Mitochondrial dysfunction in antiphospholipid syndrome: implications in the pathogenesis of the disease and effects of coenzyme Q(10) treatment

The exact mechanisms underlying the role of oxidative stress in the pathogenesis and the prothrombotic or proinflammatory status of antiphospholipid syndrome (APS) remain unknown. Here, we investigate the role of oxidative stress and mitochondrial dysfunction in the proatherothrombotic status of APS patients induced by IgG-antiphospholipid antibodies and the beneficial effects of supplementing cells with coenzyme Q(10) (CoQ(10)). A significant increase in relevant prothrombotic and inflammatory parameters in 43 APS patients was found compared with 38 healthy donors. Increased peroxide production, nuclear abundance of Nrf2, antioxidant enzymatic activity, decreased intracellular glutathione, and altered mitochondrial membrane potential were found in monocytes and neutrophils from APS patients. Accelerated atherosclerosis in APS patients was found associated with their inflammatory or oxidative status. CoQ(10) preincubation of healthy monocytes before IgG-antiphospholipid antibody treatment decreased oxidative stress, the percentage of cells with altered mitochondrial membrane potential, and the induced expression of tissue factor, VEGF, and Flt1. In addition, CoQ(10) significantly improved the ultrastructural preservation of mitochondria and prevented IgG-APS-induced fission mediated by Drp-1 and Fis-1 proteins. In conclusion, the oxidative perturbation in APS patient leukocytes, which is directly related to an inflammatory and pro-atherothrombotic status, relies on alterations in mitochondrial dynamics and metabolism that may be prevented, reverted, or both by treatment with CoQ(10).     

Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.     

Nocardiosis pulmonar en pacientes con EPOC: características y factores pronósticos

Introduction

Pulmonary nocardiosis (PN) is a severe infection with a high morbidity and mortality that mainly affects immunocompromised patients. In recent years, an increase in PN cases has been detected among patients with chronic obstructive pulmonary disease (COPD). The factors that are associated with its presence and determine its prognosis remain unknown.

Methods

Retrospective study of COPD patients diagnosed with PN over the period from 1997-2009 at the Hospital de la Santa Creu i Sant Pau, in Barcelona (Spain). Demographic, clinical, microbiological and evolution data were evaluated in all cases

Results

Thirty patients were identified with PN and COPD. Mean age (standard deviation) was 76 (7) years and the mean FEV₁ was 40 (14)%. Chronic respiratory failure was observed in 56,7% patients and 51,7% had received systemic corticosteroid therapy previous to the PN diagnosis. The most common symptoms were cough and dyspnea (90%). Alveolar infiltrates were observed in 60% of the cases. The most frequently isolated Nocardia species was N. cyriacigeorgica (68%). The one-month mortality rate was 17%, while the one-year mortality rate was 33%. The factors associated with mortality within the first year included previous systemic corticosteroid treatment, less than three months of specific antibiotic therapy and active associated neoplasm.

Conclusions

PN affects patients with moderate-severe COPD and has high short- and mid-term mortality rates. Previous corticosteroid treatment, specific antibiotic therapy for less than 3 months and active neoplasia were factors associated with mortality.     

Primera fase de validación del algoritmo europeo de evaluación funcional previa a la resección pulmonar: cuantificación del cumplimiento de las recomendaciones en la práctica clínica real

Objective

To quantify the degree of compliance with the recommendations of the clinical practice guidelines published in 2009 by the ERS and the ESTS regarding the preoperative assessment of risk of lung resection in daily clinical practice at a tertiary hospital.

Method

A prospective, observational study of real-time data collected from consecutive patients who had been referred for evaluation from September 2009 to December 2010. We recorded the presence or absence of the recommended studies included in the algorithm, their results and, when a test was missing, the reasons why it was not performed. Hospital mortality and cardio-respiratory morbidity rates are also presented.

Results

173 patients were evaluated. In 171 cases, lung resection was performed, with a mortality of 1.2% and a cardio-respiratory morbidity of 11.7%. The failure rate of the first level of the algorithm was 4.6% and for the second level (VO_2max test) it was 26%. The absence of exercise tests was mainly due to hospital structural problems and the patients’ inability to perform it. Out of the patients who performed the exercise testing, 31 reached a VO_2max of 20 ml/kg-min or more and underwent surgery without calculation of FEV₁ppo and DCLOppo; 35 patients required the calculation to determine their operability and in 2 cases the intervention was not recommended due to functional inoperability of the patient.

Conclusions

The validation process found lack of compliance with the proposed algorithm in 18.5% of the cases basically due to the absence of the exercise tests. The rate of adherence to the algorithm recommendations should be improved before performing any other validation studies.     

Análisis coste-efectividad de dabigatrán para la prevención de ictus y embolia sistémica en fibrilación auricular no valvular en España

Introduction and objectives

Assessment of the cost-effectiveness of dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Spain, from the perspective of the National Health System.

Methods

Adaptation of a Markov chain model that simulates the natural history of the disease over the lifetime of a cohort of 10 000 patients with non-valvular atrial fibrillation. Model comparators were warfarin in a first scenario, and a real world prescribing pattern in a second scenario, in which 60% of the patients were treated with vitamin K antagonists, 30% with acetylsalicylic acid, and 10% received no treatment. Deterministic and probabilistic sensitivity analyses were performed.

Results

Dabigatran reduced the occurrence of clinical events in both scenarios, providing gains in quantity and quality of life. The incremental cost-effectiveness ratio for dabigatran compared to warfarin was 17 581 euros/quality-adjusted life year gained and 14 118 euros/quality-adjusted life year gained when compared to the real world prescribing pattern. Efficiency in subgroups was demonstrated. When the social costs were incorporated into the analysis, dabigatran was found to be a dominant strategy (ie, more effective and less costly). The model proved to be robust.

Conclusions

From the perspective of the Spanish National Health System, dabigatran is an efficient strategy for the prevention of stroke in patients with non-valvular atrial fibrillation compared to warfarin and to the real-world prescribing pattern; incremental cost-effectiveness ratios were below the 30 000 euros/quality-adjusted life year threshold in both scenarios. Dabigatran would also be a dominant strategy from the societal perspective, providing society with a more effective therapy at a lower cost compared to the other 2 alternatives.Full English text available from:www.revespcardiol.org     

A family with a complex clinical presentation characterized by arrhythmogenic right ventricular dysplasia/cardiomyopathy and features of branchio‐oculo‐facial syndrome

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a familial form of cardiomyopathy typically caused by mutations in genes that encode an element of the cardiac desmosome. Branchio‐oculo‐facial syndrome (BOFS) is a craniofacial disorder caused by TFAP2A mutations. In a family segregating ARVD/C, some members also had features of BOFS. Genetic testing for ARVD/C identified a mutation in PKP2, encoding plakophilin‐2, a component of the cardiac desmosome. Evaluation of dysmorphology by chromosome microarray (CMA) identified a 4.4 Mb deletion at chromosome 6p24 that included both TFAP2A and DSP, encoding desmoplakin, an additional component of the cardiac desmosome implicated in ARVD/C. A family member with both the 6p24 deletion and PKP2 mutation had more severe cardiac dysfunction. These findings suggest that this contiguous gene deletion contributes to both ARVD/C and BOFS, and that DSP haploinsufficiency may contribute to cardiomyopathy. This family provides a clinical example that underscores the need for careful evaluation in clinical scenarios where genetic heterogeneity is known to exist. Finally, it suggests that individuals with unexplained cardiomyopathy and dysmorphic facial features may benefit from CMA analysis. © 2013 Wiley Periodicals, Inc.     

Shear bond strength evaluation of bonded molar tubes on fluorotic molars

Objective:To study the shear bond strength (SBS), sites of failure, and micromorphology of bonded molar tubes used on teeth affected by dental fluorosis.Materials and Methods:This in vitro study included 140 first molars classified according to Dean''s index for dental fluorosis. Samples were divided into seven groups: (1) healthy teeth etched for 15 seconds, (2) teeth with moderate fluorosis (MOF) etched for 15 seconds, (3) teeth with MOF etched for 150 seconds, (4) teeth with MOF microabrasion etched for 15 seconds, (5) teeth with severe fluorosis (SEF) etched for 15 seconds, (6) teeth with SEF etched for 150 seconds, and (7) teeth with SEF microabrasion etched for 15 seconds. All samples were incubated and were then submitted to the SBS test and evaluated with the modified adhesive remnant index (ARI) and analyzed by using a scanning electronic microscope.Results:The SBS mean value for healthy enamel was 20 ± 10.2 MPa. For the group with MOF, the etched 150-second mean value was the highest (19 ± 7.6 MPa); for the group with SEF treated with microabrasion and etched for 15 seconds, the mean value was (13 ± 4.1 MPa). Significant differences (P ≤ .05) were found in the ARI between healthy and fluorosed groups.Conclusions:Fluorotic enamel affects the adhesion of bonded molar tubes. The use of overetching in cases of MOF and the combination of microabrasion and etching in SEF provides a suitable adhesion for fixed appliance therapy.