The clinical spectrum of HbSC sickle cell disease-not a benign condition.

Sickle cell disease (SCD) includes a group of heterogenous disorders that result in significant morbidities. HbSS is the most common type of SCD and HbSC is the second most common type of SCD. The prevalence of HbSC disease in the United States and United Kingdom is ~1 in 7174 births and 1 in 6174 births respectively. Despite its frequency, however, HbSC disease has been insufficiently studied and was historically categorized as a more 'mild' form of SCD. We conducted this study of HbSC disease as part of the NHLBI funded Sickle Cell Disease Implementation Consortium (SCDIC). The SCDIC registry included 2282 individuals with SCD, ages 15-45 years of whom 502 (22%) had HbSC disease. Compared with people with sickle cell anaemia (SCA), the study found that people with HbSC disease had a higher frequency of splenomegaly (n (%) = 169 (33.7) vs. 392 (22.1)) and retinopathy (n (%) = 116 (23.1) vs. 189 (10.6)). A Many people with HbSC also had avascular necrosis (n (%) = 112 (22.3)), pulmonary embolism (n (%) = 43 (8.6)) and acute chest syndrome (n (%) = 228 (45.4)) demonstrating significant disease severity. HbSC disease is more clinically severe than was previously recognized and deserves additional evaluation and targeted treatments.

Evaluating the implementation of a multi-level mHealth study to improve hydroxyurea utilization in sickle cell disease.

Background: Sickle Cell Disease (SCD) is a progressive genetic disease that causes organ damage and reduces longevity. Hydroxyurea is an underutilized evidence-based medication that reduces complications and improves survival in SCD. In a multi-site clinical trial, part of the NIH-funded Sickle Cell Disease Implementation Consortium (SCDIC), we evaluate the implementation of a multi-level and multi-component mobile health (mHealth) patient and provider intervention to target the determinants and context of low hydroxyurea use. Given the complexity of the intervention and contextual variability in its implementation, we combined different behavioral and implementation theories, models, and frameworks to facilitate the evaluation of the intervention implementation. In this report, we describe engagement with stakeholders, planning of the implementation process, and final analytical plan to evaluate the implementation outcomes. Methods: During 19 meetings, a 16-member multidisciplinary SCDIC implementation team created, conceived, and implemented a project that utilized Intervention Mapping to guide designing an intervention and its evaluation plan. The process included five steps: (1) needs assessment of low hydroxyurea utilization, (2) conceptual framework development, (3) intervention design process, (4) selection of models and frameworks, and (5) designing evaluation of the intervention implementation. Results: Behavioral theories guided the needs assessment and the design of the multi-level mHealth intervention. In designing the evaluation approach, we combined two implementation frameworks to best account for the contextual complexity at the organizational, provider, and patient levels: (1) the Consolidated Framework for Implementation Research (CFIR) that details barriers and facilitators to implementing the mHealth intervention at multiple levels (users, organization, intervention characteristics, broader community), and (2) the Technology Acceptance Model (TAM), a conceptual model specific for explaining the intent to use new information technology (including mHealth). The Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM) framework was used to measure the outcomes. Discussion: Our research project can serve as a case study of a potential approach to combining different models/frameworks to help organize and plan the evaluation of interventions to increase medication adherence. The description of our process may serve as a blueprint for future studies developing and testing new strategies to foster evidence-based treatments for individuals living with SCD.

A new sickling variant 'Hb S-Wake ß[(Glu6Val-Asn139 Ser)]' found in a compound heterozygote with Hb S ß(Glu6Val) coinherited with homozygous α-thalassemia-2: phenotype and molecular characteristics.

We report the case of a 14-year-old African-American boy who was diagnosed with sickle cell disease. Laboratory tests showed that the patient was a compound heterozygote for a novel Hb variant with a double mutation detected on ß(S) allele, Hb S ßGlu6Val, and ßAsn139Ser substitution, i.e. a ß-chain variant named 'Hb S-Wake'. The patient also carried a single Hb S mutation in trans allele, leading to Hb SS-Wake disease. He had coinherited homozygous α(+)-thalassemia (-α(3.7)/-α(3.7)) simultaneously which resulted in multiple globin gene abnormalities.

Hb M Dothan [beta 25/26 (B7/B8)/(GGT/GAG-->GAG//Gly/Glu-->Glu]; a new mechanism of unstable methemoglobin variant and molecular characteristics.

A new unstable beta globin chain variant associated with methemoglobin (Met-Hb) phenotype was found in a Caucasian infant. Molecular analysis of the beta globin gene using polymerase chain reaction (PCR) amplification and sequencing led to the detection of a new in frame deletion in exon-1. Direct sequencing of the PCR product revealed a 3 bp deletion (-GTG) between codons 25/26, which resulted in the loss of a single amino acid (-Gly). We propose that this newly discovered unstable M-hemoglobin (M-Hb) variant, named Hb Dothan [GGT/GAG-->GAG//Gly/Glu-->Glu], is caused by a shift in the amino acid sequence and altered packing of the B and E helices during beta globin synthesis, and also changes the orientation of the critical proximal and distal histidine in the F and E helices respectively. Phenotype/Genotype features and molecular characteristics of this new beta chain are presented in this communication.

Hb J-Antakya or alpha 2 beta (2)65(E9)Lys----Met in a Turkish family and Hb complutense or alpha 2 beta (2)127(H5)Gln----Glu in a Spanish family; correction of a previously published identification.

Almost 10 years ago we reported in this journal the characterization of Hb Hacettepe or alpha 2 beta (2)127(H5)Gln----Glu. Unfortunately, we have to conclude that the original characterization of this Turkish variant was in error. The corrected data are presented in this short communication. The variant (alpha 2 beta (2)65(E9)Lys----Met) was (re)named Hb J-Antakya, after the city where the family resides. An abnormal Hb, observed in a Spanish family and named Hb Complutense, had the beta 127 Gln----Glu substitution, erroneously assigned to the Turkish variant.

Hb natal or alpha 2(minus Tyr-Arg) beta 2: a high oxygen affinity alpha chain variant with a deleted carboxy-terminus resulting from a TAC----TAA (Tyr----terminating codon) mutation in codon alpha 140.

The discovery is reported of a fast-moving alpha chain variant (Hb Natal) which is characterized by a shortened alpha polypeptide chain because of the deletion of the Tyr-Arg carboxy-terminal residues. Through amplification of appropriate segments of DNA and hybridization with synthetic oligonucleotide probes, it was possible to detect a C----A mutation in codon 140 of the alpha 2 globin gene, which causes a change in the codon for tyrosine to a terminating codon. Hb Natal or alpha 2 (minus Tyr-Arg) beta 2 has a high affinity for oxygen without a Bohr effect and heme-heme interaction. These results provide direct evidence for the importance of the tyrosine residue at alpha 140 in the oxygenation-deoxygenation process.

Hb Doha or alpha 2 beta 2[X-N-Met-1(NA1)Val----Glu]; a new beta-chain abnormal hemoglobin observed in a Qatari female.

Structural analysis of a fast-moving hemoglobin variant, present in three members of a Qatari family, identified a Val----Glu substitution at position 1 (NA1) of the beta-chain. The introduction of this glutamic acid residue prevents the removal of the initiator methionine, thus extending the N-terminus by one residue to Met-Glu-His-Leu-Thr-. The methionine residue is blocked by an as yet not completely identified molecule. The presence of the variant in a heterozygote does not have clinical consequences.

Postmortem molecular diagnosis of sickle beta thalassaemia.

This report describes a case in which the diagnosis of sickle cell disease (SCD) was established after death. The diagnosis of sickle cell syndrome was made in a 68 year old black patient who was found to have sickled red blood cells in many organs at necropsy although the disease had not been diagnosed during her lifetime. DNA was isolated from a peripheral blood smear obtained on the day of the patient's death. The beta globin gene was polymerase chain reaction amplified and sequenced, revealing that the patient had S-beta(+) thalassaemia. This study shows that blood smears are a suitable source for retrospective DNA analysis studies. This case illustrates that relatively "mild" forms of SCD can be overlooked, despite symptomatology suggestive of a sickle syndrome, and demonstrates the feasibility of the postmortem molecular diagnosis of haemoglobinopathies in such cases.

Autoimmune thrombocytopenia following autologous hematopoietic cell transplantation: review of literature and treatment options.

Autoimmune thrombocytopenia after high-dose chemotherapy and autologous bone marrow/peripheral blood stem cell transplantation occurs infrequently and only six cases meeting the criteria have been reported in the literature. All six of these patients had either acute myelogenous leukemia (AML) or lymphoblastic lymphoma (LBL). Immune thrombocytopenia following autologous transplantation in solid tumors has not been reported. We report the first case of autoimmune thrombocytopenia after high-dose chemotherapy and peripheral blood stem cell transplantation in a patient with breast cancer. A review of the literature has been conducted and treatment options are discussed. In two patients the condition resolved with treatment and in a third patient it improved. Immune-mediated thrombocytopenia in the post-transplant period is one of the causes of a low platelet count. It should be recognized promptly and treated.

Exercise in sickle cell anemia: effect on inflammatory and vasoactive mediators.

The aim of this study was to determine the response of inflammatory and vasoactive mediators to 3 consecutive days of exercise in African-American women with and without sickle cell anemia (SCA). Circulating inflammatory mediators [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha)] were measured before, and vasoactive mediators [endothelin-1 (ET-1), nitric oxide metabolites (NOx)] before and after each exercise bout in ten subjects with SCA and ten controls. Exercise did not affect ET-1, IL-6 or CRP concentrations (p >.05). TNFalpha was higher in SCA than controls (p < or = .0005) at all times; however, the response pattern was similar for the groups: no change from day 1 to day 2, but a decrease from day 2 to day 3 (p < or = .05). NOx increased significantly after exercise (p < or = .0001) but returned to baseline by 24 h afterward. On the 3rd day, NOx increased after exercise in SCA but not in the controls (p < or = .05). In conclusion, exercise did not cause a harmful inflammatory response in these individuals with SCA. However, NOx increased after exercise on all 3 days in SCA but appeared attenuated after 2 days in controls.

The detection of hemoglobin variants by isoelectrofocusing using EDTA-collected and filter paper-dried cord blood specimens.

A comparative study was conducted aimed at the detection of abnormal hemoglobin conditions (mainly AS, SS, AC, CC, SC, AE, AD, Hb Bart's or gamma 4) by isoelectrofocusing of cord blood samples stored as liquid blood and as dried hemoglobin on filter paper. Analyses were made within four to six days after the collection of the samples; storage conditions mimicked those of testing programs using liquid blood samples (as in Georgia) or dried blood filter paper samples (as in several other states). During analysis of hemoglobin solutions extracted from dried blood samples, considerable difficulties were encountered in detecting significant hemoglobinopathies such as SS and SC, whereas even simple abnormalities such as AS, AC, AD, and AE were also often not diagnosed. Detection of the fast-moving variant Hb Bart's or gamma 4 was not possible. These results again cause doubt regarding the general use of dried blood filter paper samples in newborn hemoglobin testing programs. Perhaps special precautions--such as speed in analyzing the samples, storage at -20 degrees C (or perhaps 4 degrees C) instead of at room temperature, and removal of unstable hemoglobin from the filter paper extract by centrifugation--might eliminate some of the problems that were observed.

Case report: alpha G-Philadelphia, beta O-Arab, and beta C globins present in a single patient.

The case of a 7-month-old Nigerian child who presented with anemia and microcytosis is described. Hemoglobin electrophoresis studies revealed a band with pronounced cathodic mobility. This represented a heterohybrid hemoglobin tetramer composed of an alpha-globin mutant, G-Philadelphia (alpha GPhil), and two variant beta-globin chains, beta C and beta O-Arab. The absolute amounts of alpha GPhil found in the propositus were less than expected for an alpha 2-globin gene product. It has not been established whether alpha G-Philadelphia interacting with beta O-Arab and beta C globin chains is the cause of the microcytosis.

Predicting the effectiveness of hydroxyurea in individual sickle cell anemia patients.

The study described in this paper was undertaken to develop the ability to predict the response of sickle-cell patients to hydroxyurea (HU) therapy. We analyzed the effect of HU on the values of 23 parameters of 83 patients. A Student's t-test was used to confirm (Rodgers GP, Dover GJ, Noguchi CT, Schechter AN, Nienhuis AW. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea, N Engl J Med 1990;322;1037-44) at the 0. 001 level that treatment with HU increases the proportion of fetal hemoglobin (HbF), and the average corpuscular volume (MCV) of the red blood cells. Correlation analysis failed to establish a statistically significant relationship between any of the 23 parameters and the HbF response. Linear regression analysis also failed to predict a patient's response to HU. On the other hand, artificial neural network (ANN) pattern-recognition analysis of the 23 parameters predicts, with 86.6% accuracy, those patients that respond positively to HU and those that do not. Furthermore, we have found that the values of only 10 of the 23 parameters (listed in the body of this paper) are sufficient to train ANNs to predict which patients will respond to HU.

An acardiac acephalic monster following in-utero anti-epileptic drug exposure.

Acardia, the absence of the heart, is one of the rarest medical anomalies. The exact mechanism which causes this anomaly is still unknown. The authors report the acardiac acephalic fetus of an epileptic mother who was on primidone therapy. The mother who received no antenatal care stopped taking primidone (her sole medication) in the third month of pregnancy with the fear of delivering a malformed baby and had three convulsions until delivery. This is the first reported case of acardia associated with anti-epileptic medication. The cause of the anomaly in this patient may be an unknown genetic defect, the maternal epileptic disorder, the convulsions, the anti-epileptic medication, or a combination of these factors.

Body composition in women with sickle cell disease.

INTRODUCTION: Adults with sickle cell disease (SCD) have increased morbidity and low perceived health status, similar to patients with other chronic conditions. These patients may be sedentary due to exercise intolerance, physical incapacity due to sickle cell-related complications or medical conservatism. Obesity is an indicator of low health status and overall well-being in the general population, and we hypothesize that adults with SCD will have a high total body fat (%BF). The purpose of this study was to assess body composition in women with SCD using dual-energy X-ray absorptiometry (DXA). METHODS: Baseline medical examination, laboratory assessments, and seven-day activity recall to estimate energy expenditure (EE) were obtained for 22 women with SCD. BMI was calculated and whole body DXA was performed [fat mass (FM), fat-free soft tissue (FFST), and bone mineral content (BMC)]. Descriptive statistics were obtained and associations between body composition indices, total hemoglobin (Hb), treatment with hydroxyurea (HU), and EE were determined. RESULTS: Patient age was 30.5+/-9.3 years and total Hb was 8.85+/-1.92 g/dL (mean+/-SD). Mean body mass index (BMI) (22.6 kg/m2) was in the 'acceptable' range, while DXA measurement of mean % fat (32.6%) indicated obesity. Fat-free mass (FFM) was 40.0+/-5.62 and bone mineral density (BMD) was 1.13+/-0.14 g/cm2 (mean+/-SD). There were no correlations between body composition indices and total Hb, HU, or EE. CONCLUSIONS: This is the first report of high levels of adiposity, low FFM, and low BMD in normal weight women with SCD. The findings were not affected by total Hb, EE, HU. Further studies are needed to better define body composition, body composition determinants, and their impact on overall health status in adults with SCD.

Helicobacter pylori infection in sickle cell disease.

Abdominal pain is a common presenting symptom in adults with sickle cell disease (SCD). One case of Helicobacter pylori gastritis has been reported in a child with sickle cell anemia. H. pylori-induced peptic ulcer disease (PUD) has not previously been reported in adults with SCD. We report eight cases of H. pylori infection in adult sickle cell patients presenting with acute or recurrent abdominal pain and/or gastrointestinal bleeding. In all cases, H. pylori serology (IgG) was positive, and three patients had gastric or duodenal ulcer by endoscopic examination. All patients responded to H. pylori treatment with complete resolution of symptoms by 4 weeks. The prevalence of H. pylori infection in SCD is unknown, but patients may be at increased risk for H. pylori-induced PUD and complications due to pre-existing anemia, increased nonsteroidal anti-inflammatory drug use, and alloimmunization which may delay necessary transfusion. It is important that the differential diagnosis of abdominal pain in adults with SCD include nonsickle cell-related disorders such as PUD. When confirmed, a definitive etiology of PUD must be determined so that appropriate treatment strategies can be initiated promptly and excess morbidity avoided.

Changes in serum CA-125 levels after laparotomy?

There is no adequate data in the medical literature defining serum CA-125 levels after laparotomy. Therefore we designed this prospective study to evaluate the effects of laparotomy for hysterectomy on serum CA-125 levels. Ninety-four women (mean age 44.6 +/- 6.9 years) were included in the study between January, 2001 and April, 2003. Hysterectomies were performed in patients with chronic pelvic pain, dysfunctional uterine bleeding and myoma uteri. Mean serum CA-125 levels of the patients before and after laparotomy were 16.29 +/- 8.11 U/ml and 16.37 +/- 8.05 U/ml, respectively. The change in serum CA-125 levels prior to the operation was statistically insignificant when compared with the levels obtained at 24 hours after laparotomy (p > 0.05). We found that laparotomy for hysterectomy did not change the levels of CA-125 at the 24th hour after the operation, indicating either serum CA-125 levels are not correlated, at least within 24 hours, with peritoneal irritation or peritoneal irritation was minimal or absent in our operations.

Chinese in west Malaysia: the geography of beta thalassaemia mutations.

The overseas Chinese in West Malaysia are almost exclusively from the south-eastern provinces of China-Kwangtung, Fukien, and Kwangsi. To institute a comprehensive thalassaemia control programme for this region we have characterised the beta thalassaemia mutations in 16 Chinese patients from West Malaysia: 4 beta thalassaemia mutations were seen: a) an A----G substitution in the TATA box [-28 base pairs (bp)], an A----T substitution in codon 17 [17 A----T], c) a 4 base pairs - TCTT deletion in codon 41-42 [frameshift mutation (FSC 41-42)], and d) a C----T substitution at the second intervening sequence (IVS 11) position 654. Similar mutations have been described in patients from the south-eastern provinces of China. The delineation of the specific mutations present will enable effective prenatal diagnosis for beta thalassaemia of ethnic Chinese in West Malaysia to be instituted.

Prenatal diagnosis of sickle cell anemia using PCR and restriction enzyme Dde I.

Prenatal diagnosis of sickle cell anemia was carried out in four fetuses using DNA technology. Fetal chorionic villus specimen were obtained at the 10th week of pregnancy from women at risk of giving birth to children with sickle cell anemia. Whole cellular DNA was obtained and the part of the DNA presumed to have a mutation increased after PCR was performed. After the application of Dde I restriction enzyme, mini gel electrophoresis was performed. The study of the electrophoretic patterns of the DNA indicated that one of the four fetuses was unaffected, one was a carrier and the remaining two were affected.

beta S-haplotypes and alpha-thalassemia along the coastal belt of Kenya.

In this paper, we present data on studies of beta S-haplotypes and alpha-thalassemia gene in subjects from the indigenous population of the Coast Province of Kenya Of the 7SS patients studied, four were homozygous for beta S-haplotype 20 characteristically associated with the severe form of sickle cell anemia found in the Central African Republic and Western Kenya. Two had haplotype 20 combined with haplotype 19 (Benin Type) and one had haplotype 20 combined with a new haplotype (20x). Alpha thalassaemia-2 gene (-3.7kb deletion) was detected in 45.6% of the 57AA subjects studied. An alpha globin gene triplication was detected in one subject whereas eight had gamma globin gene triplication.