Long-term use of mepolizumab in a case of chronic eosinophilic pneumonia: extending interval dosing.

INTRODUCTION: Mepolizumab, a humanized anti IL-5 monoclonal antibody, has been used off-label for chronic eosinophilic pneumonia (CEP), inducing disease remission and saving systemic corticosteroids. CASE STUDY: We present a case of CEP, requiring long-term corticosteroids therapy due to relapse upon withdrawal. Mepolizumab was started and maintained for 2 years and 6 months. RESULTS: Corticosteroids could be withdrawn and mepolizumab dose interval was spared up to 10 wk with no disease relapse. CONCLUSION: Mepolizumab is shown to be useful for chronic eosinophilic pneumonia, allowing corticosteroid withdrawal. Dose interval may be individualized under close monitoring, for a more efficient treatment, reducing medical costs while improving patients' quality of life.

Micronutrients in Pregnancy after Bariatric Surgery: A Narrative Review.

Bariatric surgery is increasingly used in women of childbearing age due to the rising prevalence of obesity and the effectiveness and availability of this treatment. Pregnancy in women with previous bariatric surgery deserves special attention. Weight loss induced by surgery reduces the risks that obesity poses to pregnancy. But on the other hand, decreased intake and malabsorption may increase the risk of malnutrition and micronutrient deficiency and negatively affect maternal and foetal health. The aim of this narrative review is to provide an updated analysis of the impact of different bariatric surgery techniques on mineral and micronutrient nutritional status during pregnancy and the possible effect on maternal-foetal health.

Identification of a Plasma Microrna Signature as Biomarker of Subaneurysmal Aortic Dilation in Patients with High Cardiovascular Risk.

Patients with subaneurysmal aortic dilation (SAD; 25-29 mm diameter) are likely to progress to true abdominal aortic aneurysm (AAA). Despite these patients having a higher risk of all-cause mortality than subjects with aortic size <24 mm, early diagnostic biomarkers are lacking. MicroRNAs (miRs) are well-recognized potential biomarkers due to their differential expression in different tissues and their stability in blood. We have investigated whether a plasma miRs profile could identify the presence of SAD in high cardiovascular risk patients. Using qRT-PCR arrays in plasma samples, we determined miRs differentially expressed between SAD patients and patients with normal aortic diameter. We then selected 12 miRs to be investigated as biomarkers by construction of ROC curves. A total of 82 significantly differentially expressed miRs were found by qPCR array, and 12 were validated by qRT-PCR. ROC curve analyses showed that seven selected miRs (miR-28-3p, miR-29a-3p, miR-93-3p, miR-150-5p, miR-338-3p, miR-339-3p, and miR-378a-3p) could be valuable biomarkers for distinguishing SAD patients. MiR-339-3p showed the best sensitivity and specificity, even after combination with other miRs. Decreased miR-339-3p expression was associated with increased aortic abdominal diameter. MiR-339-3p, alone or in combination with other miRs, could be used for SAD screening in high cardiovascular risk patients, helping to the early diagnosis of asymptomatic AAA.

Effect of Pectin on the Expression of Proteins Associated with Mitochondrial Biogenesis and Cell Senescence in HT29-Human Colorectal Adenocarcinoma Cells.

Mitochondria dynamic is regulated by different proteins, maintaining a balance between fission and fusion. An imbalance towards mitochondrial fission has been associated with tumor cell proliferation. The aim of this study was to analyze whether pectin modifies the viability of human colon cancer cells and the expression of proteins involved in mitochondrial fusion and fission. The human colon carcinoma cell line HT29 cells was growth in 10% fetal bovine serum in the absence and presence of pectin. Pectin reduced HT29 cell viability in a concentration-dependent manner, reaching a plateau at 150~300 µmol/L pectin. The presence of 200 µmol/L pectin reduced the expression of dynamin-related protein-1 and increased expression of the mitochondrial fusion-associated proteins mitofusin-1 and 2. Expression of cyclin B1, a protein involved in G2/M transition, was found decreased in pectin-incubated HT29 cells. Moreover, expression of p53 protein, the amount of p53 in the nucleous and ß-galactosidase activity, which are all biomarkers for cellular senescence, were significantly higher in pectin-incubated HT29 cells than in HT29 cells incubated without pectin. Expression of the protein B-cell lymphoma 2 (Bcl-2) homologous antagonist/killer was increased in response to incubation with pectin. However, incubation with pectin did not affect expression of Bcl-2-associated X protein or Bcl-2, or the caspase-3 activity. Overall, we concluded that pectin reduces the viability of human HT29 colon cancer cells, which is accompanied with a shift in the expression of proteins associated with mitochondrial dynamics towards mitochondrial fusion. Moreover, incubation with pectin favors cellular senescence over apoptosis in HT29 cells.

Functional analysis of new variants at the low-density lipoprotein receptor associated with familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of treatment, thus reducing the risk of coronary heart disease. In this study, we performed in vitro characterization of new LDLR variants found in our patients. Genetic analysis was performed by Next Generation Sequencing using a customized panel of 198 genes in DNA samples of 516 subjects with a clinical diagnosis of probable or definitive FH. All new LDLR variants found in our patients were functionally validated in CHO-ldlA7 cells. The LDLR activity was measured by flow cytometry and LDLR expression was detected by immunofluorescence. Seven new variants at LDLR were tested: c.518 G>C;p.(Cys173Ser), c.[684 G>T;694 G>T];p.[Glu228Asp;Ala232Ser], c.926C>A;p.(Pro309His), c.1261A>G;p.(Ser421Gly), c.1594T>A;p.(Tyr532Asn), and c.2138delC;p.(Thr713Lysfs*17). We classified all variants as pathogenic except p.(Ser421Gly) and p.(Ala232Ser). The functional in vitro characterization of rare variants at the LDLR is a useful tool to classify the new variants. This approach allows us to confirm the genetic diagnosis of FH, avoiding the classification as "uncertain significant variants", and therefore, carry out cascade family screening.

Usefulness of compounds with monacolin K in a case of statins intolerance / Utilidad de los compuestos con monacolina K en un caso de intolerancia a estatinas

Many patients with familial hypercholesterolaemia (FH) or in secondary prevention situations and with statin intolerance do not achieve LDL-C targets, and require treatment with PCSK9 inhibitors (iPCSK9) and ezetimibe. The case is presented on a patient with FH and total intolerance to statins. Treatment with iPCSK9 and ezetimibe failed to achieve her LDL-C target. A compound with red yeast rice derivatives containing 3mg of monacolin K was added, with good therapeutic compliance, and a very good control of LDL-C. The addition of red yeast rice derivatives containing low doses of monacolin K, together with IPCSK9 in patients with total intolerance to statins, may open a new path to obtain LDL-C targets in patients with high/very high cardiovascular risk

Muchos pacientes con hipercolesterolemia familiar (HF) o en situaciones de prevención secundaria con intolerancia a estatinas no logran objetivos a pesar del tratamiento con inhibidores de PCSK9 (iPCSK9) y ezetimiba. Presentamos el caso de un paciente con HF e intolerancia total a las estatinas. El tratamiento con iPCSK9 y ezetimiba no logró el objetivo lipídico. Se añadió un compuesto derivado de la levadura roja del arroz, que contenía 3mg de monacolina K con una excelente tolerancia, lográndose un muy buen control de los objetivos de cLDL. La suma al tratamiento de IPCSK9 de un compuesto derivado de la levadura roja del arroz, con bajas dosis de monacolina K, abre una nueva puerta para lograr los objetivos de cLDL en pacientes de muy alto riesgo cardiovascular

Usefulness of compounds with monacolin K in a case of statins intolerance.

Many patients with familial hypercholesterolaemia (FH) or in secondary prevention situations and with statin intolerance do not achieve LDL-C targets, and require treatment with PCSK9 inhibitors (iPCSK9) and ezetimibe. The case is presented on a patient with FH and total intolerance to statins. Treatment with iPCSK9 and ezetimibe failed to achieve her LDL-C target. A compound with red yeast rice derivatives containing 3mg of monacolin K was added, with good therapeutic compliance, and a very good control of LDL-C. The addition of red yeast rice derivatives containing low doses of monacolin K, together with IPCSK9 in patients with total intolerance to statins, may open a new path to obtain LDL-C targets in patients with high/very high cardiovascular risk.

Disappearance of recurrent pancreatitis after splenectomy in familial chylomicronemia syndrome.

BACKGROUND AND AIMS: Recurrent pancreatitis is a severe complication of familial chylomicronemia syndrome (FCS) mainly secondary to lipoprotein lipase deficiency. The mechanism and interindividual variability of pancreatitis in FCS are not fully understood, but abnormalities in the drainage system of pancreatic veins could be involved. METHODS AND RESULTS: Two cases of typical FCS are described with a past history of recurrent pancreatitis that dramatically improved after splenectomy performed in both cases for reasons non-related to FCS. CONCLUSIONS: These are the first reports of the disappearance of pancreatitis after splenectomy in FCS and they should be considered of anecdotal nature at this time. The disappearance of pancreatitis following splenectomy could be in part due to subsequent improvements in pancreatic drainage. Extrahepatic portal hypertension induced by hypertriglyceridemic splenomegaly leading to pancreatic congestion could also be a contributing factor.

Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia.

BACKGROUND: Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated. OBJECTIVE: We aimed to identify rare dysfunctional mutations in genes encoding regulators of lipoprotein lipase (LPL) function in patients with familial and non-familial primary HTG. METHODS: We sequenced promoters, exons, and exon-intron boundaries of LPL, APOA5, LMF1, and GPIHBP1 in 118 patients with severe primary HTG (triglycerides >500 mg/dL) and 53 normolipidemic controls. Variant functionality was analyzed using predictive software and functional assays for mutations in regulatory regions. RESULTS: We identified 29 rare variants, 10 of which had not been previously described: c.(-16A>G), c.(1018+2G>A), and p.(His80Arg) in LPL; p.(Arg143Alafs*57) in APOA5; p.(Val140Ile), p.(Leu235Ile), p.(Lys520*), and p.(Leu552Arg) in LMF1; and c.(-83G>A) and c.(-192A>G) in GPIHBP1. The c.(1018+2G>A) variant led to deletion of exon 6 in LPL cDNA, whereas the c.(-16A>G) analysis showed differences in the affinity for nuclear proteins. Overall, 20 (17.0%) of the patients carried at least one allele with a rare pathogenic variant in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant was not associated with lipid values, family history of HTG, clinical diagnosis, or previous pancreatitis. CONCLUSIONS: Less than one in five subjects with triglycerides >500 mg/dL and no major secondary cause for HTG may carry a rare pathogenic mutation in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant is not associated with a differential phenotype.

Cost-effectiveness analysis of apixaban compared to low-molecular-weight heparins and vitamin k antagonists for treatment and secondary prevention of venous thromboembolism / Coste-efectividad de apixaban versus heparinas y antagonistas de la vitamina k para el tratamiento y la prevención secundaria del tromboembolismo venoso

OBJECTIVE: Cost-effectiveness analysis of a 6-month treatment of apixaban (10 mg/12h, first 7 days; 5 mg/12h afterwards) for the treatment of the first event of venous thromboembolism (VTE) and prevention of recurrences, versus low-molecular-weight heparins/vitamin K antagonists treatment (LMWH/VKA). MATERIAL AND METHODS: A lifetime Markov model with 13 health states was used for describing the course of the disease. Efficacy and safety data were obtained from AMPLIFY and AMPLIFY-EXT clinical trials; health outcomes were measured as life years gained (LYG) and quality-adjusted life years (QALY). The chosen perspective of this analysis has been the Spanish National Health System (NHS). Drugs, management of VTE and complications costs were obtained from several Spanish data sources (€, 2014). A 3% discount rate was applied to health outcomes and costs. Univariate and probabilistic sensitivity analyses (SA) were performed in order to assess the robustness of the results. RESULTS: Apixaban was the most effective therapy with 7.182 LYG and 5.865 QALY, versus 7.160 LYG and 5.838 QALYs with LMWH/VKA. Furthermore, apixaban had a lower total cost (€13,374.70 vs €13,738.30). Probabilistic SA confirmed dominance of apixaban (led to better health outcomes with less associated costs) in 89% of the simulations. CONCLUSIONS: Apixaban 5 mg/12h versus LMWH/VKA was an efficient therapeutic strategy for the treatment and prevention of recurrences of VTE from the NHS perspective

OBJETIVO: Analizar la relación coste-efectividad de 6 meses de tratamiento con apixaban (10 mg/12 h, 7 primeros días; 5 mg/12 h después) para el primer evento de tromboembolismo venoso (TEV) y prevención de recurrencias, frente a heparinas de bajo peso molecular/antagonistas de vitamina K (HBPM/ AVK). MATERIAL Y MÉTODOS: Se ha empleado un modelo de Markov con 13 estados de salud que describen la evolución de la enfermedad a lo largo de la vida de los pacientes. Los datos de eficacia y seguridad se han obtenido de los ensayos clínicos AMPLIFY y AMPLIFY-EXT, calculándose los años de vida ganados (AVG) y los años de vida ajustados por calidad (AVAC) de las opciones terapéuticas evaluadas. En este análisis se adoptó la perspectiva del Sistema Nacional de Salud (SNS). El coste de la medicación, de las complicaciones y del manejo del TEV se obtuvo de distintas fuentes españolas (€, 2014). Se aplicó una tasa de descuento anual del 3% a costes y beneficios en salud. Se realizaron análisis de sensibilidad univariante y probabilístico (ASP) para evaluar la robustez de los resultados. RESULTADOS: Apixaban generó mejores resultados en salud con 7,182 AVG y 5,865 AVAC, frente a 7,160 AVG y 5,838 AVAC para HBPM/AVK, y con menor coste total (13.374,70 € versus 13.738,30 €). El ASP confirmó la dominancia de apixaban (produce mejores resultados con menores costes asociados) en el 89% de las simulaciones. CONCLUSIONES: Apixaban 5 mg/12 h versus HBPM/AVK fue una estrategia eficiente para el SNS en el tratamiento y prevención de recurrencias de TEV

Cost-effectiveness analysis of apixaban compared to low-molecularweight heparins and vitamin k antagonists for treatment and secondary prevention of venous thromboembolism.

OBJECTIVE: Cost-effectiveness analysis of a 6-month treatment of apixaban (10 mg/12h, first 7 days; 5 mg/12h afterwards) for the treatment of the first event of venous thromboembolism (VTE) and prevention of recurrences, versus low-molecular-weight heparins/vitamin K antagonists treatment (LMWH/VKA). MATERIAL AND METHODS: A lifetime Markov model with 13 health states was used for describing the course of the disease. Efficacy and safety data were obtained from AMPLIFY and AMPLIFY-EXT clinical trials; health outcomes were measured as life years gained (LYG) and quality-adjusted life years (QALY). The chosen perspective of this analysis has been the Spanish National Health System (NHS). Drugs, management of VTE and complications costs were obtained from several Spanish data sources (€, 2014). A 3% discount rate was applied to health outcomes and costs. Univariate and probabilistic sensitivity analyses (SA) were performed in order to assess the robustness of the results. RESULTS: Apixaban was the most effective therapy with 7.182 LYG and 5.865 QALY, versus 7.160 LYG and 5.838 QALYs with LMWH/VKA. Furthermore, apixaban had a lower total cost (€13,374.70 vs €13,738.30). Probabilistic SA confirmed dominance of apixaban (led to better health outcomes with less associated costs) in 89% of the simulations. CONCLUSIONS: Apixaban 5 mg/12h versus LMWH/VKA was an efficient therapeutic strategy for the treatment and prevention of recurrences of VTE from the NHS perspective.

Objetivo: Analizar la relación coste-efectividad de 6 meses de tratamiento con apixaban (10 mg/12 h, 7 primeros días; 5 mg/12 h después) para el primer evento de tromboembolismo venoso (TEV) y prevención de recurrencias, frente a heparinas de bajo peso molecular/antagonistas de vitamina K (HBPM/ AVK). Material y métodos: Se ha empleado un modelo de Markov con 13 estados de salud que describen la evolución de la enfermedad a lo largo de la vida de los pacientes. Los datos de eficacia y seguridad se han obtenido de los ensayos clínicos AMPLIFY y AMPLIFY- EXT, calculándose los años de vida ganados (AVG) y los años de vida ajustados por calidad (AVAC) de las opciones terapéuticas evaluadas. En este análisis se adoptó la perspectiva del Sistema Nacional de Salud (SNS). El coste de la medicación, de las complicaciones y del manejo del TEV se obtuvo de distintas fuentes españolas (€, 2014). Se aplicó una tasa de descuento anual del 3% a costes y beneficios en salud. Se realizaron análisis de sensibilidad univariante y probabilístico (ASP) para evaluar la robustez de los resultados. Resultados: Apixaban generó mejores resultados en salud con 7,182 AVG y 5,865 AVAC, frente a 7,160 AVG y 5,838 AVAC para HBPM/AVK, y con menor coste total (13.374,70 € versus 13.738,30 €). El ASP confirmó la dominancia de apixaban (produce mejores resultados con menores costes asociados) en el 89% de las simulaciones. Conclusiones: Apixaban 5 mg/12 h versus HBPM/AVK fue una estrategia eficiente para el SNS en el tratamiento y prevención de recurrencias de TEV.

Protective Effects of Cilastatin against Vancomycin-Induced Nephrotoxicity.

Vancomycin is a very effective antibiotic for treatment of severe infections. However, its use in clinical practice is limited by nephrotoxicity. Cilastatin is a dehydropeptidase I inhibitor that acts on the brush border membrane of the proximal tubule to prevent accumulation of imipenem and toxicity. The aim of this study was to investigate the potential protective effect of cilastatin on vancomycin-induced apoptosis and toxicity in cultured renal proximal tubular epithelial cells (RPTECs). Porcine RPTECs were cultured in the presence of vancomycin with and without cilastatin. Vancomycin induced dose-dependent apoptosis in cultured RPTECs, with DNA fragmentation, cell detachment, and a significant decrease in mitochondrial activity. Cilastatin prevented apoptotic events and diminished the antiproliferative effect and severe morphological changes induced by vancomycin. Cilastatin also improved the long-term recovery and survival of RPTECs exposed to vancomycin and partially attenuated vancomycin uptake by RPTECs. On the other hand, cilastatin had no effects on vancomycin-induced necrosis or the bactericidal effect of the antibiotic. This study indicates that cilastatin protects against vancomycin-induced proximal tubule apoptosis and increases cell viability, without compromising the antimicrobial effect of vancomycin. The beneficial effect could be attributed, at least in part, to decreased accumulation of vancomycin in RPTECs.

Usefulness of midregional proadrenomedullin to predict poor outcome in patients with community acquired pneumonia.

BACKGROUND: midregional proadrenomedullin (MR-proADM) is a prognostic biomarker in patients with community-acquired pneumonia (CAP). We sought to confirm whether MR-proADM added to Pneumonia Severity Index (PSI) improves the potential prognostic value of PSI alone, and tested to what extent this combination could be useful in predicting poor outcome of patients with CAP in an Emergency Department (ED). METHODS: Consecutive patients diagnosed with CAP were enrolled in this prospective, single-centre, observational study. We analyzed the ability of MR-proADM added to PSI to predict poor outcome using receiver operating characteristic (ROC) curves, logistic regression and risk reclassification and comparing it with the ability of PSI alone. The primary outcome was "poor outcome", defined as the incidence of an adverse event (ICU admission, hospital readmission, or mortality at 30 days after CAP diagnosis). RESULTS: 226 patients were included; 33 patients (14.6%) reached primary outcome. To predict primary outcome the highest area under curve (AUC) was found for PSI (0.74 [0.64-0.85]), which was not significantly higher than for MR-proADM (AUC 0.72 [0.63-0.81, p > 0.05]). The combination of PSI and MR-proADM failed to improve the predictive potential of PSI alone (AUC 0.75 [0.65-0.85, p=0.56]). Ten patients were appropriately reclassified when the combined PSI and MR-proADM model was used as compared with the model of PSI alone. Net reclassification improvement (NRI) index was statistically significant (7.69%, p = 0.03) with an improvement percentage of 3.03% (p = 0.32) for adverse event, and 4.66% (P = 0.02) for no adverse event. CONCLUSION: MR-proADM in combination with PSI may be helpful in individual risk stratification for short-term poor outcome of CAP patients, allowing a better reclassification of patients compared with PSI alone.

Incidence and prognosis of intra-abdominal hypertension in critically ill medical patients: a prospective epidemiological study.

INTRODUCTION: The aim of this study was to determine the incidence of intra-abdominal hypertension (IAH) in patients with two or more categorized risk factors (CRF) for IAH, and their morbidity and mortality during their intensive care unit (ICU) stay. METHODS: Prospective cohort study carried out at a medical ICU. A total of 151 medical patients were enrolled during a period of 3 months. After ICU whole staff training, we conducted daily screening of the four CRF for IAH based on the World Society of Abdominal Compartment Syndrome (WSACS) guidelines (namely, diminished abdominal wall compliance, increased intraluminal content, increased abdominal content, and capillary leak syndrome or fluid resuscitation). In those patients with risk factors of at least two different categories (≥2 CRF), intra-abdominal pressure (IAP) was measured every 8 h during ICU stay. Data included demographics, main diagnosis on admission, severity scores, cumulative fluid balance, daily mean IAP, resolution of IAH, days of ICU and hospital stay, and mortality. RESULTS: Eighty-seven patients (57.6%) had ≥2 CRF for IAH, 59 (67.8%) out of whom developed IAH. Patients with ≥2 CRF had a significantly higher mortality rate (41.4 vs. 14.3%, p < 0.001). Patients with IAH had higher body mass index, severity scores, organ dysfunctions/failures, number of CRF for IAH, days of ICU/hospital stay and hospital mortality rate (45.8 vs. 32.1%, p = 0.22). Non-resolution of IAH was associated with a higher mortality rate (64.7 vs. 35.3%, p = 0.001). None of the cohort patients developed abdominal compartment syndrome. The multivariate analysis showed that IAH development (odds ratio (OR) 4.09; 95% confidence interval (CI) 0.83-20.12) was a non-independent risk factor for mortality, and its non-resolution (OR 13.15; 95% CI 22.13-81.92) was an independent risk factor for mortality. CONCLUSIONS: Critically ill medical patients admitted to ICU with ≥2 CRF have high morbidity, mortality rate, and incidence of IAH, so IAP should be measured and monitored as recommended by the WSACS. Our study highlights the importance of implementing screening and assessment protocols for an early diagnosis of IAH.

Site of mitochondrial reactive oxygen species production in skeletal muscle of chronic obstructive pulmonary disease and its relationship with exercise oxidative stress.

Exercise triggers skeletal muscle oxidative stress in patients with chronic obstructive pulmonary disease (COPD). The objective of this research was to study the specific sites of reactive oxygen species (ROS) production in mitochondria isolated from skeletal muscle of patients with COPD and its relationship with local oxidative stress induced by exercise. Vastus lateralis biopsies were obtained in 16 patients with COPD (66 ± 10 yr; FEV(1), 54 ± 12% ref) and in 14 control subjects with normal lung function who required surgery because of lung cancer (65 ± 7 yr; FEV(1), 91 ± 14% ref) at rest and after exercise. In these biopsies we isolated mitochondria and mitochondrial membrane fragments and determined in vitro mitochondrial oxygen consumption (Mit$$\stackrel{.}{\hbox{ V }}$$o(2)) and ROS production before and after inhibition of complex I (rotenone), complex II (stigmatellin), and complex III (antimycin-A). We related the in vitro ROS production during state 3 respiration), which mostly corresponds to the mitochondria respiratory state during exercise, with skeletal muscle oxidative stress after exercise, as measured by thiobarbituric acid reactive substances.State 3 Mit$$\stackrel{.}{\hbox{ V }}$$o(2) was similar in patients with COPD and control subjects (191 ± 27 versus 229 ± 46 nmol/min/mg; P = 0.058), whereas H(2)O(2) production was higher in the former (147 ± 39 versus 51 ± 8 pmol/mg/h; P < 0.001). The addition of complexI, II, and III inhibitors identify complex III as the main site of H(2)O(2) release by mitochondria in patients with COPD and in control subjects. The mitochondrial production of H(2)O(2) in state 3 respiration was related (r = 0.69; P < 0.001) to postexercise muscle thiobarbituric acid reactive substance levels. Our results show that complex III is the main site of the enhanced mitochondrial H(2)O(2) production that occurs in skeletal muscle of patients with COPD, and the latter appears to contribute to muscle oxidative damage.

The effects of adiponectin and leptin on human endothelial cell proliferation: a live-cell study.

The effect of adiponectin and leptin on the proliferation of the human microvascular endothelial cell line (HMEC-1) was studied in the absence or presence of fetal bovine serum (FBS). The participation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt (PI-3K/Akt) pathways in this effect were evaluated. We studied the effect of both adipokines on the motility, mitosis, proliferation and cell death processes of HMEC-1 cells using live-cell imaging techniques. Adiponectin but not leptin further increased the proliferative effect induced by FBS on HMEC-1. This effect seems to be the consequence of an increase in the mitotic index in adiponectin-treated cells when compared to untreated ones. The presence of either the mitogen-activated protein kinase (MAPK) inhibitor (PD98059), or PI-3K inhibitor (LY294002), reduced the effect of adiponectin in a dose-dependent manner. Neither adipokine was able to affect HMEC-1 proliferation in FBS-free conditions. Duration of mitosis, cell motility and the cell death process were similar in all conditions. These data suggest that adiponectin and leptin exert different effects on endothelial cell function. Adiponectin was able to potentiate proliferation of HMEC-1. This effect involves the activation of both PI3-K/Akt and ERK/MAPK pathways. However, it seems to exert minimal effects on HMEC-1 function in the case of leptin.

Mutaciones en los genes HFE y TFR2 en un paciente español con hemocromatosis / Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis

La enfermedad por sobrecarga de hierro está originada por diversas anomalías genéticas. El estudio genético de esta enfermedad confirma su carácter hereditario y nos permite ofrecer consejo genético a los familiares en primer grado. Hemos realizado resonancia magnética y biopsia de hígado en un paciente asintomático con más de 1.000 mg/l de ferritina en suero, y hemos analizado los genes implicados en el metabolismo del hierro. El fenotipo de sobrecarga de hierro se confirmó por la presencia de un patrón de depósito de hierro en el hígado con predominio periportal que sugiere la existencia de una enfermedad genética. En el caso que presentamos, el estudio genético reveló que el paciente es doble heterocigoto para las mutaciones c.187C>G (p.H63D) y c.840C>G (p.F280L) en los genes HFE y receptor 2 de transferrina (TFR2), respectivamente(AU)

Iron overload disease has a wide variety of genotypes. The genetic study of this disease confirms its hereditary nature and enables us to provide genetic counseling for first-degree relatives. We performed magnetic resonance imaging and liver biopsy in an asymptomatic patient with more than 1,000 mg/L of serum ferritin and studied the genes involved in this condition. The phenotype of iron overload is confirmed by a predominantly periportal pattern of iron deposits in the liver suggestive of genetic disease. In the case we present the molecular study revealed a double heterozygosity for the mutations c.187C>G (p.H63D) and c.840C>G (p.F280L) in the HFE and transferrin receptor 2 (TFR2) genes, respectively(AU)

Características clínicas de los pacientes con hipertrigliceridemia remitidos a las Unidades de Lípidos: registro de hipertrigliceridemias de la Sociedad Española de Arteriosclerosis / Clinical features of patients with hypertriglyceridemia referred to lipid units: registry of hypertrigliceridemia of the Spanish Arteriosclerosis Society

Fundamento y objetivoDescribir las características clínicas de sujetos con hipertrigliceridemia remitidos a Unidades de Lípidos asociadas a la Sociedad Española de Arteriosclerosis (ULSEA).Pacientes y métodoSe trata de un estudio multicéntrico, prospectivo y observacional, de pacientes con valores de triglicéridos séricos > 200mg/dl, reclutados desde enero 2007 a diciembre de 2008. Se recogieron variables demográficas, antecedentes, consumo de medicamentos, antropometría, diagnóstico y variables analíticas de la visita de inclusión.Resultados: Se incluyeron 1.033 varones y 361 mujeres con edad media (DE) de 50 (12) años. La enfermedad vascular previa, el tabaquismo, el consumo de alcohol y la esteatosis hepática fueron mayores en los varones que en las mujeres; en ellas fueron más prevalentes la hipertensión, la diabetes y la obesidad abdominal. La actividad física habitual y la dieta cardiosaludable fue seguida escasamente en ambos sexos. La mayor parte de los pacientes tenían una hipertrigliceridemia primaria (54%), especialmente una hiperlipemia familiar combinada o una hipertrigliceridemia familiar. La obesidad, el alcohol y la diabetes fueron las causas más comunes de hipertrigliceridemia secundaria. Un 27% de los pacientes se trataban con dieta, un 44% con fármacos en monoterapia y el resto (24%) con diversas combinaciones. Conclusiones: Aunque predominan las causas primarias, se constata una elevada frecuencia de etiologías secundarias y de trastornos que agravan la hipertrigliceridemia, predominando el tabaquismo y el consumo de alcohol en los varones y la obesidad abdominal y la diabetes en las mujeres. Aunque muchos pacientes reciben terapia farmacológica, se evidencia un amplio margen para mejorar la dieta y reducir el sedentarismo (AU)

Background and objective: to show clinical features of subjects with hypertriglyceridemia (HTG) referred to the Lipid Units associated to Spanish Arteriosclerosis Society (ULSEA).Patients and method: it is a prospective, cross-sectional, multicentric study of patients with serum Tgs > 200mg/dL, recruited from January 2007 to December 2008. Demographic, drug therapies, anthropometrical, main diagnosis and biochemical parameters were registered. Results: We included 1,033 men and 361 women, 50±12 years-old. Vascular disease, smoking, alcohol intake and liver steatosis were more prevalent in men than in women; by contrast, hypertension, diabetes and abdominal obesity were they in women. Regular physical exercise and a healthy diet were kept sparsely. Most patients suffered from a primary HTG (54%), mainly familial combined hyperlipidemia or familial hypertriglyceridemia. Obesity, alcohol intake and diabetes were the most common secondary forms of HTG. Among patients, 27% were diet-only treated, 44% received drugs in monotherapy and 24% drugs in combinations. Conclusions: Although primary forms of HTG are common, we show here a high prevalence of secondary forms and conditions worsening the HTG, being smoking and alcohol intake in men and abdominal obesity and diabetes in women. Even though most patients are drug-treated, diet and regular exercise recommendations should be clearly improved (AU)

[Clinical features of patients with hypertriglyceridemia referred to lipid units: registry of hypertrigliceridemia of the Spanish Arteriosclerosis Society]. / Características clínicas de los pacientes con hipertrigliceridemia remitidos a las Unidades de Lípidos: registro de hipertrigliceridemias de la Sociedad Española de Arteriosclerosis.

BACKGROUND AND OBJECTIVE: to show clinical features of subjects with hypertriglyceridemia (HTG) referred to the Lipid Units associated to Spanish Arteriosclerosis Society (ULSEA). PATIENTS AND METHOD: it is a prospective, cross-sectional, multicentric study of patients with serum Tgs > 200mg/dL, recruited from January 2007 to December 2008. Demographic, drug therapies, anthropometrical, main diagnosis and biochemical parameters were registered. RESULTS: We included 1,033 men and 361 women, 50±12 years-old. Vascular disease, smoking, alcohol intake and liver steatosis were more prevalent in men than in women; by contrast, hypertension, diabetes and abdominal obesity were they in women. Regular physical exercise and a healthy diet were kept sparsely. Most patients suffered from a primary HTG (54%), mainly familial combined hyperlipidemia or familial hypertriglyceridemia. Obesity, alcohol intake and diabetes were the most common secondary forms of HTG. Among patients, 27% were diet-only treated, 44% received drugs in monotherapy and 24% drugs in combinations. CONCLUSIONS: Although primary forms of HTG are common, we show here a high prevalence of secondary forms and conditions worsening the HTG, being smoking and alcohol intake in men and abdominal obesity and diabetes in women. Even though most patients are drug-treated, diet and regular exercise recommendations should be clearly improved.

Insulin receptor substrate-1 expression is increased in circulating leukocytes of patients with acute coronary syndrome.

The mechanisms underlying the increased risk of cardiovascular disease associated with diabetes mellitus (DM) are not fully defined. Insulin resistance in human metabolic syndrome patients is associated with decreased expression of the insulin receptor substrate-2- (Irs2-) AKT2 axis in mononuclear leukocytes (MLs). Moreover, acute coronary syndrome (ACS) has been linked through genome-wide association studies to the 2q36-q37.3 locus, which contains the Irs1 gene. Here, we investigated the expression of insulin-signaling pathway genes in MLs from patients with DM, ACS, and ACS plus DM. Quantitative real-time PCR expression studies showed no differences in the mRNA levels of Irs2, Akt2, and Akt1 among all patients. However, Irs1 mRNA expression was significantly increased in patients with ACS-diabetics and nondiabetics-compared with diabetic patients without ACS (P < .02 and P < .005, resp.). The present study reveals for the first time an association between increased Irs1 mRNA levels in MLs of patients with ACS which is not related to DM.