The Spanish HIV BioBank: a model of cooperative HIV research

<p>Abstract</p> <p>Background</p> <p>The collection of samples from HIV-infected patients is the beginning of the chain of translational research. To carry out quality research that could eventually end in a personalized treatment for HIV, it is essential to guarantee the availability, quality and traceability of samples, under a strict system of quality management.</p> <p>Methods</p> <p>The Spanish HIV BioBank was created with the objectives of processing, storing and providing distinct samples from HIV/AIDS patients, categorized according to strictly defined characteristics, free of charge to research projects. Strict compliance to ethical norms is always guaranteed.</p> <p>Results</p> <p>At the moment, the HIV BioBank possesses nearly 50,000 vials containing different prospective longitudinal study sample types. More than 1,700 of these samples are now used in 19 national and international research projects.</p> <p>Conclusion</p> <p>The HIV BioBank represents a novel approach to HIV research that might be of general interest not only for basic and clinical research teams working on HIV, but also for those groups trying to establish large networks focused on research on specific clinical problems. It also represents a model to stimulate cooperative research among large numbers of research groups working as a network on specific clinical problems. The main objective of this article is to show the structure and function of the HIV BioBank that allow it to very efficiently release samples to different research project not only in Spain but also in other countries.</p

Mixed Th2 and non-Th2 inflammatory pattern in the asthma-COPD overlap : a network approach

Altres ajuts: The authors are grateful to all the patients who participated in the study. A number of investigators contributed to the study logistics and they are listed in the Supplementary materials. The project was endorsed by the COPD and Asthma Research Board (PII de EPOC y asma) of the Spanish Society of Pneumology and Thoracic Surgery (SEPAR).The asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical condition that combines features of those two diseases, and that is difficult to define due to the lack of understanding of the underlying mechanisms. Determining systemic mediators may help clarify the nature of inflammation in patients with ACO. We aimed at investigating the role and interaction of common markers of systemic inflammation (IL-6, IL-8, and tumor necrosis factor-α), Th2-related markers (periostin, IL-5, and IL-13), and IL-17 in asthma, COPD, and ACO. This is a cross-sectional study of patients aged ≥40 years with a post-bronchodilator forced expiratory volume in the first second/forced vital capacity 10 pack-years in a patient with a previous diagnosis of asthma or by the presence of eosinophilia in a patient with a previous diagnosis of COPD. Clinical, functional, and inflammatory parameters were compared between categories using discriminant and network analysis. In total, 109 ACO, 89 COPD, and 94 asthma patients were included. Serum levels (median [interquartile range]) of IL-5 were higher in asthma patients than in COPD patients (2.09 [0.61-3.57] vs 1.11 [0.12-2.42] pg/mL, respectively; p =0.03), and IL-8 levels (median [interquartile range]) were higher in COPD patients than in asthma patients (9.45 [6.61-13.12] vs 7.03 [4.69-10.44] pg/mL, respectively; p <0.001). Their values in ACO were intermediate between those in asthma and in COPD. Principal component and network analysis showed a mixed inflammatory pattern in ACO in between asthma and COPD. IL-13 was the most connected node in the network, with different weights among the three conditions. Asthma and COPD are two different inflammatory conditions that may overlap in some patients, leading to a mixed inflammatory pattern. IL-13 could be central to the regulation of inflammation in these conditions

Modelling the consumption of anxiolytics and its addictive behaviour

Background: Population-based anxiolytics consumption (AX) is a widely debated subject because long-term AX may lead to tolerance and addiction. This study aims to obtain mathematical models that identify the various behaviours in AX prescription in accordance with gender, age and the continuous prescription of other drugs associated with chronic diseases.Methods: Data were obtained from an electronic prescriptions database (n=12,211,992) received by patients (n=504,224) visiting the Primary Health Care Centres in the province of Castellón (East Spain) in 2009. A linear regression model was used to explain the number of defined daily doses (DDD) of AX prescribed in accordance with age, gender and more than 5 prescriptions of any drug associated with chronic diseases other than AX. We used the logistic regression model to quantify the joint influence of the explanatory variables on the likelihood (L) of prescribing increasingly high DDD of AX.Results: The mean annual DDD per patient was 133.13, and the DDD prescribed was 38.06 day/1000 inhabitants. Few differences, although significant, in prescriptions per gender were observed; males received fewer prescriptions than females. Conversely, differences in age groups were substantial; the older subjects become, the higher the prescribed DDD, although these differences disappeared after the age of 65. AX use was also positively associated with the presence of comorbidity: depression, psychosis and epilepsy. Sporadic AX prescriptions were not associated with any factor, except continuous use.Conclusions: The prevalence of prescribing AX in the general population visiting the primary health centres in Castellón is over 16%. Prescriptions and the DDD of AX are barely higher for females than for males, and age is the most influential factor; the older the patient, the higher the number of prescribed DDD. The likelihood of potentially addictive behaviours is higher among the elderly and patients with comorbidity, mainly those patients with other chronic psychiatric conditions. © 2010 Elsevier Ltd.Guadalajara Olmeda, MN.; Barrachina Martínez, I.; De La Poza, E.; Vivas Consuelo, DJJ.; Caballer Tarazona, M. (2011). Modelling the consumption of anxiolytics and its addictive behaviour. Mathematical and Computer Modelling. 54(7):1626-1633. https://doi.org/10.1016/j.mcm.2010.12.036S1626163354

Altered transcriptional regulators in response to serum in immortalized lympozytes from Alzheimer disease patients

This work has been supported by grants from the Spanish Fondo de Investigaciones Sanitarias (01/1194), Ministerio de Ciencia y Tecnología (SAF 2003-01458) and the “Fundación Rodríguez Pascual”. N.C. and U.M. are fellows from the Fondo de Investigaciones Sanitarias de la Seguridad Social and Ministerio de Educación y Cultura, respectivelyCell cycle disturbances may precede neuronal death in Alzheimer's disease (AD). We described alterations, in lymphocytes from AD patients, on the activity of two transcription factors, E2F and NF-κB, involved in cell proliferation and survival regulation, demonstrating that cell cycle dysfunction also occurs in peripheral cells. The analysis of E2F–DNA binding activity revealed lower signal intensity of protein–DNA complexes in AD cells, which correlated with increased phosphorylation of retinoblastoma (pRb) related proteins and enhanced proliferation. The calmodulin (CaM) antagonist calmidazolium (CMZ) abrogated the increased activity of AD cells by partially dephosphorylating pRb and p130. The NF-κB–DNA binding activity increased as cell progress through the cell cycle. The reduced NF-κB activation observed in AD cells appears not to be related to the increased phosphorylation of the pRb family proteins nor with the enhanced proliferative activity of AD cells, but seems to protect them from death induced by the loss of trophic support. Ca2+/CaM antagonists rescue NF-κB–DNA binding activity and sensitize AD cells to serum withdrawal. These observations suggest that disruption of Ca2+/CaM signaling pathway could be linked mechanistically to its pro cell survival actions, promoting enhanced proliferation or decreased cell death depending on the presence of growth-stimulatory signals10 páginas, 7 figuras -- PAGS nros. 615-624Peer reviewe

Impaired apoptosis in lymphoblasts from Alzheimer´s disease patients: Cross-talk of Ca(2+)/calmodulin and ERK1/2 signaling pathways

12 páginas, 11 figuras -- PAGS nros. 1437-1448We have analyzed the intracellular signals that allow lymphoblasts from Alzheimer’s disease (AD) patients to escape from serum deprivation-induced apoptosis. The following observations suggested that modulation of ERK1/2 activity by Ca2+/calmodulin (CaM) is involved in preventing apoptosis: (i) ERK1/2 activity seems to support lethality in control cells, as PD98059, the inhibitor of the activating MEK prevented cell death; (ii) control cells show a persistent and higher stimulation of ERK1/2 than that of AD cells in the absence of serum; (iii) CaM antagonists have no effects on control cells, but sensitize AD cells to death induced by serum withdrawal and increased ERK1/2 phosphorylation, and (iv) no apoptotic effects of CaM antagonists were observed in AD cells treated with PD98059. These results suggest the existence of an activation threshold of the ERK1/2 pathway setting by Ca2+/CaM-dependent mechanisms, which appears to be the critical factor controlling cell survival or death decision under trophic factor withdrawalThis work has been supported by grants from the Spanish Fondo de Investigaciones Sanitarias (FIS PI040312). F.B. holds a contract of the CSIC (I3P program). N.C. and U.M. are fellows from the Fondo de Investigaciones Sanitarias de la Seguridad Social and Ministerio de Educación y Ciencia, respectivelyPeer reviewe

Cell cycle and Alzheimer´s disease. Studies in non-neuronal cells

10 páginas, 1 figura, 1 tabla -- PAGS nros. 121-130The most common cause of dementia in the elderly is Alzheimer disease (AD). In Europe, AD is a leading cause of death. The prevalence of this disease in developed countries is increasing because of very significant shifts in life expectancy and demographic parameters. AD is characterized by progressive cognitive impairment, resulting from dysfunction and degeneration of neurons in the limbic and cortical regions of the brain. Two prominent abnormalities in the affected brain regions are extracellular deposits of beta-amyloid, and intracellular aggregates of tau protein in neurofibrillary tangles. The role of these features in AD pathogenesis and progression is not yet completely elucidated. Research over the last decade has revealed that the activation of cell cycle machinery in postmitotic neurons is one of the earliest events in neuronal degeneration in AD. Here we summarize evidence to support the hypothesis that cell cycle alterations occur in cells other than neurons in AD sufferers. Immortalized lymphocytes from AD patients have show an enhanced rate of proliferation associated with G1/S regulatory failure induced by alterations in the cyclin/CDK/pRb/E2F pathway. In addition, these cells have a higher resistance to serum deprivation-induced apoptosis. These neoplastic-like features, cell cycle dysfunction and impaired apoptosis can be considered systemic manifestations of AD diseaseWork in the authors's laboratory has been supported from grants from the Spanish Fondo de Investigaciones Sanitarias (FIS 01/1194 and PI040312), the Spanish Ministry of Science and Innovation (SAF 2003-01458 and SAF 2007-62405), and the Fundacion E. Rodriguez PascualPeer reviewe

The cyclopentenone 15-deoxy-D-12,14-Prostaglandin J2 inhibits G1/S transition and retinoblastoma protein phosphorylation in immortalized lymphocytes from Alzheimer´s disease patients

10 páginas, 9 figuras -- PAGS nros. 508-517Epidemiologic studies indicated that non-steroidal anti-inflammatory drugs (NSAIDs) might prevent or delay the clinical features of Alzheimer disease (AD). The pharmacological activity of NSAIDs is generally attributed to inhibition of cyclooxygenase and peroxisome proliferator-activated receptor γ (PPARγ) activation. Based on the antineoplastic and apoptotic effects of PPARγ activation in a number of cell types, we hypothesized that NSAIDs could protect neurons by controlling the regulation of cell cycle. Recent work suggests that uncoordinated expression of cell cycle molecules and perturbation of cell cycle checkpoints may be one of the mechanisms by which post-mitotic neurons die. Since cell cycle dysfunction is not restricted to neurons in AD, we found it interesting to study the role of PPARγ activation on cell proliferation in immortalized lymphocytes from AD patients. We report here that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), but not NSAIDs or thiazolidinediones inhibited the serum-mediated enhancement of cell proliferation in AD by blocking the events critical for G1/S transition. The cyclopentenone induced a partial inhibition of retinoblastoma protein phosphorylation and increased levels of the CDK inhibitor p27kip1This work has been supported by grants from the Spanish Fondo de Investigaciones Sanitarias (FIS PI040312), Ministerio de Ciencia y Tecnología (SAF 2003-01458). N.C. and U.M. are fellows from the Fondo de Investigaciones Sanitarias de la Seguridad Social and Ministerio de Educación y Ciencia, respectivelyPeer reviewe

Ca2+/calmodulin-dependent modulation of cell cycle elements, pRb and p27kip1 involved in the enhanced proliferation of lymphoblasts from patients with Alzheimer dementia

Failure of cell cycle regulation in neurons might be critically involved in the process of neurodegeneration in Alzheimer's disease (AD). We present here evidence to support the hypothesis that cell cycle alterations occur in cells other than neurons in AD sufferers. Lymphocytes from AD patients immortalized with Epstein-Barr virus showed an enhanced rate of proliferation and increased phosphorylation of the retinoblastoma protein (pRb) and other members of the family of pocket proteins compared with cell lines derived from normal age-matched controls. The calmodulin antagonist calmidazolium, as well as W-7 and W-13, abrogated the enhanced activity of AD cells without altering the normal basal rate of proliferation. The effect of calmidazolium was accompanied by partially dephosphorylation of pRb. No changes were found in the expression levels of the G1 cyclin/Cdks complexes. However, lymphoblasts derived from AD patients showed reduced levels of the Cdk inhibitor p27kip1, which were restored after anti-calmodulin treatment of the cultures. These observations suggest that in AD cells the enhanced rates of cell proliferation and phosphorylation of pRb and the intracellular content of p27kip1 may be interrelated events controlled by a mechanism dependent on the Ca2+/calmodulin signaling pathway. The distinct functional features of lymphoblastoid cells from AD patients offer an invaluable, noninvasive tool to investigate the etiopathogenesis, and eventually, for the early diagnosis and prognosis of this devastating disease. © 2003 Elsevier Science (USA). All rights reserved.This work has been supported by grants from the Spanish Fondo de Investigaciones Sanitarias (01/1194) and the “Fundación Rodríguez Pascual.” N.C. is a fellow from the Fondo de Investigaciones Sanitarias de la Seguridad SocialPeer Reviewe

Thermal processing effects on the IgE-reactivity of cashew and pistachio

Thermal processing can modify the structure and function of food proteins and may alter their allergenicity. This work aimed to elucidate the influence of moist thermal treatments on the IgE-reactivity of cashew and pistachio. IgE-western blot and IgE-ELISA were complemented by Skin Prick Testing (SPT) and mediator release assay to determine the IgE cross-linking capability of treated and untreated samples. Moist thermal processing diminished the IgE-binding properties of both nuts, especially after heat/pressure treatment. The wheal size in SPT was importantly reduced after application of thermally-treated samples. For cashew, heat/pressure treatedsamples still retain some capacity to cross-link IgE and degranulate basophils, however, this capacity was diminished when compared with untreated cashew. For pistachio, the degranulation of basophils after challenge with the harshest heat/pressure treatment was highly decreased. Boiling produced more variable results, however this treatment applied to both nuts for 60 min, led to an important decrease of basophil degranulation

Asthma-COPD overlap is not a homogeneous disorder : Further supporting data

Asthma-COPD ovelap (ACO) is an umbrella term that encompasses patients with COPD and eosinophilic inflammation (e-COPD) and smoking asthmatics with non-fully reversible airflow obstruction (SA). We compared the clinical characteristics and the inflammatory profile of e-COPD and SA. Patients classified as e-COPD were older and more often male and showed significantly impaired pulmonary function (likely explained by a heavier smoking habit). On the contrary, SA had more atopic features, more reversibility of airflow obstruction and higher IgE levels. The concentrations of IL-5, IL-13, IL-8, IL-6, TNF-α, IL17 in serum were similar between the 2 groups. However, Th2-related biomarkers (periostin, FeNO and blood eosinophils) shower higher median values in e-COPD patients. Our findings reinforce the notion that ACO is a heterogeneous disorder and, as a consequence, it might be unacceptable to offer the same treatment for two related but different conditions