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Ortega-Molina A.,Tumor Suppression Group | Efeyan A.,Tumor Suppression Group | Lopez-Guadamillas E.,Tumor Suppression Group | Munoz-Martin M.,Tumor Suppression Group | And 12 more authors.
Cell Metabolism | Year: 2012

Aging in worms and flies is regulated by the PI3K/Akt/Foxo pathway. Here we extend this paradigm to mammals. Pten tg mice carrying additional genomic copies of Pten are protected from cancer and present a significant extension of life span that is independent of their lower cancer incidence. Interestingly, Pten tg mice have an increased energy expenditure and protection from metabolic pathologies. The brown adipose tissue (BAT) of Pten tg mice is hyperactive and presents high levels of the uncoupling protein Ucp1, which we show is a target of Foxo1. Importantly, a synthetic PI3K inhibitor also increases energy expenditure and hyperactivates the BAT in mice. These effects can be recapitulated in isolated brown adipocytes and, moreover, implants of Pten tg fibroblasts programmed with Prdm16 and Cebpβ form subcutaneous brown adipose pads more efficiently than wild-type fibroblasts. These observations uncover a role of Pten in promoting energy expenditure, thus decreasing nutrient storage and its associated damage. © 2012 Elsevier Inc.


Sostres C.,Universitario Lozano Blesa | Sostres C.,Aragon Health science Institute | Gargallo C.J.,Universitario Lozano Blesa | Gargallo C.J.,Aragon Health science Institute | And 4 more authors.
Arthritis Research and Therapy | Year: 2013

NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. However, they are also associated with gastrointestinal (GI) adverse events. NSAIDs can damage the whole GI tract including a wide spectrum of lesions. About 1 to 2% of NSAID users experienced a serious GI complication during treatment. The relative risk of upper GI complications among NSAID users depends on the presence of different risk factors, including older age (>65 years), history of complicated peptic ulcer, and concomitant aspirin or anticoagulant use, in addition to the type and dose of NSAID. Some authors recently reported a decreasing trend in hospitalizations due to upper GI complications and a significant increase in those from the lower GI tract, causing the rates of these two types of GI complications to converge. NSAID-induced enteropathy has gained much attention in the last few years and an increasing number of reports have been published on this issue. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding and perforation to a similar extent as that seen in the upper GI tract. Selective cyclooxygenase-2 inhibitors have the same beneficial effects as nonselective NSAIDs but with less GI toxicity in the upper GI tract and probably in the lower GI tract. Overall, mortality due to these complications has also decreased, but the in-hospital case fatality for upper and lower GI complication events has remained constant despite the new therapeutic and prevention strategies. © 2013 BioMed Central Ltd.


Grzybowski A.,Poznan City Hospital | Grzybowski A.,University of Warmia and Mazury | Ascaso F.J.,Lozano Blesa University Clinic Hospital | Ascaso F.J.,Aragon Health science Institute | And 2 more authors.
Current Opinion in Ophthalmology | Year: 2015

Purpose of review The objective of this review is to evaluate the result of cataract surgery in patients continuing antiplatelet and/or anticoagulant treatment.Recent findings The number of elderly patients using anticoagulant and antiplatelet treatment in prevention of venous thromboembolism has significantly increased in recent years. It was believed for many years that those patients might be at higher risk for complications during ocular surgery. Thus, different strategies were proposed to prevent these complications, including discontinuation of anticoagulants, dose reduction, or low-molecular-weight heparin replacement. We performed a PubMed search over a period of 7 years (2007-2013) about possible intraoperative and postoperative complications in patients receiving anticoagulant and/or antiplatelet therapy at the time of cataract surgery. No significant increase in intraoperative or postoperative complications has been identified.Summary Phacoemulsification of uncomplicated cataracts with intraocular lens implantation can be performed safely in high-risk patients, taking both anticoagulants and antiplatelet drugs when topical anesthesia is administered and cataract surgery is performed through a clear corneal incision by a skilled surgeon. Copyright © Lippincott Williams & Wilkins.


Jimenez B.,University of Zaragoza | Ascaso F.J.,University of Zaragoza | Ascaso F.J.,Aragon Health science Institute | Cristobal J.A.,University of Zaragoza | Lopez del Val J.,University of Zaragoza
Movement Disorders | Year: 2014

The aims of this study were to assess the peripapillary retinal nerve fiber layer (RNFL) thickness in patients with Parkinson's disease (PD), to determine its correlation with disease severity, and to define a simple biomarker for predicting clinical severity. One hundred two eyes from 52 patients affected by PD were compared with 97 eyes from 50 age-comparable controls. In all patients, peripapillary RNFL thickness was measured by optical coherence tomography (OCT). We used the Unified Parkinson's Disease Rating Scale (UPDRS) total score and measured responses in the on medication state. Eyes from patients with PD had a statistically significant decrease in average peripapillary RNFL thickness compared with control eyes (P<0.001). This reduction was observed in every quadrant (inferior, superior, nasal [P<0.001], and temporal [P=0.017]) in patients with PD. Furthermore, a strong inverse correlation was found between the PD severity measured according to the UPDRS score and the average peripapillary RNFL thickness (r=-0.615; P<0.001) and PD duration (r=-0.303; P=0.002). From these results, we defined a regression equation that predicts the UPDRS score from the above-mentioned variables: UPDRS= 81.6+29.6 * log PD duration (years)-0.6 * RFNL thickness (μm). We observed that, as the evolution and severity of PD progress, the peripapillary RNFL layer thickness, as evaluated by OCT, gradually diminishes. These results suggest that the average peripapillary RNFL thickness measured by OCT might be useful as a biomarker to detect the early onset and progression of PD. © 2013 Movement Disorder Society.


Prados-Torres A.,University of Zaragoza | Poblador-Plou B.,University of Zaragoza | Calderon-Larranaga A.,University of Zaragoza | Gimeno-Feliu L.A.,University of Zaragoza | And 4 more authors.
PLoS ONE | Year: 2012

Objectives: The primary objective of this study was to identify the existence of chronic disease multimorbidity patterns in the primary care population, describing their clinical components and analysing how these patterns change and evolve over time both in women and men. The secondary objective of this study was to generate evidence regarding the pathophysiological processes underlying multimorbidity and to understand the interactions and synergies among the various diseases. Methods: This observational, retrospective, multicentre study utilised information from the electronic medical records of 19 primary care centres from 2008. To identify multimorbidity patterns, an exploratory factor analysis was carried out based on the tetra-choric correlations between the diagnostic information of 275,682 patients who were over 14 years of age. The analysis was stratified by age group and sex. Results: Multimorbidity was found in all age groups, and its prevalence ranged from 13% in the 15 to 44 year age group to 67% in those 65 years of age or older. Goodness-of-fit indicators revealed sample values between 0.50 and 0.71. We identified five patterns of multimorbidity: cardio-metabolic, psychiatric-substance abuse, mechanical-obesity-thyroidal, psychogeriatric and depressive. Some of these patterns were found to evolve with age, and there were differences between men and women. Conclusions: Non-random associations between chronic diseases result in clinically consistent multimorbidity patterns affecting a significant proportion of the population. Underlying pathophysiological phenomena were observed upon which action can be taken both from a clinical, individual-level perspective and from a public health or population-level perspective. © 2012 Prados-Torres et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Lanchares E.,Aragon Institute of Engineering Research | Lanchares E.,Aragon Health science Institute | Del Buey M.A.,University of Zaragoza | Cristobal J.A.,University of Zaragoza | And 3 more authors.
Graefe's Archive for Clinical and Experimental Ophthalmology | Year: 2011

Purpose: To study the biomechanical effect of riboflavin-ultraviolet A irradiation (UVA)-induced collagen cross-linking (CXL) in porcine corneas using two different exposure times of 30 and 60 min. Methods: Seventeen enucleated porcine eyes were divided into three groups: group A, six eyes without any treatment, group B, six eyes treated by UVA CXL for 30 min, and group C, five eyes treated by UVA CXL for 60 min. Riboflavin (vitamin B2) was used as a photosensitizer in both groups of treatment. Then, the stress-strain behavior of all the specimens was measured to compare the corneal biomechanical properties among the three groups. The Young's modulus E of the mean curve of each group shows the stiffness of treated and untreated tissue. The stress data necessary for stretches of 6, 8, and 12% were used to perform the statistical analysis of the values. Results: Group B (riboflavin-UVA-CXL, 30 min, E∈=∈46 MPa) showed a stiffer behavior than group A (control, E∈=∈29 MPa) . Group C (60 min CXL, E∈=∈28 MPa) showed lower stiffness than group B and a similar mechanical behavior than group A. The statistical analysis of the stress-strain curves showed significant differences in the corneal response between group B and the control at the three values of stretch considered, 6, 8, and 12% (p∈=∈0.025, p∈=∈0.025 and p∈=∈0.037, respectively) and between group B and group C (p∈=∈0.028, p∈=∈0.028, and p∈=∈0.028). No statistically significant difference was found between group C and control (p∈=∈0.855, p∈=∈0.715, and p∈=∈0.584). Conclusions: The application of 30-min UVA CXL treatment with riboflavin increased stiffness of the porcine corneal tissue. A 60-min UVA-radiated tissue presents lower stiffness than the 30-min treated tissue, showing a similar biomechanical behavior than the untreated corneas. A prolongation of the UVA irradiation time may cause structural weakening of the porcine corneas. © 2011 Springer-Verlag.


Marron S.E.,Alcaniz Hospital | Marron S.E.,Aragon Health science Institute | Tomas-Aragones L.,University of Zaragoza | Tomas-Aragones L.,Aragon Health science Institute | Boira S.,University of Zaragoza
Acta Dermato-Venereologica | Year: 2013

Oral isotretinoin is effective in the clinical control of acne, but the relationship between this treatment and its psychosocial impact on the patient has not been completely clarified. The aim of this study was to determine if the use of oral isotretinoin in total accumulated doses of 120 mg/kg in a sample of 346 patients with moderate acne was useful in controlling symptoms of anxiety and/ or depression and improving quality of life. A further objective was to ascertain the level of patient satisfaction with the treatment. After 30 weeks, there was a significant reduction in clinical symptoms (p < 0.001). The negative impact on quality of life, measured with the Dermatology Life Quality Index and the Health Survey Short-Form-36 (p < 0.001), showed a significant reduction, as did the Hospital Anxiety and Depression Scale scores for anxiety (p < 0.001) and depression (p < 0.005). At the end of the study, the mean level of patient satisfaction with improvement of symptoms was 84.4%.© 2013 Acta Dermato-Venereologica.


Grzybowski A.,Poznan City Hospital | Grzybowski A.,University of Warmia and Mazury | Pieczynski J.,University of Warmia and Mazury | Ascaso F.J.,University of Zaragoza | Ascaso F.J.,Aragon Health science Institute
Acta Ophthalmologica | Year: 2014

Silicone oil (SiO) has a well-established role as a long-term endotamponade agent in the management of complicated retinal detachments. Complications of intraocular SiO include keratopathy, glaucoma, cataract and subretinal migration of the oil droplets. SiO tamponade can also lead to a severe optic neuropathy caused by retrolaminar migration. Nevertheless, intracranial migration of the SiO through the optic nerve posterior to the lamina cribrosa to the optic chiasm and brain is uncommon. The mechanism is still under debate, but it has been suggested elevated intraocular pressure, macrophages or optic nerve head anatomical predispositions as potential explanations. Moreover, central scotoma may develop in eyes with SiO not only at the time of oil removal, but also during the period of tamponade. We performed a PubMed search of neuronal complications of silicone oil over a period of 25 years. This review summarizes our current understanding of the specific pathogenic mechanisms of intraocular SiO neuronal side effects, concluding that pre-existing glaucoma and optic nerve abnormalities are the main risk factors associated with this damage. In their absence, the risk of extraocular SiO penetration is so low that the use of SiO endotamponade in complex retinal detachment patients does not need to be modified. MRI images to assess extraocular SiO migration are only necessary in very few and special cases, such as patients with optic nerve abnormalities and glaucoma. © 2013 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.


Nita M.,Domestic and Specialized Medicine Center Dilmed | Grzybowski A.,University of Warmia and Mazury | Grzybowski A.,Jozef Strus Poznan City Hospital | Ascaso F.J.,University of Zaragoza | And 2 more authors.
Mediators of Inflammation | Year: 2014

The products of oxidative stress trigger chronic low-grade inflammation (pathophysiological parainflammation) process in AMD patients. In early AMD, soft drusen contain many mediators of chronic low-grade inflammation such as C-reactive protein, adducts of the carboxyethylpyrrole protein, immunoglobulins, and acute phase molecules, as well as the complement-related proteins C3a, C5a, C5, C5b-9, CFH, CD35, and CD46. The complement system, mainly alternative pathway, mediates chronic autologous pathophysiological parainflammation in dry and exudative AMD, especially in the Y402H gene polymorphism, which causes hypofunction/lack of the protective complement factor H (CFH) and facilitates chronic inflammation mediated by C-reactive protein (CRP). Microglial activation induces photoreceptor cells injury and leads to the development of dry AMD. Many autoantibodies (antibodies against alpha beta crystallin, alpha-actinin, amyloid, C1q, chondroitin, collagen I, collagen III, collagen IV, elastin, fibronectin, heparan sulfate, histone H2A, histone H2B, hyaluronic acid, laminin, proteoglycan, vimentin, vitronectin, and aldolase C and pyruvate kinase M2) and overexpression of Fcc receptors play role in immune-mediated inflammation in AMD patients and in animal model. Macrophages infiltration of retinal/choroidal interface acts as protective factor in early AMD (M2 phenotype macrophages); however it acts as proinflammatory and proangiogenic factor in advanced AMD (M1 and M2 phenotype macrophages). © 2014 Małgorzata Nita et al.


Calderon-Larranaga A.,Imperial College London | Calderon-Larranaga A.,Aragon Health science Institute | Carney L.,Imperial College London | Soljak M.,Imperial College London | And 6 more authors.
Thorax | Year: 2011

Background: Hospital admission rates for chronic obstructive pulmonary disease (COPD) are known to be strongly associated with population factors. Primary care services may also affect admission rates, but there is little direct supporting evidence. Objectives: To determine associations between population characteristics, diagnosed and undiagnosed COPD prevalence, primary healthcare factors, and COPD admission rates primary care trust (PCT) and general practice levels in England. Design, setting, and participants: National cross-sectional study (53,676,051 patients in 8,064 practices in 152 English PCTs), combining data on hospital admissions, populations, primary healthcare staffing, clinical practice quality and access, and prevalence. Main outcome measures: Directly and indirectly standardised hospital admission rates for COPD, for PCT and practice populations. Results: Mean annual COPD admission rates per 100 000 population varied from 124.7 to 646.5 for PCTs and 0.0 to 2175.2 for practices. Admissions were strongly associated with population deprivation at both levels. In a practice-level multivariate Poisson regression, registered and undiagnosed COPD prevalence, smoking prevalence and deprivation were risk factors for admission (p<0.001), while healthcare factors- influenza immunisation, patient-reported access to consultations within two days, and primary care staffing, were protective (p<0.05). Conclusion: Associations of COPD admission rates with deprivation, primary healthcare access and supply highlight the need for adequate services in deprived areas. An association between admission rates and undiagnosed COPD prevalence suggests that case-finding strategies should be evaluated. Of the COPD clinical quality indicators, only influenza immunisation was associated with reduced admission rates. Patients' experience of access to primary care may also be clinically important.

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