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    Nucleated red blood cell count in the differentiation of fetuses with pathologic growth restriction from healthy small-for-gestational-age fetuses. Minior V K,Shatzkin E,Divon M Y American journal of obstetrics and gynecology OBJECTIVE:The purpose of this study was to evaluate the utility of the neonatal nucleated red blood cell count in differentiating the fetus with growth restriction from the small but otherwise healthy fetus. STUDY DESIGN:Perinatal outcomes were evaluated prospectively for all neonates admitted to the neonatal intensive care unit in 1997. Nonanomalous neonates with normal phenotype and a complete blood cell count performed within the first 6 hours after birth were included in the study. All neonates with birth weights lower than the 10th percentile for gestational age were considered small for gestational age. Neonates were divided into four groups: small-for-gestational-age neonates with elevated nucleated red blood cell counts, appropriately grown neonates with elevated nucleated red blood cell counts, small-for-gestational-age neonates with normal nucleated red blood cell counts, and appropriately grown neonates with normal nucleated red blood cell counts. Analysis of variance, chi(2) tests, and stepwise regression were used for statistical analysis. RESULTS:Two hundred thirty-seven neonates met the inclusion criteria. Forty-three were small for gestational age. Small-for-gestational-age neonates with high nucleated red blood cell counts had significantly lower umbilical artery pH and were more likely to require mechanical ventilation or blood pressure support agents. Subgroup analysis demonstrated that small-for-gestational-age neonates with elevated nucleated red blood cell counts had significantly more adverse outcomes than did small-for-gestational-age neonates with normal nucleated red blood cell counts. Outcomes of small-for-gestational-age neonates with normal nucleated red blood cell counts were essentially identical to those of appropriately grown neonates. CONCLUSION:An elevated nucleated red blood cell count may distinguish the fetus with growth restriction from the small but healthy fetus. 10.1067/mob.2000.105444
    Umbilical cord blood erythroblast count as an index of intrauterine hypoxia. Thilaganathan B,Athanasiou S,Ozmen S,Creighton S,Watson N R,Nicolaides K H Archives of disease in childhood. Fetal and neonatal edition The relation of umbilical cord blood arterial pH, Apgar score, leucocyte count, and erythroblast count at delivery with the diagnosis of fetal distress in labour was studied prospectively in three groups of singleton pregnancies delivering at term vaginally (55 infants), by elective caesarean section (39 infants), or by emergency caesarean section for abnormal intrapartum fetal heart rate patterns (55 infants). In the emergency caesarean section group the umbilical cord blood arterial pH was significantly lower and the leucocyte and erythroblast counts were higher than in the elective caesarean section group. Comparison of the emergency caesarean section and spontaneous vaginal delivery groups showed significant differences for pH and erythroblast count, but not for leucocyte count. In the spontaneous vaginal delivery group erythroblastosis was associated with umbilical cord blood pH, whereas leucocytosis was associated with the length of labour. The five minute Apgar score was > or = 7 in all infants. This study suggests that leucocytosis is a non-specific response of the fetus to labour, whereas erythroblastosis reflects fetal tissue hypoxia. 10.1136/fn.70.3.f192
    Neonatal nucleated red blood cell counts in twins. Mori H,Mori K,Kojima Y,Ohkuchi A,Funamoto H,Minakami H,Sato I,Nakano T Journal of perinatal medicine We counted nucleated red blood cells (NRBC) per 100 white blood cells (WBC) in the umbilical cord blood from 98 twins born to 49 women with uncomplicated twin pregnancies at > or = 34 weeks of gestation to better characterize NRBC in twins. Twelve women with monochorionic (MC) placentas and 37 with dichorionic (DC) placentas gave birth at 36.7 +/- .9 and 36.5 +/- 2 weeks of gestation, respectively. All twins were born with an Apgar score of > or = 7 at 1 min. Log10 (NRBC/100 BC) in 98 twins exhibited a nearly normal distribution, and was significantly associated with gestational age for both MC (r = -0.457, p = 0.025) and DC twins (r = - 0.275, p = 0.018), and with birth weight for both MC (r = -0.682, p < 0.001) and DC twins (r = -0.336, p = 0.003). Log10 (NRBC/100 WBC) tended to be larger in smaller twins than in larger twins in the MC group, and significantly larger in smaller twins than in larger twins in the DC group (p < 0.05). Intertwin difference in Log10 (NRBC/100 WBC) was defined as the value of Log10 (NRBC/100 WBC) of the smaller twin minus Log10 (NRBC/100 WBC) of the larger twin, and became greater with increasing intertwin difference in birth weight (r = 0.411, p = 0.003). These findings suggest that neonatal NRBC reflected gestational age and birth weight in twins. This preliminary observation using a small number of twins suggests that the smaller twin may have experienced a relative lack of oxygen compared with the larger twin in utero. 10.1515/JPM.2001.019
    Influence of perinatal factors on hematological variables in umbilical cord blood. Redźko Sławomir,Przepieść Jerzy,Zak Janusz,Urban Jan,Wysocka Jolanta Journal of perinatal medicine OBJECTIVE:The purpose of our study was to investigate any possible relationship between the duration of labor, the mode of delivery and the duration of rupture of membranes and hematological parameters in cord blood. MATERIAL AND METHODS:We studied 298 pregnant women who delivered term normal infants. The patients were divided into three groups according to the route of delivery: vaginal (n = 165), cesarean section after labor (n = 27) and elective cesarean section (n = 106). Immediately after delivery, umbilical cord blood samples were collected. RESULTS:The mode of delivery influenced white blood cells, hemoglobin, hematocrit, red blood cell distribution, platelets count and nucleated red blood cells. There was no correlation between the cord blood hematological values and the duration of labor, as well as the duration of rupture of membranes before delivery. CONCLUSION:The influence of mode of delivery, duration of labor and duration of ruptured membranes on hematological parameters in umbilical cord blood is limited. 10.1515/JPM.2005.007
    Nucleated red blood cells as a marker in acute and chronic fetal asphyxia. Saraçoglu F,Sahin I,Eser E,Göl K,Türkkani B International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics OBJECTIVE:To investigate the variations of nucleated red blood cell (NRBC) counts in acute and chronic fetal hypoxia and to examine if it could be possible to establish a cutoff value for the number of NRBCs for prediction of fetal acidosis. METHOD:We prospectively studied 77 pregnant women. Patients were grouped as acute (n=11) and chronic fetal distress (n=21) and controls (n=45). At delivery the umbilical cord was double clamped and blood samples were collected. RESULTS:The mean NRBC counts in chronic fetal distress group was higher than acute fetal distress. NRBC counts were found to be correlated with umbilical cord pH (r=-0.57; P<0.001). The cutoff value predicting fetal acidosis was determined as 14/100 leukocytes (sensitivity 87%, specificity 81%) by using ROC analysis. CONCLUSION:The duration and the severity of fetal asphyxia may be predicted by the number of NRBCs per leukocyte.
    Cesarean section due to fetal distress increases the number of stem cells in umbilical cord blood. Manegold Gwendolin,Meyer-Monard Sandrine,Tichelli Andre,Pauli Doris,Holzgreve Wolfgang,Troeger Carolyn Transfusion BACKGROUND:Umbilical cord blood (UCB) can be used as hematopoietic stem cell source for transplantation. The success of a transplantation is highly correlated with the number of total nucleated cells (TNCs) and CD34+ cells in the UCB. Certain obstetric factors increase the yield of stem cells in the UCB. It is necessary to evaluate optimal conditions in labor to decrease the rate of sample rejection due to low cell count. No data exist regarding the difference between primary and secondary Cesarean sections in terms of efficacy of stem cell harvesting. STUDY DESIGN AND METHODS:Seventy-nine consecutive UCB units from women who had a Cesarean section between 1997 and 2003 were included. The number of TNCs, CD34+ cells, colony-forming units (CFUs), white blood cells (WBCs), nucleated red blood cells (NRBCs), and the total collection volume were compared between cases with primary and secondary Cesarean section. RESULTS:UCB obtained after a Cesarean section due to fetal distress has significantly higher numbers of TNCs, CD34+ cells, NRBCs, and WBCs compared to elective Cesarean section. Of the cases with secondary Cesarean section due to fetal distress, 67 percent resulted in UCB units with sufficient TNC numbers (> or =80 x 10(7) TNCs) compared to 42 percent of the cases with primary Cesarean section. CONCLUSION:Fetal distress increases the number of hematopoietic stem cells mobilized into UCB. Particular effort should be made to collect UCB from newborns who experienced fetal distress. 10.1111/j.1537-2995.2007.01617.x
    The opposing roles of the mTOR signaling pathway in different phases of human umbilical cord blood-derived CD34 cell erythropoiesis. Liu Qian,Luo Linhong,Ren Chunhong,Zou Muping,Yang Siqin,Cai Bozhi,Wu Libiao,Wang Yunsheng,Fu Shan,Hua Xu,Tang Nianping,Huang Shiping,Huang Xianxi,Xin Wen,Chen Feiheng,Zhang Xin Stem cells (Dayton, Ohio) As an indispensable, even lifesaving practice, red blood cell (RBC) transfusion is challenging due to several issues, including supply shortage, immune incompatibility, and blood-borne infections since donated blood is the only source of RBCs. Although large-scale in vitro production of functional RBCs from human stem cells is a promising alternative, so far, no such system has been reported to produce clinically transfusable RBCs due to the poor understanding of mechanisms of human erythropoiesis, which is essential for the optimization of in vitro erythrocyte generation system. We previously reported that inhibition of mammalian target of rapamycin (mTOR) signaling significantly decreased the percentage of erythroid progenitor cells in the bone marrow of wild-type mice. In contrast, rapamycin treatment remarkably improved terminal maturation of erythroblasts and anemia in a mouse model of β-thalassemia. In the present study, we investigated the effect of mTOR inhibition with rapamycin from different time points on human umbilical cord blood-derived CD34 cell erythropoiesis in vitro and the underlying mechanisms. Our data showed that rapamycin treatment significantly suppressed erythroid colony formation in the commitment/proliferation phase of erythropoiesis through inhibition of cell-cycle progression and proliferation. In contrast, during the maturation phase of erythropoiesis, mTOR inhibition dramatically promoted enucleation and mitochondrial clearance by enhancing autophagy. Collectively, our results suggest contrasting roles for mTOR in regulating different phases of human erythropoiesis. 10.1002/stem.3268
    Comparison of the umbilical artery blood gas, nucleated red blood cell, C-reactive protein, and white blood cell differential counts between neonates of diabetic and nondiabetic mothers. Namavar Jahromi Bahia,Ahmadi Nahid,Cohan Nader,Jahromi Mehdi Roshan Nia Taiwanese journal of obstetrics & gynecology OBJECTIVE:The aim of this study was to compare the neonatal umbilical artery blood gas values, C-reactive protein (CRP) levels, nucleated red blood cells (NRBCs), and white blood cells (WBCs) differential counts between offspring's of the diabetic mothers who needed insulin during pregnancy and normal mothers after cesarean delivery. MATERIALS AND METHODS:A prospective study was performed involving 68 pregnant diabetic women who needed insulin during pregnancy and 410 healthy pregnant women and their neonates with gestational ages between 35 weeks and 41 weeks. Arterial blood was analyzed for pH and blood gas values and venous blood was analyzed for CRP level, NRBC, and WBC differential counts. RESULTS:The mean NRBC count in the neonates of diabetic mothers and healthy mothers was 560 ± 985/μL and 202 ± 281/μL, respectively (p<0.001). The umbilical arterial blood gas showed a lower pH (7.22 ± 0.07 vs. 7.24 ± 0.04, p=0.004) and a higher pCO(2) (49.33 ± 10.08 vs. 47 ± 8.67, p=0.045) in neonates of diabetic mothers compared with the controls. Values of pO(2), HCO(3)(-), base excess, WBC differential counts, and CRP levels were almost similar in the two groups. CONCLUSION:Lower pH, higher pCO(2), and elevated NRBC counts were found in the neonates of diabetic mothers that may be suggestive of chronic intrauterine acidosis. 10.1016/j.tjog.2011.01.029
    Nucleated red blood cells in human fetal scalp capillary blood samples: a feasibility study. Ferber A,Akyol D,Kane L A,Grassi A,Divon M Y The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians OBJECTIVE:Elevated umbilical cord nucleated red blood cell (NRBC) counts have been suggested as a predictor of adverse perinatal outcome. We sought to evaluate the feasibility of obtaining fetal scalp capillary blood NRBC counts during labor and to assess their correlation with umbilical cord NRBC counts. METHODS:Fetal scalp capillary blood specimens were prospectively collected in laboring patients who underwent scalp sampling because of the presence of an abnormal fetal heart rate pattern. Matched umbilical cord blood samples were collected immediately after birth. Outcome measures were the feasibility of obtaining fetal scalp NRBC counts and their correlation with umbilical cord NRBC counts. RESULTS:Thirteen term singleton pregnancies formed the study population. In four patients, fetal scalp capillary blood sampling was performed twice. Of the attempts to evaluate fetal scalp capillary samples for NRBC counts, 16 out of 17 (94.1%) were successful. The mean fetal scalp capillary blood NRBC count per 100 white blood cells was 12.6 +/- 7.6 (+/- SD). Umbilical cord mixed, venous and arterial NRBC counts were 15.5 +/- 8.8, 13.4 +/- 10.7 and 12.6 +/- 10.7, with p = 0.09, p = 0.59 and p = 0.68, respectively, when compared to the corresponding scalp sample. The Spearman rank correlation between fetal scalp capillary samples and umbilical cord mixed, venous and arterial NRBC counts were r = 0.86, r = 0.92 and r = 0.95, respectively, with all p values < 0.001. CONCLUSION:Previous studies have established the clinical utility of umbilical cord NRBC counts. Our study demonstrated that it was possible to obtain NRBC counts from a fetal scalp capillary sample and that these counts correlated highly with umbilical cord NRBC counts. Future studies are needed to evaluate fetal scalp NRBC counts as a predictor of perinatal outcome. 10.1080/jmf.11.1.26.29
    Prediction of perinatal asphyxia with nucleated red blood cells in cord blood of newborns. Ghosh B,Mittal S,Kumar S,Dadhwal V International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics OBJECTIVE:To determine normal level of nucleated red blood cells (NRBC) per 100 white blood cells (WBC) in cord blood of term non-asphyxiated newborns and to investigate variations in NRBC counts in perinatal asphyxia. METHODS:A total of 75 cases were studied. Levels of NRBC per 100 WBC in umbilical venous blood were compared between 26 asphyxiated newborns (group I) and 49 non-asphyxiated newborns (group II). Correlation with neonatal outcome was also evaluated. RESULTS:The mean (+/-S.D.) NRBC per 100 WBC level in umbilical blood of newborns in group I was 16.5+/-6.4, range 3-25; whereas that in group II was 8.6+/-7.01, range 1-26. This difference was statistically significant (P<0.001). A statistically significant negative correlation existed between NRBC level and markers of acute intrapartum asphyxia, Apgar score and umbilical arterial pH (r=-0.50, P<0.001 and r=-0.48, P<0.001, respectively). Positive correlation was demonstrated with evidence of chronic antepartum asphyxia, presence of pregnancy induced hypertension and intrauterine growth restriction (r=2.66, P=0.02). A high NRBC count in umbilical blood correlated with poor early neonatal outcome. CONCLUSIONS:The level of NRBC per 100 WBC correlates both with acute as well as chronic antepartum asphyxia. Further, it can be used as a reliable index of early neonatal outcome.
    Placental/umbilical cord blood for unrelated-donor bone marrow reconstitution: relevance of nucleated red blood cells. Stevens Cladd E,Gladstone Jessica,Taylor Patricia E,Scaradavou Andromachi,Migliaccio Anna Rita,Visser Jan,Dobrila N Ludy,Carrier Carmelita,Cabbad Michael,Wernet Peter,Kurtzberg Joanne,Rubinstein Pablo Blood Placental/umbilical cord blood (PCB) is a source of hematopoietic stem cells for bone marrow reconstitution. Engraftment speed and survival are related to the total nucleated cell (TNC) dose of the graft. This study explored the possible influence on engraftment of nucleated red blood cells (NRBCs) in the graft. Automated hematology analyzers were used to enumerate TNCs. NRBCs were counted by visual examination or by using an automated analyzer. Hematopoietic progenitor cells were enumerated as either colony-forming cells or CD34(+) cells. Transplant centers reported on transplant outcome in 1112 patients given PCB grafts through September 2001. NRBCs correlated with progenitor cell numbers. Both white blood cell and NRBC dose were independently predictive of myeloid engraftment speed. Because NRBC dose predicted engraftment speed, inclusion of NRBCs in the TNC count does not reduce the effectiveness of the prefreezing TNC count as an index of the quality of a PCB unit as a graft. The correlation between the number of NRBCs and the number of hematopoietic progenitor cells probably reflects the involvement of early stem cells in erythroid responses. 10.1182/blood.V100.7.2662
    Significance of assay of nucleated RBCs in umbilical cord blood in neonates with meconium-stained amniotic fluid. Elsokkary M,Mamdouh A,Nossair W,Abd El Fattah O,Hemeda H,Sallam S,Taema M,Hussain M,Shafik A,Nawara M,Samy M,Abd El Aleem M,Abdelhadi R,Sakna N,Salama A,Salama D,El-Tohamy O,Elsaid N The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians BACKGROUND:Approximately 8-15% of all infants are born with evidence of meconium-stained amniotic fluid (MSAF). MSAF is a potentially serious sign of fetal compromise and may indicate fetal hypoxia Objectives and aim of the work: The present study was designed to evaluate the relationship between meconium stained amniotic fluid and fetal nucleated red blood cell counts. As well, we aim to evaluate the relationship between the presence of meconium in amniotic fluid and Apgar scores in neonates. SUBJECTS AND METHODS:A prospectively case-controlled study was performed on 40 women with clear amniotic fluid as control and 40 women with meconium-stained amniotic fluid as the study group. At delivery, 2 ml of umbilical cord blood was collected and analyzed for nucleated red blood cell (NRBC). RESULTS:The mean NRBC counts in meconium-stained amniotic fluid was significantly higher than the control group (18.35 ± 7.7 and 9.6 ± 4.96), respectively (p < .001). There were statistically significant differences concerning 1- and 5-min Apgar scores with lower values in the MSAF group (p < .001 and .001, respectively). CONCLUSION:Our results support previous studies which indicate the presence of meconium can be associated with chronic fetal hypoxia as demonstrated by elevated fetal NRBC levels. 10.1080/14767058.2017.1384457
    Nucleated red blood cells are a direct response to mediators of inflammation in newborns with early-onset neonatal sepsis. Dulay Antonette T,Buhimschi Irina A,Zhao Guomao,Luo Guoyang,Abdel-Razeq Sonya,Cackovic Michael,Rosenberg Victor A,Pettker Christian M,Thung Stephen F,Bahtiyar Mert O,Bhandari Vineet,Buhimschi Catalin S American journal of obstetrics and gynecology OBJECTIVE:The objective of the study was to test the hypothesis that inflammation modulates fetal erythroblastosis and/or the release of nucleated red blood cells (NRBCs) independent of hypoxia or fetal stress. We sought to determine whether fetal inflammation is associated with an elevation in neonatal NRBC count in the setting of inflammation-associated preterm birth. STUDY DESIGN:The relationships between peripheral NRBC count, histological chorioamnionitis, umbilical cord interleukin (IL)-6, erythropoietin (EPO), cortisol, and acid-base status were analyzed in 68 preterm singletons, born to mothers who had an amniocentesis to rule out infection. Proteomic profiling of amniotic fluid identified presence of intraamniotic inflammation according to established parameters. NRBC counts were assessed within 1 hour of birth. Early-onset neonatal sepsis (EONS) was established based on hematological and microbiological indices. IL-6, EPO, and cortisol levels were measured by immunoassays. Fetal acid-base status was determined within 10 minutes of delivery. Parametric or nonparametric statistics were used. RESULTS:Fetuses with EONS (n = 19) were delivered at earlier gestational ages (mean +/- SD: 27.1 +/- 2.8 weeks, P = .001) and more often by mothers with intraamniotic inflammation (P = .022) and histological chorioamnionitis (P < .001). Neonates with EONS had higher absolute NRBC counts (P = .011). NRBC counts were directly correlated with cord blood IL-6 levels (P < .001) but not with EPO, cortisol or parameters of acid-base status levels regardless of EONS status. These relationships remained following correction for gestational age, diabetes, intrauterine growth restriction, and steroid exposure. CONCLUSION:In the setting of inflammation-associated preterm birth and in the absence of hypoxia, elevations in NRBCs in the early neonatal period may be a direct response of exposure to inflammatory mediators in utero. 10.1016/j.ajog.2008.01.040
    Effect of maternal iron status on the number of CD34+ stem cells harvested from umbilical cord blood. Pope Belinda,Hokin Bevan,Grant Ross Transfusion BACKGROUND:Hematopoietic progenitor cells (HPCs) from umbilical cord blood (UCB) are an alternative source of stem cells. However an adequate number of HPCs must be harvested from each UCB sample to make therapeutic applications possible. This study investigated the impact of selected maternal indices (in particular iron status) on the number of CD34+ cells collected in the UCB. STUDY DESIGN AND METHODS:Blood samples were collected from 91 matched mother and umbilical cord pairs and analyzed for full blood count, iron status, and C-reactive protein. Viable CD34 enumeration was performed on the cord blood samples. RESULTS:Low CD34+ cell counts were associated with higher maternal serum ferritin (SF), older mothers, lower UCB white blood cell count (WCC), lower UCB nucleated red blood cells (NRBCs), and lower birthweight. Maternal SF correlated with maternal variables of iron status and RBC indices, newborn weight, placental weight, and NRBCs/100 WCC. CONCLUSION:This study indicates that lower numbers of CD34+ cells are more likely to occur when collected from mothers with higher SF. This finding suggests that maternal SF and associated iron status play a significant, but as yet undefined, role in the generation of CD34+ cells in UCB. 10.1111/trf.12547
    Perinatal asphyxia is associated with the umbilical cord nucleated red blood cell count in pre-eclamptic pregnancies. Bayram F,Ozerkan K,Cengiz C,Develioğlu O,Cetinkaya M Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology Nucleated red blood cells are commonly present in the blood of newborns. Our objective was to investigate the value of umbilical cord nucleated red blood cell (NRBC) count in predicting fetal asphyxia in pre-eclamptic women. NRBCs were counted in umbilical cord blood samples of neonates born to 43 pre-eclamptic and 25 healthy pregnant women. Pre-eclamptic women were further subgrouped based on the presence or absence of intrauterine growth restriction. The NRBC count differed significantly between pre-eclamptic women with and without intrauterine growth restriction, and controls (26.3 +/- 7.5; 17.1 +/- 6.8; and 9.9 +/- 2.7; p < 0.001). A NRBC count of 18.5 or above could predict fetal asphyxia with a sensitivity of 94.4% and a specificity of 80.0%. The umbilical cord NRBC count is effective in predicting fetal asphyxia in pre-eclamptic women. 10.3109/01443611003706928
    Nonreassuring fetal heart rate patterns and nucleated red blood cells in term neonates. Kovalak E Ebru,Dede F Suat,Gelisen Orhan,Dede Hulya,Haberal Ali Archives of gynecology and obstetrics PURPOSE:The aim of this study was to evaluate the association between nonreassuring fetal heart rate patterns during labor and umbilical cord nucleated red blood cell counts. METHODS:Nucleated red blood cell data was collected prospectively from 41 singleton term neonates presented with nonreassuring fetal heart rate patterns and/or meconium stained amniotic fluid during labor (study group) and from 45 term neonates without any evidence of nonreassuring fetal status (controls). Umbilical artery pH, blood gases and base excess were also determined to investigate the correlation between independent variables. RESULTS:The median nucleated red blood cells per 100 white blood cells were 13 (range 0-37) in the study group and 8 (range 0-21) in the control group. Stepwise regression analysis have identified meconium stained amniotic fluid (R(2) = 0.15, p < 0.0001) and umbilical artery PO(2) (R(2) = 0.1, p = 0.002) as independent variables associated with elevated NRBC counts in patients with nonreassuring fetal heart rate patterns. CONCLUSIONS:Nucleated red blood cells in the cord blood of newborns were found to be elevated in patients with nonreassuring FHR patterns during labor. However, the wide range and the poor correlation of NRBC count with umbilical artery pH and blood gas values limit its clinical utility as a marker for fetal hypoxia. 10.1007/s00404-010-1517-y
    Umbilical venous erythropoietin and umbilical arterial pH in relation to morphologic placental abnormalities. Maier R F,Günther A,Vogel M,Dudenhausen J W,Obladen M Obstetrics and gynecology OBJECTIVE:To investigate the relation between the biochemical markers of umbilical venous erythropoietin and umbilical arterial pH and morphologic placental abnormalities in fetal hypoxia. METHODS:Placentas from 300 high-risk newborn infants (gestational age 24-42 weeks) were examined macroscopically and microscopically following standardized criteria. The morphologic findings were correlated with the erythropoietin concentration in umbilical venous blood and with umbilical arterial pH at birth. Venous hematocrit and circulating nucleated red blood cells were measured in 112 of these infants during the first 6 hours of life. RESULTS:The umbilical venous erythropoietin concentration correlated significantly (r = 0.74) with the number of circulating nucleated red blood cells. In 26 placentas without morphologic abnormalities, the median (and 25th and 75th percentiles) erythropoietin concentration was 35.2 mU/mL (19.2-48.7) and umbilical arterial pH was 7.30 (7.20-7.33). The erythropoietin concentration was elevated significantly when placental examination showed evidence of acute villous circulatory disturbance (61.3 mU/mL; 24.2-125.1), fetal vasculopathy (85.6 mU/mL; 23.7-119.7), or chorioamnionitis with fetal reaction (51.3 mU/mL; 27.7-118.7). The erythropoietin concentration varied significantly with the stage of placental meconium phagocytosis; it was 62.7 mU/mL (16.3-125.9) if meconium phagocytosis was classified as recent, 128.2 mU/mL (44.4-1483.2) if it was classified as a few hours old, and 66.2 mU/mL (46.3-140.1) if it was classified as a few days old. Umbilical arterial pH was not altered significantly with different morphologic placental abnormalities. CONCLUSIONS:Fetal erythropoietin production is stimulated by hypoxia after a few hours' delay and leads to increased erythropoiesis. Placental examination combined with measurement of umbilical venous erythropoietin and umbilical arterial pH provides information about earlier fetal hypoxia.
    Nucleated red blood cells in uncomplicated prolonged pregnancy. Perri Tamar,Ferber Asaf,Digli Ayala,Rabizadeh Esther,Weissmann-Brenner Alina,Divon Michael Y Obstetrics and gynecology OBJECTIVE:Elevated counts of nucleated red blood cells (NRBCs), as well as prolongation of pregnancy, have been suggested as predictors of adverse perinatal outcome. However, the association between these 2 variables has received only minimal attention. We sought to evaluate fetal NRBCs in prolonged pregnancies. METHODS:Umbilical cord blood was prospectively collected at delivery from 75 prolonged (at or beyond 287 days) pregnancies. One hundred and fifty term deliveries (260-286 days) served as controls. All pregnancies were accurately dated with the use of first-trimester sonography. Fetal biophysical profile testing was initiated at 40 weeks of gestation. Patients were delivered if they were in spontaneous labor or the biophysical profile was nonreassuring or by 42 weeks of gestation. Nucleated red blood cell counts were expressed per 100 white blood cells (WBC). Umbilical artery pH studies, as well as other demographic and clinical variables, were obtained. RESULTS:Prolonged pregnancy was associated with a significantly increased incidence of induction of labor and a greater birth weight. There were no other differences between the study group and controls. The median NRBCs per 100 WBCs in prolonged pregnancy was not significantly elevated over the term values (median 3, range 0-35 versus median 3, range 0-34, respectively; P =.25). Neonatal outcome was also comparable between groups. The univariate regression analysis demonstrated a significant association between elevated NRBC counts and low arterial cord blood pH (P <.008, R = 0.175), elevated base excess (P =.02, R = 0.149), low platelet counts (P =.046, R = 0.134), and male gender (P =.028). Stepwise regression analysis revealed that low arterial cord blood pH and male gender were the only independent variables predicting elevated NRBC counts at birth. CONCLUSION:The findings of this study suggest that elevated NRBC counts are associated with specific pregnancy complications rather than uncomplicated prolonged pregnancies in general. 10.1097/01.AOG.0000133483.94020.04
    Putative regulators for the continuum of erythroid differentiation revealed by single-cell transcriptome of human BM and UCB cells. Huang Peng,Zhao Yongzhong,Zhong Jianmei,Zhang Xinhua,Liu Qifa,Qiu Xiaoxia,Chen Shaoke,Yan Hongxia,Hillyer Christopher,Mohandas Narla,Pan Xinghua,Xu Xiangmin Proceedings of the National Academy of Sciences of the United States of America Fine-resolution differentiation trajectories of adult human hematopoietic stem cells (HSCs) involved in the generation of red cells is critical for understanding dynamic developmental changes that accompany human erythropoiesis. Using single-cell RNA sequencing (scRNA-seq) of primary human terminal erythroid cells (CD34CD235a) isolated directly from adult bone marrow (BM) and umbilical cord blood (UCB), we documented the transcriptome of terminally differentiated human erythroblasts at unprecedented resolution. The insights enabled us to distinguish polychromatic erythroblasts (PolyEs) at the early and late stages of development as well as the different development stages of orthochromatic erythroblasts (OrthoEs). We further identified a set of putative regulators of terminal erythroid differentiation and functionally validated three of the identified genes, , , and , by monitoring cell differentiation and apoptosis. We documented that knockdown of suppressed the commitment of HSCs to erythroid lineage and cell proliferation and delayed differentiation of colony-forming unit-erythroid (CFU-E) to the proerythroblast stage (ProE). In contrast, the knockdown of and delayed differentiation of PolyE to OrthoE stage. Taken together, the convergence and divergence of the transcriptional continuums at single-cell resolution underscore the transcriptional regulatory networks that underlie human fetal and adult terminal erythroid differentiation. 10.1073/pnas.1915085117
    The impact of early- and late-onset preeclampsia on umbilical cord blood cell populations. Herzog Emilie M,Eggink Alex J,van der Zee Marten,Lagendijk Jacqueline,Willemsen Sten P,de Jonge Robert,Steegers Eric A P,Steegers-Theunissen Regine P M Journal of reproductive immunology Pregnancies complicated by preeclampsia (PE) are characterised by an enhanced maternal and fetal inflammatory response with increased numbers of leukocytes in maternal peripheral blood. The impact of PE on newborn umbilical cord blood cell (UCBC) populations however, has been scarcely studied. We hypothesise that PE deranges fetal haematopoiesis and subsequently UCBC populations. Therefore, the objective of this study was to investigate newborn umbilical cord blood cell populations in early- (EOPE) and late-onset PE (LOPE). A secondary cohort analysis in The Rotterdam Periconceptional Cohort was conducted comprising 23 PE cases, including 11 EOPE and 12 LOPE, and 195 controls, including 153 uncomplicated and 23 fetal growth restriction- and 19 preterm birth complicated controls. UCBC counts and differentials were quantified by flow cytometry and analysed as main outcome measures. Multivariable regression analysis revealed associations of EOPE with decreased leucocyte- (monocytes, neutrophils, eosinophils, immature granulocytes) and thrombocyte counts and increased NRBC counts (all p<0.05). EOPE remained associated with neutrophil- (β-0.92, 95%CI -1.27,-0.57, p<0.001) and NRBC counts (β1.11, 95%CI 0.27,1.95, p=0.010) after adjustment for gestational age and birth weight. LOPE did not reveal any significant association. We conclude that derangements of fetal haematopoiesis, in particular of neutrophil- and NRBC counts, are associated with EOPE only, with a potential impact for future health of the offspring. This heterogeneity in UCBC should be considered as confounder in epigenetic association studies examining EOPE. 10.1016/j.jri.2016.05.002
    Comparison of nucleated red blood cells in the umbilical cord of term neonates in healthy women and women with preeclampsia. Faraji Darkhaneh Roya,Ghanbari Atefeh,Asgharnia Maryam,Kian Mitra Iranian journal of reproductive medicine BACKGROUND:Asphyxia is a common cause of perinatal mortality in 5-10% of all births worldwide. The present parameters for determining perinatal asphyxia, e.g. preeclampsia, cannot be considered as markers per se, and require auxiliary markers, e.g. increased number of nucleated red blood (NRBC) cells, for early diagnosis of perinatal asphyxia. OBJECTIVE:In this study, we evaluated the mean NRBC count in preeclampsia and to determine the usefulness of the NRBC as independent prognostic factors of perinatal complications. MATERIALS AND METHODS:This was a cross-sectional study in order to compare the NRBC in the umbilical cord of term neonates born to 50 mothers with preeclampsia and 150 normal mothers. The exclusion criteria were mother's affliction with complications of pregnancy and inexact last menstrual period. The variables under study were maternal and neonatal data. The count of NRBC was determined with standard laboratory procedures in the blood samples from umbilical cord of the neonates. The acquired data were fed into SPSS 16 software and analyzed using statistical tests. RESULTS:The mean value of NRBC count was significantly higher in preeclamptic women (p<0.0001). The average 1(st) and 5(th) minute Apgar scores were significantly higher in normal mothers (p<0.001). CONCLUSION:Increase of NRBC in neonates born to mothers with preeclampsia may be due to chronic hypoxia; this group of neonates has increased risk and requires more precise and extensive care during delivery and after birth in order to have reduced mortality and complications during the neonatal period.
    The combined detection of umbilical cord nucleated red blood cells and lactate: early prediction of neonatal hypoxic ischemic encephalopathy. Haiju Zhang,Suyuan Hao,Xiufang Fan,Lu Yang,Sun Ruopeng Journal of perinatal medicine OBJECTIVE:To establish a simple and quick method that could be used to predict the occurrence of hypoxic ischemic encephalopathy (HIE) as early as possible by investigating the variations of nucleated red blood cells per 100 white blood cell (NRBC/100 WBC) counts and lactate levels in cord blood. METHODS:In 46 cases of acute fetal distress (AFD) and 54 cases of chronic fetal distress (CFD) neonates we measured the percentage (NRBCs/100 WBC) and lactate in the umbilical blood. RESULTS:Both lactate levels and NRBC/100WBC counts were higher in CFD and AFD groups than in controls (both P<0.01). The numbers of NRBC/100 WBC and the values of lactate in moderate-severe HIE group were higher than in mild-HIE group (P=0.002 and P=0.042, respectively). The combined sensitivity and specificity was 94% and 96% at 15NRBC/100WBC and 4.25 mmol/L level by combined detecting NRBC and lactate to predict HIE. Three infants (including 1 death and 2 survivors) had the highest levels of NRBC/100WBC and lactate in cord blood, and the 2 survivors had the lowest mental development index (MDI) and psychomotor development index (PDI). CONCLUSIONS:Combined detection with NRBC/100WBC and lactate allows early prediction of development and severity of HIE. The levels of these parameters are related to the neurodevelopment outcome of HIE infants. 10.1515/JPM.2008.035
    Nucleated red blood cells as a novel indicator of CD34 cell content in umbilical cord blood. Galel David,Crisostomo Clarence,Ortega Jennifer,Peters Kirstin,Neveu Sara,Davila Carolina,Barlow James Transfusion BACKGROUND:Umbilical cord blood (UCB) has become an important source of transplantable CD34 hematopoietic progenitor cells. Cord blood banks (CBBs) can increase their efficiency by minimizing the processing of UCB units with low CD34 content, which have a lower likelihood of transplant utilization. We sought to identify a readily available preprocessing metric that would correlate with CD34 cell counts, without the cost of additional analysis. STUDY DESIGN AND METHODS:Data were compiled for 131 UCB units processed at the regional CBB. Preprocessing hematologic metrics, including complete blood count and differential, were compared to postprocessing CD34 cell quantities. The data were divided into six groups of varying preprocessing metrics, then compared for significant differences in postprocessing CD34 cell quantities to develop a screening guidance. RESULTS:UCB units with nucleated RBC (nRBC) content of 15% or greater were found to have a significant increase in CD34 cell percentage (p < 0.00001) and total CD34 cell content (p < 0.0001). Units with preprocessing total nucleated cell count (TNC) of ≥ 1.50 × 10 with nRBC content of 15% or greater, and for TNC ≥ of 2.00 × 10 with nRBC content less than15%, had a significant increase in CD34 content (p < 0.05 and p < 0.001, respectively). Applied as a screening guideline, these units had an increase in mean CD34 content from 6.24 × 10 to 9.27 × 10 . Units originally in the bottom and top quartiles of CD34 content constitute 5% and 53% of processed units meeting these TNC/nRBC criteria, respectively. CONCLUSION:These screening criteria utilizing nRBC provides a guideline that public CBBs may use to increase their efficiency by minimizing the processing of UCB units with lower CD34 cell content. 10.1111/trf.15080
    Identification and transcriptome analysis of erythroblastic island macrophages. Li Wei,Wang Yaomei,Zhao Huizhi,Zhang Huan,Xu Yuanlin,Wang Shihui,Guo Xinhua,Huang Yumin,Zhang Shijie,Han Yongshuai,Wu Xianfang,Rice Charles M,Huang Gang,Gallagher Patrick G,Mendelson Avital,Yazdanbakhsh Karina,Liu Jing,Chen Lixiang,An Xiuli Blood The erythroblastic island (EBI), composed of a central macrophage and surrounding erythroid cells, was the first hematopoietic niche discovered. The identity of EBI macrophages has thus far remained elusive. Given that Epo is essential for erythropoiesis and that Epor is expressed in numerous nonerythroid cells, we hypothesized that EBI macrophages express Epor so that Epo can act on both erythroid cells and EBI macrophages simultaneously to ensure efficient erythropoiesis. To test this notion, we used Epor-eGFPcre knockin mouse model. We show that in bone marrow (BM) and fetal liver, a subset of macrophages express Epor-eGFP. Imaging flow cytometry analyses revealed that >90% of native EBIs comprised F4/80Epor-eGFP macrophages. Human fetal liver EBIs also comprised EPOR macrophages. Gene expression profiles of BM F4/80Epor-eGFP macrophages suggest a specialized function in supporting erythropoiesis. Molecules known to be important for EBI macrophage function such as , , , and were highly expressed in F4/80Epor-eGFP macrophages compared with F4/80Epor-eGFP macrophages. Key molecules involved in iron recycling were also highly expressed in BM F4/80Epor-eGFP macrophages, suggesting that EBI macrophages may provide an iron source for erythropoiesis within this niche. Thus, we have characterized EBI macrophages in mouse and man. Our findings provide important resources for future studies of EBI macrophage function during normal as well as disordered erythropoiesis in hematologic diseases such as thalassemia, polycythemia vera, and myelodysplastic syndromes. 10.1182/blood.2019000430
    Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes. Akilesh Holly M,Buechler Matthew B,Duggan Jeffrey M,Hahn William O,Matta Bharati,Sun Xizhang,Gessay Griffin,Whalen Elizabeth,Mason Michael,Presnell Scott R,Elkon Keith B,Lacy-Hulbert Adam,Barnes Betsy J,Pepper Marion,Hamerman Jessica A Science (New York, N.Y.) Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)-driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6C monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)-like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection. 10.1126/science.aao5213
    On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Theurl Igor,Hilgendorf Ingo,Nairz Manfred,Tymoszuk Piotr,Haschka David,Asshoff Malte,He Shun,Gerhardt Louisa M S,Holderried Tobias A W,Seifert Markus,Sopper Sieghart,Fenn Ashley M,Anzai Atsushi,Rattik Sara,McAlpine Cameron,Theurl Milan,Wieghofer Peter,Iwamoto Yoshiko,Weber Georg F,Harder Nina K,Chousterman Benjamin G,Arvedson Tara L,McKee Mary,Wang Fudi,Lutz Oliver M D,Rezoagli Emanuele,Babitt Jodie L,Berra Lorenzo,Prinz Marco,Nahrendorf Matthias,Weiss Guenter,Weissleder Ralph,Lin Herbert Y,Swirski Filip K Nature medicine Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal. In various pathophysiological conditions, however, erythrocyte life span is compromised severely, which threatens the organism with anemia and iron toxicity. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 (LY6C1, also known as Ly-6C) ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1 (FPN1, encoded by SLC40A1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1(+)Tim-4(neg) macrophages are transient, reside alongside embryonically derived T cell immunoglobulin and mucin domain containing 4 (Timd4, also known as Tim-4)(high) Kupffer cells (KCs), and depend on the growth factor Csf1 and the transcription factor Nrf2 (encoded by Nfe2l2). The spleen, likewise, recruits iron-loaded Ly-6C(high) monocytes, but these do not differentiate into iron-recycling macrophages, owing to the suppressive action of Csf2. The accumulation of a transient macrophage population in the liver also occurs in mouse models of hemolytic anemia, anemia of inflammation, and sickle cell disease. Inhibition of monocyte recruitment to the liver during stressed erythrocyte delivery leads to kidney and liver damage. These observations identify the liver as the primary organ that supports rapid erythrocyte removal and iron recycling, and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity. 10.1038/nm.4146
    Monocyte-derived macrophages expand the murine stress erythropoietic niche during the recovery from anemia. Liao Chang,Prabhu K Sandeep,Paulson Robert F Blood Anemic stress induces a physiological response that includes the rapid production of new erythrocytes. This process is referred to as stress erythropoiesis. It is best understood in the mouse where it is extramedullary and utilizes signals and progenitor cells that are distinct from bone marrow steady-state erythropoiesis. The development of stress erythroid progenitors occurs in close association with the splenic stress erythropoiesis niche. In particular, macrophages in the niche are required for proper stress erythropoiesis. Here we show that the expansion of the niche occurs in concert with the proliferation and differentiation of stress erythroid progenitors. Using lineage tracing analysis in 2 models of anemic stress, we show that the expansion of the splenic niche is due to the recruitment of monocytes into the spleen, which develop into macrophages that form erythroblastic islands. The influx in monocytes into the spleen depends in part on Ccr2-dependent signaling mediated by Ccl2 and other ligands expressed by spleen resident red pulp macrophages. Overall, these data demonstrate the dynamic nature of the spleen niche, which rapidly expands in concert with the stress erythroid progenitors to coordinate the production of new erythrocytes in response to anemic stress. 10.1182/blood-2018-06-856831
    Increased erythrophagocytosis induces ferroptosis in red pulp macrophages in a mouse model of transfusion. Youssef Lyla A,Rebbaa Abdelhadi,Pampou Sergey,Weisberg Stuart P,Stockwell Brent R,Hod Eldad A,Spitalnik Steven L Blood Macrophages play important roles in recycling iron derived from the clearance of red blood cells (RBCs). They are also a critically important component of host defense, protecting against invading pathogens. However, the effects on macrophage biology of acutely ingesting large numbers of RBCs are not completely understood. To investigate this issue, we used a mouse model of RBC transfusion and clearance, which mimics the clinical setting. In this model, transfusions of refrigerator storage-damaged (ie, "old") RBCs led to increased erythrophagocytosis by splenic red pulp macrophages (RPMs). This robust erythrophagocytosis induced ferroptosis, an iron-dependent form of cell death, in RPMs. This was accompanied by increases in reactive oxygen species and lipid peroxidation in vivo, which were reduced by treatment in vitro with ferrostatin-1, a ferroptosis inhibitor. Old RBC transfusions also induced RPM-dependent chemokine expression by splenic Ly6C monocytes, which signaled Ly6C monocyte migration from bone marrow to spleen, where these cells subsequently differentiated into RPMs. The combination of cell division among remaining splenic RPMs, along with the influx of bone marrow-derived Ly6C monocytes, suggests that, following RPM depletion induced by robust erythrophagocytosis, there is a coordinated effort to restore homeostasis of the RPM population by local self-maintenance and contributions from circulating monocytes. In conclusion, these findings may be clinically relevant to pathological conditions that can arise as a result of increased erythrophagocytosis, such as transfusion-related immunomodulation and impaired host immunity. 10.1182/blood-2017-12-822619
    Macrophage Inflammation, Erythrophagocytosis, and Accelerated Atherosclerosis in Jak2 Mice. Wang Wei,Liu Wenli,Fidler Trevor,Wang Ying,Tang Yang,Woods Brittany,Welch Carrie,Cai Bishuang,Silvestre-Roig Carlos,Ai Ding,Yang Yong-Guang,Hidalgo Andres,Soehnlein Oliver,Tabas Ira,Levine Ross L,Tall Alan R,Wang Nan Circulation research RATIONALE:The mechanisms driving atherothrombotic risk in individuals with JAK2 ( Jak2 ) positive clonal hematopoiesis or myeloproliferative neoplasms are poorly understood. OBJECTIVE:The goal of this study was to assess atherosclerosis and underlying mechanisms in hypercholesterolemic mice with hematopoietic Jak2 expression. METHODS AND RESULTS:Irradiated low-density lipoprotein receptor knockout ( Ldlr) mice were transplanted with bone marrow from wild-type or Jak2 mice and fed a high-fat high-cholesterol Western diet. Hematopoietic functions and atherosclerosis were characterized. After 7 weeks of Western diet, Jak2 mice showed increased atherosclerosis. Early atherosclerotic lesions showed increased neutrophil adhesion and content, correlating with lesion size. After 12 weeks of Western diet, Jak2 lesions showed increased complexity, with larger necrotic cores, defective efferocytosis, prominent iron deposition, and costaining of erythrocytes and macrophages, suggesting erythrophagocytosis. Jak2 erythrocytes were more susceptible to phagocytosis by wild-type macrophages and showed decreased surface expression of CD47, a "don't-eat-me" signal. Human JAK2VF erythrocytes were also more susceptible to erythrophagocytosis. Jak2 macrophages displayed increased expression and production of proinflammatory cytokines and chemokines, prominent inflammasome activation, increased p38 MAPK (mitogen-activated protein kinase) signaling, and reduced levels of MerTK (c-Mer tyrosine kinase), a key molecule mediating efferocytosis. Increased erythrophagocytosis also suppressed efferocytosis. CONCLUSIONS:Hematopoietic Jak2 expression promotes early lesion formation and increased complexity in advanced atherosclerosis. In addition to increasing hematopoiesis and neutrophil infiltration in early lesions, Jak2 caused cellular defects in erythrocytes and macrophages, leading to increased erythrophagocytosis but defective efferocytosis. These changes promote accumulation of iron in plaques and increased necrotic core formation which, together with exacerbated proinflammatory responses, likely contribute to plaque instability. 10.1161/CIRCRESAHA.118.313283
    Neglected Cells: Immunomodulatory Roles of CD71 Erythroid Cells. Elahi Shokrollah Trends in immunology The main role of red blood cells is oxygen-transportation. However, recent studies have unveiled immunomodulatory functions for their immature counterparts, CD71 erythroid cells, under different physiological and pathological conditions. Here, I provide a perspective on the recent advances in this field to highlight their importance in health and disease. 10.1016/j.it.2019.01.003
    The Evolving Erythrocyte: Red Blood Cells as Modulators of Innate Immunity. Anderson H Luke,Brodsky Igor E,Mangalmurti Nilam S Journal of immunology (Baltimore, Md. : 1950) The field of red cell biology is undergoing a quiet revolution. Long assumed to be inert oxygen carriers, RBCs are emerging as important modulators of the innate immune response. Erythrocytes bind and scavenge chemokines, nucleic acids, and pathogens in circulation. Depending on the conditions of the microenvironment, erythrocytes may either promote immune activation or maintain immune quiescence. We examine erythrocyte immune function through a comparative and evolutionary lens, as this framework may offer perspective into newly recognized roles of human RBCs. Next, we review the known immune roles of human RBCs and discuss their activity in the context of sepsis where erythrocyte function may prove important to disease pathogenesis. Given the limited success of immunomodulatory therapies in treating inflammatory diseases, we propose that the immunologic function of RBCs provides an understudied and potentially rich area of research that may yield novel insights into mechanisms of immune regulation. 10.4049/jimmunol.1800565
    Red blood cell distribution width predicts two-hours plasma glucose levels during OGTT. Tripolino Cesare,Irace Concetta,Carallo Claudio,De Franceschi Maria Serena,Scavelli Faustina Barbara,Gnasso Agostino Clinical hemorheology and microcirculation OBJECTIVE:Red blood cell distribution width (RDW) is a numerical measure, reported as part of a standard complete blood count, usually employed for differential diagnosis of anemic state. Some lines of evidence demonstrate that RDW associates with type 2 diabetes incidence and its complications. To further explore the role of RDW as predictor of abnormal glucose metabolism, we have analyzed the relationship between RDW and 2-hours plasma glucose concentration during an oral glucose tolerance test (OGTT). METHODS:Forty-five outpatients were enrolled for the present study. Participants underwent 75 g OGTT and measurements of hematological parameters. Cardiovascular disease risk factors (blood pressure, blood lipids, cigarette smoking, obesity) were evaluated by routine methods. RESULTS:In simple regression analysis 2-hours post-load glucose was directly associated with age (r = 0.36, p = 0.01), fasting glucose levels (r = 0.40, p = 0.002) and RDW (r = 0.31, p = 0.037). In multiple regression analysis fasting glucose, RDW, triglycerides and age significantly and independently predicted 2-hours plasma glucose (p <  0.01 for all coefficients). CONCLUSION:The present findings demonstrate that RDW associates with plasma glucose concentration after a 75-g oral glucose tolerance test. Our results highlight the role of RDW as predictor of glucose metabolism disturbance. 10.3233/CH-151947
    Impaired RBC deformability is associated with diabetic retinopathy in patients with type 2 diabetes. Moon J S,Kim J H,Kim J H,Park I R,Lee J H,Kim H J,Lee J,Kim Y K,Yoon J S,Won K C,Lee H W Diabetes & metabolism AIM:Red blood cell (RBC) deformability, the ability of RBCs to change shape under stress, is known to be decreased in type 2 diabetes (T2D). However, as yet little is known of the association between RBC deformability and diabetic complications in T2D. For this reason, this study has investigated the association between RBC deformability and diabetic complications. METHODS:In this cross-sectional study, 452 T2D patients were initially enrolled. RBC deformability was measured using a microfluidic ektacytometer and expressed as an elongation index at 3Pa (EI@3Pa, %). RESULTS:A final total of 373 patients (mean age: 60.04±11.93 years; males: 201) were included in the study. When categorized into quartiles of RBC deformability, the lower EI@3Pa groups had higher glycated haemoglobin (HbA), triglycerides and prevalence of diabetic retinopathy compared with the higher quartiles (P<0.05 for trend). In particular, the EI@3Pa was significantly lower in patients with retinopathy than in those without retinopathy (30.53±1.95 vs 31.20±1.53, P=0.001). Between the lowest EI@3Pa quartile (Q1) to the highest (Q4, reference), the odds ratio (OR) for Q1 was 2.81 (95% CI: 1.21-6.49, P=0.004 for trend), after adjusting for age, gender, presence of hypertension and smoking, duration of diabetes, HbA, glomerular filtration rate and triglycerides. CONCLUSION:In terms of diabetic complications, the lowest EI@3Pa group was closely associated with only the risk of diabetic retinopathy in our study. These results suggest that RBC deformability might be contributory to the development of the microvascular complication. 10.1016/j.diabet.2016.04.008
    Hyperglycemia effect on red blood cells indices. Alamri B N,Bahabri A,Aldereihim A A,Alabduljabbar M,Alsubaie M M,Alnaqeb D,Almogbel E,Metias N S,Alotaibi O A,Al-Rubeaan K European review for medical and pharmacological sciences OBJECTIVE:Hyperglycemia has an effect on all body tissues; one of them is the bone marrow. This effect is related to protein glycation and other chemical and physiological changes of red blood cells (RBCs). The aim of this study was to assess the effect of hyperglycemia on different RBCs indices along with evaluating these changes in the normal physiology and chronic diabetes complication pathology. PATIENTS AND METHODS:This is a cross-sectional hospital-based study of 1000 type 2 Saudi diabetic patients without any hematological diseases. Patients were fully evaluated clinically and biochemically with full blood hematological parameters assessment. The studied cohort matched the general characteristics of Saudi type 2 diabetic patients. RESULTS:This study shows that hyperglycemia increases the red blood cells count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC). Red blood cell distribution width (RDW) was negatively correlated with poor glycemic control. Concurrently, the presence of micro and macroangiopathies with hyperglycemia shortens the lifespan of RBCs. CONCLUSIONS:We conclude that hyperglycemia has an imposing effect on RBCs count and its physiological function, which can be normalized effectively with good glycemic control. 10.26355/eurrev_201903_17259
    Red blood cell membrane cholesterol in type 2 diabetes mellitus. Nunes J Massimo,Pretorius Etheresia Thrombosis research Type II diabetes mellitus (T2DM) affects an estimate of 450 million individuals. Hence, there remains an urgent need to explore the use of novel biomarkers with the aim of preventing and managing cardiovascular risk among these individuals. Hallmarks of this condition are lipid and glucose dyshomeostasis which are accompanied by a prothrombotic phenotype; these pose as eminent links between T2DM and cardiovascular disease. Diabetic dyslipidemia affects not only plasma lipid profiles but extends further into the haematological system, modulating the cholesterol concentration of erythrocyte membranes. Elevations in this biomarker implicate cell biophysics and contribute to an increased cardiovascular risk. Here we investigate the variation of membrane cholesterol levels in RBCs, as well as the degree of hypercoagubility between healthy and type II diabetic subjects. Furthermore, we provide an adapted method to assess erythrocyte membrane cholesterol levels using a quantitative and qualitative approach. In conclusion, individuals with type II diabetes exhibit elevated erythrocyte membrane cholesterol levels which may act as a prominent link between the diabetic state and subsequent cardiovascular complications. Ultimately, this erythrocyte parameter exhibits applicative biomarker potential and may provide clinical utility in terms of disease monitoring and prognostics. 10.1016/j.thromres.2019.04.005
    Increased red blood cell distribution width and platelet‑to‑lymphocyte ratio for predicting all‑cause mortality in patients with type 2 diabetes and advanced heart failure: a causal association or epiphenomenon? Lippi Giuseppe,Targher Giovanni Kardiologia polska 10.33963/KP.14879
    Correlation of Hemoglobin A1c with Red Cell Width Distribution and Other Parameters of Red Blood Cells in Type II Diabetes Mellitus. Bhutto Abdul Rabb,Abbasi Amanullah,Abro Ali Hassan Cureus Objective To determine the correlation of glycated hemoglobin (HbA1c) with red cell width (RDW) and other analytic parameters of red blood cells (RBCs) in type II diabetic patients. Design Cross-sectional analytical study. Place and duration of the study Al-Tibri Medical College and Hospital Karachi; from July 2017 to January 2018. Patients and methods This cross-sectional study was conducted on diagnosed type II diabetic patients visiting the outpatient department of medicine at Al-Tibri Medical College Hospital from July 2017 to January 2018. Diabetes mellitus was diagnosed according to American Diabetes Association (ADA) guidelines. After taking consent and conducting a clinical assessment (include history and physical examination), laboratory tests, such as fasting blood glucose, random blood glucose, complete blood count (CBC), and HbA1c, were collected on proforma. Results A total of 119 patients were eligible for the study with a mean age of 48.63±12.462 (range 24-76) years; among those, males were 74 (62.2%) and females were 45 (37.8%). The mean duration of diabetes mellitus (DM) was 6.735±3.759 (range 1-20) years. The mean hemoglobin of patients was 11.59±1.315 gm/dl. The mean corpuscular volume (MCV) was 76.65±11.121 fl and the mean RDW was found to be 18.287±4.352, with the highest value of 30.20. The mean MCH was 30.223±23.873 pg, with the highest value of 38.4 pg. The mean cell hemoglobin concentration (MCHC) was 28.214±4.7498 mg/dl. The HbA1c of the study population was found to be moderately uncontrolled and the mean HbA1c was 8.278±5.015%, with the highest value of 16.2%. The mean fasting blood sugar was 158±39.50 mg/dl while the mean random blood sugar was 236±57.390 mg/dl. The correlation of HbA1c with RDW turned out to be significant statistically (p-0.035) while other RBCs and/or hematological parameters, such as MCV, hemoglobin, and platelets, revealed no significant correlation. Conclusion The study highlighted that RDW has a significant correlation with HbA1c and is an inexpensive and freely available test so it may be used as a marker of glycemic status. 10.7759/cureus.5533
    Red blood cell distribution width and coronary artery disease severity in diabetic patients. Khalil Abdelrahman,Shehata Mohamed,Abdeltawab Adham,Onsy Ahmed Future cardiology The purpose of the study is to evaluate the relationship between red blood cell distribution width (RDW) and coronary calcium score in diabetic patients. Hematological parameters of 100 diabetic (Type II) patients were assessed. Computed tomographic angiography was used to asses coronary artery calcium (CAC) score. Mean age of the study cohort was 55 years (males: 60%). Mean RDW was 12.7%. Mean CAC score was 243. There was a significant correlation between RDW and each of: CAC scores (r = 0.53; p < 0.001) and severity of coronary artery disease (CAD; r = 0.25; p = 0.047). A cut-off value >14.2% (receiver operating characteristic curves) predicted CAC score >400. A cut-off value >-14.6% predicted the presence of significant CAD. Diabetic patients with high-CAC scores and significant CAD had higher RDW. 10.2217/fca-2018-0066
    Aging and glycation promote erythrocyte phagocytosis by human endothelial cells: Potential impact in atherothrombosis under diabetic conditions. Catan Aurélie,Turpin Chloé,Diotel Nicolas,Patche Jessica,Guerin-Dubourg Alexis,Debussche Xavier,Bourdon Emmanuel,Ah-You Nathalie,Le Moullec Nathalie,Besnard Mathieu,Veerapen Reuben,Rondeau Philippe,Meilhac Olivier Atherosclerosis BACKGROUND AND AIMS:Atherothrombotic plaques of type 2 diabetic (T2D) patients are characterized by an increased neovascularization and intraplaque hemorrhage. The clearance of erythrocytes may be carried out by vascular cells. We explored the potential of human endothelial cells to bind and phagocyte in vitro aged and/or glycated erythrocytes as well as erythrocytes obtained from diabetic patients. METHODS:Fresh, aged and glycated-aged erythrocytes from healthy volunteers and T2D patients were tested for their binding and phagocytosis capacity as well as the potential functional consequences on endothelial cells (viability, proliferation and wound healing capacity). Immunohistochemistry was also performed in human carotid atherothrombotic samples (from patients with or without T2D). RESULTS:Aging and glycation of erythrocytes induced phosphatidylserine (PS) exposure and oxidative stress leading to enhanced endothelial cell binding and engulfment. Phagocytosis by endothelial cells was more pronounced with aged and glycated erythrocytes than with fresh ones. Phagocytosis was enhanced with T2D versus healthy erythrocytes. Furthermore, endothelial wound healing potential was significantly blunted after exposure to glycated-aged versus fresh erythrocytes. Finally, we show that interactions between erythrocytes and endothelial cells and their potential phagocytosis may occur in vivo, in atherothrombotic conditions, in neovessels and in the luminal endothelial lining. CONCLUSIONS:Endothelial cells may play an important role in erythrocyte clearance in an atherothrombotic environment. Under diabetic conditions, erythrocyte glycation favors their engulfment by endothelial cells and may participate in endothelial dysfunction, thereby promoting vulnerable atherothrombotic plaques to rupture. 10.1016/j.atherosclerosis.2019.10.015
    Relation Between Oxidative Stress and Hematologic Abnormalities in Children With Type 1 Diabetes. Abdel-Moneim Adel,Zanaty Mohamed I,El-Sayed Amr,Khalil Rehab G,Rahman Hanan Abdel Canadian journal of diabetes OBJECTIVES:Recently, numerous studies have renewed attention to the hematologic profile in the early identification of diabetic inflammation and complications. The objective of this study was to investigate the relationship between hematologic indices abnormalities and oxidative stress among children with type 1 diabetes mellitus (T1DM). METHODS:This study included 70 children diagnosed with T1DM and 30 healthy control subjects. The children with T1DM were divided into 2 groups according to the duration of diabetes: children with newly diagnosed T1DM and children with established T1DM. RESULTS:Erythrocyte count and platelet count were decreased significantly in children with established T1DM, whereas leukocyte count and neutrophil count were increased significantly in children with newly diagnosed T1DM compared with healthy control subjects. Moreover, hemoglobin and hematocrit values revealed a significant depletion in both T1DM groups; however, values of red blood cell distribution width, mean platelet volume and platelet distribution width were significantly elevated in both T1DM groups compared with healthy control subjects. Also, microalbuminuria levels showed a significant increase in children with established T1DM, whereas lipid peroxidation biomarker (malondialdehyde) and nitric oxide levels were elevated markedly in both T1DM groups compared with the healthy group. CONCLUSIONS:The data demonstrated that the hematologic profile showed noticeable alterations in children with T1DM, and the inflammation and oxidative stress markers were contributed to the hematologic abnormalities. The results revealed that some hematologic indices can be used in the early detection of children with T1DM at risk for diabetic complications. 10.1016/j.jcjd.2019.07.153
    Modeling of Biomechanics and Biorheology of Red Blood Cells in Type 2 Diabetes Mellitus. Chang Hung-Yu,Li Xuejin,Karniadakis George Em Biophysical journal Erythrocytes in patients with type-2 diabetes mellitus (T2DM) are associated with reduced cell deformability and elevated blood viscosity, which contribute to impaired blood flow and other pathophysiological aspects of diabetes-related vascular complications. In this study, by using a two-component red blood cell (RBC) model and systematic parameter variation, we perform detailed computational simulations to probe the alteration of the biomechanical, rheological, and dynamic behavior of T2DM RBCs in response to morphological change and membrane stiffening. First, we examine the elastic response of T2DM RBCs subject to static tensile forcing and their viscoelastic relaxation response upon release of the stretching force. Second, we investigate the membrane fluctuations of T2DM RBCs and explore the effect of cell shape on the fluctuation amplitudes. Third, we subject the T2DM RBCs to shear flow and probe the effects of cell shape and effective membrane viscosity on their tank-treading movement. In addition, we model the cell dynamic behavior in a microfluidic channel with constriction and quantify the biorheological properties of individual T2DM RBCs. Finally, we simulate T2DM RBC suspensions under shear and compare the predicted viscosity with experimental measurements. Taken together, these simulation results and their comparison with currently available experimental data are helpful in identifying a specific parametric model-the first of its kind, to our knowledge-that best describes the main hallmarks of T2DM RBCs, which can be used in future simulation studies of hematologic complications of T2DM patients. 10.1016/j.bpj.2017.06.015
    Relationship between glycated haemoglobin concentration and erythrocyte survival in type 2 diabetes mellitus determined by a modified carbon monoxide breath test. Huang Zhenhe,Liu Yajing,Mao Yanfang,Chen Wenwen,Xiao Zhangang,Yu Yangyang Journal of breath research In clinical practice, an unexplained discordance between percentage haemoglobin A1c (HbA1c) and the progression of diabetes and its complication is observed. HbA1c is determined by the blood glucose level and the red blood cell (RBC) lifespan. Whether the RBC lifespan changes in diabetic patients remains undefined because of the lack of a convenient and accurate measurement method. In the present study, we aim to observe the RBC lifespan in type 2 diabetic patients with poor blood glucose control by an endogenous carbon monoxide (CO) measurement using a rapid and simplified CO breath test machine. The RBC lifespan, age, RBC count, haemoglobin, haematocrit, fasting blood glucose (FBG) level, HbA1c, blood lipids and the liver and kidney function were compared between 38 diabetic patients and 40 healthy individuals. Compared with the control group, in the diabetic patients, the RBC lifespan was significantly decreased by 17.52 ± 4.58 (86.08 ± 18.13 d versus 103.6 ± 22.02 d, p = 0.00). Although a univariate linear correlation analysis showed that the RBC lifespan was negatively correlated with the FBG level (r = -0.386, p = 0.000), haemoglobin A1c (r = -0.346, p = 0.002) and age (r = -0.291, p = 0.010), a stepwise multiple linear regression analysis showed that the RBC lifespan was most affected by the FBG level (t = -3.554, p = 0.001), but not by HbA1c or age, while HbA1c was most affected by the FBG level (t = 13.989, p = 0.000), but not the RBC lifespan. The RBC lifespan in diabetic patients with poor glycaemic control was reduced. The decrease in the RBC lifespan caused by hyperglycaemia was not associated with HbA1c. Thus, a decrease in the RBC lifespan will lead to an underestimation of the actual level of hyperglycaemia and the progression of disease by HbA1c in type 2 diabetic patients if we do not adjust the RBC lifespan. 10.1088/1752-7163/aa9081
    Red blood cell distribution width and the risk of being in poor glycemic control among patients with established type 2 diabetes. Yin Yaqi,Ye Sisi,Wang Haibin,Li Bing,Wang Anping,Yan Wenhua,Dou Jingtao,Mu Yiming Therapeutics and clinical risk management Background:The red cell distribution width (RDW) has been shown to be associated with the incidence and complications of type 2 diabetes (T2D). However, the relevance of RDW with the risk of being in poor glycemic control among patients with established T2D is largely overlooked. Methods:A total of 702 T2D participants from the REACTION study were enrolled in this study. Blood routine index, fasting plasma glucose, hemoglobin A1c and lipid profile data were available for all of the enrolled population. Results:The univariate logistic analysis revealed a significant association between RDW and the risk of being in poor glycemic control among T2D subjects with an odds ratio (OR) and a 95% confidence interval (CI) of 0.5 and 0.3-0.8, respectively, for the fourth vs the first quartile of RDW. The association strengthened after multivariable adjustment (OR [95% CI]: 0.3 [0.2-0.7]). Interaction and stratified analyses indicated that this association was seen only among T2D subjects with lower body mass index and/or serum lipid levels. Conclusion:T2D patients with higher RDW had significantly lower risk of being in poor glycemic control. RDW may contribute to risk assessment for T2D individuals at risk of being in poor glycemic control. 10.2147/TCRM.S155753
    Red Blood Cell Distribution Width Is Associated with Carotid Atherosclerosis in People with Type 2 Diabetes. Nam J S,Ahn C W,Kang S,Kim K R,Park J S Journal of diabetes research Aims:Red cell distribution width (RDW) has been shown to be associated with cardiovascular diseases (CVD). The relationship between RDW and carotid intima-media thickness (C-IMT), a marker of subclinical atherosclerosis, has been inconsistent in subjects with cardiovascular risk factors. In this study, we investigated the relationship between RDW and carotid atherosclerosis in people with type 2 diabetes. Methods:Four hundred sixty-nine people with type 2 diabetes without history of cardiovascular or cerebrovascular diseases were enrolled. Anthropometric measures and various biochemical parameters including RDW were assessed. Ultrasonographic measurement of carotid intima-media thickness was used to evaluate subclinical atherosclerosis. Results:The participants were stratified into 3 groups according to RDW. The C-IMT increased gradually according to RDW tertiles (lowest, second, highest RDW tertiles; 0.740 ± 0.120, 0.772 ± 0.138, and 0.795 ± 0.139, respectively; < 0.01). Multiple regression analysis and multivariate logistic regression analysis revealed that RDW was associated with C-IMT in people with type 2 diabetes, and it remained significant after control for various cardiovascular risk factors including body mass index, blood pressure, insulin resistance, and smoking status in multivariate logistic regression analysis. Conclusion:RDW is associated with subclinical atherosclerosis assessed by carotid IMT after control of various covariates in people with type 2 diabetes without cardiovascular or cerebrovascular diseases. 10.1155/2018/1792760
    Red Blood Cells in Type 2 Diabetes Impair Cardiac Post-Ischemic Recovery Through an Arginase-Dependent Modulation of Nitric Oxide Synthase and Reactive Oxygen Species. Yang Jiangning,Zheng Xiaowei,Mahdi Ali,Zhou Zhichao,Tratsiakovich Yahor,Jiao Tong,Kiss Attila,Kövamees Oskar,Alvarsson Michael,Catrina Sergiu-Bogdan,Lundberg Jon O,Brismar Kerstin,Pernow John JACC. Basic to translational science This study tested the hypothesis that red blood cell (RBC) arginase represents a potential therapeutic target in ischemia-reperfusion in type 2 diabetes. Post-ischemic cardiac recovery was impaired in hearts from db/db mice compared with wild-type hearts. RBCs from mice and patients with type 2 diabetes attenuated post-ischemic cardiac recovery of nondiabetic hearts. This impaired cardiac recovery was reversed by inhibition of RBCs arginase or nitric oxide synthase. The results suggest that RBCs from type 2 diabetics impair cardiac tolerance to ischemia-reperfusion via a pathway involving arginase activity and nitric oxide synthase-dependent oxidative stress. 10.1016/j.jacbts.2018.03.006
    Rubrivigilance in diabetes. Kalra Sanjay,Ruder Sundeep JPMA. The Journal of the Pakistan Medical Association Anaemia and diabetes have a multifaceted relationship. Their co-existence contributes to each other's etiopathogenesis, natural history, clinical presentation and prognosis. Anaemia may occur in autoimmune disease that coexists with type 1 diabetes, in erythropoietin deficient and in erythropoietin hyporesponsive states. Iron deficiency, haemolytic and megaloblastic anaemia occur in diabetes through various mechanisms. Anaemia is associated with, and contributes to, worsening of both microvascular and macrovascular complications. Altered red blood cell physiology may influence results of glycated haemoglobin. While certain glucose-lowering drugs and antihypertensive drugs may cause iatrogenic anaemia, others help in improving blood health. This review synthesizes all these relationships, and their underlying mechanisms, in a simple, reader-friendly format. This information should help the diabetes care professional to practice due rubrivigilance, i.e. keep a high index of clinical suspicion for anaemia in diabetes care.
    Red cell distribution width and common disease onsets in 240,477 healthy volunteers followed for up to 9 years. Pilling Luke C,Atkins Janice L,Kuchel George A,Ferrucci Luigi,Melzer David PloS one Higher Red Blood Cell Distribution Width (RDW or anisocytosis) predicts incident coronary artery disease (CAD) plus all-cause and cardiovascular mortality, but its predictive value for other common diseases in healthy volunteers is less clear. We aimed to determine the shorter and longer term associations between RDW and incident common conditions in participants free of baseline disease, followed for 9 years. We undertook a prospective analysis of RDW% using 240,477 healthy UK Biobank study volunteers aged 40-70 years at baseline, with outcomes ascertained during follow-up (≤9 years). Participants were free of anemia, CAD, type-2 diabetes, stroke, hypertension, COPD, and any cancer (except non-melanoma skin cancer) at baseline. Survival models (with competing Hazards) tested associations with outcomes from hospital admission records and death certificates. High RDW (≥15% variation, n = 6,050) compared to low (<12.5% n = 20,844) was strongly associated with mortality (HR 3.10: 95% CI 2.57 to 3.74), adjusted for age, sex, smoking status, education level, mean cell volume and hemoglobin concentration. Higher RDW was also associated with incident CAD (sub-HR 1.67: 1.40 to 1.99), heart failure, peripheral vascular disease, atrial fibrillation, stroke, and cancer (sHR 1.37: 1.21 to 1.55; colorectal cancer sHR 1.92: 1.36 to 2.72), especially leukemia (sHR 2.85: 1.63 to 4.97). Associations showed dose-response relationships, and RDW had long-term predictive value (≥4.5 years after assessment) for the majority of outcomes, which were similar in younger and older persons. In conclusion, higher RDW predicted onsets of a wide range of common conditions as well as mortality in a large healthy volunteer cohort. RDW is not just a short term predictor, as high levels were predictive 4.5 to 9 years after baseline in healthy volunteers. The wide range of outcomes reflects known RDW genetic influences, including diverse disease risks. RDW may be a useful clinical marker for inclusion in wellness assessments. 10.1371/journal.pone.0203504
    Reduction in White Blood Cell, Neutrophil, and Red Blood Cell Counts Related to Sex, HLA, and Islet Autoantibodies in Swedish TEDDY Children at Increased Risk for Type 1 Diabetes. Salami Falastin,Lee Hye-Seung,Freyhult Eva,Elding Larsson Helena,Lernmark Åke,Törn Carina, Diabetes Islet autoantibodies (IAs) precede the clinical onset of type 1 diabetes (T1D); however, the knowledge is limited about whether the prodrome affects complete blood counts (CBCs) in 4- to 12-year-old children with increased genetic risk for T1D. This study tested whether CBCs were altered in 4- to 12-year-old children without ( = 376) or with one or several IAs against insulin, GAD65, or IA-2 ( = 72). CBC was analyzed during longitudinal follow-up in 448 Swedish children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A linear mixed-effects model was used to assess potential association between IA and CBC measurements over time. The white blood cell and neutrophil counts were reduced in children with IAs, primarily in boys. In contrast, girls had lower levels of hemoglobin and hematocrit. Positivity for multiple IAs showed the lowest counts in white blood cells and neutrophils in boys and red blood cells, hemoglobin, and hematocrit in girls. These associations were primarily observed in children with the HLA-DR3-DQ2/DR4-DQ8 genotype. We conclude that the reduction in neutrophils and red blood cells in children with multiple IAs and HLA-DR3-DQ2/DR4-DQ8 genotype may signal a sex-dependent islet autoimmunity detected in longitudinal CBCs. 10.2337/db18-0355
    Red blood cell distribution width, relative lymphocyte count, and type 2 diabetes predict all‑cause mortality in patients with advanced heart failure. Szyguła-Jurkiewicz Bożena,Siedlecki Łukasz,Pyka Łukasz,Romuk Ewa,Przybyłowski Piotr,Gąsior Mariusz Polish archives of internal medicine INTRODUCTION    Early identification of patients with advanced heart failure (HF) who are at higher risk of poor outcome is an important element of patient management, both from the medical and economic standpoint. OBJECTIVES    We sought to determine the association between hematologic parameters assessed on admission and within a 3‑year follow‑up in consecutive patients with advanced HF. We also investigated the association between baseline demographic and clinical data and mortality. PATIENTS AND METHODS    We analyzed the data of consecutive patients with advanced HF from the single‑center registry COMMIT‑HF. Patients with hematologic and autoimmune disorders, acute or chronic inflammatory diseases, malignant diseases, incomplete clinical and laboratory data, and those receiving glucocorticoids were excluded from the study. RESULTS    We analyzed 785 patients with advanced HF out of the total number of 1798 patients included in the COMMIT‑HF registry between 2009 and 2013. The mean (SD) age of the patients was 61.9 (12.4) years, and 76.8% of them were male. Diabetes (hazard ratio [HR], 1.46; 95% CI, 1.15-1.86; P = 0.002), elevated red blood cell distribution width (RDW; HR, 1.05; 95% CI, 1.04-1.07; P <0.0001), and a low relative lymphocyte count (RLC%; HR, 0.942; 95% CI, 0.928-0.956; P <0.0001) were shown to be independent predictors of death. CONCLUSIONS    Our study showed that diabetes is a strong independent predictor of death in patients with advanced HF. RDW and RLC% are simple, accurate, and widely available markers predicting mortality at 3 years in patients with advanced HF. 10.20452/pamw.4149
    Diagnosis of diabetes. Consider life span of red cells. Champ Rod C BMJ (Clinical research ed.) 10.1136/bmj.b5645
    Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping. Krivega Ivan,Byrnes Colleen,de Vasconcellos Jaira F,Lee Y Terry,Kaushal Megha,Dean Ann,Miller Jeffery L Blood Induction of fetal hemoglobin (HbF) production in adult erythrocytes can reduce the severity of sickle cell disease and β-thalassemia. Transcription of β-globin genes is regulated by the distant locus control region (LCR), which is brought into direct gene contact by the LDB1/GATA-1/TAL1/LMO2-containing complex. Inhibition of G9a H3K9 methyltransferase by the chemical compound UNC0638 activates fetal and represses adult β-globin gene expression in adult human hematopoietic precursor cells, but the underlying mechanisms are unclear. Here we studied UNC0638 effects on β-globin gene expression using ex vivo differentiation of CD34(+) erythroid progenitor cells from peripheral blood of healthy adult donors. UNC0638 inhibition of G9a caused dosed accumulation of HbF up to 30% of total hemoglobin in differentiated cells. Elevation of HbF was associated with significant activation of fetal γ-globin and repression of adult β-globin transcription. Changes in gene expression were associated with widespread loss of H3K9me2 in the locus and gain of LDB1 complex occupancy at the γ-globin promoters as well as de novo formation of LCR/γ-globin contacts. Our findings demonstrate that G9a establishes epigenetic conditions preventing activation of γ-globin genes during differentiation of adult erythroid progenitor cells. In this view, manipulation of G9a represents a promising epigenetic approach for treatment of β-hemoglobinopathies. 10.1182/blood-2015-02-629972
    LIN28B-mediated expression of fetal hemoglobin and production of fetal-like erythrocytes from adult human erythroblasts ex vivo. Lee Y Terry,de Vasconcellos Jaira F,Yuan Joan,Byrnes Colleen,Noh Seung-Jae,Meier Emily R,Kim Ki Soon,Rabel Antoinette,Kaushal Megha,Muljo Stefan A,Miller Jeffery L Blood Reactivation of fetal hemoglobin (HbF) holds therapeutic potential for sickle cell disease and β-thalassemias. In human erythroid cells and hematopoietic organs, LIN28B and its targeted let-7 microRNA family, demonstrate regulated expression during the fetal-to-adult developmental transition. To explore the effects of LIN28B in human erythroid cell development, lentiviral transduction was used to knockdown LIN28B expression in erythroblasts cultured from human umbilical cord CD34+ cells. The subsequent reduction in LIN28B expression caused increased expression of let-7 and significantly reduced HbF expression. Conversely, LIN28B overexpression in cultured adult erythroblasts reduced the expression of let-7 and significantly increased HbF expression. Cellular maturation was maintained including enucleation. LIN28B expression in adult erythroblasts increased the expression of γ-globin, and the HbF content of the cells rose to levels >30% of their hemoglobin. Expression of carbonic anhydrase I, glucosaminyl (N-acetyl) transferase 2, and miR-96 (three additional genes marking the transition from fetal-to-adult erythropoiesis) were reduced by LIN28B expression. The transcription factor BCL11A, a well-characterized repressor of γ-globin expression, was significantly down-regulated. Independent of LIN28B, experimental suppression of let-7 also reduced BCL11A expression and significantly increased HbF expression. LIN28B expression regulates HbF levels and causes adult human erythroblasts to differentiate with a more fetal-like phenotype. 10.1182/blood-2012-12-472308
    Erythrocytes From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Via Arginase I. Zhou Zhichao,Mahdi Ali,Tratsiakovich Yahor,Zahorán Szabolcs,Kövamees Oskar,Nordin Filip,Uribe Gonzalez Arturo Eduardo,Alvarsson Michael,Östenson Claes-Göran,Andersson Daniel C,Hedin Ulf,Hermesz Edit,Lundberg Jon O,Yang Jiangning,Pernow John Journal of the American College of Cardiology BACKGROUND:Cardiovascular complications are major clinical problems in type 2 diabetes mellitus (T2DM). The authors previously demonstrated a crucial role of red blood cells (RBCs) in control of cardiac function through arginase-dependent regulation of nitric oxide export from RBCs. There is alteration of RBC function, as well as an increase in arginase activity, in T2DM. OBJECTIVES:The authors hypothesized that RBCs from patients with T2DM induce endothelial dysfunction by up-regulation of arginase. METHODS:RBCs were isolated from patients with T2DM and age-matched healthy subjects and were incubated with rat aortas or human internal mammary arteries from nondiabetic patients for vascular reactivity and biochemical studies. RESULTS:Arginase activity and arginase I protein expression were elevated in RBCs from patients with T2DM (T2DM RBCs) through an effect induced by reactive oxygen species (ROS). Co-incubation of arterial segments with T2DM RBCs, but not RBCs from age-matched healthy subjects, significantly impaired endothelial function but not smooth muscle cell function in both healthy rat aortas and human internal mammary arteries. Endothelial dysfunction induced by T2DM RBCs was prevented by inhibition of arginase and ROS both at the RBC and vascular levels. T2DM RBCs induced increased vascular arginase I expression and activity through an ROS-dependent mechanism. CONCLUSIONS:This study demonstrates a novel mechanism behind endothelial dysfunction in T2DM that is induced by RBC arginase I and ROS. Targeting arginase I in RBCs may serve as a novel therapeutic tool for the treatment of endothelial dysfunction in T2DM. 10.1016/j.jacc.2018.05.052
    Red cell distribution width, haemoglobin A1c and incidence of diabetes mellitus. Engström G,Smith J G,Persson M,Nilsson P M,Melander O,Hedblad B Journal of internal medicine OBJECTIVE:Hyperglycaemia has multiple effects on the red blood cell (RBC), including glycation of haemoglobin, reduced deformability and reduced lifespan. Red cell distribution width (RDW) is a measure of the heterogeneity of erythrocyte volumes. The aim of this study was to explore the relationships between RDW and glucose, haemoglobin A1c (HbA1c) and incidence of diabetes mellitus (DM). DESIGN, SETTING AND SUBJECTS:RDW and mean corpuscular volume were measured in 26 709 non-diabetic participants (aged 45-73 years) from the population-based Malmö Diet and Cancer cohort. HbA1c and fasting venous blood glucose levels were measured in 4845 subjects. MAIN OUTCOME MEASURE:Incidence of DM (n = 2944) over 14 years of follow-up was studied by linkage with national and local DM registers. RESULTS:Individuals with low RDW had significantly higher risk of developing DM [adjusted hazard ratio (HR) 1.48, 95% confidence interval (CI) 1.29-1.70, for 1st vs. 4th quartile], especially in subjects with impaired fasting glucose (n = 416) (HR 2.15, 95% CI 1.12-4.14). Low RDW was also associated with significantly higher waist circumference and glucose, insulin and triglyceride concentrations. By contrast, RDW was significantly and positively associated with HbA1c, corresponding an increase in HbA1c of 0.10% per 1 SD increase in RDW. CONCLUSION:Low RDW is associated with increased incidence of DM independently of other risk factors. We propose that low RDW could be a surrogate marker of reduced RBC survival, with lower HbA1c due to shorter duration of glucose exposure. RDW is a biomarker that could improve risk assessment for individuals at risk of developing DM. 10.1111/joim.12188
    Red cell distribution width and erythrocyte osmotic stability in type 2 diabetes mellitus. Knychala Maria Aparecida,Garrote-Filho Mario da Silva,Batista da Silva Breno,Neves de Oliveira Samantha,Yasminy Luz Sarah,Marques Rodrigues Manuela Ortega,Penha-Silva Nilson Journal of cellular and molecular medicine This study aimed to investigate the relationship between red cell distribution width (RDW) and erythrocyte osmotic stability in non-diabetic and diabetic individuals in both sexes. The study sample (N = 122) was constituted by 53 type 2 diabetics (DM) and 69 non-diabetics (ND), being 21 and 22 men in each group, respectively. The osmotic stability of erythrocytes was obtained by the variation in saline concentration (dX) capable of determining hypoosmotic lysis. Higher RDW values and lower serum iron concentrations were found in the diabetic group when compared to the non-diabetic volunteers. In the group of diabetic women, RDW was positively correlated with the reticulocyte index, and both RDW and dX were negatively correlated with iron, haemoglobin, transferrin saturation index, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration. In all the groups studied, RDW was positively correlated with dX, especially in the diabetic group, where the correlation was the strongest. RDW elevation in both women and men with type 2 diabetes mellitus was associated with decreased serum iron indicators. Furthermore, RDW has a similar meaning to dX, as small erythrocytes have less haemoglobin, resulting in both an increase of RDW and dX. 10.1111/jcmm.16184
    Assessment of red cell distribution width, glycaemic control and diabetes related complications - the ARDENT Study. Arif Mohammad Ali,Syed Fibhaa,Niazi Rauf,Arif Saba Ali,Javed Muhammad Usman,Bashir Aimen,Mansoor Sadia JPMA. The Journal of the Pakistan Medical Association OBJECTIVE:To assess the association of red cell distribution width with glycaemic control and the presence of complications in diabetes patients. METHODS:The cross-sectional study was done at the Pakistan Institute of Medical Sciences, Islamabad, Pakistan, from September to November 2017, and comprised patients with type 2 diabetes. Clinical and demographical characteristics were documented and they were subjected to complete blood count, red cell distribution width, glycated haemoglobin, fasting and random blood glucose, lipid profile, urea and creatinine. The presence of complications were assessed during clinical examination. SPSS 20 was used for data analysis.. RESULTS:There were 349 patients with a mean age of 53.14±11.77 years. The mean duration of diabetes was 8.36±6.64 years and mean glycated haemoglobin was 9.05±1.93. Red cell distribution width was significantly associated with the duration of diabetes, hypertension, macrovascular and microvascular complications and extent of glycaemic control (p<0.0001 each). A statistically significant linear relationship was observed between red cell distribution width and the number of macrovascular and microvascular complications (p<0.0001) and glycated haemoglobin (p<0.0001). Mean red cell distribution width was 13.94±1.66, 14.72±1.38, and 15.76±1.55 for optimal control, borderline control and poor control respectively. This linear incremental pattern was statistic ally significant (p<0.0001). CONCLUSIONS:The linear association of red cell distribution width with glycated haemoglobin may enable its use as a measure of the extent of hyperglycaemia.
    Relationship between red cell distribution width and early renal injury in patients with gestational diabetes mellitus. Cheng Dong,Zhao Jiangtao,Jian Liguo,Ding Tongbin,Liu Shichao Renal failure Previous studies found that red cell distribution width was related to adverse cardiovascular events. However, few studies reported the relationship between red cell distribution width and early-stage renal injury in pregnant women with gestational diabetes mellitus. Using a cross-sectional design, 334 pregnant women with gestational diabetes mellitus were enrolled according to the criterion of inclusion and exclusion. Demographic and clinical examination data were collected. Depended on the urine albumin, study population were divided into case group (n = 118) and control group (n = 216). Compared with control group, the case group tend to be higher red cell distribution width level (13.6 ± 0.9 vs.12.5 ± 0.6, p < 0.001). The red cell distribution width was positively associated with albuminuria creatinine ratio (r = 0.567, p < 0.001). Multiple logistic regressions showed that red cell distribution width was still associated with early-stage renal injury after adjusting for many other potential cofounders. Compared with the first quartile, the risk ratio of the second, the third and the fourth quartile were 1.38 (95%CI: 1.06-1.80), 1.57 (95%CI: 1.21-2.97), 2.71 (95%CI: 2.08-3.54), respectively. Besides, systolic blood pressure, estimated glomerular filtration rate, uric acid and blood urea nitrogen were also significantly associated with renal injury in gestational diabetes mellitus patients. The elevated red cell distribution width level might be a predictor of early-stage renal injury in pregnant women with gestational diabetes mellitus. As an easy and routine examination index, red cell distribution width may provide better clinical guidance when combined with other important indices. 10.1080/0886022X.2016.1207050
    The prevalence of the red cell morphology changes in patients with type 2 diabetes mellitus. NeamŢu Marius Cristian,CrăiŢoiu Ştefania,Avramescu Elena Taina,Margină Denisa Marilena,Băcănoiu Manuela Violeta,Turneanu Denisa,Dănciulescu Miulescu Rucsandra Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie Previous studies have shown that hematological alterations are a common finding in patients with diabetes. The aim of our study was to estimate the prevalence of the red cell morphology changes in diabetic patients and their correlation with markers of glycemic control. Thirty patients with type 2 diabetes mellitus were recruited for this study. Patient demographics, relevant concomitant illnesses and medical history were recorded. Anthropometric, biochemical parameters (fasting plasma glucose - FPG, glycated hemoglobin - HbA1c, glomerular filtration rate - GFR) and morphology of blood smear were assessed. Results were compared with the same measurements in 30 subjects without diabetes mellitus. The groups were similar in terms of age and gender but there were statistically significant differences for the recorded parameters in patients of study group and control subjects. Regarding the assessment of FPG, in the study group were recorded averages of 217.70±73.20 mg÷dL compared with controls that compared with controls that had a blood glucose value of 90.03±6.59 mg÷dL. In the study group, mean HbA1c was 7.95±1.99%. For the control group, the mean value of HbA1c was 5.65±0.32%. In the study group, GFR ranged between 47.70 and 118.90 mL÷min.÷1.73 m². For the control group, GFR values were between 88.00 and 130.00 mL÷min.÷1.73 m². In the analysis of blood cytology for the study group, there were changes in the smear type hypochromia, anisocytosis and poikilocyosis (20 patients - 66.66%). In terms of red cell morphology, changes were recorded anulocytes type, red cells in "mark to the target fired" (codocytes), bream (leptocytes), schizocytes, and red cells in "drop" (dacryocytes). We observed a high prevalence of the red cell morphology changes in diabetic patients compared with non-diabetic subjects. Our findings suggest the need of screening for routine hematological tests in type 2 diabetes mellitus.