Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002874 (aplastic anemia)
 5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have evaluated the endocrine changes in 10 male subjects with hemochromatosis. Two subjects initially had aplastic anemia, and the remainder had idiopathic hemochromatosis. Four of the ten patients had diabetes mellitus. Sexual dysfunction (impotence and/or decreased libido) was observed in 8 subjects. Six patients had subnormal testosterone levels; FSH levels were almost uniformly low, but LH concentrations were more variable. Only three patients had normal testosterone responses to hCG. Hypothyroidism, free T4 less than 0.9 ng/dl, was present in 4 subjects, and the etiology was heterogeneous. Basal prolactin levels were elevated in 2 patients and failed to respond adequately to TRH in 2 other patients. Growth hormone reserve was normal in all but 1 patient, and pituitary-adrenal reserve was normal in all but 1 patient. We conclude that disturbances in both pituitary and end-organ function are observed in hemochromatosis. These central and end-organ defects may exist alone or simultaneously. Hypogonadism is almost universal, and is a consequence of defective function of the hypothalamic-pituitary axis and/or primary Leydig cell disturbance. Other evidence of pituitary disturbance are observed but are rather uncommon.
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PMID:The endocrine manifestations of hemochromatosis. 634 90

We have evaluated post-transplant serum levels of prolactin with respect to source of donated bone marrow (BM) and to the occurrence of either acute and/or chronic graft-versus-host disease (GVHD). Forty adult patients underwent allogeneic (n = 35), autologous (n = 4) or syngeneic (n = 1) bone marrow transplantation for haematologic malignancy (n = 32) or aplastic anaemia (n = 8), respectively. Serum prolactin levels measured within 100 days post-transplant were related to patients' sex but otherwise proved unrelated to the occurrence or severity of GVHD and to the source of the BM graft (allogeneic, autologous, syngeneic). Beyond day 100 post-graft, however, serum prolactin levels proved significantly elevated in allogeneic recipients exhibiting chronic GVHD (p = 0.0004) and were unrelated to the patients' sex. In this group of patients, serum prolactin levels were not related to serum cyclosporin levels. In allogeneic recipients exhibiting no GVHD, serum prolactin levels were positively correlated with serum cyclosporin levels (p < 0.05). These data show that serum prolactin levels are significantly elevated beyond day 100 post-graft in recipients exhibiting chronic GVHD. Prolactin, a hormone recently shown also to be released by mononuclear leucocytes and to be involved in lymphocyte activation plays a hitherto unrecognized role in the pathogenesis of GVHD in humans.
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PMID:Prolactin: a possible mediator of graft-versus-host disease following allogeneic bone marrow transplantation in humans. 799 62

ERYTHROPOIETIN (EPO): Erythropoietin (EPO) is a hormone that promotes the proliferation and differentiation of erythroid progenitor cells and regulates the number of erythrocytes in peripheral blood. EPO is produced mainly by the kidneys, and transcription of the EPO gene is promoted by a reduction in the oxygen concentration in the blood. The existence of EPO was suggested near the end of the 19th century by the discovery that hypoxia increases the production of red blood cells. EPO was identified as a serum factor in the 1950s, and in 1970 Miyake and coworkers succeeded in purifying it by using the urine of patients with aplastic anemia as a starting material. The human EPO gene was cloned in 1985 using a partial amino acid sequence from this purified EPO, and it is well known that recombinant EPO is currently used as a drug to treat anemia associated with chronic renal failure and other illnesses. ACTION OF EPO: When human bone marrow cells are cultured in a semisolid medium containing EPO, they form small erythroblast colonies in five to seven days, and by day 10 large erythroblast colonies appear that resemble fireworks ("burst" colonies). The original cells in the former colonies are called colony forming units-erythroid (CFU-E) or late-stage erythroblast progenitor cells and in the latter colonies they are called burst forming units-erythroid (BFU-E) or early-stage erythroblast progenitor cells. As shown in Figure 1, red blood cells are produced through differentiation from stem cells to BFU-E, CFU-E, and erythroblasts. Although EPO acts on both BFU-E and CFU-E cells, CFU-E cells show greater sensitivity to EPO, and other factors such as stem cell factor (SCF), interleukin (IL)-3, IL-4, and granulocyte macrophage colony-stimulating factor (GM-CSF) must be present together with EPO for BFU-E cell proliferation. In erythroblasts beyond the CFU-E stage, sensitivity to EPO decreases as the cells mature. THE EPO RECEPTOR AND THE CYTOKINE RECEPTOR FAMILY: The EPO receptor gene was cloned by D'Andrea and coworkers in 1989 from murine erythroleukemia cells [1]. It became clear that the EPO receptor belongs to the cytokine receptor family that comprises receptors for the various interleukins, GM-CSF, granulocyte colony-stimulating factor (G-CSF), growth hormone and prolactin. The special characteristic of this family of receptors is that they are switched on (i.e., the receptor is activated) and transduce signals to the interior of the cell by the formation of homo- or hetero-oligomers (dimers or trimers). Moreover, hetero-oligomers of these receptors share a common receptor subunit. As shown in Figure 2, the IL-3, IL-5 and GM-CSF receptors have a common &bgr; subunit, and their ligand specificity is determined by the &agr; subunit. In the same manner, the IL-6, LIF and oncostatin M (OSM) receptors all share gp130, which is the &bgr; subunit of the IL-6 receptor. The IL-2, IL-4 and IL-7 receptors all share the &ggr; subunit of the IL-2 receptor. All the above receptors are activated by the formation of hetero-oligomers, but the G-CSF receptor, EPO receptor, and growth hormone receptor are activated by the formation of homodimers of the same types of molecules [2]. We can see that groups of cytokines such as the interleukins that affect a relatively wide range of cells and have redundant biological activity create this redundancy through the common use of a single receptor subunit. On the other hand, EPO and G-CSF act with high specificity on a relatively limited range of cells, so it was probably unnecessary for their receptors to share one of the subunits. EPO RECEPTOR AND JAK2 KINASE: The signal for cellular proliferation and differentiation into erythroblasts is thought to originate at the EPO receptor. The cytoplasmic domain of the EPO receptor can be divided into two major regions. Roughly half of the cytoplasmic domain, the part lying nearest the plasma membrane, is required for generating the signals for proliferation and differentiation such as the induction of globin synthesis [3, 4]. The remaining half is not required for this signaling, and, conversely, it acts to dampen the signals. It is known that a tyrosine kinase called JAK2 associates with the region near the plasma membrane, undergoes autophosphorylation, and phosphorylates the EPO receptor, and a transcription factor called a STAT [5]. It is thought that JAK2 plays an important role in promoting cellular proliferation. The STAT is activated by the phosphorylation, and it then translocates to the nucleus, recognizes a specific base sequence in the promoter region of its target gene, and initiates transcription. At present, we know that the STAT whose activation is mediated by the EPO receptor is STAT5, and the target genes are CIS [6], which has an SH2 domain (a molecular structure that recognizes a phosphorylated tyrosine) and OSM [7], which is a pleiotropic cytokine. However, activation of STAT5 and activation of the target genes are not unique to the EPO receptor, and they also occur with the IL-2 and IL-3 receptors. Moreover, the JAK2 substrate that is directly linked to cellular proliferation is still unknown. At present, studies are under way to determine the transcription factors specific to EPO and their target genes, as well as the substrates of JAK2. RECEPTOR PHOSPHORYLATION AND CESSATION OF THE SIGNAL: On the other hand, tyrosine phosphorylation of the receptor is necessary at the cytoplasmic tail region far from the plasma membrane, and the signal transduction pathway that originates with this phosphorylated tyrosine and is mediated by proteins with SH2 domains becomes activated. First, a GTP/GDP exchange factor called SOS, which is mediated by Shc and Grb2, migrates to the plasma membrane and converts a ras protein to its GTP form. The activated ras protein then activates the Raf-MAP kinase kinase-MAP kinase cascade, and ultimately initiates the transcription of oncogenes such as c-fos and c-jun. An enzyme called PI3 kinase binds to the tyrosine phosphorylation site of the receptor and a second messenger is born. It is known that this pathway is a requirement for DNA synthesis in certain types of fibroblasts. However, these signal transduction pathways are not unique to the EPO receptor, and they are also activated by most growth factor receptors, so they are not necessarily required for EPO-induced proliferation. Conversely, the tyrosine phosphatase SH-PTP1 (also called HCP) that has an SH2 domain and is specific to blood cells associates with the tyrosine phosphorylation site of the receptor and promotes the dephosphorylation of JAK2. In other words, the role of SH-PTP1 is to stop generation of the signal [8]. Therefore, in mutations lacking this cytoplasmic tail region of the receptor far from the plasma membrane, the receptors do not undergo tyrosine phosphorylation, JAK2 activation continues for a longer period of time, and thus the signal is generated more efficiently. In fact, in one patient with a mild case of familial erythrocytosis a mutation was discovered in which the C-terminus of the EPO receptor was missing 70 amino acids [9]. This was a dominant genetic trait, and the patient's erythroblasts showed an increased sensitivity to EPO. In this family the impairment was not severe enough to be called an illness, and in fact it is said that this patient was proficient enough athletically to compete for a gold medal at the Olympics. More specifically, the reason that athletes undergo training at high altitudes is to boost EPO production because of the lower oxygen partial pressure, and this brings about the desired effect of sustained athletic capability due to a resultant increase in red blood cells. However, the same effect has occurred naturally in this athlete thanks to accelerated receptor capability.
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PMID:Physician Education: The Erythropoietin Receptor and Signal Transduction. 1038 12

Remoxipride is a substituted benzamide that acts as a weak but very selective antagonist of dopamine D2 receptors. It was introduced by Astra (Roxiam) at the end of the eighties and was prescribed as an atypical antipsychotic. This article reviews its putative selective effects on mesolimbic versus nigrostriatal dopaminergic systems. In animals, remoxipride has minimal cataleptic effects at doses that block dopamine agonist-induced hyperactivity. These findings are predictive of antipsychotic activity with a low likelihood of extrapyramidal symptoms. Remoxipride also appears to be effective in more recent animal models of schizophrenia, such as latent inhibition or prepulse inhibition. In clinical studies, remoxipride shows a relatively low incidence of extrapyramidal side effects and its effects on prolactin release are short-lasting and generally mild. The clinical efficacy of remoxipride is similar to that of haloperidol or chlorpromazine. Although its clinical use was severely restricted in 1993, due to reports of aplastic anemia in some patients receiving remoxipride, this drug has been found to exhibit relatively high selectivity for dopamine D2 receptors making remoxipride an interesting tool for neurochemical and behavioral studies.
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PMID:Pharmacology of the atypical antipsychotic remoxipride, a dopamine D2 receptor antagonist. 1160 43

We compared the functional status of the hypothalamic dopaminergic tone in patients given an allogeneic hematopoietic stem cell transplantation (allo-HSCT) with chronic graft-versus-host disease (GVHD) with that observed in patients with allo-HSCT without chronic GVHD and in healthy controls. The effect of acute dopaminergic blockade with intravenous metoclopramide on serum prolactin (PRL) concentrations was evaluated. Twenty volunteers, 20 to 52 years of age, seronegative for both hepatitis C virus and the human immunodeficiency virus, were studied: (1) 10 clinically healthy men (group 1), and (2) 9 patients with leukemia, and 1 patient with refractory aplastic anemia who underwent allo-HSCT, 5 of whom (3 men and 2 women) developed chronic GVHD (group 2), and 5 (3 men and 2 women) who did not develop chronic GVHD (group 3). Serum PRL concentrations were measured both fasting and after intravenous administration of metoclopramide (10-mg bolus). The area under the PRL curve was calculated. Patients in group 2 were older than those in groups 1 and 3 (P<.018), but their body mass index was similar. Fasting serum PRL concentrations were similar among the 3 groups; however, group 2 had higher PRL concentrations throughout the test (P<.001) and a greater area under the PRL curve than groups 1 and 3 (P<.001), without differences between the last 2 groups. The differences remained significant after adjustment for age (P<.01). Our results in a small group of patients with chronic GVHD after allo-HSCT suggest the existence of an increased functional level of their hypothalamic dopamine tone, which would favor a tendency toward a diminished endogenous production, release of pituitary PRL, or both. This could represent an adaptive mechanism aiming to maintain circulating PRL concentrations within a physiological range.
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PMID:Altered functional status of the hypothalamic dopaminergic tone in patients with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a pilot study. 1663 92