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Rego-Perez I.,Complejo Hospitalario Universitario runa
Frontiers in bioscience (Scholar edition) | Year: 2013

The genetic contribution is one of the most notable factors that play a main role in the risk of OA. Despite the genetics of this disease is complex and the finding of risk-related genes has been very challenging, evidence for genetic predisposition has been reported. Besides, in the last years recent evidences indicate that the mitochondrion is implicated in OA. In this context, the mtDNA haplogroups, defined as individual groups characterized by the presence of a particular set of single nucleotide polymorphisms (SNPs) in the mtDNA sequence, emerged as new genetic variants involved in this pathology. Moreover, it has been described that mtDNA damage not only accumulates in OA chondrocytes, but also that OA chondrocytes have limited mtDNA repair capacity. In this review we will focus on the influence of mitochondrial genetics and the mtDNA haplogroups in the prevalence, severity and progression of the OA disease, as well as their incidence on many OA-related features, such as serum levels of OA-related molecular markers, Nitric Oxide production or telomere length. Source


Carames B.,Scripps Research Institute | Taniguchi N.,Scripps Research Institute | Otsuki S.,Scripps Research Institute | Blanco F.J.,Complejo Hospitalario Universitario runa | Lotz M.,Scripps Research Institute
Arthritis and Rheumatism | Year: 2010

Objective. Autophagy is a process for turnover of intracellular organelles and molecules that protects cells during stress responses. We undertook this study to evaluate the potential roles of Unc-51-like kinase 1 (ULK1), an inducer of autophagy, Beclin1, a regulator of autophagy, and microtubule-associated protein 1 light chain 3 (LC3), which executes autophagy, in the development of osteoarthritis (OA) and in cartilage cell death. Methods. Expression of ULK1, Beclin1, and LC3 was analyzed in normal and OA human articular cartilage and in knee joints of mice with aging-related and surgically induced OA, using immunohistochemistry and Western blotting. Poly(ADP-ribose) polymerase (PARP) p85 expression was used to determine the correlation between cell death and autophagy. Results. ULK1, Beclin1, and LC3 were constitutively expressed in normal human articular cartilage. ULK1, Beclin1, and LC3 protein expression was reduced in OA chondrocytes and cartilage, but these 3 proteins were strongly expressed in the OA cell clusters. In mouse knee joints, loss of glycosaminoglycans (GAGs) was observed at ages 9 months and 12 months and in the surgical OA model, 8 weeks after knee destabilization. Expression of ULK1, Beclin1, and LC3 decreased together with GAG loss, while PARP p85 expression was increased. Conclusion. Autophagy may be a protective or homeostatic mechanism in normal cartilage. In contrast, human OA and aging-related and surgically induced OA in mice are associated with a reduction and loss of ULK1, Beclin1, and LC3 expression and a related increase in apoptosis. These results suggest that compromised autophagy represents a novel mechanism in the development of OA. © 2010, American College of Rheumatology. Source


Carames B.,Scripps Research Institute | Hasegawa A.,Scripps Research Institute | Taniguchi N.,Scripps Research Institute | Miyaki S.,Scripps Research Institute | And 2 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Objectives: Osteoarthritis is associated with cell death and extracellular matrix degradation in articular cartilage. Autophagy is an essential cellular homeostasis mechanism that was found to be deficient in ageing and osteoarthritic cartilage. This study determined whether pharmacological inhibition of the mammalian target of rapamycin (mTOR), a key inhibitor of autophagy, has disease-modifying activity in experimental osteoarthritis. Methods: Experimental osteoarthritis was induced by transection of the medial meniscotibial ligament and the medial collateral ligament in 2-month-old C57Bl/6 mice (n=36). Rapamycin (1 mg/kg weight/day) (n=18 mice) or dimethyl sulphoxide vehicle control (n=18 mice) was administered intraperitoneally for 10 weeks. Histopathological changes in articular cartilage and synovium were examined by using semiquantitative scoring systems. Rapamycin effects on mTOR signalling, autophagy, cartilage homeostasis and inflammation were analysed by immunohistochemistry and immunofluorescence staining. Results: Rapamycin affected the mTOR signalling pathway in mouse knee joints as indicated by the inhibition of ribosomal protein S6 phosphorylation, a target of mTOR and activation of LC3, a main marker of autophagy. The severity of cartilage degradation was significantly (p<0.01) reduced in the rapamycin-treated group compared with the control group and this was associated with a significant (p<0.05) decrease in synovitis. Rapamycin treatment also maintained cartilage cellularity and decreased ADAMTS-5 and interleukin-1βexpression in articular cartilage. Conclusions: These results suggest that rapamycin, at least in part by autophagy activation, reduces the severity of experimental osteoarthritis. Pharmacological activation of autophagy may be an effective therapeutic approach for osteoarthritis. Source


Rendal-Vazquez M.E.,Complejo Hospitalario Universitario runa
Annals of vascular surgery | Year: 2012

The aim of the study was to analyze the mechanism of deterioration of implanted arteries. Eleven patients were included. Samples of vascular segments obtained from multiorgan donors and samples of the same vascular segments after explantation in the recipient were analyzed. Blood group, time of cold and warm ischemia, cause of death, time spent in the intensive care unit, time of storage of the cryopreserved grafts, and anatomopathological and immunohistochemical studies were analyzed using the preimplant samples obtained from the multiorgan donor. For samples obtained from the recipient, blood group, duration for which the tissue from the donor has been implanted, reason for graft explantation, and anatomopathological and immunohistochemical studies were analyzed. Histopathologically, the main finding has been the substitution of the muscular cap of the arterial wall by an intense fibrosis, in most of the cases, of a symmetrical nature. Besides this degeneration of myocytes, there is marked perivascular fibrosis and fibrointimal thickening also exists. The T lymphocytes suggest the importance of the immunological mechanism in the distortion of the architecture of the arteries. The atherosclerosis plays a less relevant role. Evidence of immune-mediated injury was found, and this mechanism seems to be responsible for the degenerative process in cryopreserved homografts. Copyright © 2012 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved. Source


Isidro M.L.,Complejo Hospitalario Universitario runa
Postgraduate Medical Journal | Year: 2012

Sexual dysfunction (SD) is common in type 2 diabetic men, but few subjects are diagnosed and treated. The prevalence of diabetes mellitus is increasing worldwide. It is expected that the number of subjects suffering from SD increases in the near future. Most studies of SD in diabetic men have focused on erectile dysfunction. There is a dearth of studies in the area of the other forms of SD. SD has consequences on the psychological well-being and reproductive function. They can be the first symptom of comorbidities or a treatment side effect. Erectile dysfunction is increasingly being recognised as an early marker of organic incipient systemic disease. Evaluation for any SD includes a complete medical history, detailed sexual history, physical examination, psychosocial assessment and, sometimes, complementary studies. Initial treatment of any SD should eliminate any modifiable factor that may lead to or aggravate the dysfunction. Phosphodiesterase type 5 inhibitors are the preferred therapy for most men with organic erectile dysfunction who do not have a specific contraindication to their use. Pharmacological treatment of premature ejaculation includes on-demand or daily dosing of certain selective serotonin reuptake inhibitors or clomipramine and on-demand topical local anaesthetics. Delayed ejaculation and anejaculation due to vascular or neuropathic damage are usually irreversible. The issue of infertility in patients with anejaculation or retrograde ejaculation seeking to have children should be addressed. No study specifically conducted in diabetic men on the treatment of hypoactive sexual desire disorder, apart from that occurring in the context of hypogonadism, has been published. Source

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