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1.
Nat Commun ; 12(1): 7102, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34876589

RESUMO

Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. However, its precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis reveals that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(αP), in line with the cryo-EM structures of the eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling analysis clarified that SFSV NSs expressed in cultured human cells attenuates the ISR triggered by thapsigargin, an endoplasmic reticulum stress inducer. Furthermore, SFSV NSs introduced in rat hippocampal neurons and human induced-pluripotent stem (iPS) cell-derived motor neurons exhibits neuroprotective effects against the ISR-inducing stress. Since ISR inhibition is beneficial in various neurological disease models, SFSV NSs may be a promising therapeutic ISR inhibitor.

2.
Sci Rep ; 11(1): 15954, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354190

RESUMO

The overall effect of lifestyle habits, such as alcohol consumption, on general health remains controversial and it is important to clarify how such habits affect aging-related health impairments. To discover novel impacts of lifestyle on general health, we employed a mathematical approach to perform a comprehensive, unbiased, cross-sectional analysis of data from 6036 subjects who participated in a Japanese health checkup. Notably, we found that moderate alcohol consumption was positively correlated with lung function, muscle mass, and strength. Health checkup data were collected periodically from the same subjects. These people were light to moderate drinkers who had high health awareness and were basically free of major underlying diseases. We next analyzed 5 years of data from 1765 of these subjects. We found that higher baseline alcohol consumption, as well as increased alcohol intake over 5 years attenuated time-related deterioration of forced vital capacity without affecting total lung volume. This effect was independent of smoking. Our study suggests a possible protective effect of moderate amounts of alcohol on lung function, due to increased muscle mass/strength and forced vital capacity.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Idoso , Envelhecimento , Estudos Transversais , Registros Eletrônicos de Saúde , Etanol/metabolismo , Etanol/farmacologia , Feminino , Saúde , Comportamentos Relacionados com a Saúde , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Substâncias Protetoras/metabolismo , Testes de Função Respiratória/métodos , Capacidade Vital/efeitos dos fármacos , Capacidade Vital/fisiologia
3.
JGH Open ; 5(8): 953-958, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34386605

RESUMO

Background and Aim: Preoperative histological evaluation of pancreatic neoplasms is important for guiding the resection strategy and preventing postoperative adverse events. However, conventional endoscopic methods have technical limitations that reduce the accuracy of the histopathological examination. Probe electrospray ionization mass spectrometry (PESI-MS) may be a useful technique for rapidly evaluating small specimens. Methods: This single-center prospective study included patients with pancreatic neoplasms between October 2018 and December 2019. Pancreatic ductal adenocarcinoma (PDAC) specimens were obtained via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and non-neoplastic tissue was obtained via surgery. Specimens were subjected to PESI-MS and the mass spectra were analyzed using partial least squares regression-discriminant analysis. Results: The study included 40 patients with 20 nonneoplastic specimens and 19 PDAC specimens (1 case of neuroendocrine carcinoma was omitted). All nonneoplastic specimens were sufficient for PESI-MS analysis, although only 7 of 19 PDAC specimens were sufficient for PESI-MS analysis because of poor sample quality or insufficient quantity (<1 mg). Among the 27 analyzed cases, the mass spectra clearly differentiated between the PDAC and nonneoplastic specimens. Conclusions: This study revealed that PESI-MS could differentiate between PDAC and nonneoplastic specimens, even in cases where EUS-FNA produced very small specimens.

4.
Clin Nutr ESPEN ; 42: 166-172, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33745573

RESUMO

BACKGROUND & AIMS: Osteosarcopenic obesity (OSO) encompassing obesity, sarcopenia and osteopenia, is due to redistribution or infiltration of fat into muscle and bone. This cross-sectional study evaluated the association between OSO and non-alcoholic fatty liver disease (NAFLD). METHODS: Obesity, sarcopenia and osteopenia was defined using the percentage of body fat mass, reduced muscle mass, and the percentage of young adult mean < 80%, measured by dual-energy x-ray absorptiometry, respectively. Non-obese and obese NAFLD was diagnosed by ultrasound and body mass index cut-off point (25 kg/m2). A total of 619 subjects ≥ 50 years who completed health checkups were divided into obesity group including OSO and sarcopenic obesity (SO) alone phenotype, and non-obesity group that did not belong to any phenotype, including standard (St). RESULTS: Overall osteopenia and OSO were detected in only 10% and 1% in males, compared with 45% and 9% in females, respectively. Multivariate analysis for females demonstrated a significant association of OSO with non-obese NAFLD (odds ratio = 3.737, 95% confidence interval = 1.365-10.233, P = 0.010), while the association between SO alone and non-obese NAFLD was equivocal. The OSO phenotype had a significantly higher proportion of slower walking speed and weaker grip strength, compared to the St phenotype. The proportion of OSO increased with age in contrast to constant prevalence of non-obese NAFLD. CONCLUSION: Non-obese NAFLD had a significant association with OSO in females, independent of plausible confounders. These results suggest that non-obese NAFLD might be an independent risk factor for OSO.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Sarcopenia , Absorciometria de Fóton , Estudos Transversais , Feminino , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Sarcopenia/epidemiologia
5.
Mol Cell ; 81(1): 88-103.e6, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33220178

RESUMO

The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(αP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR.


Assuntos
Acetamidas/química , Cicloexilaminas/química , Fator de Iniciação 2B em Eucariotos/química , Fator de Iniciação 2 em Eucariotos/química , Regulação Alostérica , Animais , Sítios de Ligação , Células CHO , Cricetulus , Microscopia Crioeletrônica , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fator de Iniciação 2B em Eucariotos/genética , Fator de Iniciação 2B em Eucariotos/metabolismo , Células HeLa , Humanos , Fosforilação
6.
Alcohol ; 89: 1-7, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32738385

RESUMO

BACKGROUND: Moderate alcohol consumption is believed to be associated with reduced mortality from cardiovascular disease (CVD) in the general population. This cross-sectional study aimed to comprehensively examine the association between alcohol consumption and subclinical cardiovascular damage or hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). METHODS: Subjects with NAFLD without a history of heart disease were extracted from 977 consecutive examinees who completed health checkups and optional cardiovascular examinations. Subclinical cardiovascular damage was assessed by coronary artery calcification (CAC), carotid artery ultrasound, and brachial-ankle pulse wave velocity (ba-PWV). CAC scores were classified into three grades (0, ≤100, and >100) by Agatston's method. Alcohol consumption was divided into three groups [Non-drinking (G0); Light (G1), 0.1-6.9 drinks/week; Moderate (G2), 7-20.9 drinks/week for men and 7-13.9 drinks/week for women]. Noninvasive markers (FIB-4, Fibrosis-4; NFS, NAFLD fibrosis score) were calculated for assessment of hepatic fibrosis and classified into low and intermediate-high grade. RESULTS: The overall mean age was 60.2 years and males were 200 (74.6%) among 268 subjects with NAFLD. Number (%) of G0, G1, and G2 were 102 (38.1%), 103 (38.4%), and 63 (23.5%). Binary logistic regression analysis showed no significant difference between G0 and G1, or G0 and G2 in any of the above subclinical cardiovascular damages (CAC score >0, or CAC score >100, carotid plaque +, intima-media thickness ≥1.1 mm, and ba-PWV >1400 cm/s). However, only G2 had a significant association with intermediate-high grade of FIB-4 or NFS [odds ratio (95% confidence intervals), p value: 1.871 (1.209-2.893), p = 0.005; 2.910 (1.715-4.939), p = 0.000], compared to G0. CONCLUSIONS: Non-heavy drinking might not reduce the risk of CVD in NAFLD subjects. On the contrary, even moderate drinking could promote hepatic fibrosis. Thus, NAFLD drinkers should not be recommended for even a moderate amount of alcohol.


Assuntos
Consumo de Bebidas Alcoólicas , Cirrose Hepática/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica , Consumo de Bebidas Alcoólicas/efeitos adversos , Índice Tornozelo-Braço , Espessura Intima-Media Carotídea , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Análise de Onda de Pulso , Fatores de Risco
7.
Clin Nutr ESPEN ; 38: 86-93, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32690183

RESUMO

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is significantly related to sarcopenia as well as obesity and its associated comorbidities. This cross-sectional study aims to examine the association between four body composition phenotypes (standard, obesity alone, sarcopenia alone, sarcopenic obesity) and non-obese NAFLD, or obese NAFLD. METHODS: Reduced muscle mass and high percentage of body fat mass was measured by dual-energy x-ray absorptiometry, and body composition phenotypes were determined, according to Asian criteria for sarcopenia. Based on body mass index (BMI) cut-off point (25 kg/m2) and hepatic steatosis on ultrasound, 748 subjects who underwent a health checkup were enrolled and divided into three groups: non-obese NAFLD, obese NAFLD, and no steatosis. RESULTS: Of 563 subjects (64.1 ± 13.0 years) without secondary causes for steatosis, the overall prevalence of non-obese NAFLD and obese NAFLD were 17% and 16%, respectively. The former prevalence remained relatively constant at around 20% from the 50s to 80's, while the proportion of sarcopenic obesity in all subjects increased gradually with age, reaching 18% in the 80's. Multivariate analysis demonstrated a significant association between sarcopenic obesity and non-obese NAFLD after adjusting for confounders (odds ratio = 2.367, 95% confidence interval = 1.317-4.254, P = 0.004). On the other hand, no significant association was found between obesity alone and obese NAFLD, when BMI and visceral adipose tissue were added as confounders, although 91% of obese NAFLD was included in obesity alone phenotype. CONCLUSION: Non-obese NAFLD had a significant association with sarcopenic obesity, independent of metabolic confounders. Early treatment intervention for non-obese NAFLD could suppress the deterioration of sarcopenic obesity because non-obese NAFLD might be a risk factor for sarcopenic obesity.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Sarcopenia , Índice de Massa Corporal , Estudos Transversais , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Sarcopenia/epidemiologia
8.
J Neurochem ; 154(1): 25-40, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31587290

RESUMO

Vanishing white matter disease (VWM) is an autosomal recessive neurological disorder caused by mutation(s) in any subunit of eukaryotic translation initiation factor 2B (eIF2B), an activator of translation initiation factor eIF2. VWM occurs with mutation of the genes encoding eIF2B subunits (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5). However, little is known regarding the underlying pathogenetic mechanisms or how to treat patients with VWM. Here we describe the identification and detailed analysis of a new spontaneous mutant mouse harboring a point mutation in the Eif2b5 gene (p.Ile98Met). Homozygous Eif2b5I98M mutant mice exhibited a small body, abnormal gait, male and female infertility, epileptic seizures, and a shortened lifespan. Biochemical analyses indicated that the mutant eIF2B protein with the Eif2b5I98M mutation decreased guanine nucleotide exchange activity on eIF2, and the level of the endoplasmic reticulum stress marker activating transcription factor 4 was elevated in the 1-month-old Eif2b5I98M brain. Histological analyses indicated up-regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5I98M forebrain and translocation of Bergmann glia in the Eif2b5I98M cerebellum, as well as increased mRNA expression of an endoplasmic reticulum stress marker, C/EBP homologous protein. Disruption of myelin and clustering of oligodendrocyte progenitor cells were also indicated in the white matter of the Eif2b5I98M spinal cord at 8 months old. Our data show that Eif2b5I98M mutants are a good model for understanding VWM pathogenesis and therapy development. Cover Image for this issue: doi: 10.1111/jnc.14751.


Assuntos
Modelos Animais de Doenças , Fator de Iniciação 2B em Eucariotos/genética , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Neuroglia/patologia , Animais , Encéfalo/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação Puntual
9.
J Eval Clin Pract ; 26(1): 256-261, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31012194

RESUMO

RATIONALE, AIMS, AND OBJECTIVES: The aim of this observational study is to identify factors by which some pancreatic cystic lesions (PCLs) were undetectable at transabdominal ultrasonography (TAUS), using magnetic resonance imaging (MRI) as reference standard. METHODS: The database for 781 consecutive subjects who underwent a health checkup including fat computed tomography and upper abdominal MRI as option was searched. The presence of fatty liver and fatty pancreas was diagnosed by TAUS, and atrophic pancreas was determined by reevaluating the image of the pancreas in the chest computed tomography for screening. Subjects with PCL detected and those undetected at TAUS were statistically compared in clinical characteristics. RESULTS: The prevalence of PCL detected at MRI was 17.8% in the general population. Multivariate logistic regression analysis showed that fatty liver, body mass index, and the size of PCL were significantly associated with the factors influencing the visualization of PCL at TAUS (odds ratio [OR]: 0.337, 95% confidence interval [CI]: 0.154-0.734, P = 0.006; OR: 0.852, 95% CI: 0.737-0.985, P = 0.030; OR:1.120, 95% CI: 1.045-1.200, P = .001). Thirty-six PCLs (64.3%) in a total of 56 PCLs were undermeasured by TAUS. Additionally, nine (56%) out of 16 PCLs (≥ 15 mm) were undermeasured by 5 mm or more by TAUS, although a significantly higher detection rate was observed for PCLs (≥ 15 mm) in comparison with that for PCLs (< 15 mm) (80% vs 33.6%, P = .000). CONCLUSIONS: It should be noted that coexisting fatty liver may lower the detection of PCL, and its size may be underestimated by TAUS.


Assuntos
Fígado Gorduroso , Cisto Pancreático , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/epidemiologia , Humanos , Imageamento por Ressonância Magnética , Pâncreas/diagnóstico por imagem , Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/epidemiologia , Ultrassonografia
10.
J Dig Dis ; 20(10): 557-562, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31322828

RESUMO

OBJECTIVE: To identify risk factors of imaging progression (increase in cyst size or main pancreatic duct size, or a new mural nodule) in low-risk branch duct intraductal papillary mucinous neoplasm (BD-IPMN), including obesity-related factors such as pancreatic fat content. METHODS: Our hospital databases were searched for patients who had completed health checkup, including upper abdominal magnetic resonance imaging (MRI) over 48 months (August 2012 to July 2016). Individuals with BD-IPMN without worrisome features and high-risk stigmata who underwent surveillance with at least one follow-up MRI, irrespective of the follow-up period, were included. Pancreatic computed tomography attenuation indexes were defined as the difference between the pancreas and spleen attenuation (P - S) and the pancreas to spleen attenuation ratio (P/S). RESULTS: Among 75 patients diagnosed as having low-risk BD-IPMN, during a median follow-up of 36 months, 11 (15%) had imaging progression in cyst size, including two with worrisome features. A multivariate logistic analysis showed that the initial cyst size and both indexes (P - S, or P/S) were significantly associated with imaging progression in IPMN, respectively (Model 1: odds ratio [OR] 1.188, 95% confidence interval [CI] 1.060-1.331, P = 0.003; OR 0.871, 95% CI 0.776-0.977, P = 0.019; Model 2: OR 1.186, 95% CI 1.064-1.322, P = 0.002; OR 0.002, 95% CI 0.000-0.970, P = 0.049). CONCLUSIONS: Pancreatic fat content and initial cyst size were significantly associated with imaging progression in low-risk BD-IPMN. Revisions of international consensus Fukuoka guidelines might be customized based on initial cyst size and pancreatic fat content.


Assuntos
Tecido Adiposo/patologia , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/patologia , Tecido Adiposo/diagnóstico por imagem , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Ductos Pancreáticos/diagnóstico por imagem , Ductos Pancreáticos/patologia , Neoplasias Intraductais Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Baço/diagnóstico por imagem , Baço/patologia , Tomografia Computadorizada por Raios X
11.
Science ; 364(6439): 495-499, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31048492

RESUMO

A core event in the integrated stress response, an adaptive pathway common to all eukaryotic cells in response to various stress stimuli, is the phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Normally, unphosphorylated eIF2 transfers the methionylated initiator tRNA to the ribosome in a guanosine 5'-triphosphate-dependent manner. By contrast, phosphorylated eIF2 inhibits its specific guanine nucleotide exchange factor, eIF2B. To elucidate how the eIF2 phosphorylation status regulates the eIF2B activity, we determined cryo-electron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. The unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active and -inactive modes, respectively. These structures explain how phosphorylated eIF2 dominantly inhibits the nucleotide exchange activity of eIF2B.


Assuntos
Fator de Iniciação 2B em Eucariotos/antagonistas & inibidores , Fator de Iniciação 2B em Eucariotos/química , Fator de Iniciação 2 em Eucariotos/química , Estresse Fisiológico , Motivos de Aminoácidos , Microscopia Crioeletrônica , Fator de Iniciação 2B em Eucariotos/metabolismo , Humanos , Fosforilação
12.
Pancreas ; 47(9): 1087-1092, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30028443

RESUMO

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are premalignant lesions of pancreatic ductal adenocarcinomas (PDACs). Fat accumulation in the pancreas is increasingly recognized as a cause of PDAC. We aimed to identify factors that are relevant between IPMN and metabolic-related factors, including pancreatic fat. METHODS: The database for 781 subjects who underwent a health checkup and upper abdominal magnetic resonance imaging was searched and computed tomography attenuation indexes (pancreatic and spleen attenuation, pancreas-to-spleen attenuation ratio) were decided by measuring the regions of interest in the pancreas and spleen on nonenhanced images, using Hounsfield units. Eighty-five subjects from each of the IPMN and noncyst groups were matched for age, sex, and glycemic status and statistically compared in clinical characteristics. RESULTS: There was no difference in metabolic-related factors except for apolipoprotein A1 and high-density lipoprotein cholesterol between the 2 groups in univariate analysis. Multivariate logistic regression analysis showed that both indexes were significantly associated with IPMN (odds ratio, 0.905 [95% confidence intervals, 0.851-0.963; P = 0.002]; odds ratio, 0.006 [95% confidence intervals, 0.000-0.152; P = 0.002]). CONCLUSIONS: Pancreatic fat content measured by computed tomography was significantly associated with IPMN. These results suggest that IPMN may develop secondary to pancreatic steatosis that could be an overlapping risk factor for PDAC and IPMN.


Assuntos
Adenocarcinoma Mucinoso/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Papilar/metabolismo , Gorduras/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/patologia , Carcinoma Papilar/diagnóstico por imagem , Carcinoma Papilar/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/metabolismo , Cisto Pancreático/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
13.
PLoS One ; 12(12): e0189817, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29267320

RESUMO

BACKGROUND: There have been many reports about a variety of factors associated with incomplete colonoscopy or difficult colonoscopy with long cecal intubation time (CIT). The aim of this retrospective study was to analyze the factors related to difficult colonoscopy under conscious sedation and demonstrate the clinical utility of a small-caliber scope as rescue by using the data from a large number of subjects who underwent health check-ups. METHODS: Consecutive 1036 cases over a 12-month period (April 2015 to March 2016) were enrolled and 619 subjects were divided into two groups: Easy colonoscopy (CS) Group (CIT ≤ 10 min); Difficult CS Group (CIT > 10 min or incomplete colonoscopy by a standard scope). The two groups were compared by subjects and colonoscopy characteristics with univariate analysis followed by multivariate logistic regression analysis. Reasons for incomplete colonoscopy were also assessed. RESULTS: Cecal intubation rate increased from 97.9% to 99.9% (1007/1008) by the rescue scope. Main reasons for incomplete colonoscopy were tortuosity in the left hemicolon (38%), redundancy in the right hemicolon (29%), pain (19%) and fixation (14%). Moreover, 95% (20/21) of rescue colonoscopies were completed without additional sedation. Higher BMI (21 kg/m2 ≤ BMI) and intermediate visceral adipose tissue (VAT) (75 cm2 ≤ VAT < 150 cm2) were significantly associated with easy CS (80.7% vs 19.3%, P = 0.004; 56.3% vs 43.7%, P = 0.001) by univariate analysis. Age, gender, and VAT, not BMI, were independently associated with difficult colonoscopy by multivariate analysis (OR (95% CI), P: 0.964 (0.942, 0.985), 0.001; 1.845 (1.101, 3.091), 0.020; 2.347 (1.395, 3.951), 0.001). Subgroup analysis by gender also showed VAT as the best predictor for both genders. CONCLUSION: Difficult colonoscopy was significantly associated with advancing age, female gender and, lower (< 75 cm2) or higher (150 cm2 ≤) VAT. These subjects may benefit from having complete and more comfortable colonoscopy examinations by using the small-caliber scope rather than the standard scope.


Assuntos
Colonoscopia/instrumentação , Gordura Intra-Abdominal , Adulto , Feminino , Humanos , Masculino
14.
Intern Med ; 56(11): 1287-1292, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28566588

RESUMO

Objective We investigated whether dual-time-point 18-Fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) could improve the positive predictive value for detecting advanced colorectal neoplasms (cancer, adenoma ≥10 mm or adenoma with high-grade dysplasia). Methods We retrospectively searched for consecutive patients with a known primary cancer, who had a colonic 18FDG uptake incidentally found by PET/CT, followed by colonoscopy between January 2013 and August 2014. The clinical characteristics including the maximum standardized uptake value (SUVmax) were compared between advanced colorectal neoplasms and non-advanced lesions. Results Forty-eight patients had 51 foci with an incidental focal colorectal uptake of 18FDG. Among these 51 foci, 28 foci were judged as being advanced neoplasms, whereas 23 foci identified as non-advanced lesions. Four cases were missed by PET/CT: two laterally spreading tumors (LSTs) with intramucosal cancer and two severe adenomas (<10 mm). The positive predictive value for the detection of advanced neoplasms was 55%. The per-spot performance of PET/CT showed that SUVmax was significantly higher in advanced neoplasms than in non-advanced lesions for the early-phase (10.1±4.9 vs. 6.5±3.2, p=0.029) and the delayed-phase (12.0±6.0 vs. 7.4±4.0, p=0.022). However, more importantly, there was a significant overlap of the SUVmax and no significant difference was found in the retention index (19.2±20.1 vs. 16.6±29.4, p=0.767). Conclusion Dual-time-point PET/CT was found to have limited impact for identifying advanced colorectal neoplasms in spite of its high sensitivity and it might therefore not be able to identify either LSTs or small advanced neoplasms.


Assuntos
Adenoma/diagnóstico , Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluordesoxiglucose F18/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/administração & dosagem , Estudos Retrospectivos
15.
Circ J ; 81(8): 1191-1197, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28420817

RESUMO

BACKGROUND: Cerebrovascular disease is a major cause of mortality and morbidity. Chronic kidney disease (CKD) is prevalent in stroke patients. This study evaluated the correlation between kidney dysfunction and asymptomatic findings on carotid ultrasonography (US) and brain magnetic resonance imaging (MRI) in a Japanese population with health checkups.Methods and Results:In total, 1,716 subjects aged 40-80 years, who received health checkups from January 1 to December 31, 2015, were included. Common carotid artery intima-media thickness (CCA-IMT) and carotid plaques by US, and the presence of old non-lacunar infarctions, lacunar infarctions, white matter lesions (WMLs), cerebral microbleeds (CMBs), and atrophy by brain MRI were evaluated. After adjusting for cardiovascular risk factors, multiple regression analyses revealed that an eGFR ranging from 15 to 44 mL/min/1.73 m2was independently associated with CCA plaques and hypoechoic or heterogeneous plaques. Proteinuria was associated with CCA or internal carotid artery plaques, the number of carotid plaques, and the presence of old non-lacunar infarctions and CMBs. CONCLUSIONS: Decreased eGFR and proteinuria were independent risk factors for asymptomatic abnormalities on carotid US and brain MRI, which are surrogate markers for cerebrovascular diseases. Evaluation of these abnormalities may be useful for prevention of symptomatic cerebrovascular events in CKD patients.


Assuntos
Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas , Espessura Intima-Media Carotídea , Nefropatias , Imageamento por Ressonância Magnética , Inquéritos e Questionários , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/epidemiologia , Feminino , Humanos , Nefropatias/diagnóstico por imagem , Nefropatias/epidemiologia , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade
16.
PLoS One ; 12(3): e0174155, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28328936

RESUMO

BACKGROUND: The guidelines for colonoscopy present withdrawal time (WT) and adenoma detection rate (ADR) as the quality indicator. The purpose of this retrospective study is to analyze the predicting factors with polyp detection rate (PDR) as a surrogate for ADR by using comprehensive health checkup data, and assess the correlation between PDR per each colonic segment and WT, and factors influencing WT. METHODS: One thousand and thirty six consecutive health checkup cases from April 2015 to March 2016 were enrolled in this study, and 880 subjects who undertook colonoscopy without polyp removal or biopsy were divided into the two groups (polyp not detected group vs polyp detected group). The two groups were compared by subjects and clinical characteristics with univariate analysis followed by multivariate analysis. Colonoscopies with longer WT (≥ 6 min) and those with shorter WT (< 6 min) were compared by PDR per each colonic segment, and also by subjects and clinical characteristics. RESULTS: A total of 1009 subjects included two incomplete colonoscopies (CIR, 99.9%) and overall PDR was 35.8%. A multiple logistic regression model demonstrated that age, gender, and WT were significantly related factors for polyp detection (odds ratio, 1.036; 1.771; 1.217). PDR showed a linear increase as WT increased from 3 min to 9 min (r = 0.989, p = 0.000) and PDR with long WT group was higher than that with short WT group per each colonic segment, significantly in transverse (2.3 times, p = 0.004) and sigmoid colon (2.1 times, p = 0.001). Not only bowel preparation quality but also insertion difficulty evaluated by endoscopist were significant factors relating with WT (odds ratio, 3.811; 1.679). CONCLUSION: This study suggests that endoscopists should be recommended to take more time up to 9 min of WT to observe transverse and sigmoid colon, especially when they feel no difficulty during scope insertion.


Assuntos
Colo Sigmoide/patologia , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Adenoma/patologia , Colonoscopia/métodos , Feminino , Humanos , Modelos Logísticos , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos
17.
Brain Nerve ; 69(1): 45-50, 2017 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-28126977

RESUMO

CACH/VWM (childhood ataxia with central nervous system hypomyelination/vanishing white matter) disease is caused by mutations in the genes encoding the subunits of eukaryotic initiation factor 2B (eIF2B), but its etiology is poorly understood. Here, we attempt to provide an explanation for the pathogenic mechanism of this disease, based on the crystal structure of eIF2B.


Assuntos
Fator de Iniciação 2B em Eucariotos/química , Leucoencefalopatias , Substância Branca/química , Fator de Iniciação 2B em Eucariotos/genética , Fator de Iniciação 2B em Eucariotos/metabolismo , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Modelos Moleculares , Mutação , Estrutura Quaternária de Proteína
18.
FEBS J ; 284(6): 868-874, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27627185

RESUMO

Eukaryotic translation initiation factor 2B (eIF2B), a heterodecameric complex of two sets of the α, ß, γ, δ, and ε subunits, is the guanine nucleotide exchange factor (GEF) specific for eIF2, a heterotrimeric G protein consisting of the α, ß, and γ subunits. The eIF2 protein binds GTP on the γ subunits and delivers an initiator methionyl-tRNA (Met-tRNAiMet ) to the ribosome. The GEF activity of eIF2B is inhibited by stress-induced phosphorylation of Ser51 in the α subunit of eIF2, which leads to lower amounts of active eIF2 and a limited quantity of Met-tRNAiMet for the ribosome, resulting in global repression of translation. However, the structural mechanism of the GEF activity inhibition remained enigmatic, and therefore the three-dimensional structure of the entire eIF2B molecule had been awaited. Recently, we determined the crystal structure of Schizosaccharomyces pombe eIF2B. In this Structural Snapshot, we present the structural features of eIF2B and the mechanism underlying the GEF activity inhibition by the phosphorylation of eIF2α, elucidated from structure-based in vitro analyses.


Assuntos
Fator de Iniciação 2B em Eucariotos/química , Fator de Iniciação 2 em Eucariotos/química , Conformação Proteica , Relação Estrutura-Atividade , Sítios de Ligação , Cristalografia por Raios X , Fator de Iniciação 2 em Eucariotos/metabolismo , Fator de Iniciação 2B em Eucariotos/metabolismo , Fatores de Troca do Nucleotídeo Guanina/química , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fosforilação , Ligação Proteica , Aminoacil-RNA de Transferência/química , Aminoacil-RNA de Transferência/genética , Ribossomos/química , Ribossomos/genética , Schizosaccharomyces/química , Schizosaccharomyces/genética
20.
Dig Endosc ; 28(6): 657-64, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27176122

RESUMO

BACKGROUND AND AIM: No randomized controlled studies comparing propofol versus no sedation have been reported. Comparative data demonstrating the efficacy and safety of propofol sedation by anesthesiologists (ANES), and gastroenterologist-led teams (GLT) using computer-assisted personalized sedation (CAPS), during routine gastrointestinal (GI) endoscopy in Japan do not exist. We aimed to demonstrate the safety and efficacy of propofol sedation versus no sedation (PLCB) when propofol is given by ANES or GLT, during routine GI endoscopy. METHODS: Two hundred and seventy two American Society of Anesthesiologists (ASA) class I or II adults were prospectively enrolled in this multicenter study and randomized into three groups (PLCB, ANES, GLT). Ability to maintain moderate sedation, defined as MOAA/S scores of 2-4 for ≥50% of all MOAA/S measurements from scope-in to scope-out, was the primary endpoint. Secondary endpoints included patient (PSSI) and clinician (CSSI) satisfaction. RESULTS: Proportion of subjects maintained in moderate sedation by ANES (88.1%) and GLT (94.5%) was significantly higher than PLCB (21.6%; P < 0.001); there was no difference between the ANES and GLT groups (P = 0.116). Mean PSSI scores for subjects sedated by ANES (81.2 ± 12.5) and GLT (80.8 ± 14.1) were significantly higher than PLCB (65.3 ± 19.7; P < 0.001) and mean CSSI scores were also significantly higher in both active treatment groups (75.5 ± 10.2, 77.9 ± 10.3) than PLCB (60.8 ± 18.6; P < 0.001). CONCLUSION: Moderate sedation can be achieved and maintained with propofol, improving both patient and physician satisfaction, when propofol is given by an anesthesiologist or a gastroenterologist-led team using CAPS.


Assuntos
Anestesiologistas , Endoscopia Gastrointestinal , Gastroenterologistas , Hipnóticos e Sedativos/uso terapêutico , Propofol/uso terapêutico , Adulto , Sedação Consciente , Feminino , Humanos , Japão , Masculino , Estudos Prospectivos
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