Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
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Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Due to the properties of inducible HO (HO-1) and its products, we hypothesized that HO-1 would play an important role in the regulation of cardiovascular function. In this article we will review the role of HO-1 in cardiovascular function, and highlight our previous studies using gene deletion and gene overexpression transgenic approaches in mice. These studies will include the investigation of HO-1 in the setting of hypertension (renovascular), atherosclerosis and vascular injury (vein graft stenosis), hypotension (endotoxemia), and ischemia/reperfusion injury (heart). In a chronic renovascular hypertension model, blood pressure elevation, cardiac hypertrophy, acute renal failure, and acute mortality induced by one kidney-one clip surgery are more severe in HO-1 null mice. Moreover, absence of HO-1 leads to accelerated atherosclerotic lesion formation and vein graft disease. In addition, HO-1 null mice with endotoxemia have earlier resolution of hypotension, yet the mortality and the incidence of end organ damage are higher in the absence of HO-1. In contrast, mice with cardiac-specific overexpression of HO-1 have an improvement in cardiac function, smaller myocardial infarcts, and reduced inflammatory and oxidative damage after coronary artery ligation and reperfusion. Taken together, these studies suggest that an absence of HO-1 has detrimental consequences, while overexpression of HO-1 plays a protective role in ischemia/reperfusion injury.
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PMID:Role of heme oxygenase-1 in cardiovascular function. 1452 47

The Dialysis Outcomes and Practice Pattern Study (DOPPS) is an international observational study of treatment conditions and medical outcomes in hemodialysis patients. Prospective sampling has yielded long-term observational data from randomly selected groups of patients receiving treatment at representative, randomly selected hemodialysis units in each country. The data shown were collected at 20 hemodialysis units/centers in Spain. The data pertaining to Spain--Sp--refers to 575 patients and their comparison with those of the Euro-DOPPS countries--Eu--(Germany, France, United Kingdom, Italy and Spain), which encompass 3,038 patients, represent the formal goal of this paper. Diabetes mellitus, at 21.5% in Eu and 21.7% in Sp, was the most common cause of renal insufficiency in dialysis and coronariopathy, as a concomitant disease, was present in 67.8% in Eu as opposed to 75.8% in Sp. Differences were observed in the incident of hypertension (73.4% in Eu vs 77.4% in Sp), hepatitis C (11.6% vs 19.5%), depression (12.7 vs 16.2%) and left ventricular hypertrophy (54.9% vs 62.3%). The patterns of vascular access were similar (79% vs 81% AV fistulas in Eu and Sp, and 10% synthetic grafts for both) and the mean applied dose of dialysis--Kt/V--smaller (1.19) in Sp than in Eu (1.24); likewise the duration of the dialysis (in minutes) was shorter (234 in Eu vs 217 in Sp) and the % of synthetic membranes used was smaller (60% in Eu vs 52% in Sp). There were no differences between the groups in the figures for urea, creatinine, albumin, nPCR, calcium, phosphate or PTH. There were also no differences in the mean values of Hb (10.7 for Eu vs 10.8 for Sp), given that the values of ferritin were noticeably lower in Sp (288 vs 355) and the dose of EPO/kg/week was higher to in Sp (115 vs 102); s.c. route was used in similar proportions (69% in Eu vs 67% in Sp). The level of medical care, understood as contact with the physician at all or almost all treatments, was noticeably better in Sp (90%) that in Eu (66%), whereas the number of patients per hour of specialized personnel and % of specialized staff, were smaller. Mortality (death/100 patients-years) was one point lower in Sp than in Eu (15.4 vs 16.3). These data suggest that an increment in dialysis time and in the percentage of synthetic membranes used, as well as in the supply of intravenous iron, would be justified.
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PMID:[Results of the international hemodialysis study DOPPS in Spain and Europe]. 1465 70

Evaluation of anemia: Before beginning epoetin treatment, it is essential to evaluate the level of anemia (Hb < 11-12g/dL) by the following measurements: -Hb concentration -Red blood cell indices (MCV, MCH, MCHC) -Reticulocyte count -Iron stores and availability -C-reactive protein (CRP) Target for anemia treatment: The minimum target Hb concentration to be attained is 11 g/dL. The upper limit is established individually on a clinical basis. Pending further data, it is advisable to maintain and not exceed 12 g/dL for patients with cardiovascular disease, diabetes, and graft access. Use of iron: At the start of epoetin treatment, 150 mg of iron are needed for every expected increase of 1 g/dL of Hb. It is important to achieve and maintain levels of TSAT > 20%, serum ferritin 100 mcg/L and hypochromic red cells > 6% both before initiating epoetin treatment and during its administration. TSAT levels should not persistently exceed > 50% and serum ferritin > 500 mcg/L. When administering oral iron the dose should be at least 200 mg/die elemental iron; on the other hand, when the intravenous route is used, the dose should be 30-60 mg/IV dose in the form of low molecular weight salts (iron sodium gluconate) while the higher doses should be reserved for patients with transferring levels > 170 mg/dL. Administration of epoetin: The dosage of epoetin is individual with more than tenfold variability among individuals and all aiming at the same target Hb concentration. There are no clinical parameters entirely capable of predicting the necessary dosage. Therapeutic range is very wide, without any toxic effects for clinical use up to 100.000 IU/week. The target Hb concentration is reached in most patients with mild anaemia after 2 months' treatment with 4.000-10.000 epoetin (20-50 mcg darbepoetin alpha) per week. The HB concentration, along with the reticulocyte count, must be checked weekly following initiation and monthly during maintenance. Patients with a stable dose-response during conservative therapy may require less frequent monitoring (every 2-3 months). Inadequate response to epoetin treatment If any resistance is encountered, after excluding all the acute and chronic conditions of inadequate response, the reticulocyte count (severe reduction in the presence of anti erythropoietin antibodies) and the erythropoietin dosage should be measured. The target Hb concentration 11-12 g/dL is maintained in 90-95% of the patients by administering 1.000-30.000 IU of epoetin (5-150 mcg darbepoetin alpha) per week in the presence of adequate reserves of iron. Higher dosages define a state of resistance. Diagnosis of pure red cell (PRCA) from anti-erythropoietin antibodies is confirmed by bone marrow examination (almost total loss of erythroblasts). If antierythropoietin antibodies are present or there is a well founded suspicion of PRCA, the administration of epoetin and other similar treatment should be avoided. Side effects of epoetin treatment: The treatment of anaemia with epoetin does not hasten the progression of CRF. Blood pressure is to be checked regularly during initiation of epoetin and the treatment should be discontinued in cases of refractory hypertension or hypertensive encephalopathy. There should be increased surveillance of graft access, especially in those patients who risk vascular depletion. In general, heparin requirements do not increase but it may be advisable to evaluate a dose increase. PRCA from anti-erythropoietin antibodies has been detected with an incidence ranging from 0.12 to 1.1 cases/every 10 thousand patients treated.
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PMID:[Guidelines for the treatment of anemia in chronic renal failure]. 1466 4

Darbepoietin alfa (NESP) is a new long-acting erythropoietin, with a half-life 3 times longer than the old epoietins. In the present study, we evaluated the efficacy of NESP in a group of children on hemodialysis. Seven children, five male and two female, with a mean age of 11.5 +/- 3 years and a mean weight of 34.1 +/- 11 kg, were enrolled in the study. All had been treated for at least 6 months with epoietin alfa at a mean dose of 106 +/- 76 IU/kg 3 times/week i.v. They were then given NESP at a mean dose of 1.59 +/- 1.19 microg/kg once a week i.v., according to the suggested conversion index (weekly epoietin alfa dose/200=weekly NESP dose). Anemia was evaluated at the end of a dialysis session. This was especially important for children less compliant with water restriction. Serum ferritin and percentage transferrin saturation (TSAT) were also monitored, as were dialysis efficacy (Kt/V), blood pressure, and heparin requirements. Before starting the new treatment, all patients had an adequate mean hemoglobin (Hb) level (11.19 +/- 1.7 g/dl) and an adequate iron status (TSAT 24.2 +/- 11.5, serum ferritin 220 +/- 105 mg/dl). Five of the seven patients were also treated with intravenous ferric gluconate (10-20 mg/kg per week). Six children were on antihypertensive treatment. After the 1st month of treatment, we observed an excessive increase in Hb, 12.3 +/- 1.7 g/dl, (P<0.05), with severe hypertension in the youngest two patients (Hb>13 g/dl). A short discontinuation of the medication, followed by restarting at a decreased dosage, allowed us to continue with the treatment. At the 2nd month of follow-up, a mean plasma Hb level of 12.2 +/- 1.2 g/dl was observed, with a NESP mean dose of 0.79 +/- 0.4 microg/kg per week. Steady state was reached at 3 months, with a mean Hb of 11.8 +/- 1.4 g/dl and a mean NESP dose of 0.51 +/- 0.18 microg/kg per week (P<0.05). These results persisted at 6 months of follow-up; only one child had a persistent increase in platelet level (373,000 vs. 555,000). Dialysis efficiency and heparin requirements during dialysis did not change significantly. The high efficacy of NESP allowed a consistent reduction in dosage. The suggested conversion index does not appear to be correct for pediatric patients. Our experience suggests that in this population the correct dose could be 0.25-0.75 microg/kg per week. Hypertension was the only major side effect reported. The influence of NESP on platelet proliferation needs to be further investigated. The single weekly administration of NESP could be effective and beneficial for both patients and clinicians.
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PMID:Clinical experience with darbepoietin alfa (NESP) in children undergoing hemodialysis. 1474 34

Psychiatric manifestations are frequently associated with pernicious anemia including depression, mania, psychosis, dementia. We report a case of a patient with vitamin B12 deficiency, who has presented severe depression with delusion and Capgras' syndrome, delusion with lability of mood and hypomania successively, during a period of two Months. Case report - Mme V., a 64-Year-old woman, was admitted to the hospital because of confusion. She had no history of psychiatric problems. She had history of diabetes, hypertension and femoral prosthesis. The red blood count revealed a normocytosis with anemia (hemoglobin=11,4 g/dl). At admission she was uncooperative, disoriented in time and presented memory and attention impairment and sleep disorders. She seemed sad and older than her real age. Facial expression and spontaneous movements were reduced, her speech and movements were very slow. She had depressed mood, guilt complex, incurability and devaluation impressions. She had a Capgras' syndrome and delusion of persecution. Her neurologic examination, cerebral scanner and EEG were postponed because of uncooperation. Further investigations confirmed anemia (hemoglobin=11,4 g/dl) and revealed vitamin B12 deficiency (52 pmol/l) and normal folate level. Antibodies to parietal cells were positive in the serum and antibodies to intrinsic factor were negative. An iron deficiency was associated (serum iron=7 micromol/l; serum ferritin concentration=24 mg/l; serum transferrin concentration=3,16 g/l). This association explained normocytocis anemia. Thyroid function, hepatic and renal tests, glycemia, TP, TCA, VS, VDRL-TPHA were normal. Vitamin B12 replacement therapy was started with hydroxycobalamin 1 000 ng/day im for 10 days and iron replacement therapy. Her mental state improved dramatically within a few days. After one week of treatment the only remaining symptoms were lability of mood, delusion of persecution, Capgras' syndrome but disappeared totally 9 days after the beginning of the treatment. A neurologic examination was possible because of cooperation. All the tendon reflexes of inferior members were absent. The plantars were in flexion and there was a left inferior member hypoesthesia. The cerebral scan and EEG were normal. Fundic biopsy, realized by fibroscopy, revealed fundic atrophia and intestinal metaplasia compatible with Biermers' disease. The iron deficiency exploration concluded diet deficiency. Mme V. appeared euphoric, her speech was very rapid with play on words and overactivity. This hypomania state totally disappeared 3 days after. Six Months after her hospitalisation, she presented an hypothyroidism (TSH=3,780; T3=1,35; T4=1,08). A thyroid hormones replacement was started and she continued to receive Monthly B12 replacement. Discussion - This case report illustrates psychiatric manifestations of Biermers' disease. The clinical arguments in favour are: white woman, more than 60 Years old, no history of psychiatric problems, atypical symptoms (confusional state with psychiatric symptoms), fluctuation of symptoms (severe depression with confusional state, delusion of persecution and Capgras' syndrome; delusion with lability of mood and hypomania), dramatic improvement after 9 days of vitamin B12 replacement therapy. The biological arguments are: anemia, vitamin B12 deficiency, normal folate level, atrophia and fundic metaplasia, positive antibodies to parietal cells in the serum, association between Biermers' disease and autoimmune disease (Haschimoto thyroidite). Psychiatric manifestations can occur in the presence of low serum B12 levels but in the absence of the other well recognized neurological and haematological abnormalities of pernicious anemia. Mental or psychological changes may precede haematological signs by Months or Years. They can be the initial symptoms or the only ones. Verbank et al. described the case of a patient with vitamin B12 deficiency in whom hypomania, paranoia and depression had been successively presented during a period of 5 Years before anemia have been developed. The case of Mme V. is similar in the succession of severe depression with delusion of persecution and Capgras' syndrome, delusion with lability of mood and hypomania, during a period of two Months. This report seems to be the first one of a sequence of several psychiatric states with pernicious anemia during a period of two Months with normocytosis anemia. To illustrate this illness we reviewed the literature regarding psychopathology associated with B12 deficiency. The most common psychiatric symptoms were depression, mania, psychotic symptoms, cognitive impairment and obsessive compulsive disorder. The neuropsychiatric severity by vitamin B12 deficiency and the therapeutic efficacy depends on the duration of signs and symptoms. Conclusion - We recommend consideration of B12 deficiency and serum B12 determinations in all the patients with organic mental disorders, atypical psychiatric symptoms and fluctuation of symptomatology. B12 levels should be evaluated with treatment resistant depressive disorders, dementia, psychosis or risk factors for malnutrition such as alcoholism or advancing age associated with neurological symptoms, anemia, malabsorption, gastrointestinal surgery, parasite infestation or strict vegetarian diet. In first intention, B12 deficiency should be researched by serum B12 determination (normal 200-950 pg/ml). Studies of methylmalonic acid and homocysteine showed that they are very sensitive functional indicators of cobalamin status especially when other evidence of cobalamin (B12) deficiency was equivocal. Measurement of methylmalonic acid (normal 73-271 nmol/l) and homocysteine (normal 5,4-13,9 micromol/l) should not replace the measurement of serum cobalamin.
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PMID:[Psychiatric manifestations of vitamin B12 deficiency: a case report]. 1502 91

A causative role of blood-brain barrier (BBB) impairment is suggested in the pathogenesis of vascular dementia with leakage of serum components from small vessels leading to neuronal and glial damage. We examined the BBB function of young adult spontaneously hypertensive rats (SHR) in order to determine earlier changes in the BBB in chronic hypertension. SHR and stroke-prone SHR (SHRSP) were injected with horseradish peroxidase (HRP) as an indicator of BBB function and compared with Wistar Kyoto rats (WKY). The brain tissues were further examined with cationized ferritin, a marker for evaluating glycocalyx. The staining for HRP was distributed around the vessels in the hippocampal fissure of SHR and SHRSP, but not in WKY. With electron microscopy, the extravasated reaction product of HRP appeared in abluminal pits of the endothelial cells of arterioles and within the basal lamina in the hippocampus, but not the cerebral cortex, of SHR and SHRSP. On the contrary, the reaction product of HRP was never seen in the abluminal pits of the endothelial cells or the basal lamina of vessels in WKY. The number of cationized ferritin particles binding to the endothelial cells of capillaries was decreased in the hippocampus of SHR and SHRSP, while the number decreased in the cerebral cortex of SHRSP compared with those in WKY. However, the cationized ferritin binding was preserved in the endothelial cells of the arterioles with an increased vascular permeability. These findings suggest that the chronic hypertensive state induces BBB dysfunction in the hippocampus at an early stage.
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PMID:Blood-brain barrier is impaired in the hippocampus of young adult spontaneously hypertensive rats. 1504 85

Heme oxygenase (HO) degrades heme to carbon monoxide (CO), ferrous ions, and the bile pigment biliverdin, which is subsequently reduced to the other important bile pigment, bilirubin, by biliverdin reductase. Fe2+ liberated from the heme molecule upregulates ferritin production, and bile pigments are potent endogenous antioxidants. The HO enzyme exists in three isophorms: HO-1 is expressed at low levels under physiological conditions, but is induced by numerous factors, including oxidative stress, inflammation, nitric oxide, an elevated level of substrate, and hypoxia. HO-2 is a constitutive enzyme involved in the baseline production of CO in the cardiovascular and nervous systems, whereas HO-3 is also ubiquitously expressed, but possesses low catalytic activity. Like nitric oxide, CO activates soluble guanylate cyclase and elevates cGMP in target tissues, which dilates blood vessels. It also does this by directly activating potassium channels in vascular smooth muscle cells. In addition, CO inhibits platelet aggregation and proliferation of vascular smooth muscle cells, inhibits apoptosis, and stimulates angiogenesis. Both deficiency, and excess of HO-1 may be involved in the pathogenesis of arterial hypertension. Induction of HO-1 attenuates atherosclerosis and myocardial ischemia-reperfusion injury. Pharmacological and genetic induction of HO-1 as well as the delivery of exogenous CO are promising therapeutic strategies for the treatment of cardiovascular diseases.
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PMID:[Heme oxygenase and carbon monoxide in the physiology and pathology of the cardiovascular system]. 1506 78

Vascular permeability and endothelial glycocalyx were examined in young adult spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP), and Wistar Kyoto rats (WKY) as a control, in order to determine earlier changes in the blood-brain barrier (BBB) in the hypothalamus in chronic hypertension. These rats were injected with horseradish peroxidase (HRP) as an indicator of vascular permeability. Brain slices were developed with a chromogen and further examined with cationized ferritin, a marker for evaluating glycocalyx. Staining for HRP was seen around vessels in the hypothalamus of SHR and SHRSP, but was scarce in WKY. The reaction product of HRP appeared in the abluminal pits of endothelial cells and within the basal lamina of arterioles, showing increased vascular permeability in the hypothalamus of SHR and SHRSP, whereas there were no leaky vessels in the frontal cortex of SHR and SHRSP, or in both areas of WKY. The number of cationized ferritin particles binding to the capillary endothelial cells was decreased in the hypothalamus of SHR and SHRSP, while the number decreased in the frontal cortex of SHRSP, compared with those in WKY. Cationized ferritin binding was preserved in some leaky arterioles, while it was scarce or disappeared in other leaky vessels. These findings suggest that BBB disruption occurs in the hypothalamus of 3-month-old SHR and SHRSP, and that endothelial glycocalyx is markedly damaged there without a close relationship to the early changes in the BBB.
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PMID:Blood-brain barrier disruption in the hypothalamus of young adult spontaneously hypertensive rats. 1525 71

The therapeutic efficacy of angiotensin II receptor antagonist, losartan, was studied in patients with nonalcoholic steatohepatitis (NASH). Seven patients with both NASH and hypertension were treated with losartan (50 mg/d) for 48 weeks. Treatment with losartan resulted in a significant decrease in blood markers of hepatic fibrosis, plasma TGF-beta1 and serum ferritin concentration concurrently with an improvement in serum aminotransferase levels. Histological assessment showed improvement of hepatic necroinflammation in five patients, reduction of hepatic fibrosis in four patients, and disappearance of iron deposition in two patients. No side effect of treatment was noted at any time during the study. In conclusion, the present data raise the possibility that an angiotensin II receptor antagonist may be therapeutically efficacious for NASH.
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PMID:Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. 1538 53

Heart failure is a common, progressive, complex clinical syndrome with high morbidity and mortality. Coronary artery disease is its most common cause. The evaluation of symptomatic patients with suspected heart failure is directed at confirming the diagnosis, determining the cause, identifying concomitant illnesses, establishing the severity of heart failure, and guiding therapy. The initial evaluation should include a focused history and physical examination, a chest radiograph, and an electrocardiogram. The presence of heart failure can be confirmed by an echocardiogram. Heart failure is highly unlikely in the absence of dyspnea and an abnormal chest radiograph or electrocardiogram. Radionuclide angiography or contrast cineangiography may be necessary when clinical suspicion for heart failure is high and the echocardiogram is equivocal. Patients with confirmed heart failure should undergo additional testing, including a more detailed history and physical examination; a complete blood count; blood glucose measurement; liver function tests; serum electrolyte, blood urea nitrogen, and creatinine measurements; lipid panel; urinalysis; and thyroid-stimulating hormone level. A serum ferritin level, human immunodeficiency virus test, antinuclear antibody assays, rheumatoid factor test, or metanephrine measurements may be required in selected patients. Patients with coronary artery disease, hypertension, diabetes mellitus, exposure to cardiotoxic drugs, alcohol abuse, or a family history of cardiomyopathy are at high risk for heart failure and may benefit from routine screening.
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PMID:Diagnosis of heart failure in adults. 1560 63


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