bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+Treg in Immune Pathophysiology of Aplastic Anemia.
Authors: He Guangsheng , Zhou Ling , Wu De Pei , Sun Aining , Miao Miao 
Published: October 2019

Abstract
Objective: To explore the possible immune pathophysiology of CD4+T regulatory (CD4+Treg) in acquired aplastic anemia (AA).
Methods: According to the markers on membrane, cytokines, and effective mechanisms of CD4+Treg, the levels of CD4+CD25+Treg,CD4+CTLA-4+Treg,CD4+ICOS+Treg,CD4+PD-1+Treg,CD3+CD8−IL-10+Treg,CD3+CD8−TGF-β1+Treg,CD3+CD8−IL-Treg in the bone marrow of 23 cases with AA at active phase, 10cases with AA at recovery phase, 15 normal controls, were measured, and the relationship between CD4+Treg and priming immune factor-CD28 or effective immune factor-IFN-γ were also evaluated respectively.
Results: [circ1]In the group of AA at active phase, at recovery phase, and normal controls, CD4+CD25+Treg: (3.36±2.05)%, (3.49±1.71)%, (2.40±0.77)%, CD4+CTLA-4+ Treg: (1.43±0.67)%, (3.46±2.26)%, (2.45±1.30)%, CD4+ICOS+Treg: (2.04±1.79)%, (2.95±2.23)%, (2.37±1.68)%, CD4+PD-1+Treg: (1.40±1.32)%, (2.34±0.87)%, (2.07±1.64)%, CD3+CD8−IL-10+Treg: (2.14±1.19)%, (2.37±1.20)%, (2.04±1.25)%, CD3+CD8−TGF-β1+Treg: (1.83±0.99)%, (1.52±0.73)%, (2.15±1.17)%, CD3+CD8−IL-4+Treg: (2.46±1.65)%, (2.53±1.61)%, (1.99±1.27)%; costimulatory of CD3+CD4+CD28+ was: (39.84±10.89)%, (22.72±9.08)%, 31.40±10.83)%, the Th1cells CD3+CD8−IFN-γ+ were: (11.13±4.96)%, (5.39±4.29)%, (4.21±2.11)%. [circ2] Contrast to normal controls, while CD4+CTLA-4+Treg of AA at active phase deceased markedly (p=<0.01), levels of other CD4+Treg which marked by membrane moleculars or cytokines: CD4+CD25+Treg, CD4+PD-1+Treg, CD4+ICOS+Treg, CD3+CD8−IL-10+Treg, CD3+CD8−TGF-β1+Treg, CD3+CD8−IL-4+Treg did not change significantly (p>0.05); [circ3] Contrast to normal controls, the ratio of membrane costimulatory of CD28/ICOS CD28/CTLA-4, CD28/PD-1 were all increased significantly (p<0.05) in AA at active phase; the ratio of cytokines in cell plasma of IFN-γ+IL-4, IFN-γ/TGF-β, and IFN-γ/IL-10, were also increased significantly (p<0.05).
Conclusion: [circ1] In AA, the positive regulatory costimulatory increased while the negative regulatory costimulatory did not change or decreased, which shifted the immune balance to intensification. [circ2] Not only at priming stage but also at effective stage, the immune strengthened factors were higher than attenuated factors in AA.
The Role of Nitric Oxide in γ-Globin Induction by Hydroxyurea.
Authors: Lou Tzu-Fang , Williams Ashley , Li Wei , Pace Betty S. 
Published: October 2019

Abstract
Hydroxyurea (HU) has been shown to induce fetal hemoglobin (HbF) synthesis through activation of the soluble guanosine cyclase/cyclic guanosine monophosphate signaling pathway. The release of NO from HU by heme iron is thought to be involved in this mechanism of HbF induction. Studies completed in sickle cell patients confirmed increased serum NO levels after oral HU therapy but NO generation in red blood cells and the effect on γ-gene transcription have not been extensively investigated. Therefore, we performed studies to quantify NO generated by HU in K562 cells and normal erythroid progenitors as a mechanism for γ-globin activation. NO levels were measured after drug treatments using the Nitric Oxide Assay Kit (Calbiochem) and γ-globin mRNA was measured using quantitative PCR. HU (100μM) increased NO 1.4 to 1.8-fold at 24–72 hrs in K562 cells compared to a 2.0 to 2.5-fold increase in NO produced by the known NO donor, deta-nonoate (DE; 400μM). NO levels were also measured in erythroid progenitors grown in liquid cultures; a 1.6-fold increase in NO was produced by 30μM HU after 48 hrs with comparable increases produced by 200μM DE. To understand the effects of HU on normal NO synthesis from L-arginine through the action of NO synthase (NOS), we performed studies with the NOS inhibitor, NG-Monomethyl-L-arginine (L-NMMA). Interestingly, HU increased NO levels 2.5-fold at 24 hrs when combined L-NMMA compared a 1.4-fold increase produced by HU alone; this pattern persisted up to 72 hrs. Parallel with these findings γ-globin activation by HU was augmented approximately 25% by L-NMMA; DE combined with L-NMMA did not produce the same effect. These data suggest a novel mechanism for NOS regulation by HU compared to DE. Subsequent studies were completed to determine if HbF synthesis could be augmented by combining NO donors since they have different mechanisms of action. HbF levels in K562 cells were measured by ELISA (Bethyl Laboratories) and normalized by total hemoglobin and protein. Treatment with HU or DE increased HbF 3.6-fold and 4.6-fold respectively; when HU was combined with DE an additive 7.6-fold increase in HbF was produced. These data confirm that HU treatment lead to NO generation in K562 cells and normal erythroid progenitors which plays a role in its mechanism of γ-globin activation. HU combined with DE had an additive effect on HbF synthesis. These findings are relevant to current research efforts to develop novel HbF inducers for therapy in sickle cell patients.
A Randomized Controlled Trial of Patient Controlled Analgesia Versus Continuous Infusion of Morphine during Vaso-Occlusive Crisis in Sickle Cell Disease.
Authors: van Eduard J. Beers , van Charlotte F.J. Tuijn , Nieuwkerk Pythia T. , Friederich Philip W. , Levi Marcel M. , Franken Jan H. , Biemond Bart J. 
Published: October 2019

Abstract
Intravenous morphine is the treatment of choice for severe pain during vaso-occlusive crisis in sickle cell disease (SCD). However, side-effects of morphine may hamper effective treatment and high plasma levels of morphine are associated with severe complications such as acute chest syndrome. Furthermore, adequate dosing remains a problem since no objective measurement of pain severity exists and analgesia should be titrated upon the patient’s reported pain. Patient-controlled analgesia (PCA) may therefore be an interesting alternative since patients can titrate the level of analgesia themselves. Although PCA is currently used for the treatment of vaso-occlusive crises in SCD, no randomized controlled trials have been performed in admitted patients with a vaso-occlusive crisis so far. In the present study, we conducted a randomized controlled trial to compare the administration of morphine with PCA versus CI in sickle cell patients with vaso-occlusive crises. Patients were randomized between PCA and CI of morphine within 24 hours after hospital admission. Endpoints of the study were: the mean and cumulative morphine dose, pain intensity, incidence of side-effects (nausea, constipation, pruritus and drowsiness) and quality of life (QoL). Pain intensity was measured daily using a ten-point-scale verbal pain score. Reduction of pain intensity was measured by subtracting a pain score on a ten point visual analogue scale (VAS) before randomization from the same measurement two days after randomization. Side-effects were measured four times per day on a 11-point numerical rating scale. QoL was measured using the 36-item Short Form Healthy Survey (SF36). Twenty five consecutive episodes of vaso-occlusive crisis in 19 patients with SCD were included in the study. No difference in the mean daily pain scores were found between the two groups (4.9 versus 5.3). However, patients in the PCA-group demonstrated to have a strongly reduced mean and cumulative morphine consumption as compared to the patients in the CI-group (0.5 mg/h versus 2.4 mg/h (P<0.001) and 33 mg versus 260 mg (P=0.018) respectively). The lower mean and cumulative morphine consumption in the PCA-group led to significant less nausea and constipation during treatment as compared to the CI-group (area under the curve respectively 11 versus 18 (P= 0.045) and 30 versus 45 (P= 0.021)). Furthermore, a non-significant reduction in the duration of hospital admission of 3 days was observed in the PCA-group. Patient controlled analgesia results in adequate pain relief at a much lower morphine consumption and should considered to be first choice in morphine administration to sickle cell patients admitted with vaso-occlusive crisis.
Figure. Mean morphine dose per patient Figure. Mean morphine dose per patient
Time Series Analysis of the Pain Diary Data Obtained during the Multicenter Study for Hydroxyurea (MSH) Clinical Trial.
Authors: McCarthy William F. , Bauserman Robert L. , Barton Bruce A. , Guo Nan , Ballas Samir K. , Smith Wally 
Published: October 2019

Abstract
The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) was a randomized double-blind placebo-controlled trial to test whether hydroxyurea could reduce the rate of painful crises in adult patients who had at least three painful crises per year. Daily pain diaries were collected biweekly for 299 MSH patients. Patients rated daily pain on a linear scale 0 through 9. The daily pain data was collected to provide useful information regarding the efficacy of hydroxyurea in reducing the rate of painful crises. The objective of this analysis was to determine if there was an underlying time series pattern associated with the MSH pain diary data, especially one indicative of a calendar or seasonal association. An Unobserved Component Model (UCM) was used to determine, based on empirical data, if there was a cycle and/or trend associated with the time series. The times series started on December 1991 and ended on December 1994. The series was equally spaced and univariate. The equal spacing was a monthly interval. The average pain score for each two- week diary period was used to create each unit of analysis. This analysis considered three groupings of patients: all patients, hydroxyurea patients and placebo patients. The results of the modeling indicated that there was indeed both a cycle and a trend associated with the MSH pain diary data. This is the case for each group of patients considered. All three groups had a cycle pattern that seemed to show a seasonal behavior of average pain scores (the changing of the season seemed to show an approximate transition from trough (Spring) to peak (Fall/Winter) and peak to trough). There was a downward trend in average pain scores for both the all patientsgroup and the hydroxyurea patientsgroup. However, there was an upward trend in average pain score for the placebo patientsgroup. This may reflect the result shown in the MSH Clinical Trial, that HU usage reduced the average pain scores reported by patients.
AHSP Promoter Homopolymer in Beta-Thalassemia Syndromes.
Authors: Galanello Renzo , Satta Stefania , Cipollina Maria Dolores , Perra Chiara , Perseu Luciana 
Published: October 2019

Abstract
Alpha hemoglobin stabilizing protein (AHSP) is an erythroid protein that binds specifically to the alpha globin chains to form a stable complex, preventing their precipitation before the assembly of the hemoglobin tetramere. Studies have shown that
AHSP is required for normal erythropoiesis, knock-out mice has a phenotype similar to beta thalassemia, loss of AHSP worsens the severity of the disease in thalassemic mice.
Therefore, altered AHSP expression or function could account for some of the variability in beta-thalassemia phenotype. At position -160bp upstream of exon 1 of the AHSP gene, two main homopolymers (T18 and T15) have been reported that may influence the AHSP expression and hence the hematological phenotype. In particular the frequence of the shorter T15 homopolymer, which is associated with a lower AHSP expression, was much higher than expected (on the basis of the allele frequency in the healthy population) in a group of 9 patients with thalassemia intermedia, due the compound heterozygosity for beta-thalassemia and the triple alpha globin gene (Mei et al, 2006). We have studied the frequency of T15 and T18 homolpolymers in a group of 20 normal subjects and in patients with different thalassemia syndromes, i.e. beta zero 39 homozygotes with thalassemia major (14 patients) and intermedia (19), compound heterozygotes for beta-thalassemia and triple alpha globin gene (13) and simple carriers for beta thalassemia with thalassemia intermedia phenotype (5). We found the following genotype distribution reported in figure1. There is no difference in the frequency of the genotypes among the groups, except in the severe beta-thalassemia carriers, where the short T15 homopolymer is more common. These findings are consistent with the reduced AHSP expression previously reported in the reticulocytes and in the erythroid cultures of these unusually severe beta thalassemia carriers. (Galanello et al, abs 1881. ASH 2003). Therefore, only in the peculiar group of beta-thalassemia carriers with the clinical features of thalassemia intermedia, the AHSP genotype appears to be a relevant contributory factor in the hematological phenotype.
Figure Figure
The Involvement of Regulatory T Cells in Immunopathophysiology of Autoimmune Neutropenia in Infancy.
Authors: Nakamura Kazuhiro , Miki Mizuka , Kawaguchi Hiroshi , Sato Takashi , Kurita Emi , Onodera Rie , Hiraoka Asako , Kobayashi Masao 
Published: October 2019

Abstract
CD4+25+ regulatory T cells (Treg) have been recognized to play a significant role in the immunopathogenesis of autoimmune disease, tumors, and organ transplantation. Several human autoimmune diseases in adulthood have been reported to associate with alternations in Treg. To date little is known about the standard value of Treg in infancy and childhood and its involvement in pediatric autoimmune disease. Autoimmune neutropenia (AIN) in infancy is a common disorder characterized by chronic neutropenia, the detection of antineutrophil antibodies in sera, and spontaneous resolution of neutropenia within several months to a few years. In this study, to elucidate the involvement of Treg in AIN known as a representative autoimmune disease in infancy and early childhood, we examined the frequencies of Treg in various normal age groups and AIN patient. Blood samples from normal neonates (n=22), infants (1 month through 3 years in age, n=21), adults (n=12) and AIN patients (1 month through 3 year in age, n=22) were obtained after informed consent. The frequency of Treg was assessed by the expression of CD4, CD25, and FOXP3 using flow cytometry. As shown in Table, the frequency of CD4+25high Treg known as pure Treg fraction was highest in neonates and decreased by aging. Notably CD4+25high Treg in AIN patients was fewer than age-matched control infants (P<0.01). Furthermore, the ratio of intracytosolic FOXP3 expression of each Treg fraction in AIN patients was fewer than age-matched control infants (P<0.05). The spontaneous disappearance of antineutrophil antibody and the restoration of the frequency of CD4+25high cells that preceded the normalization of the neutrophil count were found in two patients with AIN. These results suggest that Treg could contribute to the immunopathophysiology of AIN in infancy.
Percentage of CD25+, CD25high, and CD25low in CD4+ cells Neonates Infants Adults Patients with AIN Date represent mean±SD. CD25+ 11.9±2.6 10.1±2.0 18.5±3.9 9.5±1.9 CD25high 8.3±2.7 5.6±1.9 4.2±1.1 4.0±1.6 CD25low 3.6±1.2 4.5±1.9 14.3±3.6 5.5±1.5
The Outcome of 129 Korean Children with Hemophagocytic Lymphohistiocytosis.
Authors: Youn Hoi Soo , Song Joon Sup , Im Ho Joon , Seo Jong Jin , Moon Hyung Nam , Park Byoung Gyu , Kim Thad T. , Kang Hyoung Jin , Shin Hee Young , Ahn Hyo Seop , Yoo Keon Hee , Sung Ki Woong , Koo Hong Hoe , Jeong Dae Chul , Cho Bin , Kim Hack Ki , Lee Mee Jeong , Park Eun Sil , Kim Hwang Min , Lim Young Tak , Kim Heung Sik , Lyu Chuhl Joo , Kim Sun Young , Park Jun Eun , Lee Young Ho , You Chur Woo , Kim Ji Yoon , Kang Im Ju , Lee Kun Soo , Kook Hoon , Hwang Tai Ju 
Published: October 2019

Abstract
Chemotherapy and immunotherapy based treatments improved survival of patients with hemophagocytic lymphohistiocytosis(HLH), but the outcome is still unsatisfactory. We analyzed the putative prognostic factors in a nationwide cohort of patients with HLH. Retrospective data recruitment for the patients diagnosed as HLH during the past 10-year period from 1996 to 2005 was carried out by the Histiocytosis Working Party of the Korean Society of Hematology. The HLH diagnostic criteria of the Histiocyte Society were strictly applied to confirm the eligibility of patients for this study. We analyzed the outcome of pediatric patients with HLH according to the age at diagnosis, sex, central nervous system(CNS) involvement, disease condition(familial or secondary), treatment modalities and disease state after 2 months of initial treatment. One hundred twenty nine patients from 19 centers fulfilled the diagnostic criteria(n=112) and/or had affected siblings together with some of the criteria(n=17). The male to female ratio was 0.95:1. The probability of 3 year overall survival(OS) in HLH patients was 41% with a median follow-up of 51 months. The 3 year OS in patients under 12 months of age at presentation(n=23) was 21.7%, and 44.3% in those over 12 months of age(n=106)(p=0.001). The 3 year OS in patients with CNS involvement(n=16) was 29.1%, and 44.4% in patients without CNS involvement(n=112)(p=0.01). The 3 year OS in patients with active state after 2 months of initial treatment(n=63) was 14.1% compared to 77.2% in those with inactive state(n=61)(p=0.0001). The 3 year OS in patients who received hematopoietic stem cell transplantation(HSCT)(n=17) was 82.3%, and 35.2% in patients treated with chemoimmunotherapy only(n=112)(p=0.03). Among the HSCT patients, complete remission was obtained in 14 patients except 3 other patients who died of infection and graft failure at early post-transplant period. The reasons for HSCT were active disease after chemoimmunotherapy(n=8), relapsed disease(n=5), and familial HLH(n=4). Other prognostic factors were not significantly correlated with outcome in our survey. The age and CNS involvement at diagnosis, disease state after 2 months of initial treatment were important prognostic factors which affected the outcome of HLH significantly in this cohort. This survey also demonstrated excellent outcome of familial or relapsed, persistent secondary HLH after HSCT compared to chemoimmunotherapy only.
Prion Clearance Capacity Is Improved by Modification of a Filtration Step in the Gamunex® (IGIV) Manufacturing Process.
Authors: Mink Michael , Hartwell Randal , Bauman Patricia , Burdick Michael , Kislan Michele , Nelson Mark , Oquendo Renea’ , Pifat Dominique , Cai Kang 
Published: October 2019

Abstract
Prions are misfolded pathogenic proteins associated with the transmission of transmissible spongiform encephalopathies (TSEs). Although no TSE transmission through human plasma products has been documented to date, the risk of transmission exists. To provide assurance for product safety with respect to the risk of TSE transmission, this study evaluates the prion clearance potential of a modified intravenous immunoglobulin (Gamunex®) manufacturing process (Figure 1).
Figure 1. Gamunex® Manufacturing Process Figure 1. Gamunex® Manufacturing Process
In the process prior to modification, an intermediate material was subjected to cloth filtration. In the modified process, the cloth filtration is replaced with a depth filtration to improve pathogen removal capacity. Both processes were studied using validated scaled-down models, along with a spiked prion agent. The modified process reduced the prion level to below the limit of detection by Western blot assay. The animal bioassay for infectivity confirmed that the modified process has a marked improvement in prion clearance. This modified process has been implemented in actual Gamunex® manufacturing process. Gamunex® is the only liquid IGIV with FDA approved prion clearance data.
Prognostic Factors for HIV-Associated Lymphoma - Experience in a Tertiary Referral Center in Hong Kong.
Authors: Lau SzeMan June , Lee ManPo , Chan CheukHung , Li ChungKi Patrick 
Published: October 2019

Abstract
Objective: To review the clinical and pathological profile of HIV-associated lymphomas in the local population in order to identify prognostic factors that may define a subgroup of patients who may have better outcome.
Methods: The clinical records of a cohort of 874 cases of HIV infection first seen in our institute from March 1994 to March 2006 were reviewed.
Results: Twenty patients with HIV-associated lymphomas were identified. All were males. Median age was 42 (18 – 72) years. Three had primary central nervous system lymphoma (PCNSL) and 17 had systemic non-Hodgkin’s lymphoma (NHL). All PCNSLs were of B-cell origin. For systemic NHLs, 15 patients had aggressive B-cell lymphoma (diffuse large B cell lymphoma: 12, burkitt-like lymphoma: 2, mantle cell lymphoma: 1) and 2 patients had plasmablastic lymphoma. For the 3 patients with PCNSL, 1 patient deteriorated rapidly and died 12 days after diagnosis, 1 patient survived 20 months after whole-brain radiation therapy (WBRT) and died of CMV pneumonia later and 1 patient is still surviving at 88 months (mons) after WBRT while maintaining on highly active anti-retroviral therapy (HAART). For patients with systemic NHL (n = 17), 2 patients had spontaneous disease regression upon treatment with HAART, 6 received curative intent chemotherapy, 3 received palliative treatment with chemotherapy or radiotherapy, 6 patients could not receive any treatment because of poor performance status and rapid deterioration after diagnosis. The following baseline variables were included as potential predictors of survival among all patients with systemic NHL: prior AIDS diagnosis; CD4 cell count; use of HAART and treatment intent. Number of adverse factors according to International Prognostic Index (IPI) for aggressive NHL (stage III or IV disease, age > 60 years, elevated lactate dehydrogenase, ECOG performance status ≥ 2, ≥ 2 extranodal sites) was calculated. Use of HAART was a favorable prognostic factor for overall survival (p = 0.008). Median overall survival for patients receiving HAART (n = 11) was 15 mons versus 1.6 mons for those without (n = 6). Patients with ≤ 2 adverse factors according to IPI were associated with longer overall survival (p = 0.0002). Patients with IPI > 2 (n = 11) had median survival of 2 mons whereas median survival for patients with IPI ≤ 2 (n = 6) had not been reached (range of follow up duration: 7 to 120 mons).
Conclusion: In our cohort, for patients with HIV-associated systemic NHL, use of HAART and IPI score ≤ 2 were associated with better survival.
Figure Figure Figure Figure