Riesgo de trombosis en pacientes con beta-talasemia / Risk of thrombosis in patients with beta-thalassemia

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Hypertrophic pachymeningitis associated with cerebral spinal fluid hypovolemia as initial presentation of systemic lupus erythematous.

We report a case of a 61-year-old man with thickening of the dura mater associated with the presence of subdural collections as a consequence of cerebral spinal fluid hypovolemia (CSFH) and hypertrophic pachymeningitis (HP) as presentation of systemic lupus erythematous (SLE). The patient complained about fatigue, musculoskeletal pain, headache and skin lesions. In the laboratory tests minimal normocytic anemia, mild leukopenia, polyclonal hypergammaglobulinemia and antinuclear antibodies (ANA), anti-double-stranded DNA antibodies (dsDNA), antibodies against extractable nuclear antigens (ENA) type SSA-Ro, anti-Smith antigen antibodies (anti-Sm) and anti-ribonucleoprotein antibodies (anti-RNP) were detected. Cranial magnetic resonance imaging (MRI), with and without gadolinium enhancement, revealed generalized thickening of the dura mater more severe at the right parieto-occipital lobes with the presence of subdural collections. The patient was diagnosed with SLE associated both with CSFH and HP. A conservative treatment with prednisone 60 mg daily, mycophenolate mofetil (MMF) 1 g daily and hydroxychloroquine 200 mg twice a day was started with significant clinical and radiological improvement (almost complete resolution of the subdural collections and clear decrease of meningeal thickness). The authors emphasize that HP associated with CSFH in the context of SLE is a rare entity, which makes this case unique.

[New advances in anticoagulation: is it time to forget about heparin and vitamin K antagonists? Yes]. / Novedades en anticoagulación. Nos olvidamos ya de la heparina y las antivitaminas K? Sí

For the last 60 years, heparin and vitamin K antagonists have been the cornerstone of anticoagulation. Nowadays, the new anticoagulants, such as dabigatran, rivaroxaban and apixaban, show potential advantages over classical treatments. These agents inhibit specific coagulation factors and are administered orally at fixed doses. Furthermore, heparin and vitamin K antagonists have a fast onset of action, short-duration and predictable therapeutic effects. No interactions with foods have been described, although some drug-drug interactions have been reported. At the moment, no antidotes are available. However, due to the short half-life of these agents, antidotes are less essential. The new anticoagulants are at least as effective and safe as traditional treatments in the prevention of venous thromboembolism after orthopedic surgery, as well as in the prevention of stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran and rivaroxaban have also been shown to be effective in the treatment of acute venous thromboembolism. Due to their properties, these drugs could gradually replace heparin and especially vitamin K antagonists. Hopefully, many of our patients will be able to discontinue classical anticoagulant treatment and others will never begin it.

Novedades en anticoagulación. ¿Nos olvidamos ya de la heparina y las antivitaminas K? Sí / New advances in anticoagulation: is it time to forget about heparin and vitamin K antagonists? Yes

El tratamiento anticoagulante ha estado basado en las heparinas y los antagonistas de la vitamina K durante los últimos 60 años. En la actualidad existen nuevos anticoagulantes como dabigatran, rivaroxaban y apixaban que poseen ventajas importantes frente al tratamiento clásico. Estos fármacos están dirigidos a un solo factor de la cascada de la coagulación y se administran por vía oral y a dosis fija. Además, no precisan monitorización de su efecto de forma rutinaria, el comienzo de su acción es rápido, la vida media corta y no presentan interferencias con los alimentos, aunque se han descrito interacciones con algunos fármacos. De momento no se dispone de antídoto específico, pero su vida media corta lo hace menos imprescindible. Han demostrado una eficacia y seguridad similares, o incluso superiores, al tratamiento clásico en la prevención del tromboembolismo venoso en los enfermos sometidos a cirugía ortopédica de rodilla o cadera, y en la prevención del ictus y del embolismo sistémico en la fibrilación auricular no valvular. Dabigatran y rivaroxaban también han demostrado su eficacia en el tratamiento de la enfermedad tromboembólica venosa. Las características de estos fármacos los convierten en una opción muy atractiva para sustituir a las heparinas y, especialmente, a los antagonistas de la vitamina K de forma progresiva y prudente. Muchos de nuestros enfermos van a poder olvidarse del tratamiento anticoagulante clásico y, sobre todo, muchos de ellos ni siquiera van a conocerlo (AU)

For the last 60 years, heparin and vitamin K antagonists have been the cornerstone of anticoagulation. Nowadays, the new anticoagulants, such as dabigatran, rivaroxaban and apixaban, show potential advantages over classical treatments. These agents inhibit specific coagulation factors and are administered orally at fixed doses. Furthermore, heparin and vitamin K antagonists have a fast onset of action, short- duration and predictable therapeutic effects. No interactions with foods have been described, although some drug-drug interactions have been reported. At the moment, no antidotes are available. However, due to the short half-life of these agents, antidotes are less essential. The new anticoagulants are at least as effective and safe as traditional treatments in the prevention of venous thromboembolism after orthopedic surgery, as well as in the prevention of stroke and systemic embolism in non valvular atrial fibrillation. Dabigatran and rivaroxaban have also been shown to be effective in the treatment of acute venous thromboembolism. Due to their properties, these drugs could gradually replace heparin and especially vitamin K antagonists. Hopefully, many of our patients will be able to discontinue classical anticoagulant treatment and others will never begin it (AU)

Venous thromboembolism during pregnancy, postpartum or during contraceptive use.

Venous thromboembolism (VTE) is a leading cause of maternal death during pregnancy or postpartum, and in women using hormonal contraceptives. However, important issues concerning its natural history and therapy remain unsolved, and most of the protocols for treatment of VTE in this patient population are based on data extrapolated from other populations. RIETE is an ongoing registry of consecutive patients with objectively confirmed, symptomatic, acute VTE. We examined the clinical characteristics and three-month outcome of all enrolled women with pregnancy, postpartum or using hormonal contraceptives. As of December 2008, 173 pregnant women, 135 postpartum, and 798 contraceptive users were enrolled. Of these, 438 (40%) presented with pulmonary embolism (PE) and 668 with deep-vein thrombosis (DVT). Most women with acute PE had dyspnea (72%) or chest pain (75%), but only 2.0% had hypoxaemia. During the three-month study period, five women (0.45%; 95% CI: 0.17-1.00) died (3 had fatal PE), 13 (1.18%; 95% CI: 0.66-1.95) had VTE recurrences, and seven (0.63%; 95% CI: 0.28-1.25) major bleeding. Two of the three women with fatal PE died during the first few hours after arriving at the emergency ward, with no time to start any therapy. The outcome of pregnant or postpartum women with VTE is similar to that in contraceptive users, even though the treatment is different. The non-specific nature of PE signs may have caused some delay in PE diagnosis.

[Anticoagulation treatment withdrawal in primary antiphospholipid syndrome when anticardiolipin antibodies become negative]. / Retirada de la anticoagulación en el síndrome antifosfolípido primario cuando se negativizan los anticuerpos anticardiolipina.

OBJECTIVES: The recommended treatment in patients with primary antiphospholipid syndrome (APS) after a thrombotic event is long-term anticoagulation. However, it is still not exactly known how to manage patients who remain stable for years and whose antiphospholipid antibodies (APA) decrease until becoming negative. This study aims to assess the course of the primary APS in a group of patients after anticoagulation therapy is discontinued. PATIENTS AND METHOD: Ten patients with primary APS who had developed deep venous thrombosis in the limbs (9) or in the aorta (1) were included. After a minimum period of 12 months of anticoagulation therapy, this was discontinued if the patients were negative APA during the follow-up in two consecutive measurements. RESULTS: Six patients (60%) developed persistent negative APA. Four had transient risk factors (2 pregnant, 1 immobilization, 2 oral contraceptives). No new thrombosis episode was observed after a follow-up period of 21 +/- 4.9 months. CONCLUSIONS: Our data suggest that anticoagulation can be discontinued in those patients with primary APS and persistent negative APA, especially if the thrombotic event was venous and occurred in association with a transient risk factor, such as immobilization or pregnancy. Extensive studies are required to confirm these results.

Retirada de la anticoagulación en el síndrome antifosfolípido primario cuando se negativizan los anticuerpos anticardiolipina / Anticoagulation treatment withdrawal in primary antiphospholipid syndrome when anticardiolipin antibodies become negative

Objetivos. La anticoagulación a largo plazo es el tratamiento recomendado en el síndrome antifosfolípido primario (SAF) tras un evento trombótico. Sin embargo, no se conoce con precisión cómo se deben manejar los enfermos que permanecen estables durante años, y cuos anticuerpos antifosfolípido (AAF) descienden hasta negativizarse. El objetivo de este trabajo es valorar la evolución del SAF primario, tras la suspensión de la anticoagulación, en este grupo de pacientes. Población y métodos. Se incluyeron diez pacientes diagnosticados de SAF primario que habían sufrido una trombosis venosa profunda en las extremidades (9) y en la aorta(1). Tras un período mínimo de 12 meses de anticoagulación se retiró el tratamiento a los pacientes que presentaron AAF negativos a lo largo del seguimiento en dos determinaciones consecutivas. Resultados. Los AAF se negativizaron de forma persistente en seis enfermos (60%). Cuatro presentaban factores de riesgo transitorios (2 gestación, 1 inmovilización, 2 anticonceptivos), y tras la retirada de la coagulación ninguno desarrolló nuevos eventos trombóticos. Conclusiones. Nuestros datos sugieren que la retirada del tratamiento anticoagulante puede ser adecuada en un grupo de pacientes con SAF primario que, tras un periodo prolongado de anticoagulación, negativizan los AAF de forma estable. Esta actitud sería más segura si el evento trombótico era venoso y ocurrió durante la presencia de un factor de riesgo transitorio. No obstante, son necesarios estudios más amplios que confirmen estos hallazgos

Objectives. The recommended treatment in patients with primary antiphospholipid syndrome (APS) after a thrombotic event is long-term anticoagulation. However, it is still not exactly known how to manage patients who remain stable for years and whose antiphospholipid antibodies (APA) decrease until becoming negative. This study aims to assess the course of the primary APS in a group of patients after anticoagulation therapy is discontinued. Patients and method. Ten patients with primary APS who had developed deep venous thrombosis in the limbs (9) or in the aorta (1) were included. After a minimum period of 12 months of anticoagulation therapy, this was discontinued if the patients were negative APA during the follow-up in two consecutive measurements. Results. Six patients (60%) developed persistent negative APA. Four had transient risk factors (2 pregnant, 1 immobilization, 2 oral contraceptives). No new thrombosis episode was observed after a follow-up period of 21 ± 4.9 months. Conclusions. Our data suggest that anticoagulation can be discontinued in those patients with primary APS and persistent negative APA, especially if the thrombotic event was venous and occurred in association with a transient risk factor, such as immobilization or pregnancy. Extensive studies are required to confirm these results

The -675 4G/5G polymorphism at the Plasminogen Activator Inhibitor 1 (PAI-1) gene modulates plasma Plasminogen Activator Inhibitor 1 concentrations in response to dietary fat consumption.

The objective of the study was to determine whether Plasminogen Activator Inhibitor Type 1 (PAI-1) -675 4G/5G polymorphism is associated with the response of functional plasma PAI-1 concentrations to changes in the amount and quality of dietary fat in healthy subjects. PAI-1 is the major inhibitor of fibrinolysis, and a lower level of fibrinolytic activity could be implicated in an increased risk of IHD. Fifty-nine healthy Spanish volunteers (ten 4G/4G homozygotes, twenty-eight heterozygotes 4G/5G and twenty-one 5G/5G homozygotes) consumed three diets for periods of 4 weeks each: a SFA-rich diet (38 % fat, 20 % SFA), followed by a carbohydrate-rich diet (30 % fat, 55 % carbohydrate) and a MUFA-rich diet (38 % fat, 22 % MUFA) according to a randomized crossover design. At the end of each dietary period plasma lipid and functional plasma PAI-1 concentrations were determined. Subjects carrying the 4G allele (4G/4G and 4G/5G) showed a significant decrease in PAI-1 concentrations after the MUFA diet, compared with the SFA-rich and carbohydrate-rich diets (genotype x diet interaction: P = 0.028). 5G/5G homozygotes had the lowest plasma PAI-1 concentrations compared with 4G/4G and 4G/5G subjects (genotype: P = 0.002), without any changes as a result of the amount and the quality of the dietary fat. In summary, no differences in plasma PAI-1 concentration response were found after changes in dietary fat intake in 5G/5G homozygotes, although these subjects displayed the lowest concentrations of PAI-1. On the other hand, carriers of the 4G allele are more likely to hyper-respond to the presence of MUFA in the diet because of a greater decrease in PAI-1 concentrations.

A Mediterranean and a high-carbohydrate diet improve glucose metabolism in healthy young persons.

AIMS/HYPOTHESIS: Insulin resistance usually precedes the diagnosis of Type II (non-insulin-dependent) diabetes mellitus. However, in most patients, the clinical expression of the disease could be prevented by dietary and lifestyle changes. We investigated the effects of a diet enriched in monounsaturated fatty acids (Mediterranean diet) and a low fat, high-carbohydrate diet on in vivo and in vitro glucose metabolism in 59 young subjects (30 men and 29 women). METHODS: We carried out an intervention dietary study with a saturated fat phase and two randomized-crossover dietary periods: a high-carbohydrate diet and a Mediterranean diet for 28 days each. We analysed the plasma lipoproteins fractions, free fatty acids, insulin sensitivity and glucose uptake in isolated monocytes at the end of the three dietary periods. RESULTS: In comparison to the saturated fat diet, the CHO and Mediterranean diets induced a decrease of LDL-cholesterol (p < 0.001) and HDL-cholesterol (p < 0.001). Steady-state plasma glucose decreased (p = 0.023) and basal and insulin-stimulated 2-deoxiglucose uptake in peripheral monocytes increased in both diets (CHO and Mediterranean), (p = 0.007) indicating an improvement in insulin sensitivity. Fasting free fatty acids plasma values were correlated positively with steady state plasma glucose (r = 0.45; p < 0.0001). In addition, there was an inverse correlation between the mean glucose of the steady state plasma glucose period and logarithmic values of basal (r = -0.34; p = 0.003) and insulin stimulated glucose uptake in monocytes (r = -0.32; p = 0.006). CONCLUSION/INTERPRETATION: Isocaloric substitution of carbohydrates and monounsaturated fatty acids for saturated fatty acids improved insulin sensitivity in vivo and in vitro, with an increase in glucose disposal. Both diets are an adequate alternatives for improving glucose metabolism in healthy young men and women.

[Influence of genetic variation at apoprotein A-1 gene promoter region on plasma lipid levels in heart transplantation patients]. / Influencia de la variación genética en la región promotora del gen de la apoproteína A-I sobre las concentraciones de lípidos en pacientes con transplante de corazón.

BACKGROUND: To study if the presence of the G/A polymorphism at the apo A-I gene promoter region could determine the lipid profile in patients with hyperlipidemia after heart transplantation, or if it is related with the type of heart disease that determined the transplantation. PATIENTS AND METHODS: This study included 31 patients with hyperlipidemia after heart transplantation. Anthropometric parameters, basic analytic and lipid study were measured in these subjects. Identification of the G/A mutation in the promoter region of the apo A-I gene was performed. RESULTS: 22 patients had the G/G genotype and 9 the G/A. 14 were transplanted by coronary heart disease and 17 by non ischemic heart disease. Patients with the A allele had higher cHDL (63 [SD 15] vs 53 [10]; p = 0.034) and apo A-I plasma levels (156 [34] vs 132 [24]; p = 0.040) than G/G subjects. The A allele was present in the 18% of the patients transplanted by ischemic heart disease and in the 43% of the transplanted by another etiology (p = 0.073). CONCLUSIONS: The presence of the G/A genotype in the promoter region of the apo A-I gene determines higher plasma levels of cHDL in patients with hyperlipidemia after heart transplantation.

Effects of different dietary cholesterol concentrations on lipoprotein plasma concentrations and on cholesterol efflux from Fu5AH cells.

BACKGROUND: The fatty acid composition of the diet can modulate the effect of dietary cholesterol on plasma lipoproteins. However, HDL composition and its capacity to promote cholesterol efflux can be influenced by the diet. OBJECTIVE: Modifications in plasma lipids and in the capacity of serum to stimulate the cholesterol efflux induced by a low-fat diet [National Cholesterol Education Program (NCEP) Step I diet], by a monounsaturated fatty acid (MUFA)-rich diet, and by addition of cholesterol to both diets was studied. DESIGN: Fifteen young, healthy men followed 2 NCEP Step I diets (<30% of fat as energy, with <10% saturated fat and 14% MUFAs) for 24 d, providing 0.027 or 0.068 mg cholesterol x kJ(-1) x d(-1), and 2 oleic acid-enriched diets (38% of energy as fat, with 24% MUFAs) providing the same amount of dietary cholesterol as the NCEP Step I diets. RESULTS: Total cholesterol, LDL cholesterol, apolipoprotein (apo) B, and apo A-I concentrations decreased after the NCEP Step I and MUFA diets compared with the usual diet. HDL cholesterol also decreased after the NCEP Step I diet. Total:HDL cholesterol, apo B, and apo B:apo A-I were lower after the MUFA diets than after the NCEP Step I diets. There were no significant differences between the lipid profiles obtained after the NCEP Step I and MUFA diets were enriched with cholesterol. The capacity of serum to promote cholesterol efflux was significantly higher after the cholesterol-enriched NCEP Step I diet than after the NCEP Step I diet. CONCLUSIONS: The MUFA diet induced a better lipid profile than the NCEP Step I diet; however, the increase in the cholesterol content of both diets produced similar plasma lipid changes. The cholesterol in the NCEP Step I diet increased the cholesterol efflux induced by total serum.

Dietary fat clearance in normal subjects is modulated by genetic variation at the apolipoprotein B gene locus.

Apolipoprotein B (apo B) plays a dominant role in cholesterol homeostasis. Several polymorphic sites within or adjacent to the gene locus for apo B have been detected. The X+ allele (XbaI restriction site present) of the XbaI restriction fragment polymorphism on the apo B gene has been found in some studies to be associated with higher serum cholesterol and/or triglyceride levels and with greater dietary response. The present study was designed to evaluate whether the apo B XbaI polymorphism was associated with the interindividual variability observed during postprandial lipemia. Fifty-one healthy young male volunteers [20 X-/X- (X-), and 31 X+/X- or X+/X+ (X+)], homozygotes for the apo E3 allele, were subjected to a vitamin A-fat load test. Subjects with the X- genotype had significantly greater retinyl palmitate (RP) and apo B-48 postprandial responses on both the large and the small TRL lipoprotein fractions compared with X+ subjects. In summary, subjects with the X-/X- genotype at the apo B locus have a greater postprandial response than X+ subjects. These differences observed in postprandial lipoprotein metabolism could explain some of the reported associations of this polymorphism to coronary heart disease risk.

Lovastatin versus bezafibrate for hyperlipemia treatment after heart transplantation.

BACKGROUND: Elevation in total and low-density lipoprotein cholesterol levels and a decrease in high-density lipoprotein cholesterol plasma concentrations are common in heart transplant recipients. The pathogenesis of this hyperlipemia after heart transplantation is complex. Currently available antilipemic agents are difficult to use because their adverse effects are potentiated by immunosuppressor treatment. The present investigation was carried out to test the safety and efficacy of lovastatin and bezafibrate in 18 patients with hyperlipemia after heart transplantation. METHODS: In this crossover study, after 3 months of dietary recommendations, the subjects were randomly assigned to an 8-week period of lovastatin treatment (10 mg/day) followed by an additional 8-week period of treatment with bezafibrate (400 mg/day) or vice versa. The two treatments were separated by an 8-week washout period. RESULTS: Both drugs reduced total and low-density lipoprotein cholesterol and apoprotein B concentrations. High-density lipoprotein cholesterol was only increased with bezafibrate. The total cholesterol/high-density lipoprotein cholesterol and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratios were decreased under both treatments, but these changes were greater with bezafibrate. Apo AI levels increased with lovastatin. Bezafibrate produced a rise in high-density lipoprotein cholesterol and reduced total and very low-density lipoprotein triglycerides and very low-density lipoprotein cholesterol. Both drugs decreased intermediate density lipoprotein cholesterol and triglyceride levels, but the effect of bezafibrate on intermediate-density lipoprotein triglycerides was significantly greater. The two drugs were well tolerated and liver enzymes, creatine kinase, and renal function remained stable.

The effect of cyclosporine and methylprednisolone on plasma lipoprotein levels in rats.

The aim of this study was to evaluate in rats the effects of cyclosporine, methylprednisolone, and the combination of both (CyP) on plasma lipids and lipoproteins levels. Three groups received a low doses of cyclosporine, methylprednisolone, and CyP (cyclosporine, 15 mg/kg/day; methylprednisolone, 1 mg/kg/day; and CyP, 15 plus 1 mg/kg/day of cyclosporine and methylprednisolone, respectively). Three additional groups received high doses (cyclosporine, 30 mg/kg/day; methylprednisolone, 2 mg/kg/day; and CyP, 30 plus 2 mg/kg/day of cyclosporine and methyprednisolone, respectively). The administration of cyclosporine produced an increase in plasma levels of triglycerides, very low density lipoprotein (VLDL) triglycerides, low-density lipoprotein (LDL) cholesterol and in total cholesterol/HDL cholesterol and LDL cholesterol/high-density lipoprotein (HDL) cholesterol ratios. In addition, cyclosporine decreased plasma HDL cholesterol and HDL2 cholesterol levels. The administration of methylprednisolone produced an increase in triglycerides and VLDL triglycerides and a decrease in HDL cholesterol and HDL2 cholesterol levels. Total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios did not change after administration of methylprednisolone. The association of both drugs resulted in a greater increase in triglycerides and VLDL triglycerides than the separated administration of either cyclosporine or methylprednisolone alone. In rats receiving cyclosporine the increase in triglycerides and VLDL triglycerides may be due to a significant decrease in plasma lipoprotein lipase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

'In vitro' action of histamine and cimetidine on amylase secretion in the rat pancreas.

We report here the effect of histamine on amylase secretion in isolated lobules from the rat pancreas. Different concentrations of histamine increased amylase secretion, while the stimulatory effect was reduced by cimetidine although not by chlorpheniramine. These findings suggest that pancreatic lobules have H2 receptors. On the other hand, bethanechol induced a stimulatory effect on pancreatic lobules that was inhibited by cimetidine. Vibrio cholerae toxin stimulated amylase secretion, but this effect was not reduced by cimetidine. Cimetidine may thus block the stimulated amylase secretion interfering with the Ca2+ messenger system.