How can corporate taxes contribute to sub-Saharan Africa's Sustainable Development Goals (SDGs)? A case study of Vodafone.

BACKGROUND: The COVID-19 pandemic and the climate emergency threaten progress in reaching many of the Sustainable Development Goal (SDG) targets by 2030. The under-5 mortality and maternal mortality rates are well below the targets, and if we progress at the current pace, there is a high risk of not meeting the 2030 goals. Furthermore, the initial progress in the decline in child and maternal mortality since 1990 is likely to be eroded. Much of this progress has resulted from increased sanitation, drinking water, education, and health service coverage. The adequate provision of public services is possible if there is sufficient government funding. When governments have more income, they spend more on public services, which increases access to fundamental economic and social rights and, thus, contributes to the SDGs. One of the key drivers of government financing, taxation, constitutes 70% of government revenue in low- and lower-middle-income countries. Corporate income tax constitutes 18.8% of tax revenue in African countries compared to 10% of tax revenue in OECD countries. Therefore, it plays a critical role in SDG progress. This paper aims to quantify the contribution of one large taxpayer, that publishes their tax payments, (Vodafone Group Plc) on progress towards SDGs in six African countries. We use econometric modelling to estimate the impact of an increase in government revenue equivalent to Vodafone's average tax paid between 2007-2017. RESULTS: We find that government revenue equivalent to Vodafone's taxes made a significant contribution to progress in attaining selected SDGs. We found that the revenue equivalent to Vodafone's taxes allowed 966,188 people to access clean water and 1,371,972 people to access basic sanitation each year. Over the time period studied, 858,054 children spent an extra year in school and 54,275 children under five years and 3,655 mothers survived. In just one of these countries, Tanzania, the revenue equivalent to Vodafone's tax contribution allowed 174,121 people to access clean water and 223,586 to access sanitation each year. Over the time studied 187,023 children spent an additional year at school, 6,569 additional children under five and 625 additional mothers survived. CONCLUSIONS: These findings demonstrate that the reported contributions from a single multinational corporation drive SDG progress. Furthermore, it highlights the importance of transparent taxes and explores the responsibilities of global institutions, governments, investors, and multinational corporations.

Optimizing Artemia Enrichment: A Low DHA/High EPA Protocol for Enhanced n-3 LC-HUFA Levels to Support Greater Amberjack (Seriola dumerili) Larval Rearing.

Most commercial products available for Artemia sp. enrichment include high levels of docosahexaenoic acid (DHA) to boost its nutritional value, though with limited success. In this regard, the present study evaluated the alternative utilization of eicosapentaenoic acid (20 : 5n-3; EPA) oils to improve the n-3 long-chain highly unsaturated fatty acid content (n-3 LC-HUFA) in enriched Artemia sp. to feed greater amberjack (Seriola dumerili) larvae. Five experimental emulsions containing increasing levels of EPA from 0.8% to 60% of total fatty acids (TFA) and n-3 LC-HUFA (1.3%-70.6% TFA) were formulated. Each diet was fed to greater amberjack larvae (17-35 days posthatch (dph)) in three replicate 200-L tanks. The dietary EPA supplementation significantly improved larval growth during the feeding trial and survival at 35 dph (P < 0.05). In addition, larval fatty acid profiles showed a positive correlation with dietary EPA. Finally, despite the sum of total skeletal anomalies and column anomalies were not significantly affected by dietary EPA, increasing dietary EPA, and n-3 LC-HUFA tended to reduce the incidence of these types of anomalies in greater amberjack larvae at 35 dph. Based on these results, S. dumerili larvae could be successfully grown with low DHA but high EPA-rich oil enrichment products when n-3 LC-HUFA content in Artemia sp. is maintained in sufficient amounts.

High Rates of Extensively Drug-Resistant Pseudomonas aeruginosa in Children with Cystic Fibrosis.

Pseudomonas aeruginosa has a high adaptive capacity, favoring the selection of antibiotic-resistant strains, which are currently considered a global health problem. The purpose of this work was to investigate the rate and distribution of extensively drug-resistant (XDR) P. aeruginosa in pediatric patients with cystic fibrosis (CF) with recurrent infections and to distinguish the current efficacy of antibiotics commonly used in eradication therapy at a Mexican institute focused on children. A total of 118 P. aeruginosa isolates from 25 children with CF (2015-2019) underwent molecular identification, antimicrobial sensitivity tests, and Random Amplified Polymorphic DNA genotyping (RAPD-PCR). The bacterial isolates were grouped in 84 RAPD profiles, revealing a cross-infection between two sisters, whose resistance profile remained unchanged for more than 2 years. Furthermore, 77.1% (91/118) and 51.7% (61/118) of isolates showed in vitro susceptibility to ceftazidime and amikacin, respectively, antibiotics often used in eradication therapy at our institution. As well, 42.4% (50/118) were categorized as multi-drug resistant (MDR) and 12.7% (15/118) were XDR. Of these resistant isolates, 84.6% (55/65) were identified from patients with recurrent infections. The high frequency of XDR strains in children with CF should be considered a caution mark, as such resistance patterns are more commonly found in adult patients. Additionally, amikacin may soon prove ineffective. Careful use of available antibiotics is crucial before therapeutic possibilities are reduced and "antibiotic resistance crisis" worsens.

Alcohol intake potentiates clozapine adverse effects associated to CYP1A2*1C in patients with refractory psychosis.

Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation-dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR = 3.55 CI95  = 1.041-12.269, p = .043) and demonstrated that this effect is doubled by concomitant alcohol consumption (OR = 7.9 CI95  = 1.473-42.369, p = .016). Clinicians should be aware of this information before starting CLZ use, when treating patients with refractory psychosis, who are alcohol drinkers and carriers of this genetic variant in order to prevent CLZ-related adverse reactions. Nevertheless, our findings should be replicated in larger samples.

Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy.

Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A4*1b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A4*1b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.

[Current situation of pediatric liver transplantation in Chile. Inequities associated with the MELD/PELD prioritization system]. / Situación actual del trasplante hepático pediátrico por hepatopatías crónicas en Chile: Inequidades asociadas a la priorización por sistema MELD/PELD.

BACKGROUND: The Chilean allocation system for liver transplantation (LT) uses the MELD/PELD score to prioritize candidates on the waiting list. AIM: To assess if the Chilean allocation system for LT is equitable for pediatric candidates compared to their adult counterparts. MATERIAL AND METHODS: We used the Public Health Institute's registry between October 2011 and December 2017. We analyzed candidates with chronic hepatic diseases listed for LT. The primary outcome was the cadaveric liver transplantation (CLT) rate. Secondary outcomes were death or disease progression in the waiting list and living donor liver transplant (LDLT) rate. RESULTS: We analyzed 122 pediatric and 735 adult candidates. Forty one percent of pediatric candidates obtained a CLT compared to 48% of adults (p = NS). Among patients aged under two years of age, the access to CLT on the waiting list there was 28% of CLT, compared to 48% in adults (p = 0.001). Fifty-seven percent of candidates aged under two years were listed for cholestatic diseases, obtaining a CLT in 18% and requiring a LDLT in 49%. The median time in the waiting list for CLT was 5.9 months in pediatric candidates and 5.1 in adults, while the median time to death in the waiting list was 2.8 and 5.6 months, respectively. The mortality rate at one year in candidates under two years old was 38.1% compared to 32.5% in adults. CONCLUSIONS: Pediatric candidates with chronic liver diseases, especially under two years of age, have greater access difficulties to CLT than adults. Half of the pediatric candidates die on the waiting list before three months. The mortality among candidates under two years of age in the waiting list is excessively high.

Niemann-Pick disease A or B in four pediatric patients and SMPD1 mutation carrier frequency in the Mexican population.

INTRODUCTION AND OBJECTIVES: Niemann-Pick disease type A (NPD-A) and B (NPD-B) are lysosomal storage diseases with a birth prevalence of 0.4-0.6/100,000. They are caused by a deficiency in acid sphingomyelinase, an enzyme encoded by SMPD1. We analyzed the phenotype and genotype of four unrelated Mexican patients, one with NPD-A and three with NPD-B. PATIENTS AND METHODS: Four female patients between 1 and 7 years of age were diagnosed with NPD-A or NPD-B by hepatosplenomegaly, among other clinical characteristics, and by determining the level of acid sphingomyelinase enzymatic activity and sequencing of the SMPD1 gene. Additionally, a 775bp amplicon of SMPD1 (from 11:6393835_6394609, including exons 5 and 6) was analyzed by capillary sequencing in a control group of 50 unrelated healthy Mexican Mestizos. RESULTS: An infrequent variant (c.1343A>G p.Tyr448Cys) was observed in two patients. One is the first NPD-A homozygous patient reported with this variant and the other a compound heterozygous NPD-B patient with the c.1829_1831delGCC p.Arg610del variant. Another compound heterozygous patient had the c.1547A>G p.His516Arg variant (not previously described in affected individuals) along with the c.1805G>A p.Arg602His variant. A new c.1263+8C>T pathogenic variant was encountered in a homozygous state in a NPD-B patient. Among the healthy control individuals there was a heterozygous carrier for the c.1550A>T (rs142787001) pathogenic variant, but none with the known pathogenic variants in the 11:6393835_6394609 region of SMPD1. CONCLUSIONS: The present study provides further NPD-A or B phenotype-genotype correlations. We detected a heterozygous carrier with a pathogenic variant in 1/50 healthy Mexican mestizos.

Unhealthy Levels of Phthalates and Bisphenol A in Mexican Pregnant Women with Gestational Diabetes and Its Association to Altered Expression of miRNAs Involved with Metabolic Disease.

Several studies indicate that bisphenol A (BPA) and phthalates may have a role in the development of metabolic diseases using different molecular pathways, including epigenetic regulatory mechanisms. However, it is unclear whether exposure to these chemicals modifies serum levels of miRNAs associated with gestational diabetes mellitus (GDM) risk. In the present study, we evaluated the serum levels of miRNAs associated with GDM (miR-9-5p, miR-16-5p, miR-29a-3p and miR-330-3p) and urinary levels of phthalate metabolites (mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP) and mono(2-ethyl hexyl) phthalate (MEHP)) and bisphenol A in GDM patients and women without GDM during the second trimester of gestation. We observed higher levels of miR-9-5p, miR-29a-3p and miR-330-3p in sera of patients with GDM compared to non-diabetic subjects. Phthalates were detected in 97-100% of urine samples, while BPA only in 40%. Urinary MEHP and BPA concentrations were remarkably higher in both study groups compared to previously reported data. Unadjusted MEHP levels and adjusted BPA levels were higher in non-diabetics than in GDM patients (p = 0.03, p = 0.02). We found positive correlations between adjusted urinary MBzP levels and miR-16-5p expression levels (p < 0.05), adjusted MEHP concentrations and miR-29a-3p expression levels (p < 0.05). We also found negative correlations between unadjusted and adjusted MBP concentrations and miR-29a-3p expression levels (p < 0.0001, p < 0.05), unadjusted MiBP concentrations and miR-29a-3p expression levels (p < 0.01). Urinary MEHP levels reflect a striking exposure to di(2-ethylhexyl) phthalate (DEHP) in pregnant Mexican women. This study highlights the need for a regulatory strategy in the manufacture of several items containing endocrine disruptors in order to avoid involuntary ingestion of these compounds in the Mexican population.

Genetic variability among Mexican Mestizo and Amerindian populations based on three ABCB1 polymorphisms.

The most widely studied polymorphisms of the ABCB1 gene are rs1128503 (c.1236C>T), rs2032582 (c.2677G>T/A), and rs1045642 (c.3435C>T). Although variation in ABCB1 allele frequencies among Mexican Mestizos (admixed) from different regions has been observed, Mexican Amerindians have been poorly studied. We aimed to describe the genetic variability of these three ABCB1 polymorphisms in a total sample of 273 Mexican volunteers that included Mestizos from the state of Yucatán, and Amerindians from seven populations (Tarahumara, Mayo, Huichol, Purépecha, Nahua, Tojolabal, and Maya). Genotypes were determined by means of Taq Man probes (qPCR). Genotype distribution was in Hardy-Weinberg equilibrium for all three ABCB1polymorphisms in the eight Mexican populations analyzed. For c.1236C>T and c.3435C>T, the heterozygous C/T was the most frequent genotype in the majority of the studied Mexican populations (range 30.8-65.4%), while heterozygous G/T was the most common genotype for c.2677G>T/A (range 25.9-51.2%), mainly followed by G/G (range 3.2-47.1%) and T/T (range 7.0-35.5%). 12 haplotypes were estimated from the three ABCB1 polymorphisms analyzed, with TTT the most frequent haplotype (mean, 37.0%). Genetic differentiation was demonstrated among the studied Mexican populations (Fst p value < 0.0001), which could imply a diverse drug response or a risk for adverse drug reactions to ABCB1 substrates. Although differences among Amerindians are probably due to genetic drift effects, for Mestizos this could imply variation in admixture composition. In conclusion, interpopulation variability in the observed frequencies of ABCB1 polymorphisms among Mexican Mestizos and Amerindians allow predicting diverse drug responses to ABCB1 substrates in these populations.

[Genetic factors associated with dementia in Parkinson's disease (PD)]. / Factores genéticos de la demencia en la enfermedad de Parkinson (EP).

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Dementia is a frequent complication of idiopathic Parkinsonism or PD, usually occurring later in the protracted course of the illness. Some risk factors to develop dementia in PD are aging, severe Parkinson´s symptoms, rigid-akinetic form, hallucinations, and mild cognitive impairment documented at the first examinations. It is not yet clear if some genetic factors are either risk or protector for progression to dementia. In a review of the literature, we found that mutations in the alpha-synuclein gene are the most responsible for developing dementia, either from PARK1 or 4 mutations. GBA (glucocerebrosidase) is another accountable factor. However, the vast majority of patients suffer from non-Mendelian or complex forms of PD, which are likely caused by the combined effects of genetic and environmental factors. There is not until now a clear relation between some polymorphisms in candidate genes and cognitive deterioration, as many studies have not clearly identified this phenotype.

Factors associated with degree of atopy in Latino children in a nationwide pediatric sample: the Genes-environments and Admixture in Latino Asthmatics (GALA II) study.

BACKGROUND: Atopy varies by ethnicity, even within Latino groups. This variation might be due to environmental, sociocultural, or genetic factors. OBJECTIVE: We sought to examine risk factors for atopy within a nationwide study of US Latino children with and without asthma. METHODS: Aeroallergen skin test responses were analyzed in 1830 US Latino subjects. Key determinants of atopy included country/region of origin, generation in the United States, acculturation, genetic ancestry, and site to which subjects migrated. Serial multivariate zero-inflated negative binomial regressions stratified by asthma status examined the association of each key determinant variable with the number of positive skin test responses. In addition, the independent effect of each key variable was determined by including all key variables in the final models. RESULTS: In baseline analyses African ancestry was associated with 3 times (95% CI, 1.62-5.57) as many positive skin test responses in asthmatic participants and 3.26 times (95% CI, 1.02-10.39) as many positive skin test responses in control participants. Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, asthmatic patients of Puerto Rican (exp[ß] [95% CI], 1.31 [1.02-1.69]) and mixed (exp[ß] [95% CI], 1.27 [1.03-1.56]) ethnicity had a greater probability of positive skin test responses compared with Mexican asthmatic patients. Ancestry associations were abrogated by recruitment site but not region of origin. CONCLUSIONS: Puerto Rican ethnicity and mixed origin were associated with degree of atopy within US Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization.

Genetic mutations in early-onset Parkinson's disease Mexican patients: molecular testing implications.

Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed.

Impact of higher-income countries on child health in lower-income countries from a climate change perspective. A case study of the UK and Malawi.

Climate change is the number one threat to child health according to the World Health Organisation. It increases existing inequalities, and lower-income countries are disproportionately affected. This is unjust. Higher-income countries have contributed and continue to contribute more to climate change than lower-income countries. This has been recognised by the United Nations Committee on the Rights of the Child, which has ruled that states can be held responsible if their carbon emissions harm child rights both within and outside their jurisdiction. Nevertheless, there are few analyses of the bilateral relationship between higher- and lower-income countries concerning climate change. This article uses the UK and Malawi as a case study to illustrate higher-income countries' impact on child health in lower-income countries. It aims to assist higher-income countries in developing more targeted policies. Children in Malawi can expect more food insecurity and reduced access to clean water, sanitation, and education. They will be more exposed to heat stress, droughts, floods, air pollution and life-threatening diseases, such as malaria. In 2019, 5,000 Malawian children died from air pollution (17% of under-five deaths). The UK needs to pay its 'fair share' of climate finance and ensure adaptation is prioritised for lower-income countries. It can advocate for more equitable and transparent allocation of climate finance to support the most vulnerable countries. Additionally, the UK can act domestically to curtail revenue losses in Malawi and other lower-income countries, which would free up resources for adaptation. In terms of mitigation, the UK must increase its nationally determined commitments by 58% to reach net zero and include overseas emissions. Land use, heating systems and renewable energy must be reviewed. It must mandate comprehensive scope three emission reporting for companies to include impacts along their value chain, and support businesses, multinational corporations, and banks to reach net zero.

Evaluation of the Effect of a Recent Comparative Intradermal Tuberculin Test on the Humoral Diagnosis of Paratuberculosis Using Serum and Milk Samples from Goats.

Paratuberculosis (PTB) and tuberculosis (TB) are two mycobacterial diseases with a severe economic and health impact on domestic ruminants. The ante mortem diagnosis of PTB is hampered, among other factors, by the limited sensitivity of all the available diagnostic techniques. Since TB-infected goats subjected to the comparative intradermal tuberculin test (CITT) may experience a booster effect on their antibody titer and a potential enhancement to the sensitivity of humoral techniques for tuberculosis, in the present study we aimed to evaluate this diagnostic strategy on the humoral diagnosis of PTB in serum and milk samples collected from a caprine herd that was TB free and PTB infected. The results from 120 goats indicated a significant increase (p < 0.001) in the quantitative response detected using an ELISA technique, conducted using serum and milk samples taken 15 and 30 days after performing a CITT (day 0 of the study); although, it did not translate into a significant increase in the number of reactors during any of the testing events (0, 3,15, 30 and 60 days post-CITT). Additionally, the number of ELISA-positive animals was higher for the serum versus the milk samples at both 15 and 30 days post-CITT. The increase in the quantitative ELISA result suggested a diagnostic strategy that maximizes ELISA sensitivity, mainly using serum samples, in PTB-infected herds; although, it may depend on individual differences and the interpretation criteria.

Interactions Between the Ubiquitin-Proteasome System, Nrf2, and the Cannabinoidome as Protective Strategies to Combat Neurodegeneration: Review on Experimental Evidence.

Neurodegenerative disorders are chronic brain diseases that affect humans worldwide. Although many different factors are thought to be involved in the pathogenesis of these disorders, alterations in several key elements such as the ubiquitin-proteasome system (UPS), the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, and the endocannabinoid system (ECS or endocannabinoidome) have been implicated in their etiology. Impairment of these elements has been linked to the origin and progression of neurodegenerative disorders, while their potentiation is thought to promote neuronal survival and overall neuroprotection, as proved with several experimental models. These key neuroprotective pathways can interact and indirectly activate each other. In this review, we summarize the neuroprotective potential of the UPS, ECS, and Nrf2 signaling, both separately and combined, pinpointing their role as a potential therapeutic approach against several hallmarks of neurodegeneration.

Anandamide and WIN 55212-2 Afford Protection in Rat Brain Mitochondria in a Toxic Model Induced by 3-Nitropropionic Acid: an In Vitro Study.

Mitochondrial dysfunction plays a key role in the development of neurodegenerative disorders. In contrast, the regulation of the endocannabinoid system has been shown to promote neuroprotection in different neurotoxic paradigms. The existence of an active form of the cannabinoid receptor 1 (CB1R) in mitochondrial membranes (mitCB1R), which might exert its effects through the same signaling mechanisms as the cell membrane CB1R, has been shown to regulate mitochondrial activity. Although there is evidence suggesting that some cannabinoids may induce protective effects on isolated mitochondria, substantial evidence on the role of cannabinoids in mitochondria remains to be explored. In this work, we developed a toxic model of mitochondrial dysfunction induced by exposure of brain mitochondria to the succinate dehydrogenase inhibitor 3-nitropropionic acid (3-NP). Mitochondria were also pre-incubated with the endogenous agonist anandamide (AEA) and the synthetic CB1R agonist WIN 55212-2 to evaluate their protective effects. Mitochondrial reduction capacity, reactive oxygen species (ROS) formation, and mitochondrial swelling were assessed as toxic markers. While 3-NP decreased the mitochondrial reduction capacity and augmented mitochondrial ROS formation and swelling, both AEA and WIN 55212-2 ameliorated these toxic effects. To explore the possible involvement of mitCB1R activation on the protective effects of AEA and WIN 55212-2, mitochondria were also pre-incubated in the presence of the selective CB1R antagonist AM281, which completely reverted the protective effects of the cannabinoids to levels similar to those evoked by 3-NP. These results show partial protective effects of cannabinoids, suggesting that mitCB1R activation may be involved in the recovery of compromised mitochondrial activity, related to reduction of ROS formation and further prevention of mitochondrial swelling.

Interethnic differences in UGT1A4 genetic polymorphisms between Mexican Mestizo and Spanish populations.

UDP-glucuronosyltransferase 1A4 (UGT1A4) is a phase II drug-metabolizing enzyme that catalyzes the glucuronidation of many clinically-important drugs. Interethnic differences in the genetic polymorphism of UGT1A4 have been reported; however, there is no information in Mexican Mestizos (MMs) and Spaniards (SPs). Furthermore, MM is an admixed population with 26 % of Caucasian genes mainly from Spain. Therefore, this study aimed to investigate the potential differences between 318 SPs and 248 MMs healthy individuals regarding UGT1A4*1b, UGT1A4*2 and UGT1A4*3 alleles and to compare the observed frequencies with those previously reported in different populations. The allelic frequencies of the three UGT1A4 polymorphisms showed interethnic differences between MMs and SPs (p < 0.05). The analyzed SNPs variants in this genetic region were not in linkage disequilibrium (LD) for the MM population, suggesting that these mutations have arisen independently in the same genetic background. In contrast, UGT1A4*2 and UGT1A4*3 were in LD in the SP population. Comparison of present data with other in different ethnic groups revealed that the frequencies of UGT1A4*2 and UGT1A4*3 in SP were similar to other Caucasians and higher than in Asians, whereas in MMs were lower than in Caucasians and higher than in Asians only for UGT1A4*2. Present results could be helpful to improve the use of UGT1A4 drug substrates in order to adjust them to the ethnic background of a given population, specifically for Hispanics.

Amyloid Beta Peptide-Mediated Alterations in Mitochondrial Dynamics and its Implications for Alzheimer's Disease.

Alzheimer's disease (AD) is considered the most frequent neurodegenerative disorder worldwide, compromising cognitive function in patients, with an average incidence of 1-3% in the open population. Protein aggregation into amyloidogenic plaques and neurofibrillary tangles, as well as neurodegeneration in the hippocampal and cortical areas, represent the neuropathological hallmarks of this disorder. Mechanisms involved in neurodegeneration include protein misfolding, augmented apoptosis, disrupted molecular signaling pathways and axonal transport, oxidative stress, inflammation, and mitochondrial dysfunction, among others. It is precisely through a disrupted energy metabolism that neural cells trigger toxic mechanisms leading to cell death. In this regard, the study of mitochondrial dynamics constitutes a relevant topic to decipher the role of mitochondrial dysfunction in neurological disorders, especially when considering that amyloid-beta peptides can target mitochondria. Specifically, the amyloid beta (Aß) peptide, known to accumulate in the brain of AD patients, has been shown to disrupt overall mitochondrial metabolism by impairing energy production, mitochondrial redox activity, and calcium homeostasis, thus highlighting its key role in the AD pathogenesis. In this work, we review and discuss recent evidence supporting the concept that mitochondrial dysfunction mediated by amyloid peptides contributes to the development of AD.

Longitudinal Changes in Mitochondrial DNA Copy Number and Telomere Length in Patients with Parkinson's Disease.

Parkinson's disease (PD) pathophysiology includes mitochondrial dysfunction, neuroinflammation, and aging as its biggest risk factors. Mitochondrial DNA copy number (mtDNA-CN) and telomere length (TL) are biological aging markers with inconclusive results regarding their association with PD. A case-control study was used to measure TL and mtDNA-CN using qPCR in PBMCs. PD patients were naive at baseline (T0) and followed-up at one (T1) and two (T2) years after the dopaminergic treatment (DRT). Plasmatic cytokines were determined by ELISA in all participants, along with clinical parameters of patients at T0. While TL was shorter in patients vs. controls at all time points evaluated (p < 0.01), mtDNA-CN showed no differences. An increase in mtDNA-CN and TL was observed in treated patients vs. naive ones (p < 0.001). Our statistical model analyzed both aging markers with covariates, showing a strong correlation between them (r = 0.57, p < 0.01), and IL-17A levels positively correlating with mtDNA-CN only in untreated patients (r = 0.45, p < 0.05). TL and mtDNA-CN could be useful markers for monitoring inflammation progression or treatment response in PD. DRT might modulate TL and mtDNA-CN, reflecting a compensatory mechanism to counteract mitochondrial dysfunction in PD, but this needs further investigation.

Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders.

OBJECTIVE: The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls. METHODS: The sample included 75 patients with psychotic disorders on clozapine therapy and 40 paired healthy controls. Plasma clozapine/N-desmethylclozapine, GSH concentrations, and GPx activity were determined, along with genotyping of GCLC and GSTP1 variants and copy number variations of GSTP1, GSTT1, and GSTM1. Clinical, molecular and biochemical data were analyzed with a logistic regression model. RESULTS: GSH levels were significantly reduced and, conversely, GPx activity was higher in PD patients compared to controls. GCLC_GAG-7/9 genotype (OR=4.3, CI95=1.40-14.31, p=0.019) and hetero-/homozygous genotypes of GCLC_rs761142 (OR=6.09, CI95=1.93-22.59, p=0.003) were found as risk factors for psychosis. The genetic variants were not related to clozapine/N-desmethylclozapine levels or to metabolic ratio. CONCLUSIONS: GCLC variants were associated with the oxidative stress profile of PD patients raising opportunities for intervention to improve their antioxidant defenses. Further studies with larger samples should explore this proposal.