bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-Term Follow up of Patients with Cold Agglutinin Disease.
Authors: Go Ronald S. , Serck Stephanie L. , Davis Jeffrey J. , Bottner Wayne A. , Cole Craig E. , Farnen John P. , Jumonville Alcee J. 
Published: April 2020

Abstract
Background: Data regarding long-term follow up of patients (pts) with cold agglutinin disease (CAD) are limited.
Methods: We reviewed our institutional database of pts with CAD from 1981–2003. The diagnosis of CAD was confirmed by the following criteria: hemolysis and/or cold induced agglutination symptoms, cold agglutinin titre of ≥ 1:40, and typical direct anti-globulin test findings. We retrospectively collected pertinent clinical data including: demographics, dates of diagnosis and last follow up, associated hematologic diseases, baseline laboratory test results, treatment, clinical course, and subsequent development of lymphoproliferative diseases.
Results: We identified 18 pts with CAD. Most (15) were females. The median age at diagnosis was 71.5 years (range, 22–92). While all pts presented with hemolysis, only 2 had cold-induced acral signs or symptoms. The median presenting hemoglobin level was 8.4 gm/dl (range, 4.5–13.5). The cause was considered idiopathic in 10 pts, while 8 pts had concomitant lymphoproliferative disorders at diagnosis: chronic lymphocytic leukemia, 1 pt; non-Hodgkin lymphoma (NHL), 3 pts; and monoclonal gammopathy of undetermined significance (MGUS), 5 pts. A serum protein electrophoresis was obtained in 16 pts. Five pts had monoclonal proteins, all IgM (3 κ, 2 λ). Thirteen (72%) pts required treatment for CAD or associated lymphoid malignancies at some point in the course of their disease. The most common treatments administered for CAD were prednisone (9 pts) and cyclophosphamide (3 pts). Prednisone produced an overall response rate of 78%. The responses were durable with a median of 95 months (range, 15–414). No one responded to cyclophosphamide. After a median follow up of 55.5 months (mean, 99.5; range, 12–449), 8 pts were alive, 5 in complete remission (2 maintained on prednisone), and 3 in partial remission (all off therapy). Of those who died (10 pts), only 1 died of CAD due to complications from severe anemia. Two pts subsequently developed lymphoproliferative diseases, MGUS (IgMk) and low grade NHL, 125 and 175 months after diagnosis, respectively. The clinical course of CAD did not seem to be any worse in pts with lymphoid malignancies.
Conclusions: In our series, pts with CAD are frequently associated (44%) with lymphoproliferative disease at diagnosis. They have a relatively benign clinical course with a good likelihood of long-term disease remission. Unlike previous reports, prednisone is quite effective. Among those pts considered to have idiopathic CAD, a lymphoproliferative disease may develop later during the course of their disease.
Initial Screening Transferrin Saturation Values, Serum Ferritin Concentrations, and HFE Genotypes in Native Americans and Whites in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.
Authors: Barton James C. , Acton Ronald T. , Lovato Laura , Speechley Mark R. , McLaren Christine E. , Harris Emily L. , Reboussin David M. , Adams Paul C. , Dawkins Fitzroy W. , Gordeuk Victor R. , Walker Ann P. 
Published: April 2020

Abstract
There are few reports of transferrin saturation (TfSat) and serum ferritin (SF) phenotypes and HFE C282Y and H63D genotypes in native Americans. We compared initial screening data of 645 native American and 43,453 white HEIRS Study participants who reported a single race/ethnicity and who did not report a previous diagnosis of hemochromatosis or iron overload. Each underwent TfSat and SF measurements without regard to fasting, and HFE C282Y and H63D genotyping. Elevated measurements were defined as: TfSat &gt;50% (men), &gt;45% (women); and SF &gt;300 ng/mL (men), &gt;200 ng/mL (women). Mean TfSat was lower in native American men than in white men (31% vs. 32%, respectively; p = 0.0337), and lower in native American women than in white women (25% vs. 27%, respectively; p &lt;0.0001). Mean SF was similar in native American and white men (153 μg/L vs. 151 μg/L; p = 0.8256); mean SF was lower in native American women than in white women (55 μg/L vs. 63 μg/L, respectively; p = 0.0015). The respective percentages of native American men and women with elevated TfSat or elevated SF were similar to those of white men and women. The respective mean TfSat and SF values of native American and white participants with genotype HFE wt/wt were similar. The C282Y allele frequency was 0.0340 in native Americans and 0.0683 in whites (p &lt;0.0001). The H63D allele frequency was 0.1150 in native Americans and 0.1532 in whites (p = 0.0001). We conclude that the screening TfSat and SF phenotypes of native Americans do not differ greatly from those of whites. The respective allele frequencies of HFE C282Y and H63D are significantly lower in native Americans than in whites.
Comparison of Liver Iron Concentration Measured by the SQUID Biosusceptometers at Hamburg, Torino and Oakland in Patients with Thalassemia and Sickle Cell Disease.
Authors: Fung Ellen B. , Longo Filomena , Fischer Roland , Engelhardt Rainer , Pakbaz Zahra , Optiz Herbert , Fagaly Robert L. , Nick Hanspeter , Nielsen Peter , Vichinsky Elliott , Piga Antonio , Harmatz Paul 
Published: April 2020

Abstract
Assessing iron chelator efficacy in clinical trials requires standardization of liver iron concentration measurements. In a blinded round-robin test, liver iron concentration (LIC) was measured within 1 month in 18 patients with thalassemia or sickle cell disease and in 10 normal subjects at the 3 SQUID biosusceptometer systems located in Hamburg (UKE), Torino (TOR), and Oakland (CHO). Mean LIC values (range: normal up to 8000 μg/g-liver) were determined from 5 separate vertical scans. The observed intrasite precision (SD of Altman-Bland differences from duplicate measurements with repositioning) was found in the expected range of ±130 (UKE), ±200 (TOR), and 220 μg/g-liver (with 3 operators involved at CHO). Prediction of LIC at TOR and CHO in comparison with UKE was very good, with coefficients of determination between sites of R2 = 0.97, resulting in intersite standard deviations (SD) of 247 and 326 μg/g-liver, respectively. Differences of 24, 20, and 5% were noted for the comparisons UKE-TOR, CHO-TOR, and UKE-CHO, respectively (see Fig. 1). This suggests the need for further standardization of analysis methods. In conclusion, we found that intra-site precision was within an acceptable range for repeat measurements in the majority of iron overloaded subjects. Prediction of liver iron concentration at the three centers was highly correlated.
Figure 1. Agreement (Passing-Bablok regression) between liver iron measurements (mean LIC from 2 positions) by the SQUID biosusceptometer system in Hamburg (LIC-UKE) and the systems in Torino (LIC-TOR) and Oakland (LIC-CHO). Figure 1. Agreement (Passing-Bablok regression) between liver iron measurements (mean LIC from 2 positions) by the SQUID biosusceptometer system in Hamburg (LIC-UKE) and the systems in Torino (LIC-TOR) and Oakland (LIC-CHO).
Three Kinships with ALAS2 P520L Mutations, Two in Association with Severe Iron Overload, and One with Sideroblastic Anemia and Severe Iron Overload.
Authors: Lee Pauline L. , Barton James C. , Rao Sreenivas V. , Acton Ronald T. , Adler Brian K. , Beutler Ernest 
Published: April 2020

Abstract
Aminolevulinate synthase 2 (ALAS2) is an erythroid-expressed gene located on chromosome Xp11.21. Mutations in ALAS2 have been shown to be associated with sideroblastic anemia. We have identified a novel mutation in ALAS2, P520L, in three kinships. The P520L mutation was not found in 316 white male control subjects. The proline in this position is highly conserved across species from humans to zebrafish.
In the C kinship, the P520L mutation was first identified in a white man who presented with severe iron overload at an early age and was a HFE C282Y homozygote. Genetic analyses of members of the C kinship suggest that the presence of P520L alone in hemizygous males, or simple heterozygosity in females, is not associated with anemia or iron overload. Females heterozygous for both HFE C282Y and ALAS2 P520L also had normal ferritin levels. Only subjects homozygous for HFE C282Y and hemizygous or heterozygous for ALAS2 P520L had severe iron overload. Sequencing studies revealed that the propositus did not have missense mutations in HAMP, HJV, FPN1, ABC7, IL6, or RAG1.
In the H kinship, the propositus was a white woman with severe iron overload who was heterozygous for ALAS2 P520L; she had a wildtype HFE genotype. The pedigree of the H kinship identified 5 additional females who were heterozygous for the P520L ALAS2 mutation. Only the propositus had iron overload and none of the subjects with P520L had sideroblastic anemia. The propositus did not have missense mutations in FPN1, HAMP, HJV, TFR2, B2M, IRP2, ABC7, or SFT. We speculate that the propositus in the H kinship has a mutation in a currently unknown gene that contributes to her severe iron overload. In the S kinship, the P520L mutation was identified in a white man with sideroblastic anemia and severe iron overload. The patient had a second mutation in ALAS2, R560H, a mutation previously described in two brothers with sideroblastic anemia of variable penetrance (Blood100:4236–4238, 2002). It is not possible to determine the effect of the P520L mutation on the penetrance of the R560H-associated sideroblastic anemia and iron overload.
We conclude that the ALAS2 P520L occurs at a very low allele frequency in the white population. The present observations also suggest that there is no distinctive phenotype associated with the P520L mutation alone, but that P520L may act as a modifier of iron overload in the presence of HFE homozygosity, other missense mutations of ALAS2, or mutations of uncharacterized iron regulatory genes.
Defective Recycling and Exocytosis of Transferrin in Reticulocytes of hbd (Hemoglobin Deficit) Mice.
Authors: Garrick Michael D. , Gniecko Kathleen , Garrick Laura M. 
Published: April 2020

Abstract
Mice with hemoglobin deficit (hbd) have a hypochromic, microcytic anemia inherited as an autosomal recessive. The mice also exhibit reticulocytosis, hyperferremia and elevated free protoporphyrin in red cells (Bannerman et al 1986 Proc Soc Exp Biol Med 182:52). The spontaneous mutation has been mapped to chromosome 19 (Bloom et al 1998 Mamm Genome 9:666), making it ripe for identification of the gene, given the power of mouse genetics. Until the actual locus is determined, however, some mice must be identified as +/? as dominant inheritance obscures the second allele. Prior studies established that hbd/hbd reticulocytes take up 125I-labelled transferrin as well as +/? controls, but are less effective at incorporating 59Fe from transferrin (Garrick et al 1987 Exp Hemato 15:671). Scatchard analysis showed the affinity of transferrin receptors for transferrin was similar in hbd/hbd versus +/? reticulocytes; slightly more receptors were present, however, on the surface of hbd/hbd reticulocytes.
We now report on aspects of transferrin-dependent iron metabolism in hbd/hbd reticulocytes to resolve the nature of the alterations in the transferrin cycle in these rodent mutants. Improved time resolution for 59Fe uptake from transferrin by hbd/hbd versus +/? reticulocytes reveals that uptake in the first 2.5 min is indistinguishable; but that, by 5 min, incorporation by the mutant cells lags behind. Similarly, endocytosis of 125I-labelled transferrin by mutant versus control reticulocytes occurs at essentially the same rate; while exocytosis is about 4-fold slower for hbd/hbd reticulocytes compared to +/? reticulocytes. We conclude that recycling and exocytosis of transferrin in reticulocytes of hbd/hbd mice is strikingly impaired. The mutation in these mice should be in a gene that causes this impairment.
The Course of Plasmodium.yoelii Infection in Hereditary Persistence of Fetal Hemoglobin.
Authors: Nishino Tamon , Yaegashi Junko , Ohashi Toya , Matsumoto Yoshitsugu , Yoshikatsu Eto 
Published: April 2020

Abstract
Malaria, caused by plasmodium species has great impact on human generations. Each year 300–500 million of people are diagnosed and 1 million die of the disease. Malaria probably become endemic about 10,000 years ago and it has affected human genome by strong selective pressure. Several human genetic diseases are thought to be the outcome of this pressure. Our current research is focused on understanding natural host defense mechanism of this disease, especially effect to human fetal hemoglobin expression to plasmodium species.
Other investigator indicated growth of Plasmodium falciparum is retarded in the cell containing human fetal hemoglobin in vivo (Nature, 270:171), and transgenic mouse (transgenic of human fetal hemoglobin and knockout of mouse beta-major gene) infected with Plasmodium has longer survival compare to control.(Blood, 92:2520). Here we use transgenic mouse express human fetal hemoglobin (human Gamma globin) which simulate human hereditary persistence of fetal hemoglobin (PNAS86:7033) to investigate fetal hemoglobin itself has a protective effect on Plasmodium infection in vivo.
We injected 1,000 Plasmodium.yoelii infected RBCs to transgenic mouse expressing human fetal hemoglobin (n=5) and C57BL6J mouse (n=8). Blood smears obtained daily and smears were stained with Giemsa. Parasitemia is calculated from about 1000 RBCs. 5 days after injection, infected RBCs was 26.4 ±4.7% for C57BL6J and 32.6± 17.3% for human fetal hemoglobin transgenic mouse. We couldn’t show significant difference between these groups. And 60% of C57BL6J mice (3 of 5) were recovered from illness. In contrast, 20% of transgenic mouse (1of 5) was recovered from illness.
These results demonstrates only human fetal hemoglobin expression is not enough to contribute defense mechanism against plasmodium species.
Nitrite Ion Fluxes in Human Erythocytes.
Authors: d’Agostino Chiara , Dejam Andre , Pelletier Mildred , Sibmooh Nathawut , Rizzatti Fabiola , Schechter Alan N. 
Published: April 2020

Abstract
Our recent studies suggest that nitrite ions serve as a storage pool of nitric oxide (NO•) bioactivity, with reduction of nitrite to NO• within red blood cells (RBC), thus potentially explaining endocrine effects of NO•. We have investigated nitrite uptake and decay in human RBC using recently described methodologies based on assaying after stabilization of nitrite to reaction with hemoglobin by treatment with ferricyanide and quantificating by reductive chemiluminescence. Uptake of nitrite added to whole blood is very rapid (sec) and independent of temperature (from 4°C to 37°C) and state of oxygenation of the cells, or treatment with carbon monoxide. We obtain intracellular values as high as 711 ± 45.44 nM/l with an extracellular value of 10,935.089 ± 897.370 nM/l. Decay of nitrite levels within the RBC is, however, strongly temperature and ligand dependent. At 37°C only 22% of the original maximal value remains at 30 minutes (half life: 5.24 min), while there is no apparent decay at 4°C. Carbon monoxide also prevents nitrite destruction. If the nitrite-containing RBC are suspended in nitrite-free plasma, decay of nitrite levels is faster (half life 2.1min) suggesting export of nitrite as well as reaction with hemoglobin. We have also observed whole blood and RBC artery-to-vein gradients of nitrite levels in human forearm circulation suggesting rapid loss during RBC transit of the microcirculation. These results suggest rapid fluxes of nitrite ions into and out of RBC, as well as controlled intra-erythrocytic metabolism, which could contribute to local, rapid modulation of blood flow by mechanisms involving nitrite activation to NO• by intra-erythrocytic hemoglobin.
Maintenance Dosing with Epoetin alfa Every Two Weeks (Q2W) in Anemic Patients with Cancer Receiving Chemotherapy Every One or Four Weeks: Final Results.
Authors: Gregory Stephanie A. , Xie John , Woodman Richard C. 
Published: April 2020

Abstract
Epoetin alfa administered weekly is a proven treatment for chemotherapy (CT)-induced anemia. To increase patient convenience we examined a dosing regimen that would allow patients to receive epoetin alfa 60,000 U Q2W during maintenance therapy. This open-label, multi-center study had two phases: Initiation Phase (IP) of 60,000 U once weekly (QW) to achieve a target hemoglobin (Hb) of 12 g/dL (maximum duration 12 weeks), followed by a Maintenance Phase (MP) of 60,000 U Q2W to maintain Hb between 11.0 and 12.5 g/dL. Only those patients achieving Hb ≥ 12 g/dL in the IP entered the MP. Patients were withdrawn from the MP if Hb decreased to &lt; 11 g/dL. Doses were held for Hb &gt; 13 g/dL and reduced for rate of rise of &gt; 1.3 g/dL/2weeks. Maximum study duration (IP + MP) was 24 weeks. Patients ≥ 18 years of age with non-myeloid malignancy, baseline Hb ≤ 11 g/dL, and CT planned QW or every 4 weeks for at least 16 weeks were enrolled. Endpoints included proportion of patients achieving hematopoietic response in the IP (≥ 2 g/dL Hb increase from baseline or Hb ≥ 12 g/dL) and proportion maintaining mean Hb between 11.0 and 12.5 g/dL in the MP. A total of 129 patients were enrolled and received at least one dose of epoetin alfa; mean age was 62.6 ± 13.0 years, 65.9% were female, mean baseline Hb was 10.0 ± 0.9 g/dL, and 92.2% had solid tumors. During the IP, 84 of 129 (65.1%) patients achieved hematopoietic response (≥ 2 g/dL Hb increase from baseline or Hb ≥ 12 g/dL). The eighty-four patients who achieved Hb ≥ 12 g/dL entered the MP after a median of 4.0 weeks in IP; treatment duration in MP was 13.2 weeks on average. Fifty-one of 84 (60.7%) maintained an average Hb between 11.0 and 12.5 g/dL over the course of the MP. Sixteen (19.0%) patients were withdrawn from the MP because Hb decreased to &lt; 11 g/dL. Of 129 patients dosed in IP, 14 (10.9%) had doses reduced and 8 (6.2%) had doses held; of 84 patients dosed in MP, 47 (36.4%) had doses reduced and 53 (41.1%) had doses held. Sixty-five (50.4%) patients experienced serious adverse events. Fifteen (11.6%) patients experienced clinically relevant thrombotic vascular events. Three and 5 patients discontinued due to adverse events in the IP and MP, respectively. Fifteen (11.6%) patients died during the study or within 30 days after last study dose. Although 60,000 U QW was used during the IP to achieve a HR, 40,000 U QW is the recommended initiation dose of epoetin alfa. This study of patients receiving CT every 1 or 4 weeks, demonstrated that the majority of those who achieved a HR are able to maintain an acceptable Hb level with epoetin alfa 60,000 U every two weeks.
Hydroxyurea Therapy Reduces the Gene Expression of Adhesion Molecules VLA-4 and CD36 in Sickle Erythrocytes, with a Concomitant Decrease in Adhesion to Fibronectin.
Authors: Gambero Sheley , Conran Nicola , Albuquerque Dulcineia M. , Santos Camila O. , Saad Sara T.O. , Costa Fernando F. 
Published: April 2020

Abstract
Adhesive interactions between sickle red cells, leukocytes and the endothelium are thought to initiate vaso-oclusive events in the microcirculation. An increased expression of adhesion molecules such as CD 36 (thrombospondin receptor) and VLA-4 integrin (α4β1, CD49d/CD29) has been observed on the surface of sickle reticulocytes and the increased adhesive properties of sickle erythrocytes are well documented. Gene expression of adhesion molecules and their modulation by drugs such as hydroxyurea (HU) have yet to be fully explored. We compared the expression of the CD36 gene and the VLA-4 integrin subunit genes, CD29 and CD49d, in the reticulocytes of steady-state SCD patients and patients on HU therapy (20–30 mg/Kg/day) using Real Time PCR and also compared the basal adhesion of erythrocytes from these subjects using static adhesion assays. Basal adhesion of sickle erythrocytes (2x108 cells/ml) to fibronectin (20mg/ml) - coated plates was significantly higher than normal erythrocyte adhesion (15.4 ± 2.8% compared to 5.9 ± 1.1%, n=9, p=0.008). In contrast, the adhesion of erythrocytes from SS patients on HU therapy to fibronectin was significantly lower than that of SS erythrocytes of patients not on HU (5.8 ± 0.7%, n=9, p=0.006). Pre-treatment of cells, in vitro, with varying concentrations of HU (0.1 → 250μM, 30 minutes, 37oC), had no significant effect on either normal or sickle cell erythrocyte adhesion under our experimental conditions, suggesting that HU may not reduce sickle cell adhesion by altering adhesion molecule function due to affinity changes. We next used real time PCR to investigate the expression of the mRNA of the CD36 gene and the genes for the VLA-4 subunits, CD49d and CD29, in the reticulocytes of steady-state SCD patients and patients on HU therapy. CD 36 gene expression was reduced by 62.5% ± 10.4% in the reticulocytes of patients on HU compared to the reticulocytes of SCD patients not on HU (n=8, p &lt; 0.001). The β1 (CD29) integrin subunit expression was reduced by 87.9 ± 8.7% (n=8, p &lt; 0.001) in patients on HU compared to SS reticulocytes; likewise α4 integrin (CD49d), expression was reduced by 50.0% ± 2.6% (n=8, p &lt;0.001). In addition, reticulocyte mRNA was collected from one steady-state SCD patient before and 3 months after initiation of HU therapy and decreases of 99.5%, 98.0% and 98.0% were observed in the expressions of CD36, CD29 and CD49d mRNA, respectively, in the reticulocytes of this patient following HU therapy. We speculate that the decrease in adhesive properties observed in the erythrocytes of sickle cell patients during HU therapy may be the consequence of a down-regulation of the gene expressions of adhesion molecules and, consequently, protein expression by sickle cells rather than as a result of alterations in adhesion molecule function.