Instruct: Given a scientific claim, retrieve relevant passages that support or refute the claim.
Query: A high microerythrocyte count protects against severe anemia in homozygous alpha (+)- thalassemia trait subjects.
BACKGROUND The heritable haemoglobinopathy alpha(+)-thalassaemia is caused by the reduced synthesis of alpha-globin chains that form part of normal adult haemoglobin (Hb). Individuals homozygous for alpha(+)-thalassaemia have microcytosis and an increased erythrocyte count. Alpha(+)-thalassaemia homozygosity confers considerable protection against severe malaria, including severe malarial anaemia (SMA) (Hb concentration < 50 g/l), but does not influence parasite count. We tested the hypothesis that the erythrocyte indices associated with alpha(+)-thalassaemia homozygosity provide a haematological benefit during acute malaria. METHODS AND FINDINGS Data from children living on the north coast of Papua New Guinea who had participated in a case-control study of the protection afforded by alpha(+)-thalassaemia against severe malaria were reanalysed to assess the genotype-specific reduction in erythrocyte count and Hb levels associated with acute malarial disease. We observed a reduction in median erythrocyte count of approximately 1.5 x 10(12)/l in all children with acute falciparum malaria relative to values in community children (p < 0.001). We developed a simple mathematical model of the linear relationship between Hb concentration and erythrocyte count. This model predicted that children homozygous for alpha(+)-thalassaemia lose less Hb than children of normal genotype for a reduction in erythrocyte count of >1.1 x 10(12)/l as a result of the reduced mean cell Hb in homozygous alpha(+)-thalassaemia. In addition, children homozygous for alpha(+)-thalassaemia require a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02) for Hb concentration to fall to 50 g/l, the cutoff for SMA. We estimated that the haematological profile in children homozygous for alpha(+)-thalassaemia reduces the risk of SMA during acute malaria compared to children of normal genotype (relative risk 0.52; 95% confidence interval [CI] 0.24-1.12, p = 0.09). CONCLUSIONS The increased erythrocyte count and microcytosis in children homozygous for alpha(+)-thalassaemia may contribute substantially to their protection against SMA. A lower concentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologically advantageous strategy against the significant reduction in erythrocyte count that occurs during acute infection with the malaria parasite Plasmodium falciparum. This haematological profile may reduce the risk of anaemia by other Plasmodium species, as well as other causes of anaemia. Other host polymorphisms that induce an increased erythrocyte count and microcytosis may confer a similar advantage.
Percentile curves were calculated for hemoglobin and mean corpuscular volume in children between 0.5 and 16 years of age. The curves were derived from several populations of non-indigent white children who lived near sea level. Subjects were excluded from the reference population if they had laboratory evidence of iron deficiency, thalassemia minor, and/or hemoglobinopathy. The final reference populations included 9,946 children for the derivation of the hemoglobin curves and 2,314 for the MCV curves. The percentile curves should be particularly applicable to the diagnosis and screening of iron deficiency and thalassemia minor.
We examined the morphological and functional characteristics of erythroblasts derived from marrow erythroid progenitor cells grown in a methylcellulose microculture, which were taken from a female child with rare atypical sideroblastic anaemia (SA) partially responsive to pyridoxine. Colony formation was within the normal range in three successive cultures (median values: 82.25 CFU-E and 16.4 BFU-E derived colonies/6.6 X 10(4) cells) compared to growth by normal cells (65-315 CFU-E and 9-40 BFU-E). We evaluated in vitro differentiation by biochemical microassay of a cytosol enzyme involved in the haem pathway: uroporphyrinogen I synthase (UROS). The UROS values in the erythroid colonies from SA marrow were at the lowere end of the normal range (median values: 6.7 +/- 0.3 and 14.4 +/- 3.8 pmol uroporphyrinogen/h in CFU-E and BFU-E-derived colonies respectively versus 17.4 +/- 7.3 and 25 +/- 7.2 pmol/h in CFU-E and BFU-E colonies from normal subjects. Ultrastructural examination of the SA erythroblasts from non-cultured bone marrow or derived from cultured BFU-E revealed the characteristic deposition of iron in mitochondria around the nucleus of most cells (ringed sideroblasts). However, the majority of cultured cells had marked dyserythropoietic features, with a large number of bilobulated or trilobulated erythroblasts, multiple cytoplasmic vacuoles, numerous abnormalities of the nucleus, and excessive membrane material beneath the plasma membrane, all features difficult to observe in non-cultured marrows.
Down syndrome (DS) children have a high frequency of acute megakaryoblastic leukemia (AMKL) in early childhood. At least 2 in utero genetic events are required, although not sufficient, for DS-AMKL: trisomy 21 (T21) and N-terminal-truncating GATA1 mutations. To investigate the role of T21 in DS-AMKL, we compared second trimester hemopoiesis in DS without GATA1 mutations to gestation-matched normal controls. In all DS fetal livers (FLs), but not marrows, megakaryocyte-erythroid progenitor frequency was increased (55.9% +/- 4% vs 17.1% +/- 3%, CD34(+)CD38(+) cells; P < .001) with common myeloid progenitors (19.6% +/- 2% vs 44.0% +/- 7%) and granulocyte-monocyte (GM) progenitors (15.8% +/- 4% vs 34.5% +/- 9%) commensurately reduced. Clonogenicity of DS-FL versus normal FL CD34(+) cells was markedly increased (78% +/- 7% vs 15% +/- 3%) affecting megakaryocyte-erythroid ( approximately 7-fold higher) and GM and colony-forming unit-granulocyte, erythrocyte macrophage, megakaryocyte (CFU-GEMM) progenitors. Replating efficiency of CFU-GEMM was also markedly increased. These data indicate that T21 itself profoundly disturbs FL hemopoiesis and they provide a testable hypothesis to explain the increased susceptibility to GATA1 mutations in DS-AMKL and DS-associated transient myeloproliferative disorder.
The concentration of hemoglobin in blacks was found to be 0.5 to 1.0 g/dl lower than that of income-matched whites in several large surveys. This difference could be a racial characteristic of blacks, or it might be due to a higher frequency of genetic traits such as thalassemia minor and hemoglobinopathies, or to environmental factors such as iron deficiency. To help in making this distinction, we analyzed the data from multiphasic examinations (1973 to 1975) on 1718 white, 741 black, and 315 Oriental healthy, nonindigent children between 5 and 14 years of age. In the entire population, the median hemoglobin concentration averaged 0.5 g/dl lower in blacks than in whites of both sexes (t test, P less than 0.001). The differences still averaged 0.5 g/dl (P less than 0.001) after exclusion of all those with abnormal hemoglobin by electrophoresis (Hgb S and C) and those whose mean corpuscular volume was more than 5% below the normal mean for age (to exclude iron deficiency or thalassemia minor). The data strengthen the impression that blacks normally have a concentration of hemoglobin averaging about 0.5 g/dl less than in whites. If this is the case, about 10% of normal blacks will be mistakenly designated anemic, if the same norms are applied.
BACKGROUND & OBJECTIVES Anaemia is commonly observed in children with malaria, but reports on leucocyte and platelet count abnormalities associated with malaria are inconsistent. This study examined the effect of age, gender, parasite density and temperature on haematological parameters in children with acute uncomplicated malaria. METHODS Haematological parameters were determined in children with acute uncomplicated malaria, and these were correlated with age, sex, temperature and parasite density. Statistical analysis was done using SAS 9.1. RESULTS Six hundred and ninety five children with acute uncomplicated malaria participated in the study. The mean age was 51.7 months +/- 33.8. At presentation, anaemia occurred in 43.8% of the patients and children <5 yr had a significantly lower haematocrit (28.4% +/- 4.8) than that of older children (32.8% +/- 4.8) (p <0.001), but the haematocrit was not significantly different by days 14 and 28. There was no difference between both sexes. Leucocytosis was more frequently seen than leucopenia (9.5% vs 3%). Thrombocytopenia was found in 59.3% of enrolled patients. More than half of the patients with thrombocytopenia had recovered by Day 28. Baseline platelet count was related to Day 14 (r = 0.6, p < 0.0001) and Day 28 (r = 0.2, p = 0.0015) and the haematocrit on Day 28 (r = 0.12, p = 0.00197). Platelet count showed no correlation with temperature, parasite density and leucocyte count. Haematocrit correlated with age (r = 0.4, p < 0.0001); but not with parasite density or temperature. Leucocyte count showed no correlation with age or parasite density. CONCLUSION While thrombocytopenia was the most common haematological finding and may be of diagnostic importance, anaemia and leucocytosis were more common in the under fives.
BACKGROUND Malaria is considered as the main differential diagnosis of acute febrile illness in the tropics, and alteration of various hematological parameters has been observed in patients with malaria. AIM To ascertain if certain hematological parameters increase the probability of malaria in patients with acute febrile illnesses. SETTINGS AND DESIGN Hospital based, prospective cohort study. METHODS AND MATERIAL All consecutive in patients with fever of less than seven days in duration were included in the study. Patients where localizing cause for fever could be determined were excluded. Hematological parameters (Hemoglobin, Red cell distribution width (RDW), Leukocyte count, and platelet counts) were determined by using automated counter, and peripheral smear examination for malarial parasite was taken as gold standard for the diagnosis of malaria. STATISTICAL ANALYSIS USED Diagnostic accuracy was measured by computing sensitivity, specificity, predictive values and likelihood ratios. The precision of these estimates was evaluated using 95% confidence intervals. RESULTS AND CONCLUSIONS A total of 184 patients were included in the study and 70 (38%) had a positive peripheral smear for malarial parasite. Thrombocytopenia alone (platelet countless than 150,000/mm3) was a predictor for malaria (Sn 60%, Sp 88%, LR+ 5.04) and in combination with anemia (Hb < 10 g/dl) it was next best parameter (Sn 69%, Sp 74%, LR+ 2.77). RDW and leukocyte count were not predictive. The conclusion of this study is that the presence of thrombocytopenia in a patient with acute febrile illness increases the probability of malarial infection.
Mouse bone marrow hematopoietic stem cells were isolated with the use of a variety of phenotypic markers. These cells can proliferate and differentiate with approximately unit efficiency into myelomonocytic cells, B cells, or T cells. Thirty of these cells are sufficient to save 50 percent of lethally irradiated mice, and to reconstitute all blood cell types in the survivors.
The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous," and "erythropoietic cutaneous" diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overload-induced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroid-specific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic porphyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders.
Delayed T cell recovery and restricted T cell receptor (TCR) diversity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and cancer relapse. Technical challenges have limited faithful measurement of TCR diversity after allo-HSCT. Here we combined 5' rapid amplification of complementary DNA ends PCR with deep sequencing to quantify TCR diversity in 28 recipients of allo-HSCT using a single oligonucleotide pair. Analysis of duplicate blood samples confirmed that we accurately determined the frequency of individual TCRs. After 6 months, cord blood-graft recipients approximated the TCR diversity of healthy individuals, whereas recipients of T cell-depleted peripheral-blood stem cell grafts had 28-fold and 14-fold lower CD4(+) and CD8(+) T cell diversities, respectively. After 12 months, these deficiencies had improved for the CD4(+) but not the CD8(+) T cell compartment. Overall, this method provides unprecedented views of T cell repertoire recovery after allo-HSCT and may identify patients at high risk of infection or relapse.
We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis.
Emerging evidence suggests that pulmonary iron accumulation is implicated in a spectrum of chronic lung diseases. However, the mechanism(s) involved in pulmonary iron deposition and its role in the in vivo pathogenesis of lung diseases remains unknown. Here we show that a point mutation in the murine ferroportin gene, which causes hereditary hemochromatosis type 4 (Slc40a1C326S), increases iron levels in alveolar macrophages, epithelial cells lining the conducting airways and lung parenchyma, and in vascular smooth muscle cells. Pulmonary iron overload is associated with oxidative stress, restrictive lung disease with decreased total lung capacity and reduced blood oxygen saturation in homozygous Slc40a1C326S/C326S mice compared to wild-type controls. These findings implicate iron in lung pathology, which is so far not considered a classical iron-related disorder.
Erythrocytes carrying a variant hemoglobin allele (HbS), which causes sickle cell disease and resists infection by the malaria parasite Plasmodium falciparum. The molecular basis of this resistance, which has long been recognized as multifactorial, remains incompletely understood. Here we show that the dysregulated microRNA (miRNA) composition, of either heterozygous HbAS or homozygous HbSS erythrocytes, contributes to resistance against P. falciparum. During the intraerythrocytic life cycle of P. falciparum, a subset of erythrocyte miRNAs translocate into the parasite. Two miRNAs, miR-451 and let-7i, were highly enriched in HbAS and HbSS erythrocytes, and these miRNAs, along with miR-223, negatively regulated parasite growth. Surprisingly, we found that miR-451 and let-7i integrated into essential parasite messenger RNAs and, via impaired ribosomal loading, resulted in translational inhibition. Hence, sickle cell erythrocytes exhibit cell-intrinsic resistance to malaria in part through an atypical miRNA activity, which may represent a unique host defense strategy against complex eukaryotic pathogens.
Objectives. To evaluate the predictive value of thrombocytopenia in malaria. Patients and Methods. It was a prospective observational study on all febrile patients with thrombocytopenia presenting to the Medical Unit of Hayat Abad Medical Complex during November 2008 to November 2010. Results. Of the total of 228 patients with fever and thrombocytopenia, 121 patients (53%) proved to be suffering from malaria. Of them 82 patients (68%) had falciparum malaria while 39 patients (32%) had vivax infection. Of these 121 patients, platelet counts ranged between 25,000 and 150,000/dL with a mean value of 101,000/dL (SD ± 47, 500) and a median of 75,000/dL. Of the 107 patients who were not suffering from malaria, the counts ranged between 10,000 and 150,000/dL with a mean value of 58,000/dL (SD ± 54, 000) and median of 50,000/dL. Conclusions. The presence of thrombocytopenia may be a predictor of malaria in adult population.
Little is known about the changes in white blood cells and platelets in children with falciparum malaria in endemic areas. We measured the white cell count (WCC) and platelets of 230 healthy children from the community, 1369 children admitted to hospital with symptomatic malaria, and 1461 children with other medical conditions. Children with malaria had a higher WCC compared with community controls, and leucocytosis was strongly associated with younger age, deep breathing, severe anaemia, thrombocytopenia and death. The WCC was not associated with a positive blood culture. In children with malaria, high lymphocyte and low monocyte counts were independently associated with mortality. A platelet count of less than 150 x 109/l was found in 56.7% of children with malaria, and was associated with age, prostration and parasite density, but not with bleeding problems or mortality. The mean platelet volume was also higher in children with malaria compared with other medical conditions. This may reflect early release from the bone marrow in response to peripheral platelet destruction. Thus, leucocytosis was associated with both severity and mortality in children with falciparum malaria, irrespective of bacteraemia, whereas thrombocytopenia, although very common, was not associated with adverse outcome.
Importance Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it. Objective To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans. Design, Setting, and Participants Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures. Exposures Presence of SCT. Main Outcomes and Measures Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure. Results The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, −0.29%; 95% CI, −0.35% to −0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of −0.30% (95% CI, −0.39% to −0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons). Conclusions and Relevance Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.
Maintaining hematopoietic stem cell (HSC) quiescence is a critical property for the life-long generation of blood cells. Approximately 75% of cells in a highly enriched long-term repopulating HSC (LT-HSC) pool (Lin(-)Sca1(+)c-Kit(hi)CD150(+)CD48(-)) are quiescent, with only a small percentage of the LT-HSCs in cycle. Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages in the thymus and for Th2 differentiation in the peripheral organs. Although it is well documented that GATA-3 is expressed in HSCs, a role for GATA-3 in any prethymic progenitor cell has not been established. In the present study, we show that Gata3-null mutant mice generate fewer LT-HSCs and that fewer Gata3-null LT-HSCs are in cycle. Furthermore, Gata3 mutant hematopoietic progenitor cells fail to be recruited into an increased cycling state after 5-fluorouracil-induced myelosuppression. Therefore, GATA-3 is required for the maintenance of a normal number of LT-HSCs and for their entry into the cell cycle.
BACKGROUND This study sought to describe and quantify microcirculatory changes in the mucosal surfaces of patients with severe malaria, by direct in vivo observation using orthogonal polarization spectral (OPS) imaging. METHODS The microcirculation in the rectal mucosa of adult patients with severe malaria was assessed by use of OPS imaging, at admission and then daily. Comparison groups comprised patients with uncomplicated falciparum malaria, patients with bacterial sepsis, and healthy individuals. RESULTS Erythrocyte velocities were measured directly in 43 adult patients with severe falciparum malaria, of whom 20 died. Microcirculatory blood flow was markedly disturbed, with heterogeneous obstruction that was proportional to severity of disease. Blocked capillaries were found in 29 patients (67%) and were associated with concurrent hyperdynamic blood flow (erythrocyte velocity, >750 mm/s) in adjacent vessels in 27 patients (93%). The proportion of blocked capillaries correlated with the base deficit in plasma and with the concentration of lactate. Abnormalities disappeared when the patients recovered. In healthy individuals and in patients with uncomplicated malaria or sepsis, no stagnant erythrocytes were detected, and, in patients with sepsis, hyperdynamic blood flow was prominent. CONCLUSION Patients with severe falciparum malaria show extensive microvascular obstruction that is proportional to the severity of the disease. This finding underscores the prominent role that microvascular obstruction plays in the pathophysiology of severe malaria and illustrates the fundamental difference between the microvascular pathophysiology of malaria and that of bacterial sepsis.
OBJECTIVE To determine whether hypoalbuminemia is an independent risk factor for poor outcome in the acutely ill, and to assess the potential of exogenous albumin administration for improving outcomes in hypoalbuminemic patients. SUMMARY BACKGROUND DATA Hypoalbuminemia is associated with poor outcomes in acutely ill patients, but whether this association is causal has remained unclear. Trials investigating albumin therapy to correct hypoalbuminemia have proven inconclusive. METHODS A meta-analysis was conducted of 90 cohort studies with 291,433 total patients evaluating hypoalbuminemia as an outcome predictor by multivariate analysis and, separately, of nine prospective controlled trials with 535 total patients on correcting hypoalbuminemia. RESULTS Hypoalbuminemia was a potent, dose-dependent independent predictor of poor outcome. Each 10-g/L decline in serum albumin concentration significantly raised the odds of mortality by 137%, morbidity by 89%, prolonged intensive care unit and hospital stay respectively by 28% and 71%, and increased resource utilization by 66%. The association between hypoalbuminemia and poor outcome appeared to be independent of both nutritional status and inflammation. Analysis of dose-dependency in controlled trials of albumin therapy suggested that complication rates may be reduced when the serum albumin level attained during albumin administration exceeds 30 g/L.   CONCLUSIONS Hypoalbuminemia is strongly associated with poor clinical outcomes. Further well-designed trials are needed to characterize the effects of albumin therapy in hypoalbuminemic patients. In the interim, there is no compelling basis to withhold albumin therapy if it is judged clinically appropriate.
During ageing thymic function declines and is unable to meet the demand for peripheral T helper (Th) cell replenishment. Therefore, population maintenance of naive Th cells must be at least partly peripherally based. Such peripheral postthymic expansion of recent thymic emigrants (RTEs) during ageing consequently should lead to loss or dilution of T cell receptor excision circles (TRECs) from a subset of naive T cells. We have identified two subsets of naive Th cells in human adult peripheral blood characterized by a striking unequal content of TRECs, indicating different peripheral proliferative histories. TRECs are highly enriched in peripheral naive CD45RA+ Th cells coexpressing CD31 compared with peripheral naive CD45RA+ Th cells lacking CD31 expression, in which TRECs can hardly be detected. Furthermore we show that CD31−CD45RA+ Th cells account for increasing percentages of the naive peripheral Th cell pool during ageing but retain phenotypic and functional features of naive Th cells. As CD31 is lost upon T cell receptor (TCR) engagement in vitro, we hypothesize that TCR triggering is a prerequisite for homeostatically driven peripheral postthymic expansion of human naive RTEs. We describe here the identification of peripherally expanded naive Th cells in human adult blood characterized by the loss of CD31 expression and a highly reduced TREC content.
Malaria parasites and immune responses in an infected human interact on a dynamic landscape, in which a population of replicating parasites depletes a population of replenishing red blood cells (RBCs). These underlying dynamics receive relatively little attention, but they offer unique insights into the processes that control most malaria infections. Here, we focus on the observation that three of the four malaria-parasite species that infect humans are restricted to particular age classes of RBC. We explicitly incorporate this observation in models of infection dynamics to distinguish common from species-specific pressures on host immune responses, and we find that age structuring has profound effects on the course of infection. For all four species conditions exist under which the parasites may persist at low densities, or may clear, even in the absence of an immune response. Catastrophic anemia can occur even with the two species that attack only the youngest RBCs, although only a small fraction of cells are parasitized at any point. Furthermore, with these two, compensatory erythropoetic responses in the host accelerate parasite population growth. A "basic reproduction rate" characterizes these differences in outcomes.
Androgens are widely used for treating Fanconi anemia (FA) and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanism of action. Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug's action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure.
Survivin is a member of the chromosome passenger complex, which plays an important role in chromosome alignment, separation, and cytokinesis. Although survivin is required for the proliferation and survival of hematopoietic stem and progenitor cells, the extent to which it is necessary for endomitosis of megakaryocytes remains controversial. To determine whether survivin is required for polyploidization, we analyzed mice with a megakaryocyte-specific deletion. PF4-Cre/survivin(fl/fl) mice harbored normal platelet counts with megakaryocytes that reached ploidy states comparable with those of control littermates. The CD41(+) cells within these animals showed little excision but increased annexin V staining, implying that survivin is required for survival of megakaryocyte progenitors in vivo. In contrast, megakaryocytes in which survivin was excised ex vivo showed robust excision and an increased degree of polyploidization. These results demonstrate that survivin is necessary for survival of megakaryocyte progenitors, but is not required for polyploidization of committed megakaryocytes.
INTRODUCTION Elevated plasma total homocysteine is a major risk for coronary artery disease (CAD). Methyltetrahydrofolate reductase (MTHFR) is a main regulatory enzyme in homocysteine metabolism; a common C677T mutation in the MTHFR gene results in decreased enzyme activity, and contributes to increased homocysteine levels and decreased folate levels. We investigated the frequency of MTHFR C677T alleles in a Korean population, determined the genotype-specific threshold levels of folate or vitamin B12, and investigated the relationship between the TT genotype and the risk of CAD. MATERIALS AND METHODS We enrolled a study population of 163 CAD patients and 50 control subjects, and screened the MTHFR C677T polymorphism using real-time PCR with melting point analysis. Levels of plasma homocysteine, folate and vitamin B12 were also determined. We then defined the genotype-specific threshold values of folate and vitamin B12 required to keep homocysteine levels in a normal range for individuals of each MTHFR C677T genotype. RESULTS The frequency of the TT genotype was 18% in control subjects and 26% in patients group (P>0.05). Individuals homozygous for the TT genotype had significantly elevated homocysteine levels (P<0.05). The genotype-specific folate threshold level was significantly higher in TT individuals than in the CC or CT genotypes. The OR of individuals with low folate status and the TT genotype to estimate the relative risk of CAD was 2.2 and the OR of those with high folate status and the TT genotype was 1.5 (95% CI, 0.5-9.6 and 0.7-3.2, respectively). CONCLUSION We were able to define a gene-nutrient interaction that shows a higher risk for CAD based on specific threshold folate levels required by different MTHFR C677T genotypes in a Korean population.
Cancer stem cells have been proposed to be important for initiation, maintenance and recurrence of various malignancies, including acute myeloid leukemia (AML). We have previously reported that CD34+CD38− human primary AML stem cells residing in the endosteal region of the bone marrow are relatively chemotherapy resistant. Using a NOD/SCID/IL2rγnull mouse model of human AML, we now show that the AML stem cells in the endosteal region are cell cycle quiescent and that these stem cells can be induced to enter the cell cycle by treatment with granulocyte colony-stimulating factor (G-CSF). In combination with cell cycle-dependent chemotherapy, G-CSF treatment significantly enhances induction of apoptosis and elimination of human primary AML stem cells in vivo. The combination therapy leads to significantly increased survival of secondary recipients after transplantation of leukemia cells compared with chemotherapy alone.