Understanding the mechanisms of food intake and obesity in Down syndrome is supported by behavioral and neurochemical abnormalities

[eng] Obesity prevalence is higher in Down syndrome (DS) than in the general population. Beyond metabolic alterations, individuals with DS present increased impulsivity, a trait observed in obese people and in compulsive eaters that may affect their control of food intake. In this Thesis, we used a trisomic DS mouse model (Ts65Dn) to understand the behavioral component of obesity in DS and explore some possible underlying mechanisms. Our meal pattern analysis revealed longer and slowly meals in Ts65Dn mice, leading to reduced eating rate, which may be associated to the mandible hypoplasia described in both human and mice. When exposed to obesogenic environments, Ts65Dn mice showed higher preference for energy-dense food, gained more weight in specific conditions and scored higher in compulsivity and inflexibility tests than WT mice, as measured by binge eating during limited access and persistence of consumption of quine adulteration of energy-dense food. High performance liquid chromatography revealed reduced levels of dopamine in prefrontal cortex in Ts65Dn mice. This could lead to higher reward sensitivity that in turn would facilitate overeating as a compensatory response to restore optimal dopamine levels. Feeding behavior is also regulated by hormones and other circulating signals. We detected higher plasma leptin and glucose levels along with reduced insulin levels in Ts65Dn mice. Upon a glucose challenge, Ts65Dn mice showed reduced glucose-stimulated insulin response both in vivo and in vitro, suggesting a deficient insulin secretion or the reduced pancreatic mass. Indeed, we detected that Ts65Dn mice had altered plasma profile for some markers of inflammation and oxidative damage, in agreement with the high prevalence of autoimmune diseases and diabetes in DS people. We also explored the involvement of the serine/threonine kinase DYRK1A, a candidate DS gene, in obesity and feeding behavior. Dyrk1A overexpression was sufficient to recapitulate some behavioral aspects associated to overeating in DS, but with a distinct profile. We conclude that increased obesity prevalence in DS is explained by both metabolic and behavioral alterations, in part driven by a hypodopaminergic status, and that Dyrk1A overexpression is only involved in specific DS obesity phenotypes.[spa] La prevalencia de obesidad es más alta en el síndrome de Down (SD) que en la población general. Más allá de las alteraciones metabólicas, los individuos con SD tienen mayor impulsividad, rasgo común en personas obesas y en comedores compulsivos, que pueden afectar el control de la ingesta de alimentos. En esta Tesis, se ha utilizado un modelo de ratón trisómico (Ts65Dn) para comprender el componente de comportamiento en el desarrollo de la obesidad en SD. Nuestro análisis del patrón de ingesta mostró que los ratones Ts65Dn comen más lento que los euploides, lo que podría estar asociado con la hipoplasia mandibular descrita en ratones y humanos con SD. Cuando los ratones Ts65Dn son expuestos a ambientes obesogénicos, comen mayores cantidades de dietas hipercalóricas, engordan más en determinadas condiciones y puntúan más alto en pruebas de compulsividad e inflexibilidad que los ratones euploides. La cuantificación de los niveles de monoaminas mediante cromatografía líquida reveló que los ratones Ts65Dn presentan niveles más bajos de dopamina en corteza prefrontal. Dado que las dietas hipercalóricas promueven la liberación del neurotransmisor en el circuito de recompensa, el sobre consumo de las mismas podría indicar un intento de restaurar los niveles óptimos de dopamina. La regulación de la ingesta también depende de otras señales circulantes. Detectamos que los ratones Ts65Dn tienen mayores niveles de leptina y glucosa en plasma y niveles más bajos de insulina que los euploides. La administración exógena de glucosa produjo una menor respuesta secretoria de insulina en los ratones Ts65Dn in vivo e in vitro. Además, diversos marcadores de inflamación y estrés oxidativo son más elevados en los ratones Ts65Dn, en consonancia con la mayor incidencia de enfermedades autoinmunes y diabetes en personas con SD. En esta Tesis también se ha explorado la contribución de la proteína serina / treonina quinasa DYRK1A, un gen candidato para SD en la obesidad e ingesta. La sobreexpresión de Dyrk1A es suficiente para recapitular algunos comportamientos asociados a la ingesta compulsiva, pero con un perfil distinto al observado en el modelo trisómico. Concluimos que la prevalencia de la obesidad en SD se explica por alteraciones tanto metabólicas como conductuales, en parte como consecuencia de un estado de hipodopaminergia, y que la sobreexpresión de Dyrk1A está implicada en fenotipos específicos de la obesidad en SD

Prevalence of attention deficit hyperactivity disorder in detention settings: A systematic review and meta-analysis

© 2018 Baggio, Fructuoso, Guimaraes, Fois, Golay, Heller, Perroud, Aubry, Young, Delessert, Gétaz, Tran and Wolff. Background: Previous studies have reported a high prevalence of attention deficit hyperactivity disorder (ADHD) among people living in detention (PLD) corresponding to a five- to ten-fold increase compared to the general population. Our main study objective was to provide an updated ADHD prevalence rate for PLD, including PLD in psychiatric units. Sub-objectives included (i) comparing different ways of assessing ADHD, including DSM-5 criteria and (ii) identifying which types of PLD are more likely to have ADHD. Methods: We conducted a systematic review and meta-analysis following the PRISMA guidelines and the MOOSE checklist. PubMed/Medline, PsycINFO, and Web of Sciences were searched combining "ADHD" and "prison" keywords and synonyms for articles published between January 1, 1966 and January 2, 2018. Potential sources of variation to the meta-analytic ADHD prevalence rate were investigated using meta-regressions and subgroups analyses. Results: The meta-analysis pooled 102 original studies including 69,997 participants. The adult ADHD prevalence rate was 26.2% (95% confidence interval: 22.7-29.6). Retrospective assessments of ADHD in childhood were associated with an increased prevalence estimate (41.1, 95% confidence interval: 34.9-47.2, p < 0.001). There was no significant difference in the prevalence estimate between screenings and clinical interviews in adulthood. Only three studies used the DSM-5 definition of ADHD and results were non-significantly different with other DSM versions. We found no difference according to participants' characteristics. Conclusion: Our results confirmed the high prevalence rate of ADHD among PLD, corresponding to a five-fold increase compared to the general population. In light of such high ADHD prevalence, our results reinforce the importance of addressing this critical public health issue by (i) systematically offering ADHD screening and diagnosis to all individuals entering detention, and (ii) delivering treatment, monitoring, and care for ADHD during and after detention. These strategies may help reduce recidivism and reincarceration, as well as violence in detention settings, in addition to improving the health and wellbeing of people living in detention. Additionally, our study suggests that using screening scales may be a reliable way of assessing ADHD, although caution is needed because a complete evaluation by an experienced clinician is required to provide a formal diagnosis

Direct-acting Antivirals for the Treatment of Kidney Transplant Patients With Chronic Hepatitis C Virus Infection in Spain: A Long-term Prospective Observational Study

Background: Direct-acting antivirals (DAA) allow effective and safe eradication of hepatitis C virus (HCV) in most patients. There are limited data on the long-term effects of all-oral, interferon-free DAA combination therapies in kidney transplant (KT) patients infected with HCV. Here we evaluated the long-term tolerability, efficacy, and safety of DAA combination therapies in KT patients with chronic HCV infection. Methods: Clinical data from KT patients treated with DAA were collected before, during, and after the treatment, including viral response, immunosuppression regimens, and kidney and liver function. Results: Patients (N = 226) were mostly male (65.9%) aged 56.1 +/- 10.9 years, with a median time from KT to initiation of DAA therapy of 12.7 years and HCV genotype 1b (64.6%). Most patients were treated with sofosbuvir-based therapies. Rapid virological response at 1 month was achieved by 89.4% of the patients and sustained virological response by week 12 by 98.1%. Liver function improved significantly after DAA treatment. Tacrolimus dosage increased 37% from the beginning of treatment (2.5 +/- 1.7 mg/d) to 1 year after the start of DAA treatment (3.4 +/- 1.9 mg/d, P < 0.001). Median follow-up was 37.0 months (interquartile range, 28.4-41.9) and death-censored graft survival was 91.1%. Adverse events resulting from DAA treatment, especially anemia, were reported for 31.0% of the patients. Conclusions: Chronic HCV infection can be treated efficiently and safely with DAA therapy in KT patients. Most patients retained stable kidney function and improved liver function. Tacrolimus dose had to be increased in most patients, potentially as a result of better liver function

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

La renovación de la palabra en el bicentenario de la Argentina : los colores de la mirada lingüística

El libro reúne trabajos en los que se exponen resultados de investigaciones presentadas por investigadores de Argentina, Chile, Brasil, España, Italia y Alemania en el XII Congreso de la Sociedad Argentina de Lingüística (SAL), Bicentenario: la renovación de la palabra, realizado en Mendoza, Argentina, entre el 6 y el 9 de abril de 2010. Las temáticas abordadas en los 167 capítulos muestran las grandes líneas de investigación que se desarrollan fundamentalmente en nuestro país, pero también en los otros países mencionados arriba, y señalan además las áreas que recién se inician, con poca tradición en nuestro país y que deberían fomentarse. Los trabajos aquí publicados se enmarcan dentro de las siguientes disciplinas y/o campos de investigación: Fonología, Sintaxis, Semántica y Pragmática, Lingüística Cognitiva, Análisis del Discurso, Psicolingüística, Adquisición de la Lengua, Sociolingüística y Dialectología, Didáctica de la lengua, Lingüística Aplicada, Lingüística Computacional, Historia de la Lengua y la Lingüística, Lenguas Aborígenes, Filosofía del Lenguaje, Lexicología y Terminología

Protocol for measuring compulsive-like feeding behavior in mice

Obesity is an important health problem with a strong environmental component that is acquiring pandemic proportion. The high availability of caloric dense foods promotes overeating potentially causing obesity. Animal models are key to validate novel therapeutic strategies, but researchers must carefully select the appropriate model to draw the right conclusions. Obesity is defined by an increased body mass index greater than 30 and characterized by an excess of adipose issue. However, the regulation of food intake involves a close interrelationship between homeostatic and non-homeostatic factors. Studies in animal models have shown that intermittent access to sweetened or calorie-dense foods induces changes in feeding behavior. However, these studies are focused mainly on the final outcome (obesity) rather than on the primary dysfunction underlying the overeating of palatable foods. We describe a protocol to study overeating in mice using diet-induced obesity (DIO). This method can be applied to free choice between palatable food and a standard rodent chow or to forced intake of calorie-dense and/or palatable diets. Exposure to such diets is sufficient to promote changes in meal pattern that we register and analyze during the period of weight gain allowing the longitudinal characterization of feeding behavior in mice. Abnormal eating behaviors such as binge eating or snacking, behavioral alterations commonly observed in obese humans, can be detected using our protocol. In the free-choice procedure, mice develop a preference for the rewarding palatable food showing the reinforcing effect of this diet. Compulsive components of feeding are reflected by maintenance of feeding despite an adverse bitter taste caused by adulteration with quinine and by the negligence of standard chow when access to palatable food is ceased or temporally limited. Our strategy also enables to identify compulsive overeating in mice under a high-caloric regime by using limited food access and finally, we propose complementary behavioral tests to confirm the non-homeostatic food-taking triggered by these foods. Finally, we describe how to computationally explore large longitudinal behavioral datasets.This work was supported by Fondation Jérôme Lejeune (Paris, France), MINECO (SAF2016-79956-R), CDTI (‘Smartfoods’), EU (Era Net Neuron PCIN-2013-060) and the Catalan foundation ‘La Marató de TV3’ (#2016/20-30) and the EU Joint Programme–Neurodegenerative Disease Research (JPND) project under grant agreement HEROES AC17/00006. The CRG is a Center of Excellence Severo Ochoa SEV-2012-0208. The CIBER of Rare Diseases is an initiative of the ISCIII

Protocol for measuring compulsive-like feeding behavior in mice

Obesity is an important health problem with a strong environmental component that is acquiring pandemic proportion. The high availability of caloric dense foods promotes overeating potentially causing obesity. Animal models are key to validate novel therapeutic strategies, but researchers must carefully select the appropriate model to draw the right conclusions. Obesity is defined by an increased body mass index greater than 30 and characterized by an excess of adipose issue. However, the regulation of food intake involves a close interrelationship between homeostatic and non-homeostatic factors. Studies in animal models have shown that intermittent access to sweetened or calorie-dense foods induces changes in feeding behavior. However, these studies are focused mainly on the final outcome (obesity) rather than on the primary dysfunction underlying the overeating of palatable foods. We describe a protocol to study overeating in mice using diet-induced obesity (DIO). This method can be applied to free choice between palatable food and a standard rodent chow or to forced intake of calorie-dense and/or palatable diets. Exposure to such diets is sufficient to promote changes in meal pattern that we register and analyze during the period of weight gain allowing the longitudinal characterization of feeding behavior in mice. Abnormal eating behaviors such as binge eating or snacking, behavioral alterations commonly observed in obese humans, can be detected using our protocol. In the free-choice procedure, mice develop a preference for the rewarding palatable food showing the reinforcing effect of this diet. Compulsive components of feeding are reflected by maintenance of feeding despite an adverse bitter taste caused by adulteration with quinine and by the negligence of standard chow when access to palatable food is ceased or temporally limited. Our strategy also enables to identify compulsive overeating in mice under a high-caloric regime by using limited food access and finally, we propose complementary behavioral tests to confirm the non-homeostatic food-taking triggered by these foods. Finally, we describe how to computationally explore large longitudinal behavioral datasets.This work was supported by Fondation Jérôme Lejeune (Paris, France), MINECO (SAF2016-79956-R), CDTI (‘Smartfoods’), EU (Era Net Neuron PCIN-2013-060) and the Catalan foundation ‘La Marató de TV3’ (#2016/20-30) and the EU Joint Programme–Neurodegenerative Disease Research (JPND) project under grant agreement HEROES AC17/00006. The CRG is a Center of Excellence Severo Ochoa SEV-2012-0208. The CIBER of Rare Diseases is an initiative of the ISCIII

Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia

Hyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse cognitive dysfunction. Considering the role of the serine/threonine kinase DYRK1A, not only in developmental defects with life-long structural and functional consequences, but also in multiple neurodegenerative diseases, its protein expression and kinase activity has been analyzed in brain of heterozygous CBS deficient mice and found to be increased. We previously demonstrated that specific liver treatment with an adenovirus expressing Dyrk1A normalizes hepatic DYRK1A level and decreases hyperhomocysteinemia in mice with moderate to intermediate hyperhomocysteinemia. We here use a hepatocyte-specific recombinant adeno-associated viral (AAV) serotype 8-mediated DYRK1A gene therapy (AAV2/8-DYRK1A) to analyze the effect of hepatic Dyrk1A gene transfer on some altered molecular mechanisms in brain of mice with intermediate hyperhomocysteinemia. Our selective hepatic treatment alleviates altered DYRK1A protein level and signaling pathways in brain of mice, the MAPK/ERK and PI3K/Akt pathways initiated by receptor tyrosine kinase, the BDNF dependent TrkB pathway, and NFkB pathway. These results demonstrate the positive effect of AAV2/8-DYRK1A gene transfer on neuropathological and inflammatory processes in brain of mice with intermediate hyperhomocysteinemia

Down syndrome is a metabolic disease: altered insulin signaling mediates peripheral and brain dysfunctions

Down syndrome (DS) is the most frequent chromosomal abnormality that causes intellectual disability, resulting from the presence of an extra complete or segment of chromosome 21 (HSA21). In addition, trisomy of HSA21 contributes to altered energy metabolism that appears to be a strong determinant in the development of pathological phenotypes associated with DS. Alterations include, among others, mitochondrial defects, increased oxidative stress levels, impaired glucose, and lipid metabolism, finally resulting in reduced energy production and cellular dysfunctions. These molecular defects seem to account for a high incidence of metabolic disorders, i.e., diabetes and/or obesity, as well as a higher risk of developing Alzheimer's disease (AD) in DS. A dysregulation of the insulin signaling with reduced downstream pathways represents a common pathophysiological aspect in the development of both peripheral and central alterations leading to diabetes/obesity and AD. This is further strengthened by evidence showing that the molecular mechanisms responsible for such alterations appear to be similar between peripheral organs and brain. Considering that DS subjects are at high risk to develop either peripheral or brain metabolic defects, this review will discuss current knowledge about the link between trisomy of HSA21 and defects of insulin and insulin-related pathways in DS. Drawing the molecular signature underlying these processes in DS is a key challenge to identify novel drug targets and set up new prevention strategies aimed to reduce the impact of metabolic disorders and cognitive decline.This work was supported by Fondi Ateneo grant funded by the Sapienza University n° RM11715C77336E99 to EB and n° C26H15JT9X to MP, Fondation Jérôme Lejeune (2019b – Project #1887) to EB; Fondation Jérôme Lejeune, MINECO (SAF2016-79956-R), H2020 SC1, GO-DS21- 848077, CDTI (“Smartfoods”), Fundació La Marató De TV3 (201620-31_MDierssen), and JPND HEROES (tHE cRossroad Of dEmentia Syndromes to MD). The CRG was a Center of Excellence Severo Ochoa SEV-2016-0571