Bexarotene Impairs Cognition and Produces Hypothyroidism in a Mouse Model of Down Syndrome and Alzheimer’s Disease

All individuals with Down syndrome (DS) eventually develop Alzheimer's disease (AD) neuropathology, including neurodegeneration, increases in ?-amyloid (A?) expression, and aggregation and neurofibrillary tangles, between the third and fourth decade of their lives. There is currently no effective treatment to prevent AD neuropathology and the associated cognitive degeneration in DS patients. Due to evidence that the accumulation of A? aggregates in the brain produces the neurodegenerative cascade characteristic of AD, many strategies which promote the clearance of A? peptides have been assessed as potential therapeutics for this disease. Bexarotene, a member of a subclass of retinoids that selectively activates retinoid receptors, modulates several pathways essential for cognitive performance and A? clearance. Consequently, bexarotene might be a good candidate to treat AD-associated neuropathology. However, the effects of bexarotene treatment in AD remain controversial. In the present study, we aimed to elucidate whether chronic bexarotene treatment administered to the most commonly used murine model of DS, the Ts65Dn (TS) mouse could reduce A? expression in their brains and improve their cognitive abilities. Chronic administration of bexarotene to aged TS mice and their CO littermates for 9 weeks diminished the reference, working, and spatial learning and memory of TS mice, and the spatial memory of CO mice in the Morris water maze. This treatment also produced marked hypoactivity in the plus maze, open field, and hole board tests in TS mice, and in the open field and hole board tests in CO mice. Administration of bexarotene reduced the expression of A?1-40, but not of A?1-42, in the hippocampi of TS mice. Finally, bexarotene increased Thyroid-stimulating hormone levels in TS mice and reduced Thyroid-stimulating hormone levels in CO mice, while animals of both karyotypes displayed reduced thyroxine levels after bexarotene administration. The bexarotene-induced hypothyroidism could be responsible for the hypoactivity of TS and CO mice and their diminished performance in the Morris water maze. Together, these results do not provide support for the use of bexarotene as a potential treatment of AD neuropathology in the DS population.FUNDING: This study was supported by the Institute of Research Valdecilla (IDIVAL) (NVAL 16/21 and NVAL 19/23) and the Consejería de Universidades, Igualdad, Cultura y Deporte del Gobierno de Cantabria (16. VP39.64662)

Proteinen desnaturalizazio termalaren bidezko analisia konposatu bioeraginkor berriak aurkitzeko

Bioactive compounds are either natural or synthetic chemicals that can affect both the cellular and/or physiological activity in living organisms. Included among these are, for example, drugs that can have beneficial effects on health, through the modulation of biological processes. The development of new strategies to search new bioactive compounds and their new biological targets is a high impact challenge. In order to find target proteins and mechanisms of action, several different methodologies have been developed, including the method discussed in this paper. It is based on the analysis of the modifications caused by bioactive compounds on the protein thermal denaturation process. This work describes the basics of this methodology suitable in the search of bioactive compounds as well as the criteria for its implementation.; Konposatu bioeraginkorrak bizidunetan jarduera zelularraren edota fisiologikoaren gain eragin dezaketen substantzia kimiko naturalak zein sintetikoak dira. Horien artean daude, adibidez, farmakoak, prozesu biologikoen modulazioaren bitartez osasunaren gain efektu onuragarriak bideratu ditzaketenak. Konposatu bioeraginkor berrien eta horien itu biologikoak bilatzeko estrategia berrien garapena inpaktu handiko erronka da. Itu proteinak edota ekintza mekanismoak aurkitzeko metodologia ezberdinak garatu dira. Itu proteinak aurkitzeko metodoen artean, lan honetan jorratzen dena daukagu: konposatu bioeraginkorrek proteinen desnaturalizazio termalean eragindako aldaketen azterketan oinarritutako metodoa. Lan honetan, konposatu bioeraginkorrak bilatzeko metodologia horren oinarriak eta haren inplementaziorako irizpideak azaltzen dira

Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene

Down syndrome (DS) is characterized by a marked reduction in the size of the brain and cerebellum. These changes play an important role in the motor alterations and cognitive disabilities observed in this condition. The Ts65Dn (TS) mouse, the most commonly used model of DS, reflects many DS phenotypes, including alterations in cerebellar morphology. One of the genes that is overexpressed in both individuals with DS and TS mice is DYRK1A/Dyrk1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which has been implicated in the altered cerebellar structural and functional phenotypes observed in both populations. The aim of this study was to evaluate the effect of Dyrk1A on different alterations observed in the cerebellum of TS animals. TS mice were crossed with Dyrk1A +/- KO mice to obtain mice with a triplicate segment of Mmu16 that included Dyrk1A (TS +/+/+), mice with triplicate copies of the same genes that carried only two copies of Dyrk1A (TS +/+/-), euploid mice that expressed a normal dose of Dyrk1A (CO +/+) and CO animals with a single copy of Dyrk1A (CO +/-). Male mice were used for all experiments. The normalization of the Dyrk1A gene dosage did not rescue the reduced cerebellar volume. However, it increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization. Furthermore, it improved the excitatory/inhibitory balance and walking pattern of TS +/+/- mice. These results support the hypothesis that Dyrk1A is involved in some of the structural and functional cerebellar phenotypes observed in the TS mouse model.This work was supported by grants from the Jerome Lejeune Foundation and Fundación Tatiana Pérez de Guzmán el Bueno and the Spanish Ministry of Economy and Competitiveness (PSI-2016-76194-R, AEI/FEDER, EU) and “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, CB06/05/0037)” from Spain

Factores asociados a baja agudeza visual en una población escolar de la ciudad de Bucaramanga, Colombia

Introducción. La baja agudeza es un problema de salud pública en el mundo, que aumenta año tras año, relacionada con factores comportamentales poco saludables como el sedentarismo. La baja agudeza afecta especialmente a escolares, en quienes la visión representa uno de los sistemas más importantes para su desarrollo, tanto para el aprendizaje como para las relaciones sociales. El objetivo es establecer asociación entre baja agudeza visual y características sociodemográficas y comportamentales en una población escolar de la ciudad de Bucaramanga, Colombia. Metodología. Estudio observacional de corte transversal basado en datos recolectados de encuestas a estudiantes de una institución educativa de Bucaramanga entre los años 2006 y 2017, sobre las cuales se realizó un análisis bivariado entre características sociodemográficas y comportamentales con baja agudeza visual. Resultados. La prevalencia de baja agudeza visual fue de 33.57%, con mayor prevalencia de baja agudeza visual en mujeres y aquellos con mayor índice de masa corporal. La agudeza visual baja no tuvo asociación estadísticamente significativa con las otras variables estudiadas. Discusión. Las mujeres tienen una mayor prevalencia de baja agudeza visual. Parece existir una relación entre la actividad física y la agudeza visual. Conclusiones. Las diferencias encontradas según el sexo pueden deberse a patrones comportamentales diferentes entre hombres y mujeres, como la actividad física y el sedentarismo. Hacen falta estudios que evalúen la causalidad de la asociación entre los problemas de agudeza visual y los hábitos de vida poco saludables. Introduction. Low visual acuity is a public health problem worldwide, which is increasing year by year, and it is associated with unhealthy behavioral factors such as sedentary lifestyle. Low visual acuity particularly affects schoolchildren, whom eyesight is one of the most important abilities for their development, both in terms of learning and social interactions. The objective of this study is to establish an association between low visual acuity, sociodemographic, and behavioral characteristics of a student population in Bucaramanga, Colombia. Methodology. This was a cross-sectional observational study based on data collected from surveys of students within an educational institution sited in Bucaramanga between 2006 and 2017. A bivariate analysis was conducted between sociodemographic and behavioral characteristics and low visual acuity. Results. The prevalence of low visual acuity was 33.57%, with a higher prevalence of low visual acuity in women and those with a higher body mass index. However, low visual acuity didn’t have a statistically significant association with the other variables studied. Discussion. Women have a higher prevalence of low visual acuity. There appears to be an association between physical activity and visual acuity. Conclusions. The encountered differences according to sex may be due to different behavioral patterns between males and females, such as physical activity and sedentary lifestyle. Further studies are needed to assess the causality of the association. Introdução. A baixa acuidade é um problema de saúde pública no mundo, que aumenta a cada ano, relacionada a fatores comportamentais pouco saudáveis, como o sedentarismo. A baixa acuidade atinge especialmente as crianças em idade escolar, para as quais a visão representa um dos sistemas mais importantes para o seu desenvolvimento, tanto para a aprendizagem quanto para as relações sociais. O objetivo é estabelecer uma associação entre baixa acuidade visual e características sociodemográficas e comportamentais em uma população escolar na cidade de Bucaramanga, Colômbia. Metodologia. Estudo observacional transversal baseado em dados coletados em pesquisas com estudantes de uma instituição de ensino de Bucaramanga entre 2006 e 2017, nos quais foi realizada uma análise bivariada entre características sociodemográficas e comportamentais com baixa acuidade visual. Resultados. A prevalência de baixa acuidade visual foi de 33.57%, com maior prevalência de baixa acuidade visual em mulheres e naqueles com maior índice de massa corporal. A baixa acuidade visual não teve associação estatisticamente significativa com as demais variáveis estudadas. Discussão. As mulheres apresentam maior prevalência de baixa acuidade visual. Parece haver uma relação entre atividade física e acuidade visual. Conclusões. As diferenças encontradas segundo o sexo podem ser decorrentes de diferentes padrões comportamentais entre homens e mulheres, como atividade física e sedentarismo. Estudos são necessários para avaliar a causalidade da associação entre problemas de acuidade visual e hábitos de vida pouco saudáveis

Cimp-Positive Status is More Representative in Multiple Colorectal Cancers than in Unique Primary Colorectal Cancers

We thank the Tumor Registry of the Pathology Department of the 12 de Octubre University Hospital for providing the paraffin-embedded tissues, and Ron Hartong for his help with the English revision of this manuscript. This work was funded by Projects PI10/00683 and PI16/01650 to J.P, and PI16/01920 to R.G.S, from the Spanish Ministry of Health and Consumer Affairs and FEDER, and by Project 2012-0036 from the Mutua Madrileña Foundation. This work was supported by R01 (CA72851, CA181572, CA184792, CA202797) and U01 (CA187956, CA214254) grants from the National Cancer Institute, NIH; RP140784 from the CancerPrevention Research Institute of Texas; grants from the Baylor Foundation and Baylor Scott & White Research Institute, Dallas, TX, USA to AG.Colorectal cancer (CRC) with CpG island methylator phenotype (CIMP) is recognized as a subgroup of CRC that shows association with particular genetic defects and patient outcomes. We analyzed CIMP status of 229 individuals with CRC using an eight-marker panel (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); CIMP-(+) tumors were defined as having ≥ 5 methylated markers. Patients were divided into individuals who developed a "unique" CRC, which were subclassified into early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and patients with multiple primary CRCs subclassified into synchronous CRC (SCRC) and metachronous CRC (MCRC). We found 9 (15.2%) CIMP-(+) EOCRC patients related with the proximal colon (p = 0.008), and 19 (26.8%) CIMP-(+) LOCRC patients associated with tumor differentiation (p = 0.045), MSI status (p = 0.021) and BRAF mutation (p = 0.001). Thirty-five (64.8%) SCRC patients had at least one CIMP-(+) tumor and 20 (44.4%) MCRC patients presented their first tumor as CIMP-(+). Thirty-nine (72.2%) SCRC patients showed concordant CIMP status in their simultaneous tumors. The differences in CIMP-(+) frequency between groups may reflect the importance of taking into account several criteria for the development of multiple primary neoplasms. Additionally, the concordance between synchronous tumors suggests CIMP status is generally maintained in SCRC patients.S

Henoch-Schönlein purpura in northern Spain: clinical spectrum of the disease in 417 patients from a single center

The severity of clinical features and the outcomes in previous series of patients reported with Henoch-Schönlein purpura (HSP) vary greatly, probably due to selection bias. To establish the actual clinical spectrum of HSP in all age groups using an unselected and wide series of patients diagnosed at a single center, we performed a retrospective review of 417 patients classified as having HSP according to the criteria proposed by Michel et al. Of 417 patients, 240 were male and 177 female, with a median age at the time of disease diagnosis of 7.5 years (interquartile range [IQR], 5.3-20.1 yr). Three-quarters of the patients were children or young people aged 20 years or younger (n = 315), and one-quarter were adults (n = 102). The most frequent precipitating events were a previous infection (38%), usually an upper respiratory tract infection, and/or drug intake (18.5%) shortly before the onset of the vasculitis. At disease onset the most common manifestations were skin lesions (55.9%), nephropathy (24%), gastrointestinal involvement (13.7%), joint symptoms (9.1%), and fever (6.2%). Cutaneous involvement occurring in all patients, mainly purpuric skin lesion, was the most common manifestation when the vasculitis was fully established, followed by gastrointestinal (64.5%), joint (63.1%), and renal involvement (41.2%). The main laboratory findings were leukocytosis (36.7%), anemia (8.9%), and increased serum IgA levels (31.7%). The most frequent therapies used were corticosteroids (35%), nonsteroidal antiinflammatory drugs (14%), and cytotoxic agents (5%). After a median follow-up of 12 months (IQR, 2-38 mo), complete recovery was observed in most cases (n = 346; 83.2%), while persistent, usually mild, nephropathy was observed in only 32 (7.7%) cases. Relapses were observed in almost a third of patients (n = 133; 31.9%).In conclusion, although HSP is a typical vasculitis affecting children and young people, it is not uncommon in adults. The prognosis is favorable in most cases, depending largely on renal involvement

Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome–negative adult lymphoblastic leukemia

The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph− adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph− adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance

Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice

Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., ?-amyloid (A?) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than A? plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble A? species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, A? peptide expression and neuroinflammation). Administration of anti-IL17 for 5?months, starting at the age of 7?months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and A?1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics.This study was supported by the Jerome Lejeune Foundation, Fundación Tatiana Pérez de Guzmán el Bueno, the Spanish Ministry of Economy and Competitiveness (PSI-2016-76194-R, SAF2014-55088-R, SAF2016-75195-R, AEI/FEDER, EU) and Luchamos por la Vida Foundatio