Reduced mitochondrial respiratory capacity in patients with acute episodes of bipolar disorder: Could bipolar disorder be a state-dependent mitochondrial disease?

BACKGROUND: Bipolar disorder (BD) is a chronic and recurrent disease characterized by acute mood episodes and periods of euthymia. The available literature postulates that a biphasic dysregulation of mitochondrial bioenergetics might underpin the neurobiology of BD. However, most studies focused on inter-subject differences rather than intra-subject variations between different mood states. To test this hypothesis, in this preliminary proof-of-concept study, we measured in vivo mitochondrial respiration in patients with BD during a mood episode and investigated differences compared to healthy controls (HC) and to the same patients upon clinical remission. METHODS: This longitudinal study recruited 20 patients with BD admitted to our acute psychiatric ward with a manic (n = 15) or depressive (n = 5) episode, and 10 matched HC. We assessed manic and depressive symptoms using standardized psychometric scales. Different mitochondrial oxygen consumption rates (OCRs: Routine, Leak, electron transport chain [ETC], Rox) were assessed during the acute episode (T0) and after clinical remission (T1) using high-resolution respirometry at 37°C by polarographic oxygen sensors in a two-chamber Oxygraph-2k system in one million of peripheral blood mononuclear cells (PMBC). Specific OCRs were expressed as mean ± SD in picomoles of oxygen per million cells. Significant results were adjusted for age, sex, and body mass index. RESULTS: The longitudinal analysis showed a significant increase in the maximal oxygen consumption capacity (ETC) in clinical remission (25.7 ± 16.7) compared to the acute episodes (19.1 ± 11.8, p = 0.025), and was observed separately for patients admitted with a manic episode (29.2 ± 18.9 in T1, 22.3 ± 11.9 in T0, p = 0.076), and at a trend-level for patients admitted with a depressive episode (15.4 ± 3.9 in T1 compared to 9.4 ± 3.2 in T0, p = 0.107). Compared to HC, significant differences were observed in ETC in patients with a bipolar mood episode (H = 11.7; p = 0.003). Individuals with bipolar depression showed lower ETC than those with a manic episode (t = -3.7, p = 0.001). Also, significant differences were observed in ETC rates between HC and bipolar depression (Z = 1.000, p = 0.005). CONCLUSIONS: Bioenergetic and mitochondrial dysregulation could be present in both manic and depressive phases in BD and, importantly, they may restore after clinical remission. These preliminary results suggest that mitochondrial respiratory capacity could be a biomarker of illness activity and clinical response in BD. Further studies with larger samples and similar approaches are needed to confirm these results and identify potential biomarkers in different phases of the disease.

Metabolic, Mitochondrial, and Inflammatory Effects of Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate in Asymptomatic Antiretroviral-Naïve People with HIV.

This study aimed to comprehensively assess the metabolic, mitochondrial, and inflammatory effects of first-line efavirenz, emtricitabine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) single-tablet regimen (STR) relative to untreated asymptomatic HIV infection. To this end, we analyzed 29 people with HIV (PWH) treated for at least one year with this regimen vs. 33 antiretroviral-naïve PWH. Excellent therapeutic activity was accompanied by significant alterations in metabolic parameters. The treatment group showed increased plasmatic levels of glucose, total cholesterol and its fractions (LDL and HDL), triglycerides, and hepatic enzymes (GGT, ALP); conversely, bilirubin levels (total and indirect fraction) decreased in the treated cohort. Mitochondrial performance was preserved overall and treatment administration even promoted the recovery of mitochondrial DNA (mtDNA) content depleted by the virus, although this was not accompanied by the recovery in some of their encoded proteins (since cytochrome c oxidase II was significantly decreased). Inflammatory profile (TNFα, IL-6), ameliorated after treatment in accordance with viral reduction and the recovery of TNFα levels correlated to mtDNA cell restoration. Thus, although this regimen causes subclinical metabolic alterations, its antiviral and anti-inflammatory properties may be associated with partial improvement in mitochondrial function.

Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies.

OBJECTIVES: Myositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the chromodomain helicase DNA-binding protein 4 (CHD4)/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients. METHODS: RNA sequencing was performed on muscle biopsies (n=171) from patients with anti-Mi2-positive DM (n=18), DM without anti-Mi2 autoantibodies (n=32), AS (n=18), IMNM (n=54) and IBM (n=16) as well as 33 normal muscle biopsies. Genes specifically upregulated in anti-Mi2-positive DM were identified. Muscle biopsies were stained for human immunoglobulin and protein products corresponding to genes specifically upregulated in anti-Mi2-positive muscle biopsies. RESULTS: A set of 135 genes, including SCRT1 and MADCAM1, was specifically overexpressed in anti-Mi2-positive DM muscle. This set was enriched for CHD4/NuRD-regulated genes and included genes that are not otherwise expressed in skeletal muscle. The expression levels of these genes correlated with anti-Mi2 autoantibody titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei. CONCLUSIONS: Based on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.

Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea.

Hematocrit control below 45% is associated with a lower rate of thrombosis in polycythemia vera. In patients receiving hydroxyurea, this target can be achieved with hydroxyurea alone or with the combination of hydroxyurea plus phlebotomies. However, the clinical implications of phlebotomy requirement under hydroxyurea therapy are unknown. The aim of this study was to evaluate the need for additional phlebotomies during the first five years of hydroxyurea therapy in 533 patients with polycythemia vera. Patients requiring 3 or more phlebotomies per year (n=85, 16%) showed a worse hematocrit control than those requiring 2 or less phlebotomies per year (n=448, 84%). There were no significant differences between the two study groups regarding leukocyte and platelet counts. Patients requiring 3 or more phlebotomies per year received significantly higher doses of hydroxyurea than the remaining patients. A significant higher rate of thrombosis was found in patients treated with hydroxyurea plus 3 or more phlebotomies per year compared to hydroxyurea with 0-2 phlebotomies per year (20.5% vs. 5.3% at 3 years; P<0.0001). In multivariate analysis, independent risk factors for thrombosis were phlebotomy dependency (HR: 3.3, 95%CI: 1.5-6.9; P=0.002) and thrombosis at diagnosis (HR: 4.7, 95%CI: 2.3-9.8; P<0.0001). The proportion of patients fulfilling the European LeukemiaNet criteria of resistance/intolerance to hydroxyurea was significantly higher in the group requiring 3 or more phlebotomies per year (18.7% vs. 7.1%; P=0.001) mainly due to extrahematologic toxicity. In conclusion, phlebotomy requirement under hydroxyurea therapy identifies a subset of patients with increased proliferation of polycythemia vera and higher risk of thrombosis.

Density and duration of pneumococcal carriage is maintained by transforming growth factor ß1 and T regulatory cells.

RATIONALE: Nasopharyngeal carriage of Streptococcus pneumoniae is a prerequisite for invasive disease, but the majority of carriage episodes are asymptomatic and self-resolving. Interactions determining the development of carriage versus invasive disease are poorly understood but will influence the effectiveness of vaccines or therapeutics that disrupt nasal colonization. OBJECTIVES: We sought to elucidate immunological mechanisms underlying noninvasive pneumococcal nasopharyngeal carriage. METHODS: Pneumococcal interactions with human nasopharyngeal and bronchial fibroblasts and epithelial cells were investigated in vitro. A murine model of nasopharyngeal carriage and an experimental human pneumococcal challenge model were used to characterize immune responses in the airways during carriage. MEASUREMENTS AND MAIN RESULTS: We describe the previously unknown immunological basis of noninvasive carriage and highlight mechanisms whose perturbation may lead to invasive disease. We identify the induction of active transforming growth factor (TGF)-ß1 by S. pneumoniae in human host cells and highlight the key role for TGF-ß1 and T regulatory cells in the establishment and maintenance of nasopharyngeal carriage in mice and humans. We identify the ability of pneumococci to drive TGF-ß1 production from nasopharyngeal cells in vivo and show that an immune tolerance profile, characterized by elevated TGF-ß1 and high nasopharyngeal T regulatory cell numbers, is crucial for prolonged carriage of pneumococci. Blockade of TGF-ß1 signaling prevents prolonged carriage and leads to clearance of pneumococci from the nasopharynx. CONCLUSIONS: These data explain the mechanisms by which S. pneumoniae colonize the human nasopharynx without inducing damaging host inflammation and provide insight into the role of bacterial and host constituents that allow and maintain carriage.

[Medication adherence and use of health services in patients with psychosis in the region of Osona (Catalonia, Spain)]. / Adherencia al tratamiento y utilización de servicios de salud pacientes con psicosis.

OBJECTIVE: To describe and analyze sociodemographic and clinical characteristics, medication adherence and use of health resources by country of birth of psychosis diagnosed patients treated with long-term antipsychotic injectable drugs in the region of Osona (Catalonia, Spain). METHOD: Descriptive observational study in psychosis diagnosed patients over 18 years old, receiving long-term antipsychotic injectable treatment and treated at a Mental Health Center for adults in Vic (Catalonia, Spain). RESULTS: 185 patients were included, of them: 163 (88.1%) were born in Spain and 22 (17.9%) abroad. The sample was gender homogeneous with differences in age, employment status, family situation and diagnosis (p < 0.05). Findings about medication adherence to long-term antipsychotic injectable ambulatory treatment reflected good compliance in both populations. 57.7% of Spain-born patients and 9.1% of abroad-born patients received the injectable treatment at Primary Care Center (p < 0.001). The rest of them received the treatment at Mental Health Center for adults. 22 patients (711.9%) were admitted at psychiatry hospitalization ward, 16 (9.8%) of them were born in Spain and 6 (27.3%) abroad (p = 0.012). CONCLUSIONS: All patients diagnosed with psychosis, either born or not in Spain, describe good adherence to long-term antipsychotic injectable treatment, with similar use of health resources from a quantitative point of view and some differences in the type of visits.

Classifying glaucoma exclusively with OCT: comparison of three clustering algorithms derived from machine learning.

BACKGROUND/AIMS: To objectively classify eyes as either healthy or glaucoma based exclusively on data provided by peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform (GCIPL) measurements derived from spectral-domain optical coherence tomography (SD-OCT) using machine learning algorithms. METHODS: Three clustering methods (k-means, hierarchical cluster analysis -HCA- and model-based clustering-MBC-) were used separately to classify a training sample of 109 eyes as either healthy or glaucomatous using solely 13 SD-OCT parameters: pRNFL average and sector thicknesses and GCIPL average and minimum values together with the six macular wedge-shaped regions. Then, the best-performing algorithm was applied to an independent test sample of 102 eyes to derive close estimates of its actual performance (external validation). RESULTS: In the training sample, accuracy was 91.7% for MBC, 81.7% for k-means and 78.9% for HCA (p value = 0.02). The best MBC model was that in which subgroups were allowed to have variable volume and shape and equal orientation. The MBC algorithm in the independent test sample correctly classified 98 out of 102 cases for an overall accuracy of 96.1% (95% CI, 92.3-99.8%), with a sensitivity of 94.3 and 100% specificity. The accuracy for pRNFL was 92.2% (95% CI, 86.9-97.4%) and for GCIPL 98.0% (95% CI, 95.3-100%). CONCLUSIONS: Clustering algorithms in general (and MBC in particular) seem promising methods to help discriminate between healthy and glaucomatous eyes using exclusively SD-OCT-derived parameters. Understanding the relative merits of one method over others may also provide insights into the nature of the disease.

Aerobic capacity and mitochondrial function in bipolar disorder: a longitudinal study during acute phases and after clinical remission.

Background: Aerobic capacity has shown to predict physical and mental health-related quality of life in bipolar disorder (BD). However, the correlation between exercise respiratory capacity and mitochondrial function remains understudied. We aimed to assess longitudinally intra-individual differences in these factors during mood episodes and remission in BD. Methods: This study included eight BD patients admitted to an acute psychiatric unit. Incremental cardiopulmonary exercise test (CPET) was conducted during acute episodes (T0), followed by constant work rate cycle ergometry (CWRCE) to evaluate endurance time, oxygen uptake at peak exercise (VO2peak) and at the anaerobic threshold. The second test was repeated during remission (T1). Mitochondrial respiration rates were assessed at T0 and T1 in peripheral blood mononuclear cells. Results: Endurance time, VO2peak, and anaerobic threshold oxygen consumption showed no significant variations between T0 and T1. Basal oxygen consumption at T1 tended to inversely correlate with maximal mitochondrial respiratory capacity (r=-0.690, p=0.058), and VO2peak during exercise at T1 inversely correlated with basal and minimum mitochondrial respiration (r=-0.810, p=0.015; r=-0.786, p=0.021, respectively). Conclusions: Our preliminary data showed that lower basal oxygen consumption may be linked to greater mitochondrial respiratory capacity, and maximum oxygen uptake during the exercise task was associated with lower basal mitochondrial respiration, suggesting that lower oxygen requirements could be associated with greater mitochondrial capacity. These findings should be replicated in larger samples stratified for manic and depressive states.

Low prostaglandin E2 and cyclooxygenase expression in nasal mucosa fibroblasts of aspirin-intolerant asthmatics.

BACKGROUND AND OBJECTIVE: Anomalies in the regulation of cyclooxygenase (COX)-1 and -2 have been described in nasal polyps of aspirin-induced asthma (AIA). Whether these anomalies are specific to nasal polyps or affect all the nasal mucosa (NM) of upper airways is still unclear. The objective of this study was to compare the COX pathway in NM of AIA patients with the NM of control subjects. METHODS: Fibroblasts were isolated from NM of five AIA patients (AIA-NM) and five control subjects (control-NM). Cells were treated with 10 ng/mL interleukin (IL)-1ß for up to 72 h. Prostaglandin E2 (PGE2 ) production was measured by enzyme-linked immunosorbent assay (ELISA), expression of COX-1 protein by Western blot and COX-2 protein by ELISA, Western blot and immunofluorescence techniques. RESULTS: IL-1ß increased PGE2 production and COX-1 protein expression in control-NM fibroblasts, but no changes were found in AIA-NM. IL-1ß provoked a significant time-dependent increase in COX-2 protein expression in control-NM fibroblasts but had a very mild effect on COX-2 protein expression in AIA-NM. CONCLUSIONS: Our data suggest that abnormalities in the COX pathway are not a phenomenon exclusive to nasal-polyp mucosa as they are also present in all the NM of AIA patients. These anomalies may be involved in the pathogenesis of airway inflammation and non-steroidal anti-inflammatory drug intolerance in asthma patients with chronic rhinosinusitis and nasal polyposis.

An Unusual Case of Lacrimal Gland Dacryops in a 10-Year-Old Child.

Lacrimal gland dacryops are an unusual type of benign epithelial neoplasm. Most of the literature refers to dacryops of the lacrimal palpebral lobe, with orbital lobe involvement less frequent. The authors report a case of dacryops in a 10-year-old child involving the orbital lobe of the lacrimal gland. [J Pediatr Ophthalmol Strabismus. 2023;60(6):e79-e82.].

Integrated Multi-Omics Analysis for Inferring Molecular Players in Inclusion Body Myositis.

Inclusion body myositis (IBM) is an acquired inflammatory myopathy affecting proximal and distal muscles that leads to weakness in patients over 50. It is diagnosed based on clinical and histological findings in muscle related to inflammation, degeneration, and mitochondria. In relation to IBM, a shortage of validated disease models and a lack of biomarkers and effective treatments constitute an unmet medical need. To overcome these hurdles, we performed an omics analysis of multiple samples from IBM patients (saliva, fibroblasts, urine, plasma, and muscle) to gain insight into the pathophysiology of IBM. Degeneration was evident due to the presence of amyloid ß peptide 1-42 (Aß1-42) in the saliva of the analyzed IBM patients. The presence of metabolic disarrangements in IBM was indicated by an imbalanced organic acid profile in fibroblasts and urine. Specifically, abnormal levels of L-pyroglutamic and orotic acid were supported by the abnormal expression of related metabolites in plasma and urine (glutathione and pyrimidines) and the aberrant expression of upstream gene regulators (L2HGDH, IDH2, OPLAH, and ASL) in muscle. Combined levels of L-pyroglutamic and orotic acid displayed an outstanding biomarker signature in urine with 100% sensitivity and specificity. The confirmation of systemic metabolic disarrangements in IBM and the identification of novel biomarkers reported herein unveil novel insights that require validation in larger cohorts.

Preparing Enteral Formulas for Adult Patients with Phenylketonuria: A Minor Necessity but Major Challenge-A Case Report.

Phenylketonuria (PKU) is the most frequent of the congenital errors of amino acid (AA) metabolism worldwide. It leads to the accumulation of the essential AA phenylalanine (Phe) and it is associated with severe neurological defects. The early diagnosis and treatment of this rare disease, achieved through newborn screening and low-Phe diet, has profoundly changed its clinical spectrum, resulting in normal cognitive development. We face the first generation of PKU patients perinatally diagnosed and treated who have reached adulthood, whose special needs must be addressed, including feeding through enteral nutrition (EN). However, recommendations regarding EN in PKU constitute a gap in the literature. Although protein substitutes for patients with PKU are offered in multiple forms (Phe-free L-amino acid or casein glycomacropeptide supplements), none of these commercial formulas ensures the whole provision of daily total energy and protein requirements, including a safe amount of Phe. Consequently, the combination of different products becomes necessary when artificial nutrition via tube feeding is required. Importantly, the composition of these specific formulas may result in physicochemical interactions when they are mixed with standard EN products, leading to enteral feeding tubes clogging, and also gastrointestinal concerns due to hyperosmolality. Herein, we present the first reported case of EN use in an adult patient with PKU, where the separate administration of protein substitutes and the other EN products avoided physicochemical interactions.

Unravelling inclusion body myositis using a patient-derived fibroblast model.

BACKGROUND: Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non-established biomarkers or effective treatments are available, partly due to the lack of validated disease models. METHODS: We have performed transcriptomics and functional validation of IBM muscle pathological hallmarks in fibroblasts from IBM patients (n = 14) and healthy controls (n = 12), paired by age and sex. The results comprise an mRNA-seq, together with functional inflammatory, autophagy, mitochondrial and metabolic changes between patients and controls. RESULTS: Gene expression profile of IBM vs control fibroblasts revealed 778 differentially expressed genes (P-value adj < 0.05) related to inflammation, mitochondria, cell cycle regulation and metabolism. Functionally, an increased inflammatory profile was observed in IBM fibroblasts with higher supernatant cytokine secretion (three-fold increase). Autophagy was reduced considering basal protein mediators (18.4% reduced), time-course autophagosome formation (LC3BII 39% reduced, P-value < 0.05), and autophagosome microscopic evaluation. Mitochondria displayed reduced genetic content (by 33.9%, P-value < 0.05) and function (30.2%-decrease in respiration, 45.6%-decline in enzymatic activity (P-value < 0.001), 14.3%-higher oxidative stress, 135.2%-increased antioxidant defence (P-value < 0.05), 11.6%-reduced mitochondrial membrane potential (P-value < 0.05) and 42.8%-reduced mitochondrial elongation (P-value < 0.05)). In accordance, at the metabolite level, organic acid showed a 1.8-fold change increase, with conserved amino acid profile. Correlating to disease evolution, oxidative stress and inflammation emerge as potential markers of prognosis. CONCLUSIONS: These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients' derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies.

Reduced expression of COXs and production of prostaglandin E(2) in patients with nasal polyps with or without aspirin-intolerant asthma.

BACKGROUND: Researchers have debated whether regulation of the COX enzymes (COX-1 and COX-2), which mediate production of prostaglandins (PGs), affects the pathogenesis of nasal polyps (NPs) and aspirin-intolerant asthma (AIA). OBJECTIVE: We investigated the roles of PGE(2), COX-1 and COX-2, and PGE(2) receptors in the development of NPs and AIA by measuring their expression in fibroblasts derived from nasal mucosa (NM) and NPs. METHODS: Fibroblasts were isolated from the NM of subjects without asthma who had septal deviation, turbinate hypertrophy, or both (control subjects, n = 7); NPs of aspirin-tolerant nonasthmatic patients (n = 7); and NPs of patients with asthma who were intolerant of aspirin (n = 7). Polyp samples were collected during endoscopic surgery. Cultures were stimulated with IL-1ß (10 ng/mL) for 72 hours. We used ELISA, immunoblotting, and immunofluorescence analyses to measure secretion of PGE(2), expression of COX-1 and COX-2, and expression of the PGE(2) receptors EP1 to EP4. RESULTS: Compared with NM from control subjects, PGE(2) concentrations were significantly lower in IL-1ß-stimulated fibroblasts from patients with NPs who were tolerant to aspirin and even lower in polyps from patients with AIA. Similarly, IL-1ß exposure induced the expression of COX-1 and COX-2 in fibroblasts from NM of control subjects, had only moderate effects on fibroblasts from NPs of aspirin-tolerant nonasthmatic patients, and almost no effect on fibroblasts from NPs of patients with AIA. IL-1ß also induced expression of EP2 in fibroblasts from control NM but not in fibroblasts from NPs of aspirin-tolerant nonasthmatic patients or those with AIA. CONCLUSION: Alterations in the COX pathway (ie, reduced production of PGE(2) and lack of upregulation of COX-1, COX-2, and EP2 under conditions of inflammation) are associated with NPs in patients with or without AIA.

Relevance of sex-differenced analyses in bioenergetics and nutritional studies.

Sex-biased analyses still remain as one of the biggest limitations to obtain universal conclusions. In biomedicine, the majority of experimental analyses and a significant amount of patient-derived cohort studies exclusively included males. In nutritional and molecular medicine, sex-influence is also frequently underrated, even considering maternal-inherited organelles such as mitochondria. We herein illustrate with in-house original data examples of how sex influences mitochondrial homeostasis, review these topics and highlight the consequences of biasing scientific analyses excluding females as differentiated entities from males.

Comment on Yeste et al. Polyphenols and IUGR Pregnancies: Intrauterine Growth Restriction and Hydroxytyrosol Affect the Development and Neurotransmitter Profile of the Hippocampus in a Pig Model. Antioxidants 2021, 10, 1505.

Intrauterine growth restriction (IUGR) affects 5-10% of newborns and increases the risks of intrauterine demise, neonatal morbidity, and death. In their recent publication, Yeste et al. found the benefits of hydroxytyrosol supplementation on brain remodeling from an IUGR pig model. Additionally, we found a significant decrease in phenolic alcohol (tyrosol and hydroxytyrosol) intake in IUGR pregnant women. Altogether, these findings support the notion that dietetic interventions, through supplementation but mostly via a balanced diet, can ameliorate IUGR complications. Furthermore, diet intervention combined with early biomarkers may allow clinicians to eventually anticipate IUGR diagnosis and help avoid one of the most frequent causes of newborn mortality and morbidity.

Neuronal induction and bioenergetics characterization of human forearm adipose stem cells from Parkinson's disease patients and healthy controls.

Neurodegenerative diseases, such as Parkinson's disease, are heterogeneous disorders with a multifactorial nature involving impaired bioenergetics. Stem-regenerative medicine and bioenergetics have been proposed as promising therapeutic targets in the neurologic field. The rationale of the present study was to assess the potential of human-derived adipose stem cells (hASCs) to transdifferentiate into neuronal-like cells (NhASCs and neurospheres) and explore the hASC bioenergetic profile. hASC neuronal transdifferentiation was performed through neurobasal media and differentiation factor exposure. High resolution respirometry was assessed. Increased MAP-2 neuronal marker protein expression upon neuronal induction (p<0.05 undifferentiated hASCs vs. 28-36 days of differentiation) and increased bIII-tubulin neuronal marker protein expression upon neuronal induction (p<0.05 undifferentiated hASCs vs. 6-28-36 days of differentiation) were found. The bioenergetic profile was detectable through high-resolution respirometry approaches in hASCs but did not lead to differential oxidative capacity rates in healthy or clinically diagnosed PD-hASCs. We confirmed the capability of transdifferentiation to the neuronal-like profile of hASCs derived from the forearms of human subjects and characterized the bioenergetic profile. Suboptimal maximal respiratory capacity trends in PD were found. Neuronal induction leading to positive neuronal protein expression markers is a relevant issue that encourages the suitability of NhASC models in neurodegeneration.

Assessment of mitochondrial toxicity in newborns and infants with congenital cytomegalovirus infection treated with valganciclovir.

BACKGROUND: Ganciclovir/valganciclovir is currently indicated during the first 6 months of life in symptomatic children with congenital cytomegalovirus (CMV) infection. However, this treatment may have the potential to induce mitochondrial toxicity due to off-target inhibition of DNA-polymerases. Similar anti-HIV drugs have been associated with mitochondrial toxicity but this has never been explored in CMV. OBJECTIVE: To determine the potential mitochondrial toxicity profile at the genetic, functional and biogenesis level in peripheral blood mononuclear cells from a cohort of newborns and infants with symptomatic congenital CMV infection (treated with valganciclovir, untreated and uninfected controls). DESIGN: Longitudinal, observational and controlled study. SETTING AND PATIENTS: Subjects were recruited at the tertiary referral Hospital Sant Joan de Déu and experiments were conducted at IDIBAPS-Hospital Clínic of Barcelona, Spain. CMV-infected newborns underwent comprehensive monthly clinical follow-up. METHODS: Mitochondrial parameters, audiometry and neurological assessment were measured at baseline, 3-6 and 12 months after inclusion in the study. The Kruskal-Wallis test for k-independent samples and Friedman tests for repeated measurements were applied. RESULTS: Complex IV, citrate synthase enzymatic activities and mtDNA remained preserved in congenital CMV-infected infants treated with valganciclovir compared with controls (p>0.05 in all cases). CONCLUSIONS: No evidence of mitochondrial toxicity was found in infants treated with valganciclovir for congenital CMV.

Multicentric Standardization of Protocols for the Diagnosis of Human Mitochondrial Respiratory Chain Defects.

The quantification of mitochondrial respiratory chain (MRC) enzymatic activities is essential for diagnosis of a wide range of mitochondrial diseases, ranging from inherited defects to secondary dysfunctions. MRC lesion is frequently linked to extended cell damage through the generation of proton leak or oxidative stress, threatening organ viability and patient health. However, the intrinsic challenge of a methodological setup and the high variability in measuring MRC enzymatic activities represents a major obstacle for comparative analysis amongst institutions. To improve experimental and statistical robustness, seven Spanish centers with extensive experience in mitochondrial research and diagnosis joined to standardize common protocols for spectrophotometric MRC enzymatic measurements using minimum amounts of sample. Herein, we present the detailed protocols, reference ranges, tips and troubleshooting methods for experimental and analytical setups in different sample preparations and tissues that will allow an international standardization of common protocols for the diagnosis of MRC defects. Methodological standardization is a crucial step to obtain comparable reference ranges and international standards for laboratory assays to set the path for further diagnosis and research in the field of mitochondrial diseases.

Nutrition, Bioenergetics, and Metabolic Syndrome.

According to the World Health Organization (WHO), the global nutrition report shows that whilst part of the world's population starves, the other part suffers from obesity and associated complications. A balanced diet counterparts these extreme conditions with the proper proportion, composition, quantity, and presence of macronutrients, micronutrients, and bioactive compounds. However, little is known on the way these components exert any influence on our health. These nutrients aiming to feed our bodies, our tissues, and our cells, first need to reach mitochondria, where they are decomposed into CO2 and H2O to obtain energy. Mitochondria are the powerhouse of the cell and mainly responsible for nutrients metabolism, but they are also the main source of oxidative stress and cell death by apoptosis. Unappropriated nutrients may support mitochondrial to become the Trojan horse in the cell. This review aims to provide an approach to the role that some nutrients exert on mitochondria as a major contributor to high prevalent Western conditions including metabolic syndrome (MetS), a constellation of pathologic conditions which promotes type II diabetes and cardiovascular risk. Clinical and experimental data extracted from in vitro animal and cell models further demonstrated in patients, support the idea that a balanced diet, in a healthy lifestyle context, promotes proper bioenergetic and mitochondrial function, becoming the best medicine to prevent the onset and progression of MetS. Any advance in the prevention and management of these prevalent complications help to face these challenging global health problems, by ameliorating the quality of life of patients and reducing the associated sociosanitary burden.