bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of Complementary and Alternative Medical Practices in a Pediatric Sickle Cell Population.
Authors: Faust Douglas S. , Gardner Renee , Rayford Christopher 
Published: April 2020

Abstract
There is a substantive body of literature on the use of Complementary and Alternative Medicine (CAM) therapies among adult populations generally, and chronically ill populations specifically, however less is known about its utilization with sick children. The use of CAM approaches to the treatment of sickle cell (SC)disease and the associated pain crises has focused largely on the use of hypnosis, musculoskeletal manipulations, or relaxation techniques for acute pain relief. The more general use of CAM therapies in the treatment of sickle disease by families is less well surveyed. Numerous studies have found utilization of CAM therapies in up to 70% in both general and sick adult populations, with somewhat lower incidence in pediatric populations. Adults attending sickle cell clinics with their children were asked to participate in structured interviews detailing the use of vitamins and supplements, physical and somatic therapies, and spiritual/holistic therapies, working from a standard list of interventions used in other studies. 47% of the sample regard treatment with CAM therapies as harmless, however the majority of respondents indicated they were aware of the potential for a potential interaction between prescriptive medication and CAM practices. Most believed that CAM therapies were widely used by adults, and both healthy and physically ill children. In this sample, 80% of those sampled reported the use of CAM therapies in the home, but only 53% reported using CAM therapies with the chronically ill child. The most frequently endorsed CAM approaches included prayer (70%), relaxation (55%) and general vitamins (45). Removing prayer as an alternative failed to significantly reduce the incidence of CAM usage with either the family or the physically ill child. Of the various supplements considered in the treatment of SC disease and discussed in the literature, none of the families reported use of Niprisan, one family reported use of aged garlic, two families reported use of Noni Juice, and 17% of the families reported the use of iron supplements for their child with SC. Further research with other chronically ill pediatric populations is underway, with additional data to be gathered on the use of cultural or regional folk remedies, typically not sampled in other CAM surveys.
A Clinical Database Supports Better Patient Care, and Clinical Research in a Sickle Cell Center at a Large County Hospital.
Authors: Jonas William S. , Cooper Melanie , Platt Allan F. , Beasley JoAnn , Palmer Sheila , Khoury Hanna J. , Eckman James R. 
Published: April 2020

Abstract
The Georgia Comprehensive Sickle Cell Center at Grady Health System was enabled in 1985 by an appropriation of the Georgia State Legislature. The Center developed as the World’s first dedicated 24 hour acute care center is committed to patients with sickle cell syndromes. The Acute Care Center is equipped with 12 observation beds and patients are treated for up to 8 hours before a decision about hospital admission is made. Continuity follow-up clinics are held in the adjacent clinic area with 6 exam rooms, a waiting room, reception area, staff offices, and a multimedia teaching center for patients. Care is provided by a multidisciplinary team of physicians, nurses, physician assistants, nurse practitioners, clinic assistants, secretarial support, social workers, psychologists, and a clinical nurse specialist in psychiatry. The state contract required 16 demographic characteristics on each patient seen by the center staff. To accomplish this, a relational database was developed to manage this large dataset. This database was initially established in R-Base format but subsequently transitioned to Windows based Access in 1995. The database was designed and implemented mainly to coordinate patient care containing demographics, problem lists, current medications, radiology results and laboratory data. The database also is utilized to manage the business aspects of the Center including making appointments, tracking visits, monitoring transfusions, ordering supplies, and tracking inventory. The database also provides support for research by identifying patients who qualify for research studies, tracking participation in clinical trials, correlating molecular genetic characterization with clinical findings and outcomes. The database presently has over 3500 registered patients. There are over 1608 active patients defined as being seen in the past two years. Phenotypes and ages are outlined in Table 1. The number of active patients in many age groups allows for cross-sectional, age specific analysis of complications in sickle cell disease. The database also facilitates identifying subjects for intervention trials by entry of study inclusion and exclusion criteria as search criteria for inquiries. The use of the database as a clinical management tool captures information during patient care activities minimizing the need for separate data entry. Data from 20 years of following patients in this data set also provides information on natural history, frequency of complications, and impact of interventions in patients with sickle syndromes
Table 1. Phenotypes and Ages of Active Patients Phenotype HbSS HbSC Sβ+ thal Sβo thal Other Unkn Total Number 711 214 112 18 237 316 1608 Percent 44% 13% 7% 1% 15% 20% 100% Age 0 – 9 10–19 20–29 30–39 40–49 50–59 ≥ 60 Number 321 339 414 283 172 58 21
Dietary Hypercholesterolemia Enhances Heparin-Induced Thrombocytopenia/Thrombosis: A Prothrombotic Risk Factor in a Transgenic Mouse Model.
Authors: Reilly Michael P. , Dessain Scott K. , Taylor Scott M. , Kowalska M. Anna , Poncz Mortimer , Sachais Bruce S. , Cines Douglas B. , Arepally Gowthami , Williams Kevin Jon , McKenzie Steven E. 
Published: April 2020

Abstract
Heparin-induced thrombocytopenia/thrombosis (HIT/T), the most frequent drug-induced immune thrombocytopenia, is a common cause of life- and limb-threatening thrombosis. Although heparin/platelet factor 4 (PF4) antibodies are detected in many patients treated with heparin, there is little understanding of why only a subset of patients develops thrombosis. We recently produced and characterized the first mouse model that recapitulates the salient features of the disease. A second generation model, designated IIA/hPF4-mPF4KO, expresses human FcγRIIA and PF4 but lacks endogenous mouse PF4. These models allow systematic investigations of factors that contribute to pathogenic consequences of HIT/T antibodies. In the current study, we hypothesize that hypercholesterolemia, a known stimulus for atherosclerosis, endothelial dysfunction, and platelet hyperreactivity, would augment thrombosis in our mouse model of HIT/T. Age and sex-matched IIA/hPF4-mPF4KO mice were fed an atherogenic diet (Paigen diet) (AD; 15% cocoa butter, 1% cholesterol, 0.5% cholate) (n=10) or maintained on standard diet (SD; 4.5% fat, no cholate) (n=10). Mice fed the AD for only 4 weeks had significantly increased cholesterol levels (173 ± 29 mg/dl vs. 50 ± 18 mg/dl for SD-fed; p &lt; 0.0001). Mice were then injected with 30 U heparin and KKO, a mouse monoclonal heparin/PF4 antibody. The mean nadir platelet count in AD-fed mice was 34.6% ± 9.1 lower than that in the SD-fed mice (p&lt; 0.0001). Thrombin-anti-thrombin III (TAT) levels, which reflect thrombin generation in vivo, in the AD-fed mice increased from 32 ± 5 μg/at baseline to 79 ± 16 μg/l (p &lt; 0.0001) coincident with the platelet nadir. In contrast, SD-fed mice, with a less profound fall in platelets, showed no increase in TAT. Histological examination showed multiple platelet-fibrin thrombi in lungs and livers of AD-fed mice, whereas the SD-fed mice showed no histological evidence of thrombosis. Thus, in our mouse model, short-term diet-induced hyperlipidemia significantly increases the severity of heparin/PF4 antibody-mediated thrombocytopenia and thrombosis. Our studies provide evidence that a specific host factor can enhance the pathologic effects of heparin/PF4 antibodies in vivo and contribute to thrombotic risk in patients with HIT/T. An increased understanding of the contribution of prothrombotic factors not only will facilitate identification of patients with heparin/PF4 antibodies who are at increased risk of thrombosis, but also provide novel approaches to treatment of HIT/T.
Effects of HLA-C and HLA-DQB1 Mismatching on Outcome of Unrelated Donor Marrow Transplantation for Patients with Severe Aplastic Anemia.
Authors: Kojima Seiji , Yabe Hiromasa , Kato Koji , Kigasawa Hisato , Sakamaki Hisashi , Tsuchida Masahiro , Kato Shunichi , Morishima Yasuo , Kodera Yoshihisa 
Published: April 2020

Abstract
Prior studies assessing the effects of HLA mismatching on outcomes of unrelated donor marrow transplantation (UBMT) have yielded conflicting results. Our previous study revealed that mismatching of HLA-A and -B antigens, and not of HLA-DRB1 antigen, was the most crucial risk factor for survival for patients with SAA who received UBMT (Kojima S et al, Blood100: 799, 2002). Because only the data of HLA-A, -B, and DRB1 were available, the role of HLA-C and DQB1 mismatching was not clarified in that study. The current study aimed to evaluate the effects of HLA-C and DQB1 mismatching. From Feb 1993 to April 2003, 260 consecutive patients with acquired aplastic anemia (AA) received UBMT through the Japan Marrow Donor Program. We selected 79 recipient-donor pairs in which molecular analysis of HLA-A, -B, -C, -DRB1, and DQB1 were performed. Patient ages ranged from 3 to 46 years (median, 15 years). Various preconditioning regimens were used by individual centers. In 69 patients (87%), cyclosporine and methotrexate were used for the prophylaxis against GVHD. Of the 79 pairs, 26 (33%) were found to be matched at HLA-A, -B, -C, -DRB1, and DQB1; 18 (23%) were mismatched at a single HLA antigen (6 HLA-A or -B, 7 HLA-C, 5 HLA-DRB1 or HLA-DQB1); 31 (39%) were mismatched at two HLA antigens (5 HLA- and HLA-DQB1, 18 HLA-A or -B and HLA-C or -DRB1 or -DQB1, 8 HLA-C and HLA-DRB1 or -DQB1); and 9 (11%) were mismatched at 3 HLA antigens. Transplant-related toxicities such as graft failure, grade 3 to 4 acute GVHD, and chronic GVHD were found in 7/74, 14/70, and 16/59, respectively. In a univariate analysis, any single HLA mismatching including HLA-A, -B, or -C did not increase the incidence of acute GVHD. Of 79 patients, 44 survived. The 5-year survival rate did not differ between recipients transplanted from a full-matched donor (68.5%) and those from any single HLA mismatched donors (66.7 to 80.0%). In addition, the 5-year survival rate was not worse (62.5%) in patients transplanted from HLA-C and HLA-DRB1 or -DQB1 mismatched donors. However, the 5-year survival rate was significantly worse (38.9%) in recipients who transplanted from HLA-A or -B mismatched and -C or -DRB1 or -DQB1 mismatched donors and it was 0% in patients who were mismatched at 3 antigens. In a multivariate analysis, the relative risk for HLA-A or -B and -C or -DRB1 or -DQB1 mismatching was 4.24 (95% CI, 1.6–11.5) and for 3 antigen mismatching, it was 20.0 (95% CI, 5.6–71.6). The current JMDP study showed that mismatching of a single HLA antigen did not result in increased mortality. However, in patients with HLA-A or -B mismatching, additional mismatching at HLA-C, -DRB1, or -DQB1 had a significant adverse effect on survival. Matching of HLA-C and -DQB1 should be incorporated into algorithms for unrelated donor selection.
Identification of Novel Erythropoietic Genes and Alleles Using a Large-Scale Chemical Mutagenesis Screen in Mice.
Authors: Jane Stephen M. , Sutton Rosemary , Rank Gerhard , Auden Alana , Alexander Warren , Kile Benjamin , Hilton Douglas , Cunningham John M. , Curtis David 
Published: April 2020

Abstract
Genome-wide chemical mutagenesis screens have been successfully performed in zebrafish to identify genes involved in erythropoiesis. We have now executed a large-scale screen for genes involved in red cell production in mice by using N-ethyl-N-nitrosurea mutagenesis. Five thousand G1 mice were screened by automated haematological analysis at 7 weeks of age for abnormalities of their red cell indices that lay more than 3 standard deviations outside the normal population average. Mice with co-incident abnormalities in white cell or platelet counts were excluded. Six mutant lines were identified with microcytosis (RBC1-6) that was heritable with subsequent backcrossing. Three of these lines (RBC 1, 4, 5) were found by gene mapping and candidate gene sequence analysis to harbour different mutations in the transferrin receptor gene (TfR) that led to embryonic lethality in their homozygous state. These mutations were clustered in the sequence encoding the domain involved in receptor homodimerisation, providing, for the first time, in vivo functional correlations of the previous structural analyses. The RBC3 line was also mapped to the interval containing the TfR gene, although no mutations were present in the TfR coding region or splice donor/acceptor sites in this line, raising the possibility of a regulatory sequence mutation, which we are investigating. The RBC2 line was mapped to chromosome 8, and found to contain a splice acceptor mutation in the ankyrin gene. This mutation results in a 22 bp deletion with a resultant frame shift in the regulatory domain. Mice homozygous for this mutation are born jaundiced with massive splenomegaly and a blood film consistent with severe spherocytosis, and die within 6 weeks of progressive anemia. As such, this line represents a new mouse model of severe hereditary spherocytosis. The final line, RBC6 displays a profound hypochromic, microcytic anemia in the homozygous state at birth, with apparent normality of all other organ systems. The mutation has been mapped to a chromosomal interval containing only a few genes, none of which have been previously linked to red cell production or differentiation, and therefore represents a novel erythropoietic gene/allele.
ADAMTS13 Levels Support Hypothesis of Distinct Mechanistic Pathways for Early Versus Late-Onset of Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura (TTP).
Authors: Kwaan H.C. , McKoy June M. , McCaffrey Kathryn R. , Yarold Paul R. , Kim Benjamin , Zakarija Anaadriana , Bandarenko Nicholas , Pandey Dilip K. , George James N. , Zheng X. Long , Carson Kenneth R. , Bennett Charles L. 
Published: April 2020

Abstract
Background: Ticlopidine and clopidogrel, thienopyridine derivatives used for cerebrovascular events and coronary artery syndromes, are the first and third most common causes of drug-related TTP reported to the FDA. Ticlopine-associated TTP has been characterized as having later onset, having higher relapse rates, and being more responsive to plasmapheresis—findings associated with ADAMTS13-deficiency. Based on a limited number of ADAMTS13 measurements, Moake (NEJM 2002) and Bennett (NEJM 2000) speculated that antibody-mediated ADAMTS13-deficiency appeared to be the cause of both ticlopidine- and clopidogrel-associated TTP.
Methods: Clinical and ADAMTS13 laboratory data for TTP associated with ticlopidine (n=116 and 12 cases, respectively) and clopidogrel (n= 46 and 7 cases, respectively) were reviewed.
Results: Clinical Evaluation: Mortality of ticlopidine-associated TTP was 34.5%. Mortality of clopidogrel-associated TTP was 22.2%. Overall moretlaity rate was 31%. Among 162 thienopyridine-associated TTP cases, late-onset TTP (89% of the cases) occurred after &gt; 5 days of thienopyridine use and was 4-times more common with ticlopidine than clopidogrel. Early onset TTP (11% of the cases) occurred within 5-days of thienopyridine initiation and was 4-times less common with ticlopidine than clopidogrel. Laboratory Evaluation: Among 12-ticlopidine and 7-clopidogrel-associated TTP patients, laboratory assays prior to plasmapheresis identified severe ADAMTS13 deficiency 3.3-fold more often with ticlopidine (92% versus 29%, p &lt; 0.01) and presence of inhibitory autoantibody almost 3-fold more common with ticlopidine (83% vs 30%) than clopidogrel. Among thienopyridine-associated TTP cases, patients with severe ADAMTS13-deficiency (&lt;5% of normal) experienced higher relapses rates (15% versus 0%).
Conclusions: Contrary to previously proposed mechanistic hypotheses, thienopyridine-associated TTP appears to manifest as an ADAMTS13-deficiency mediated syndrome (primarily with &gt; 5 days of ticlopidine) that has occasional relapses and an ADAMTS13-normal syndrome (primarily with &lt; 5 days of clopidogrel) that is not associated with relapse. Although in the same drug class, the metabolites of ticlopidine and clopidogrel are different, which may account for the distinct mechanistic pathways. Immunologically mediated ADAMTS13 -deficient TTP, like ticlopidine-associated TTP, may result from immunogenic exposures that occurred 1 to 2 weeks prior to syndrome onset. In contrast, ADAMTS13-normal TTP cases, like clopidogrel-associated TTP, may result from recent exposure that occurred within 5 days prior to TTP onset leading to direct endothelial cell injury.
Immunogenetic Profiling of Follicular Lymphoma Reveals Universal N-Glycosylation Sites Introduced into the B Cell Receptor by Somatic Mutation and Suggests Relevance to Lymphoma Pathogenesis.
Authors: Ottensmeier Christian H. , McCann Katy J. , Johnson Peter , Stevenoson Freda K. 
Published: April 2020

Abstract
Immunogenetic analysis of B-cell malignancies can provide important information that relates to the cellular origin and clonal history of these lymphomas and give clues as to possible pathogenic mechanisms. In follicular lymphoma (FL), immunoglobulin variable region (V) genes are commonly somatically mutated and display intraclonal heterogeneity consistent with location in the germinal centre (GC). In this analysis of 44 cases of FL we find that, with minor exceptions, both the VH and VL gene usage reflects that of the normal B cell repertoire, indicative of a common antigenic drive and in support of a final transforming event in the GC. We have previously reported a high incidence of potential N-glycosylation sites in the VH genes of FL, which have been introduced by the process of somatic mutation. Here we have assessed both the VH and VL genes and find that sites are universally present and further demonstrate that they are available for functional glycosylation. The majority of sites are found in VH (81%) and are located predominantly within CDR2 and CDR3, with few sites present in the FRs. Sites are also evident in VL (45%) where they are focused mainly in CDR3 and CDR1. A minor subset (10%) has sites in VL only. In total, 26 different N-glycosylation motifs were observed, with NIS being the most commonly used. The natural motif in the V4–34 germline gene appears unimportant, and can be lost. Scrutiny of the somatic mutations giving rise to these motifs reveals that the acquisition of sites was predominantly (73%) achieved by a single amino acid (aa) replacement to Asn at position 1 of the motif, either with or without an additional, non-essential aa replacement at another position. Common ‘hotspots’ were observed within the CDR2 for the VH gene segments V3–23, V3–48, V3–07 and V3–15. It appears likely that the acquisition of N-glycosylation sites in the antigen-binding site during somatic mutation in the GC and the subsequent addition of oligosaccharides is important to the lifestyle of FL and may provide a critical second tumorigenic event. In turn, it may be possible to exploit this seemingly essential feature to develop novel therapeutic approaches.
Adoptive Transfer of In Vitro Generated T Cell Precursors Enhances Donor T Cell Reconstitution and Graft-Versus-Tumor Activity in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.
Authors: Zakrzewski Johannes L. , Kochman Adam A. , Lu Sidney X. , Terwey Theis H. , Kim Theo D. , Hubbard Vanessa M. , Muriglan Stephanie J. , Suh David , Cabrera-Perez Javier , Radhakrishnan Radhika , Heller Glenn , Zuniga-Pflucker Juan Carlos , Alpdogan Onder , van den Brink Marcel R.M. 
Published: April 2020

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with a varying period of immunoincompetence that particularly affects he T cell lineage resulting in significant morbidity and mortality from opportunistic infections. Recent studies have shown that murine T cells and their precursors can be generated from hematopoietic stem cells (HSC) in vitro using a OP9-DL1 coculture system consisting of OP9 bone marrow stromal cells expressing the Notch 1 ligand Delta-like 1 and growth factors (interleukin 7 and fms-like tyrosine kinase-3 ligand). In this study we determined the effects of adoptively transferred in vitro generated T cell precursors on T cell reconstitution after allogeneic HSCT. We selected HSC (Lin- Sca-1hi c-kithi) from bone marrow (BM) of C57BL/6 mice and cultured these cells on a monolayer of OP9-DL1 cells in the presence of growth factors. These HSC expanded 2,000–5,000-fold within 3–4 weeks and consisted of &gt;95% CD4-CD8-double negative (DN) T cell precursors after 16–28 days of culture. We infused these cells (8x106) with T cell depleted (TCD) BM (5x106) or purified HSC into allogeneic recipients using minor antigen mismatched and MHC class I/II mismatched transplant models. Control mice received TCD BM or purified HSC only. Progeny of OP9-DL1 derived T cell precursors were found in thymus and spleen increasing thymic cellularity and significantly improving thymic and splenic donor T cell chimerism. This effect was even more pronounced when purified HSC instead of whole BM were used as allograft. T cell receptor repertoire and proliferative response to foreign antigen (determined by third party MLR) of in vivo differentiated OP9-DL1 derived mature T cells were intact. Administration of in vitro generated T cell precursors did not induce graft-versus-host disease (GVHD) but mediated significant graft-versus-tumor (GVT) activity (determined by in vivo bioluminescence imaging) resulting in a subsequent significant survival benefit. This advantage was associated with better cytokine responses (IL-2, INF-g, TNF-a) in T cells originating from OP9-DL1 derived T cell precursors compared to BM donor derived T cells. We conclude that the adoptive transfer of OP9-DL1 derived T cell precursors significantly enhances post-transplant T cell reconstitution and GVT activity in the absence GVHD.
AML1-ETO9a, an Alternatively Spliced Form of AML1-ETO, Collaborates with AML1-ETO To Promote Leukemogenesis.
Authors: Yan Ming , Wang Yang , Peterson Luke F. , Kanbe Eiki , Boyapati Anita , Zhang Dong-Er 
Published: April 2020

Abstract
t(8;21) is a common chromosome translocation in acute myeloid leukemia (AML). AML1-ETO is the fusion protein produced by t(8;21). Results from our work and others indicate that full length AML1-ETO is not leukemogenic and needs additional mutations to promote leukemia. Most recently, we have identified an alternatively spliced form of AML1-ETO, AML1-ETO9a, that lacks the C-terminal NHR3 and NHR4 domains of AML1-ETO. Here, we report that unlike the negative effect of full length AML1-ETO in cell cycle progression, AML1-ETO9a enhances cell proliferation by shortening G1 phase of cell cycle in the IL-3 dependent multipotent hematopoietic progenitor cell line FDCPmix. Using retroviral mediated gene expression in murine hematopoietic cells and bone marrow transplantation in mice, we have demonstrated that AML1-ETO9a is highly leukemogenic. Most importantly, we show that AML1-ETO9a expression in transgenic MRP-8 AML1-ETO hematopoietic cells results in earlier onset of AML than AML1-ETO9a expression alone controls. Furthermore, the presence of full length AML1-ETO also alters the phenotype of leukemia progenitor cells from CD34- to CD34+. These results suggest that the alternatively spliced form AML1-ETO9a cooperates with full length AML1-ETO in leukemogenesis when coexpressed in t(8;21) patients.