Alonso-Arias R.,Hospital Universitario Central Of Asturias |
Moro-Garcia M.A.,Hospital Universitario Central Of Asturias |
Vidal-Castineira J.R.,Hospital Universitario Central Of Asturias |
Solano-Jaurrieta J.J.,Hospital Monte Naranco |
And 3 more authors.
Aging Cell | Year: 2011
One of the most prominent changes during T-cell aging in humans is the accumulation of CD28 null T cells, mainly CD8+ and also CD4+ T cells. Enhancing the functional properties of these cells may be important as they provide an antigen-specific defense against chronic infections. Recent studies have shown that IL-15 does in fact play an appreciable role in CD4 memory T cells under physiological conditions. We found that treatment with IL-15 increased the frequency of elderly CD4+CD28 null T cells by the preferential proliferation of these cells compared to CD4+CD28+ T cells. IL-15 induced an activated phenotype in CD4+CD28 null T cells. Although the surface expression of IL-15R α-chain was not increased, the transcription factor STAT-5 was preferentially activated. IL-15 augmented the cytotoxic properties of CD4+CD28 null T cells by increasing both the mRNA transcription and storage of granzyme B and perforin for the cytolytic effector functions. Moreover, pretreatment of CD4+CD28 null T cells with IL-15 displayed a synergistic effect on the IFN-γ production in CMV-specific responses, which was not observed in CD4+CD28+ T cells. IL-15 could play a role enhancing the effector response of CD4+CD28 null T cells against their specific chronic antigens. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
Martin-Trujillo A.,Hospital Duran i Reynals |
Iglesias-Platas I.,Hospital Sant Joan Of Deu |
Coto E.,Hospital Universitario Central Asturias |
Corral-Juan M.,Health science Institute Germans Trias i Pujol |
And 5 more authors.
Epigenetics | Year: 2011
A fundamental challenge in the post-genomics era is to understand how genetic variants can influence phenotypic variability and disease. Recent observations from a number of studies have highlighted a mechanism by which common genetic polymorphisms can influence DNA methylation, a major epigenetic silencing mechanism. We report that the alternative promoter of the human TRPC3 gene is regulated by allelic DNA methylation, dictated by the genotype of a single base pair polymorphism, rs13121031, located within the promoter CpG island. The common G allele is associated with high levels of methylation, while the less prevalent C allele is unmethylated. This methylation profile is observed in many tissue types, despite the expression of TRPC3 being restricted to brain and heart. TRPC3 is prominently expressed in the hindbrain, and a heterozygous brain sample showed modest skewing according to the allelic methylation, with preferential expression from the C allele. The TRPC3 gene encodes a transient receptor potential channel that has been implicated in cerebellar ataxia and heart hypertrophy. The genotype-frequencies of rs13121031 were determined in cohorts of ataxia patients and in individuals with cardiac hypertrophy. These analyses revealed a statistical trend for the rare unmethylated homozygous C genotype to be present at a higher frequency in idiopathic ataxia patients (Fisher's test p = 0.06), but not in those patients with known mutations (Fisher's test p = 0.55) or in individuals with heart disease (Fisher's test p = 0.807), when compared to a control population. Our results suggest that the TRPC3 alternative promoter is a methylation quantitative-trait locus that may be involved in modulating the ataxia phenotype. © 2011 Landes Bioscience.
PubMed | Hospital Universitario La Paz, Hospital Universitario Of Leon, Hospital Universitario Central Asturias, Ico Hospitalet Of Llobregat and 10 more.
Type: Journal Article | Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | Year: 2016
Erythroleukemia was considered an acute myeloid leukemia in the 2008 World Health Organization (WHO) classification and is defined by the presence of 50% bone marrow erythroblasts, having <20% bone marrow blasts from total nucleated cells but 20% bone marrow myeloblasts from nonerythroid cells. Erythroleukemia shares clinicopathologic features with myelodysplastic syndromes, especially with erythroid-predominant myelodysplastic syndromes (50% bone marrow erythroblasts). The upcoming WHO revision proposes to eliminate the nonerythroid blast cell count rule and to move erythroleukemia patients into the appropriate myelodysplastic syndrome category on the basis of the absolute blast cell count. We conducted a retrospective study of patients with de novo erythroleukemia and compared their clinico-biological features and outcome with those of de novo myelodysplastic syndromes, focusing on erythroid-predominant myelodysplastic syndromes. Median overall survival of 405 erythroid-predominant myelodysplastic syndromes without excess blasts was significantly longer than that observed in 57 erythroid-predominant refractory anemias with excess blasts-1 and in 59 erythroleukemias, but no significant difference was observed between erythroid-predominant refractory anemias with excess blasts-1 and erythroleukemias. In this subset of patients with 50% bone marrow erythroblasts and excess blasts, the presence of a high-risk karyotype defined by the International Prognostic Scoring System or by the Revised International Prognostic Scoring System was the main prognostic factor. In the same way, the survival of 459 refractory anemias with excess blasts-2, independently of having 20% bone marrow blasts from nonerythroid cells or not, was almost identical to the observed in 59 erythroleukemias. Interestingly, 11 low-blast count erythroleukemias with 5 to <10% bone marrow blasts from total nucleated cells showed similar survival than the rest of erythroleukemias. Our data suggest that de novo erythroleukemia is in the spectrum of myelodysplastic syndromes with excess blasts and support its inclusion into future classifications of myelodysplastic syndromes.
PubMed | Hospital Universitario La Paz, Hospital Universitario 12 Of Octubre, University of Cordoba, Spain, Hospital Universitario Central Asturias and 13 more.
Type: | Journal: American journal of hematology | Year: 2016
Myelodysplastic syndromes (MDS) are the commonest hematologic malignancies in the elderly. Since many patients with MDS actually die from age-related ailments, the very disease burden of MDS remains largely unknown. This registry-based study was aimed at investigating the excess mortality attributable to MDS. We analyzed 7,408 adult patients diagnosed with primary MDS from 1980 to 2014. Excess mortality was estimated by comparing the patients survival with that expected in the matched general population. Median age of patients was 74 years, 58% were males, and 65% belonged to the lower risk categories of the Revised International Prognostic Scoring System (IPSS-R). Excess mortality accounted for three-fourths of the all-cause mortality and was mainly driven by factors unrelated to leukemic transformation. Excess mortality increased with the IPSS-R risk category [Incidence rate ratio (IRR): 2.1, 95% CI: 1.9-2.3; P<.001]. Older age and male sex retained an independent association with higher excess mortality after discounting demographic effects. Excess mortality increased in the most recent periods just in the higher risk IPSS-R categories (IRR: 1.2; 95% CI: 1.1-1.3 when comparing periods 2007-14, 2000-06, and 1980-99). In conclusion, MDS carry a significant excess mortality, even in the lower risk categories, that is mainly driven by factors unrelated to leukemic transformation, and increases with older age, male sex, and poorer risk categories. Excess mortality has increased in recent years in the higher risk patients, which might be ascribed to a parallel increase in age-related comorbidities. Our results claim for more comprehensive treatment strategies for patients with MDS.
PubMed | Hospital Universitario Central Asturias, University of Monastir, Habib Thameur Hospital and Abderrahmen Mami Hospital
Type: Journal Article | Journal: Genetic testing and molecular biomarkers | Year: 2016
Hypertrophic cardiomyopathy (HCM) is a common cardiac genetic disorder associated with heart failure and sudden death. Mutations in the cardiac sarcomere genes are found in approximately half of HCM patients and are more common among cases with a family history of the disease. Data about the mutational spectrum of the sarcomeric genes in HCM patients from Northern Africa are limited. The population of Tunisia is particularly interesting due to its Berber genetic background. As founder mutations have been reported in other disorders.We performed semiconductor chip (Ion Torrent PGM) next generation sequencing of the nine main sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1) as well as the recently identified as an HCM gene, FLNC, in 45 Tunisian HCM patients.We found sarcomere gene polymorphisms in 12 patients (27%), with MYBPC3 and MYH7 representing 83% (10/12) of the mutations. One patient was homozygous for a new MYL3 mutation and two were double MYBPC3 + MYH7 mutation carriers. Screening of the FLNC gene identified three new mutations, which points to FLNC mutations as an important cause of HCM among Tunisians.The mutational background of HCM in Tunisia is heterogeneous. Unlike other Mendelian disorders, there were no highly prevalent mutations that could explain most of the cases. Our study also suggested that FLNC mutations may play a role on the risk for HCM among Tunisians.
Garcia-Cabo C.,Hospital Universitario Central Asturias |
Moris G.,Hospital Universitario Central Asturias
European Journal of Internal Medicine | Year: 2015
Background and aims One of the most frequent neurologic complications reported in inflammatory bowel disease population is peripheral neuropathy; however, clinical aspects of peripheral nerve damage are not well characterized. The aim of the review is to present the existing literature on peripheral neuropathy in inflammatory bowel disease patients. Methods A literature search identified the publications reporting on epidemiology, clinical features, underlying mechanisms and management of ulcerative colitis and Crohn's disease patients with peripheral nerve involvement. Results The pathogenesis of peripheral nervous system damage in inflammatory bowel disease has yet to be elucidated, although it seems to be related to immune mechanisms; therefore, treatment with immunotherapy is recommended. In addition, peripheral neuropathy may appear as iatrogenic-related disorders associated with several drugs used in controlling inflammatory bowel disease activity; finally, peripheral neuropathy may also be caused by micronutrient deficiencies secondary to malabsorption-related disorders. Conclusions Although peripheral nervous nerve damage associated with inflammatory bowel disease is rarely reported, clinicians should be aware of the peripheral neuropathy clinical manifestations in order to recognize it and provide early treatment, which is crucial for preventing major neurologic morbidity. Heightened awareness is necessary for the successful management of these patients. © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Gonzalez-Lara L.,University of Oviedo |
Batalla A.,University of Oviedo |
Coto E.,Hospital Universitario Central Asturias |
Coto E.,University of Oviedo |
And 5 more authors.
Archives of Dermatological Research | Year: 2015
Genetic factors are involved not only in the overall risk of suffering psoriasis, but also in their clinical characteristics and eventually in drug outcome. Biological therapies have dramatically improved the prognosis of Psoriasis. However, these treatments are very expensive and patients often exhibit a heterogeneous response that could be partially attributed to their genetic background. Thus, the research for genetic markers in psoriatic patients that could predict a poor response to biological therapies is an important issue. Our aim was to evaluate the effect of DNA variants at the “TNFα pathway” that could affect the risk of developing Psoriasis or the response to biological therapies among these patients. The genetic association study included a total of 518 Psoriatic patients and 480 healthy controls. Ninety of these patients received biological treatment and based on the change in the PASI score after 24 weeks were classified as good (PASI score ≥75 %), intermediate (PASI 50–75), and non-responders (PASI <50). Next generation sequencing (NGS) with semiconductor-array technology was used to identify the nucleotide variants in the TNF α, TNFRSF1A and TNFRSF1B, and we only found three missense amino acid changes, all in TNFRSF1B. Interestingly, we found a significantly higher frequency of rs1061622 G carriers among CW6-positive patients (p = 0.004; OR = 1.69, 95 % CI = 1.18–2.41). Allele G (p.196R) carriers were significantly more frequent in the non-responder group (56 %) (p = 0.05). In conclusion, we report a significant association between the TNFRSF1B p.M196R variant and the risk for psoriasis and the response to treatment with anti-TNF or anti-Il-12/Il-23. The genotyping of this polymorphism could help to optimize the treatment by identifying patients with a likely poor response to biological drugs. © 2014, Springer-Verlag Berlin Heidelberg.
Benavente L.,Hospital Universitario Central Asturias |
Moris G.,Hospital San Agustin
European Journal of Neurology | Year: 2011
Background and purpose: The study is aimed to report neurologic manifestations in a population of patients with inflammatory bowel disease in order to address its clinical characteristics.Methods: We conducted a retrospective study based on a computer-guided search, of patients with Crohn's disease or ulcerative colitis diagnosed at three hospitals in Spain spanning from 2000 through 2008. Patients were classified into different clinical groups based on the type of neurologic involvement. Only patients without iatrogenic complications, vitamin deficiencies, or known cerebrovascular risk factors were included.Results: We identified and reviewed the records of eighty-four inflammatory bowel disease patients with neurologic symptoms: thirteen patients with ulcerative colitis and twelve patients with Crohn's disease associated with neurologic complications were identified. Their ages ranged from 17 to 74 years. There was a slight predominance of women. Only four of them have another extra-intestinal manifestation. Most of the patients developed neurologic manifestations coincidental or after digestive symptoms appeared. Demyelinating disease was the most frequent manifestation observed (8 patients). Cerebrovascular, peripheral nerve, and epilepsy disorders were diagnosed in 6, 5, and 3 patients, respectively. One patient with myoclonus, one with amyotrophic lateral sclerosis, and one with sensorineural hearing loss were found.Conclusions: Although an incidence could not be obtained, this population of patients with inflammatory bowel disease have a low frequency of severe neurologic disorders. Neurologic diseases, such as cerebrovascular disease, demyelinating disease, and peripheral neuropathy, could be associated with Crohn's disease and ulcerative colitis. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.
Gomez J.,Hospital Universitario Central Asturias |
Reguero J.R.,Hospital Universitario Central Asturias |
Moris C.,Hospital Universitario Central Asturias |
Moris C.,University of Oviedo |
And 3 more authors.
Journal of Cardiovascular Translational Research | Year: 2014
DNA variants at the genes encoding cardiac channels have been associated with inherited arrhythmias and the QT interval in the general population. Next generation sequencing technologies would be of special interest to uncover the genetic variation at these genes. The amplification and sequencing of DNA pools (instead of single individuals) would facilitate the rapid and cost-effective screening of large amounts of individuals. However, this pooling strategy could result in a signal of the rare variants below the detection capacity. To validate this approach, a pool of 20 individuals with known rare unique variants in five genes was amplified in only two tubes and sequenced using the non optical semi-conductor (Ion Torrent PGM, Life Technologies) technology. We show that this could be an effective strategy for the screening of large cohorts. Among others, this would facilitate the discovery of new sequence variants linked to cardiac arrhythmia in the general population. © 2013 Springer Science+Business Media New York.
Moris G.,Hospital Universitario Central Asturias
World Journal of Gastroenterology | Year: 2014
Only a very few systematic studies have investigated the frequency of neurologic disorders in patients with Crohn's disease (CD) and ulcerative colitis (UC), which are the two main types of inflammatory bowel disease (IBD). Results have been inconsistent and variable, owing to differences in case-finding methods and evaluated outcomes in different studies. The most frequent neurologic manifestations reported in CD and UC populations are cerebrovascular disease (with either arterial or venous events), demyelinating central nervous system disease, and peripheral neuropathy (whether axonal or demyelinating); however, the literature describes numerous nervous system disorders as being associated with IBD. The pathogenesis of nervous system tissue involvement in IBD has yet to be elucidated, although it seems to be related to immune mechanisms or prothrombotic states. The recently-introduced tumor necrosis factor (TNF) inhibitors have proven successful in controlling moderate to severe IBD activity. However, severe neurologic disorders associated with TNF inhibitors have been reported, which therefore raises concerns regarding the effect of anti-TNF-α antibodies on the nervous system. Although neurological involvement associated with IBD is rarely reported, gastroenterologists should be aware of the neurologic manifestations of IBD in order to provide early treatment, which is crucial for preventing major neurologic morbidity. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.