Early heart and skeletal muscle mitochondrial response to a moderate hypobaric hypoxia environment.

In eukaryotic cells, aerobic energy is produced by mitochondria through oxygen uptake. However, little is known about the early mitochondrial responses to moderate hypobaric hypoxia (MHH) in highly metabolic active tissues. Here, we describe the mitochondrial responses to acute MHH in the heart and skeletal muscle. Rats were randomly allocated into a normoxia control group (n = 10) and a hypoxia group (n = 30), divided into three groups (0, 6, and 24 h post-MHH). The normoxia situation was recapitulated at the University of Granada, at 662 m above sea level. The MHH situation was performed at the High-Performance Altitude Training Centre of Sierra Nevada located in Granada at 2320 m above sea level. We found a significant increase in mitochondrial supercomplex assembly in the heart as soon as the animals reached 2320 m above sea level and their levels are maintained 24 h post-exposure, but not in skeletal muscle. Furthermore, in skeletal muscle, at 0 and 6 h, there was increased dynamin-related protein 1 (Drp1) expression and a significant reduction in Mitofusin 2. In conclusion, mitochondria from the muscle and heart respond differently to MHH: mitochondrial supercomplexes increase in the heart, whereas, in skeletal muscle, the mitochondrial pro-fission response is trigged. Considering that skeletal muscle was not actively involved in the ascent when the heart was beating faster to compensate for the hypobaric, hypoxic conditions, we speculate that the different responses to MHH are a result of the different energetic requirements of the tissues upon MHH. KEY POINTS: The heart and the skeletal muscle showed different mitochondrial responses to moderate hypobaric hypoxia. Moderate hypobaric hypoxia increases the assembly of the electron transport chain complexes into supercomplexes in the heart. Skeletal muscle shows an early mitochondrial pro-fission response following exposure to moderate hypobaric hypoxia.

Whole-Exome Sequencing Study of Fibroblasts Derived From Patients With Cerebellar Ataxia Referred to Investigate CoQ10 Deficiency.

Background and Objectives: Coenzyme Q10 (CoQ10)-deficient cerebellar ataxia can be due to pathogenic variants in genes encoding for CoQ10 biosynthetic proteins or associated with defects in protein unrelated to its biosynthesis. Diagnosis is crucial because patients may respond favorably to CoQ10 supplementation. The aim of this study was to identify through whole-exome sequencing (WES) the pathogenic variants, and assess CoQ10 levels, in fibroblasts from patients with undiagnosed cerebellar ataxia referred to investigate CoQ10 deficiency. Methods: WES was performed on genomic DNA extracted from 16 patients. Sequencing data were filtered using a virtual panel of genes associated with CoQ10 deficiency and/or cerebellar ataxia. CoQ10 levels were measured by high-performance liquid chromatography in 14 patient-derived fibroblasts. Results: A definite genetic etiology was identified in 8 samples of 16 (diagnostic yield = 50%). The identified genetic causes were pathogenic variants of the genes COQ8A (ADCK3) (n = 3 samples), ATP1A3 (n = 2), PLA2G6 (n = 1), SPG7 (n = 1), and MFSD8 (n = 1). Five novel mutations were found (COQ8A n = 3, PLA2G6 n = 1, and MFSD8 n = 1). CoQ10 levels were significantly decreased in 3/14 fibroblast samples (21.4%), 1 carrying compound heterozygous COQ8A pathogenic variants, 1 harboring a homozygous pathogenic SPG7 variant, and 1 with an unknown molecular defect. Discussion: This work confirms the importance of COQ8A gene mutations as a frequent genetic cause of cerebellar ataxia and CoQ10 deficiency and suggests SPG7 mutations as a novel cause of secondary CoQ10 deficiency.

ß-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight.

Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to the abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remain challenging. Here, we show that beta-resorcylic acid (ß-RA), which is a natural phenolic compound, competed in vivo with 4-hydroxybenzoic acid, which is the natural precursor of coenzyme Q biosynthesis. This led to a decrease in demethoxyubiquinone, which is an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9R239X mice. As a consequence, ß-RA rescued the phenotype of Coq9R239X mice, which is a model of primary mitochondrial encephalopathy. Moreover, we observed that long-term treatment with ß-RA also reduced the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to the prevention of hepatic steatosis and an increase in survival at the elderly stage of life. The reduction in WAT content was due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that ß-RA acted through different cellular mechanisms, with effects on mitochondrial metabolism; as such, it may be used for the treatment of primary coenzyme Q deficiency, overweight, and hepatic steatosis.

Composition and Antioxidant Properties of Spanish Extra Virgin Olive Oil Regarding Cultivar, Harvest Year and Crop Stage.

The health benefits of extra virgin olive oil (EVOO) are related to its chemical composition and the presence of bioactive compounds with antioxidant properties. The aim of this study was to evaluate antioxidant compounds (pigments, coenzyme Q10 (CoQ10) and phenolic compounds) and antioxidant properties of EVOO from the same region comparing different cultivars (Hojiblanca and Arbequina), harvest year and crop stage. Antioxidant properties of oils were studied before and after a gastrointestinal digestion process, by in vitro assays (DPPH, ABTS and FRAP) and antioxidant markers in Caco-2 cells (reactive oxygen species production). The content of bioactive compounds measured was significantly affected by cultivar and harvest year (except for carotenoids) and by the crop stage (except for coenzyme Q10). Higher amounts of coenzyme Q10 were observed in Hojiblanca than in Arbequina EVOO. Total phenol content and antioxidant properties were also different depending on cultivar and harvest year and the in vitro digestion process strongly improved antioxidant marker values. Antioxidant potential in bioaccessible fractions was mainly related to the content of coenzyme Q10 and phenolic compounds in EVOO. Chemometric analysis showed that the oils were clearly classified by cultivars, harvest and crop stage, according to the chemical composition and antioxidant activity analyzed in the present study.

Hydroxytyrosol influences exercise-induced mitochondrial respiratory complex assembly into supercomplexes in rats.

Hydroxytyrosol (HT) has been demonstrated to improve mitochondrial function, both in sedentary and in exercised animals. Herein, we assessed the effects of two different doses of HT on exercise-induced mitochondrial respiratory complex (C) assembly into supercomplexes (SCs) and the relation of the potential results to OPA1 levels and oxidative stress. Wistar rats were allocated into six groups: sedentary (SED), sedentary consuming 20 mg/kg/d of HT (SED-20), sedentary consuming 300 mg/kg/d of HT (SED-300); exercised (EXE), exercised consuming 20 mg/kg/d of HT (EXE-20) and exercised consuming 300 mg/kg/d of HT (EXE-300). Animals were exercised and/or supplemented for 10 weeks, and assembly of SCs, mitochondrial oxidative status and expression of OPA1 were quantified in the gastrocnemius muscle. Both EXE and EXE-20 animals exhibited increased assembly of CI into SCs, but this effect was absent in EXE-300 animals. Levels of CIII2 assembled into SCs were only increased in EXE-20 animals. Notably EXE-300 animals showed a decreased relative expression of s-OPA1 isoforms. Therefore, HT exerted dose-dependent effects on SC assembly in exercised animals. Although the mechanisms leading to SCs assembly in response to exercise and HT are unclear, it seems that a high HT dose can prevent SCs assembly during exercise by decreasing the expression of the s-OPA1 isoforms.

Melatonin protects rats from radiotherapy-induced small intestine toxicity.

Radiotherapy-induced gut toxicity is among the most prevalent dose-limiting toxicities following radiotherapy. Prevention of radiation enteropathy requires protection of the small intestine. However, despite the prevalence and burden of this pathology, there are currently no effective treatments for radiotherapy-induced gut toxicity, and this pathology remains unclear. The present study aimed to investigate the changes induced in the rat small intestine after external irradiation of the tongue, and to explore the potential radio-protective effects of melatonin gel. Male Wistar rats were subjected to irradiation of their tongues with an X-Ray YXLON Y.Tu 320-D03 irradiator, receiving a dose of 7.5 Gy/day for 5 days. For 21 days post-irradiation, rats were treated with 45 mg/day melatonin gel or vehicle, by local application into their mouths. Our results showed that mitochondrial oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in the development of radiotherapy-induced gut toxicity. Oral treatment with melatonin gel had a protective effect in the small intestine, which was associated with mitochondrial protection and, consequently, with a reduced inflammatory response, blunting the NF-κB/NLRP3 inflammasome signaling activation. Thus, rats treated with melatonin gel showed reduced intestinal apoptosis, relieving mucosal dysfunction and facilitating intestinal mucosa recovery. Our findings suggest that oral treatment with melatonin gel may be a potential preventive therapy for radiotherapy-induced gut toxicity in cancer patients.

Melatonin enhances neural stem cell differentiation and engraftment by increasing mitochondrial function.

Neural stem cells (NSCs) are regarded as a promising therapeutic approach to protecting and restoring damaged neurons in neurodegenerative diseases (NDs) such as Parkinson's disease and Alzheimer's disease (PD and AD, respectively). However, new research suggests that NSC differentiation is required to make this strategy effective. Several studies have demonstrated that melatonin increases mature neuronal markers, which reflects NSC differentiation into neurons. Nevertheless, the possible involvement of mitochondria in the effects of melatonin during NSC differentiation has not yet been fully established. We therefore tested the impact of melatonin on NSC proliferation and differentiation in an attempt to determine whether these actions depend on modulating mitochondrial activity. We measured proliferation and differentiation markers, mitochondrial structural and functional parameters as well as oxidative stress indicators and also evaluated cell transplant engraftment. This enabled us to show that melatonin (25 µM) induces NSC differentiation into oligodendrocytes and neurons. These effects depend on increased mitochondrial mass/DNA/complexes, mitochondrial respiration, and membrane potential as well as ATP synthesis in NSCs. It is also interesting to note that melatonin prevented oxidative stress caused by high levels of mitochondrial activity. Finally, we found that melatonin enriches NSC engraftment in the ND mouse model following transplantation. We concluded that a combined therapy involving transplantation of NSCs pretreated with pharmacological doses of melatonin could efficiently restore neuronal cell populations in PD and AD mouse models depending on mitochondrial activity promotion.

Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.

Mitochondria are key cellular signaling platforms, affecting fundamental processes such as cell proliferation, differentiation and death. However, it remains unclear how mitochondrial signaling affects other organelles, particularly lysosomes. Here, we demonstrate that mitochondrial respiratory chain (RC) impairments elicit a stress signaling pathway that regulates lysosomal biogenesis via the microphtalmia transcription factor family. Interestingly, the effect of mitochondrial stress over lysosomal biogenesis depends on the timeframe of the stress elicited: while RC inhibition with rotenone or uncoupling with CCCP initially triggers lysosomal biogenesis, the effect peaks after few hours and returns to baseline. Long-term RC inhibition by long-term treatment with rotenone, or patient mutations in fibroblasts and in a mouse model result in repression of lysosomal biogenesis. The induction of lysosomal biogenesis by short-term mitochondrial stress is dependent on TFEB and MITF, requires AMPK signaling and is independent of calcineurin signaling. These results reveal an integrated view of how mitochondrial signaling affects lysosomes, which is essential to fully comprehend the consequences of mitochondrial malfunction, particularly in the context of mitochondrial diseases.

[Hematological changes induced by erythrocytapheresis]. / Cambios hematológicos inducidos por la eritroféresis.

BACKGROUND: Although automated cell separators (apheresis) have undergone a lot of technical refinements, the effect of the procedure on hematological indices of donors is rarely taken into account. The purpose of this study is to identify potential hematologic changes in donors undergoing erythrocytapheresis. METHODS: 30 apparently healthy adult donors were evaluated. Erythrocytapheresis procedure was performed using automated equipment. Hematologic measurements (hemoglobin, hematocrit, white blood cells counts and platelets) were analyzed before and after erythrocytapheresis in all donors. RESULTS: We observed a significant decrease in the donors in hemoglobin (p <0.0001), hematocrit (p <0.0001), leukocytes (p <0.0001), lymphocytes (p = 0.0267), and platelets (p <0.0001). On the other hand, we found no changes in segmented, monocytes, eosinophils and basophils post erythrocytapheresis. CONCLUSION: In this study we found a significant drop in complete blood count in blood donation procedure by erythrocytapheresis; there are hematological changes in both red and white cells in all donors; however, none of donors manifested symptoms of thrombocytopenia or anemia. This study demonstrates hematological changes post-donation and therefore requires larger multicenter studies, in order to establish guidelines for donors' safety in apheresis and also help in assessing donor suitability, especially given the present trend of double product apheresis collections.

Introducción: El efecto del procedimiento en los índices hematológicos del donador rara vez se determina al finalizar una sesión de donación. El propósito de este estudio es identificar las posibles alteraciones hematológicas en los donadores sometidos a eritroféresis. Métodos: Se evaluaron 30 donadores adultos, aparentemente sanos. El procedimiento de eritroféresis se realizó utilizando un equipo automatizado. Las mediciones hematológicas (hemoglobina, hematocrito, células blancas y plaquetas) se realizaron antes y después de la eritroféresis. Resultados: Existe disminución significativa en hemoglobina (p < 0.0001), hematocrito (p < 0.0001), leucocitos totales (p < 0.0001), linfocitos (p = 0.0267), y plaquetas (p < 0.0001) tras el procedimiento de donación. Por otro lado, los segmentados tienen un ligero aumento. No se encontraron cambios en monocitos, eosinófilos ni en basófilos poseritroféresis. Conclusiones: durante el procedimiento de donación sanguínea mediante eritroféresis se producen cambios hematológicos tanto en la formula roja como blanca en los donadores estudiados, a pesar de ello, ninguno de los donadores manifestaron signos de trombocitopenia o anemia. Este trabajo demuestra que existen cambios hematológicos postdonación y por ello se requiere de estudios amplios y multicéntricos, con el fin de establecer directrices para establecer un procedimiento seguro para el donador y mejorar la evaluación de idoneidad de los donadores.

The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene.

Primary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype-phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9(Q95X) and Coq9(R239X)), and their responses to 2,4-dihydroxybenzoic acid (2,4-diHB). Coq9(R239X) mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4-diHB increasing CoQ levels. In contrast, Coq9(Q95X) mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late-onset mild mitochondrial myopathy, which does not respond to 2,4-diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9(R239X) mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype-phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.

Cord blood-derived CD34+ hematopoietic cells with low mitochondrial mass are enriched in hematopoietic repopulating stem cell function.

The homeostasis of the hematopoietic stem/progenitor cell pool relies on a fine-tuned balance between self-renewal, differentiation and proliferation. Recent studies have proposed that mitochondria regulate these processes. Although recent work has contributed to understanding the role of mitochondria during stem cell differentiation, it remains unclear whether the mitochondrial content/function affects human hematopoietic stem versus progenitor function. We found that mitochondrial mass correlates strongly with mitochondrial membrane potential in CD34(+) hematopoietic stem/progenitor cells. We, therefore, sorted cord blood CD34(+) cells on the basis of their mitochondrial mass and analyzed the in vitro homeostasis and clonogenic potential as well as the in vivo repopulating potential of CD34(+) cells with high (CD34(+) Mito(High)) versus low (CD34(+) Mito(Low)) mitochondrial mass. The CD34(+) Mito(Low) fraction contained 6-fold more CD34(+)CD38(-) primitive cells and was enriched in hematopoietic stem cell function, as demonstrated by its significantly greater hematopoietic reconstitution potential in immuno-deficient mice. In contrast, the CD34(+) Mito(High) fraction was more enriched in hematopoietic progenitor function with higher in vitro clonogenic capacity. In vitro differentiation of CD34(+) Mito(Low) cells was significantly delayed as compared to that of CD34(+) Mito(High) cells. The eventual complete differentiation of CD34(+) Mito(Low) cells, which coincided with a robust expansion of the CD34(-) differentiated progeny, was accompanied by mitochondrial adaptation, as shown by significant increases in ATP production and expression of the mitochondrial genes ND1 and COX2. In conclusion, cord blood CD34(+) cells with low levels of mitochondrial mass are enriched in hematopoietic repopulating stem cell function whereas high levels of mitochondrial mass identify hematopoietic progenitors. A mitochondrial response underlies hematopoietic stem/progenitor cell differentiation and proliferation of lineage-committed CD34(-) cells.

Mitochondrial DNA and inflammatory diseases.

Increasing experimental evidence supports a connection between inflammation and mitochondrial dysfunction. Both acute and chronic inflammatory diseases course with elevated free radicals production that may affect mitochondrial proteins, lipids, and mtDNA. The subsequent mitochondrial impairment produces more reactive oxygen species that further reduce the ATP generation, increasing the probability of cell death. Mitochondrial impairment in now considered a key factor in inflammation because (1) there are specific pathologies directly derived from mtDNA mutations, causing chronic inflammatory diseases such as neuromuscular and neurodegenerative disorders, (2) there are neurodegenerative, metabolic, and other inflammatory diseases in which their progression is accompanied by mitochondrial dysfunction, which is directly involved in the cell death. Recently, a direct implication of mitochondrial reactive oxygen species and, particularly, mtDNA in the innate immune response has been reported. Thus, the mitochondria should be considered targets for new therapies related to the treatment of acute and chronic inflammatory diseases, including the auto-inflammatory ones.

Determination of coenzyme Q10, coenzyme Q9, and melatonin contents in virgin argan oils: comparison with other edible vegetable oils.

Virgin argan oil possesses high antioxidant capacity (AC), which may be partially explained by its high content in antioxidant molecules such as polyphenols and tocopherols. However, the content in other antioxidant molecules, for example, coenzyme Q10 (CoQ(10)), coenzyme Q9 (CoQ(9)), and melatonin (Mel), which have been identified in other edible vegetable oils, have not been evaluated in virgin argan oil. Consequently, it was decided to evaluate the contents of CoQ(10), CoQ(9), and Mel in virgin argan oils and compare the results to those obtained in extra virgin olive oils and some varieties of seed oils. By the use of sensitive HPLC-EC/F methods, the results showed that virgin argan oil is a rich source of CoQ(10) and Mel, but no CoQ(9) was detected. Extra virgin olive oil showed higher levels of CoQ(10) and lower levels of Mel than virgin argan oil. Between the seed oil samples, only virgin soybean oil showed higher CoQ(10) and Mel levels than virgin argan oil. The results may be relevant for the contribution of CoQ(10) and Mel to the biological activities of virgin argan oil.

[The sick individual as a concept]. / El enfermo como concepto.

We start from the premise, shared by some current philosophical movements and by the author, which states that philosophy is not contemplation, or reflection, or introspection or communication. Philosophy is the art of shaping, inventing and creating concepts. It is an explicit way of introducing new differences in life, a different reading level, a specific jargon, which may imply revealing the flip side of the coin, or a dissimilar view of the side facing us. The philosopher is the friend of the concept, he holds it in his power, which means, basically and in all honesty, that philosophy is the discipline of creating concepts. Let us remember the brilliant idea of the Russian director Tarkovsky, who announced his greatest ambition as an artist: "To capture time". At the same time, we must recall one of the sayings of this director: "Every film I have directed and I intend to direct is always tied to characters who have something to overcome". The healthy individual lives in a specific time, with precise coordinates, aware that his life consists only of living that time. That is, living as defined by Josep María Esquirol: "Then we could also see that the best way of living the present is not to run after the fleeing time, but to see and live the opportunity that appears before us". One of the many circumstances that can intercept the way we see and live the opportunity that appears before us is sickness, one of those inescapable experiences we have not been taught how to pay an adequate attention to, and the meaning of which can, in a way, go unnoticed. As "time" goes by, the circumstance that we consider to be the basis on which existence is founded, sickness can appear, thus introducing a new dimension in the time of the healthy individual. For this reason we, as doctors and professionals, know that sickness "is tied to characters who have something to overcome". In view of the fact that a sickness invades a healthy individual and transforms him into a sick one, this paper supports the philosophical idea of the creation of a new concept: We have to create the concept of the sick with a philosophical basis, we must establish the idea that the sick individual lives, since the very moment he starts being sick, in a new and different time. The sick individual lives in a different time and, if we identify--with a certain boldness, just as Esquirol points out--"time" and "life", then we shall be bold enough to create a new entity, the sick individual, whose circumstances and new supports turn him into a new concept, they turn him into an idea--which shall be well defined and better shaped--after which we can think and act according to the belief of the sick individual as a concept, which is radically different from the healthy individual as a concept. The sick individual has nothing to do, if we can say so with a certain emphasis, with the healthy individual. They live in different times, although those times are not entirely unknown for each other. Every individual has the ability of thought. I think that the doctor, now become philosopher, must integrate the creation in its routine in order to be a better professional. He must create the concept of the sick individual, whose time has more different connotations than those found in the healthy individual. Accordingly, we want to think that the fabricated reality of the time of the healthy individual is not useful anymore, because the sick individual is an entity "in the distance", in which the course of time is fragmented as soon as he assimilates the crisis brought by the sickness. We have to properly shape and define that crisis and use it to philosophically establish the concept of the sick individual. Our plan is to produce a book after this conference.

Adverse drug reactions in internal medicine units at a university hospital: a descriptive pilot study / Reacciones adversas a medicamentos en salas de medicina interna de un hospital universitario: estudio descriptivo piloto

Introduction: Adverse drug reactions (ADRs) are an important cause of morbidity and mortality among hospitalized patients.Objectives: This study was designed to describe the frequency, severity, and causality of ADRs in internal medicine units at a third-level university hospital.Materials and methods: A descriptive study was performed at internal medicine units, by means of a structured format, review of clinical records, and interview of hospitalized patients. The Naranjo algorithm was applied to patient adverse events to define causality. Additionally, ADRs were classified according to the Rawlins and Thompson criteria.Results: One hundred patients (50 men and 50 women) were included in the study. Ninety nine (99) adverse events were found among the patients. The Naranjo algorithm was applied to adverse events, resulting in twenty nine (29) probable ADRs, twenty (20) possible ADRs and fifty (50) doubtful ADRs. Cardiovascular drugs and antibiotics were the most frequent therapeutic groups associated with ADRs. In addition, two preventable medication errors were identified.Conclusions: Frequency of ADRs was similar to the number reported in other studies in internal medicine units. It is necessary to systematize efforts of pharmacological surveillance in hospital wards, toward an opportune detection and prevention of ADRs.

Introducción: Las reacciones adversas a medicamentos (RAM) son una importante causa de morbilidad y mortalidad en pacientes hospitalizados.Objetivos: Este estudio se diseñó para describir la frecuencia, severidad y causalidad de las RAM en las salas de Medicina Interna de un hospital universitario de tercer nivel.Materiales y métodos: Se realizó un estudio descriptivo en las salas de hospitalización de Medicina Interna, con un formato estructurado, revisión de historia clínica y entrevista a los pacientes. Para definir causalidad, se aplicó el algoritmo de Naranjo a los eventos adversos de los enfermos. Además, se clasificaron las RAM de acuerdo con los criterios de Rawlins y Thompson.Resultados: En el estudio se incluyeron 100 pacientes (50 hombres y 50 mujeres). Se informaron 99 sucesos adversos; con el algoritmo de Naranjo se clasificaron como RAM probables (n=29), RAM posibles (n=21) y RAM dudosos (n=49). Los medicamentos cardiovasculares y los antibióticos fueron los grupos terapéuticos más relacionados con efectos adversos. Se descubrieron dos errores de medicación prevenibles.Conclusiones: La frecuencia que se encontró de estas reacciones adversas fue similar a la que informaron otras investigaciones en servicios de Medicina Interna. Es necesario sistematizar los esfuerzos de fármaco-vigilancia hospitalaria para prevenir y evitar oportunamente las RAM.

The role of mitochondria in brain aging and the effects of melatonin.

Melatonin is an endogenous indoleamine present in different tissues, cellular compartments and organelles including mitochondria. When melatonin is administered orally, it is readily available to the brain where it counteracts different processes that occur during aging and age-related neurodegenerative disorders. These aging processes include oxidative stress and oxidative damage, chronic and acute inflammation, mitochondrial dysfunction and loss of neural regeneration. This review summarizes age related changes in the brain and the importance of oxidative/nitrosative stress and mitochondrial dysfunction in brain aging. The data and mechanisms of action of melatonin in relation to aging of the brain are reviewed as well.

ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a metabolic disorder due to dysfunction of electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETF-QO). Mutations in ETFDH, encoding ETF-QO have been associated with both riboflavin-responsive and non-responsive MADD as well as a myopathic form of CoQ(10) deficiency, although pathomechanisms responsible for these different phenotypes are not well-defined. We performed mutation analysis in four Taiwanese MADD patients. Three novel ETFDH mutations were identified in four patients and all harbored the p.A84T mutation. Muscle CoQ(10) levels and respiratory chain activities measured in two patients were normal. Three patients improved on riboflavin together with carnitine. Our results show that not all MADD patients have CoQ(10) deficiency. Based upon our data, riboflavin and carnitine may be the first-line treatment for MADD.

Clinical and genetic analysis of lipid storage myopathies.

Causative genes have been identified only in four types of lipid storage myopathies (LSMs): SLC22A5 for primary carnitine deficiency (PCD); ETFA, ETFB, and ETFDH for multiple acyl-coenzyme A dehydrogenation deficiency (MADD); PNPLA2 for neutral lipid storage disease with myopathy (NLSDM); and ABHD5 for neutral lipid storage disease with ichthyosis. However, the frequency of these LSMs has not been determined. We found mutations in only 9 of 37 LSM patients (24%): 3 in SLC22A5; 4 in MADD-associated genes; and 2 in PNPLA2. This low frequency suggests the existence of other causative genes. Muscle coenzyme Q(10) levels were normal or only mildly reduced in two MADD patients, indicating that ETFDH mutations may not always be associated with CoQ(10) deficiency. The 2 patients with PNPLA2 mutations had progressive, non-episodic muscle disease with rimmed vacuoles. This suggests there is a different pathomechanism from other LSMs.