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Theoretical work suggests that reinforcement can cause the strengthening of prezygotic isolation in sympatry by mitigating the costs of maladaptive hybridization. However, only a handful of studies have simultaneously tested multiple predictions of this theory in natural populations. We investigated reinforcement in a mottled hybrid zone between the damselflies Ischnura elegans and I. graellsii, which are characterized by incomplete and asymmetric reproductive isolation and exhibit reproductive character displacement in mating-related structures. We tested the conditions for reinforcement by quantifying whether hybridization was costly and prezygotic isolation stronger in sympatry compared with allopatry. Additionally, we investigated two specific predictions of reinforcement: i) greater premating asymmetries in sympatry; and ii) weaker postzygotic isolation in sympatry than in allopatry. Our findings indicate the presence of maladaptive hybrids, which suggests Bateson-Dobzhansky-Müller incompatibilities in allopatry. We also found that reinforcement has strengthened mechanical isolation, at least in one direction in sympatry. We observed evidence for greater premating asymmetries in sympatry than in allopatry, which is consistent with reinforcement. However, fully testing the prediction of weaker postzygotic isolation in sympatry compared to allopatry was hindered by the highly asymmetrical levels of reproductive isolation between the two reciprocal cross directions. Our study highlights a case where reinforcement and heterospecific gene flow exert opposite effects on reproductive isolation between reciprocal crosses, where reinforcement increases reproductive isolation in one direction while gene flow weakens it in the opposite direction., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Evolutionary Biology.)

This paper discusses the mechanisms by which fungi manipulate plant physiology and suppress plant defense responses by producing effectors that can target various host proteins. Effector-triggered immunity and effector-triggered susceptibility are pivotal elements in the complex molecular dialogue underlying plant-pathogen interactions. Pathogen-produced effector molecules possess the ability to mimic pathogen-associated molecular patterns or hinder the binding of pattern recognition receptors. Effectors can directly target nucleotide-binding domain, leucine-rich repeat receptors, or manipulate downstream signaling components to suppress plant defense. Interactions between these effectors and receptor-like kinases in host plants are critical in this process. Biotrophic fungi adeptly exploit the signaling networks of key plant hormones, including salicylic acid, jasmonic acid, abscisic acid, and ethylene, to establish a compatible interaction with their plant hosts. Overall, the paper highlights the importance of understanding the complex interplay between plant defense mechanisms and fungal effectors to develop effective strategies for plant disease management.

Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin-sensitive tissues post-prandially, this anabolic hormone restores blood glucose levels to pre-prandial levels. Maintaining physiological glucose levels thus relies on proper β-cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type-specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (GCK), whereas other genes are selectively "disallowed", including lactate dehydrogenase A (LDHA) and monocarboxylate transporter 1 (MCT1). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life-threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply-driven rather than demand-driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β-cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients., (© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Deep brain stimulation (DBS) is an interdisciplinary and reversible therapy that uses high-frequency electrical stimulation to correct aberrant neural pathways in motor and cognitive neurological disorders. However, the high frequency of the waves used in DBS can interfere with electrical recording devices (e.g., electrocardiogram, electroencephalogram, cardiac monitor), creating artifacts that hinder their interpretation. The compatibility of DBS with these devices varies and depends on factors such as the underlying disease and the configuration of the neurostimulator. In emergencies where obtaining an electrocardiogram is crucial, the need for more consensus on reducing electrical artifacts in patients with DBS becomes a significant challenge. Various strategies have been proposed to attenuate the artifact generated by DBS, such as changing the DBS configuration from monopolar to bipolar, temporarily deactivating DBS during electrocardiographic recording, applying frequency filters both lower and higher than those used by DBS, and using non-standard leads. However, the inexperience of medical personnel, variability in DBS models, or the lack of a controller at the time of approach limit the application of these strategies. Current evidence on their reproducibility and efficacy is limited. Due to the growing elderly population and the rising utilization of DBS, it is imperative to create electrocardiographic methods that are easily accessible and reproducible for general physicians and emergency services., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Sierra-Fernández, Garnica-Geronimo, Huipe-Dimas, Ortega-Hernandez, Ruiz-Mafud, Cervantes-Arriaga, Hernández-Medrano and Rodríguez-Violante.)

Background: SARS-CoV2 induces flu-like symptoms that can rapidly progress to severe acute lung injury and even death. The virus also invades the central nervous system (CNS), causing neuroinflammation and death from central failure. Intravenous (IV) or oral dexamethasone (DXM) reduced 28 d mortality in patients who required supplemental oxygen compared to those who received conventional care alone. Through these routes, DMX fails to reach therapeutic levels in the CNS. In contrast, the intranasal (IN) route produces therapeutic levels of DXM in the CNS, even at low doses, with similar systemic bioavailability., Aims: To compare IN vs. IV DXM treatment in hospitalized patients with COVID-19., Methods: A controlled, multicenter, open-label trial. Patients with COVID-19 (69) were randomly assigned to receive IN-DXM (0.12 mg/kg for three days, followed by 0.6 mg/kg for up to seven days) or IV-DXM (6 mg/d for 10 d). The primary outcome was clinical improvement, as defined by the National Early Warning Score (NEWS) ordinal scale. The secondary outcome was death at 28 d between IV and IN patients. Effects of both treatments on biochemical and immunoinflammatory profiles were also recorded., Results: Initially, no significant differences in clinical severity, biometrics, and immunoinflammatory parameters were found between both groups. The NEWS-2 score was reduced, in 23 IN-DXM treated patients, with no significant variations in the 46 IV-DXM treated ones. Ten IV-DXM-treated patients and only one IN-DXM patient died., Conclusions: IN-DMX reduced NEWS-2 and mortality more efficiently than IV-DXM, suggesting that IN is a more efficient route of DXM administration., Competing Interests: Conflict of Interest The authors have no other relevant affiliations or financial involvement with any organization or entity that has a financial interest in, or financial conflict with, the subject matter or materials discussed in the manuscript, except as stated., (Copyright © 2024. Published by Elsevier Inc.)

The two monoamines serotonin and melatonin have recently been highlighted as potent regulators of islet hormone secretion and overall glucose homeostasis in the body. In fact, dysregulated signaling of both amines are implicated in β-cell dysfunction and development of type 2 diabetes mellitus (T2DM). Serotonin is a key player in β-cell physiology and plays a role in expansion of β-cell mass. Melatonin regulates circadian rhythm and nutrient metabolism and reduces insulin release in human and rodent islets in vitro. Herein, we focus on the role of serotonin and melatonin in islet physiology and the pathophysiology of T2DM. This includes effects on hormone secretion, receptor expression, genetic variants influencing β-cell function, melatonin treatment, and compounds that alter serotonin availability and signaling., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This research examined the antioxidant and cryoprotective effects of melatonin (ME) and caffeine (CAF) supplementation in freezing medium on the cryosurvival of Peruvian Paso horse sperm using a two-step accelerating cooling rate. Twenty ejaculates from four adult and fertile stallions were recovered, initially diluted with INRA-96 ® , and finally frozen with INRA-Freeze ® with either no supplementation (as control), 1 μM ME, or 2 mM CAF using a two-ramp freezing system content inside a cryogenic-box and liquid nitrogen vapors. The sperm kinematic parameters and integrity of the plasma and acrosomal membranes of fresh semen and cryopreserved samples were evaluated using the CASA system (SCA-Evolution ® 2018) and PI/fluorescein isothiocyanate-conjugated peanut (Arachis hypogaea) agglutinin double fluorescent test, respectively. The oxidative stress of post-thaw sperm samples was also assessed using the CellRox Deep Red fluorescence test. The results showed that curvilinear velocity and average-path velocity were greater ( p  < 0.05) after freezing with CAF than the control group. In addition, there were significance differences ( p  < 0.01) between stallions (1-4) in post-thaw kinematic parameters regardless of ME or CAF addition. Both ME and CAF improved ( p  < 0.05) the proportion of sperm with intact plasma membranes and intact acrosomes. Nevertheless, neither CAF nor ME improved the oxidative stress after the cryopreservation process.

This article deals with the analysis of [Formula: see text] emissions in Latin America by using a long memory process based on fractional integration. Using data of [Formula: see text] emission and [Formula: see text] emissions per capita, for 32 Latin American and Caribbean countries, the results show significant differences according to the variable examined, the model used, and the country under examination. In particular, for the [Formula: see text] emissions, mean reversion is found in Belize and also under some circumstances in Antigua and Barbuda, Colombia, Dominica, Dominican Republic, Ecuador, Grenada, Honduras, Nicaragua, Panama, Peru, and Uruguay. Thus, shocks in these series have a transitory effect. With respect to the time trends, only for some Caribbean countries, namely, Antigua and Barbuda, Aruba, Bahamas, Cuba, and Jamaica, the trend is insignificant; on the other hand, large countries like Brazil, Mexico, and Argentina display the highest time trend coefficients; for the [Formula: see text] emissions per capita, there are eleven countries where mean reversion is detected, and there are ten that share a lack of significance for the trend. The most significant trends now take place in Trinidad and Tobago, British Virgin Islands, Barbados, and Guyana. Policy implications of the results obtained are reported at the end of the paper., (© 2023. The Author(s).)

Background: The purpose is to compare youth- and caregiver-reported characteristics of family environment, within and between families with a child experiencing a first manic episode of bipolar disorder (BPD), and families without a child with BPD or familial history of psychiatric disorders (HF)., Methods: Family environment of 61 families with a child with BPD and 44 HF were assessed with Family Environment Scale (FES). We compared FES subscale scores between families with BPD and HF, and caregiver- and youth-rated scores., Results: Families with BPD differed significantly from HF on 8/10 FES subscales scores. Youth differed significantly from their caregivers on 7/10 subscales. An interaction effect was observed such that youth with BPD reported lower cohesion and organization, and higher conflict than their caregivers; however, HF did not differ significantly on these domains., Conclusions: Our results suggest that families with BPD have higher conflict and lower cohesion and organization compared to HF. Results also indicate differences between youth and caregiver perspectives in both groups, which may contribute to family discord. Interventions targeting areas of cohesion, organization, and conflict may be beneficial for youth with BPD and their families, specifically those that identify and bridge perceptual divides.

Fungal threats to public health, food security, and biodiversity have escalated, with a significant rise in mycosis cases globally. Around 300 million people suffer from severe fungal diseases annually, while one-third of food crops are decimated by fungi. Vertebrate, including livestock, are also affected. Our limited understanding of fungal virulence mechanisms hampers our ability to prevent and treat cattle mycoses. Here we aim to bridge knowledge gaps in fungal virulence factors and the role of melanin in evading bovine immune responses. We investigate mycosis in bovines employing a PRISMA-based methodology, bioinformatics, and data mining techniques. Our analysis identified 107 fungal species causing mycoses, primarily within the Ascomycota division. Candida , Aspergillus , Malassezia , and Trichophyton were the most prevalent genera. Of these pathogens, 25% produce melanin. Further research is required to explore the involvement of melanin and develop intervention strategies. While the literature on melanin-mediated fungal evasion mechanisms in cattle is lacking, we successfully evaluated the transferability of immunological mechanisms from other model mammals through homology. Bioinformatics enables knowledge transfer and enhances our understanding of mycosis in cattle. This synthesis fills critical information gaps and paves the way for proposing biotechnological strategies to mitigate the impact of mycoses in cattle.

The study of cerebellar development has been at the forefront of neuroscience since the pioneering work of Wilhelm His Sr., Santiago Ramón y Cajal and many others since the 19th century. They laid the foundation to identify the circuitry of the cerebellum, already revealing its stereotypic three-layered cortex and discerning several of its neuronal components. Their work was fundamental in the acceptance of the neuron doctrine, which acknowledges the key role of individual neurons in forming the basic units of the nervous system. Increasing evidence shows that the cerebellum performs a variety of homeostatic and higher order neuronal functions beyond the mere control of motor behaviour. Over the last three decades, many studies have revealed the molecular machinery that regulates distinct aspects of cerebellar development, from the establishment of a cerebellar anlage in the posterior brain to the identification of cerebellar neuron diversity at the single cell level. In this review, we focus on summarizing our current knowledge on early cerebellar development with a particular emphasis on the molecular determinants that secure neuron specification and contribute to the diversity of cerebellar neurons., (© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objective: To conduct a pilot study to examine topiramate for the treatment of weight gain associated with olanzapine in manic adolescents with bipolar disorder. Methods: We conducted a 12-week double-blind randomized placebo-controlled pilot study of topiramate (300-400 mg/day) versus placebo in manic youth (ages 10-18 years) with bipolar disorder who were treated with olanzapine (10-20 mg/day). The primary outcome measure was gender- and weight-normed change in body mass index (BMI z-score). Results: Thirty manic adolescents were treated with olanzapine and were randomized to either topiramate ( n  = 16) or placebo ( n  = 14). There was a significantly greater increase in BMI z-scores in the placebo group (0.28 standard deviations [SDs]) compared with the topiramate group (0.10 SDs) when analyzed by longitudinal regression ( p  = 0.049). The placebo group had greater increases in raw BMI and weight (2.25 kg/m 2 and 6.9 kg, respectively) compared with the topiramate (0.99 kg/m 2 and 2.9 kg) group ( p  = 0.011 for BMI, p  = 0.016 for weight). The most common adverse events in the topiramate group were headache ( n  = 7, 44%), gastrointestinal upset ( n  = 3, 19%), and muscle stiffness ( n  = 3, 19%). Conclusions: Topiramate may minimize the weight gain associated with olanzapine treatment in adolescents with bipolar disorder. Moreover, topiramate in combination with olanzapine was well tolerated. Larger studies that are adequately powered are necessary to determine the efficacy of topiramate for second-generation antipsychotic-related weight gain. Trial Registration: ClinicalTrials.gov Identifier number NCT00394095.

Reversible phosphorylation is an important regulatory mechanism. Regulation of protein phosphorylation in β-cells has been extensively investigated, but less is known about protein dephosphorylation. To understand the role of protein dephosphorylation in β-cells and type 2 diabetes (T2D), we first examined mRNA expression of the type 2C family (PP2C) of protein phosphatases in islets from T2D donors. Phosphatase expression overall was changed in T2D, and that of PPM1E was the most markedly downregulated. PPM1E expression correlated inversely with HbA1c. Silencing of PPM1E increased glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells and/or islets from patients with T2D, whereas PPM1E overexpression decreased GSIS. Increased GSIS after PPM1E silencing was associated with decreased oxidative stress, elevated cytosolic Ca2+ levels and ATP to ADP ratio, increased hyperpolarization of the inner mitochondrial membrane, and phosphorylation of CaMKII, AMPK, and acetyl-CoA carboxylase. Silencing of PPM1E, however, did not change insulin content. Increased GSIS, cell viability, and activation of AMPK upon metformin treatment in β-cells were observed upon PPM1E silencing. Thus, protein dephosphorylation via PPM1E abrogates GSIS. Consequently, reduced PPM1E expression in T2D may be a compensatory response of β-cells to uphold insulin secretion under metabolic duress. Targeting PPM1E in β-cells may thus represent a novel therapeutic strategy for treatment of T2D., (© 2023 by the American Diabetes Association.)

Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from approximately 300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing β cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we have identified molecular alterations in human pancreatic islets that contribute to β cell dysfunction in T2D pathophysiology.

Multiple paternity (MP) is defined as the behaviour in which females successfully mate with multiple males leading to offspring from different sires within the same litter. MP seems to be frequent and an evolutionary advantage in elasmobranchs. Here the authors report for the first time the occurrence of MP in the cosmopolitan blue shark Prionace glauca L. The evidence, gathered via microsatellite genotyping of pregnant females and their embryos, suggests that MP is very frequent in this species. Knowledge of MP in P. glauca should help describe more precisely its reproductive biology and contribute to the management of its populations., (© 2022 Fisheries Society of the British Isles.)

Objectives: This observational cross-sectional study examined changes in substance use during the coronavirus disease 2019 (COVID-19) pandemic in the Mexican population and evaluated whether depression or anxiety was associated with these new consumption patterns., Methods: An online survey was distributed to the general population. Participants were questioned about their demographics, situation during the COVID-19 pandemic, and substance consumption patterns. The Patient Health Questionnaire-9 for depression and the Coronavirus Anxiety Scale were used., Results: A total of 866 individuals completed the survey. The mean scores for the Patient Health Questionnaire-9 and Coronavirus Anxiety Scale were 8.89 ± 6.20 and 3.48 ± 3.22, respectively. The preferred substances were alcohol (19%), tobacco (16.5%), and marijuana (5.6%). Consumption of alcohol ( p = 0.042) significantly increased during the pandemic and it was higher in women than in men ( p = 0.040)., Conclusions: Substance use patterns were affected by the pandemic, with an increase in the number of users and consumption rate, as well as the reported psychiatric symptoms.

Objective: Ependymin-Related Protein 1 (EPDR1) was recently identified as a secreted human batokine regulating mitochondrial respiration linked to thermogenesis in brown fat. Despite that EPDR1 is expressed in human pancreatic β-cells and that glucose-stimulated mitochondrial metabolism is critical for stimulus-secretion coupling in β-cells, the role of EPDR1 in β-cell metabolism and function has not been investigated., Methods: EPDR1 mRNA levels in human pancreatic islets from non-diabetic (ND) and type 2 diabetes (T2D) subjects were assessed. Human islets, EndoC-βH1 and INS1 832/13 cells were transfected with scramble (control) and EPDR1 siRNAs (EPDR1-KD) or treated with human EPDR1 protein, and glucose-stimulated insulin secretion (GSIS) assessed by ELISA. Mitochondrial metabolism was investigated by extracellular flux analyzer, confocal microscopy and mass spectrometry-based metabolomics analysis., Results: EPDR1 mRNA expression was upregulated in human islets from T2D and obese donors and positively correlated to BMI of donors. In T2D donors, EPDR1 mRNA levels negatively correlated with HbA1c and positively correlated with GSIS. EPDR1 silencing in human islets and β-cell lines reduced GSIS whereas treatment with human EPDR1 protein increased GSIS. Epdr1 silencing in INS1 832/13 cells reduced glucose- and pyruvate- but not K + -stimulated insulin secretion. Metabolomics analysis in Epdr1-KD INS1 832/13 cells suggests diversion of glucose-derived pyruvate to lactate production and decreased malate-aspartate shuttle and the tricarboxylic acid (TCA) cycle activity. The glucose-stimulated rise in mitochondrial respiration and ATP/ADP-ratio was impaired in Epdr1-deficient cells., Conclusion: These results suggests that to maintain glucose homeostasis in obese people, upregulation of EPDR1 may improve β-cell function via channelling glycolysis-derived pyruvate to the mitochondrial TCA cycle., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Confinement and a lack of social interaction are associated with depressive symptoms, low self-esteem, and suicidal thoughts. We report the results of a cross-sectional survey of 1414 junior high school students. The aim was to evaluate the prevalence of depression, anxiety, and stress in Guadalajara, Mexico, during the COVID-19 pandemic. Mean scores on the validated Spanish version of the Depression, Anxiety, and Stress Scale (DASS-21) were found to be 6.15 ± 5.6 for depression, 5.8 ± 5.2 for anxiety, and 8.08 ± 5.3 for stress. Female students scored higher in all three conditions ( p < 0.001). Students who had relatives infected with COVID-19 showed significantly more anxiety than those who did not ( p < 0.004). Although certain demographic groups are at higher risk of manifesting depression, anxiety, and stress, the student population has also been affected by the global impact of the pandemic.

We are currently witnessing a shift in the approach to combat traffic and consumption of illegal harmful drugs, being cannabis legalization a prominent example. In this paper, we study how to optimally regulate the market for cannabis, in a setting where consumers differ in their utility from consumption of the psychoactive component of cannabis, THC, and suffer from misperception of the health damage it causes. We analyze this problem through a vertical differentiation model, where a black market firm and a public firm compete in prices and qualities (THC content). A paternalistic government would like to correct for the misperceived health damage caused by cannabis consumption, as well as to reduce the size of the black market. It is the undesirability of black market profits what explains that the first-best allocation cannot be decentralized. We find two possible equilibria, depending on whether the public firm serves those consumers with the highest or lowest willingness to pay for quality. Paradoxically, when the public firm serves those consumers with higher taste for THC, a lower average health damage is achieved together with a better economic result for the public firm., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

This paper presents a new dataset of infectious disease outbreaks collected from the Disease Outbreak News and the Coronavirus Dashboard produced by the World Health Organization. The dataset contains information on 70 infectious diseases and 2227 public health events that occurred over the period from January 1996 to March 2022 in 233 countries and territories around the world. We illustrate the potential use of this dataset to the research community by analysing the spatial distribution of disease outbreaks. We find evidence of spatial clusters of high incidences ("hot spots") in Africa, America, and Asia. This spatial analysis enables policymakers to identify the regions with the greatest likelihood of suffering from disease outbreaks and, taking into account their degree of preparedness and vulnerability, to develop policies that may help contain the spreading of future outbreaks. Further applications could focus on combining our data with other information sources to study, for instance, the link between environmental, globalization, and/or socioeconomic factors with disease outbreaks., (© 2022. The Author(s).)

Objective: To identify clinical and central features that differentiate ADHD youth with and without familial risk for bipolar I disorder (BD). Methods: Psychostimulant-free ADHD youth (10-18 years) with and without a first-degree relative with BD and healthy controls were enrolled. Bilateral ventrolateral prefrontal cortex (VLPFC) proton magnetic resonance spectroscopy ( 1 H MRS) scans and a range of symptom ratings were performed. Results: A total of n  = 145 youth were enrolled. ADHD youth with a family history of BD exhibited greater manic and depressive symptom severity, ADHD hyperactivity/impulsive symptom severity, and higher parent-reported ratings of dysregulation compared with ADHD youth without a BD family history. Although VLPFC metabolite levels did not differ across groups, choline levels in the left VLPFC correlated with different symptom ratings. Conclusion: Symptom profiles including more severe mood and externalizing symptoms, but not VLPFC neurochemistry, differentiate psychostimulant-free ADHD youth with and without a family history of BD.

Background: Mindfulness-based cognitive therapy for children (MBCT-C), as a psychotherapeutic intervention, has been shown to be effective for treating mood dysregulation (MD). While previous neuroimaging studies of MD have reported both pre-treatment structural and functional alterations, the effects of MBCT-C on brain morphological network organisation has not been investigated., Methods: We investigated brain morphological network organisation in 10 mood-dysregulated youth with familial risk for bipolar disorder and 15 matched healthy comparison youth (HC). Effects of 12 weeks of MBCT-C were examined in the mood-dysregulated youth. Topological properties of brain networks used for analyses were constructed based on morphological similarities in regional grey matter using a graph-theory approach using MRI data., Results: At baseline, compared with the HC group, the mood-dysregulated group exhibited increased global efficiency (E glob ), decreased path length (L p ), and abnormal nodal properties, mainly in the limbic system. Right temporal pole alterations at baseline predicted change in Child and Adolescent Mindfulness Measure scores after treatment. The mood-dysregulated group showed significant decreases in both the E glob and L p metrics after MBCT-C, suggesting an improved capacity for optimal information processing. Changes in L p were correlated with changes in Emotion Regulation Checklist scores. Our results show significant topological alterations in the mood-dysregulated group as compared to controls at baseline. After MBCT-C, disrupted topological properties in the mood-dysregulated group were significantly reduced., Conclusion: MBCT-C may facilitate clinically meaningful changes in the brain structural network in mood-dysregulated individuals., (© 2021 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

The Metropolitan Region of Recife and its surroundings are heavily exploited to capture water for public supply through tubular wells. However, a survey of the levels of natural radionuclides from these sources had never been carried out, even though part of this region contains a phosphate deposit that has a high concentration of natural uranium. In this context, this research aimed to identify 228 Ra and 226 Ra levels in groundwater in the coastal region of Pernambuco, Brazil. About 110 points (wells) of drinking water for public supply were identified and studies were carried out to estimate the level of ingestion and subsequent risk due to the presence of this radionuclide. The average concentration of combined radium was 104 mBq.L -1 . For 228 Ra an effective dose of 0.46, 0.11, 0.12 and 0.0276 mSv.y -1 for infants, children aged 1 and 10 and adults, respectively, were obtained. Although doses above those recommended by WHO were found, the equivalent dose and the induction of bone sarcoma did not indicate a risk to the population. Groundwater with higher dose values is influenced by local geology., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Deep soft tissue sarcomas are frequently in contact with bone. The therapeutic decision of a composite resection strategy may be challenging, which is usually based on clinical and radiological criteria. The aims of the study were to evaluate the overall frequency of bone and periosteal infiltration in these patients in whom composite resection was indicated, and evaluate the role of magnetic resonance imaging and bone scintigraphy in this scenario., Methods: Forty-nine patients with a composite surgical resection (soft tissue sarcoma and bone), treated at a single institution between 2006 and 2018, were retrospectively included. Presurgical planning of the resection limits was based on clinical and imaging findings (magnetic resonance imaging and bone scintigraphy). Magnetic resonance imaging was performed in all patients (100%) and bone scintigraphy in 41 (83.7% of the cases). According to magnetic resonance imaging results, patients were divided into two groups: Group A, in which the tumor is adjacent to the bone without evidence of infiltration (n = 24, 48,9%), and Group B, patients with evidence of bone involvement by magnetic resonance imaging (n = 25, 51,1%). BS showed a pathological deposit in 28 patients (68.3%). Histological analysis of the resection specimen was preceded to identify bone and periosteal infiltration. For the analysis of the diagnostic validity of imaging tests, histological diagnosis was considered as the gold standard in the evaluation of STS bone infiltration., Results: Histological bone infiltration was identified in 49% of patients and isolated periosteal infiltration in 14.3%. In terms of diagnostic accuracy, magnetic resonance imaging and bone scintigraphy sensitivity values were 92% and 90%, and their specificity values were 91.7% and 52.4%, respectively., Conclusions: The incidence of bone and periosteal infiltration of soft tissue sarcomas in contact with bone is high. Presurgical bone assessment by MRI has proven to be a sensitive and specific tool in the diagnosis of bone infiltration. Due to its high negative predictive value, BS is a useful test to rule out it. In those cases, in which there is suspicion of bone infiltration not confirmed by MRI, new diagnostic protocols should be established in order to avoid inappropriate resections., (© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

We previously reported that loss of mitochondrial transcription factor B1 (TFB1M) leads to mitochondrial dysfunction and is involved in the pathogenesis of type 2 diabetes (T2D). Whether defects in ribosomal processing impact mitochondrial function and could play a pathogenetic role in β-cells and T2D is not known. To this end, we explored expression and the functional role of dimethyladenosine transferase 1 homolog (DIMT1), a homolog of TFB1M and a ribosomal RNA (rRNA) methyltransferase implicated in the control of rRNA. Expression of DIMT1 was increased in human islets from T2D donors and correlated positively with expression of insulin mRNA, but negatively with insulin secretion. We show that silencing of DIMT1 in insulin-secreting cells impacted mitochondrial function, leading to lower expression of mitochondrial OXPHOS proteins, reduced oxygen consumption rate, dissipated mitochondrial membrane potential, and a slower rate of ATP production. In addition, the rate of protein synthesis was retarded upon DIMT1 deficiency. Consequently, we found that DIMT1 deficiency led to perturbed insulin secretion in rodent cell lines and islets, as well as in a human β-cell line. We observed defects in rRNA processing and reduced interactions between NIN1 (RPN12) binding protein 1 homolog (NOB-1) and pescadillo ribosomal biogenesis factor 1 (PES-1), critical ribosomal subunit RNA proteins, the dysfunction of which may play a part in disturbing protein synthesis in β-cells. In conclusion, DIMT1 deficiency perturbs protein synthesis, resulting in mitochondrial dysfunction and disrupted insulin secretion, both potential pathogenetic processes in T2D., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effects of fish oil (FO), a source of the omega-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on emotion-generated corticolimbic functional connectivity in depressed youth at high risk for developing bipolar I disorder., Methods: Thirty-nine antidepressant-free youth with a current depressive disorder diagnosis and a biological parent with bipolar I disorder were randomized to 12-week double-blind treatment with FO or placebo. At baseline and endpoint, fMRI (4 Tesla) scans were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Seed-to-voxel functional connectivity analyses were performed using bilateral orbitofrontal cortex (OFC) and amygdala (AMY) seeds. Measures of depression, mania, global symptom severity, and erythrocyte fatty acids were obtained., Results: Erythrocyte EPA+DHA composition increased significantly in the FO group (+47%, p ≤ 0.0001) but not in the placebo group (-10%, p = 0.11). Significant group by time interactions were found for functional connectivity between the left OFC and the left superior temporal gyrus (STG) and between the right AMY and right inferior temporal gyrus (ITG). OFC-STG connectivity increased in the FO group (p = 0.0001) and decreased in the placebo group (p = 0.0019), and AMY-ITG connectivity decreased in the FO group (p = 0.0014) and increased in the placebo group (p < 0.0001). In the FO group, but not placebo group, the decrease in AMY-ITG functional connectivity correlated with decreases in Childhood Depression Rating Scale-Revised and Clinical Global Impression-Severity Scale scores., Conclusions: In depressed high-risk youth FO supplementation alters emotion-generated corticolimbic functional connectivity which correlates with changes in symptom severity ratings., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Neimeier, in 1934, proposed a classification for gallbladder perforation. The first type is fistulation between the gallbladder and adjacent viscerae. The second type is a subacute perforation surrounded by an abscess walled off by adhesions from the general peritoneal cavity; and the third type is a peritonitis due to free biliary spillage into the peritoneal cavity without protective adhesions. We will analyze a Neimeier's type 1 perforation. The patient is a 72-year-old male diagnosed with a cholecystolithiasis and empyema due to a cholecystopleural fistula. Was operated by laparoscopic surgery because its low rate of complications, and lower days at hospital staying. Everything went as planned with no complications. Even though it is not a common presentation, it sets a precedent for it to be furthermore researched, and for it to be used as a literary option in a discussion to know which type of surgery is better for these cases., (Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2022.)

Background: By end December of 2021, COVID-19 has infected around 276 million individuals and caused over 5 million deaths worldwide. Infection results in dysregulated systemic inflammation, multi-organ dysfunction, and critical illness. Cells of the central nervous system are also affected, triggering an uncontrolled neuroinflammatory response. Low doses of glucocorticoids, administered orally or intravenously, reduce mortality among moderate and severe COVID-19 patients. However, low doses administered by these routes do not reach therapeutic levels in the CNS. In contrast, intranasally administered dexamethasone can result in therapeutic doses in the CNS even at low doses., Methods: This is an approved open-label, multicenter, randomized controlled trial to compare the effectiveness of intranasal versus intravenous dexamethasone administered in low doses to moderate and severe COVID-19 adult patients. The protocol is conducted in five health institutions in Mexico City. A total of 120 patients will be randomized into two groups (intravenous vs. intranasal) at a 1:1 ratio. Both groups will be treated with the corresponding dexamethasone scheme for 10 days. The primary outcome of the study will be clinical improvement, defined as a statistically significant reduction in the NEWS-2 score of patients with intranasal versus intravenous dexamethasone administration. The secondary outcome will be the reduction in mortality during hospitalization., Conclusions: This protocol is currently in progress to improve the efficacy of the standard therapeutic dexamethasone regimen for moderate and severe COVID-19 patients., Trial Registration: ClinicalTrials.gov NCT04513184 . Registered November 12, 2020. Approved by La Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS) with identification number DI/20/407/04/36. People are currently being recruited., (© 2022. The Author(s).)

Background: The present case report describes a complication after a percutaneous spine surgery technique that is highly uncommon in clinical practice: a bone cement cardiac embolism. This rare complication emphasizes the importance of this case, which is also interesting considering the midterm follow-up. Documented cardiac embolisms published in the literature (which are scarce) describe the acute phase of these cases but lack follow-up. There are no systematic reviews on this topic, only case-by-case presentations, and surgeons are not aware of its real implications., Case: We report a case of an 84-year-old man who developed sudden thoracic and spinal pain associated with 82% saturation and dyspnea a few hours after 4-level thoracic spine vertebroplasty and kyphoplasty. Imaging revealed multiple bone cement embolisms in his lung and heart. Because the patient was hemodynamically stable, cardiologists recommended conservative treatment with low molecular weight heparin, without embolus removal. At 4-year follow-up, the patient remained asymptomatic., Conclusion: Cardiac cement embolization following percutaneous techniques represents a life-threatening situation that should be ruled out if the patient presents symptoms during the early postoperative period. Treatment may vary from conservative to emergency open-heart surgery., Competing Interests: Declaration of Conflicting Interests: The authors report no conflicts of interest in this work., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2022 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

Aims: Reduced expression of exocytotic genes is associated with functional defects in insulin exocytosis contributing to impaired insulin secretion and type 2 diabetes (T2D) development. MAFA and MAFB transcription factors regulate β-cell physiology, and their gene expression is reduced in T2D β cells. We investigate if loss of MAFA and MAFB in human β cells contributes to T2D progression by regulating genes required for insulin exocytosis., Methods: Three approaches were performed: (1) RNAseq analysis with the focus on exocytosis-related genes in MafA -/- mouse islets, (2) correlational analysis between MAFA, MAFB and exocytosis-related genes in human islets and (3) MAFA and MAFB silencing in human islets and EndoC-βH1 cells followed by functional in vitro studies., Results: The expression of 30 exocytosis-related genes was significantly downregulated in MafA -/- mouse islets. In human islets, the expression of 29 exocytosis-related genes correlated positively with MAFA and MAFB. Eight exocytosis-related genes were downregulated in MafA -/- mouse islets and positively correlated with MAFA and MAFB in human islets. From this analysis, the expression of RAB3A, STXBP1, UNC13A, VAMP2, NAPA, NSF, STX1A and SYT7 was quantified after acute MAFA or MAFB silencing in EndoC-βH1 cells and human islets. MAFA and MAFB silencing resulted in impaired insulin secretion and reduced STX1A, SYT7 and STXBP1 (EndoC-βH1) and STX1A (human islets) mRNA expression. STX1A and STXBP1 protein expression was also impaired in islets from T2D donors which lack MAFA expression., Conclusion: Our data indicate that STXBP1 and STX1A are important MAFA/B-regulated exocytosis genes which may contribute to insulin exocytosis defects observed in MAFA-deficient human T2D β cells., (© 2022 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background: We used Illumina paired-end sequencing to isolate and characterize microsatellites of Canthon cyanellus, a Neotropical roller dung beetle, encompassing several lineages within its distribution range., Methods and Results: We examined C. cyanellus specimens collected at eight different localities in Mexico (two or three specimens per locality). We initially performed amplification tests with 16 loci, but two of which were unsuccessful. The 14 remaining microsatellites were polymorphic, with 2-16 alleles each. The expected and observed heterozygosity ranged from 0.11 to 0.76 and from 0.20 to 0.78, respectively., Conclusions: These microsatellites will help to assess structure at the population and lineage levels, identify zones of potential hybridization between lineages, and draw a more precise geographic delimitation of C. cyanellus lineages., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a demyelinating autoimmune disease of the central nervous system, more prevalent in individuals of non-European ancestry. Few studies have analyzed genetic risk factors in NMOSD, and HLA class II gene variation has been associated NMOSD risk in various populations including Mexicans. Thymopoietin ( TMPO ) has not been tested as a candidate gene for NMOSD or other autoimmune disease, however, experimental evidence suggests this gene may be involved in negative selection of autoreactive T cells and autoimmunity. We thus investigated whether the missense TMPO variant rs17028450 (Arg630Cys, frequent in Latin America) is associated with NMOSD, and whether this variant shows an interaction with HLA-class II rs9272219, previously associated with NMOSD risk. A total of 119 Mexican NMOSD patients, 1208 controls and 357 Native Mexican individuals were included. The HLA rs9272219 "T" risk allele frequency ranged from 21 to 68%, while the rs17028450 "T" minor allele frequency was as high as 18% in Native Mexican groups. Both rs9272219 and rs17028450 were significantly associated with NMOSD risk under additive models ( OR = 2.48; p = 8 × 10 -10 and OR = 1.59; p = 0.0075, respectively), and a significant interaction between both variants was identified with logistic regression models ( p = 0.048). Individuals bearing both risk alleles had an estimated 3.9-fold increased risk of NMOSD. To our knowledge, this is the first study reporting an association of TMPO gene variation with an autoimmune disorder and the interaction of specific susceptibility gene variants, that may contribute to the genetic architecture of NMOSD in admixed Latin American populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rosas-Madrigal, Villarreal-Molina, Flores-Rivera, Rivas-Alonso, Macias-Kauffer, Ordoñez, Chima-Galán, Acuña-Alonzo, Macín-Pérez, Barquera, Granados, Valle-Rios, Corona, Carnevale and Romero-Hidalgo.)

The quality of the water consumed by a given community is related to its quality of life. In this sense, this study aimed to evaluate, from the perspective of health risk, the physical, chemical, and microbiological quality of drinking water, in a quilombola community, and the qualitative aspects intrinsic to its use and storage. For this, water samples, collected at the exits of the collective water supply system and from eight cisterns that store rainwater, used for human consumption, were analyzed. The samples were subjected to physical, chemical, and microbiological analysis, including adenovirus (HAdV) and enterovirus (EV). The probability of an individual acquiring infection through water consumption was determined by quantitative microbiological risk analysis using HAdV and Escherichia coli (EC) as reference pathogens. The results showed that the water in the deep tubular well had 270.8 mg/L of total hardness, leading to the rejection of its consumption by ingestion. Alternativity, the people in the community consume rainwater stored in cisterns. For this type of water, the presence of heterotrophic bacteria was found in 75%, total coliform was present in 100%, and Enterococci were detected in 25%. Furthermore, EC was present in 25%, EV in 50%, and HAdV in 100% of the samples. The probability of annual infection with HAdV and EC was, in the worst situation, 100% and 1.3%, respectively. Regarding the qualitative and quantitative aspects, there was a significant positive correlation between the absence of EC and the withdrawal of water from the cistern using a pump and the opposite when the withdrawal was carried out using a bucket or hose. Based on the results found, it is important to carry out actions aimed at improving water quality and, consequently, the quality of life of people living in the study community., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: the frequency of distal femur fractures in the elderly is rapidly increasing. A study of these fractures was conducted in our center in order to evaluate the comorbidities and the mortality associated with this entity., Material and Methods: all the distal femur fractures by low energy in patients over 65 years old at a tertiary center were included, between January 2010 and December 2016. Baseline characteristics, the type of fracture, comorbidities, and functional status before admission, were collected. The relationship of each of these variables to the final functional class, immediate and late complications and mortality during the follow-up. Fifty-nine patients were included, with a median age of 85.3 years (IQR 78.6-91.6). Fifty-one patients were women. In 10 patients, the fractures were atraumatic (postural change mainly in non-walking patients), and in 54 of the cases were treated surgically (6 with retrograde intramedullary nailing and 48 with lateral locking plate). The median time to surgery was 4.5 days (IQR 2-6) and 14 patients were operated within 48 hours. The median follow-up was 26.3 months., Results: fourteen patients died during the first year of follow-up. Factors independently associated with death during the first year after the fracture were: conservative treatment, and the inability to ambulate before the episode. The absence of certain comorbidities, such as chronic heart disease, and cancer, and an age under 80 years, behaved as protective factors., Conclusion: low-energy distal femur fractures comprise a severe injury in the elderly and are associated with high mortality. Surgical treatment showed better outcomes in terms of survival, with no significant differences depending on the type of fracture, the type of implant or the median time to surgery., Competing Interests: Declaration of Competing Interest Nothing to declare, (Copyright © 2021. Published by Elsevier Ltd.)

Sin good consumption entails health damage, which is in general not fully perceived by individuals, what results in its overconsumption. One way to tackle this problem is to tax these unhealthy goods. However, not all the individual choices that affect health status can be easily observed and effectively taxed by the government. This paper considers a setting where individuals can consume two types of sin goods that differ in their observability (taxability) by the government. As a benchmark, the first-best taxes for the observable and non-observable sin good are derived, considering homogeneous individuals. In the second-best setting, where observability on sin good consumption is limited, the rule for the taxable sin good is shown to depend on the degree of complementarity or substitutability with the unobservable sin good. Finally, redistributional considerations are incorporated by extending the analysis to a setting where individuals differ in their wealth and in their degree of misperception of the health damage caused by sin good consumption. Policy implications are illustrated considering physical inactivity and illicit drugs as examples of non-taxable sin goods, while alcohol, tobacco, fat and sugar account for the taxable sin goods., (© 2021 John Wiley & Sons Ltd.)

The amplification of glucose-stimulated insulin secretion (GSIS) through incretin signaling is critical for maintaining physiological glucose levels. Incretins, like glucagon-like peptide 1 (GLP1), are a target of type 2 diabetes drugs aiming to enhance insulin secretion. Here we show that the protein phosphatase 1 inhibitor protein 1A (PPP1R1A), is expressed in β-cells and that its expression is reduced in dysfunctional β-cells lacking MafA and upon acute MafA knock down. MafA is a central regulator of GSIS and β-cell function. We observed a strong correlation of MAFA and PPP1R1A mRNA levels in human islets, moreover, PPP1R1A mRNA levels were reduced in type 2 diabetic islets and positively correlated with GLP1-mediated GSIS amplification. PPP1R1A silencing in INS1 (832/13) β-cells impaired GSIS amplification, PKA-target protein phosphorylation, mitochondrial coupling efficiency and also the expression of critical β-cell marker genes like MafA, Pdx1, NeuroD1 and Pax6. Our results demonstrate that the β-cell transcription factor MafA is required for PPP1R1A expression and that reduced β-cell PPP1R1A levels impaired β-cell function and contributed to β-cell dedifferentiation during type 2 diabetes. Loss of PPP1R1A in type 2 diabetic β-cells may explains the unresponsiveness of type 2 diabetic patients to GLP1R-based treatments., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Given that psychopharmacological approaches routinely used to treat mood-related problems may result in adverse outcomes in mood dysregulated adolescents at familial risk for bipolar disorder (BD), Mindfulness-Based Cognitive Therapy for Children (MBCT-C) provides an alternative effective and safe option. However, little is known about the brain mechanisms of beneficial outcomes from this intervention. Herein, we aimed to investigate the network-level neurofunctional effects of MBCT-C in mood dysregulated adolescents., Methods: Ten mood dysregulated adolescents at familial risk for BD underwent a 12-week MBCT-C intervention. Resting-state functional magnetic resonance imaging (fMRI) was performed prior to and following MBCT-C. Topological metrics of three intrinsic functional networks (default mode network (DMN), fronto-parietal network (FPN) and cingulo-opercular network (CON)) were investigated respectively using graph theory analysis., Results: Following MBCT-C, mood dysregulated adolescents showed increased global efficiency and decreased characteristic path length within both CON and FPN. Enhanced functional connectivity strength of frontal and limbic areas were identified within the DMN and CON. Moreover, change in characteristic path length within the CON was suggested to be significantly related to change in the Emotion Regulation Checklist score., Conclusions: 12-week MBCT-C treatment in mood dysregulated adolescents at familial risk for BD yield network-level neurofunctional effects within the FPN and CON, suggesting enhanced functional integration of the dual-network. Decreased characteristic path length of the CON may be associated with the improvement of emotion regulation following mindfulness training. However, current findings derived from small sample size should be interpreted with caution. Future randomized controlled trials including larger samples are critical to validate our findings.

Schizophrenia and bipolar disorder include patients with different characteristics, which may hamper the definition of biomarkers. One of the dimensions with greater heterogeneity among these patients is cognition. Recent studies support the identification of different patients' subgroups along the cognitive domain using cluster analysis. Our aim was to validate clusters defined on the basis of patients' cognitive status and to assess its relation with demographic, clinical and biological measurements. We hypothesized that subgroups characterized by different cognitive profiles would show differences in an array of biological data. Cognitive data from 198 patients (127 with chronic schizophrenia, 42 first episodes of schizophrenia and 29 bipolar patients) were analyzed by a K-means cluster approach and were compared on several clinical and biological variables. We also included 155 healthy controls for further comparisons. A two-cluster solution was selected, including a severely impaired group and a moderately impaired group. The severely impaired group was associated with higher illness duration and symptoms scores, lower thalamus and hippocampus volume, lower frontal connectivity and basal hypersynchrony in comparison to controls and the moderately impaired group. Moreover, both patients' groups showed lower cortical thickness and smaller functional connectivity modulation than healthy controls. This study supports the existence of different cognitive subgroups within the psychoses with different neurobiological underpinnings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose.

Neuromyelitis Optica (NMO) is an autoimmune disease with a higher prevalence in non-European populations. Because the Mexican population resulted from the admixture between mainly Native American and European populations, we used genome-wide microarray, HLA high-resolution typing and AQP4 gene sequencing data to analyze genetic ancestry and to seek genetic variants conferring NMO susceptibility in admixed Mexican patients. A total of 164 Mexican NMO patients and 1,208 controls were included. On average, NMO patients had a higher proportion of Native American ancestry than controls (68.1% vs 58.6%; p = 5 × 10 -6 ). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 × 10 -10 ). Class II HLA alleles HLA-DQB1*03:01, -DRB1*08:02, -DRB1*16:02, -DRB1*14:06 and -DQB1*04:02 showed the most significant associations with NMO risk. Local ancestry estimates suggest that all the NMO-associated alleles within the HLA region are of Native American origin. No novel or missense variants in the AQP4 gene were found in Mexican patients with NMO or multiple sclerosis. To our knowledge, this is the first study supporting the notion that Native American ancestry significantly contributes to NMO susceptibility in an admixed population, and is consistent with differences in NMO epidemiology in Mexico and Latin America.

Background: The mucocutaneous clinical profile of patients with amyloidosis in Latin America has been scarcely reported., Objective: To describe clinical characteristics of skin and mucosal manifestations in systemic amyloidosis in a tertiary care center in Mexico City., Methods: A cross sectional, retrospective analytical study was performed in patients with systemic amyloidosis over a 15-year period. Statistical analysis was done., Results: A total of 98 patients were included (53 [54%] men; overall median age = 49 years old). Acquired systemic immunoglobulin light chain amyloidosis (AL) was the most common (49%) type, followed by (24.5%) wild-type transthyretin amyloidosis (H-TTR) (24.5%), undetermined cases (21%), and reactive systemic amyloidosis (AA) (6.1%). There were mucocutaneous manifestations in 34.7% of cases, mostly multiple myeloma-related AL (ALMM). Head and neck was the most often affected site (38.2%), and purpuric macules were the most common morphology (44.1%). Mucocutaneous affectation was predominantly observed in AL (50.0%) compared to other types (20.0%) of amyloidosis (P = 0.01). Likewise, involvement of organs was also significantly different among the diverse amyloidosis types (P < 0.05). The most frequent comorbidities were hypertension (18.3%) and hypothyroidism (18.3%)., Conclusion: The clinical spectrum of manifestations in amyloidosis is wide. Involvement of skin and mucosa in amyloidosis is common; significant differences were observed concerning distribution of mucocutaneous amyloid manifestations among the different types of amyloidosis., (© 2019 The International Society of Dermatology.)

Social cognition deficits are found in schizophrenia and bipolar disorder, but its neural underpinnings are poorly understood. Given the complexity of psychological functions underlying this kind of cognition, we hypothesized that alterations in global structural connectivity could contribute to those deficits. To test this hypothesis, we studied a group of schizophrenia and bipolar patients with connectomics based on diffusion magnetic resonance imaging and assessments of general and social cognition. The latter was assessed using the Mayer, Salovey and Caruso Emotional Intelligence Test (MSCEIT) for emotional intelligence and the Spanish Group for Schizophrenia Treatment Optimization (Grupo Español para la OPtimización del Tratamiento de la Esquizofrenia, GEOPTE) test for behavioral aspects of social cognition. Graph theory applied to fractional anisotropy for the connections among cortical regions was used to obtain the small-world (SW) index of the structural connectivity network. In addition, we assessed the possibility of predicting the response of social cognition deficits to Meta-cognitive Training based on their possible underpinnings in a subgroup of patients. Patients showed lower scores in emotional intelligence and behavioral social cognition. MSCEIT scores were associated with SW index and working memory, and GEOPTE scores were related to verbal memory. Improvement in social cognition after Meta-cognitive Training was associated with lower scores of the social cognition in the baseline, according to the GEOPTE scale. Our findings support structural connectivity as one of the factors underlying emotional intelligence in schizophrenia, and the use of Meta-cognitive Training to improve social cognition in patients with larger deficits., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Hyperglycaemia and type 2 diabetes (T2D) are associated with impaired insulin secretion and/or insulin action. Since few studies have addressed the relation between DNA methylation patterns with elaborated surrogates of insulin secretion/sensitivity based on the intravenous glucose tolerance test (IVGTT), the aim of this study was to evaluate the association between DNA methylation and an insulin sensitivity index based on IVGTT (calculated insulin sensitivity index (CSi)) in peripheral white blood cells from 57 non-diabetic female volunteers. The CSi and acute insulin response (AIR) indexes, as well as the disposition index (DI = CSi × AIR), were estimated from abbreviated IVGTT in 49 apparently healthy Chilean women. Methylation levels were assessed using the Illumina Infinium Human Methylation 450k BeadChip. After a statistical probe filtering, the two top CpGs whose methylation was associated with CSi were cg04615668 and cg07263235, located in the catenin delta 2 ( CTNND2 ) and lipoprotein lipase ( LPL ) genes, respectively. Both CpGs conjointly predicted insulin sensitivity status with an area under the curve of 0.90. Additionally, cg04615668 correlated with homeostasis model assessment insulin-sensitivity (HOMA-S) and AIR, whereas cg07263235 was associated with plasma creatinine and DI. These results add further insights into the epigenetic regulation of insulin sensitivity and associated complications, pointing the CTNND2 and LPL genes as potential underlying epigenetic biomarkers for future risk of insulin-related diseases.

Previous studies based on graph theory parameters applied to diffusion tensor imaging support an alteration of the global properties of structural connectivity network in schizophrenia. However, the specificity of this alteration and its possible relation with chronicity and treatment have received small attention. We have assessed small-world (SW) and connectivity strength indexes of the structural network built using fractional anisotropy values of the white matter tracts connecting 84 cortical and subcortical regions in 25 chronic and 18 first episode (FE) schizophrenia and 24 bipolar patients and 28 healthy controls. Chronic schizophrenia and bipolar patients showed significantly smaller SW and connectivity strength indexes in comparison with controls and FE patients. SW reduction was driven by increased averaged path-length (PL) values. Illness duration but not treatment doses were negatively associated with connectivity strength, SW and PL in patients. Bipolar patients exposed to antipsychotics did not differ in SW or connectivity strength from bipolar patients without such an exposure. Executive functions and social cognition were related to SW index in the schizophrenia group. Our results support a role for chronicity but not treatment in structural network alterations in major psychoses, which may not differ between schizophrenia and bipolar disorder, and may hamper cognition., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The study of cerebral underpinnings of schizophrenia may benefit from the high temporal resolution of electromagnetic techniques, but its spatial resolution is low. However, source imaging approaches such as low-resolution brain electromagnetic tomography (LORETA) allow for an acceptable compromise between spatial and temporal resolutions., Methods: We combined LORETA with 32 channels and 3-Tesla diffusion magnetic resonance (Dmr) to study cerebral dysfunction in 38 schizophrenia patients (17 first episodes, FE), compared to 53 healthy controls. The EEG was acquired with subjects performing an odd-ball task. Analyses included an adaptive window of interest to take into account the interindividual variability of P300 latency. We compared source activation patters to distractor (P3a) and target (P3b) tones within- and between-groups., Results: Patients showed a reduced activation in anterior cingulate and lateral and medial prefrontal cortices, as well as inferior/orbital frontal regions. This was also found in the FE patients alone. The activation was directly related to IQ in the patients and controls and to working memory performance in controls. Symptoms were unrelated to source activation. Fractional anisotropy in the tracts connecting lateral prefrontal and anterior cingulate regions predicted source activation in these regions in the patients., Conclusions: These results replicate the source activation deficit found in a previous study with smaller sample size and a lower number of sensors and suggest an association between structural connectivity deficits and functional alterations.

Most peripheral serotonin (5-hydroxytryptamine (5HT)) is synthetized in the gut with platelets being its main circulating reservoir. 5HT is acting as a hormone in key organs to regulate glucose and lipid metabolism. However, the relation between platelet 5HT levels and traits related to glucose homeostasis and lipid metabolism in humans remains poorly explored. The objectives of this study were (a) to assess the association between platelet 5HT levels and plasma concentration of nonesterified fatty acids (NEFAs) and some adipokines including leptin and its soluble leptin receptor (sOb-R), (b) to assess the association between platelet 5HT levels and anthropometric traits and indexes of insulin secretion/sensitivity derived from oral glucose tolerance test (OGTT), and (c) to evaluate changes in platelet 5HT levels in response to OGTT. In a cross-sectional study, 59 normoglycemic women underwent a standard 2-hour OGTT. Plasma leptin, sOb-R, total and high molecular weight adiponectin, TNF α , and MCP1 were determined by immunoassays. Platelet 5HT levels and NEFAs were measured before and after OGTT. The free leptin index was calculated from leptin and sOb-R measurements. Insulin sensitivity indexes derived from OGTT (HOMA-S and Matsuda ISICOMP) and plasma NEFAs (Adipose-IR, Revised QUICKI) were also calculated. Our data show that among metabolic traits, platelet 5HT levels were associated with plasma sOb-R ( r = 0.39, p = 0.003, corrected p = 0.018). Platelet 5HT levels were reduced in response to OGTT (779 ± 237 vs.731 ± 217 ng/10 9 platelets, p = 0.005). In conclusion, platelet 5HT levels are positively associated with plasma sOb-R concentrations and reduced in response to glucose intake possibly indicating a role of peripheral 5HT in leptin-mediated appetite regulation.

The respiratory rhythm is generated by the preBötzinger complex in the medulla oblongata, and is modulated by neurons in the retrotrapezoid nucleus (RTN), which are essential for accelerating respiration in response to high CO 2 Here we identify a LBX1 frameshift ( LBX1 FS ) mutation in patients with congenital central hypoventilation. The mutation alters the C-terminal but not the DNA-binding domain of LBX1 Mice with the analogous mutation recapitulate the breathing deficits found in humans. Furthermore, the mutation only interferes with a small subset of Lbx1 functions, and in particular with development of RTN neurons that coexpress Lbx1 and Phox2b. Genome-wide analyses in a cell culture model show that Lbx1 FS and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1 FS is unable to cooperate with Phox2b. Thus, our analyses on Lbx1 FS (dys)function reveals an unusual pathomechanism; that is, a mutation that selectively interferes with the ability of Lbx1 to cooperate with Phox2b, and thus impairs the development of a small subpopulation of neurons essential for respiratory control., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is a mitochondrial-derived peptide that attenuates weight gain and hyperinsulinemia when administered to high fat-fed mice. MOTS-c is therefore a potential regulator of metabolic homeostasis under conditions of high-energy supply. However, the effect of insulin resistance and obesity on plasma MOTS-c concentration in humans is unknown. To gain insight into MOTS-c regulation, we measured plasma MOTS-c concentration and analyzed its relationship with insulin sensitivity surrogates, in lean and obese humans (n=10 per group). Obese individuals had impaired insulin sensitivity as indicated by low Matsuda and high Homeostatic Model Assessment (HOMA) indexes. Although plasma MOTS-c concentration was similar in lean and obese individuals (0.48±0.16 and 0.52±0.15 ng/mL; p=0.60), it was correlated with HOMA (r=0.53; p<0.05) and Matsuda index (r=-0.46; p<0.05). Notably, when the groups were analyzed separately, the associations remained only in lean individuals. We conclude that plasma MOTS-c concentration is unaltered in human obesity. However, MOTS-c associates positively with insulin resistance mostly in lean individuals, indicating that plasma MOTS-c concentration depends on the metabolic status in this population. Such dependence seems altered when obesity settles. The implications of plasma MOTS-c for human metabolic homeostasis deserve future examination., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)