bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Phosphatidylserine Receptor-Phosphatidylserine Axis Promotes Sickle Erythrocyte Retention in the Lung Microcirculation.
Authors: Ofori-Acquah Solomon F. , Obiako Boniface , Haynes Johnson 
Published: April 2020

Abstract
Pulmonary vascular occlusion is a major cause of morbidity and mortality in sickle cell disease. Adhesion between sickle erythrocytes, leukocytes and the endothelium are intimately involved in pulmonary vascular occlusion, which contributes to the pathogenesis of the acute chest syndrome. Despite this significance, specific molecules and cognate mechanisms responsible for trapping sickle erythrocytes in the lung microcirculation are poorly understood. In this study, we show for the first time that products released by activated neutrophils act through the phosphatidyserine and phosphatidylserine receptor axis to promote retention of sickle erythrocytes in the lung microcirculation. We demonstrated that co-incubation with autologous activated neutrophils increased 2-fold the proportion of phosphatidylserine exposed sickle erythrocytes. This effect was abrogated by prior treatment of neutrophils with zileuton a pharmacological inhibitor of 5-lipoxygenase. We next determined that primary endothelial cells derived from the pulmonary vasculature expressed the stereospecific receptor for phosphatidylserine. Transcripts for phosphatidylserine receptor (PSR) were 2-fold more abundant in endothelial cells from the pulmonary microvasculature compared to those from the pulmonary artery. To determine the relevance of neutrophil activation in PSR expression, cultures of PMVECs were treated with supernatants of activated neutrophils from patients with sickle cell anemia, and this resulted in 2-fold increase in PSR transcripts. To unravel the pathophysiological relevance of these findings, isolated rat lungs were perfused with 51Cr labeled sickle erythrocytes pre-incubated with annexin V, and retention of sickle erythrocytes quantified by 51Cr radioactivity. The number of sickle erythrocytes trapped in isolated lungs was 2-fold lower compared to the value in control experiments performed with untreated sickle erythrocytes. In agreement with our previous findings activated neutrophils significantly increased sickle erythrocyte retention in the lung (P=0.0004), however cloaking of sickle erythrocytes with annexin V reduced retention by 3-fold. Collectively, these data show that activation of neutrophils increases expression of PSR and its cognate ligand on endothelial cells and sickle erythrocytes respectively, providing the molecular basis for an adhesion complex that increases retention of sickle erythrocytes in the pulmonary endothelium. The PSR-phosphatidylserine adhesion complex therefore offers a novel therapeutic target to reduce pulmonary vascular occlusive events in sickle cell disease.
Survival of Children with Sickle Cell Disease: An Update from the Dallas Newborn Cohort.
Authors: Quinn Charles T. , Lee Nancy J. , Rogers Zora R. , Buchanan George R. 
Published: April 2020

Abstract
The Dallas Newborn Cohort is the largest newborn inception cohort of individuals who have sickle cell disease (SCD), and it has provided modern pediatric SCD survival data (Blood2004;103:4023–7). The Cohort includes subjects who were diagnosed at birth by universal newborn screening and followed at our center up to 18 years of age. All subjects with sickle cell anemia (SS) or sickle-β° thalassemia (Sβ°) were prescribed prophylactic penicillin until 5 years of age. The first report from the Cohort showed an overall survival of 85.6% at 18 years for individuals with SS or Sβ°. The standard error of this estimate was high because only 8 individuals remained at risk at 18 years of age at the time of the analysis, which included follow-up until July 2002. Accrual and follow-up of cohort members has continued. We therefore sought to update the survival estimates through age 18 by including three further years of follow-up. By definition the Dallas Newborn Cohort includes all individuals with SS, Sβ°, sickle-hemoglobin C disease (SC), or sickle-β+-thalassemia (Sβ+) who were born in Texas after November 1, 1983, diagnosed by the newborn screening program of Texas, and seen at least once in our center. New members of the Cohort who came to our center between July 2002 and July 2005 were identified. Follow-up of existing members was updated. All deaths and their causes were determined. Subjects were analyzed in two separate groups because of known clinical similarities: SS/Sβ° and SC/Sβ+. Overall survival was analyzed by the Kaplan-Meier method. Subjects were censored at the time of their last clinical encounter. We identified 115 new subjects, and included 1627 additional patient-years of follow-up. The cohort now includes 826 subjects (SS 503, Sβ° 18, SC 247, Sβ+ 58; male:female 427:399) and it provides 7275 patient-years of follow-up. Mean follow-up was 8.9 years (range 0.9–19.5 years). 62 patients (7.5%) were lost to follow-up. There were 25 deaths in the cohort; none was new and all were previously reported. Of the deaths, 15 were likely related to SCD (5 sepsis, 3 acute chest syndrome, 2 multi-organ failure syndrome, 5 other) and 10 were apparently unrelated to SCD (4 trauma or accidental death, 6 other diseases). There were 22 and 3 deaths in the SS/Sβ° and SC/Sβ+ groups, respectively. All the SC/Sβ+ deaths were apparently unrelated to SCD. Overall survival at 18 years for SS/Sβ° and SC/Sβ+ subjects was 92.4% (standard error [SE] 1.9; 52 at risk) and 98.1% (SE 1.3; 12 at risk), respectively. The overall incidence of death through 18 years of age was 0.46 and 0.12 per 100 patient-years, respectively. In conclusion, this updated survival analysis of the Dallas Newborn Cohort now shows that over 90% of children with SS/Sβ° survive childhood, and nearly 100% of children with SC/Sβ+ become adults.
Hemoglobin H Hydrops Fetalis Associated with Homozygous Hemoglobin Constant Spring. Case Report.
Authors: Gallivan Monica V.E. , Vlastos Emmanuel J. , Hanson Robin D. , Bettinoti Maria P. , Schonberg Steven A. , Pratt Victoria M. , Ou Ching-Nan , Mikula Mario , McGinniss Matthew J. , Sun Weimin , Strom Charles M. 
Published: April 2020

Abstract
While Barts hydrops is predicted when all 4 α globin genes are absent or non functional, hydrops has rarely been described with a hemoglobin H (Hb H) genotype. Hb H disease has a varied hematologic phenotype ranging from asymptomatic to transfusion dependant. The severest clinical expression is non immune hydrops and may result in fetal demise. The commonest form of Hb H disease is deletional-type. This occurs when there is deletion of α2 and α1 genes in cis and deletion of either α2 or α1 in trans. The less frequent type, but clinically more severe, is non-deletional. This is usually due to a mutation in either α2 or α1 in cis and a deletion of both α2 and α1 in trans. There are rare reports of non-deletional Hb H due to homozygous α2 mutations without any α1 deletions or mutations. Heretofore, there have been no reports of hydrops with homozygous hemoglobin Constant Spring (Hb CS). A 31-year-old Laotian woman presented at 22 weeks with polyhydramnios. Besides this, the pregnancy was uneventful for the mother. On ultrasound the fetus had a pericardial effusion and signs of congestive heart failure. The hematological and genotypic parameters of the parents and fetus are outlined in table 1. Intrauterine transfusions were performed at 22 and 29 weeks. A male infant was born vaginally at 36 weeks gestation weighing 2.3 kg. The hemoglobin was 15.9 g/dL and bilirubin was 8.4mg/dL. There was no evidence of maternofetal alloimmunization. G6PD screen was negative. By 4 weeks post-partum, the bilirubin had decreased to 0.9 mg/dL but the hemoglobin had progressively fallen to 6.9 g/dL, requiring transfusion. He had two additional transfusions at 6 and 8 weeks of life but has subsequently maintained a hemoglobin above 10 g/dL and has steadily gained weight. As in this patient, the genotypes of the other reported cases of Hb H hydrops are usually associated with a thalassemia intermedia phenotype. Thus the α globin genotypes alone do not explain why hydrops occurs. This suggests that there may be unknown genetic and/or acquired modifiers contributing to the severity of Hb H disease that results in hydrops as in this fetus with homozygous Hb CS.
[Table 1] Mother Father Fetus at 22 weeks Hemoglobin g/dL 10.0 12.5 5.2 MCV fL 86.3 81.8 143.8 MCH pg 26.5 25.6.8 46.4 RDW % 16.7 13.6 21.4 Reticulocyte % 9.9 ND 19.0 NRBC/100WBC 1 0 4756 Hemoglobin Fractions by HPLC Hb A 73.3% 97.8% 3.4% Hb F 0.8% 0.0% 77.7% Hb A2 0.9% 2.1% 0.0% Barts 0.0% 0.0% 17.7% Hb Constant Spring 2.8% 0.1% 1.2% Hb E 22.2% 0.0% 0.0% αGlobin Gene Dosage Assay by Linear PCR 4 4 4 αGlobin Gene Deletions by PCR - 3.7, - 4.2, _SEA, - 20.5, _MED,_FIL,_THAI None detected None detected None detected α2 Globin Gene Sequencing α-2CS/α-2CS α-2CS/WTα-2CS/α-2CS α1 Globin Gene Sequencing WT/WT WT/WT WT/WT βGlobin Gene Sequencing Heterozygous Hb E WT/WTWT/WT E
Allogeneic Hematopoietic Stem Cell Transplantation for Pesaro IIIβ-Thalassemia Major Using Fludarabine-Based Myeloablative or Non-Myeloablative Conditioning Regimen.
Authors: Zhu Kanger , Gu Jian , Zhang Tao , Zhong Juan 
Published: April 2020

Abstract
Objective : To explore the efficacy of Fludarabine-based myeloablative or non-myeloablative conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for classIII thalassemia major with regard to regimen toxicity, graft rejection, and disease-free survival (DFS).
Methods: From June 2001 to October 2004, 8 patients underwent allo-HSCT in our BMT unit, including 5 male and 3 female, with median age 5 (3 ~ 19) years. Four patients received graft from sibling donor, including cord blood and peripheral blood stem cells, and the remaining 4 patients received graft from unrelated donors, including bone marrow and peripheral blood stem cells. Fludarabine (FDR) was added into the standard BU/CY regimen, consisting of FDR, BU, CY and ATG. Six patients received myeloablative stem cell transplantation and the remaining 2 patients with evidence of organ damage from iron-overload received nonmyeloablative unrelated donor stem cell transplantation. All patients received Cyclosporine A and Methotrexate for GVHD prophylaxis.
Results: Eight patients were successfully engrafted with the median time of absolute neutrophil count (ANC) more than 0.5 ×109 /L was day +13 (+9 ~ +14), and the median time of platelet count more than 20 ×109 /L was day +25 (+8 ~ +39). Two patients died of grade IV aGVHD. The regimen-related toxicity (gradeImucositis, gradeII hemorrhagic cystitis, and gradeIhepatic toxicity) occurred in 3 patients. At a median follow up of 24 (8~48) months, the probability of DFS was 75%, including the two patients given nonmyeloablative stem cell transplantation from unrelated donor.
Conclusion: Fludarabine-based conditioning regimen for allo-HSCT in Pesaro III thalassemia major was well tolerated, without increasing toxicity, and associated with durable engraftment and higher rate of DFS (75%). The successful transplantation from unrelated donors using nonmyeloablative conditioning showed that thalassemia clone can be eradicated by the reduced intensity HSCT, which relies upon immunosuppressive rather than myeloablative conditioning to facilitate engraftment of donor cells, and is a novel approach for the treatment of the patients with evidence of organ damage from iron-overload.
Multi-Centre Validation of the Cardiovascular Magnetic Resonance Multi Breath-Hold T2* Technique for Myocardial Iron Quantification in Thalassaemia Major.
Authors: Tanner Mark A. , He Taigang , Westwood Mark A. , Galanello Renzo , Matta Gildo , Cohen Alan R. , Fogel Mark , Piga Antonio , Forni Gianluca , Economides Charalambos , Firmin David N. , Dudley Pennell J. 
Published: April 2020

Abstract
Introduction: Beta thalassaemia major (TM) is a hereditary anaemia affecting 60 000 births worldwide each year. Survival is dependent upon lifelong blood transfusions resulting in iron overload. Cardiac siderosis can result in a cardiomyopathy which is the leading cause of death in TM. The validated cardiac magnetic resonance (CMR) T2* technique allows non-invasive and reproducible quantification of myocardial iron. Assessment of myocardial iron loading is essential in determining appropriate chelation therapy. This technique has the potential to become the new gold standard in the assessment of cardiac siderosis but is currently available at only a few sites worldwide. For maximal healthcare benefit its inter-scanner reproducibility must be demonstrated before being widely disseminated.
Objective: To demonstrate that CMR T2* quantification of myocardial iron can be reproducibly transferred to MR scanners of different manufacturers in different centres. This project was sponsored by the Thalassemia International Federation.
Methods: The previously described multi breath-hold gradient echo T2* technique was installed on MR scanners (all 1.5Tesla) at 6 different centres. Scanner details were as follows: Site 1, Phillips Intera (Turin, Italy), Site 2, Siemens Sonata (Philadelphia, USA), Site 3 GE Signa (Limassol, Cyprus) Site 4, Phillips Intera (Nicosia, Cyprus), Site 5, GE Signa (Cagliari, Sardinia) and Philips Intera (Genova, Italy). 34 patients (mean age 30+/− 5.7years) were scanned in total. All patients were subsequently re-scanned at the standardization centre in London, UK (Siemens Sonata, 1.5T) within 31 days of their original scan.
Results: The T2* sequence was successfully installed on all 6 scanners. Myocardial T2* values ranged from 3.6ms to 51ms (14.2 +/− 11ms). The overall inter-scanner reproducibility (SD/mean) was 5.3% (figure 1). The mean difference between T2* values at the standardization centre and visited sites was 0.32ms.
Conclusion: We have demonstrated that the multi breath-hold T2* technique for the quantification of myocardial iron can be reproducibly transferred to 1.5T MR scanners at different sites and of different manufacturers. There is therefore real potential to roll out this technique worldwide to facilitate maximal healthcare impact in the management of patients with iron overload conditions such as thalassaemia.
Figure Figure
Serum Ferritin and Liver Iron Concentration in Patients with Iron Overload.
Authors: Pakbaz Zahra , Fischer Roland , Fung Ellen , Nielsen Peter , Engelhardt Rainer , Harmatz Paul , Vichinsky Elliott 
Published: April 2020

Abstract
Despite its limitations, serum ferritin (SF) is commonly used to monitor chelation therapy in primary and secondary hemochromatosis. To better predict liver iron concentration (LIC), we prospectively investigated the relationship between SF and LIC in a total of 421 patients with primary (HFE-1 associated, n=241) or secondary hemochromatosis (n=180), consisting of chronically transfused thalassemia (Tx-Thal: n=89) or sickle cell disease patients (Tx-SCD: n=45) and transfusion independent thalassemia patients (nTx-Thal: n=26). In all patients, LIC was measured by SQUID biosusceptometry. SF correlated with LIC (RS = 0.51–0.83, p &lt; 0.001) but was a poor predictor for LIC. SF was significantly lower (p &lt; 0.001) in nTx-Thal and HFE-1 patients despite similar LIC (421 – 5524 μg/g-liver) and it was higher in Tx-SCD compared to Tx-Thal (p = 0.03). In order to improve the value of SF, we calculated the SF/LIC ratio for each group. SF/LIC remained stable over time in patients whose therapy did not change. In iron loaded patients without blood transfusion therapy (nTx-Thal and HFE-1), the median SF/LIC ratio was significant lower (0.32 and 0.43) as compared to transfused patients (Tx-Thal: 0.87, HCV-Thal: 0.99, Tx-SCD: 1.2), probably, indicating differences in the secretion of ferritin into plasma. We conclude that SF alone can mislead the iron unloading therapy as it underestimates LIC in nTx-Thal patients and overestimates LIC in Tx-SCD patients. Once the initial LIC value is obtained and the individual SF/LIC ratio is determined in a patient, the ratio together with SF may be more useful than SF alone to monitor iron overload and predict LIC.
Pregnancy in Thalassemia Patients and Their Partners in a Canadian Population.
Authors: Apostoli Anthony , Cipolla Amanda , Kinghorn Maureen , Kaufman Jacob , Muraca Giulia , Olivieri Nancy 
Published: April 2020

Abstract
Although successful pregnancy is not an uncommon outcome in patients with homozygous beta thalassemia over the last 20 years, most of these have been reported in case reports and small series, while many publications do not appear to distinguish between pregnancies in thalassemia intermedia and those in thalassemia major. For example, of the total of 150 pregnancies in women with thalassemia reported in the literature from 1984 to 2004, 74 pregnancies appear clearly to be documented in patients with thalassemia major, while in the other 76, a reportedly late onset of transfusions suggests a milder phenotype of thalassemia intermedia. We examined the records of all thalassemia patients managed at the Toronto General Hospital, Canada (n = 82 patients with thalassemia major; 23 patients with thalassemia intermedia; 7 patients with hemoglobin E thalassemia = 112 patients over 18 years, of whom 54 are female) to determine the incidence and complications of pregnancy in our population. A surprisingly high number (17) and proportion (31%) of all female thalassemia patients over age 18 years have attempted to become pregnant. A total of 14 (82% of those who attempted pregnancy) of patients (9 thalassemia major; 4 thalassemia intermedia; 1 Hemoglobin E thalassemia) successfully conceived 26 times. The maternal age at first attempt to become pregnant was 29.6 ± 4.9 (range 18–37) years; average age at delivery was 27.2 ± 4.1 (range 19–33) years. Of the 26 conceptions, 20 were carried to term; 19 live births resulted. Six abortions and one fetal death occurred. Deferoxamine was avoided in all patients during pregnancy; control of body iron was followed using hepatic iron concentration. Pre-pregnancy hepatic iron concentration, obtained 2.8 ± 1.8 (range 1–7) years prior to conception, was 9.3 ± 7.9 (range 0.9–31) mg/gram dry weight; post partum hepatic iron concentration, obtained 3 ± 3.2 (range 0.2–10) years following parturition, was 17.4 ± 9.6 (range 1.25–32.5) mg/gram dry weight. There were one reported significant worsening in cardiac function during pregnancy; diabetes (present in one woman prior to pregnancy) developed in another woman during pregnancy. Other complications occurring or worsening during pregnancy included immune thrombocytopenic purpura and post- transfusional thrombocytopenia. In 13 of the 58 men in this population, 13 (8 with thalassemia major; 4 with thalassemia intermedia and one with Hemoglobin E thalassemia) fathered 20 children at 33.5 ± 4.8 (range 24–44) years. These data report the largest North American series of pregnancy in thalassemics and their partners and while raising issues of the safety of pregnancy in thalassemic women offer encouragement to those patients managed with adequate control of body iron burden.
Application of the Luminex Platform for Multiplexed Genotyping of Non-Deletional Alpha Thalassemia Mutations.
Authors: Aslanian Sharon , Mahin Azimi , Hoppe Carolyn 
Published: April 2020

Abstract
Objectives: Certain point mutations in the alpha globin gene may lead to unstable hemoglobins such as Hb Constant-Spring and Hb Quong-Sze. These alpha chain variants, when inherited with deletional α-thalassemia mutations cause more severe forms of HbH disease. To evaluate the utility of the Luminex xMAP platform for rapid screening of non-deletional α-thalassemia mutations, we developed a multiplexed genotyping assay to detect six mutations in the α2-globin gene. that are clinically significant or, when coinherited with α-thalassemia-1, result in HbH disease.
Methods: A panel of positive controls with known heterozygosity for Hb Constant-Spring, Hb Quong-Sze, Hb J-Toronto, Hb Hasharon, Hb G-Philadelphia and Hb G-Norfolk, was obtained from anonymized whole blood or newborn dried blood spots. The α2 gene was amplified using nested PCR and single base chain extension (SBCE) was carried out using the PCR products, capture-tagged primers, thermosequenase, and one of four biotinylated ddNTPs. Biotinylated amplicons were hybridized to fluorescent microspheres containing allele-specific capture probes and analyzed by flow cytometry on the Luminex100.
Results: Median flourescent intensity (MFI) values uniformly discriminated between wild type and mutant alleles in three independent experiments. Mean background-subtracted MFIs ranged from 255 to 1000 for all positive alleles and genotypes were correctly identified in all of the samples tested.
Conclusions: As HbH disease is becoming more prevalent in the U.S., early detection of this disorder using accurate, affordable diagnostic methods will permit timely delivery of health care and prevention of severe clinical manifestations of disease. As the severity of many of these disorders has not been well-characterized, an understanding the phenotypic expression of these hemoglobin disorders is essential to providing adequate counseling and treatment options.
Prevalence of Hypoparathyroidism in Children and Young Adults with Thalassemia Major.
Authors: Yadav Satya Prakash , Sachdeva Anupam , Arya Subash C. , Khanna Virender K. , Arya Archana D. 
Published: April 2020

Abstract
Endocrinopathies are frequently reported in children with thalassemia major. Affected children at our center are transfused regularly to maintain hemoglobin of at least 8–9 gm/dl. Most subjects are chelated with Desferrioxamine or Deferiprone or a combination of the two drugs, although a majority of children have poor compliance and are poorly chelated. Hypoparathyroidism usually occurs in thalassemia major due to excess iron deposition in the parathyroid glands. All patients suffering from thalassemia major are screened routinely at our clinic for their bone metabolism. The fasting serum calcium, phosphorus, intact parathormone and alkaline phosphatase levels are checked annually to screen for hypoparathyroidism and Vitamin D deficiency. A diagnosis of hypoparathyroidism is made if the serum calcium is low, phosphorus is high, alkaline phosphatase level is normal and serum parathormone level (intact) is low normal. Mean S. ferritin levels of all the subjects were calculated by averaging the ferritin values over the last 5 years. We analyzed the screening results for hypoparathyroidism in 110 subjects with Thalassemia Major between the ages of 10–25 years. Of these 110 subjects 19 (17.3%) were found to be suffering from hypoparathyroidism and 91 patients had a normal screen. Mean S. ferritin level was 5997ng/ml in the affected subjects (ranging from 2900 to 10,904 ng/ml), compared with the mean S. ferritin level of 3793ng/ml in the unaffected subjects, which was clinically significant, showing a direct correlation between the poor chelation and development of hypoparathyroidism. Only 2 subjects from our affected group had an average ferritin of 2000–3000 ng/ml, although they also had other endocrine disorders such as short stature and hypothyroidism. Of the affected subjects, 9 were males and 10 were females (M: F = 1.1:1). The reported male: female ratio for hypoparathyroidism in thalassemics is 3:1. Age of onset of hypoparathyroidism ranged from 10.9 years to 23 years with mean age of onset being 16 years. The youngest subject (10.9 years) had an average ferritin of 2908 ng/ml. All the affected subjects above 15 years of age had hypogonadism, 7 of the 19 affected subjects (36.84%) had diabetes, 4 (21%) of them had an abnormal glucose tolerance test, and 5 (26.3%) had hypothyroidism. The incidence of hypoparathyroidism reported in our group of patients is higher compared to those reported from other continents (3.6–4.5%) probably due to poor chelation., both males and females are equally affected and the age of onset is earlier compared to reports from other countries.. This suggests that high ferritin levels due to poor chelation is a major factor in the development of hypoparathyroidism and most subjects who develop it, have multiple endocrine disorders.