RECERCAT - Medicina

Predictors of death among patients who completed tuberculosis treatment: a population-based cohort study.

Predictors of death among patients who completed tuberculosis treatment: a population-based cohort study. Millet, J.P.; Orcau, A.; Rius, C.; Casals, M.; Garcia de Olalla, P.; Moreno, A.; Nelson, J.L.; Caylà, J.A.; Miró Meda, José M.; Barcelona Tuberculosis Working Group. Background: Mortality among patients who complete tuberculosis (TB) treatment is still high among vulnerable populations. The objective of the study was to identify the probability of death and its predictive factors in a cohort of successfully treated TB patients. Methods: A population-based retrospective longitudinal study was performed in Barcelona, Spain. All patients who successfully completed TB treatment with culture-confirmation and available drug susceptibility testing between 1995
1997 were retrospectively followed-up until December 31, 2005 by the Barcelona TB Control Program. Socio-demographic, clinical, microbiological and treatment variables were examined. Mortality, TB Program and AIDS registries were reviewed. Kaplan-Meier and a Cox regression methods with time-dependent covariates were used for the survival analysis, calculating the hazard ratio (HR) with 95% confidence intervals (CI). Results: Among the 762 included patients, the median age was 36 years, 520 (68.2%) were male, 178 (23.4%) HIV-infected, and 208 (27.3%) were alcohol abusers. Of the 134 (17.6%) injecting drug users (IDU), 123 (91.8%) were HIV-infected. A total of 30 (3.9%) recurrences and 173 deaths (22.7%) occurred (mortality rate: 3.4/100 person-years of follow-up). The predictors of death were: age between 41
60 years old (HR: 3.5; CI:2.1
5.7), age greater than 60 years (HR: 14.6; CI:8.9
24), alcohol abuse (HR: 1.7; CI:1.2
2.4) and HIV-infected IDU (HR: 7.9; CI:4.7
13.3). Conclusions: The mortality rate among TB patients who completed treatment is associated with vulnerable populations such as the elderly, alcohol abusers, and HIV-infected IDU. We therefore need to fight against poverty, and promote and develop interventions and social policies directed towards these populations to improve their survival.

Survival outcomes and effect of early vs. deferred cART among HIV-infected patients diagnosed at the time of an AIDS-defining event: a cohort analysis.

Survival outcomes and effect of early vs. deferred cART among HIV-infected patients diagnosed at the time of an AIDS-defining event: a cohort analysis. Miro, J.M.; Manzardo, C.; Mussini, C.; Johnson, M.; d'Arminio Monforte, A.; Antinori, A.; Gill, M.J.; Sighinolfi, L.; Uberti-Foppa, C.; Borghi, V.; Sabin, C.; Late Presenters Investigators. Objectives: We analyzed clinical progression among persons diagnosed with HIV at the time of an AIDS-defining event, and assessed the impact on outcome of timing of combined antiretroviral treatment (cART). Methods: Retrospective, European and Canadian multicohort study.. Patients were diagnosed with HIV from 1997
2004 and had clinical AIDS from 30 days before to 14 days after diagnosis. Clinical progression (new AIDS event, death) was described using Kaplan-Meier analysis stratifying by type of AIDS event. Factors associated with progression were identified with multivariable Cox regression. Progression rates were compared between those starting early (< 30 days after AIDS event) or deferred (30
270 days after AIDS event) cART. Results: The median (interquartile range) CD4 count and viral load (VL) at diagnosis of the 584 patients were 42 (16, 119) cells/ mL and 5.2 (4.5, 5.7) log 10 copies/mL. Clinical progression was observed in 165 (28.3%) patients. Older age, a higher VL at diagnosis, and a diagnosis of non-Hodgkin lymphoma (NHL) (vs. other AIDS events) were independently associated with disease progression. Of 366 patients with an opportunistic infection, 178 (48.6%) received early cART. There was no significant difference in clinical progression between those initiating cART early and those deferring treatment (adjusted hazard ratio 1.32 [95% confidence interval 0.87, 2.00], p=0.20). Conclusions: Older patients and patients with high VL or NHL at diagnosis had a worse outcome. Our data suggest that earlier initiation of cART may be beneficial among HIV-infected patients diagnosed with clinical AIDS in our setting.

Influence of M. tuberculosis lineage variability within a clinical trial for pulmonary tuberculosis.

Influence of M. tuberculosis lineage variability within a clinical trial for pulmonary tuberculosis. Nahid, P.; Bliven, E.E.; Kim, E.Y.; Mac Kenzie, W.R.; Stout, J.E.; Diem, L.; Johnson, J.L.; Gagneux, S.; Hopewell, P.C.; Kato-Maeda, M. Recent studies suggest that M. tuberculosis lineage and host genetics interact to impact how active tuberculosis presents clinically. We determined the phylogenetic lineages of M. tuberculosis isolates from participants enrolled in the Tuberculosis Trials Consortium Study 28, conducted in Brazil, Canada, South Africa, Spain, Uganda and the United States, and secondarily explored the relationship between lineage, clinical presentation and response to treatment. Large sequence polymorphisms and single nucleotide polymorphisms were analyzed to determine lineage and sublineage of isolates. Of 306 isolates genotyped, 246 (80.4%) belonged to the Euro-American lineage, with sublineage 724 predominating at African sites (99/192, 51.5%), and the Euro-American strains other than 724 predominating at non-African sites (89/114, 78.1%). Uneven distribution of lineages across regions limited our ability to discern significant associations, nonetheless, in univariate analyses, Euro-American sublineage 724 was associated with more severe disease at baseline, and along with the East Asian lineage was associated with lower bacteriologic conversion after 8 weeks of treatment. Disease presentation and response to drug treatment varied by lineage, but these associations were no longer statistically significant after adjustment for other variables associated with week-8 culture status.

Modelling the evolution and spread of HIV immune escape mutants.

Modelling the evolution and spread of HIV immune escape mutants. Fryer, H.R.; Frater, J.; Duda, A.; Roberts, M.G.; SPARTAC Trial Investigators; Phillips, R.E.; McLean, A.R.; Miró Meda, José M. During infection with human immunodeficiency virus (HIV), immune pressure from cytotoxic T-lymphocytes (CTLs) selects for viral mutants that confer escape from CTL recognition. These escape variants can be transmitted between individuals where, depending upon their cost to viral fitness and the CTL responses made by the recipient, they may revert. The rates of within-host evolution and their concordant impact upon the rate of spread of escape mutants at the population level are uncertain. Here we present a mathematical model of within-host evolution of escape mutants, transmission of these variants between hosts and subsequent reversion in new hosts. The model is an extension of the well-known SI model of disease transmission and includes three further parameters that describe host immunogenetic heterogeneity and rates of within host viral evolution. We use the model to explain why some escape mutants appear to have stable prevalence whilst others are spreading through the population. Further, we use it to compare diverse datasets on CTL escape, highlighting where different sources agree or disagree on within-host evolutionary rates. The several dozen CTL epitopes we survey from HIV-1 gag, RT and nef reveal a relatively sedate rate of evolution with average rates of escape measured in years and reversion in decades. For many epitopes in HIV, occasional rapid within-host evolution is not reflected in fast evolution at the population level.

Common genetic variation and the control of HIV-1 in humans

Common genetic variation and the control of HIV-1 in humans Fellay, J.; Ge, D.; Shianna, K.V.; Colombo, S.; Ledergerber, B.; Cirulli, E.T.; Urban, T.J.; Zhang, K.; Gumbs, C.E.; Smith, J.P.; Castagna, A.; Cozzi-Lepri, A.; De Luca, A.; Easterbrook, P.; Günthard, H.F.; Mallal, S.; Mussini, C.; Dalmau, J.; Martinez-Picado, J.; Miró Meda, José M. To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

A risk score to predict type 2 diabetes mellitus in an elderly spanish mediterranean population at high cardiovascular risk.

A risk score to predict type 2 diabetes mellitus in an elderly spanish mediterranean population at high cardiovascular risk. Guasch Ferré, M.; Bulló, M.; Costa, B.; Martínez Gonzalez, M.A.; Ibarrola Jurado, N.; Estruch Riba, Ramon; Barrio, F.; SalasSalvadó, J. Introduction: To develop and test a diabetes risk score to predict incident diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk. Materials and Methods: A diabetes risk score was derived from a subset of 1381 nondiabetic individuals from three centres of the PREDIMED study (derivation sample). Multivariate Cox regression model ß-coefficients were used to weigh each risk factor. PREDIMED-personal Score included body-mass-index, smoking status, family history of type 2 diabetes, alcohol consumption and hypertension as categorical variables; PREDIMED-clinical Score included also high blood glucose. We tested the predictive capability of these scores in the DE-PLAN-CAT cohort (validation sample). The discrimination of Finnish Diabetes Risk Score (FINDRISC), German Diabetes Risk Score (GDRS) and our scores was assessed with the area under curve (AUC). Results: The PREDIMED-clinical Score varied from 0 to 14 points. In the subset of the PREDIMED study, 155 individuals developed diabetes during the 4.75-years follow-up. The PREDIMED-clinical score at a cutoff of $6 had sensitivity of 72.2%, and specificity of 72.5%, whereas AUC was 0.78. The AUC of the PREDIMED-clinical Score was 0.66 in the validation sample (sensitivity = 85.4%; specificity = 26.6%), and was significantly higher than the FINDRISC and the GDRS in both the derivation and validation samples. Discussion: We identified classical risk factors for diabetes and developed the PREDIMED-clinical Score to determine those individuals at high risk of developing diabetes in elderly individuals at high cardiovascular risk. The predictive capability of the PREDIMED-clinical Score was significantly higher than the FINDRISC and GDRS, and also used fewer items in the questionnaire.

A new multidisciplinary home care telemedicine system to monitor stable chronic human immunodeficiency virus-infected patients: a randomized study.

A new multidisciplinary home care telemedicine system to monitor stable chronic human immunodeficiency virus-infected patients: a randomized study. León, A.; Cáceres, C.; Fernández, E.; Chausa, P.; Martin, M.; Codina, C.; Rousaud, A.; Blanch, J.; Mallolas Masferrer, Josep; Martínez Chamorro, Esteban José; Blanco, J.L.; Laguno, M.; Larrousse, M.; Milinkovic, A.; Zamora, L.; Canal, N.; Miró Meda, José M.; Gatell, José M.; Gómez, E.J.; García, F. Background: Antiretroviral therapy has changed the natural history of human immunodeficiency virus (HIV) infection in developed countries, where it has become a chronic disease. This clinical scenario requires a new approach to simplify follow-up appointments and facilitate access to healthcare professionals. Methodology: We developed a new internet-based home care model covering the entire management of chronic HIV-infected patients. This was called Virtual Hospital. We report the results of a prospective randomised study performed over two years, comparing standard care received by HIV-infected patients with Virtual Hospital care. HIV-infected patients with access to a computer and broadband were randomised to be monitored either through Virtual Hospital (Arm I) or through standard care at the day hospital (Arm II). After one year of follow up, patients switched their care to the other arm. Virtual Hospital offered four main services: Virtual Consultations, Telepharmacy, Virtual Library and Virtual Community. A technical and clinical evaluation of Virtual Hospital was carried out. Findings: Of the 83 randomised patients, 42 were monitored during the first year through Virtual Hospital (Arm I) and 41 through standard care (Arm II). Baseline characteristics of patients were similar in the two arms. The level of technical satisfaction with the virtual system was high: 85% of patients considered that Virtual Hospital improved their access to clinical data and they felt comfortable with the videoconference system. Neither clinical parameters [level of CD4 + T lymphocytes, proportion of patients with an undetectable level of viral load (p = 0.21) and compliance levels 90% (p = 0.58)] nor the evaluation of quality of life or psychological questionnaires changed significantly between the two types of care. Conclusions: Virtual Hospital is a feasible and safe tool for the multidisciplinary home care of chronic HIV patients. Telemedicine should be considered as an appropriate support service for the management of chronic HIV infection.

Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk

Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk Valls-Pedret, Cinta; Lamuela Raventós, Rosa Ma.; Medina Remón, Alexander; Quintana, Melibea; Corella Piquer, Dolores; Pintó, Xavier; Martínez-González, Miguel Ángel, 1957-; Estruch Riba, Ramon; Ros Rahola, Emilio Brain oxidative processes play a major role in age-related cognitive decline, thus consumption of antioxidant-rich foods might help preserve cognition. Our aim was to assess whether consumption of antioxidant-rich foods in the Mediterranean diet relates to cognitive function in the elderly. In asymptomatic subjects at high cardiovascular risk (n = 447; 52% women; age 55
80 y) enrolled in the PREDIMED study, a primary prevention dietary-intervention trial, we assessed food intake and cardiovascular risk profile, determined apolipoprotein E genotype, and used neuropsychological tests to evaluate cognitive function.We also measured urinary polyphenols as an objective biomarker of intake. Associations between energy-adjusted food consumption, urinary polyphenols, and cognitive scores were assessed by multiple linear regression models adjusted for potential confounders. Consumption of some foods was independently related to better cognitive function. The specific associations [regression coefficients (95% confidence intervals)] were: total olive oil with immediate verbal memory [0.755 (0.151
1.358)]; virgin olive oil and coffee with delayed verbal memory [0.163 (0.010
0.316) and 0.294 (0.055
0.534), respectively];walnuts with working memory [1.191 (0.061
2.322)]; and wine with Mini-Mental State Examination scores [0.252 (0.006
0.496)]. Urinary polyphenols were associated with better scores in immediate verbal memory [1.208 (0.236
2.180)]. Increased consumption of antioxidant-rich foods in general and of polyphenols in particular is associated with better cognitive performance in elderly subjects at high cardiovascular risk. The results reinforce the notion that Mediterranean diet components might counteract age-related cognitive decline.

Inflammatory and coagulation biomarkers and mortality in patients with HIV infection.

Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. Kuller, L.H.; Tracy, R.; Belloso, W.; De Wit, S.; Drummond, F.; Lane, H.C.; Ledergerber, B.; Lundgren, J.; Neauhaus, J.; Nixon, D.; Paton, N.I.; Neaton, J.D.; Gatell, José M. Background In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]). We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis. Methods and Findings Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1þ2. Two studies were conducted: (1) a nested case
control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n¼170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0
4.1; p¼0.05), 8.3 (95% CI, 3.3
20.8; p , 0.0001), and 12.4 (95% CI, 4.2
37.0; p , 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p , 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p , 0.0001). In an expanded case
control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1
3.1; p¼0.02) to 1.5 (95% CI, 0.8
2.8) and 1.4 (95% CI, 0.8
2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively. Conclusions IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.

Identification of the bHLH factor Math6 as a novel component of the embryonic pancreas transcriptional network.

Identification of the bHLH factor Math6 as a novel component of the embryonic pancreas transcriptional network. Lynn, F.C.; Sanchez, L.; Gomis, Ramon, 1946; German, M.S.; Gasa, R. Background: Basic helix-loop-helix (bHLH) transcription factors play important roles in differentiation processes during embryonic development of vertebrates. In the pancreas, the atonal -related bHLH gene Neurogenin3 (Neurog3) controls endocrine cell fate specification in uncommitted progenitor cells. Therefore, it is likely that Neurog3-regulated factors will have important functions during pancreatic endocrine cell differentiation. The gene for the atonal -related bHLH factor Math6 was recognized as a potential target of Neurog3 in a genomic scale profiling during endocrine differentiation. Herein we have explored the role of Math6 during endocrine pancreas development. Results: We demonstrate that the Math6 gene is a direct target of Neurog3 in vitro and that, during mouse development, Math6 is expressed in both endocrine and exocrine pancreatic precursor cells. We have investigated the role of Math6 in endocrine differentiation by over-expressing this factor in pancreatic duct cells. Math6 possesses intrinsic transcriptional repressor activity and, in contrast to Neurog3 it does not induce the endocrine differentiation program; however, it can modulate some of the pro-endocrine functions of Neurog3 in this system. In addition, we show that Math6 is broadly expressed in mouse embryonic tissues and its expression is induced by tissue-specific bHLH genes other than Neurog3. Furthermore, inactivation of the Math6 gene in the mouse results in early embryonic lethality demonstrating an essential role of this factor in organismal development. Conclusions: These data demonstrate that Math6 is a novel component of the pancreatic transcriptional network during embryonic development and suggest a potential role for Math6 as a modulator of the differentiation program initiated by the pro-endocrine factor Neurog3. Furthermore, our results demonstrate that Math6 is indispensable for early embryonic development and indicate a more widespread function for this factor in tissue-specific differentiation processes that are dependent on class II bHLH genes.

Statistical Reviewers Improve Reporting in Biomedical Articles: a Randomized Trial.

Statistical Reviewers Improve Reporting in Biomedical Articles: a Randomized Trial. Cobo, E.; Selva O'Callaghan, A.; Ribera, J. M.; Cardellach, Francesc; Dominguez, R.; Vilardell, M. Background. Although peer review is widely considered to be the most credible way of selecting manuscripts and improving the quality of accepted papers in scientific journals, there is little evidence to support its use. Our aim was to estimate the effects on manuscript quality of either adding a statistical peer reviewer or suggesting the use of checklists such as CONSORT or STARD to clinical reviewers or both. Methodology and Principal Findings. Interventions were defined as 1) the addition of a statistical reviewer to the clinical peer review process, and 2) suggesting reporting guidelines to reviewers; with"no statistical expert" and"no checklist" as controls. The two interventions were crossed in a 262 balanced factorial design including original research articles consecutively selected, between May 2004 and March 2005, by the Medicina Clinica (Barc) editorial committee. We randomized manuscripts to minimize differences in terms of baseline quality and type of study (intervention, longitudinal, cross-sectional, others). Sample-size calculations indicated that 100 papers provide an 80% power to test a 55% standardized difference. We specified the main outcome as the increment in quality of papers as measured on the Goodman Scale. Two blinded evaluators rated the quality of manuscripts at initial submission and final post peer review version. Of the 327 manuscripts submitted to the journal, 131 were accepted for further review, and 129 were randomized. Of those, 14 that were lost to follow-up showed no differences in initial quality to the followed-up papers. Hence, 115 were included in the main analysis, with 16 rejected for publication after peer review. 21 (18.3%) of the 115 included papers were interventions, 46 (40.0%) were longitudinal designs, 28 (24.3%) cross-sectional and 20 (17.4%) others. The 16 (13.9%) rejected papers had a significantly lower initial score on the overall Goodman scale than accepted papers (difference 15.0, 95% CI: 4.6
24.4). The effect of suggesting a guideline to the reviewers had no effect on change in overall quality as measured by the Goodman scale (0.9, 95% CI: 20.3
+2.1). The estimated effect of adding a statistical reviewer was 5.5 (95% CI: 4.3
6.7), showing a significant improvement in quality. Conclusions and Significance. This prospective randomized study shows the positive effect of adding a statistical reviewer to the field-expert peers in improving manuscript quality. We did not find a statistically significant positive effect by suggesting reviewers use reporting guidelines.

Sinusoidal Endothelial Dysfunction Precedes Inflammation and Fibrosis in a Model of NAFLD

Sinusoidal Endothelial Dysfunction Precedes Inflammation and Fibrosis in a Model of NAFLD Pasarín, M.; La Mura, V.; Gracia Sancho, J.; García Calderó, H.; Rodríguez Vilarrupla, A.; García Pagán, Juan Carlos; Bosch i Genover, Jaume; González-Abraldes Iglesias, Juan Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associated with the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenic factor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. The aims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolic syndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet (CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolic syndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosis without inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liver perfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependent vasodilation. This was associated with a decreased Akt-dependent eNOS phosphorylation and NOS activity. In summary, we demonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunction occurs before the development of fibrosis or inflammation.

Role of Myotonic Dystrophy Protein Kinase [DMPK] in Glucose Homeostasis and Muscle Insulin Action

Role of Myotonic Dystrophy Protein Kinase [DMPK] in Glucose Homeostasis and Muscle Insulin Action Llagostera Martín, Esther; Catalucci, D.; Marti, L.; Liesa Torre-Marín, Montserrat; Camps Camprubí, Marta; Ciaraldi, T.; Kondo, R.; Reddy, S.; Dillmann, W.; Palacín Prieto, Manuel; Zorzano Olarte, Antonio; Rúiz Lozano, P.; Gomis, Ramon, 1946-; Kaliman, P. Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3′-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk−/−) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk−/− mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk−/− mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes.

Increased alpha-defensins 1-3 production by dendritic cells in HIV-infected individuals is associated with slower disease progression.

Increased alpha-defensins 1-3 production by dendritic cells in HIV-infected individuals is associated with slower disease progression. Rodríguez García, M.; Climent, N.; Oliva, H.; Casanova, V.; Franco Fernández, Rafael; Leon, A.; Gatell, José M.; García, F.; Gallart, T. Defensins are natural endogenous antimicrobial peptides with potent anti-HIV activity and immuno-modulatory effects. We recently demonstrated that immature dendritic cells (DC) produce α-defensins1-3 and that α-defensins1-3 modulate DC generation and maturation. Since DC-HIV interaction plays a critical role during the first steps of HIV infection, we investigated the possible impact of α-defensins1-3 production by DC on disease progression.

Reversible mitochondrial respiratory chain impairment during symptomatic hyperlactatemia associated with antiretroviral therapy

Reversible mitochondrial respiratory chain impairment during symptomatic hyperlactatemia associated with antiretroviral therapy Miró, Òscar; López, Sònia; Martínez, Esteban; Rodríguez Santiago, Benjamín; Blanco, José L.; Milinkovic, Ana; Miró Meda, José M.; Nunes Martínez, Virginia; Casademont, Jordi; Gatell, José M.; Cardellach, Francesc Direct evidence confirming the hypothesis that a dysfunction of the mitochondrial respiratory chain (MRC) underlies the pathogenesis of hyperlactatemia associated with highly active antiretroviral therapy (HAART) is scarce. We studied mitochondrial DNA (mtDNA) content and MRC function in the skeletal muscle of an HIV-infected patient during an episode of symptomatic hyperlactatemia. Skeletal muscle biopsy was performed during the episode when the patient was symptomatic and 3 months later when the patient was clinically recovered. Assessment of mitochondria was performed using histological, polarographic, spectrophotometrical, and Southern blot and real time PCR DNA quantification methods. The histological study disclosed extensive mitochondrial impairment in the form of ragged-red fibers or equivalents on oxidative reactions. These findings were associated with an increase in mitochondrial content and a decrease in both mitochondrial respiratory capacity and MRC enzyme activities. Mitochondrial DNA content declined to 53% of control values. Mitochondrial abnormalities had almost disappeared later when the patient became asymptomatic. Our findings support the hypothesis that MRC dysfunction stands at the basis of HAART-related hyperlactatemia.

Respiratory chain dysfunction associated with multiple mitochondrial DNA deletions in antiretroviral therapy-related lipodystrophy.

Respiratory chain dysfunction associated with multiple mitochondrial DNA deletions in antiretroviral therapy-related lipodystrophy. Miró, Òscar; Gómez, Montserrat; Pedrol, Enric; Cardellach, Francesc; Nunes Martínez, Virginia; Casademont i Pou, Jordi Highly-active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome characterized by peripheral fat wasting and central adiposity, usually associated with hyperlipidaemia and insulin resistance [1,2]. Indirect data have led some authors to propose that mitochondrial dysfunction could play a role in this syndrome [3,4].To date, as recently outlined by Kakuda et al. [5] in this journal, HIV-infected patients developing lipodystrophy have not been studied for mitochondrial changes or respiratory chain capacity...

A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci

A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci Pillai, S. G.; Ge, D.; Zhu, G.; Kong, X.; Shianna, K. V.; Need, A. C.; Feng, S.; Hersh, C. P.; Bakke, P.; Gulsvick, A.; Ruppert, A.; Lødrup, K. C.; Roses, A.; Anderson, W.; Agustí García-Navarro, Àlvar; Rennard, S. I.; Lomas, D. A.; Silverman, E. K.; Goldstein, D. B. There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of alpha(1)-antitrypsin, which is present in 1-2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the alpha-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48 x 10(-10), (rs8034191) and 5.74 x 10(-10) (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.

Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial.

Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial. Alonso-Fernández, A.; García Río, F.; Arias, M. A.; Hernanz, Á.; Peña, M. de la; Piérola, J.; Barceló, A.; López Collazo, E.; Agustí García-Navarro, Àlvar Background: Previous studies have presented contradictory data concerning obstructive sleep apnoea syndrome (OSAS), lipid oxidation and nitric oxide (NO) bioavailability. This study was undertaken to (1) compare the concentration of 8-isoprostane and total nitrate and nitrite (NOx) in plasma of middle-aged men with OSAS and no other known co-morbidity and healthy controls of the same age, gender and body mass index; and (2) test the hypothesis that nasal continuous positive airway pressure (CPAP) therapy attenuates oxidative stress and nitrate deficiency. Methods: A prospective, randomised, placebo controlled, double-blind, crossover study was performed in 31 consecutive middle-aged men with newly diagnosed OSAS and 15 healthy control subjects. Patients with OSAS were randomised to receive sham CPAP or effective CPAP for 12 weeks. Blood pressure, urinary catecholamine levels and plasma 8-isoprostane and NOx concentrations were obtained before and after both treatment modalities. Results: Patients with OSAS had significantly higher 8-isoprostane levels (median (IQR) 42.5 (29.2
78.2) vs 20.0 (12.5
52.5) pg/ml, p = 0.041, Mann-Whitney test) and lower NOx levels (264 (165
650) vs 590 (251
1465) mmol/l, p = 0.022) than healthy subjects. Body mass index, blood pressure and urinary catecholamines were unchanged by CPAP therapy, but 8-isoprostane concentrations decreased (38.5 (24.2
58.7) pg/ml at baseline vs 22.5 (16.2
35.3) pg/ml on CPAP, p = 0.0001) and NOx levels increased (280 (177
707) vs 1373 (981
1517) mmol/l, p = 0.0001) after CPAP. Conclusions: OSAS is associated with an increase in oxidative stress and a decrease in NOx that is normalised

Cardiovascular mechanisms of death in severe COPD exacerbation: time to think and act beyond guidelines.

Cardiovascular mechanisms of death in severe COPD exacerbation: time to think and act beyond guidelines. Fabbri, Leonardo M.; Beghé, Bianca; Agustí García-Navarro, Àlvar Three important studies on acute exacerbations of chronic obstructive pulmonary disease (ECOPD)have been published in Thorax. Two of them, by Chang et al1(see page 764) and Hoiset et al2 (see page 775), show the importance of the cardiac biomarkers troponin T and NT-BNP (Nterminal pro-B-type natriuretic peptide) as strong predictors of the increased risk of death of patients hospitalised because of ECOPD.1 2.....

Effects of exercise on mitochondrial DNA content in skeletal muscle of patients with COPD

Effects of exercise on mitochondrial DNA content in skeletal muscle of patients with COPD Puente Maestu, L.; Lazaro, A.; Tejedor, A.; Camano S.; Fuentes M.; Cuervo, M.; Olaiz Navarro, B.; Agustí García-Navarro, Àlvar Background Exhausting exercise reduces the mitochondrial DNA (mtDNA) content in the skeletal muscle of healthy subjects due to oxidative damage. Since patients with chronic obstructive pulmonary disease (COPD) suffer enhanced oxidative stress during exercise, it was hypothesised that the mtDNA content will be further reduced. Objective To investigate the effects of exercise above and below the lactate threshold (LT) on the mtDNA content of skeletal muscle of patients with COPD. Methods Eleven patients with COPD (676 8 years; forced expiratory volume in 1s (FEV1)456 8%ref) and 10 healthy controls (666 4 years; FEV1 906 7% ref) cycled 45 min above LT (65% peak oxygen uptake (V9O2 peak)and another 7 patients (656 6 years; FEV1 506 4%ref)and 7 controls (566 9 years;FEV1 926 6%ref) cycled 45 min below their LT (50% V9O2 peak). Biopsies from the vastus lateralis muscle were obtained before exercise, immediately after and 1 h, 1 day and 1 week later to determine by PCR the mtDNA/nuclear DNA (nDNA) ratio (a marker of mtDNA content) and the expression of the peroxisome proliferator-activated receptor- g coactivator-1 a (PGC-1a)mRNA and the amount of reactive oxygen species produced during exercise was estimated from total V9O2. Results Skeletal muscle mtDNA/nDNA fell significantly after exercise above the LT both in controls and in patients with COPD, but the changes were greater in those with COPD. These changes correlated with production of reactive oxygen species, increases in manganese superoxide dismutase and PGC-1 a mRNA and returned to baseline values 1 week later. This pattern of response wa was also observed, albeit minimised, in patients exercising below the LT. Conclusions In patients with COPD, exercise enhances the decrease in mtDNA content of skeletal muscle and the expression of PGC-1 a mRNA seen in healthy subjects probably due to oxidative stress.

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease Jones, Paul W.; Rennard, Stephen I.; Agustí García-Navarro, Àlvar; Channez, Pascal; Magnusen, Helgo; Fabbri, Leonardo; Donohue, James F.; Bateman, Eric D.; Gross, Nicholas J.; Lamarca, Rosa; Caracta, Cynthia; Garcia Gil,Esther Background: The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Methods: In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843) and II (n = 804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1 <80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George"s Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation. Results: At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p < 0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p < 0.001). More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p = 0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p = 0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p = 0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p = 0.9). Adverse events were minor in both studies. Conclusion: Aclidinium is effective and well tolerated in patients with moderate to severe COPD. Trial registration: ClinicalTrials.gov: NCT00363896 ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

Dendritic cells exposed to MVA-based HIV-1 vaccine induce highly functional HIV-1-specific CD8+ T cell responses in HIV-1-infected individuals

Dendritic cells exposed to MVA-based HIV-1 vaccine induce highly functional HIV-1-specific CD8+ T cell responses in HIV-1-infected individuals Climent i Vidal, Núria; Guerra, Susana; García Alcaide, Felipe; Rovira Ollé, Cristina; Miralles Escofet, Laia; Gómez Rodríguez, Carmen Elena; Piqué i Clusella, Núria; Gil Roda, Cristina; Gatell, José M.; Esteban Rodrígez, Mariano; Gallart, T. Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC) and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B) in human monocyte-derived dendritic cells (MDDC) and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α). MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA) and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B.

Problemas de salud y la vulnerabilidad social en pacientes inmigrantes ingresados con patología infecciosa: estudio caso-control

Problemas de salud y la vulnerabilidad social en pacientes inmigrantes ingresados con patología infecciosa: estudio caso-control Faura Vendrell, Teresa; García Alcaide, Felipe; Isla Pera, Ma. Pilar (María Pilar); López Matheu, Carme; Robau Gassiot, M.; Moreno, A.; Tricas, A.; Ligero, C.; Robles, D.; Carmona, S.; Miró Meda, José M.; Gatell, José M. Introducción. La necesidad de recursos sanitarios de la población inmigrante ha aumentado en los últimos años. El estudio de los problemas de salud y la vulnerabilidad social planteados durante el ingreso hospitalario de estos pacientes ayudaría a mejorar su cuidado. Pacientes y métodos. Estudio caso-control realizado en el Hospital Clínic de Barcelona. Se incluyeron pacientes inmigrantes ingresados con patología infecciosa de octubre de 2002 a septiembre de 2003. Los casos fueron apareados por edad, sexo e infección por virus de la inmunodeficiencia humana (VIH). Se evaluaron variables clínicas (visitas a Urgencias, días y número de ingresos, cantidad de procedimientos y fármacos, diagnóstico etiológico y control post alta) y de vulnerabilidad social (utilización de trabajo social, tarjeta sanitaria, cuidador de referencia, consumo de tóxicos, barrera idiomática y alta de enfermería). Resultados. Se estudiaron 102 pacientes (51 casos y 51 controles, todos varones). El 56% estaban infectados por VIH en ambos grupos. El número de procedimientos diagnósticos o terapéuticos fue mayor en el grupo de inmigrantes (p = 0,02), se llegó en menor proporción a un diagnóstico etiológico (el 82% frente al 98%, p = 0,021) y el número de visitas post alta fue inferior (el 55% frente al 77%, p = 0,04). Los pacientes inmigrantes tuvieron unos índices de vulnerabilidad social mayores que la población autóctona y en un 35% de ellos existía una barrera idiomática. Un menor número tenían tarjeta sanitaria (el 63% frente al 94%, p < 0,0001) y un número mayor tuvieron necesidad de traslado a un centro sociosanitario (el 16% frente al 2%, p = 0,01). Discusión La vulnerabilidad social de los pacientes inmigrantes influye en una menor obtención del diagnóstico etiológico, mayor número de procedimientos durante la hospitalización y un menor seguimiento posterior al alta.

Proteasome inhibition reduces proliferation, collagen expression, and inflammatory cytokine production in nasal mucosa and polyp fibroblasts

Proteasome inhibition reduces proliferation, collagen expression, and inflammatory cytokine production in nasal mucosa and polyp fibroblasts Pujols Tarrés, Laura; Fernández-Bertolín, L.; Fuentes-Prado, M.; Alobid, Isam; Roca i Ferrer, Jordi; Agell i Jané, Neus; Mullol i Miret, Joaquim; Picado Vallés, César Proteasome inhibitors, used in cancer treatment for their proapoptotic effects, have anti-inflammatory and antifibrotic effects on animal models of various inflammatory and fibrotic diseases. Their effects in cells from patients affected by either inflammatory or fibrotic diseases have been poorly investigated. Nasal polyposis is a chronic inflammatory disease of the sinus mucosa characterized by tissue inflammation and remodeling. We tested the hypothesis that proteasome inhibition of nasal polyp fibroblasts might reduce their proliferation and inflammatory and fibrotic response. Accordingly, we investigated the effect of the proteasome inhibitor Z-Leu-Leu-Leu-B(OH)2 (MG262) on cell viability and proliferation and on the production of collagen and inflammatory cytokines in nasal polyp and nasal mucosa fibroblasts obtained from surgery specimens. MG262 reduced the viability of nasal mucosa and polyp fibroblasts concentration- and time-dependently, with marked effects after 48 h of treatment. The proteasome inhibitor bortezomib provoked a similar effect. MG262-induced cell death involved loss of mitochondrial membrane potential, caspase-3 and poly(ADP-ribose) polymerase activation, induction of c-Jun phosphorylation, and mitogen-activated protein kinase phosphatase-1 expression. Low concentrations of MG262 provoked growth arrest, inhibited DNA replication and retinoblastoma phosphorylation, and increased expression of the cell cycle inhibitors p21 and p27. MG262 concentration-dependently inhibited basal and transforming growth factor-β-induced collagen mRNA expression and interleukin (IL)-1β-induced production of IL-6, IL-8, monocyte chemoattractant protein-1, regulated on activation normal T cell expressed and secreted, and granulocyte/macrophage colony-stimulating factor in both fibroblast types. MG262 inhibited IL-1β/tumor necrosis factor-α-induced activation of nuclear factor-κB. We conclude that noncytotoxic treatment with MG262 reduces the proliferative, fibrotic, and inflammatory response of nasal fibroblasts, whereas high MG262 concentrations induce apoptosis.

Quality of life in simultaneous pancreas-kidney transplant recipients

Quality of life in simultaneous pancreas-kidney transplant recipients Isla Pera, Ma. Pilar (María Pilar); Moncho Vasallo, Joaquín; Torras Rabasa, Alberto; Oppenheimer Salinas, Federico; Fernández-Cruz, Laureano; Ricart Brulles, Ma. José Currently, simultaneous pancreas-kidney transplantation (SPK Tx) is the treatment of choice in selected patients with type 1 diabetes mellitus (DM1) and terminal kidney failure (TRF). A functioning SPK transplant allows dialysis and insulin therapy to be discontinued and stabilizes or improves the complications of DM1. Nevertheless, to a greater or lesser degree, these complications (physical and psychological alterations, secondary effects of immunosuppressive therapy and the need for lifelong medication and medical follow-up) can persist after SPK Tx. Health professionals have mainly investigated the clinical features of transplant recipients. However, in the last few years, interest in analyzing perceived health and health-related quality of life (QoL) has increased. This latter concept includes the features of QoL most closely associated with a particular disease, its treatment and follow-up and therefore those elements most susceptible to modification by the health system. The general aim of this study was to measure health-related QoL in our population with SPK Tx and to determine whether there are significant differences between these patients and those with DM1 and TRF who continue to receive renal replacement therapy (RRT) and insulin therapy. More specific aims were to evaluate whether there are significant differences between the study groups and the means of the Spanish reference population in the distinct dimensions of a QoL questionnaire and whether other variables such as age, sex, years" duration of DM1, length of dialysis, and time since SPK Tx significantly affect health-related QoL.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient Colom Codina, Helena; Lloberas Blanch, Núria; Caldés, Ana; Andreu, Franc; Torras Ambròs, Joan; Oppenheimer Salinas, Federico; Sanchez-Plumed, Jaime; Gentil, Miguel A.; Kuypers, Dirk R.; Brunet i Serra, Mercè; Ekberg, Henrik; Grinyo Boira, Josep M. Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.; Podeu consultar el llibre complet a: http://hdl.handle.net/2445/32393

Role of triple fixed combination valsartan, amlodipine and hydrochlorothiazide in controlling blood pressure

Role of triple fixed combination valsartan, amlodipine and hydrochlorothiazide in controlling blood pressure Doménech, Mónica; Coca, Antonio. Abstract: Hypertension is one of the main risk factors for the development of cardiovascular diseases and the search for new therapeutic strategies aimed at optimizing its control remains an ongoing research and clinical challenge. In recent years, there has been a marked increase in the use of combinations of antihypertensive drugs with complementary mechanisms of action, with the aims of reducing blood pressure levels more rapidly and vigorously than strategies employing monotherapy and improving treatment compliance and adhesion. Therefore, as recommended by the 2009 reappraisal of the European Society of Hypertension/European Society of Cardiology Guidelines, the use of a triple combination that combines a calcium channel blocker, an angiotensin II receptor blocker and a thiazide diuretic seems a reasonable and efficacious combination for the management of hypertensive patients with moderate, high or very high risk. This article reviews the clinical trials carried out with the fixed combination of amlodipine/valsartan/hydrochlorothiazide at the doses recommended for each drug in monotherapy. The data show that this combination achieved greater reductions in mean sitting diastolic and systolic blood pressure than amlodipine, valsartan or hydrochlorothiazide in monotherapy, with favorable pharmacodynamic and pharmacokinetic profiles. The triple combination at high single doses should be used with caution in elderly patients and those with renal or liver failure. Although the tolerability and safety of the triple combination are good, the mostfrequently reported adverse effects were peripheral edema, headache and dizziness. Analytical alterations were consistent with the already-known biochemical effects of amlodipine, valsartan or hydrochlorothiazide in monotherapy. In summary, triple-therapy with amlodipine/valsartan/hydrochlorothiazide in a single pill contributes additional advantages to fixed -combinations of two drugs, achieving a greater and more rapid reduction in blood pressure levels in a safe, well-tolerated manner.

Protocolo de sedo-analgesia para prevención del espasmo radial en hemodinámica cardíaca

Protocolo de sedo-analgesia para prevención del espasmo radial en hemodinámica cardíaca Gabaldà Martínez, S.; Trilla Colominas, M.; Niebla Bellido, M.; Pardo González, M.; Canales Gutiérrez, T.; Tejedor Navarro, M.; González Ribelles, E.; Puig Serra, Neus; Freixa Rofastes, X.; Masotti Centol, M. Introducción y objetivo: El espasmo es la complicación más habitual en los cateterismos por arteria radial. Su frecuencia oscila entre el 10-30% y puede ser un factor limitante que impida la realización del cateterismo por esa vía. El objetivo de este estudio es evaluar con un nuevo protocolo de sedo-analgesia la reducción de la frecuencia del espasmo radial y la disminución de la ansiedad del paciente. Material y método: Estudio aleatorizado y prospectivo de 300 pacientes sometidos a cateterismo radial. Se randomizaron dos grupos, el Grupo I (n=150) con la pauta de sedación habitual (10mg diazepam sl) y el Grupo II (n=150) con una pauta de sedación con 2 mg de Midazolam + 0,035 mg/kg de Cloruro Mórfico y en caso de procedimientos de más de 45 minutos se añadía Fentanilo a 1 mcgr/kg. Resultados y conclusión: No se observaron diferencias significativas entre los dos grupos estudiados en cuanto a las características basales. La edad media de la población fue de 65 ± 11 años; 223 pacientes (74%) fueron hombres y el índice de masa corporal (IMC) medio 27,7 ± 3,8. Los pacientes del Grupo II presentaron reducción significativa del espasmo respecto a los del Grupo I (9,3% frente a 22,6%; p=0,002). También se objetivó una reducción significativa del dolor (2,05 frente a 2,77; p=0,007). La pauta sedo-analgésica propuesta demostró ser eficaz en la reducción del espasmo radial y del dolor durante el cateterismo.

Estudio comparativo de dos estrategias para el tratamiento del dolor durante la ablación de fibrilación auricular: analgesia frente a sedación

Estudio comparativo de dos estrategias para el tratamiento del dolor durante la ablación de fibrilación auricular: analgesia frente a sedación Alsina Restoy, Xavier; Eseverri Rovira, M.; Matas Avella, M.; Ruvira López, S.; Barbarin Morras, M. C.; Tamborero Noguera, David; Mont Girbau, Lluís; Brugada Terradellas, Josep, 1958- Antecedentes: Las aplicaciones de radiofrecuencia durante la ablación de la fibrilación auricular (FA) producen dolor y ansiedad. El tratamiento habitual se basa en la administración de analgésicos y sedación. La sedación intensa puede producir inestabilidad hemodinámica y desaturaciones.Objetivos: Comparar la incidencia de desaturaciones en relación a la utilización de dos protocolos distintos de tratamiento del dolor durante la ablación de FA. Uno de los protocolos está basado en la sedación con propofol (protocolo 1) y el otro en la analgesia intensa (protocolo 2).Resultados: Hemos analizado los datos de recogidos durante el procedimiento en un grupo de 43 pacientes tratados según el protocolo 1 y otro grupo de 43 pacientes tratados según el protocolo 2. Las variables analizadas han sido: la desaturación máxima, la dosis media de propofol y la dosis media de fentanilo. Las dosis de propofol necesarias en los pacientes del protocolo 1 han sido mayores que con el protocolo 2 (2,4±1,4mg/kg vs 1,7±0,5 mg/kg; p=0,005). La dosis de fentanilo en los pacientes del protocolo 1 han sido menores que en los del protocolo 2 (35,4±17,3mg vs 51,1±18,6mg vs; p&0,001). El 83,65% de los pacientes del protocolo 2 se mantuvo por encima del 94% de saturación frente al 58,1% de pacientes del protocolo 1. Conclusiones: Con el tratamiento basado en la analgesia para los procedimientos de ablación de FA se consigue que una menor proporción de pacientes tengan desaturaciones.

Reassessing the status of antiphospholipid syndrome in systemic lupus erythematosus.

Reassessing the status of antiphospholipid syndrome in systemic lupus erythematosus. Vianna, J. L.; Haga, H. J.; Tripathi, P.; Cervera i Segura, Ricard, 1960-; Khamashta, Munther A.; Hughes, Graham R. V. (Graham Robert Vivian) The antiphospholipid syndrome was initially described in 1986. To reassess the validity of antiphospholipid antibodies in systemic lupus erythematosus (SLE), 95 patients with SLE were studied. Their antiphospholipid antibody profile was analysed and correlated with clinical findings such as thrombosis, abortions, or thrombocytopenia. A low prevalence of these antibodies was found (13 patients; 14%) with a high specificity for thrombosis (92%) and abortions (92%). The importance of anticardiolipin antibodies as a risk factor for thrombosis or abortions, or both, in patients with SLE is reaffirmed by this work.