bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of Intravenous Immunoglobulin for Treatment of Neurological Conditions: A Systematic Review.
Authors: Hutton Brian , Fergusson Dean , Sharma Michael , Tinmouth Alan , Wilson Kumanan , Cameron Bill , Hebert Paul C. 
Published: October 2019

Abstract
Purpose: Given the increasing use of intravenous immunoglobulin for various neurological conditions, its significant cost and the uncertainty pertaining to its benefits and harms, we conducted a systematic review of randomized controlled trials that compared intravenous immunoglobulin to other current therapies.
Methods: A systematic search strategy of Medline (1966-June 2003) and the Cochrane Registry of Controlled Trials (June 2003 edition) was developed to identify randomised controlled trials. Two authors (BH, DF) independently reviewed all citations retrieved from the electronic search to identify all potentially relevant trials for this review. In cases where a unanimous decision could not be reached, a third party was consulted. To be eligible, studies had to be randomised controlled trials comparing intravenous immunoglobulin to either placebo or an active control and evaluating clinical outcomes. Measures of effect were calculated for each trial independently, and studies were pooled based on clinical and methodologic judgment as to its appropriateness. Fixed effects and random effects models were selected for each meta-analysis based on appraisal of the clinical homogeneity of patients across studies, as well as from testing for heterogeneity between studies. In circumstances where pooling of trials was inappropriate or not feasible, a qualitative discussion of the findings was developed.
Results: Thirty-seven trials representing 14 conditions were identified. Results from meta-analysis suggest that intravenous immunoglobulin therapy is effective for the treatment of multiple sclerosis (pooled 1-year EDSS change −0.46, 95% CI [−0.92,0.01] in favor of IVIG; pooled change in annual exacerbation rate −0.82, 95% CI [−1.54, −0.11] in favor of IVIG; pooled odds of remaining exacerbation free 0.24, 95% CI [0.12, 0.50] in favor of IVIG ) and idiopathic chronic inflammatory demyelinating polyneuropathy (pooled change in disability score −0.67, 95% CI [−1.04, −0.30] in favor of IVIG; pooled odds of achieving treatment response 4.43, 95% CI [2.20, 8.91] in favor of IVIG). There was insufficient evidence to determine whether this therapy was more effective for Guillain-Barré Syndrome than plasma exchange (pooled change in disability score −0.11, 95% CI [−0.37,0.14]; pooled odds of improving by 1 or more grades on the Hughes disability scale 1.91, 95% CI [1.11, 3.28] in favor of IVIG; pooled odds of mortality 0.84, 95% CI [0.31, 2.29]). There was also insufficient evidence regarding paraprotein-associated chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. No evidence of benefit was observed for inclusion body myositis and myasthenia gravis. Based on evidence from lone randomised trials, there also exists evidence indicating that IVIG may be useful for treatment of dermatomyositis, stiff person syndrome and Lambert-Eaton Syndrome.
A VWF Fragment Spanning the A1, A2, and A3 Domains Supports Platelet Adhesion Better Than the Isolated A1 Domain and Is Considerably More Resistant to Cleavage by Adamts-13 Than the Isolated A2 Domain.
Authors: Padilla Arnoldo A. , Lopez Jose A. , Cruz Miguel A. 
Published: October 2019

Abstract
von Willebrand factor (VWF) is a large multimeric protein whose monomers are of the domain structure D’-D3-A1-A2-A3-D4-B1-B2-B3C1-C2. The three tandem A domains mediate several important functions of the protein including supporting platelet adhesion, through an interaction of A1 with the platelet GP Ib-IX-V complex, and binding collagen, through A3 and A1. Further, the A2 domain contains the cleavage site for the plasma metalloprotease ADAMTS-13, which processes the newly synthesized and extremely adhesive ultra-large forms of VWF (ULVWF) to the forms normally found in plasma. Our goal was to compare the functions of the individual A domains as isolated domains to their function in the context of the A1-A2-A3 fragment. All recombinant domains were produced in bacteria. The A1-A2-A3 fragment contained an N-terminal thioredoxin-tag and a C-terminal 6Xhis tag and was purified in 2 steps using nickel and heparin columns. The recombinant protein was correctly folded, as indicated by the fact that it was recognized by a number of conformation-specific antibodies. Using ELISA, we examined the interaction of the fragment with both glycocalicin (the soluble extracellular domain of GP Iba) and collagen. At equivalent concentrations, A1-A2-A3 bound collagen better than did the isolated A1 and A3 domains, but the binding to glycocalicin was approximately 7.5 times lower than the A1 domain. We then tested the ability of the fragment to support platelet adhesion under flow, by coating the fragment onto a coverslip that made up the bottom of a parallel-plate flow chamber. In contrast to the findings with immobilized glycocalicin, immobilized A1-A2-A3 supported the attachment, rolling, and firm adhesion of the platelets to the surface, whereas A1 did not support firm adhesion. Finally, we tested cleavage of the fragment by plasma ADAMTS-13, using both ELISA and western blotting to detect cleavage. The rate of cleavage of the A1-A2-A3 fragment was much slower than that of the recombinant A2 domain, needing a longer incubation time to achieve a similar percentage of cleavage in a 15 fold higher concentration of plasma. These results show clearly that within the triplicate A domains of VWF, adjacent A domains influence each other’s functions, possibly by binding each other or by conformational modulation. The fact that the fragment is able to support firm platelet adhesion in isolation suggests that it may contain a second, previously unidentified binding site for platelet receptors.
Three New Mutations of Glucose-6-Phosphate Isomerase Associated with Chronic Hemolytic Anemia.
Authors: Vercellati Cristina , Fermo Elisa , Marcello Anna , Mariani Mariagabriella , Bianchi Paola , Barcellini Wilma , Ladogana Saverio , De Fanti Alessandro , Zanella Alberto 
Published: October 2019

Abstract
Glucose-6-phosphate isomerase (GPI, EC 5.3.1.9) is a dimeric enzyme that catalyses the reversible isomerisation of glucose-6-phosphate (G6P) to fructose-6-phosphate (F6P), the second reaction step of glycolysis. GPI deficiency is the second most common erythro-enzymopathy of anaerobic glycolysis, after pyruvate kinase. The gene locus encoding GPI is located on chromosome 19q13.1 and contains 18 exons. So far about 50 cases of GPI deficiency have been described, and 29 mutations have been reported at the nucleotide level: 25 missense, 2 nonsense and 2 splice site. The aim of this study is to describe the hematological, biochemical and molecular characteristics of two new families affected by GPI deficiency with chronic hemolytic anemia.
Case1: The propositus was a 1 yrs old boy of Northern Italian origin with chronic hemolytic anemia and need for blood transfusion in concomitance of infectious episodes. At the time of the study Hb was 7.6 g/dL, reticulocytes 231x109/L, total bilirubin 1.4 mg/dL. The study of the most important red cell enzymes revealed a very low GPI activity (12.5% of normal). The parents were not consanguineous, and displayed intermediate GPI activity (66% of normal in both). The sequence of complete erythrocyte GPI gene revealed the presence of two new missense mutations: G145C (Gly49Arg) and C921A (Phe307Leu). Since both these aminoacids are conserved in eukaryotic GPI enzymes, the mutations G145C and C921A are likely to impair the enzyme function or stability.
Case2:The propositus was a 8 yrs. old girl of Southern Italian origin with a history of chronic hemolytic anemia and occasional need for blood transfusion. At the age of 7 yrs. she was splenectomised reducing the need for blood transfusion. At the time of the study Hb was 9.4 g/dL, reticulocytes 364x109/L, total bilirubin 12.3 mg/dL. The propositus was homozygote for Gilbert’s syndrome. GPI activity was 20% of normal. The parents were not consanguineous, and displayed intermediate GPI activity (55% and 61% of normal). The sequence of complete erythrocyte GPI gene revealed the presence of two missense mutations, G301A (already described in an Italian patient by Baronciani et al Blood 88:2306,1996) and the new variant G1009A, which result in the aminoacidic substitutions Val101Met and Ala337Thr respectively.
Changes of Subsets of DC 1 in the Bone Marrow of Severe Aplastic Anemia Patients.
Authors: He Guangsheng , Shao Zhonghong , Wu De Pei , Ma Xiao , Sun Aining 
Published: October 2019

Abstract
Objective To measure the changes of subsets of dendritic cells 1 (DC1) in the bone marrow of severe aplastic anemia (SAA) patients and evaluate the relationships between the CD11c+CD83+cells and Th1 cells, CD3+CD8+ cells or hematopoietic function.
Methods By FACS, the quantity and ratio of CD11c+CD1a+ cells, CD11c+CD83+ cells, Th1 cells, and CD3+CD8+ cells in the bone marrow of SAA patients and normal controls were detected respectively. The relationships between CD3+CD8+ cells and Ret or ANC, between Th1 cells and CD3+CD8+ cells, Ret or ANC, between CD11c+CD83+ cells, and Th1 cells, CD3+CD8+ cells, Ret or ANC were evaluated.
Results In normal control’s bone marrow, the percentages of Th1 cells, CD11c+CD1a+ cells, CD11c+CD83+ cells and ratio of CD11c+CD83+ /CD11c+CD1a+ was 0.42±0.30%, 0.38±0.29%, 0.37±0.32% and 1.07±0.10 respectively. In the untreated SAA patient’s bone marrow, they were 4.87±0.54%, 1.73±0.24%, 3.38±0.56% and 2.21±0.32 respectively, and increased markedly(p<0.01). In recovering SAA patient’s bone marrow, the percentages of Th1 cells, CD11c+CD1a+ cells and CD11c+CD83+ cells decreased significantly[0.53±0.22%, 0.61±0.23%, 0.65±0.22%, respectively (p<0.01)]. The ratio of CD11c+CD83+/CD11c+ CD1a+ of recovering SAA patients was 1.37±0.25 which was similar to that of normal controls (p>0.05). The percentages of CD3+CD8+ cells of untreated SAA patients was 32.32±10.22%, and that of recovering SAA patients decreased to 13.67%±5.24 significantly (p<0.01). The percentages of CD3+CD8+ cells of SAA patients were correlated to their Ret and ANC (P<0.05) negatively. Their Th1 cell percentages were correlated to their CD3+CD8+ cells positively (P<0.01), but to their Ret and ANC negatively(p<0.01). SAA patient’s CD11c+CD83+ cell percentages were correlated to their Th1 cell and CD3+CD8+ cells positively (P<0.01, P<0.05), but to their Ret and ANC negatively(p<0.01).
Conclusion Both immature DC1 and activated DC1 increased in the bone marrow of SAA patients, and the balance of subsets of DC1 shifted from stable form to active one, which might promote Th0 cells to polarize to Th1 cells, then cause the over-function of T lymphocytes and hematopoietic failure in SAA.
Development of an In Vivo Model To Assess Factors That May Stimulate the Generation of an Immune Reaction to Epoetin Alfa.
Authors: Ryan Mary H. , Shanahan Mary F. , McMahon Frank , Jolliffe Linda , Brigham-Burke Mike , Heavner George A. , Farrell Francis X. 
Published: October 2019

Abstract
The incidence of pure red cell aplasia (PRCA) in patients with chronic kidney disease associated with the subcutaneous (sc) administration of epoetin alfa (EPREX®) began to increase in 1998. As part of an intensive investigation into the reasons for this increase, an in vivo model was developed to assess the ability of potential causative factors to stimulate an immune response to recombinant human erythropoietin (rHuEPO). Due to species differences in protein sequence and as well as antigen processing and/or presentation, animal models cannot fully predict immunogenicity in humans. However, changes in relative immunogenicity have been readily detected in animal models. Moreover, transgenic animals have been utilized to negate the effects due to sequence differences between species. The EPO sequence is highly homologous between mouse and man. We found it difficult to generate anti-EPO antibodies in both human EPO transgenic mice and two normal mouse strains (Balb/c and BD-F1). To mitigate the complicating factors associated with the transgenic model (e.g. difficulty breeding, improper regulation of EPO production), normal mouse strains were selected for the development of animal models. Mice were injected sc with rHuEPO weekly for 4–6 weeks. Serum samples were analyzed 1–2 weeks following the last injection to ensure complete clearance of the injected protein. Serum samples were screened by an ELISA and/or by a surface plasmon resonance (BIAcore) method. In animals injected with rHuEPO alone, anti-EPO antibodies were either absent or present at very low levels. The addition of an adjuvant to the immunization protocol was able to boost both the rate of occurrence and titer of the immune response and resulted in the generation of anti-EPO antibodies that, in most cases, recognized both human and mouse EPO. Some of the mice exhibited a dramatic reduction in hematocrit, suggesting that the anti-EPO antibodies neutralized endogenous EPO. The development of an anti-EPO antibody response in humans is an extremely rare event that cannot be reproduced in an animal model without significant manipulation of the system (e.g. use of an adjuvant with doses of EPO considerably higher than therapeutic levels). Nevertheless, the fact that anti-EPO antibodies can develop with an appropriate immunization protocol allows for this model to be used to evaluate factors that may potentiate an immune response to rHuEPO.
L-Glutamine Therapy Increases Exercise Endurance of Sickle Cell Anemia Patients.
Authors: Macan Henry R. , Casaburi Richard , Tsurugaya Hideki , Porszasz Janos , Koh Han , Tanaka Kouichi R. , Niihara Yutaka 
Published: October 2019

Abstract
We have demonstrated previously that oral L-glutamine administration can improve NAD redox potential in sickle red blood cells (RBC) and decrease the endothelial adhesion rate of sickle RBC. Clinically, there was subjective reporting of increased energy level. To confirm the reporting of increased energy level objectively, a study incorporating exercise tolerance testing was designed. After proper consent, 7 homozygous sickle cell anemia volunteers participated in the study, which was composed of two parts. The first is incremental work rate test where the work rate increased incrementally. The second part is the constant work rate test. In this test the 80% maximum work rate for the incremental test is utilized and the patients are tested for duration of exercise. These tests were conducted at baseline and after 8 to 12 weeks of therapy with oral L-glutamine at 30 grams a day. Two of the patients withdrew prior to completion of the follow up testing. There were 6 patients who completed the incremental work rate test and 4 patients who completed constant work rate test, respectively, at baseline and after treatment. Two of the 6 patients who completed the incremental work rate test at baseline declined to have the constant work rate test, resulting in 4 patients completing the constant work rate test. The results were as following: The work rates were 88 watts at baseline and 91.5 watts after treatment, with p = 0.18, for the incremental work protocol and 5.87 minutes at baseline and 7.27 minutes after treatment, with p = 0.02, for constant work protocol. For the incremental work rate, the data show a trend for increase with L-glutamine treatment. For the constant work protocol, there was a significant improvement in the work rate after treatment with L-glutamine. The data are consistent with the subjective reporting from a previous study suggesting that L-glutamine therapy improved the exercise endurance of sickle cell anemia patients
Test Incremental Constant Mean value Peak work rate SD± Duration SD± Pre- 88 watts 25.58± 5.87 minutes 1.65± Post- 91.5 watts 21.69± 7.27 minutes 1.14± Significance P value One-tail test 0.18 0.02
Outcome of Transitioning Pediatric Patients with Sickle Cell Disease to Adult Programs.
Authors: Ballas Samir K. , Dampier Carlton 
Published: October 2019

The transition of medical care of patients with sickle cell disease (SCD) from pediatric to adult providers represents a milestone in their lives. Major concerns among adolescents and young adults about transition include taking responsibility for self, making own decisions, cost of medical care, fear of suboptimal pain management, and reluctance to leave known providers. In this study we present our experience in the process of transition to adult care and its outcome over the last ten years. Adolescents and young adults were given information about the nature of medical care provided by adult internists and hematologists. The sickle cell programs available in the city were described. Moreover, site visits to the hospitals where adult care was to be provided were arranged. During these visits, adolescents and young adults had the chance to meet the hematologist and other potential providers and ask questions, visit the emergency room, the clinic, and the sickle day unit if applicable. Patients were empowered to choose the program to which they wished to be transitioned. During the last 10 years, 90 adolescents and young adults (See Table) with SCD (Sickle Cell Anemia [SS], Hemoglobin SC Disease, and Sickle Thalassemia [ST]) were transitioned to the adult sickle cell program of Thomas Jefferson University. Age of transition varied between 18 and 25 years. Eighteen patients (20%) died. Age at death was 24.9 ± 2.95 years and the male/female ratio was 10:8. Complications of sickle cell disease after transition included leg ulcers, stroke, avascular necrosis, anxiety, depression, and priapism. Nineteen patients (10 males, 9 females) were employed. Twenty-nine (32%) patients developed chronic pain syndrome and its sequelae. Many patients failed to achieve their childhood goals. The data show that a significant number of patients die within 10 years after transition. The quality of life of survivors is suboptimal and drifts into issues of chronic pain management in the adult environment. Identifying these issues may provide predictors that identify children at risk to have undesirable outcomes after transition. Aggressive management and refining the process of transition should improve the outcome after transition.
Distribution of the Transitioned Patients
SS SC ST Total Male 31 8 4 43 Female 34 8 5 47 Total 65 16 9 90
Finding of 8 New Therapeutic Agents by the Use of New High-Throughput Drug Screening Methods Established by the Nhlbi Sicke Cell Disease Reference Laboratory.
Authors: Asakura Toshio , Abdulmalik Osheiza , Iyamu Efe , Chen Qiukan , Yang Jisheng , Brugnara Carlo , Evans Greg 
Published: October 2019

Abstract
The NHLBI Sickle Cell Disease (SCD) Reference Laboratory (Ref Lab) was established in 1997 to facilitate rapid, efficient, accurate and economical evaluation of agents or therapies that may be beneficial for the treatment of patients with sickle cell disease. On the basis of the assumption that the unsuccessful finding of antisickling agents in the past was attributed to insufficient pre-clinical drug evaluation, the SCD Ref Lab proposed to screen drugs using more than 10 in vitro tests to study if a drug inhibits or promotes sickling, hydrates or dehydrates SS cells, prolongs or shortens the delay time prior to deoxy-Hb S polymerization, induces Hb F, increases or decreases the solubility of deoxy-Hb S; Hb oxygen affinity; membrane ion transport, adhesion of SS cells to endothelial cells; met-Hb S formation; hemolysis and the amount of intracellular denatured Hb S. In addition, drugs that showed a beneficial effect without significant adverse effects in these tests were further studied using transgenic mice that produce human sickle hemoglobin. To perform many in vitro tests efficiently, the SCD Ref Lab established a new high-throughput drug evaluation protocol by which many tests are conducted simultaneously using a small volume of SS blood samples or Hb S. To date, we have found 8 new antisickling agents. They are NS3623 (Blood97:1451–7, 2001); MX-1520 (Brit. J. Haematol.125:788–795,2004); NIPRISAN [Brit. J. Haematol.118: 337–343, 2002 and 122: 1001–8 (2003)]; FLOCOR (manuscript in preparation); and 5HMF which forms a Schiff base adduct with Hb S. In vivo studies using transgenic sickle mice showed that pretreatment with each of these drugs prevented the formation of sickled cells in the blood and prolonged the survival time under severe hypoxic conditions. We also found that Amidox, Didox and Trimidox increased the synthesis of Hb F in K562 cells (Am J. Hematol.63: 176–183, 2000).
Prevalence of Respiratory Symptoms in Children with Sickle Cell Disease Compared to Children with Other Hematological Diseases.
Authors: Mueller Brigitta Ursula , Acosta Monica , Dinu Marlen , Sockrider Marianna , Shardonofski Felix , Smith E. O’Brian 
Published: October 2019

Abstract
Acute chest syndrome (ACS) and pulmonary hypertension are complications of sickle cell disease (SCD). The effects of pre-existing respiratory symptoms on the frequency of complications of SCD, such as vaso-occlusive crises and ACS, have not been fully explored. Many therapeutic options exist for patients with reactive airway disease or other recurrent respiratory problems. Control of associated symptoms may help prevent the occurrence of ACS and other sickle cell-related problems. We compared the prevalence of respiratory symptoms in SCD patients compared to patients with other hematological disorders.
Methods: Two questionnaires (one for patients with SCD, one for patients with other hematological disorders) were developed, which included questions regarding respiratory symptoms (especially wheezing and cough, frequency of these symptoms, previous diagnosis of asthma), personal history and environmental exposure. The study was approved by the Institutional Review Board, and patients and their caregivers were interviewed during a routine visit to the outpatient hematology clinic after giving informed consent.
Results: To date, 124 subjects have been interviewed (62 males and 58 females, ages 3–18 years, mean age 10.1yrs), and 120 questionnaires were evaluable, including 59 from patients with SCD and 61 from the comparison group. Respiratory symptoms (wheezing and cough) were more frequent in SCD patients compared to patients with other hematological diseases. Wheezing was present in 34 (58%) SCD patients and in 20 (33%) patients in the other group (p<0.01). Twelve patients (20%) in the SCD group missed school due to respiratory problems (over half of them missed more than 7 days of school) compared to 4 (6%) patients (only 1 missing school for more than 7 days) in the other group (p<0.04). Hospitalization due to respiratory problems before the age of 2 years was more common in SCD patients: 23 (39%) compared to 8 (13%) in other hematological patients (p<0.003).
Conclusions: The prevalence of pulmonary symptoms is higher in patients with SCD compared to patients with other hematological disorders and associated with frequent hospitalizations and school absences.