Platelet-Derived Growth Factor C in Alcoholics.

AIMS: Platelet-derived growth factor (PDGF) promotes liver collagen deposition, acting on hepatic stellate cells. Despite this, low serum PDGF levels were reported in chronic hepatitis C or B infection, although some studies yield the opposite result. Since PDGF may be related not only to fibrosis but also with vascular, neuronal or muscle disease, it is important to analyze its behavior in alcoholics. METHODS: In total, 17 controls and 62 alcoholic patients consecutively admitted to the hospitalization unit of the Internal Medicine Service were included. We determined serum levels of PDGF C, routine laboratory evaluation, tumor necrosis factor-α, interleukin (IL)-6 and IL-8 and malondialdehyde (MDA) levels. We analyzed the relationships between PDGF and liver function, ethanol intake and inflammatory reaction by both univariate and multivariate analysis to discern which variables PDGF levels depend on. RESULTS: Serum PDGF levels were significantly lower among patients (675 ± 466 pg/ml) than among controls (1074 ± 337 pg/ml; Z = 3.70; P < 0.001), and even lower among cirrhotics (549 ± 412 among cirrhotics vs 778 ± 487 among non-cirrhotics; Z = 2.33; P = 0.02). PDGF levels showed a direct correlation with prothrombin activity (ρ = 0.50; P < 0.001), platelet count (ρ = 0.44; P < 0.001) and inverse ones with bilirubin (ρ = -0.39; P = 0.002), IL-6 (ρ = -0.33; P = 0.016), IL-8 (ρ = -0.47; P < 0.001), and MDA levels (ρ = -0.44; P < 0.001). By multivariate analysis, only prothrombin activity and platelet count were independently related to PDGF. CONCLUSION: PDGF-C levels are decreased in alcoholics, especially among cirrhotics. Multivariate analysis discloses that only prothrombin activity and platelet count are independently related to PDGF-C levels.

Influence of meteorological conditions on hospital admission in patients with acute coronary syndrome with and without ST-segment elevation: Results of the AIRACOS study. / Influencia de las condiciones meteorológicas en el ingreso hospitalario en pacientes con síndrome coronario agudo con y sin elevación del segmento ST: resultados del estudio AIRACOS.

OBJECTIVE: Evaluate whether the meterological parameters affecting revenues in patients with ST-segment and non-ST-segment elevation ACS. DESIGN: A prospective cohort study was carried out. SETTING: Coronary Care Unit of Hospital Universitario de Canarias PATIENTS: We studies a total of 307 consecutive patients with a diagnosis of ST-segment and non-ST-segment elevation ACS. We analyze the average concentrations of particulate smaller than 10 and 2.5µm diameter, particulate black carbon, the concentrations of gaseous pollutants and meteorological parameters (wind speed, temperature, relative humidity and atmospheric pressure) that were exposed patients from one day up to 7 days prior to admission. INTERVENTIONS: None. VARIABLES OF INTEREST: Demographic, clinical, atmospheric particles, concentrations of gaseous pollutants and meterological parameters. RESULTS: A total of 138 (45%) patients were classified as ST-segment and 169 (55%) as non-ST-segment elevation ACS. No statistically significant differences in exposure to atmospheric particles in both groups. Regarding meteorological data, we did not find statistically significant differences, except for higher atmospheric pressure in ST-segment elevation ACS (999.6±2.6 vs. 998.8±2.5 mbar, P=.008). Multivariate analysis showed that atmospheric pressure was significant predictor of ST-segment elevation ACS presentation (OR: 1.14, 95% CI: 1.04-1.24, P=.004). CONCLUSIONS: In the patients who suffer ACS, the presence of higher number of atmospheric pressure during the week before the event increase the risk that the ST-segment elevation ACS.

[Influence of diurnal variation in the size of acute myocardial infarction]. / Influencia de la variabilidad diurna en el tamaño del infarto agudo de miocardio.

OBJECTIVE: To evaluate whether the size of acute myocardial infarction (AMI) shows circadian variability. DESIGN: An observational, prospective study. SETTING: A 12-bed coronary care unit. PATIENTS: Consecutive patients diagnosed with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. INTERVENTIONS: The patients were divided into two groups according to the time of onset of AMI symptoms (Group A: 0-12hours, Group B: 12-24hours). MAIN VARIABLES OF INTEREST: Age, sex, cardiovascular risk factors, coronary anatomy, left ventricular ejection fraction, infarct location, time from onset of symptoms to reperfusion, presence of heart failure upon admission, and peak troponin I value. RESULTS: A total of 108 patients with a diagnosis of STEMI were included. Patients in group A showed a higher troponin I concentration compared to group B (troponin I: 70.85±16.38 versus 60.90±22.92ng / ml, p=0.003). In the multivariate analysis the onset of AMI between 0-12hours was identified as an independent predictor of infarct size (OR: 1.133, 95%CI 1.012-1.267, p=0.01). CONCLUSIONS: An onset of AMI between 0-12hours results in a significantly larger final size of necrosis compared with any other time of presentation.

[Differential characteristics of patients with acute coronary syndrome without ST-segment elevation compared to those with transient ST-segment elevation]. / Características diferenciales de los pacientes con síndrome coronario agudo sin elevación del segmento ST con respecto a los que tienen elevación transitoria del segmento ST.

OBJECTIVE: To evaluate different characteristics of patients with acute coronary syndrome (ACS) without ST-segment elevation compared with transient St-segment elevation. DESIGN: An observational, prospective study. SETTING: A 12-bed coronary care unit. PATIENTS: Consecutive patients of ACS without persistent ST-segment elevation. MAIN VARIABLES OF INTEREST: The population was divided intro 2 groups according to the presence of transient ST-segment elevation. Variables of interest were age, cardiovascular risk factors, troponin I and glucose concentrations on admission, coronary anatomy, left ventricular ejection fraction, inhospital mortality and drugs. RESULTS: Patients identified as ACS with transient ST-segment elevation were significantly younger, smokers and predominantly male. At the same time, they showed a minor peak elevation of troponin I, a higher ejection fraction and, mainly single-vessel coronary disease. CONCLUSIONS: Patients with ACS with transient ST-segment elevation differ in the type of population, myocardial damage and coronary angiographic results with respect to patients with ACS without ST-segment elevation. More research is needed to clarify whether these differences imply a different therapeutic approach.

DNA and RNA oxidative damage are associated to mortality in patients with cerebral infarction.

OBJECTIVE: Secondary injury due to oxidation may occur during ischemic stroke, possibly leading to oxidative damage to deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Higher blood concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG) (through the oxidation of guanosine from DNA) have been found in ischemic stroke patients than in healthy subjects, and in patients with versus without post-ischemic stroke depression. The present study was carried out to explore the possible association between serum DNA and RNA oxidative damage and mortality in patients with cerebral infarction. METHODS: A prospective, multicenter observational study was carried out in the Intensive Care Units of 6 Spanish hospitals. We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as ischemic changes evidenced by computed tomography in more than 50% of the middle cerebral artery territory and a Glasgow Coma Score (GCS)<9. Serum concentrations of the three oxidized guanine species (OGS) (8-hydroxyguanine from DNA or RNA, 8-hydroxyguanosine from RNA, and 8-OHdG from DNA) on the day of MMCAI diagnosis were determined. The study endpoint was 30-day mortality. RESULTS: We found higher serum OGS levels (p<0.001) in non-surviving (n=34) than in surviving patients (n=34). Logistic regression analyses showed serum OGS levels to be associated to 30-day mortality controlling for lactic acid, GCS and platelet count (OR=1.568; 95%CI=1.131-2.174; p=0.01). CONCLUSIONS: The novel observation in this study is the association between global serum OGS concentration and mortality in ischemic stroke patients.

Alcoholic myopathy: vitamin D deficiency is related to muscle fibre atrophy in a murine model.

AIMS: Chronic myopathy has been described in alcoholics, characterized by atrophy of type II fibres, and vitamin D deficiency. Low serum vitamin D levels are frequent in alcoholics. The possibility exists that serum vitamin D levels are related to muscle changes in a murine experimental model. METHODS: Histological analysis of the right gastrocnemius muscle was performed in four groups of adult Sprague-Dawley rats, sacrificed after 5 weeks of treatment following the Lieber-DeCarli model. We studied the association between muscle histological changes and the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD) and lipid peroxidation products (malondialdehyde); parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), free testosterone, 1,25 dihydroxyvitamin D3 (vitamin D) and corticosterone; and serum calcium and magnesium. RESULTS: Alcoholic animals showed type IIa and IIb fibre atrophy, especially the low-protein-fed ones, an effect dependent on protein deficiency. A significant relationship was observed between serum vitamin D levels and IIa fibre area (rho = 0.56, P = 0.002), and also, as a trend, between vitamin D and type IIb fibre area (rho = 0.39, p = 0.053); between vitamin D and muscle GPX (rho = 0.40, P = 0.025) and SOD activities (rho = 0.43, P = 0.012). Muscle GPX activity was significantly related with type I fibre area (rho = 0.49, P = 0.01) and muscle SOD, with type IIa fibre area (rho = 0.38, P = 0.045). Serum testosterone was also related with type IIa fibre area (rho = 0.61, P < 0.001). No relation was observed between serum PTH, corticosterone, or IGF-1 and fibre area PTH and antioxidant systems. Multiple regression analysis disclosed that the only parameter independently related with type IIa fibre area was serum vitamin D. CONCLUSION: Low vitamin D levels are related to muscle fibre atrophy, and altered levels of muscle antioxidant enzymes could play a role in alcoholic myopathy.

Relation between body fat and liver fat accumulation and cytokine pattern in non-alcoholic patients with chronic HCV infection.

BACKGROUND: Liver steatosis in chronic hepatitis C virus (HCV) infection is multifactorial. Therefore, there is not necessarily a relation between obesity and liver fat.On the other hand, body fat secretes cytokines, and cytokines and oxidative damage play important roles on progression of liver disease. METHODS: We analyzed the relationships between liver fat (assessed by histomorphometry) and trunk and subcutaneous fat (waist perimeter, triceps skinfold, BMI); the relationships between liver and body fat and cytokines (IL-6, TNF-alpha, IL-8, IFN-gamma, IL-4), adipokines (adiponectin and TIMP-1), and serum malondiladehyde and antioxidants (glutathione peroxidase and superoxide dismutase (SOD) activities); and the relationships of these data with histological changes in 40 HCV-infected non-alcoholic patients. RESULTS: Significant correlations were found between liver fat and waist perimeter and BMI, and between serum TIMP-1 and liver fat. Serum TIMP-1 was significantly related to body fat stores; serum IL-6 and IFN-gamma were related to histological inflammation. Patients with waist perimeter >102 cm (men) or 88 cm (women) showed increased liver fat. In 38.8% of non-obese patients, liver fat accumulation was intense. CONCLUSIONS: There is a relationship between visceral fat, serum TIMP-1 and liver steatosis. However, at least in some patients, factors different from mere adiposity play a role in liver steatosis.

Hematological, immunological and neurochemical effects of chronic amphetamine treatment in male rats.

In the present study, we have analyzed the effect of chronic amphetamine sulfate (AMPH) treatment on haematological, immunological and neurochemical parameters in the male rat. AMPH increased the total peripheral leukocyte count, and altered its differential counts, decreasing lymphocytes and increasing neutrophils. Flow cytometry study showed that the decline in circulating lymphocytes was caused by the loss of a particular lymphocyte subset, B-cell, which reduced both in percentage and in absolute number by 50%. T-cell population increased by 15% but not in absolute number, however there was no difference in either CD4+ or CD8+ T lymphocyte subsets between experimental groups. Neurochemically, AMPH reduced norepinephrine (NE) and serotonin (5-HT) contents in the hypothalamus and increased dopamine (DA) content in the striatum. Chronic AMPH increased in a dose-dependent manner serum corticosterone levels, had no effect on circulating catecholamines, reduced adrenal weights, and did not affect spleen weights although reduced their cellularities. These results show that chronic AMPH have important effects on immune function, particularly on humoral immune response because it reduced the circulating B cell population by half. In addition, AMPH plays an important role in the redistribution and trafficking of leukocytes, and both effects seem to be mediated by sympathetic innervation of the lymphoid organs.

New pharmacologic options in the treatment of acute coronary syndromes and myocardial ischemia-reperfusion injury: potential role of levosimendan.

Modern and effective therapeutic possibilities have improved the management and outcomes in acute coronary syndromes and acute myocardial infarction. However, substantial morbidity and mortality still remain. Myocardial ischemia-reperfusion injury may contribute to additional damage to myocardial necrosis and apoptosis. Therefore, it has been focused on attention and field of therapeutic actions in the last years. The main mechanisms involved in the pathogenesis of ischemia-reperfusion injury are depressed energy metabolism, elevated oxidative damage, and altered calcium homeostasis. In experimental trials, a variety of drugs have proved effectiveness for the prevention and treatment of the ischemia-reperfusion injury. However, its efficacy, not always confirmed, has not yet been established in clinical practice. On the basis of the strong evidence linking potassium ATP dependent channels opening in the myocardium and its proved cardioprotective role during ischemia, these channels have been pointed out as possible and promising pharmacological targets in this setting. Some evidences suggest that the calcium sensitizing agent levosimendan may have of beneficial and exerts cardioprotective effects on myocardial ischemia and ischemia-reperfusion injury. Further investigation is warranted on this novel application of levosimendan.

Tetrahydrobiopterin stimulates L-DOPA release from striatal tissue.

In the present study we have analyzed the effect of tetrahydrobiopterin (BH4) essential cofactor for tyrosine hydroxylase and nitric oxide synthase, on the 3,4-dihydroxyphenylalanine (L-DOPA) release from in vitro incubated striatal tissue. dl-6-methyl-5,6,7,8 tetrahydropterine (6-MPH4)-stimulated L-DOPA release in a concentration-dependent manner in the range from 25 to 100 microM. At these concentrations 6-MPH4 did not have any effect on dopamine release. Presence of Nomega-Nitro-L-arginine methyl ester (L-NAME, 200 microM), a nitric oxide synthase inhibitor, but not of alpha-methyl-rho-tyrosine (alpha-MPT, 100 microM), a tyrosine hydroxylase inhibitor, blocked L-DOPA release induced by 6-MPH4 (200 microM). Also, the addition to the incubation medium of melatonin (MEL, 300 microM), which is a scavenger of NO and other free radicals, blocked the L-DOPA release induced by 6-MPH4 (200 microM) but this effect did not occur with the addition of the peroxynitrite scavenger uric acid (UA, 300 microM). Sodium nitroprusside (SNP, 100 muM), a NO generator and l-DOPA releaser as previously reported, potentiated the L-DOPA releasing effect of 6-MPH4 (200 microM) which was also blocked by melatonin. In summary 6-MPH4 stimulates L-DOPA release from striatal fragments incubated in vitro by a mechanism which involves NO or other free radicals derived from NO but not peroxynitrite.

Elevated levels of oxidized low-density lipoprotein and impaired nocturnal synthesis of melatonin in patients with myocardial infarction.

This study was designed to investigate the relationship between nocturnal serum melatonin (MEL) levels and oxidized low-density lipoprotein (OxLDL) in patients with acute coronary syndrome (ACS). OxLDL plays a pivotal role in the development of atherosclerosis. Patients with coronary heart disease have an impaired nocturnal secretion of MEL. To date, there are no clinical human studies concerning the relationship of MEL to low-density lipoprotein (LDL) oxidation in patients with acute myocardial infarction (AMI). The study population contained 60 patients with AMI and 60 control subjects. Levels of circulating OxLDL were measured by a monoclonal antibody 4E6-based competition ELISA. Levels of circulating MEL were measured by an enzyme-immunoassay kit after chloroform extraction. Comparison of levels between AMI and controls, adjusted for age, revealed significantly higher nocturnal serum OxLDL levels (95.47+/-6.81 versus 68.35+/-4.07 U/l; p=0.004) in the AMI subjects. Nocturnal serum levels of MEL were lower in AMI than the control group (20.97+/-3.90 versus 53.19+/-7.80 pg/ml; p=0.009). Serum levels of total, high-density lipoprotein (HDL), and LDL cholesterol did not differ between the groups. Multiple regression analysis was performed on cases to study the association between AMI and serum levels of OxLDL and MEL (OR: 2.93; 95% CI, 2.89-2.98, p=0.01 and OR: 0.94; 95% CI, 0.89-0.97, p=0.02, respectively). This study demonstrates for the first time an independent association between nocturnal levels of OxLDL and MEL in patients with AMI. Additional population studies are necessary to further document these.

Alcoholic myopathy: lack of effect of zinc supplementation.

A chronic form of myopathy has been described in alcoholics, characterized by atrophy of type II fibers, due both to reduced protein synthesis and increased protein breakdown. Increased production of reactive oxygen species could probably play a role in increased protein breakdown. In addition, treatment with zinc might be beneficial, since it acts as a cofactor of several enzymes involved in the synthesis of proteins and antioxidants as copper-zinc-superoxidedismutase (SOD) and selenium dependent glutathione peroxidase (GPX). Based on these facts, we analyze the relative and combined effects of ethanol, protein malnutrition and treatment with zinc, 227 mg/l in form of zinc sulphate, on muscle changes in 8 groups of adult Sprague-Dawley rats fed following the Lieber-de Carli model during 5 weeks. We also study the association between muscle histological changes and the activity of GPX, SOD and lipid peroxidation products (MDA), with hormones such as IGF-1, and with trace elements involved in antioxidant systems and/or in lipid peroxidation, such as selenium, copper, zinc, and iron. We found type IIa and IIb fiber atrophy in the alcoholic animals, especially in the low-protein fed ones. This effect was mainly due to protein deficiency. Zinc played no role at all. Muscle iron increased in ethanol, low protein fed rats, either with or without zinc, and was directly related with muscle MDA levels, which in turn were related with muscle atrophy, as was also found for serum IGF-1 levels. Ethanol was the main responsible for all these changes, although protein undernutrition also played an independent role in MDA levels. A positive interaction between ethanol and protein deficiency on serum IGF-1 was also detected. These results suggest that both protein deficiency and ethanol contribute to muscle atrophy observed in alcoholized rats; this atrophy is associated with increased lipid peroxidation and muscle iron overload. Treatment with zinc sulphate confers no benefit.

Protein deficiency and muscle damage in carbon tetrachloride induced liver cirrhosis.

Protein undernutrition, alterations of hormones such as IGF-1, testosterone and cortisol, and increased lipid peroxidation-which may be related with deranged metabolism of some elements such as iron (Fe), zinc (Zn), manganese (Mn), selenium (Se) or copper (Cu)-may contribute to muscle damage in non alcoholic cirrhosis. Here, we analyse the effect of protein deficiency on muscle Cu, Fe, Zn, Mn and Se in carbon-tetrachloride (CCl(4)) induced liver cirrhosis. We also study the association between protein undernutrition and these trace elements with the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD) and lipid peroxidation products, and how all these are related with muscle morphological changes in 40 male adult Sprague-Dawley rats. Liver cirrhosis was induced by intraperitoneal injection of CCl(4) to 10 rats fed a 2% protein diet, and to another 10 fed a 18% protein control diet. Two further groups included rats without cirrhosis fed the 2% protein and the 18% protein diets. After sacrifice (6 weeks later), we found type IIa fibre atrophy in the cirrhotic animals, especially in the low-protein fed ones and this was due to protein deficiency. Muscle Fe increased in low protein fed cirrhotic rats. No relationship was found between muscle changes and any of the hormones, enzymes and trace elements analysed, or with liver fibrosis. These results suggest that muscle atrophy observed in CCl(4)-induced cirrhosis is related with protein deficiency, but not with cirrhosis itself.

Effects of protein deficiency on liver trace elements and antioxidant activity in carbon tetrachloride-induced liver cirrhosis.

In liver cirrhosis, liver tissue becomes progressively substituted by fibrosis, ultimately leading to architectural distortion, liver circulatory changes, and liver failure. Some data support the hypothesis that protein undernutrition may play a role in the development and progression of nonalcoholic liver cirrhosis and that this progression is at least partially mediated by changes in glutathione peroxidase (GPX), superoxide dismutase (SOD), and other antioxidative systems, leading to an increase in lipid peroxidation. We analyzed the effects of protein deficiency on liver Cu, Fe, Zn, Mn, and Se in carbon tetrachloride (CCl4)-induced liver cirrhosis, the relation of protein undernutrition and these trace elements with the activity of some hepatic antioxidative enzymatic mechanisms, and the relation of all of them with morphological and biochemical changes in 40 male adult Sprague-Dawley rats divided in four groups. Liver cirrhosis was induced by intraperitoneal injection of CCl4 to 10 rats fed a 2% protein diet and another 10 fed a 18% protein control diet; two further groups included rats without cirrhosis fed the 2% protein and the 18% protein diets. The study period lasted 6 wk. GPX, SOD, and lipid peroxidation products as well as Zn, Cu, Mn, Se, and Fe were determined in liver samples. We found that liver GPX and Se were reduced in the cirrhotic animals, especially in the low-protein-fed ones, protein deficiency, but not cirrhosis, exerting the main effects. A close correlation was found between liver GPX and serum albumin and weight loss and an inverse one among GPX and hepatocyte ballooning, liver fibrosis, and fat, histomorphometrically determined. These results suggest a pathogenetic role of decreased GPX in the progression of liver disease, which may become enhanced by concomitant protein undernutrition. In addition to iron, the levels of which were increased in the malnourished rats, no differences were found regarding the other trace elements, SOD activity, and lipid peroxidation products.

[Plasma homocysteine levels in Spanish patients with coronary artery disease]. / Concentraciones de homocisteína en plasma en pacientes españoles con enfermedad arterial coronaria.

OBJECTIVE: A rise in plasma levels of the amino acid homocysteine (HCY) is a possible risk factor in cardiovascular disease. The mechanisms proposed to explain how HCY can increase the risk of vascular disease include its direct effect on the vascular endothelium and its role in increasing the risk of thrombosis. The present work has been designed to determine HCY levels in patients with coronary artery disease (CAD) residents in the Canary Islands and to establish whether hyperhomocysteinemia can be considered as an risk factor. METHODS: The sample studied consisted of 132 patients with, angiographically demonstrated, CAD and 18 controls with normal coronary arteries. Biochemical parameters determined included: HCY, vitamin B12, vitamin B6, folic acid, creatinine, cholesterol and its fractions, triglycerides, glucose and fibrinogen. RESULTS: Mean levels of HCY were not significantly different between the cases and controls (p = 0.37). In the distribution of HCY levels into quintiles there was no significant association between the quintiles and the occurrence of CAD (p = 0.57). Multiple logistic regression analysis in which the risk factors were compared with quintiles 2, 3, 4 and 5 of HCY did not reveal a significant relation between HCY levels and risk of CAD. CONCLUSIONS: This study questions the previously accepted consideration that hyperhomocysteinemia is a risk factor of CAD. Controlled intervention trials are, therefore, necessary to clarify the possible association between total HCY levels and cardiovascular disease.

Relative and combined effects of selenium, protein deficiency and ethanol on hepatocyte ballooning and liver steatosis.

Oxidative damage plays a key role in alcohol-mediated liver alterations. Selenium, a potent antioxidant, is decreased in alcoholics. This study was conducted to analyse if the supplementation with selenium may alter liver changes in a murine model fed ethanol and/or a 2 % protein-containing diet, following the Lieber-DeCarli design. Adult male Sprague Dawley rats were divided into eight groups which received the Lieber-DeCarli control diet; an isocaloric, 36 % ethanol-containing diet; an isocaloric, 2 % protein-containing diet; and an isocaloric diet containing 2 % protein and 36 % ethanol diet; and other similar four groups to which selenomethionine (1 mg/kg body weight) was added. After sacrifice (5 weeks later), liver fat amount and hepatocyte areas of pericentral and periportal cells were measured, and liver and serum selenium, activity of liver glutathione peroxidase (GPX), and liver malondialdehyde were determined. Ethanol-fed rats showed increased hepatocyte areas and fat accumulation especially when ethanol was added to a 2 % protein diet. Selenium caused a decrease in hepatocyte ballooning and liver fat amount, but an increase in GPX activity, and a marked increase in serum and liver selenium. The present study demonstrates that selenium, added to the diet of rats in the form of seleniomethionine, prevents the appearance of early signs of ethanol-mediated liver injury under the conditions of the Lieber-DeCarli experimental design.