samples were analyzed by this protocol and demonstrated good correlation to percent Hb F results determined by high pressure liquid chromatography (HPLC). In addition, a number of samples were fixed and permeabilized using this method as well as a previously-described method that uses dimethyl 3,3'dithiobispropionimadate (DTBP) as a fixative as well as a different anti-Hb F monoclonal. Good correlation (r = 0.96, r2 = 0.93, P<0.001) was observed between the two protocols. CONCLUSIONS: This procedure is easy, reproducible, and gives accurate F cell results. It can be used to measure a wide range of F cell percentages and may also be used to dual-stain Hb F along with other hemoglobin variants and erythrocyte surface antigens.

Anemia, Sickle Cell↗
PubMed1999

Hemoglobin S/O(Arab): thirteen new cases and review of the literature.

Hemoglobin S/O(Arab) (Hb S/O(Arab)) is a rare compound heterozygous hemoglobinopathy characterized by the presence of two variant beta-globin chains: beta6Glu --> Val (Hb S) and beta121Glu --> Lys (Hb O(Arab)). The diagnosis of Hb S/O(Arab) requires electrophoresis on both cellulose acetate and citrate agar, since Hb O(Arab) co-migrates with Hb C at alkaline pH and close to Hb S at acidic pH. To date only case reports and small series of patients with Hb S/O(Arab) have been described. To better characterize the clinical and laboratory aspects of this unusual disorder, we reviewed the Duke University Medical Center experience. We identified 13 African-American children and adults with Hb S/O(Arab) ranging in age from 2.7 to 62.5 years. All patients had hemolytic anemia with a median Hb of 8.7 gm/dL (range 6.1-9.9 gm/dL), and a median reticulocyte count of 5.8% (range 1.2-10.3%). The peripheral blood smear typically showed sickled erythrocytes, target cells, polychromasia, and nucleated red blood cells. All 13 patients have had significant clinical sickling events including acute chest syndrome (11), recurrent vasoocclusive painful events (10), dactylitis (7), gallstones (5), nephropathy (4), aplastic crises (2), avascular necrosis (2), leg ulcers (2), cerebrovascular accident (CVA) (1), osteomyelitis (1), and retinopathy (1). Four patients have died, including two from pneumococcal sepsis/meningitis at ages 5 and 10 years, one of acute chest syndrome at age 14 years, and one of multiorgan failure at age 35 years. We conclude that Hb S/O(Arab) disease is a severe sickling hemoglobinopathy with laboratory and clinical manifestations similar to those of homozygous sickle cell anemia.

Adolescent↗
PubMed1999

Genetic instability and the etiology of somatic PIG-A mutations in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematologic disorder characterized by acquired PIG-A gene mutations that lead to defective bioassembly of glycosylphosphatidylinositol (GPI) anchors and the absence of GPI-linked surface proteins. As the etiology of these acquired PIG-A gene mutations is unknown, we hypothesized that patients with PNH have overall genetic instability and acquire somatic mutations throughout their genome. We first analyzed microsatellite sequences and found equivalent size variation using DNA from GPI-negative granulocytes compared with the DNA of paired GPI-positive B cell lines or normal granulocytes. We next quantitated the frequency of mutations at the hypoxanthine-guanine phosphoribosyl transferase (hprt) gene locus, and found 1 PNH patient with a large increase in hprt mutant frequency (256.7 x 10(-6) vs. 27.8 +/- 19.9 x 10(-6) for normal adults) that was confirmed on 4 independent blood samples. We also quantitated "illegitimate" VDJ genetic recombination events between the T cell receptor V gamma and J beta gene loci, and found a second PNH patient with a large increase (43.5 events per microgram of DNA vs. 1.3 +/- 0.8 events per microgram of DNA for normal adults), confirmed on 4 independent DNA samples. Both of these PNH patients are young females with no history of aplastic anemia. Our data show that PNH patients can have increased numbers of acquired somatic mutations in gene loci distinct from PIG-A. These data suggest that genetic instability may be associated with the development of PIG-A mutations that lead to the clinical picture of PNH.

Adolescent↗
PubMed1999

Erythrocyte autoantibodies in paediatric patients with sickle cell disease receiving transfusion therapy: frequency, characteristics and significance.

The formation of erythrocyte autoantibodies following transfusion therapy has been described in case reports and small series. To determine the frequency, serological characteristics, and clinical significance of this phenomenon in paediatric patients with sickle cell disease, we analysed the patient database at the Duke University Pediatric Hematology Clinic. We identified children who received multiple erythrocyte transfusions, then reviewed clinical records to identify children who developed erythrocyte autoantibodies in association with transfusions. Among 184 paediatric patients who received multiple erythrocyte transfusions, 14 children (7.6%) developed warm (IgG) erythrocyte autoantibodies. Median transfusion exposure at the time of autoantibody formation was 24 erythrocyte units, range 3-341 units. The autoantibody reacted as a panagglutinin in 11 cases but had anti-e specificity in three patients. Surface complement also was detected in five patients. Clinically significant haemolysis was documented in four patients, each of whom had both surface IgG and C3 detected. The development of erythrocyte autoantibodies was associated with the presence of erythrocyte alloantibodies. Formation of warm erythrocyte autoantibodies in association with transfusions is not rare in paediatric patients with sickle cell disease. Clinicians should be aware of this complication and recognize that the presence of surface C3 is often associated with significant haemolysis.

Adolescent↗
PubMed1999

MR features of soft-tissue abnormalities due to acute marrow infarction in five children with sickle cell disease.

OBJECTIVE: The purpose of this investigation was to illustrate a variety of soft-tissue abnormalities on MR imaging encountered in connection with acute marrow infarction in children with sickle cell disease. CONCLUSION: Extraosseous abnormalities on MR imaging preclude differentiation of acute marrow infarction from osteomyelitis in children with sickle cell disease.

Adolescent↗
PubMed1999

Autoimmune hemolytic and thrombocytopenic disease in the adolescent patient.

Adolescent patients with immune-mediated hematologic disorders present a challenging clinical picture. The combination of a careful history, physical examination, and appropriate laboratory tests will help establish the correct diagnosis. Thoughtful consideration of therapeutic options will result in the best treatment outcomes.

Adolescent↗
PubMed1998

Identification of mutations and polymorphisms in the factor XI genes of an African American family by dideoxyfingerprinting.

Congenital deficiency of factor XI is a rare condition associated with a mild to moderate bleeding diathesis that is most commonly found in persons of Jewish ancestry. The disorder has been reported sporadically in a number of other ethnic groups, but rarely in the black population. We report on the genetic analysis of the factor XI genes of two African American patients: a 9-year-old boy (the propositus) with mild factor XI deficiency and his mother. Both individuals have lifelong histories of excessive bleeding. Dideoxyfingerprinting, a technique combining components of single-strand conformational polymorphism analysis and dideoxy-chain termination sequencing, was used in the analysis. Both patients were found to be heterozygous for a mutation changing serine 248 to asparagine [corrected], whereas the propositus was heterozygous for an additional mutation on the paternal allele changing glutamine 226 to arginine. Both mutations reside in the third apple domain of the factor XI heavy chain, an area that has been shown to contain binding sites for factor IX, platelets, and glycosaminoglycans. Previously reported mutations in the factor XI gene seem to cause deficiency primarily by reducing protein expression. Because both alleles in the propositus contain amino acid substitutions, the significant amount of circulating factor XI in his plasma must be comprised entirely of abnormal molecules. Factor XI circulates as a homodimer, and the presence of mutations in both alleles of the factor XI gene suggests that his bleeding disorder is caused in part by the effect of the two abnormal gene products forming dimers in different combinations. Three neutral (not associated with amino acid changes) DNA polymorphisms were also identified in the two subjects: a C to T change at nucleotide 472 in exon 5, A to G at nucleotide 844 in exon 8, and T to C at nucleotide 1234 in exon 11. Analysis of a random sample of normal volunteers showed that these polymorphisms are relatively common, with allele frequencies of 7.4%, 19%, and 18%, respectively. This suggests that there is considerable genetic heterogeneity in the factor XI gene.

Adult↗
PubMed1998

The PIG-A mutation and absence of glycosylphosphatidylinositol-linked proteins do not confer resistance to apoptosis in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal stem cell disorder characterized by complement-mediated hemolysis and deficient hematopoiesis. The development of PNH involves an acquired mutation in the X-linked PIG-A gene, which leads to incomplete bioassembly of glycosylphosphatidylinositol (GPI) anchors and absent or reduced surface expression of GPI-linked proteins. The origin and mechanisms by which the PNH clone becomes dominant are not well understood, but recently resistance to apoptosis has been postulated. To test the hypothesis that the PIG-A mutation and absence of GPI-linked surface proteins directly confer resistance to apoptosis, we isolated peripheral granulocytes from 26 patients with PNH and 20 normal controls and measured apoptosis induced by serum starvation. Granulocytes from patients with PNH were relatively resistant to apoptosis (38.8% +/- 14.1%) as compared with granulocytes from controls (55.0% +/- 12.0%, P < .001). However, this resistance to apoptosis was not related to the dominance of the PNH clone because patients with a low percentage of GPI-deficient granulocytes had a similar rate of apoptosis as those with a high percentage of GPI-deficient granulocytes. Similarly, the resistance to granulocyte apoptosis was not influenced by the degree of neutropenia or a prior history of aplastic anemia. To investigate formally the importance of GPI-linked surface proteins in apoptosis, we introduced the PIG-A cDNA sequence into the JY5 GPI-negative B-lymphoblastoid cell line using two different methods: (1) stable transfection of a plasmid containing PIG-A, and (2) stable transduction of a retroviral vector containing PIG-A. We then measured rates of apoptosis induced either by Fas antibody, serum starvation, or gamma-irradiation. With each stimulus, apoptosis of JY5 with stable surface expression of GPI-linked proteins was not statistically different from the parent JY5 cell line or the JY25 (GPI-positive) cell line. Our data confirm that granulocytes from patients with PNH have a relative resistance to apoptosis as compared with normal granulocytes. However, this resistance does not vary with the level of expression of GPI-linked proteins, and stable introduction of PIG-A cDNA with correction of GPI-linked surface expression does not change the rate of apoptosis. Taken together, our data do not support the hypothesis that the PIG-A mutation and absence of GPI-linked surface proteins directly confer resistance to apoptosis in PNH. We conclude that the resistance to apoptosis in PNH is not related to the PIG-A mutation, indicating that other factors must be important in the origin of this phenomenon and the clonal dominance observed in PNH.

Adolescent↗
PubMed1998

Immunologic effects of anti-D (WinRho-SD) in children with immune thrombocytopenic purpura.

Intravenous immunoglobulin (IVIG) is an effective treatment for immune thrombocytopenic purpura (ITP) that induces transient blockade of the reticuloendothelial system (RES) with additional effects including alteration of T lymphocyte subsets and suppression of in vitro T lymphocyte proliferation. As anti-D also is an effective treatment for ITP, we investigated its in vitro and in vivo immunologic effects. The in vitro effects of various agents used in ITP therapy were compared using T lymphocyte proliferation assays. Anti-D caused significantly less inhibition than IVIG or dexamethasone, but non-specific protein was as suppressive as IVIG. Six children with chronic ITP were studied following anti-D administration. Patients received a single dose of anti-D (WinRho-SD, 50 microg/kg i.v. over 5 min) and were studied on day 0, day 7, and 1 month later. Anti-D did not affect T lymphocyte subsets including the T cell receptor variable beta repertoire, in vitro T lymphocyte proliferation to mitogens, recall antigens, or interleukin-2, in vitro IgG synthesis induced by pokeweed mitogen, or T lymphocyte cytokine mRNA levels. We conclude that anti-D has no demonstrable in vitro or in vivo effects on lymphocyte enumeration or function, and therefore likely is effective in the treatment of ITP primarily through RES blockade.

Child↗
PubMed1998

Inherited DNA mutations contributing to thrombotic complications in patients with sickle cell disease.

Thrombosis may play an important role in the pathophysiology of certain complications of sickle cell disease (SCD), including stroke and avascular necrosis (AVN). Currently there is no laboratory or clinical parameter that can identify patients who are at highest risk of developing these thrombotic complications. We hypothesized that some patients with SCD have an inherited hypercoagulable state that results in an increased risk of developing stroke or AVN. We examined the role of two common inherited thrombophilic mutations that, in other populations, have been associated with arterial and venous thrombosis and are amenable to screening with DNA restriction enzyme analysis. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the C1565T mutation in the platelet glycoprotein IIIa (GPIIIa) gene were evaluated. We analyzed genomic DNA from 86 children and adults with SCD, including 16 patients with a history of a clinical stroke and 14 patients with AVN, for the presence of these mutations. The C677T MTHFR mutation was found in 19% of patients with stroke, 14% of patients with AVN, and 14% of patients with neither complication (P = NS). The C1565T GPIIIa mutation was found in 25% of patients with stroke, 14% of patients with AVN, and 18% of patients with neither complication (P = NS). Although each of these mutations is relatively common in patients with SCD, neither is independently associated with an increased risk of developing stroke or AVN.

Adolescent↗
PubMed1998

Successful surgical outcome in children with sickle hemoglobinopathies: the Duke University experience.

BACKGROUND/PURPOSE: Surgery in patients with sickle hemoglobinopathies can be problematic because of the potential for sickling events in the perioperative and postoperative period. The authors and others have previously reported successful surgical outcomes using an aggressive erythrocyte transfusion regimen, designed to alleviate anemia and to reduce the percentage of sickle hemoglobin to below 30%. Recently, a randomized trial compared this aggressive regimen with a more conservative transfusion regimen and found no differences in perioperative complications. The incidence of complications, however, was very high in each group (31% to 35%). METHODS: The authors therefore analyzed retrospectively their surgical experience in children with sickle hemoglobinopathies over the past 10 years to determine the efficacy of an aggressive transfusion regimen and skilled perioperative care in their patient population. RESULTS: A total of 130 surgical procedures were performed on 92 children including 54 cholecystectomies (42%), 23 splenectomies (18%), 12 ENT procedures (9%), 11 central line placements and removals (8%), 7 herniorrhaphies (5%), 7 appendectomies (5%), and 16 miscellaneous operations (13%). The mean age of the children was 10 years (range, 1 to 22 years), and the mean weight was 32.1 kg (range, 9.9 to 76.8 kg). The average hemoglobin (mean +/- 1 SD) at the time of surgery was 11.2+/-1.3 g/dL, and the average percent hemoglobin S was 21+/-11%. CONCLUSIONS: Relatively few transfusions were required to achieve these endpoints, and the complications resulting from transfusions were minimal. Similarly, the number of perioperative and postoperative events was very low.

Adolescent↗
PubMed1998

Anti-D: mechanisms of action.

Immunoglobulin that recognizes and binds specifically to the erythrocyte D antigen (anti-D globulin, WinRho SDF; Nabi, Boca Raton, FL) has recently been shown to be an effective therapy for many patients with idiopathic thrombocytopenic purpura (ITP). Its mechanisms of action are not completely understood. Intravenous (IV) infusion of anti-D into a D-positive recipient leads to antibody coating of circulating erythrocytes that are cleared primarily by the spleen. This immune-mediated clearance of sensitized erythrocytes occupies the reticuloendothelial system and allows survival of antibody-coated platelets. Based on clinical observations, experimental data, and theoretical calculations, the efficacy of anti-D therapy in ITP depends on several factors that influence the amount of erythrocyte sensitization and the rate of immune-mediated erythrocyte clearance by the spleen. Antibody characteristics, including the antibody concentration, binding affinity, and dissociation constants, may be important, as well as the number of D-antigen binding sites on the erythrocytes. Although the primary mechanism of action of anti-D is believed to be immunologic blockade of Fc receptors (FcR) within the reticuloendothelial system (RES), other immunomodulatory effects are also possible.

Hemolysis↗