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BACKGROUND: Cystic fibrosis (CF) is a multisystem disorder that leads to abnormal transport of chloride and sodium across secretory epithelia resulting in thickened, viscous secretions in the bronchi, biliary tract, pancreas, intestine, and the reproductive system. Defects in the biliary tract can predispose to stone formation requiring endoscopic retrograde cholangiopancreatography (ERCP). However, there is a paucity of data assessing ERCP outcomes in patients with CF. METHODS: We identified patients from the Healthcare Cost and Utilization Project (HCUP)-National Inpatient Sample (NIS) between the years 2016 and 2020. Our study group included patients with CF of all ages who underwent an inpatient ERCP. We used ICD10 diagnostic and procedural codes to identify patients, procedures, and complications of the procedure. RESULTS: From 2016 to 2020, a total of 860,679 inpatient ERCPs were identified. Of these procedures, 535 (0.06%) were performed in patients with CF. The mean age of patients with CF undergoing ERCP was 60.62 years, of which 48% were males and 52% were females. Patients in the CF group had a higher incidence of post-ERCP pneumothorax (0.93%) than the patients in the non-CF group (0.15%). The occurrence of other ERCP-related adverse events was similar in both groups (P>0.05). On multivariate regression analysis, patients with CF were 1.75 times more likely to develop post-ERCP infections [odds ratio (OR): 1.75; 95% CI: 1.03-2.94; P=0.035) and 7.64 times more likely to develop post-ERCP pneumothorax (OR: 7.64; 95% CI: 1.03-56.5; P=0.046) compared to patients without CF after adjusting for confounders. The groups had no significant difference in mortality, post-ERCP pancreatitis, bleeding, perforation, pneumoperitoneum, and gas embolism. There was also no significant difference in the length of stay between the study and control groups. CONCLUSIONS: ERCP is a safe procedure in patients with CF with a comparable risk of postprocedural complications and mortality to those who do not have cystic fibrosis. However, patients with CF may experience a higher risk of post-ERCP infections and post-ERCP pneumothorax. Further studies are needed to prospectively evaluate outcomes of ERCP in patients with CF and to determine methods of mitigating adverse events.
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PURPOSE: Stomach and esophageal cancers are among the highest mortality from cancers worldwide. Microbiota has an interplaying role within the human gastrointestinal (GI) tract. Dysbiosis occurs when a disruption of the balance between the microbiota and the host happens. With this narrative review, we discuss the main alterations in the microbiome of gastroesophageal cancer, revealing its potential role in the pathogenesis, early detection, and treatment. RESULTS: Helicobacter pylori plays a major role the development of a cascade of preneoplastic conditions ranging from atrophic gastritis to metaplasia and dysplasia, ultimately culminating in gastric cancer, while other pathogenic agents are Fusobacterium nucleatum, Bacteroides fragilis, Escherichia coli, and Lactobacillus. Campylobacter species (spp.)'s role in the progression of esophageal adenocarcinoma may parallel that of Helicobacter pylori in the context of gastric cancer, with other esophageal carcinogenic agents being Escherichia coli, Bacteroides fragilis, and Fusobacterium nucleatum. Moreover, gut microbiome could significantly alter the outcomes of chemotherapy and immunotherapy. The gut microbiome can be modulated through interventions such as antibiotics, probiotics, or prebiotics intake. Fecal microbiota transplantation has emerged as a therapeutic strategy as well. CONCLUSIONS: Nowadays, it is widely accepted that changes in the normal gut microbiome causing dysbiosis and immune dysregulation play a role gastroesophageal cancer. Different interventions, including probiotics and prebiotics intake are being developed to improve therapeutic outcomes and mitigate toxicities associated with anticancer treatment. Further studies are required in order to introduce the microbiome among the available tools of precision medicine in the field of anticancer treatment.
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Disbiose , Neoplasias Esofágicas , Microbioma Gastrointestinal , Neoplasias Gástricas , Humanos , Neoplasias Esofágicas/microbiologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/terapia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Disbiose/diagnóstico , Disbiose/microbiologia , Disbiose/terapia , Probióticos/uso terapêutico , Probióticos/administração & dosagem , Adenocarcinoma/microbiologia , Adenocarcinoma/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologiaRESUMO
BACKGROUND: A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examine whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. RESULTS: We generate large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients-those most likely involved in clinical trials. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirms the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observe changes in the homeostasis of extracellular vesicles, where we find consistent changes of genes and proteins involved in this process. In-depth single nucleotide polymorphism data across the HTT gene are derived from the generated primary cell lines. CONCLUSIONS: Our 'omics data document the involvement of inflammation, energy metabolism, and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. The generated data, complemented by the primary cell lines established from peripheral tissues, and a large panel of iPSC lines that can serve as human models of HD are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis.
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Doença de Huntington , Doenças Neurodegenerativas , Metabolismo Energético , Humanos , Doença de Huntington/genética , Inflamação/complicações , ProteômicaRESUMO
Although much has been discussed about the link between renewable energy, globalisation and carbon dioxide (CO2) emissions, yet the impact of total factor productivity (TFP) on CO2 emissions is less known in the existing literature. Therefore, the present study considers TFP as one of the determinants of CO2 as it is believed that technological enhancement plays an essential role in improving the environmental quality by raising efficiency in energy use and pollution treatment. In contrast, it may also have unfavourable impacts. In particular, this study analyses how TFP along with renewable energy and globalisation affect the aggregate and source of CO2 emissions (oil, coal and gas) in the case of top ten carbon emitters from the developing economies over the period 1980-2018. To achieve the above objective, we use the second-generation panel unit root, cointegration and causality tests. We also implement a cross-sectional autoregressive distributed lag model (CS-ARDL) to find the long-run and short-run coefficients. Findings from panel cointegration tests show that there exists a significant long-run relationship between renewable energy, non-renewable energy, globalisation, total factor productivity and CO2. Moreover, findings show that renewable energy consumption has a negative and significant impact on CO2 emissions while non-renewable energy consumption significantly increases the CO2 at aggregate and disaggregated levels. Further, our results confirm that TFP increases the CO2 emissions whereas globalisation decreases CO2. From the policy point of view, TFP growth needs to be accelerated to a higher level so that it enables low carbon growth. The slower TFP growth may enhance output which requires more energy and produces more emissions. Thus, there should be a promotion of emissions' reducing technology along with better TFP growth. Also, our findings recommend that CO2 in sample countries can be reduced through promoting low carbon technology, and globalisation.
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Dióxido de Carbono , Desenvolvimento Econômico , Dióxido de Carbono/análise , Carvão Mineral , Estudos Transversais , Energia RenovávelRESUMO
Although several studies explored the issue of CO2/Ecological footprint convergence across the countries, study on biomass material footprint (BMF) convergence is scant. This study bridges this research gap by examining the "BMF convergence hypothesis" across 172 countries for the period from 1990 to 2017. To attain our objective, we use the novel Phillips and Sul (J Appl Econom 24(7):1153-1185, 2007a; Econometrica 75:1771-1855, 2007b) approach. We find that there is no evidence of convergence, while 172 countries are taken together. This implies that all the countries together are having different transition paths. Thus, Phillips and Sul test implements the clustering algorithms to identify the club convergence. Our results show the existence of six different steady-state (or club convergence) equilibriums for BMF. Thus, our findings show that climate change policies are required to be designed as per the existing clubs of the sample countries.
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Mudança Climática , Organizações , BiomassaRESUMO
This paper aims at estimating the dynamic impact of renewable and non-renewable energy consumption, globalization, urbanization, and economic growth on the environmental quality. Unlike previous study, this study used multi-dimensional indicator of environmental quality that is ecological footprint. Given the importance of renewable energy, a sample of top renewable energy consuming countries has been selected for analysis spanning the period 1991-2016. The analysis is carried out in panel data framework that considers the issues of cross sectional dependence and heterogeneity. The results of cointegration test show the existence of long-run equilibrium relationship among the variables. The long-run elasticity of pooled mean group shows positive impact of economic growth and non-renewable energy consumption on ecological footprint while negative impact is observed in case of renewable energy consumption, globalization and urbanization. The sensitivity of long-run elasticity has been checked with the help of fully modified ordinary least square and dynamic ordinary least square. Based on empirical findings, some policy implication has also been provided.
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Dióxido de Carbono , Energia Renovável , Estudos Transversais , Desenvolvimento Econômico , InternacionalidadeRESUMO
Esophageal adenocarcinoma arises after a normal squamous mucosa undergoes metaplasia to the specialized columnar epithelium, which can then ultimately progress to dysplasia and subsequent malignancy. It typically presents at an advanced stage, and despite optimal management, the prognosis remains poor. Recently, the ToGA (Trastuzumab for Gastric Cancer) trial evaluated the role of trastuzumab (Herceptin®) in human epidermal growth factor receptor 2 (HER2) over-expressing gastric and gastroesophageal junction (GEJ) adenocarcinoma and showed improvement in overall survival when trastuzumab was added to the standard chemotherapy compared to standard chemotherapy without trastuzumab. However, data and experience are lacking in the literature regarding the use of trastuzumab outside of combination chemotherapy. The optimal length and safety of trastuzumab use as maintenance therapy in the long-term are also unclear in patients with gastric or GEJ adenocarcinomas after sustained remission. We report a case of metastatic GEJ adenocarcinoma, where the patient first showed an exceptional response to standard chemotherapy combined with trastuzumab and subsequently could sustain a long-lasting remission on maintenance therapy with trastuzumab alone. Trastuzumab was ultimately discontinued owing to the lack of clear knowledge regarding its length and safety of use as maintenance therapy in the long-term.
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This study aims to examine the convergence hypothesis of per capita carbon dioxide emission and its component such as coal, oil, and gas in the case of 53 countries covering the period of 1980 to 2016. In particular, we study whether countries are moving toward a common steady-state equilibrium condition in the per capita carbon emission or converging into different groups. To do so, this study used Phillips and Sul (Econometrica 75(6): 1771-1855, 2007, J Appl Econ 24(7): 1153-1185, 2009) technique. Our results show no evidence of convergence for full sample. However, our results support the evidence of two club convergence of total emission, emission from gas and petroleum consumption, while three clubs are noticed in case of per capita carbon dioxide emission from coal use. This invalidates the equality rule of participation of each country in climate change policy. Further, similar results emerge in case of total emission and petroleum where club 1 consists of mostly developed countries while club 2 has a large number of developing countries. Interestingly, we do not find any divergence behavior across all countries in the sample. We find that natural gas is the major component to drive the total carbon emission convergence in case of our sample countries.
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Dióxido de Carbono/análise , Mudança Climática , Carvão Mineral/análise , Países Desenvolvidos , Países em Desenvolvimento , Monitoramento Ambiental , Gás Natural/análise , Petróleo/análiseRESUMO
Starch-based films possess potential application in food packaging, due to their biodegradability, lower cost, stretchability and clarity. The aim of this work was to develop novel edible films from native, acetylated and hydroxypropylated pearl millet starches with improved flexibility, transparency and water barrier properties. Each film contained a fixed concentration of starch (3â¯g/100â¯g) and glycerol (30%, w/w based on starch weight). The effect of levels of acetylation (4% and 8%, w/w) and hydroxypropylation (10% and 30%, w/v) on the rheological, physical, thermal, mechanical and barrier properties of films was investigated. SEM results showed that modified starch films possessed smoother surface in comparison to native starch film (NF). Rheological evaluation depicted that filmogenic solution of 30% hydroxypropylated starch was more viscous than other solutions. Films containing 4% and 8% acetylated starches showed excellent moisture barrier property as depicted by their low water vapor permeability (WVP) and water solubility (WS). The extent of these improvements depended on the levels of acetylation. Elongation at break (%EAB) and transparency (%T) of 10% and 30% hydroxypropylated starch films were higher than NF and increased with increasing amount of propylene oxide. Glass transition temperature (Tg) was lowered by addition of modified starches in film formulation.
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Compostos de Epóxi/química , Embalagem de Alimentos , Pennisetum/química , Amido/química , Acetilação , Glicerol/química , Permeabilidade , Solubilidade , Vapor , Temperatura , Resistência à Tração , Água/químicaRESUMO
Acquired periodic alternating nystagmus (PAN) describes a horizontal jerk nystagmus that reverses its direction with a predictable cycle, and is thought to arise from lesions involving the brainstem and cerebellum. We report a 20-year-old patient with PAN who presented with an acute vertiginous episode and developed an involuntary head movement that initially masked the PAN. The involuntary head movements were abolished with a subtherapeutic dose of botulinum toxin to the neck muscles. We propose that the head movements initially developed as a compensatory movement to the nystagmus, to maintain visual fixation in the presence of the underlying nystagmus, and became an entrained involuntary behavior. This case highlights the importance of disambiguating psychogenic from organic pathology as this may have clinical therapeutic implications, in this case resolution of the most disabling symptom which was her head oscillations, leading to improved day-to-day function despite PAN.
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BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative condition caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Optimizing peripheral quantification of huntingtin throughout the course of HD is valuable not only to illuminate the natural history and pathogenesis of disease, but also to detect peripheral effects of drugs in clinical trial. RATIONALE: We previously demonstrated that mutant HTT (mHTT) was significantly elevated in purified HD patient leukocytes compared with controls and that these levels track disease progression. Our present study investigates whether the same result can be achieved with a simpler and more scalable collection technique that is more suitable for clinical trials. METHODS: We collected whole blood at 133 patient visits in two sample sets and generated peripheral blood mononuclear cells (PBMCs). Levels of mHTT, as well as N-, and C-terminal and mid-region huntingtin were measured in the PBMCs using ELISA-based Meso Scale Discovery (MSD) electrochemiluminescence immunoassay platforms, and we evaluated the relationship between different HTT species, disease stage, and brain atrophy on magnetic resonance imaging. CONCLUSIONS: The assays were sensitive and accurate. We confirm our previous findings that mHTT increases with advancing disease stage in patient PBMCs, this time using a simple collection protocol and scalable assay.
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Ensaio de Imunoadsorção Enzimática/métodos , Proteína Huntingtina/sangue , Doença de Huntington/sangue , Leucócitos/metabolismo , Encéfalo/diagnóstico por imagem , Estudos Transversais , Eletroquímica , Humanos , Proteína Huntingtina/genética , Doença de Huntington/diagnóstico por imagem , Luminescência , MutaçãoRESUMO
Huntington's disease (HD) is a monogenic neurodegenerative disorder with an underlying pathology involving the toxic effect of mutant huntingtin protein primarily in striatal and cortical neurons. Phosphodiesterase 10A (PDE10A) regulates intracellular signalling cascades, thus having a key role in promoting neuronal survival. Using positron emission tomography (PET) with [(11)C]IMA107, we investigated the in vivo extra-striatal expression of PDE10A in 12 early premanifest HD gene carriers. Image processing and kinetic modelling was performed using MIAKAT™. Parametric images of [(11)C]IMA107 non-displaceable binding potential (BPND) were generated from the dynamic [(11)C]IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding. We set a threshold criterion for meaningful quantification of [(11)C]IMA107 BPND at 0.30 in healthy control data; regions meeting this criterion were designated as regions of interest (ROIs). MRI-based volumetric analysis showed no atrophy in ROIs. We found significant differences in mean ROIs [(11)C]IMA107 BPND between HD gene carriers and healthy controls. HD gene carriers had significant loss of PDE10A within the insular cortex and occipital fusiform gyrus compared to healthy controls. Insula and occipital fusiform gyrus are important brain areas for the regulation of cognitive and limbic function that is impaired in HD. Our findings suggest that dysregulation of PDE10A-mediated intracellular signalling could be an early phenomenon in the course of HD with relevance also for extra-striatal brain areas.
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Encéfalo/metabolismo , Doença de Huntington/patologia , Diester Fosfórico Hidrolases/metabolismo , Adulto , Análise de Variância , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono/farmacocinética , Feminino , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Humanos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/genética , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Quinoxalinas/farmacocinéticaRESUMO
There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.
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Regulação Enzimológica da Expressão Gênica , Doença de Huntington/enzimologia , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Transdução de Sinais/fisiologia , Adolescente , Adulto , Mapeamento Encefálico , Feminino , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Proteínas do Tecido Nervoso/genética , Tomografia por Emissão de Pósitrons , Quinoxalinas/farmacocinética , Índice de Gravidade de Doença , Transdução de Sinais/genética , Sequências Repetidas Terminais/genética , Adulto JovemRESUMO
BACKGROUND: Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously. METHODS: We developed an ultrasensitive single-molecule counting (SMC) mHTT immunoassay that was used to quantify mHTT levels in CSF samples from individuals bearing the HD mutation and from control individuals in 2 independent cohorts. RESULTS: This SMC mHTT immunoassay demonstrated high specificity for mHTT, high sensitivity with a femtomolar detection threshold, and a broad dynamic range. Analysis of the CSF samples showed that mHTT was undetectable in CSF from all controls but quantifiable in nearly all mutation carriers. The mHTT concentration in CSF was approximately 3-fold higher in patients with manifest HD than in premanifest mutation carriers. Moreover, mHTT levels increased as the disease progressed and were associated with 5-year onset probability. The mHTT concentration independently predicted cognitive and motor dysfunction. Furthermore, the level of mHTT was associated with the concentrations of tau and neurofilament light chain in the CSF, suggesting a neuronal origin for the detected mHTT. CONCLUSIONS: We have demonstrated that mHTT can be quantified in CSF from HD patients using the described SMC mHTT immunoassay. Moreover, the level of mHTT detected is associated with proximity to disease onset and diminished cognitive and motor function. The ability to quantify CSF mHTT will facilitate the study of HD, and mHTT quantification could potentially serve as a biomarker for the development and testing of experimental mHTT-lowering therapies for HD. TRIAL REGISTRATION: Not applicable. FUNDING: CHDI Foundation Inc.; Medical Research Council (MRC) UK; National Institutes for Health Research (NIHR); Rosetrees Trust; Swedish Research Council; and Knut and Alice Wallenberg Foundation.
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Doença de Huntington/líquido cefalorraquidiano , Imunoensaio/métodos , Proteínas do Tecido Nervoso/líquido cefalorraquidiano , Adulto , Idade de Início , Idoso , Colúmbia Britânica , Estudos de Coortes , Progressão da Doença , Feminino , Triagem de Portadores Genéticos , Humanos , Proteína Huntingtina , Londres , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas Recombinantes de Fusão/metabolismo , Sensibilidade e Especificidade , Método Simples-Cego , Expansão das Repetições de Trinucleotídeos , Proteínas tau/líquido cefalorraquidianoRESUMO
OBJECTIVES: To evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on rapid efficacy readouts for disease-modifying trials. METHODS: 40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies. RESULTS: Longitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision. CONCLUSIONS: To exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months.
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Doença de Huntington/terapia , Projetos de Pesquisa , Adulto , Idoso , Estudos de Casos e Controles , Córtex Cerebral/patologia , Cognição , Progressão da Doença , Feminino , Humanos , Doença de Huntington/patologia , Doença de Huntington/psicologia , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
BACKGROUND: In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology and both the mutant gene and the protein are found in cells and tissues throughout the body. Despite the adipose tissue gene expression alterations described in HD mouse models, adipose tissue and its gene expression signature have not been previously explored in human HD. OBJECTIVE: We investigated gene expression signatures in subcutaneous adipose tissue obtained from control subjects, premanifest HD gene carriers and manifest HD subjects with the aim to identify gene expression changes and signalling pathway alterations in adipose tissue relevant to HD. METHODS: Gene expression was assessed using Affymetrix GeneChip® Human Gene 1.0 ST Array. Target genes were technically validated using real-time quantitative PCR and the expression signature was validated in an independent subject cohort. RESULTS: In subcutaneous adipose tissue, more than 500 genes were significantly different in premanifest HD subjects as compared to healthy controls. Pathway analysis suggests that the differentially expressed genes found here in HD adipose tissue are involved in fatty acid metabolism pathways, angiotensin signalling pathways and immune pathways. Transcription factor analysis highlights CREB1. Using RT-qPCR, we found that MAL2, AGTR2, COBL and the transcription factor CREB1 were significantly upregulated, with CREB1 and AGT also being significantly upregulated in a separate cohort. CONCLUSIONS: Distinct gene expression profiles can be seen in HD subcutaneous adipose tissue, with CREB1 highlighted as a key transcription factor.
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Tecido Adiposo Branco/metabolismo , Doença de Huntington/genética , Fatores de Transcrição/metabolismo , Adulto , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Humanos , Doença de Huntington/metabolismo , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , TranscriptomaRESUMO
AIMS: Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers. RESULTS: Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen. CONCLUSIONS: Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.
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Carbazóis/uso terapêutico , Doença de Huntington/tratamento farmacológico , Sirtuína 1/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Carbazóis/administração & dosagem , Carbazóis/efeitos adversos , Carbazóis/sangue , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Doença de Huntington/sangue , Doença de Huntington/psicologia , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Índice de Gravidade de Doença , Distribuição Tecidual , Resultado do Tratamento , Adulto JovemRESUMO
The cerebellum has received limited attention in Huntington's disease (HD), despite signs of possible cerebellar dysfunction, including motor incoordination and impaired gait, which are currently attributed to basal ganglia atrophy and disrupted fronto-striatal circuits. This study is the first to investigate a potential contribution of macro- and microstructural cerebellar damage to clinical manifestations of HD. T1- and diffusion-weighted 3T magnetic resonance imaging (MRI) scans were obtained from 12 controls and 22 early-stage HD participants. Manual delineation and voxel-based morphometry were used to assess between-group differences in cerebellar volume, and diffusion metrics were compared between groups within the cerebellar gray and white matter. Associations between these imaging measures and clinical scores were examined within the HD group. Reduced paravermal volume was detected in HD compared with controls using voxel-based morphometry (P < 0.05), but no significant volumetric differences were found using manual delineation. Diffusion abnormalities were detected in both cerebellar gray matter and white matter. Smaller cerebellar volumes, although not significantly reduced, were significantly associated with impaired gait and psychiatric morbidity and of borderline significance with pronate/supinate-hand task performance. Abnormal cerebellar diffusion was associated with increased total motor score, impaired saccade initiation, tandem walking, and timed finger tapping. In conclusion, atrophy of the paravermis, possibly encompassing the cerebellar nuclei, and microstructural abnormalities within the cerebellum may contribute to HD neuropathology. Aberrant cerebellar diffusion and reduced cerebellar volume together associate with impaired motor function and increased psychiatric symptoms in stage I HD, potentially implicating the cerebellum more centrally in HD presentation than previously recognized.