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Sangro B.,University of Navarra | Sangro B.,CIBER ISCIII | Gomez-Martin C.,Hospital Universitario 12 Of Octubre | De La Mata M.,CIBER ISCIII | And 18 more authors.
Journal of Hepatology | Year: 2013

Background & Aims: Tremelimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an inhibitory co-receptor that interferes with T cell activation and proliferation. The purpose of this pilot clinical trial was to test the antitumor and antiviral effect of tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection; and to study the safety of its administration to cirrhotic patients. Methods: Tremelimumab at a dose of 15 mg/kg IV every 90 days was administered until tumor progression or severe toxicity. Twenty patients were assessable for toxicity and viral response and 17 were assessable for tumor response. Most patients were in the advanced stage and 43% had an altered liver function (Child-Pugh class B). Results: A good safety profile was recorded and no patient needed steroids because of severe immune-mediated adverse events. Some patients had a transient albeit intense elevation of transaminases after the first dose, but not following subsequent cycles. Partial response rate was 17.6% and disease control rate was 76.4%. Time to progression was 6.48 months (95% CI 3.95-9.14). A significant drop in viral load was observed while new emerging variants of the hypervariable region 1 of HCV replaced the predominant variants present before therapy, particularly in those patients with a more prominent drop in viral load. This antiviral effect was associated with an enhanced specific anti-HCV immune response. Conclusions: Tremelimumab safety profile and antitumor and antiviral activity, in patients with advanced HCC developed on HCV-induced liver cirrhosis, support further investigation. © 2013 European Association for the Study of the Liver. Published.


Collazo E.,Hospital Universitario Reina Sofia | Munoz E.,Instituto Maimonides Of Investigacion Biomedica Of Cordoba
Revista Internacional de Acupuntura | Year: 2012

Objective: To evaluate a method to identify which patients with chronic pain could benefit from acupuncture and to compare response to acupuncture between patients with fibromyalgia and those with other types of chronic pain. Design: Observational, prospective, longitudinal, independent evaluation study. Setting: Acupuncture Unit, Reina Sofia University Hospital, Cordoba, Spain. Participants: A total of 150 consecutive patients with chronic pain referred for acupuncture treatment were divided into a fibromyalgia group and a general chronic pain group. Twenty patients withdrew from the study. Interventions: Dung's indirect method was applied in the arm to determine the patient's pain grade and pain sensitivity category before receiving personalized acupuncture treatment. Main outcome measures: Differences in the pain scale before and after treatment. Results: Multiple linear regression did not demonstrate that pain reduction was related to the pain grade of the pain sensitivity categories, age, sex or number of acupuncture sessions. Pain reduction was related only to the disease. Response to acupuncture was 57% lower in patients with fibromyalgia in those with chronic pain (p < 0.001; 95% confidence interval). Conclusions: Response to acupuncture in patients with chronic pain does not seem to depend on the categories of pain in Dung's abbreviated predictive method applied in the arm.


Merchante N.,Hospital Universitario Of Valme | Merino E.,Hospital General Universitario Of Alicante | Lopez-Aldeguer J.,Polytechnic University of Valencia | Jover F.,Hospital Clinico Universitario Of San Juan | And 14 more authors.
Clinical Infectious Diseases | Year: 2013

Background. To report the clinical and epidemiological characteristics of hepatocellular carcinoma (HCC) diagnosed in a cohort of human immunodeficiency virus (HIV)-infected patients in Spain.Methods. All HIV-infected patients diagnosed of HCC in 18 hospitals in Spain before 31 December 2010 were included. The main characteristics of HCC cases are described and comparisons between cases according to the year of diagnosis are presented.Results. Eighty-two cases of HCC in HIV-infected patients were included, all of them related to viral hepatitis coinfection: hepatitis C virus (HCV) in 66 (81%), hepatitis B virus (HBV) in 6 (7%), and HBV/HCV in 10 (12%). From 1999, when the first case of HCC was diagnosed, a progressive increment in the incidence of HCC in the cohort has occurred. In patients coinfected with HIV/HCV-coinfected patients, the incidence HCC increased from 0.2 to 2.8 cases per 1000 person-years between 2000 and 2009. Death occurred in 65 patients (79%), with a median survival of 91 days (interquartile range, 31-227 days). Three of 11 patients (28%) who received potentially curative therapy died, compared with 62 of 71 patients (87%) who did not receive curative therapy (P =. 0001). Compared with cases of HCC diagnosed before 2005, cases diagnosed later did not show a higher survival rate.Conclusions. HCC is an emerging complication of cirrhosis in HIV-infected patients. A sharp increase in its incidence has occurred in those also infected by HCV in the recent years. Unfortunately, HCC is frequently diagnosed at an advanced stage, and mortality continues to be very high, with no significant changes in recent years. Earlier diagnosis, which may allow potentially curative therapy, is necessary. © 2012 The Author.


Juanola Roura X.,Hospital Universitari Of Bellvitge | Juanola Roura X.,Institute Dinvestigacio Biomedica Of Bellvitge | Collantes Estevez E.,Grupo de Estudio de las Espondiloartritis de la SER | Collantes Estevez E.,Instituto Maimonides Of Investigacion Biomedica Of Cordoba | And 10 more authors.
Reumatologia Clinica | Year: 2015

Objective: To design a strategy for the early detection and referral of patients with possible spondyloarthritis based on recommendations developed, agreed upon, and directed to primary care physicians. Methods: We used a modified RAND/UCLA methodology plus a systematic literature review. The information was presented to a discussion group formed by rheumatologists and primary care physicians. The group studied the process map and proposed recommendations and algorithms that were subsequently submitted in two Delphi rounds to a larger group of rheumatologists and primary care physicians. The final set of recommendations was derived from the analysis of the second Delphi round. Results: We present the recommendations, along with their mean level of agreement, on the early referral of patients with possible spondyloarthritis. The panel recommends that the study of chronic low back pain in patients under 45 years be performed in four phases 1) clinical: key questions, 2) clinical: extra questions, 3) physical examination, and 4) additional tests. Conclusions: The level of agreement with these simple recommendations is high. It is necessary to design strategies for the education and sensitization from rheumatology services to maintain an optimal collaboration with primary care and to facilitate referral to rheumatology departments. © 2014 Elsevier España, S.L.U.


Fernandez-Ramos J.A.,Hospital UniversitarioReina Sofia | Lopez-Laso E.,Instituto Maimonides Of Investigacion Biomedica Of Cordoba | Lopez-Laso E.,Hospital UniversitarioReina Sofia | Camino-Leon R.,Hospital UniversitarioReina Sofia | And 2 more authors.
Revista de Neurologia | Year: 2015

Introduction. Charcot-Marie-Tooth (CMT) is the most common hereditary sensory motor neuropathy. Advances in moleculardiagnosis have increased the diagnostic possibilities of these patients. Patients and methods. Retrospective study of 36 pediatric patients diagnosed with CMT in a tertiary center in 2003-2015. Results. We found 16 patients were diagnosed by a duplication in PMP22; two cases were diagnosed of hereditary neuropathy with liability to pressure palsies, one with a point mutation in PMP22; a male with a mild demyelinating phenotype, without family history, was diagnosed with GJB1 mutation; in a patient with a peripheral hypotonia at birth and axonal pattern in EMG by mutation in MFN2; a gypsy patient, with consanguineous family, CMT4D, was identified by a mutation in the gene NDRG1; a patient with multiplex congenital arthrogryposis and vocal cord paralysis, whose mother had a scapular-peroneal syndrome, had a congenital spinal muscular atrophy with mild distal axonal neuropathy by mutation in gene TRPV4; three girls, from a gypsy consanguineous family, with axonal CMT with neuromyotonic discharges were diagnosed by a mutation in the gene HINT1; twelve patients haven’t molecular diagnosis currently. Conclusions. CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series. © 2015 Revista de Neurología.


Fernandez-Ramos J.A.,Hospital Universitario Reina Sofia | Lopez-Laso E.,Hospital Universitario Reina Sofia | Lopez-Laso E.,Instituto Maimonides Of Investigacion Biomedica Of Cordoba | Simon-De las Heras R.,Hospital Universitario Doce Of Octubre | And 5 more authors.
Revista de Neurologia | Year: 2013

Introduction. The Aicardi syndrome is a disorder presumably X-linked dominant, classically defined by the triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms, with lethality in males. Patients and methods. Retrospective descriptive study of patients diagnosed with Aicardi syndrome over a period of 29 years in two tertiary pediatric hospitals. Results. We found seven women that developed infantile spasms before 6 months of age, epileptic spasms persisting beyond infancy in two cases, a refractory symptomatic partial epilepsy in three patients, and well-controlled partial epilepsy in one girl. Six cases presented severe-profound mental retardation and moderate-severe in a girl. Two girls died at 2 and 6 years-old. In all patients neuroimaging studies showed agenesis of the corpus callosum, intracranial cysts and malformations of cortical development. Ophthalmological lesions were chorioretinal lacunae in seven cases, anophthalmia/microphthalmia in four girls and optic nerve coloboma in three patients. Other findings were congenital heart disease, costovertebral abnormalities, cervical lymphangioma and focal hypertrichosis. Conclusions. The Aicardi syndrome should be suspected in girls with infantile spasms and agenesis of the corpus callosum. It is necessary to rule out these ophthalmologic abnormalities, malformations of cortical development and intracranial cysts. The prognosis is poor due to its high mortality and its evolution to refractory epilepsy and profound mental retardation. © 2013 Revista de Neurología.


Garcia-Jerez A.,University of Alcalá | Garcia-Jerez A.,REDinREN Institute Salud Carlos III | Luengo A.,University of Alcalá | Luengo A.,REDinREN Institute Salud Carlos III | And 12 more authors.
Journal of Physiology | Year: 2015

Key points: Patients with chronic kidney disease have a higher risk of developing cardiovascular diseases than the general population. Their vascular endothelium is dysfunctional, among other things, because it is permanently exposed to uraemic toxins, several of which have poor clearance by conventional dialysis. Recent studies have demonstrated the important role of integrin-linked kinase (ILK) in the maintenance of endothelial integrity and in this study we investigate the involvement of ILK in the mechanism underlying vascular endothelial damage that occurs in uraemia. For the first time, we demonstrate the implication of ILK in the protection against endothelial cell damage (inhibition of proliferation, toxicity, oxidative stress and programed cell death) induced by uraemic serum from chronic kidney disease patients and uraemic toxins. This molecular mechanism may have clinical relevance because it highlights the importance of maintaining high levels of ILK activity to help preserve endothelial integrity, at least in early stages of chronic kidney disease. Patients with chronic kidney disease (CKD) have a higher risk of developing cardiovascular diseases. Their vascular endothelium is dysfunctional, among other things, because it is permanently exposed to uraemic toxins, several of which, mostly protein-bound compounds such as indoxyl sulfate (IS) and p-cresyl sulphate, having poor clearance by conventional dialysis, induce endothelial toxicity. However, the molecular mechanism by which uraemic toxins regulate early stages of endothelial dysfunction remains unclear. Recent studies have demonstrated the important role of integrin-linked kinase (ILK) in the maintenance of endothelial integrity. In this study, we investigate the involvement of ILK in the mechanism underlying vascular endothelial damage that occurs in uraemia. First, we show that incubation of EA.hy926 cells with human uraemic serum from CKD patients upregulates ILK activity. This ILK activation also occurs when the cells are exposed to IS (25-100 μg ml-1), p-cresol (10-100 μg ml-1) or both combined, compared to human serum control. Next, we observed that high doses of both toxins together induce a slight decrease in cell proliferation and increase apoptosis and reactive oxygen species production. Interestingly, these toxic effects displayed a strong increase when the ILK protein is knocked down by small interfering RNA, even at low doses of uraemic toxins. Abrogation of AKT has demonstrated the ILK/AKT signalling pathway involved in these processes. This study has demonstrated the implication of ILK in the protection against endothelial cell damage induced by uraemic toxins, a molecular mechanism that could play a protective role in the early stages of endothelial dysfunction observed in uraemic patients. © 2014 The Physiological Society.


Navarrete C.M.,University of Cordoba, Spain | Perez M.,University of Cordoba, Spain | de Vinuesa A.G.,University of Cordoba, Spain | Collado J.A.,University of Cordoba, Spain | And 5 more authors.
Biochemical Pharmacology | Year: 2010

Cerebral microvascular endothelial cells play an active role in maintaining cerebral blood flow, microvascular tone and blood brain barrier (BBB) functions. Endogenous N-acyl-dopamines like N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine (OLDA) have been recently identified as a new class of brain neurotransmitters sharing endocannabinoid and endovanilloid biological activities. Endocannabinoids are released in response to pathogenic insults and may play an important role in neuroprotection. In this study we demonstrate that NADA differentially regulates the release of PGE2 and PGD2 in the microvascular brain endothelial cell line, b.end5. We found that NADA activates a redox-sensitive p38 MAPK pathway that stabilizes COX-2 mRNA resulting in the accumulation of the COX-2 protein, which depends on the dopamine moiety of the molecule and that is independent of CB1 and TRPV1 activation. In addition, NADA inhibits the expression of mPGES-1 and the release of PGE2 and upregulates the expression of L-PGD synthase enhancing PGD2 release. Hence, NADA and other molecules of the same family might be included in the group of lipid mediators that could prevent the BBB injury under inflammatory conditions and our findings provide new mechanistic insights into the anti-inflammatory activities of NADA in the central nervous system and its potential to design novel therapeutic strategies to manage neuroinflammatory diseases. © 2010 Elsevier Inc.


Chanclon B.,University of Cordoba, Spain | Chanclon B.,Instituto Maimonides Of Investigacion Biomedica Of Cordoba | Chanclon B.,Research Center Biomedica en Red | Martinez-Fuentes A.J.,University of Cordoba, Spain | And 5 more authors.
Frontiers in Endocrinology | Year: 2012

Somatostatin (SST), cortistatin (CORT), and its receptors (sst1-5), and ghrelin and its receptors (GHS-R) are two highly interrelated neuropeptide systems with a broad range of overlapping biological actions at central, cardiovascular, and immune levels among others. Besides their potent regulatory role on GH release, its endocrine actions are highlighted by SST/CORT and ghrelin influence on insulin secretion, glucose homeostasis, and insulin resistance. Interestingly, most components of these systems are expressed at the endocrine pancreas and are actively involved in the modulation of pancreatic islet function and, consequently influence glucose homeostasis. In addition, some of them also participate in islet survival and regeneration. Furthermore, under severe metabolic condition as well as in endocrine pathologies, their expression profile is severely deregulated. These findings suggest that SST/CORT and ghrelin systems could play a relevant role in pancreatic function under metabolic and endocrine pathologies. Accordingly, these systems have been therapeutically targeted for the prevention or amelioration of certain metabolic conditions (obesity) as well as for tumor growth inhibition and/or hormonal regulation in endocrine pathologies (neuroendocrine tumors). This review focuses on the interrelationship between SST/CORT and ghrelin systems and their role in severe metabolic conditions and some endocrine disorders. © 2012 Chanclón, Martínez-Fuentes and Gracia-Navarro.


Sanchez-Duffhues G.,University of Cordoba, Spain | Sanchez-Duffhues G.,Instituto Maimonides Of Investigacion Biomedica Of Cordoba | Vo M.Q.,University of Cordoba, Spain | Vo M.Q.,Instituto Maimonides Of Investigacion Biomedica Of Cordoba | And 7 more authors.
Current Drug Targets | Year: 2011

The persistence of latent HIV-infected cellular reservoirs represents the major hurdle to virus eradication in patients treated with highly active antiretroviral therapy. The molecular mechanisms by which integrated HIV-1 is repressed during latency have been partially identified in different models of HIV-1 latency, and the involvement of multiple processes has been demonstrated. Therefore, several molecular targets amenable to pharmacological manipulation have emerged to antagonize HIV-1 latency in the viral reservoirs. In this context, it has been suggested that successful depletion of such latent reservoirs will require a combination of therapeutic agents that can specifically and efficiently act on cells harbouring latent HIV-1 provirus. HIV-1 reactivation therapy is a potential therapeutic option to purge the viral reservoirs. The goal of this therapy is to enhance the transcriptional activity of the latent HIV-1 without inducing the polyclonal activation of non-infected cells. In this sense natural or semisynthetic protein kinase C agonists lacking tumour-promoter activities clearly fulfil this criterion, thereby opening new research avenues to purge HIV-1 reservoirs. In this review article, we have succinctly summarized the known effects of natural products, focusing on phorboids like prostratin and ingenols, macrolides like bryostatin 1, and macrocyclic polyesters like ingols and jatrophanes. A comprehensive view on the molecular mechanisms underlying the principle of HIV-1 reactivation from latency is provided, discussing the combination of natural products with other experimental or conventional therapeutics. © 2011 Bentham Science Publishers Ltd.

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