Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice with mutations at the W locus have a hemopoietic stem cell defect characterized by an apparent deficiency of spleen colony forming cells (CFU-S). In the present report, we provide evidence that mutant cells form colonies and we compare the characteristics of the colonies derived from mutant and normal cells. To perform the colony-derivation studies, marrow cells were transferred into lethally irradiated congenic hosts that differed from the donors in the ubiquitous genetic marker, glucose phosphate isomerase (GPI-1). Donor GPI-1 comprised over 50% of the marker in the host spleen and marrow by 12 days post injection, regardless of whether the donor was mutant or normal. To characterize the colonies, serially sectioned host spleens were examined microscopically. Colonies are present by 8 days post-transplantation regardless of donor genotype, but mutant colonies are distinctly different from normal colonies. The proportion of blast and granulocyte colonies is always greater in W/Wv than in +/+ recipients. Unlike the W/Wv donors, the +/+ donors generate primarily erythrocyte colonies at 8, 10, and 14 days and mixed colonies at 12 days post-injection. Colonies from the mutant mice are generally smaller but visible colonies do appear by 12 days. The results are consistent with the notion that the anemia in W/Wv mice is caused by the early restriction of differentiating cells to a non-erythrocyte lineage accompanied by the delayed amplification of mutant hemopoietic cells. Whether this means erythrocyte-committed cells are absent or are present but unable to respond to the appropriate cytokines is not possible to determine from the current experiments.
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PMID:Characterization of spleen colonies derived from mice with mutations at the W locus. 174 74

Paroxysmal nocturnal hemoglobinuria is an acquired clonal disorder of the hematopoietic stem cell in which intravascular hemolysis is due to an intrinsic defect in the membrane of red cells that makes them increasingly susceptible to lysis by complement. The phenotypic hallmark of PNH cells is an absence or marked deficiency of GPI-anchored proteins such as CD 59+, CD 55+ and others which normally protect cells from the action of complement. PHN is closely associated with aplastic anemia. Some degree of bone marrow failure is always present. Management of PNH is complicated by a highly variable clinical picture and course. Some patients have severe anemia aggravated by hemolytic crises and associated thromboses. Bone marrow failure is accompanied with frequent infections and hemorrhagic manifestations due to thrombocytopenia. With the exception of marrow transplantation, no definite therapy is available. In the exceptional circumstance in which the patient has a syngeneic twin, bone marrow transplantation is the most appropriate therapy for severe PNH because of absence of graft-versus-host disease. In general syngeneic transplantation without preconditioning has been unsuccessful because abnormal hematopoiesis returns. Allogeneic bone marrow transplantation has been used, but the transplant-associated morbidity and mortality are high due mainly to the fatal graft-versus-host disease and severe posttransplant marrow failure. Use of an unrelated donor transplant has to be considered as contraindicated. PNH is associated with striking predisposition to intravascular thrombosis which often involves the portal system or the brain. Fatal thromboses account for about 40-50% of all deaths in patients with PNH. The etiology of the thrombophilia in PNH is not fully clarified. Anticoagulation or thrombolytic therapy is required for treatment of venous thrombosis, the latter vena cava. Prophylactic anticoagulation in patients without contraindications such as severe thrombocytopenia seems to be justified. However, whether such therapy may be efficacious in reducing the incidence of thromboses or affect survival is conjectural. PNH patients have varying degree of platelet activation and some authors suggest that antiplatelet therapy might be efficacious in reducing the incidence and severity of venous thrombosis in PNH. Pregnancy is hazardous. Female patients should avoid the use of oral contraceptives. Pregnant patients require combined care of an experienced hematologist and obstetrician specialized in the management of high-risk pregnancies.
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PMID:[Treatment of paroxysmal nocturnal hemoglobinuria (PNH)]. 1182 54

The GPI-anchored trypanosome variant surface glycoprotein (VSG) triggers macrophages to produce TNF, involved in trypanosomiasis-associated inflammation and the clinical manifestation of sleeping sickness. Aiming at inhibiting immunopathology during experimental Trypanosoma brucei infections, a VSG-derived GPI-based treatment approach was developed. To achieve this, mice were exposed to the GPI before an infectious trypanosome challenge. This GPI-based strategy resulted in a significant prolonged survival and a substantial protection against infection-associated weight loss, liver damage, acidosis, and anemia; the latter was shown to be Ab-independent and correlated with reduced macrophage-mediated RBC clearance. In addition, GPI-based treatment resulted in reduced circulating serum levels of the inflammatory cytokines TNF and IL-6, abrogation of infection-induced LPS hypersensitivity, and an increase in circulating IL-10. At the level of trypanosomiasis-associated macrophage activation, the GPI-based treatment resulted in an impaired secretion of TNF by VSG and LPS pulsed macrophages, a reduced expression of the inflammatory cytokine genes TNF, IL-6, and IL-12, and an increased expression of the anti-inflammatory cytokine gene IL-10. In addition, this change in cytokine pattern upon GPI-based treatment was associated with the expression of alternatively activated macrophage markers. Finally, the GPI-based treatment also reduced the infection-associated pathology in Trypanosoma congolense and Trypanosoma evansi model systems as well as in tsetse fly challenge experiments, indicating potential field applicability for this intervention strategy.
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PMID:A glycosylphosphatidylinositol-based treatment alleviates trypanosomiasis-associated immunopathology. 1778 39

In the many areas where human malaria and helminthiases are co-endemic, schoolchildren often harbour the heaviest infections and suffer much of the associated morbidity, especially when co-infected. In one such area, the Buea district, in south-western Cameroon, two cross-sectional surveys, together covering 263 apparently healthy schoolchildren aged 4-12 years, were recently conducted. The prevalences of fever, malarial parasitaemia and intestinal helminth infections, the seroprevalences of anti-Plasmodium falciparum IgG and IgE and anti-glycosylphosphatidylinositol (anti-GPI) IgG, plasma concentrations of total IgE, and the incidence of anaemia were all investigated. The mean (S.D.) age of the study children was 7.56 (1.82) years. Overall, 156 (59.3%) of the children were found parasitaemic, with a geometric mean parasitaemia of 565 parasites/microl. Parasitaemia and fever were significantly associated (P=0.042). The children who lived at low altitude, attending schools that lay 400-650 m above sea level, had significantly higher parasitaemias than their high-altitude counterparts (P<0.01). At low altitude, the children attending government schools had significantly higher parasitaemias than their mission-school counterparts (P=0.010). Of the 31 children (11.9%) found anaemic, 22 (70.4%) had mild anaemia and none had severe anaemia. A significant negative correlation (r=-0.224; P=0.005) was observed between haemoglobin concentration and level of parasitaemia. Infection with Plasmodium appeared to reduce erythrocyte counts (P=0.045), a condition that was exacerbated by co-infection with helminths (P=0.035). Plasma concentrations of total IgE were higher in the children found to be excreting helminth eggs than in those who appeared helminth-free, while levels of anti-P. falciparum IgE were higher in the children with low-grade parasitaemias than in those with more intense parasitaemias. Levels of anti-GPI IgG increased with age and were relatively high in the children who lived at low altitude and in those who were aparasitaemic. The survey results confirm that asymptomatic malarial parasitaemia frequently co-exists with helminth infections in schoolchildren and indicate links with fever, altitude and school type. Immunoglobulin E may play a role in immune protection against helminthiasis whereas anti-GPI antibodies may be important in the development of antimalarial immunity in such children. In Cameroon, as in other areas with endemic malaria, control programmes to reduce the prevalences of infections with intestinal helminths and malarial parasites in schoolchildren, which may effectively reduce the incidence of anaemia, are clearly needed.
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PMID:Febrile status, malarial parasitaemia and gastro-intestinal helminthiases in schoolchildren resident at different altitudes, in south-western Cameroon. 1831 32

Following exposure to synthetic Plasmodium falciparum glycosylphosphatidylinositol (P.f.-GPI), red blood cells (RBCs) reacted with antibodies in the serum of a patient with severe acute P. falciparum malaria. Carbohydrate microarray analysis of the patient's serum confirmed the presence of both, IgM and IgG antibodies against P.f.-GPI. The antibodies failed to bind to RBCs when P.f.-GPI lacking the lipid portion was applied. Addition of the detergent Triton X-100 during preincubation with P.f.-GPI resulted in increased recognition. Recognition of P.f.-GPI was dependent on the concentrations of synthetic P.f.-GPI, the serum and the numbers of RBCs. IgM antibodies dominated P.f.-GPI-sensitized RBCs recognition. Recognition by IgM antibodies proved highest during the 1st week of acute malaria and decreased during the following 2 weeks as assessed by flow cytometry and carbohydrate microarray analysis. These results strongly support the notion that released P.f.-GPI can insert into non-parasitized RBC membranes and results in recognition by circulating anti-GPI antibodies and possibly subsequent elimination. This process may contribute to malaria-associated anemia.
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PMID:Plasmodium falciparum glycosylphosphatidylinositol toxin interacts with the membrane of non-parasitized red blood cells: a putative mechanism contributing to malaria anemia. 1865 59

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells. PNH is related to a somatic mutation in the phosphatidylinositol glycan class A (PIG-A), X-linked gene, responsible for a deficiency in glycosylphosphatidylinositol-anchored proteins (GPI-AP). The lack of one of the GPI-AP complement regulatory proteins (CD59) leads to haemolysis. The disease is diagnosed with haemolytic anemia, marrow failure or episodes of venous thrombosis. The diagnosis is based on flow cytometry, which allowed direct quantification of the GPI-AP-deficient cells. From earlier descriptions, the clinical polymorphism of PNH has been recognized by two presentations; one form, predominantly haemolytic without overt marrow failure, referred to classic PNH and the other one, with marrow failure, was often described as the aplastic anemia PNH syndrome (AA-PNH). Thromboses remain a major life threatening complication affecting outcomes in both disease subcategories. Thrombotic events are characterized by involvement of unusual sites (hepatic, mesenteric, cerebral, dermal veins). In classic PNH, recent studies have focused on inhibiting the complement cascade with encouraging clinical results using eculizumab, a C5-inhibitor humanized monoclonal antibody. Concerning the AA-PNH syndrome, bone marrow transplantation (BMT) is the reference treatment in young patients with a sibling donor. Immunosuppressive therapy remains an important treatment modality in this subcategory for patients without a donor or ineligible for BMT. Recurrent thrombotic events remains even now associated with bad prognosis, whatever the form of the disease.
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PMID:[Paroxysmal nocturnal hemoglobinuria]. 1930 77

Diseases caused by animal retroviruses have been recognized since 19th century in veterinary field. Most livestock and companion animals have own retroviruses. To disclose the receptors for these retroviruses will be useful for understanding retroviral pathogenesis, developments of anti-retroviral drugs and vectors for human and animal gene therapies. Of retroviruses in veterinary field, receptors for the following viruses have been identified; equine infectious anemia virus, feline immunodeficiency virus, feline leukemia virus subgroups A, B, C, and T, Jaagsiekte sheep retrovirus, enzootic nasal tumor virus, avian leukosis virus subgroups A, B, C, D, E, and J, reticuloendotheliosis virus, RD-114 virus (a feline endogenous retrovirus), and porcine endogenous retrovirus subgroup A. Primate lentiviruses require two molecules (CD4 and chemokine receptors such as CXCR4) as receptors. Likewise, feline immunodeficiency virus also requires two molecules, i.e., CD134 (an activation marker of CD4 T cells) and CXCR4 in infection. Gammaretroviruses utilize multi-spanning transmembrane proteins, most of which are transporters of amino acids, vitamins and inorganic ions. Betaretroviruses and alpharetroviruses utilize transmembrane and/or GPI-anchored proteins as receptors. In this review, I overviewed receptors for animal retroviruses in veterinary field.
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PMID:[Receptors for animal retroviruses]. 2021 31

Ceruloplasmin (Cp), a multicopper ferroxidase, is expressed as both a secreted (sCp) plasma enzyme from the liver and a membrane-bound glycosylphosphatidylinositol-anchored (GPI-Cp) splice variant protein. Cp is thought to be essential for iron mobilization as selective iron overload occurs in aceruloplasminemia in humans and in Cp null mice. Dietary copper-deficient (CuD) rodents have near total loss of Cp activity, severe loss of Cp protein and develop anemia. Hepatic iron augmentation is often observed, suggesting that loss of Cp function may be correlated with anemia. The impact of CuD treatment on GPI-Cp has not previously been evaluated. Our hypothesis was that CuD rodents would have lower levels of GPI-Cp and this would correlate with higher tissue iron retention. In these studies, GPI-Cp was detected in purified membranes of multiple organs of rats and mice but not Cp -/- mice. Immunoreactive Cp protein was released with phosphatidylinositol phospholipase C treatment and expressed ferroxidase activity. Following perinatal and postnatal copper restriction, GPI-Cp was markedly lower in the spleen and modestly lower in the liver of CuD rats and mice, when compared with copper-adequate (CuA) rodents. However, spleen non-heme iron (NHI) was lower in CuD than CuA rats, and not different in CuD mice. Hepatic iron was higher only in CuD mice. Spleen and liver membranes of CuD rats expressed augmented levels of ferroportin, the iron efflux transporter, which may explain lower NHI content in the spleen of CuD rats despite a greater than 50% lower level of the multicopper ferroxidase GPI-Cp. Spleen and liver levels of GPI-Cp mRNA were not impacted in CuD rats, suggesting that turnover rather than biosynthesis may explain the lower steady-state levels of GPI-Cp following dietary copper restriction. Lower GPI-Cp did not correlate with tissue iron retention and thus the role, if any, of Cp in anemia of copper deficiency is unknown.
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PMID:Glycosylphosphatidylinositol-linked ceruloplasmin is expressed in multiple rodent organs and is lower following dietary copper deficiency. 2135 16

Interactions between copper and iron homeostasis have been known since the nineteenth century when anemia in humans was first described due to copper limitation. However, the mechanism remains unknown. Intestinal and liver iron concentrations are usually higher following copper deficiency (CuD). This may be due to impaired function of the multicopper oxidases hephaestin or ceruloplasmin (Cp), respectively. However, iron retention could be due to altered ferroportin (Fpn), the essential iron efflux transporter in enterocytes and macrophages. Fpn mRNA is controlled partially by intracellular iron and IRE dependence. CuD should augment Fpn based on iron level. Some argue that Fpn stability is controlled partially by membrane ferroxidase (GPI-Cp). CuD should result in lower Fpn since GPI-Cp expression and function is reduced. Fpn turnover is controlled by hepcidin. CuD results in variable Hamp (hepcidin) expression. Fpn mRNA and protein level were evaluated following dietary CuD in rats and mice. To correlate with Fpn expression, measurements of tissue iron were conducted in several rodent models. Following CuD there was little change in Fpn mRNA. Previous work indicated that under certain circumstances Fpn protein was augmented in liver and spleen following CuD. Fpn levels in CuD did not correlate with either total iron or non-heme iron (NHI), as iron levels in CuD liver were higher and in spleen lower than copper adequate controls. Fpn steady state levels appear to be regulated by a complex set of factors. Changes in Fpn do not explain the anemia of CuD.
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PMID:Copper deficiency has minimal impact on ferroportin expression or function. 2229 64

Copper deficiency leads to anemia but the mechanism is unknown. Copper deficiency also leads to hypoferremia, which may limit erythropoiesis. The hypoferremia may be due to limited function of multicopper oxidases (MCO) hephaestin in enterocytes or GPI-ceruloplasmin in macrophages of liver and spleen whose function as a ferroxidase is thought essential for iron transfer out of cells. Iron release may also be limited by ferroportin (Fpn), the iron efflux transporter. Fpn may be lower following copper deficiency because of impaired ferroxidase activity of MCO. Fpn is also dependent on the liver hormone hepcidin as Fpn is degraded when hepcidin binds to Fpn. Anemia and hypoferremia both down regulate hepcidin by separate mechanisms. Current studies confirmed and extended earlier studies with copper-deficient (CuD) rats that suggested low hepicidin resulted in augmented Fpn. However, current studies in CuD dams failed to confirm a correlation that hepcidin expression was associated with low transferrin receptor 2 (TfR2) levels and also challenged the dogma that holotransferrin can explain the correlation with hepcidin. CuD dams exhibited hypoferremia, low liver TfR2, anemia in some rats, yet no depression in Hamp expression, the hepcidin gene. Normal levels of GDF-15, the putative erythroid cytokine that suppresses hepcidin, were detected in plasma of CuD and iron-deficient (FeD) dams. Importantly, FeD dams did display greatly lower Hamp expression. Normal hepcidin in these CuD dams is puzzling since these rats may need extra iron to meet needs of lactation and the impaired iron transfer noted previously.
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PMID:Suppressed hepcidin expression correlates with hypotransferrinemia in copper-deficient rat pups but not dams. 2245 45


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