Publications by authors named "Sergio Mora"

22 Publications

  • Page 1 of 1

Seasonal dynamics of biochemical composition and fatty acids of swordfish (Xiphias gladius) in the Southeast Pacific Ocean off the coast of Chile.

Mar Environ Res 2021 Jul 9;169:105388. Epub 2021 Jun 9.

Centro de Investigación en Biodiversidad y Ambientes Sustentables (CIBAS), Universidad Católica de la Santísima Concepción, Concepción, Chile; Departamento de Ecología, Facultad de Ciencias, Universidad Católica de la Santísima Concepción, Casilla 297, Concepción, Chile. Electronic address:

In the Southeast Pacific Ocean, Xiphias gladius migrates through the Chilean coastal zone for feeding. Here, it forages for different prey items from autumn to spring, acquiring a great variety of energy and nutritional reserves. We evaluated seasonal variations in the biochemical reserves (i.e., contents of lipids, proteins, and glucose), total energy content and fatty acid profile of specimens captured during the austral autumn, winter, and spring. Our results show that higher amounts of lipids were found in the winter and spring, while protein and glucose were higher in the autumn. Thus, the energy content showed significant differences, with higher levels in winter and spring. Furthermore, the fatty acid profile was more diverse in the spring than the autumn and winter and was characterized by higher amounts of polyunsaturated fatty acids. These findings suggest that temporal changes in the biochemical reserves, total energy content and fatty acid profile support the idea of a "trophic migration" (i.e., the feeding period) established by the dynamics of fishery fleets. The high amounts of lipids and diverse fatty acid profile found in the spring could indicate the end of the trophic migration during this season. Thus, X. gladius may reach an optimum nutritional condition in the spring and make energetic adjustments to carry out its reproductive migration during the austral summer. Therefore, this species seems to meet the high energy demands of the reproductive season by foraging for a wide range of prey items from autumn to spring and storing an increased amount of lipids at the end of the feeding period. Overall, our data provides crucial baseline knowledge for future research on the ecophysiology of X. gladius, as well as for the management and conservation of this fishery resource under an ecosystem approach.
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http://dx.doi.org/10.1016/j.marenvres.2021.105388DOI Listing
July 2021

The age again in the eye of the COVID-19 storm: evidence-based decision making.

Immun Ageing 2021 May 20;18(1):24. Epub 2021 May 20.

Department of Immunology, Hospital Torrecárdenas, Almería, Spain.

Background: One hundred fifty million contagions, more than 3 million deaths and little more than 1 year of COVID-19 have changed our lives and our health management systems forever. Ageing is known to be one of the significant determinants for COVID-19 severity. Two main reasons underlie this: immunosenescence and age correlation with main COVID-19 comorbidities such as hypertension or dyslipidaemia. This study has two aims. The first is to obtain cut-off points for laboratory parameters that can help us in clinical decision-making. The second one is to analyse the effect of pandemic lockdown on epidemiological, clinical, and laboratory parameters concerning the severity of the COVID-19. For these purposes, 257 of SARSCoV2 inpatients during pandemic confinement were included in this study. Moreover, 584 case records from a previously analysed series, were compared with the present study data.

Results: Concerning the characteristics of lockdown series, mild cases accounted for 14.4, 54.1% were moderate and 31.5%, severe. There were 32.5% of home contagions, 26.3% community transmissions, 22.5% nursing home contagions, and 8.8% corresponding to frontline worker contagions regarding epidemiological features. Age > 60 and male sex are hereby confirmed as severity determinants. Equally, higher severity was significantly associated with higher IL6, CRP, ferritin, LDH, and leukocyte counts, and a lower percentage of lymphocyte, CD4 and CD8 count. Comparing this cohort with a previous 584-cases series, mild cases were less than those analysed in the first moment of the pandemic and dyslipidaemia became more frequent than before. IL-6, CRP and LDH values above 69 pg/mL, 97 mg/L and 328 U/L respectively, as well as a CD4 T-cell count below 535 cells/μL, were the best cut-offs predicting severity since these parameters offered reliable areas under the curve.

Conclusion: Age and sex together with selected laboratory parameters on admission can help us predict COVID-19 severity and, therefore, make clinical and resource management decisions. Demographic features associated with lockdown might affect the homogeneity of the data and the robustness of the results.
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http://dx.doi.org/10.1186/s12979-021-00237-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134808PMC
May 2021

Design of an algorithm for the diagnostic approach of patients with joint pain.

Clin Rheumatol 2021 Apr 25;40(4):1581-1591. Epub 2020 Aug 25.

Hospital General Luis Vernaza, Universidad de Especialidades Espíritu Santo, Guayaquil, Ecuador.

Background: Rheumatic diseases are a reason for frequent consultation with primary care doctors. Unfortunately, there is a high percentage of misdiagnosis.

Objective: To design an algorithm to be used by primary care physicians to improve the diagnostic approach of the patient with joint pain, and thus improve the diagnostic capacity in four rheumatic diseases.

Methods: Based on the information obtained from a literature review, we identified the main symptoms, signs, and paraclinical tests related to the diagnosis of rheumatoid arthritis, spondyloarthritis with peripheral involvement, systemic lupus erythematosus with joint involvement, and osteoarthritis. We conducted 3 consultations with a group of expert rheumatologists, using the Delphi technique, to design a diagnostic algorithm that has as a starting point "joint pain" as a common symptom for the four diseases.

Results: Thirty-nine rheumatologists from 18 countries of Ibero-America participated in the Delphi exercise. In the first consultation, we presented 94 items to the experts (35 symptoms, 31 signs, and 28 paraclinical tests) candidates to be part of the algorithm; 74 items (25 symptoms, 27 signs, and 22 paraclinical tests) were chosen. In the second consultation, the decision nodes of the algorithm were chosen, and in the third, its final structure was defined. The Delphi exercise lasted 8 months; 100% of the experts participated in the three consultations.

Conclusion: We present an algorithm designed through an international consensus of experts, in which Delphi methodology was used, to support primary care physicians in the clinical approach to patients with joint pain. Key Points • We developed an algorithm with the participation of rheumatologists from 18 countries of Ibero-America, which gives a global vision of the clinical context of the patient with joint pain. • We integrated four rheumatic diseases into one tool with one common symptom: joint pain. It is a novel tool, as it is the first algorithm that will support the primary care physician in the consideration of four different rheumatic diseases. • It will improve the correct diagnosis and reduce the number of paraclinical tests requested by primary care physicians, in the management of patients with joint pain. This point was verified in a recently published study in the journal Rheumatology International (reference number 31).
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http://dx.doi.org/10.1007/s10067-020-05323-wDOI Listing
April 2021

COVID-19: age, Interleukin-6, C-reactive protein, and lymphocytes as key clues from a multicentre retrospective study.

Immun Ageing 2020 14;17:22. Epub 2020 Aug 14.

Laboratory Unit. Complejo Hospitalario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain.

Background: The SARS-CoV-2 infection has widely spread to become the greatest public health challenge to date, the COVID-19 pandemic. Different fatality rates among countries are probably due to non-standardized records being carried out by local health authorities. The Spanish case-fatality rate is 11.22%, far higher than those reported in Asia or by other European countries. A multicentre retrospective study of demographic, clinical, laboratory and immunological features of 584 Spanish COVID-19 hospitalized patients and their outcomes was performed. The use of renin-angiotensin system blockers was also analysed as a risk factor.

Results: In this study, 27.4% of cases presented a mild course, 42.1% a moderate one and for 30.5% of cases, the course was severe. Ages ranged from 18 to 98 (average 63). Almost 60 % (59.8%) of patients were male. Interleukin 6 was higher as severity increased. On the other hand, CD8 lymphocyte count was significantly lower as severity grew and subpopulations CD4, CD8, CD19, and NK showed concordant lowering trends. Severity-related natural killer percent descents were evidenced just within aged cases. A significant severity-related decrease of CD4 lymphocytes was found in males. The use of angiotensin-converting enzyme inhibitors was associated with a better prognosis. The angiotensin II receptor blocker use was associated with a more severe course.

Conclusions: Age and age-related comorbidities, such as dyslipidaemia, hypertension or diabetes, determined more frequent severe forms of the disease in this study than in previous literature cohorts. Our cases are older than those so far reported and the clinical course of the disease is found to be impaired by age. Immunosenescence might be therefore a suitable explanation for the hampering of immune system effectors. The adaptive immunity would become exhausted and a strong but ineffective and almost deleterious innate response would account for COVID-19 severity. Angiotensin-converting enzyme inhibitors used by hypertensive patients have a protective effect in regards to COVID-19 severity in our series. Conversely, patients on angiotensin II receptor blockers showed a severer disease.
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http://dx.doi.org/10.1186/s12979-020-00194-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426672PMC
August 2020

Effects of Cycloleucine in the Nucleus Accumbens Septi on the Elevated plus Maze Test in Rats.

Neuropsychobiology 2020 10;79(3):191-197. Epub 2020 Jan 10.

Laboratory of Neurosciences and Experimental Psychology, CONICET, Department of Pathology, Faculty of Medical Sciences, National University of Cuyo, Mendoza, Argentina,

Introduction: In recent years, an important number of studies have emphasized the psychopharmacological actions of cycloleucine (1-aminocyclopentanecarboxylic acid) acting on the NR1 subunit (glycine allosteric site) of NMDA (N-methyl-D-aspartic acid) receptor. We studied the effects of its injection in an anxiety test.

Methods: The elevated plus maze test was used. Male rats bilaterally cannulated into the nucleus accumbens septi (NAS) were employed. Rats were divided into 5 groups that received either 1 µL injections of saline or cycloleucine (0.5, 1, 2, or 4 µg) 15 min before testing.

Results: Time spent in the open arm was significantly increased by cycloleucine treatment with all doses (1 and 2 µg, p < 0.05; 0.5 and 4 µg, p < 0.01), like number of extreme arrivals (0.5 and 1 µg, p < 0.05; 2 µg, p < 0.01; and 4 µg, p < 0.001). Open arm entries were increased by the highest dose only (4 µg, p < 0.01).

Discussion/conclusion: Present results show no difference between all doses in the time spent in the open arm, suggesting an indirect, noncompetitive action of the drug. The increase in extreme arrivals and open arm entries suggests a dose influence in these parameters. We conclude that cycloleucine influence on the NMDA receptors within NAS leads to anxiolytic-like effects and behavioral disinhibition, which once more confirms the involvement of NAS in anxiety processing.
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http://dx.doi.org/10.1159/000505069DOI Listing
January 2021

Drug reaction with eosinophilia and systemic symptoms (DRESS) and multiple organ dysfunction syndrome (MODS): one more reason for a new effective treatment against leishmaniasis.

Int J Dermatol 2018 Nov 29;57(11):1304-1313. Epub 2018 Aug 29.

Advanced Training in Medicine & Postgraduate Medical Residency, University Hospital of the Samaritan ESE, Bogotá, Colombia.

Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe drug-induced reaction associated with eosinophilia and systemic manifestations. Anticonvulsants, sulfonamides, and antivirals are the most related and described drugs in DRESS syndrome.

Methods And Case: We present a case of severe multiple organ dysfunction syndrome (MODS) with the risk of death associated with DRESS syndrome due to antileishmanial pentavalent antimonial drug and its simultaneous toxicity. Consequently, a comprehensive review of the main clinical problems and comparative discussion of both clinical conditions was made.

Discussion: The overlap of DRESS syndrome and antileishmanial pentavalent antimonial drug toxicity can be life-threatening. Both conditions represent a true clinical, diagnostic, and therapeutic challenge. We exposed specific clinical and laboratory results with rare occurrence.

Conclusion: Any physician and dermatologists should keep in mind the broad spectrum of clinical manifestations and laboratory findings associated with the use of pentavalent antimonial drugs. The clinical suspicion, an early diagnosis, and aggressive treatment are essential to prevent complications and death.
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http://dx.doi.org/10.1111/ijd.14126DOI Listing
November 2018

The effect of an educational intervention, based on clinical simulation, on the diagnosis of rheumatoid arthritis and osteoarthritis.

Musculoskeletal Care 2018 03 13;16(1):147-151. Epub 2017 Dec 13.

Clinical Epidemiology and Biostatistics Department, Medical School, Pontificia Universidad Javeriana, Bogota, Colombia.

Objective: The aim of the present study was to evaluate the effectiveness of an educational tool for general physicians, based on rheumatological clinical simulation, for the diagnosis of rheumatoid arthritis and osteoarthritis.

Methods: A randomized clinical study was carried out, in which the physician research subjects were assigned to one of two groups: the experimental group (educational intervention for rheumatoid arthritis with clinical simulation) or the control group (educational intervention for the basic aspects of the diagnosis and treatment of osteoporosis). Four weeks after the educational intervention, the members of both groups completed an examination that included four clinical cases with real patients, two clinical cases with two clinical simulation models and six virtual clinical cases. In this examination, the participants noted clinical findings, established a diagnosis and defined the complementary tests they would request, if necessary, to corroborate their diagnosis.

Results: A total of 160 doctors participated (80 in the active educational intervention for rheumatoid arthritis and 80 in the control group), of whom 89 were women (56%). The mean age was 35 (standard deviation 7.7) years. Success was defined as a physician correctly diagnosing at least 10 of the 12 cases presented. A significant difference of 81.3% (95% confidence interval 72-90%; p < 0.001) in success was found in favour of the active group (88.8% versus 7.5%). A greater number of correct answers was found in the active group compared with the control group in the detection of clinical findings and in the number of complementary tests requested (p < 0.001).

Conclusions: The study showed the effectiveness of an educational intervention based on clinical simulation to improve the diagnostic approach to rheumatoid arthritis and osteoarthritis. The results open a new horizon in the teaching of rheumatology.
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http://dx.doi.org/10.1002/msc.1228DOI Listing
March 2018

Relapsing polychondritis, an underestimated dermatological urgency: case report and literature review.

Int J Dermatol 2017 Dec 9;56(12):1379-1386. Epub 2017 Oct 9.

Dermatology Service, Samaritana University Hospital - ESE, Bogotá, Colombia.

Background: Relapsing polychondritis is an autoimmune multisystemic disease with primary chondral involvement. Its high mortality and morbidity make it a real clinical challenge.

Case Description: A 32-year-old woman with a history of relapsing polychondritis, refractory to multiple treatments, with multisystem compromise, imminent risk of death due to severe tracheobronchial damage and difficult ventilatory support, and successful treatment with infliximab.

Discussion And Evaluation: Several treatments have been described in the literature, such as nonsteroidal anti-inflammatory drugs, corticosteroids, dapsone, azathioprine, cyclosporine, cyclophosphamide, and methotrexate. However, the cases refractory to conventional therapy may lead to chronicity, irreversibility, and death. As a result, a third-line therapy could improve the prognosis of these patients.

Conclusions: Biological therapy is a good option for disease control and quality of life improvement. In addition, the physician should consider these treatments to avoid the chronicity and risk of death of these patients.
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http://dx.doi.org/10.1111/ijd.13755DOI Listing
December 2017

On the Role of DT-Diaphorase Inhibition in Aminochrome-Induced Neurotoxicity In Vivo.

Neurotox Res 2017 Jul 11;32(1):134-140. Epub 2017 Mar 11.

Molecular & Clinical Pharmacology, Faculty of Medicine, University of Chile, Independencia 1027, Casilla, 70000, Santiago 7, Chile.

Dopamine oxidation in the pathway leading to neuromelanin formation generates the ortho-quinone aminochrome, which is potentially neurotoxic but normally rapidly converted by DT-diaphorase to nontoxic leukoaminochrome. However, when administered exogenously into rat striatum, aminochrome is able to produce damage to dopaminergic neurons. Because of a recent report that substantia nigra pars compacta (SNpc) tyrosine hydroxylase (T-OH) levels were unaltered by aminochrome when there was cell shrinkage of dopaminergic neurons along with a reduction in striatal dopamine release, the following study was conducted to more accurately determine the role of DT-diaphorase in aminochrome neurotoxicity. In this study, a low dose of aminochrome (0.8 nmol) with or without the DT-diaphorase inhibitor dicoumarol (0.2 nmol) was injected into the left striatum of rats. Intrastriatal 6-hydroxydopamine (6-OHDA, 32 nmol) was used as a positive neurotoxin control in other rats. Two weeks later, there was significant loss in numbers of T-OH immunoreactive fibers in SNpc, also a loss in cell density in SNpc, and prominent apomorphine (0.5 mg/kg sc)-induced contralateral rotations in rats that had been treated with aminochrome, with aminochrome/dicoumarol, or with 6-OHDA. Findings demonstrate that neurotoxic aminochrome is able to exert neurotoxicity only when DT-diaphorase is suppressed-implying that DT-diaphorase is vital in normally suppressing toxicity of in vivo aminochrome, generated in the pathway towards neuromelanin formation.
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http://dx.doi.org/10.1007/s12640-017-9719-8DOI Listing
July 2017

The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus.

Int J Neuropsychopharmacol 2017 04;20(4):336-345

Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.

Background: Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss.

Methods: Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed.

Results: Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudil-treated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration.

Conclusion: Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity.
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http://dx.doi.org/10.1093/ijnp/pyw108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409106PMC
April 2017

Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson's disease.

Cell Mol Life Sci 2016 09 21;73(18):3583-97. Epub 2016 Mar 21.

Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.

L-Dopa continues to be the gold drug in Parkinson's disease (PD) treatment from 1967. The failure to translate successful results from preclinical to clinical studies can be explained by the use of preclinical models which do not reflect what happens in the disease since these induce a rapid and extensive degeneration; for example, MPTP induces a severe Parkinsonism in only 3 days in humans contrasting with the slow degeneration and progression of PD. This study presents a new anatomy and develops preclinical model based on aminochrome which induces a slow and progressive dysfunction of dopaminergic neurons. The unilateral injection of aminochrome into rat striatum resulted in (1) contralateral rotation when the animals are stimulated with apomorphine; (2) absence of significant loss of tyrosine hydroxylase-positive neuronal elements both in substantia nigra and striatum; (3) cell shrinkage; (4) significant reduction of dopamine release; (5) significant increase in GABA release; (6) significant decrease in the number of monoaminergic presynaptic vesicles; (7) significant increase of dopamine concentration inside of monoaminergic vesicles; (8) significant increase of damaged mitochondria; (9) significant decrease of ATP level in the striatum (10) significant decrease in basal and maximal mitochondrial respiration. These results suggest that aminochrome induces dysfunction of dopaminergic neurons where the contralateral behavior can be explained by aminochrome-induced ATP decrease required both for anterograde transport of synaptic vesicles and dopamine release. Aminochrome could be implemented as a new model neurotoxin to study Parkinson's disease.
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http://dx.doi.org/10.1007/s00018-016-2182-5DOI Listing
September 2016

Development of a High Irradiance LED Configuration for Small Field of View Motion Estimation of Fertilizer Particles.

Sensors (Basel) 2015 Nov 12;15(11):28627-45. Epub 2015 Nov 12.

Institute of Agricultural and Fisheries Research, Burg. van Gansberghelaan 115, Merelbeke 9820, Belgium.

Better characterization of the fertilizer spreading process, especially the fertilizer pattern distribution on the ground, requires an accurate measurement of individual particle properties and dynamics. Both 2D and 3D high speed imaging techniques have been developed for this purpose. To maximize the accuracy of the predictions, a specific illumination level is required. This paper describes the development of a high irradiance LED system for high speed motion estimation of fertilizer particles. A spectral sensitivity factor was used to select the optimal LED in relation to the used camera from a range of commercially available high power LEDs. A multiple objective genetic algorithm was used to find the optimal configuration of LEDs resulting in the most homogeneous irradiance in the target area. Simulations were carried out for different lenses and number of LEDs. The chosen configuration resulted in an average irradiance level of 452 W/m² with coefficient of variation less than 2%. The algorithm proved superior and more flexible to other approaches reported in the literature and can be used for various other applications.
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http://dx.doi.org/10.3390/s151128627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701300PMC
November 2015

Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation.

Pediatr Res 2015 Dec 3;78(6):603-8. Epub 2015 Sep 3.

Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency characterized by chronic lymphoproliferation, autoimmune manifestations, expansion of double-negative T-cells, and susceptibility to malignancies. Most cases of ALPS are caused by germline or somatic FAS mutations. We report the case of an ALPS patient due to a novel homozygous Fasligand gene mutation (ALPS-FASLG).

Methods: ALPS biomarkers were measured and FASLG mutation was identified. Functional characterization was carried out based on activation-induced cell death (AICD) and cytotoxicity assays.

Results: This report describes the cases of a patient who presented a severe form of ALPS-FASLG, and his brother who had died due to complications related to ALPS. Moreover, in another family, we present the first case of lymphoma in a patient with ALPS-FASLG. Functional studies showed defective Fasligand-mediated apoptosis, cytotoxicity, and AICD in T-cell blasts. Otherwise, expression of the FASLG gene and corresponding protein was normal, but the shedding of the Fasligand was impaired in T-cells. Additionally, analyzing Epstein-Barr virus (EBV)-transformed B-cells, our results indicate impaired AICD in ALPS-FASLG patients.

Conclusion: Patients with autosomal recessive inheritance of ALPS-FASLG have a severe phenotype and a partial defect in AICD in T- and B-cell lines. The Fasligand could play a key role in immune surveillance preventing malignancy.
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http://dx.doi.org/10.1038/pr.2015.170DOI Listing
December 2015

Association of N-cadherin levels and downstream effectors of Rho GTPases with dendritic spine loss induced by chronic stress in rat hippocampal neurons.

J Neurosci Res 2015 Oct 23;93(10):1476-91. Epub 2015 May 23.

Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.

Chronic stress promotes cognitive impairment and dendritic spine loss in hippocampal neurons. In this animal model of depression, spine loss probably involves a weakening of the interaction between pre- and postsynaptic cell adhesion molecules, such as N-cadherin, followed by disruption of the cytoskeleton. N-cadherin, in concert with catenin, stabilizes the cytoskeleton through Rho-family GTPases. Via their effector LIM kinase (LIMK), RhoA and ras-related C3 botulinum toxin substrate 1 (RAC) GTPases phosphorylate and inhibit cofilin, an actin-depolymerizing molecule, favoring spine growth. Additionally, RhoA, through Rho kinase (ROCK), inactivates myosin phosphatase through phosphorylation of the myosin-binding subunit (MYPT1), producing actomyosin contraction and probable spine loss. Some micro-RNAs negatively control the translation of specific mRNAs involved in Rho GTPase signaling. For example, miR-138 indirectly activates RhoA, and miR-134 reduces LIMK1 levels, resulting in spine shrinkage; in contrast, miR-132 activates RAC1, promoting spine formation. We evaluated whether N-cadherin/β-catenin and Rho signaling is sensitive to chronic restraint stress. Stressed rats exhibit anhedonia, impaired associative learning, and immobility in the forced swim test and reduction in N-cadherin levels but not β-catenin in the hippocampus. We observed a reduction in spine number in the apical dendrites of CA1 pyramidal neurons, with no effect on the levels of miR-132 or miR-134. Although the stress did not modify the RAC-LIMK-cofilin signaling pathway, we observed increased phospho-MYPT1 levels, probably mediated by RhoA-ROCK activation. Furthermore, chronic stress raises the levels of miR-138 in accordance with the observed activation of the RhoA-ROCK pathway. Our findings suggest that a dysregulation of RhoA-ROCK activity by chronic stress could potentially underlie spine loss in hippocampal neurons.
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http://dx.doi.org/10.1002/jnr.23602DOI Listing
October 2015

Isolated IgA anti- β2 glycoprotein I antibodies in patients with clinical criteria for antiphospholipid syndrome.

J Immunol Res 2014 23;2014:704395. Epub 2014 Mar 23.

Servicio de Inmunología, Instituto de Investigación Hospital Universitario 12 de Octubre, Avenida Córdoba s/n, 28041 Madrid, Spain ; Sección de Inmunología, Universidad San Pablo-CEU, Campus de Monteprincipe, 28668 Madrid, Spain.

Seronegative antiphospholipid syndrome (SNAPS) is an autoimmune disease present in patients with clinical manifestations highly suggestive of Antiphospholipid Syndrome (APS) but with persistently negative consensus antiphospholipid antibodies (a-PL). IgA anti-β 2 Glycoprotein I (aB2-GPI) antibodies are associated with APS. However, they are not currently considered to be laboratory criteria due to the heterogeneity of published works and the use of poor standardized diagnostic systems. We have aimed to assess aPL antibodies in a group of patients with clinical manifestations of APS (C-APS) to evaluate the importance of the presence of IgA aB2GPI antibodies in APS and its relation with other aPL antibodies. Only 14% of patients with C-APS were positive for any consensus antibody, whereas the presence of isolated IgA aB2GPI antibodies was found in 22% of C-APS patients. In patients with arterial thrombosis IgA aB2GPI, antibodies were the only aPL antibodies present. Serologic profile in primary APS (PAPS) is different from systemic autoimmune disorders associated APS (SAD-APS). IgA aB2GPI antibodies are more prevalent in PAPS and IgG aB2GPI antibodies are predominant in SAD-APS. The analysis of IgA aB2GPI antibodies in patients with clinical manifestations of PAPS might avoid underdiagnosed patients and provide a better diagnosis in patients with SAD-APS. Laboratory consensus criteria might consider including analysis of IgA aB2GPI for APS diagnosis.
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http://dx.doi.org/10.1155/2014/704395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987939PMC
December 2014

Heterogeneity between diagnostic tests for IgA anti-beta2 glycoprotein I: explaining the controversy in studies of association with vascular pathology.

Anal Chem 2013 Dec 26;85(24):12093-8. Epub 2013 Nov 26.

Department of Immunology and ‡Department of Nephrology, Instituto de Investigación Hospital Universitario , 12 de Octubre, Madrid, Spain.

IgA antibeta 2 Glycoprotein I (β2GPI) antibodies test can identify some patients with antiphospholipid syndrome (APS) that are negative for other isotypes. Controversy exists because some studies have reported a strong association of these antibodies with vascular disease, while others have not confirmed this observation. Our hypothesis is that these contradictory results may be due to differences among commercial diagnostic kits. To answer this question, we have compared the results obtained with several of the most commonly used commercial IgA anti β2GPI antibodies (aβ2GPI) diagnostic assays on specimens from individuals suspected of having APS. Sera from 69 patients (37 positive and 32 negative for IgA aβ2GPI) were analyzed with seven different commercial ELISA kits for IgA aβ2GPI, following instructions and cutoffs provided by the manufacturer. Our results showed important differences in the sensitivity and specificity of the different assays. Two of the seven kits tested had a sensitivity level below 65% for IgA aβ2GPI, and three showed levels of specificity lower than 80%. Some commercial kits to detect IgA aβ2GPI are suboptimal. Variability between kits may account for the discrepancy in results obtained and for the lack of consensus concerning their clinical significance. It is important that the scientific community work to standardize assay performance so that the true clinical significance of this important clinical marker can be clearly established.
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http://dx.doi.org/10.1021/ac403194tDOI Listing
December 2013

Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease.

EMBO Mol Med 2012 May 8;4(5):380-95. Epub 2012 Mar 8.

Institute for Biomedicine (IBUB), University of Barcelona, Barcelona, Spain.

Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type.
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http://dx.doi.org/10.1002/emmm.201200215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403296PMC
May 2012

Desipramine prevents stress-induced changes in depressive-like behavior and hippocampal markers of neuroprotection.

Behav Pharmacol 2009 May;20(3):273-85

Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.

Extracellular signal-regulated kinases (ERKs) are widely implicated in multiple physiological processes. Although ERK1/2 has been proposed as a common mediator of antidepressant action in naive rodents, it remains to be determined whether the ERK1/2 pathway plays a role in depressive disorder. Here, we investigated whether chronic restraint stress (14 days) and antidepressant treatment [desipramine (DMI), 10 mg/kg intraperitoneally] induce changes in animal behavior and hippocampal levels of phospho-ERK1/2 and its substrate phospho-cAMP response element-binding protein (CREB). The results indicated that stress-induced depressive-like behaviors were correlated with an increase in P-ERK1/2 and P-CREB in the hippocampus evaluated by immunoblot analysis. As an indication of CREB activity, we evaluated changes in mRNA levels of its target genes. Brain-derived neurotrophic factor (BDNF) mRNA was reduced by stress, an effect prevented by DMI only in the CA3 area of hippocampus. Bcl-2 mRNA was reduced in all hippocampal regions by stress, an effect independent of DMI treatment. However, immunoblot from hippocampal extracts revealed that stress increased BCL-2 levels, an effect prevented by chronic DMI. These results suggest that ERKs and BDNF may be altered in depressive disorder, modifications that are sensitive to DMI action. In contrast, the stress-induced increase in BCL-2 may correspond to a neuroprotective response.
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http://dx.doi.org/10.1097/FBP.0b013e32832c70d9DOI Listing
May 2009

Copper neurotoxicity in rat substantia nigra and striatum is dependent on DT-diaphorase inhibition.

Chem Res Toxicol 2008 Jun 23;21(6):1180-5. Epub 2008 May 23.

Molecular & Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, University Santo Tomas and University Andres Bello, Vina del Mar, Chile.

The dependence of copper neurotoxicity on DT-diaphorase inhibition was suggested from results obtained from a cell line derived from substantia nigra. Therefore, the aim of this study was to evaluate whether CuSO4 neurotoxicity in vivo, which was evaluated by determining the contralateral rotation and loss of tyrosine hydroxylase immunostaining, was dependent on DT-diaphorase inhibition by dicoumarol. Animals unilaterally and intranigrally injected with 0.25 nmol of CuSO4 and 2 nmol of dicoumarol presented a significant and characteristic contralateral rotational behavior ( P < 0.01) when they were systemically stimulated with apomorphine (0.5 mg/kg s.c.), similar to that observed in rats injected unilaterally with 6-hydroxydopamine as a positive control. The behavioral effects correlated with the lost of tyrosine hydroxylase-positive staining, since animals unilaterally and intranigrally injected with 0.25 nmol of CuSO4 together with 2 nmol of dicoumarol exhibited extensive loss of tyrosine hydroxylase-positive fiber density in the striatum ( P < 0.01) and cell loss in the substantia nigra ( P < 0.01). Our results support the idea that CuSO4 neurotoxicity is dependent upon DT-diaphorase inhibition.
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http://dx.doi.org/10.1021/tx8001143DOI Listing
June 2008

Chronic stress induces upregulation of brain-derived neurotrophic factor (BDNF) mRNA and integrin alpha5 expression in the rat pineal gland.

Brain Res 2006 May 13;1086(1):27-34. Epub 2006 Apr 13.

Department of Psychiatry and Center for Medical Research, Faculty of Medicine, Pontificia Universidad Católica de Chile, Ave. Marcoleta N 387, piso 2, Casilla 114-D, Santiago 1, Chile.

Chronic stress affects brain areas involved in learning and emotional responses. These alterations have been related with the development of cognitive deficits in major depression. Moreover, stress induces deleterious actions on the epithalamic pineal organ, a gland involved in a wide range of physiological functions. The aim of this study was to investigate whether the stress effects on the pineal gland are related with changes in the expression of neurotrophic factors and cell adhesion molecules. Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, we analyzed the effect of chronic immobilization stress on the BDNF mRNA and integrin alpha5 expression in the rat pineal gland. We found that BDNF is produced in situ in the pineal gland. Chronic immobilization stress induced upregulation of BDNF mRNA and integrin alpha5 expression in the rat pineal gland but did not produce changes in beta-actin mRNA or in GAPDH expression. Stressed animals also evidenced an increase in anxiety-like behavior and acute gastric lesions. These results suggest that BDNF and integrin alpha5 may have a counteracting effect to the deleterious actions of immobilization stress on functionally stimulated pinealocytes. Furthermore, this study proposes that the pineal gland may be a target of glucocorticoid damage during stress.
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http://dx.doi.org/10.1016/j.brainres.2006.02.118DOI Listing
May 2006

Antidepressant and anxiolytic effects of hydroalcoholic extract from Salvia elegans.

J Ethnopharmacol 2006 Aug 28;107(1):53-8. Epub 2006 Feb 28.

Centro de Investigación Biomédica del Sur, IMSS. Argentina 1, Xochitepec, Morelos, Mexico.

Salvia elegans Vahl (Lamiaceae), popularly known as "mirto", is a shrub that has been widely used in Mexican traditional medicine for the treatment of different central nervous system (CNS) diseases, principally, anxiety. Nevertheless, the available scientific information about this species is scarce and there are no reports related to its possible effect on the CNS. In this work, the antidepressant and anxiolytic like effects of hydroalcoholic (60%) extract of Salvia elegans (leaves and flowers) were evaluated in mice. The extract, administered orally, was able to increase the percentage of time spent and the percentage of arm entries in the open arms of the elevated plus-maze, as well as to increase the time spent by mice in the illuminated side of the light-dark test, and to decrease the immobility time of mice subjected to the forced swimming test. The same extract was not able to modify the spontaneous locomotor activity measured in the open field test. These results provide support for the potential antidepressant and anxiolytic activity of Salvia elegans.
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http://dx.doi.org/10.1016/j.jep.2006.02.003DOI Listing
August 2006

Behavioral effects of manganese injected in the rat substantia nigra are potentiated by dicumarol, a DT-diaphorase inhibitor.

Pharmacol Biochem Behav 2004 Feb;77(2):245-51

Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biológicas (ICBM), Facultad de Medicina, Universidad de Chile, P.O. Box 16038, 9, Santiago, Chile.

The purpose of this study was to evaluate the contribution of DT-diaphorase inhibition to in vivo neurodegenerative effects of dopamine (DA) oxidation to the corresponding o-quinones. The neurotoxicity to nigrostriatal DA neurons was induced by injection of manganese pyrophosphate (Mn(3+)) complex as a prooxidizing agent alone or together with the DT-diaphorase inhibitor dicumarol into the right rat substantia nigra. The behavioral effects were compared with those induced after selective lesions of dopaminergic neurons with 6-hydroxydopamine (6-OHDA). Intranigral injection of Mn(3+) and Mn(3+) plus dicumarol produced significant impairment in motor behavior compared with control animals. However, the effect seen in the Mn(3+) plus dicumarol injected group was significantly more severe than that observed in the Mn(3+) alone injected group. In motor activity and rearing behavior, the simultaneous injection of Mn(3+) plus dicumarol produced a 6-OHDA-like impairment. Similar effects were observed in the acquisition of a conditioned avoidance response (CAR). Dicumarol significantly impaired avoidance conditioning although without affecting the motor behavior. The behavioral effects were correlated to the extent of striatal tyrosine hydroxylase (TH)-positive fiber loss. Rats receiving unilateral intranigral Mn(3+) and Mn(3+) plus dicumarol injections exhibited a significant reduction in nigrostriatal TH-positive fiber density in medial forebrain bundle compared with the contralateral noninjected side. In conclusion, this study provides evidence that the neurotoxicity of Mn(3+) in vivo is potentiated by DT-diaphorase inhibition, suggesting that this enzyme could play a neuroprotective role in the nigrostriatal DA systems.
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http://dx.doi.org/10.1016/j.pbb.2003.10.016DOI Listing
February 2004
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