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Resumen: Objetivo: a) Conocer la prescripción preventiva (estatinas, antiagregantes, bifosfonatos, calcio/vitamina D y vitamina B12) de los pacientes con patología crónica compleja (PCC) y de los pacientes con enfermedad crónica avanzada (ENCA) y esperanza de vida inferior a 12 meses que fallecieron durante el 2015. b) Valorar la correcta indicación en el uso de inhibidores de la bomba de protones (IBP) para determinar medicación evitable. Diseño: Estudio transversal retrospectivo. Emplazamiento: Cuatro centros de salud de Castellar del Vallès, Barcelona. Participantes: Un total de 128 pacientes (70 ENCA y 58 PCC). Variables: Fármacos activos en el momento de morir de los 6 grupos seleccionados, desprescripción (6 meses previos a la muerte por motivos de enfermedad crónica avanzada), indicación en prevención primaria o secundaria y adecuación en la prescripción IBP. Resultados: Edad media en el momento de la muerte: 85,3 (10,3) años. El 40% de PCC/ENCA tomaban un antiagregante. En el 60% de los ENCA que tomaban un antiagregante no había evento cardiovascular previo. El 20% de PCC/ENCA tomaban una estatina y en el 48% de los casos por prevención primaria. La prescripción total de IBP fue del 67%, con indicación inadecuada del 49%. El 20% tomaban calcio/vitamina D y un 1,6% de los ENCA un bifosfonato. Hubo un 16% de desprescripción. Conclusiones: Un porcentaje elevado de pacientes con enfermedad crónica avanzada y esperanza de vida corta siguen tomando tratamientos preventivos hasta sus últimos días, evitables en muchos casos y no exentos de efectos secundarios. Deberíamos aumentar la desprescripción de medicamentos con beneficios a largo plazo en este grupo de pacientes. Abstract: Objectives: 1-To know the preventive prescription (statin, antiplatelet drugs, bisphosphonates, calcium and vitamin D and Vit B12) of elderly patients previously identified as a CCD (with a complex chronic disease) and ACD (with advanced chronic disease and lifetime expectancy of less than 12 months) who died during 2015. 2-To assess the correct indication of Proton Pump Inhibitors (PPI) to determine potentially avoidable medication. Design: Retrospective observational study. Location: Four Primary Health Centres, Castellar del Vallès (Barcelona). Participants: 128 patients, 70 ACD and 58 PCC. Main measurements: Number of drugs at the time of death from the 6 selected group, deprescription (6 months prior to death due to advanced chronic disease), primary or secondary prevention and inappropriate prescription of PPI. Results: Average age of 85’3 years (10,3). 40% took an antiplatelet drug, avoidable in 60% of the ACD, since they did not present any previous cardiovascular episode. 20% of the patients took statins, in which 48% of the cases were primary prevention. The PPI prescription was 67% with inadequate indication for use in 49% of these cases. 20% took calcium / Vitamin D and 1,6% of the ACD a bisphosphonate. There was a 16% deprescription. Conclusions: A high percentage of our patients with advanced chronic disease and short life expectancy still continue to take preventive and avoidable treatments, potentially dangerous due to their side effects. There is a need to reflect on what we do with these vulnerable patients. Palabras clave: Desprescripción, Prescripciones inadecuadas, Seguridad del paciente, Keywords: Deprescription, Inappropriate Prescribing's, Patient safety

Background: Leigh syndrome (LS) is a serious genetic disease that can be caused by mutations in dozens of different genes. Methods: Clinical study of a deafness pedigree in which some members developed LS. Cellular, biochemical and molecular genetic analyses of patients’ tissues and cybrid cell lines were performed. Results: mitochondrial DNA (mtDNA) m.1555A>G/MT-RNR1 and m.9541T>C/MT-CO3 mutations were found. The first one is a well-known pathologic mutation. However, the second one does not appear to contribute to the high hearing loss penetrance and LS phenotype observed in this family. Conclusion: The m.1555A>G pathological mutation, accompanied with an unknown nuclear DNA (nDNA) factor, could be the cause of the phenotypic manifestations in this pedigree.

Besides the advance in scientific knowledge and the production of different compounds, cell culture can now be used to obtain cells for regenerative medicine. To avoid microbial contamination, antibiotics were usually incorporated into culture media. However, these compounds affect cell biochemistry and may modify the differentiation potential of cultured cells. To check this possibility, we grew human adipose tissue-derived stem cells and differentiated them to adipocyte with or without antibiotics commonly used in these culture protocols, such as a penicillin-streptomycin-amphotericin mix or gentamicin. We show that these antibiotics affect cell differentiation. Therefore, antibiotics should not be used in cell culture because aseptic techniques make these compounds unnecessary.

Resumen Objetivo a) Conocer la prescripción preventiva (estatinas, antiagregantes, bifosfonatos, calcio/vitamina D y vitamina B12) de los pacientes con patología crónica compleja (PCC) y de los pacientes con enfermedad crónica avanzada (ENCA) y esperanza de vida inferior a 12 meses que fallecieron durante el 2015. b) Valorar la correcta indicación en el uso de inhibidores de la bomba de protones (IBP) para determinar medicación evitable. Diseño Estudio transversal retrospectivo. Emplazamiento Cuatro centros de salud de Castellar del Vallès, Barcelona. Participantes Un total de 128 pacientes (70 ENCA y 58 PCC). Variables Fármacos activos en el momento de morir de los 6 grupos seleccionados, desprescripción (6 meses previos a la muerte por motivos de enfermedad crónica avanzada), indicación en prevención primaria o secundaria y adecuación en la prescripción IBP. Resultados Edad media en el momento de la muerte: 85,3 (10,3) años. El 40% de PCC/ENCA tomaban un antiagregante. En el 60% de los ENCA que tomaban un antiagregante no había evento cardiovascular previo. El 20% de PCC/ENCA tomaban una estatina y en el 48% de los casos por prevención primaria. La prescripción total de IBP fue del 67%, con indicación inadecuada del 49%. El 20% tomaban calcio/vitamina D y un 1,6% de los ENCA un bifosfonato. Hubo un 16% de desprescripción. Conclusiones Un porcentaje elevado de pacientes con enfermedad crónica avanzada y esperanza de vida corta siguen tomando tratamientos preventivos hasta sus últimos días, evitables en muchos casos y no exentos de efectos secundarios. Deberíamos aumentar la desprescripción de medicamentos con beneficios a largo plazo en este grupo de pacientes.

Mitochondrial DNA mutations at MT-ATP6 gene are relatively common in individuals suffering from striatal necrosis syndromes. These patients usually do not show apparent histochemical and/or biochemical signs of oxidative phosphorylation dysfunction. Because of this, MT-ATP6 is not typically analyzed in many other mitochondrial disorders that have not been previously associated to mutations in this gene. To correct this bias, we have performed a screening of the MT-ATP6 gene in a large collection of patients suspected of suffering different mitochondrial DNA (mtDNA) disorders. In three cases, biochemical, molecular-genetics and other analyses in patient tissues and cybrids were also carried out. We found three new pathologic mutations. Two of them in patients showing phenotypes that have not been commonly associated to mutations in the MT-ATP6 gene. These results remark the importance of sequencing the MT-ATP6 gene in patients with striatal necrosis syndromes, but also within other mitochondrial pathologies. This gene should be sequenced at least in all those patients suspected of suffering an mtDNA disorder disclosing normal results for histochemical and biochemical analyses of respiratory chain.

Background Mutations causing Leber hereditary optic neuropathy are usually homoplasmic, show incomplete penetrance, and many of the affected positions are not well conserved through evolution. A large percentage of patients harbouring these mutations have no family history of disease. Moreover, the transfer of the mutation in the cybrid model is frequently not accompanied by the transfer of the cellular, biochemical and molecular phenotype. All these features make difficult their classification as the etiologic factors for this disease. We report a patient who exhibits typical clinical features of Leber hereditary optic neuropathy but lacks all three of the most common mitochondrial DNA mutations. Methods The diagnosis was made based on clinical studies. The mitochondrial DNA was completely sequenced, and the candidate mutation was analysed in more than 18 000 individuals around the world, its conservation index was estimated in more than 3100 species from protists to mammals, its position was modelled in the crystal structure of a bacteria ortholog subunit, and its functional consequences were studied in a cybrid model. Results Genetic analysis revealed an m.3472T>C transition in the MT-ND1 gene that changes a phenylalanine to leucine at position 56. Bioinformatics, molecular-genetic analysis and functional studies suggest that this transition is the etiological factor for the disorder. Conclusions This mutation expands the spectrum of deleterious changes in mitochondrial DNA-encoded complex I polypeptides associated with this pathology and highlights the difficulties in assigning pathogenicity to new homoplasmic mutations that show incomplete penetrance in sporadic Leber hereditary optic neuropathy patients.

Background and aims Tacrolimus (Tac) is an immunosuppressive drug widely used to avoid organ rejection. New-onset diabetes after transplantation (NODAT) is a major complication among transplanted patients who receive Tac. The increased risk for NODAT could be partly mediated by the effect of Tac on mitochondria from pancreatic beta-cells. Common and rare mitochondrial DNA variants have been linked to the risk of diabetes. Our aim was to determine whether mtDNA polymorphisms/haplogroups were associated with NODAT in Tac-treated kidney transplanted. Methods Seven polymorphisms that define the common European haplogroups were determined in 115 NODAT and 197 no-NODAT patients. Results Haplogroup H was significantly more frequent in the NODAT group (50% vs. 35%; p = 0.01, OR = 1.82). There was no difference between patients without and with (n = 106) D2M prior to the transplant. Conclusions Mitochondrial haplogroup H was associated with the risk for NODAT among Tac-treated transplanted patients. The reported differences between the mtDNA variants could explain the increased NODAT-risk among H-patients.

FK506 is an important immunosuppressive medication. However, it can provoke neurotoxicity, nephrotoxicity, and diabetes as adverse side effects. The decrease in oxygen consumption of rat cells treated with pharmacologically relevant concentrations of FK506, along with other evidences, has insinuated that some of the toxic effects are probably caused by drug-induced mitochondrial dysfunction at the level of gene expression. To confirm this suggestion, we have analyzed cell respiration and mitochondrial protein synthesis in human cell lines treated with FK506. This drug provokes an important decrease in oxygen consumption, accompanied by a slight reduction in the synthesis of mitochondria DNA-encoded proteins. These results are similar to those triggered by rapamycin, another macrolide with immunosuppressive properties, therefore insinuating a common toxic pathway.

Preclinical Research Several key components of the oxidative phosphorylation system are coded in mitochondrial DNA. In humans, the mutation rate of the mitochondrial genome is higher than that of nuclear DNA. Some of these mutations can modify the interaction of mitochondrial DNA-encoded products with different therapeutic drugs. Several of these mutations have survived evolution, therefore generating different mitochondrial DNA genetic backgrounds. Thus, personalized medicine approaches must consider these particular interactions. However, before incorporating this knowledge into patient treatments, cellular and molecular studies are required. In this review, we discuss the cybrid model as a tool for this type of analysis, along with the pitfalls and improvements that are necessary before the translation of such models to medical practice.

Background: The oxidative phosphorylation system (OXPHOS) includes nuclear chromosome (nDNA)– and mitochondrial DNA (mtDNA)–encoded polypeptides. Many rare OXPHOS disorders, such as striatal necrosis syndromes, are caused by genetic mutations. Despite important advances in sequencing procedures, causative mutations remain undetected in some patients. It is possible that etiologic factors, such as environmental toxins, are the cause of these cases. Indeed, the inhibition of a particular enzyme by a poison could imitate the biochemical effects of pathological mutations in that enzyme. Moreover, environmental factors can modify the penetrance or expressivity of pathological mutations. Objectives: We studied the interaction between mitochondrially encoded ATP synthase 6 (p.MT-ATP6) subunit and an environmental exposure that may contribute phenotypic differences between healthy individuals and patients suffering from striatal necrosis syndromes or other mitochondriopathies. Methods: We analyzed the effects of the ATP synthase inhibitor tributyltin chloride (TBTC), a widely distributed environmental factor that contaminates human food and water, on transmitochondrial cell lines with or without an ATP synthase mutation that causes striatal necrosis syndrome. Doses were selected based on TBTC concentrations previously reported in human whole blood samples. Results: TBTC modified the phenotypic effects caused by a pathological mtDNA mutation. Interestingly, wild-type cells treated with this xenobiotic showed similar bioenergetics when compared with the untreated mutated cells. Conclusions: In addition to the known genetic causes, our findings suggest that environmental exposure to TBTC might contribute to the etiology of striatal necrosis syndromes. Citation: López-Gallardo E, Llobet L, Emperador S, Montoya J, Ruiz-Pesini E. 2016. Effects of tributyltin chloride on cybrids with or without an ATP synthase pathologic mutation. Environ Health Perspect 124:1399–1405; http://dx.doi.org/10.1289/EHP182

Mutations causing Leber hereditary optic neuropathy are usually homoplasmic, show incomplete penetrance, and many of the affected positions are not well conserved through evolution. A large percentage of patients harbouring these mutations have no family history of disease. Moreover, the transfer of the mutation in the cybrid model is frequently not accompanied by the transfer of the cellular, biochemical and molecular phenotype. All these features make difficult their classification as the etiologic factors for this disease. We report a patient who exhibits typical clinical features of Leber hereditary optic neuropathy but lacks all three of the most common mitochondrial DNA mutations.The diagnosis was made based on clinical studies. The mitochondrial DNA was completely sequenced, and the candidate mutation was analysed in more than 18 000 individuals around the world, its conservation index was estimated in more than 3100 species from protists to mammals, its position was modelled in the crystal structure of a bacteria ortholog subunit, and its functional consequences were studied in a cybrid model.Genetic analysis revealed an m.3472TC transition in the MT-ND1 gene that changes a phenylalanine to leucine at position 56. Bioinformatics, molecular-genetic analysis and functional studies suggest that this transition is the etiological factor for the disorder.This mutation expands the spectrum of deleterious changes in mitochondrial DNA-encoded complex I polypeptides associated with this pathology and highlights the difficulties in assigning pathogenicity to new homoplasmic mutations that show incomplete penetrance in sporadic Leber hereditary optic neuropathy patients.

Multiple sclerosis is likely caused by a complex interaction of multiple genes and environmental factors. The contribution of mitochondrial DNA genetic backgrounds has been frequently reported. To evaluate the effect of mitochondrial DNA haplogroups in the same genetic and environmental circumstances, we have built human transmitochondrial cell lines and simulated the effect of axon demyelination, one of the hallmarks of multiple sclerosis pathology, by altering the ionic gradients through the plasmalemma and increasing ATP consumption. In this model, mitochondrial biogenesis is observed. This process is larger in Uk cybrids, which mirrors their lower oxidative phosphorylation capacity in basal conditions. This model replicates a process occurring in both patients suffering from multiple sclerosis and several animal models of axon demyelination. Therefore, it can be used to analyze the contribution of various mitochondrial DNA genotypes to multiple sclerosis. In this sense, a longer or stronger energy stress, such as that associated with demyelinated axons in multiple sclerosis, could make Uk individuals more susceptible to this pathology. Finally, pharmacologic compounds targeted to mitochondrial biogenesis could be a potential therapy for multiple sclerosis.