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)

[Structure-see text] 2-Methylimidazole and 4-methylimidazole are intermediate/starting materials or components in the manufacture of pharmaceuticals, photographic and photothermographic chemicals, dyes and pigments, agricultural chemicals, and rubber; these chemicals have been identified as undesirable by-products in several foods and have been detected in mainstream and sidestream tobacco smoke. The National Cancer Institute nominated 2- and 4-methylimidazole as candidates for toxicity and carcinogenicity studies. Toxicity studies were carried out in male and female F344/N rats and B6C3F1 mice. Animals were exposed to 2- or 4-methylimidazole in feed for 15 days or 14 weeks; clinical pathology studies were conducted in the 14-week studies on days 8, 29, and 86 and at week 14. Genetic toxicity studies were conducted in Salmonella typhimurium, rat and mouse bone marrow, and mouse peripheral blood. Groups of five male and five female rats and mice were fed diets containing 0, 1,200, 3,300, or 10,000 ppm 2-methylimidazole (equivalent to average daily doses of approximately 115, 290, or 770 mg 2-methylimidazole/ kg body weight to rats; 220, 640, or 2,100 mg/kg to male mice; 300, 800, or 2,400 to female mice) for 15 days. Groups of five male and five female rats and mice were fed diets containing 0, 300, 800, or 2,500 ppm 4-methylimidazole (equivalent to average daily doses of approximately 30, 80, or 220 mg/kg for rats and 65, 170, or 500 mg/kg for mice) for 15 days. In the 15-day 2-methylimidazole studies, all animals survived to the end of the studies. The mean body weights of 10,000 ppm male rats and female mice were significantly less than those of the controls. Feed consumption by 10,000 ppm male and female rats was reduced. Enlarged thyroid glands were observed in 3,300 and 10,000 ppm male and female rats. The incidences of diffuse hyperplasia of follicular cells of the thyroid gland in 3,300 and 10,000 ppm male and female rats and pars distalis hypertrophy of the pituitary gland in 3,300 and 10,000 ppm males and 10,000 ppm females were increased compared to the controls. In all exposed groups of male and female mice, the incidences and severities of follicular cell hypertrophy of the thyroid gland and the severities of hematopoietic cell proliferation of the spleen generally increased with increasing exposure concentration. In the 4-methylimidazole studies, all animals survived to the end of the studies, and there were no significant differences in mean body weights, clinical findings, organ weights, or gross or microscopic lesions between exposed and control groups. Groups of 10 male and 10 female rats and mice were fed diets containing 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm 2- or 4-methylimidazole (equivalent to average daily doses of approximately 40, 80, 160, 300, or 560 mg/kg 2- or 4-methylimidazole to rats; and 100, 165, 360, 780, or 1,740 mg/kg 2-methylimidazole or 100, 240, 440, 915, or 1,840 mg/kg 4-methylimidazole to male mice; and 90, 190, 400, 800, or 1,860 mg/kg 2-methylimidazole or 110, 240, 540, 1,130, or 3,180 mg/kg 4-methylimidazole to females) for 14 weeks. All animals survived to the end of the 14-week 2-methylimidazole studies. Compared to the controls, the mean body weights were significantly decreased in groups of male rats and mice exposed to 2,500 ppm or greater and in 5,000 and 10,000 ppm female rats and mice. In rats, 2-methylimidazole induced a transient erythrocytosis in females and a minimal, exposure concentration-related, microcytic, normochromic, nonresponsive anemia. 2-Methylimidazole increased thyroid-stimulating hormone concentrations and decreased thyroxine and triiodothyronine concentrations of male and female rats in an exposure concentration-related manner. 2-Methylimidazole induced a mild to moderate, exposure concentration-related, macrocytic, hyperchromic, responsive anemia in mice. Triiodothyronine concentrations were increased in exposed male and female mice, and thyroxine concentrations were decreased in exposed females. Relative to the control groups, clinical chemistry evaluations on day 29 and at week 14 identified decreases in alanine aminotransferase concentrations and total protein and albumin concentrations of rats. In the 2-methylimidazole studies, absolute spleen weights were significantly increased in all exposed groups of male rats. The heart and liver weights were increased in all exposed groups of male mice, as were the spleen weights of female mice exposed to 2,500 ppm or greater. Spermatid heads per testis and mean spermatid count were significantly decreased in 10,000 ppm male rats. The estrous cycle of 10,000 ppm female rats was significantly increased. Gross pathology observations included enlarged thyroid glands, small uteri, and mottled spleen in 5,000 and 10,000 ppm mice. The incidences of diffuse follicular cell hyperplasia of the thyroid gland were significantly increased in male rats exposed to 1,250 ppm or greater and female rats exposed to 2,500 ppm or greater. The incidence of testicular degeneration was significantly increased in 10,000 ppm male rats, and two males in the 10,000 ppm group had follicular cell adenoma of the thyroid gland. In mice, there were generally significant increases in the incidences of follicular cell hypertrophy of the thyroid gland, hematopoietic cell proliferation of the spleen, and hemosiderin pigmentation of the renal tubule in males exposed to 1,250 ppm or greater and females exposed to 2,500 ppm or greater. In the 14-week 4-methylimidazole studies, one 10,000 ppm male mouse was found dead during week 4, and seven 10,000 ppm female mice were found dead during weeks 1 and 2. Mean body weights were significantly less than those of the controls for male rats exposed to 2,500 ppm or greater, 5,000 and 10,000 ppm female rats, male mice exposed to 1,250 ppm or greater, and all exposed groups of female mice. Reduced feed consumption was observed in 5,000 and 10,000 ppm male and female rats. Clinical findings included nasal/eye discharge, ruffled fur, thinness, ataxia, and abnormal breathing in rats, and ruffled fur and dull coats in female mice. On days 29 and 82, functional observations in 5,000 and 10,000 ppm rats included labored or increased respiration, mild tremors, walking on tiptoes, hunched posture, piloerection, crouching over, impaired coordination of movement, ataxia, and pupillary constriction. 4-Methylimidazole induced a transient erythrocytosis and a minimal, exposure concentration-related, microcytic, normochromic, nonresponsive anemia in male and female rats. Clinical chemistry evaluations generally showed a cholestatic effect in exposed male and female rats. At week 14, there was a significant decrease in total protein and albumin concentrations of female rats exposed to 5,000 or 10,000 ppm. In mice, 4-methylimidazole induced a macrocytic, hyperchromic, responsive anemia and, particularly in males, increases in triiododthyronine concentrations and transient decreases in thyroxine concentrations. In the 4-methylimidazole studies, the liver weights of male rats exposed to 2,500 ppm or greater were significantly increased; spleen weights of female rats exposed to 2,500 ppm or greater were decreased. The absolute liver weight was decreased in 10,000 ppm male mice, and relative weights were significantly increased in all exposed groups of mice. In female mice, there was a significant decrease in the absolute weights and increase in the relative weights of the heart, right kidney, and liver in groups exposed to 2,500 ppm or greater. The epididymal spermatozoal concentration was significantly increased in 5,000 ppm male rats. Gross pathology observations included pale livers in male rats exposed to 2,500 ppm or greater and small testes and uteri in 10,000 ppm male and female rats. Microscopic analysis identified significantly increased incidences of cytoplasmic hepatocyte vacuolization of the liver of male rats exposed to 2,500 ppm or greater and 10,000 ppm female rats, hypospermia of the epididymis in 10,000 ppm male rats, atrophy and inflammation of the prostate gland in 10,000 ppm male rats, and degeneration of the testes in 5,000 and 10,000 ppm male rats. 2-Methylimidazole and 4-methylimidazole were negative in the S. typhimurium mutation assay when tested in strains TA97, TA98, TA100, and TA1535, with and without S9 activation enzymes. Testing of 2-methylimidazole in vivo for induction of chromosomal damage, as measured by micronucleated erythrocyte frequency, produced mixed results. When administered by intraperitoneal injection three times at 24-hour intervals, 2-methylimidazole produced negative results in bone marrow micronucleus tests in rats and mice. However, in the 14-week study of 2-methylimidazole, a significant exposure-related increase in the frequency of micronucleated normochromatic erythrocytes was noted in peripheral blood of male and female mice. In vivo, 4-methylimidazole produced uniformly negative results in three-injection bone marrow micronucleus tests in rats and mice and in 14-week peripheral blood micronucleus tests in male and female mice.
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PMID:NTP technical report on the toxicity studies of 2- and 4-Methylimidazole (CAS No. 693-98-1 and 822-36-6) administered in feed to F344/N rats and B6C3F1 mice. 1514 14

We present two Japanese students with thalassemia identified during screening for anemia in their junior high school. Blood test results revealed marked hypochromic and microcytic erythrocytosis in one patient and microcytic anemia in the other. Both cases showed a mean corpuscular volume/red blood cell (MCV/RBC) ratio less than 13. Their beta/alpha synthesis ratio was elevated. Deletion of psialpha2, psialpha1, alpha2, alpha1 and theta1 genes in the alpha-globin gene clusters were noted in the first case. This pattern of gene deletion was consistent with heterozygous alpha-thalassemia 1 of the Southeast Asian type. On the other hand, an increased hemoglobin A2 level and reduced beta/alpha synthesis ratio were found in the second case. Direct cloning and DNA sequencing identified a point mutation (guanine to adenine) at position 1 of intervening sequence II in the beta-globin gene (IVS II-1 G-->A). These results suggest that this patient had heterozygous beta0-thalassemia. Diagnosis of thalassemia should be confirmed by molecular analysis in cases with microcytic anemia or hypochromic microcytosis with a MCV/RBC ratio of 13 or less.
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PMID:Two children with thalassemia identified during screening for anemia in junior high school. 1532 91

Anemia and erythrocytosis (PTE) are common after kidney transplantation. We sought to determine the influence of sirolimus compared to mycophenolate mofetil (MMF) on post-transplant erythropoiesis. A total of 214 patients with recent kidney or kidney-pancreas transplants were treated with either sirolimus-based (n = 87) or MMF-based (n = 127) therapy. At 12 months, the prevalence of anemia was 31% with MMF and 57% with sirolimus (p < 0.001). Linear regression was used to examine the independent influence of sirolimus on hemoglobin at 12 months, controlling for multiple factors including gender and renal function. Sirolimus remained a significant correlate of lower hemoglobin in all patients (slope =-1.060, 95% CI: -1.76 to -0.362, p = 0.003), and in patients without PTE (slope =-0.671, 95% CI: -1.32 to -0.028, p = 0.041). PTE, defined as a persistent hematocrit above 51%, occurred in 19% with MMF and 7% with sirolimus (p = 0.013). PTE was examined using logistic regression analysis. Sirolimus use correlated negatively with PTE (odds ratio with sirolimus = 0.33, 95% CI: 0.12 to 0.89, p = 0.028). Our results indicate that, compared to treatment with MMF, treatment of kidney or kidney-pancreas recipients with sirolimus is associated with a higher prevalence of anemia, lower hemoglobin levels and lower incidence of PTE.
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PMID:Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant patients. 1557 91

Angiotensin II converting enzyme inhibitors (ACE) and angiotensin II receptor blockers (ARB) are frequently avoided as treatment for hypertension in the early posttransplant period (0 to 90 days) for fear of nephrotoxicity. The following retrospective study was designed to explore the safety of these drugs in the early posttransplant period and determine appropriate clinical criteria for starting these medications. The records of all adult renal transplants performed between January 1997 and December 2000 (N = 290) were reviewed. All patients started on ACE or ARB for treatment of hypertension within 90 days of their transplant were included in the analysis (n = 17). Controls (n = 19) were patients who were treated with a calcium channel blocker (CCB) for hypertension. Cases and controls were matched for gender and type of transplant, living or cadaver. Patients were considered to be enrolled whey they met the following criteria: hypertension, serum creatinine < or =3.0 mg/dL, or falling 1 mg/dL/d and serum potassium < or =5.5 mEq/L. Exclusion criteria were coexistent pancreas transplant, anaphylaxis to ACE, and use of ACE or ARB for treatment of posttransplant erythrocytosis. There were no differences between cases and controls in hemoglobin or serum potassium concentrations or calculated glomerular filtration rate at 3, 6, and 9 months. In renal transplant patients with reasonable allograft function, administration of ACE and ARB to treat hypertension in the early posttransplant period appears to be well tolerated and not associated with excess hyperkalemia, anemia, or acute renal dysfunction.
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PMID:Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers used for the treatment of hypertension appear to be safe in the early posttransplant period. 1562 Nov 21

Hemoglobin (Hb) electrophoresis is widely used in thalassemia screening. Most Hb variants express a specific abnormal band on the cellulose acetate membrane. The technique is useful in the diagnosis of the type of thalassemia but is not sensitive enough to detect alpha-thalassemia minor because the quantity of the HbH is too small to be expressed on the supporting medium. We used simple staining of blood smears rather than the sophisticated molecular method to detect HbH inclusions. To evaluate the effectiveness of this method, we used brilliant cresyl blue (BCB) staining of red blood cells in 509 patients with microcytosis and erythrocytosis caused by various conditions. The results indicate that BCB staining is useful in the identification of subjects who possess alpha-thalassemia traits. Coexisting conditions such as beta-thalassemia and iron-deficiency anemia did not affect the detection of the HbH inclusions with the use of BCB staining. We conclude that BCB staining is helpful and reliable as an auxiliary method of detecting HbH inclusions in the diagnosis of alpha-thalassemia traits, especially in places where medical resources are limited.
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PMID:Usefulness of brilliant cresyl blue staining as an auxiliary method of screening for alpha-thalassemia. 1574 52

We describe the characterization of a new hemoglobin (Hb) variant found in a 77-year-old Dutch woman, suspected of hypoxia-mediated erythrocytosis. The typical blood parameters (Hb 17.3 g/dL; PCV 0.525 L/L; RBC 5.82 x 10(12)/L) could not be explained by any of the pathological or physiological conditions causing erythrocytosis. The patient was preventively phlebotomized because of intermittent claudication and erythrocytosis. At the hematological and biochemical levels, no anemia or hemolysis were present and no abnormal Hb fractions were detectable on alkaline electrophoresis or high performance liquid chromatography (HPLC). Molecular analysis revealed intact alpha-globin genes and a heterozygosity for a GTT-->GCT transition at codon 23 of the beta-globin gene, causing a Val-->Ala amino acid substitution. The P50 measured in full blood indicated that this mutant has an elevated oxygen affinity. This is the fourth single nucleotide substitution at codon 23 of the beta gene and the second associated with erythrocytosis. Because the family was not available for investigation no information was obtained as to whether the mutation represents a de novo event or was inherited, and might be a more common cause of erythrocytosis in Dutch patients. Considering the relatively high frequency of beta-thalassemia (thal) in the large allochthonous population in The Netherlands, combinations of Hb Zoeterwoude and beta-thal traits may lead to hemizygosity, with severe hypoxia and erythrocytosis from a few months after birth.
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PMID:Hb zoeterwoude [beta23(B5)Val-->Ala)]: a new beta-globin variant found in association with erythrocytosis. 1576 51

The state of iron deposits in long-term kidney graft recipients is not well-known. Angiotensin enzyme inhibitors (ACEIs) reduce hematocrit levels in patients with posttransplant erythrocytosis (PTE), but their action on iron deposits has not been sufficiently evaluated. We designed this study to investigate the prevalence of iron deficiency among patients without anemia, the efficacy of ACEI treatment and its influence on iron deposits, and the risks of iron treatment in patients with symptomatic iron deficiency but no anemia. One hundred thirty eight patients were included if they had a kidney transplant for more than a year, with good renal function, with no anemia, and with neither iron nor rHuEpo, ARA, or ACEI treatment. One hundred seventeen had a normal Ht (group 1) and 21 had PTE (group 2). Iron deficiency was found in 73 (62.4%) group 1 patients and in 10 (47%) group 2 patients. Two group 1 patients with symptoms of iron deficiency were treated with oral iron. Their symptoms disappeared, but one developed PTE. Enalapril treatment decreased Ht levels in PTE but not in control patients. Furthermore, this drug increased iron deposits in PTE and controls with a baseline iron deficiency. We conclude that there is a high prevalence of iron deficiency in long-term transplanted patients without anemia. Furthermore, iron treatment must be carefully administered because of the risk of PTE. Enalapril treatment decreased Ht levels in PTE but not in control patients and increased iron deposits in patients with baseline iron deficiency.
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PMID:Iron deficiency--an underrecognized problem in nonanemic and erythrocytic kidney transplant recipients: risks and effects of ACEI and of iron treatment. 1584 6

Hb Crete, an electrophoretically neutral, unstable, high oxygen affinity variant, was characterized by protein and DNA analyses in the homozygous state in a 32-year-old woman from Crete, with erythrocytosis and microcytosis. The proband and members of her family over 3 generations, including 5 carriers of Hb Crete, were subject to clinical, hematological and biochemical investigations, and DNA, RNA and protein studies were carried out. The proband demonstrated features associated with disturbed hemoglobin (Hb) structure and function, including erythrocytosis and additionally a state of functional anemia, the latter reflected by increased erythropoetin levels and cardiac output. In addition, all the carriers surprisingly had hematological and biosynthetic findings more usually associated with thalassemia trait. The structural change in Hb Crete only partly explains all the pathological manifestations of this variant, and other mechanisms are discussed.
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PMID:The homozygous state for Hb Crete [beta129 (H7) Ala-->Pro] is associated with a complex phenotype including erythrocytosis and functional anemia. 1588 7

Losartan is a safe, effective long-term treatment for hypertension or posttransplant erythrocytosis (PTE) in renal transplant recipients. There were only a few studies in patients without PTE and their results were different. Starting from week 6 and continuing to the week 12 we observed a decrease in hemoglobin (Hb) and hematocrit (Hct) levels in patients without PTE. Anemia developed in 42.8% of the patients, and Hb levels increased after the withdrawal of losartan treatment. There was a significant decrease in Hct levels beginning from week 3 when compared with the control group. Our study suggests that losartan therapy can decrease Hb beyond its antihypertensive efficacy. Based on the capacity of losartan to decrease Hb and Hct, this drug should be carefully used in patients with preexistent anemia or low Hb levels.
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PMID:Anemia due to losartan in hypertensive renal transplant recipients without posttransplant erythrocytosis. 1596 63

The number of red blood cells is normally tightly regulated by a classic homeostatic mechanism based on oxygen sensing in the kidney. Decreased oxygen delivery resulting from anemia induces the production of erythropoietin, which increases red cell production and hence oxygen delivery. Investigations of erythropoietin regulation identified the transcription factor hypoxia-inducible factor (HIF). HIF is now recognized as being a key regulator of genes that function in a comprehensive range of processes besides erythropoiesis, including energy metabolism and angiogenesis. HIF itself is regulated through the alpha-subunit, which is hydroxylated in the presence of oxygen by a family of three prolyl hydroxylase domain proteins (PHDs)/HIF prolyl hydroxylases/egg-laying-defective nine enzymes. Hydroxylation allows capture by the von Hippel-Lindau tumor suppressor gene product, ubiquitination, and destruction by the proteasome. Here we describe an inherited mutation in a mammalian PHD enzyme. We show that this mutation in PHD2 results in a marked decrease in enzyme activity and is associated with familial erythrocytosis, identifying a previously unrecognized cause of this condition. Our findings indicate that PHD2 is critical for normal regulation of HIF in humans.
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PMID:A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. 1640 30


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