The outlook for patients with sickle cell disease has improved steadily during the last two decades. In spite of these improvements, curative therapies are currently available only to a small minority of patients. The main theme of this chapter is to describe new therapeutic options that are at different stages of development that might result in further improvements in the outlook for patients with these disorders. Dr. Joseph DeSimone and his colleagues had previously made the important observation that the hypomethylating agent 5-azacytidine can reverse the switch from adult to fetal hemoglobin in adult baboons. Although similar activity was demonstrated in patients with sickle cell disease and beta-thalassemia, concern about the toxicity of 5-azacytidine prevented its widespread use in these disorders. In Section I, Dr. DeSimone discusses the role of DNA methylation in globin gene regulation and describe recent clinical experience with decitabine (an analogue of 5-azacytidine) in patients with sickle cell disease. These encouraging studies demonstrate significant fetal hemoglobin inducing activity of decitabine in patients who fail to respond to hydroxyurea. In Section II, Dr. George Atweh continues the same theme by describing recent progress in the study of butyrate, another inducer of fetal hemoglobin, in patients with sickle cell disease and beta-thalassemia. The main focus of his section is on the use of a combination of butyrate and hydroxyurea to achieve higher levels of fetal hemoglobin that might be necessary for complete amelioration of the clinical manifestations of these disorders. Dr. Atweh also describes novel laboratory studies that shed new light on the mechanisms of fetal hemoglobin induction by butyrate. In Section III, Dr. Ronald Nagel discusses the different available transgenic sickle mice as experimental models for human sickle cell disease. These experimental models have already had a significant impact on our understanding of the pathophysiology of sickle cell disease. Dr. Nagel describes more recent studies in which transgenic sickle mice provide the first proof of principle that globin gene transfer into hematopoietic stem cells inhibits in vivo sickling and ameliorates the severity of the disease. Although stroke in adult patients with sickle cell disease is not as common as in children, adult hematologists, like their pediatric colleagues, need to make management decisions in adult patients with a stroke or a history of stroke. Dr. Robert Adams has led several large clinical studies that investigated the role of transfusions in the prevention of stroke in children with sickle cell disease. Much less is known, however, about the prevention of first or subsequent strokes in adult patients with sickle cell disease. In Section IV, Dr. Adams provides some general guidelines for the management of adult patients with stroke while carefully distinguishing between recommendations that are evidence-based and those that are anecdotal in nature. (+info)
Spontaneous mutation of the hemoglobin Leiden (beta 6 or 7 Glu-->0) in a Thai girl.
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We report a case of 12-year old Thai girl suffering from mild non-transfusion-dependent thalassemia intermedia. She is the single child in her family. On examination she looked pale; there was no hepatosplenomegaly. The Hb concentration was 9 g/dL. Hb typing and molecular mutation study revealed compound heterozygosity for HbE and Hb Leiden (alpha2beta26/7-Glu, codon 6/7-GAG). The proportion of HbE was 47% whereas that of Hb Leiden was 39%. The patient had no HbA. Hb typing of her father and mother revealed HbE trait, and no Hb Leiden was demonstrated. As the paternity test confirmed the parenthood, we assume that Hb Leiden has arisen by spontaneous mutation. A study of the beta< or= -globin gene framework by molecular cloning and subsequent DNA sequencing of the beta-globin gene in the members of the family indicated that the Hb Leiden mutation occurred on a maternal inherited chromosome. The deletion of codon 6 or 7 (-GAG) of the beta-globin gene in the patient may be due to an unequal crossing over during the mother's oogenesis. (+info)
Hemoglobinopathy and pattern of musculoskeletal infection in children.
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BACKGROUND: The bacterial pathogens associated with osteomyelitis in patients with hemoglobinopathy (HbSS) are controversial. There is insufficient data on the common musculoskeletal (MSS) infections in patients with hemoglobinopathies and the associated bacterial pathogens in Nigeria. OBJECTIVES: To identify the common MSS infections in children and the associated bacterial pathogens, especially in those with abnormal hemoglobin genotypes. METHODS: A retrospective case review was done of pediatric and adolescent patients admitted with bone and soft tissue infections over a seven-year period in a Nigerian teaching hospital. RESULTS: One-hundred-nineteen patients were studied, with mean age 7.9+/-5.6 years and male-female ratio of 1.3:1. Out of 78 patients with known genotype, 62.8% had HbAA, 20.5% HbSS, 9% HbAS, and 7.7% HbAC. The most common MSS infections were osteomyelitis (64.7%), pyomyositis (17.6%), and septic arthritis (10.1%). Others were cellulitis (5.9%), tuberculous arthritis (0.8%), and necrotizing fasciitis (0.8%). Staphylococcus aureus (S. aureus) was isolated from 62% of chronic osteomyelitis (COM) and 58% of pyomyositis, while gram-negative bacilli accounted for 34% and 42%, respectively. S. aureus was isolated from 63% of patients with HbAA, 40% with HbSS, 58% with HbAS, and 58% with HbAC, while gram-negative bacilli accounted for 33%, 60%, 33%, and 33%, respectively. Osteomyelitis and pyomyositis appear to be similarly common in patients with and without HbSS (RR 1.29; 95% CI 0.47-3.50). Osteomyelitis and soft tissue infections in general also appear to be equally common in them (RR 1.16; 95% CI 0.39-4.11). However, osteomyelitis appears to be more common among patients with HbSS than those with HbAA (RR 2.29; 95% CI 0.58-8.99) and those with other hemoglobinopathies (RR 2.23; 95% CI 0.66-7.49) CONCLUSIONS: Osteomyelitis, pyomyositis and septic arthritis are common MSS infections in hospitalized pediatric and adolescent patients, while tuberculous arthritis is uncommon. The most common bacterial pathogen in these infections is S. aureus-even in patients with HbSS and other hemoglobinopathies. Gram-negative bacilli are important causes of MSS infections in hospitalized children with HbSS. HbSS may be an independent risk factor for osteomyelitis in these patients. (+info)
C677T polymorphism of the MTHFR gene and variant hemoglobins: a study in newborns from Salvador, Bahia, Brazil.
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The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR) is associated with an increase in total homocysteine serum levels (tHcy), described as a risk factor for cardiovascular disease. Eight hundred forty-three neonates from two different maternity hospitals, one public and another private, in Salvador, Bahia, Brazil were screened for this polymorphism by PCR and RFLP. The T-allele frequency in the total sample was 0.23, and the prevalence rates of heterozygous and homozygous carriers were 36.2% and 5.3%, respectively. The T-allele frequency differed and the T/T genotype was more prevalent at the private maternity hospital. The hemoglobin (Hb) profile was investigated by HPLC in 763 newborns. The frequency of variant Hb was higher at the public than at the private maternity hospital. The association of the C677T polymorphism and the Hb profile was investigated in 683 newborns, showing a relatively high frequency of variant Hbs and the T allele. These data could provide an important basis for further studies focusing on potential risks of vaso-occlusive events in these individuals. (+info)
Hemolytic anemia.
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Hemolysis presents as acute or chronic anemia, reticulocytosis, or jaundice. The diagnosis is established by reticulocytosis, increased unconjugated bilirubin and lactate dehydrogenase, decreased haptoglobin, and peripheral blood smear findings. Premature destruction of erythrocytes occurs intravascularly or extravascularly. The etiologies of hemolysis often are categorized as acquired or hereditary. Common acquired causes of hemolytic anemia are autoimmunity, microangiopathy, and infection. Immune-mediated hemolysis, caused by antierythrocyte antibodies, can be secondary to malignancies, autoimmune disorders, drugs, and transfusion reactions. Microangiopathic hemolytic anemia occurs when the red cell membrane is damaged in circulation, leading to intravascular hemolysis and the appearance of schistocytes. Infectious agents such as malaria and babesiosis invade red blood cells. Disorders of red blood cell enzymes, membranes, and hemoglobin cause hereditary hemolytic anemias. Glucose-6-phosphate dehydrogenase deficiency leads to hemolysis in the presence of oxidative stress. Hereditary spherocytosis is characterized by spherocytes, a family history, and a negative direct antiglobulin test. Sickle cell anemia and thalassemia are hemoglobinopathies characterized by chronic hemolysis. (+info)
Molecular basis and hematologic characterization of deltabeta-thalassemia and hereditary persistence of fetal hemoglobin in Thailand.
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BACKGROUND AND OBJECTIVES: Hereditary persistence of fetal hemoglobin (HPFH) and deltabeta-thalassemia are heterogeneous disorders characterized by increased levels of Hb F in adult life. The distinction between these two conditions is not always possible from routine hematologic analyses. This study investigated the hematologic and molecular characteristics of high HbF determinants in Thailand, and describes a rapid DNA-based assay to facilitate diagnosis in a routine laboratory. DESIGN AND METHODS: A multiplex allele-specific polymerase chain reaction (PCR) system for rapid detection of three common DNA deletions causing (deltabeta)0-thalassemia and HPFH in South-east Asians was developed and used to examine the molecular basis for the high Hb F phenotypes in 273 unrelated Thai individuals. Hematologic data were recorded and correlated to the molecular findings. RESULTS: The multiplex PCR system was validated and results were completely concordant with those of other established methods. DNA analysis identified GgAg(deltabeta)0-thalassemia in 148 cases (54.2%), deletional HPFH-6 in 83 (30.4 %) and the deletion-inversion Ggamma(Agammadeltabeta)0-thalassemia in 22 (8.1 %) cases, while another 20 (7.3 %) subjects remained uncharacterized. Genotype-phenotype relationships are discussed. INTERPRETATION AND CONCLUSIONS: These data emphasize the high frequencies of deltabeta-thalassemia and HPFH in Thailand and the need for differential diagnostic methods since the hematologic parameters associated with the conditions are very similar and overlap. The multiplex allele-specific PCR approach should prove useful in complementing routine Hb analysis for the differential diagnosis of these three common causes of high Hb F determinants and should facilitate a program of hemoglobinopathy screening in the region. (+info)
Screening cord blood for hemoglobinopathies and thalassemia by HPLC.
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We evaluated the use of an HPLC method for screening hemoglobins in cord blood. We studied the genotype frequencies of the structural hemoglobin variants HbS and HbC and the synthesis variants alpha- and beta(+)-thalassemia in babies born on Curacao. During three months, 67.2% of all (748) newborns were screened: 122 (24.3%) had an abnormal hemoglobin pattern, of which 53 (43.4%) had a hemoglobinopathy (HbS or HbC), 64 (52.2%) had alpha-thalassemia (HbBarts greater than 0.5%, corresponding to heterozygous or homozygous alpha-thalassemia-2), and 5 (4.1%) had a hemoglobinopathy plus alpha-thalassemia. None of the newborns with heterozygous HbS and HbC had concomitant beta(+)-thalassemia. The population genotype frequency of heterozygous alpha-thalassemia-2 was calculated to be 30.7%. The data are in excellent agreement with those previously established for the adult population and those available from the black population in the United States and Jamaica. Based on the HPLC results, we estimate that 67.1% of newborns with heterozygous alpha-thalassemia-2 remain undetected. A coincidental finding was a relation between demonstrable alpha-thalassemia and short gestation. Because of its superior separating power and high sensitivity for quantifying relatively low percentages of hemoglobins in the presence of HbF0, the HPLC method was preeminently suitable for screening cord-blood samples. (+info)
Assessing the need to update prevention guidelines: a comparison of two methods.
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BACKGROUND: An important concern for developers of clinical practice guidelines is how best to determine when guidelines require updating to ensure they remain current and evidence based. Because of the high costs associated with updating guidelines, recent attention has focused on approaches that can reliably assess the extent of updating required. Recently, Shekelle and colleagues proposed a model of limited literature searches with modest expert involvement as a way to reduce the cost and time requirements for assessing whether a guideline needs updating. METHODS: The main objective of this study was to compare the Shekelle et al. assessment model (review approach) and a conventional process using typical systematic review methods (traditional approach) in terms of comprehensiveness and effort. We modeled the review approach on that by Shekelle and colleagues but refined it iteratively over three phases to achieve greater efficiency. Using both methods independently, we assessed the need to update six topics from the 1996 Guide to Clinical Preventive Services from the US Preventive Services Task Force. Main outcomes included completeness of study identification, importance of missed studies and the effort involved. RESULTS: Although the review approach identified fewer eligible studies than the traditional approach, none of the studies missed was rated as important by task force members acting as liaisons to the project with respect to whether the topic required an update. On average, the review approach produced substantially fewer citations to review than the traditional approach. The effort involved and potential time saving depended largely on the scope of the topic. CONCLUSIONS: The revised review approach provides an efficient and acceptable method for judging whether a guideline requires updating. (+info)