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The severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-κB-mediated sepsis. However, its role in sterile inflammation is unknown. We hypothesised that Stat2 determines the severity of non-infective inflammation in the pancreas. Wild type (WT) and Stat2-/- mice were injected i.p. with caerulein or l-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1 and 24 h after the final dose of caerulein and up to 96 h post l-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2-/- bone marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells. Stat2-/- mice were protected from caerulein- and l-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2-/- mice had lower cytokine levels, including TNF-α and IL-10, and reduced NF-κB nuclear localisation in pancreatic tissue compared with WT. Inhibition of TNF-α improved (inhibition of IL-10 worsened) caerulein-induced pancreatitis in WT but not Stat2-/- mice. Phosphoproteomics showed downregulation of MAPK mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre ) reduced pancreatic TNF-α expression, but not histological injury or serum amylase. WT/Stat2-/- bone marrow chimera mice were protected from pancreatitis irrespective of host or recipient genotype. Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF-κB in non-acinar and/or bone marrow-derived cells. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Inflamación/genética , Páncreas/metabolismo , Pancreatitis/genética , Factor de Transcripción STAT2/genética , Enfermedad Aguda , Animales , Arginina , Ceruletida , Citocinas/sangre , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Ratones , Ratones Noqueados , Páncreas/patología , Pancreatitis/inducido químicamente , Pancreatitis/metabolismo , Pancreatitis/patología , Fosforilación , Factor de Transcripción STAT2/metabolismo , Transducción de Señal/fisiología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Survival from ovarian cancer (OC) is improved with surgery, but surgery can be complex and tumour identification, especially for borderline ovarian tumours (BOT), is challenging. The Rapid Evaporative Ionisation Mass Spectrometric (REIMS) technique reports tissue histology in real-time by analysing aerosolised tissue during electrosurgical dissection. METHODS: Aerosol produced during diathermy of tissues was sampled with the REIMS interface. Histological diagnosis and mass spectra featuring complex lipid species populated a reference database on which principal component, linear discriminant and leave-one-patient-out cross-validation analyses were performed. RESULTS: A total of 198 patients provided 335 tissue samples, yielding 3384 spectra. Cross-validated OC classification vs separate normal tissues was high (97·4% sensitivity, 100% specificity). BOT were readily distinguishable from OC (sensitivity 90.5%, specificity 89.7%). Validation with fresh tissue lead to excellent OC detection (100% accuracy). Histological agreement between iKnife and histopathologist was very good (kappa 0.84, P < 0.001, z = 3.3). Five predominantly phosphatidic acid (PA(36:2)) and phosphatidyl-ethanolamine (PE(34:2)) lipid species were identified as being significantly more abundant in OC compared to normal tissue or BOT (P < 0.001, q < 0.001). CONCLUSIONS: The REIMS iKnife distinguishes gynaecological tissues by analysing mass-spectrometry-derived lipidomes from tissue diathermy aerosols. Rapid intra-operative gynaecological tissue diagnosis may improve surgical care when histology is unknown, leading to personalised operations tailored to the individual.
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Electrocirugia/métodos , Metabolismo de los Lípidos/genética , Lípidos/aislamiento & purificación , Neoplasias Ováricas/cirugía , Femenino , Humanos , Lípidos/genética , Márgenes de Escisión , Metabolómica , Monitoreo Intraoperatorio/métodos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/fisiopatología , Análisis de Componente Principal , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
The endosymbiotic theory states that plastids are derived from a single cyanobacterial ancestor that possessed a cell wall. Peptidoglycan (PG), the main component of the bacteria cell wall, gradually degraded during plastid evolution. PG-synthesizing Mur genes have been found to be retained in the genomes of basal streptophyte plants, although many of them have been lost from the genomes of angiosperms. The enzyme encoded by bacterial MurE genes catalyzes the formation of the UDP-N-acetylmuramic acid (UDP-MurNAc) tripeptide in bacterial PG biosynthesis. Knockout of the MurE gene in the moss Physcomitrella patens resulted in defects of chloroplast division, whereas T-DNA-tagged mutants of Arabidopsis thaliana for MurE revealed inhibition of chloroplast development but not of plastid division, suggesting that AtMurE is functionally divergent from the bacterial and moss MurE proteins. Here, we could identify 10 homologs of bacterial Mur genes, including MurE, in the recently sequenced genomes of Picea abies and Pinus taeda, suggesting the retention of the plastid PG system in gymnosperms. To investigate the function of gymnosperm MurE, we isolated an ortholog of MurE from the larch, Larix gmelinii (LgMurE) and confirmed its presence as a single copy per genome, as well as its abundant expression in the leaves of larch seedlings. Analysis with a fusion protein combining green fluorescent protein and LgMurE suggested that it localizes in chloroplasts. Cross-species complementation assay with MurE mutants of A. thaliana and P. patens showed that the expression of LgMurE cDNA completely rescued the albefaction defects in A. thaliana but did not rescue the macrochloroplast phenotype in P. patens. The evolution of plastid PG and the mechanism behind the functional divergence of MurE genes are discussed in the context of information about plant genomes at different evolutionary stages.
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Arabidopsis/genética , Cycadopsida/genética , Larix/genética , Proteínas de Unión a las Penicilinas/genética , Peptidoglicano/genética , Fenotipo , Proteínas de Plantas/genética , Arabidopsis/enzimología , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas Bacterianas/genética , Bryopsida/genética , Bryopsida/metabolismo , Pared Celular/genética , Pared Celular/metabolismo , Cloroplastos/genética , Cloroplastos/metabolismo , Cianobacterias/genética , Cianobacterias/metabolismo , Cycadopsida/metabolismo , ADN Bacteriano , Regulación de la Expresión Génica de las Plantas , Técnicas de Inactivación de Genes , Genes Bacterianos , Genes de Plantas , Genoma de Planta , Proteínas Fluorescentes Verdes , Larix/metabolismo , Magnoliopsida/genética , Mutación , Proteínas de Unión a las Penicilinas/metabolismo , Peptidoglicano/metabolismo , Picea/genética , Pinus taeda/genética , Hojas de la Planta/genética , Proteínas de Plantas/metabolismo , Plastidios/genética , Plastidios/metabolismo , Semillas/genética , Semillas/metabolismoRESUMEN
In order to evaluate internal exposure to radon and thoron, concentrations for radon, thoron, and thoron progeny were measured for 259 dwellings located in high background radiation areas (HBRAs, outdoor external dose: 3-5 mGy y-1) and low background radiation areas (control areas, outdoor external dose: 1 mGy y-1) in Karunagappally Taluk, Kerala, India. The measurements were conducted using passive-type radon-thoron detectors and thoron progeny detectors over two six-month measurement periods from June 2010 to June 2011. The results showed no major differences in radon and thoron progeny concentrations between the HBRAs and the control areas. The geometric mean of the annual effective dose due to radon and thoron was calculated as 0.10 and 0.44 mSv, respectively. The doses were small, but not negligible compared with the external dose in the two areas.
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Contaminantes Radiactivos del Aire/análisis , Contaminación del Aire Interior/análisis , Carcinógenos Ambientales/análisis , Exposición a Riesgos Ambientales/análisis , Vivienda , Monitoreo de Radiación/métodos , Hijas del Radón/análisis , Radón/análisis , Radiación de Fondo , Humanos , IndiaRESUMEN
BACKGROUND & AIMS: Hirmi Valley liver disease was first reported in 2001 in Tigray, Ethiopia. 591 cases, including 228 deaths, were reported up to December 2009. The pyrrolizidine alkaloid acetyllycopsamine was detected in stored grain and residents reported adding the pesticide DDT (dichlorodiphenyldichloroethylene) directly to their food stores. We aimed to characterise the clinical features of the disease, and explore the role of these chemicals in its aetiology. METHODS: 32 cases were examined and full clinical histories taken. Nine cases underwent liver biopsy in hospitals. Serum and urine samples were collected from cases and controls. Urine was analysed for acetyllycopsamine by UPLC-MS. Total DDT in serum was measured by ELISA. Hepatotoxicity of DDT and acetyllycopsamine alone or in combination was explored in C57BL/6J mice. RESULTS: Clinical presentation included epigastric pain, abdominal swelling, bloody diarrhoea, hepatomegaly, splenomegaly, and ascites. Histology revealed acute injury characterised by centrilobular necrosis or chronic injury with bile ductular reaction, cytomegaly and fibrosis but no hepatic vein occlusion. Acetyllycopsamine was detected in urine samples taken in the affected area with significantly greater concentrations in 45 cases than in 43 controls (p=0.02). High levels of DDT (>125 ppb) were detected in 78% of serum samples. In mice, DDT (3 × 75 mg/kg) significantly increased the hepatotoxicity (plasma ALT, p=0.0065) of acetyllycopsamine (750 mg/kg), and in combination induced liver pathology similar to Hirmi Valley liver disease including centrilobular necrosis and cytomegaly. CONCLUSIONS: This novel form of disease appears to be caused by co-exposure to acetyllycopsamine and DDT.
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Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , DDT/toxicidad , Alcaloides de Pirrolicidina/toxicidad , Adolescente , Adulto , Fosfatasa Alcalina/análisis , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Niño , Preescolar , DDT/sangre , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana EdadRESUMEN
Cellular senescence is a stress response with broad pathophysiological implications. Senotherapies can induce senescence to treat cancer or eliminate senescent cells to ameliorate ageing and age-related pathologies. However, the success of senotherapies is limited by the lack of reliable ways to identify senescence. Here, we use nuclear morphology features of senescent cells to devise machine-learning classifiers that accurately predict senescence induced by diverse stressors in different cell types and tissues. As a proof-of-principle, we use these senescence classifiers to characterise senolytics and to screen for drugs that selectively induce senescence in cancer cells but not normal cells. Moreover, a tissue senescence score served to assess the efficacy of senolytic drugs and identified senescence in mouse models of liver cancer initiation, ageing, and fibrosis, and in patients with fatty liver disease. Thus, senescence classifiers can help to detect pathophysiological senescence and to discover and validate potential senotherapies.
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Envejecimiento , Senescencia Celular , Animales , Ratones , Humanos , Envejecimiento/fisiología , Senescencia Celular/fisiología , FibrosisRESUMEN
BACKGROUND: Bipolar radiofrequency (RF) induced tissue fusion is believed to have the potential to seal and anastomose intestinal tissue thereby providing an alternative to current techniques which are associated with technical and functional complications. This study examines the mechanical and cellular effects of RF energy and varying compressive pressures when applied to create ex vivo intestinal seals. METHODS: A total of 299 mucosa-to-mucosa fusions were formed on ex vivo porcine small bowel segments using a prototype bipolar RF device powered by a closed-loop, feedback-controlled RF generator. Compressive pressures were increased at 0.05 MPa intervals from 0.00 to 0.49 MPa and RF energy was applied for a set time period to achieve bowel tissue fusion. Seal strength was subsequently assessed using burst pressure and tensile strength testing, whilst morphological changes were determined through light microscopy. To further identify the subcellular tissue changes that occur as a result of RF energy application, the collagen matrix in the fused area of a single bowel segment sealed at an optimal pressure was examined using transmission electron microscopy (TEM). RESULTS: An optimal applied compressive pressure range was observed between 0.10 and 0.25 MPa. Light microscopy demonstrated a step change between fused and unfused tissues but was ineffective in distinguishing between pressure levels once tissues were sealed. Non uniform collagen damage was observed in the sealed tissue area using TEM, with some areas showing complete collagen denaturation and others showing none, despite the seal being complete. This finding has not been described previously in RF-fused tissue and may have implications for in vivo healing. CONCLUSIONS: This study shows that both bipolar RF energy and optimal compressive pressures are needed to create strong intestinal seals. This finding suggests that RF fusion technology can be effectively applied for bowel sealing and may lead to the development of novel anastomosis tools.
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Ablación por Catéter/métodos , Intestino Delgado/cirugía , Ondas de Radio , Anastomosis Quirúrgica , Animales , Ablación por Catéter/instrumentación , Diseño de Equipo , Técnicas In Vitro , Microscopía Electrónica , Presión , Porcinos , Resistencia a la TracciónRESUMEN
Portable-type electrostatic-collection radon monitors (RAD7) are often used for in-situ measurements of radon in water. In this study, we evaluated the calibration factors and their uncertainties for two RAD7 monitors based on comparative measurements with the liquid scintillation counting method. In the first experiment, we found that both RAD7 monitors had relatively large uncertainties due to leakage of radon gas that bubbled from the gaps between the lids of the desiccant container and the glass vial. Therefore, for the second experiment, these gaps were closed as much as possible using parafilm and clay, respectively. As a result, the relative uncertainties for both RAD7 monitors were significantly decreased. Furthermore, we collected spring water samples to confirm the reliability of radon concentrations. After closing the leakage point, the uncertainty of radon concentrations in spring water we measured using the typical protocol of the RAD7 were significantly lower, which improves the measurement.
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Agua Potable , Monitoreo de Radiación , Radón , Radón/análisis , Calibración , Electricidad Estática , Reproducibilidad de los Resultados , Monitoreo de Radiación/métodosRESUMEN
OBJECTIVE: The study clarified differences in understanding and satisfaction between face-to-face and online training on radiation emergency medical preparedness (REMP) training. METHODS: The training was held at Hirosaki University between 2018 and 2022, with 46 face-to-face participants and 25 online participants. RESULTS: Face-to-face training was significantly more understandable than online for the use of the Geiger counter (P < 0.05), but the educational effect of virtual reality (VR) was not significantly different from the actual practice. For the team exercise of taking care of the victims, online resulted in a significantly higher understanding (P < 0.05). CONCLUSIONS: Interactive exercises can be done online with equipment sent to learners, and VR is also as effective. The use of videos was more effective for first-timers to learn the practical process from a bird's-eye view, especially for team-based medical procedures.
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Aprendizaje , Realidad Virtual , HumanosRESUMEN
Immune checkpoint inhibitors (CPIs) are a relatively newly licenced cancer treatment, which make a once previously untreatable disease now amenable to a potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe the impact of immune checkpoints on intestinal homoeostasis, mice are challenged with anti-CTLA4 and anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. The immune profile of the colon of these mice with CPI-colitis is analysed using bulk RNA sequencing, single-cell RNA sequencing and flow cytometry. CPI-colitis in mice is dependent on the composition of the intestinal microbiota and by the induction of lymphocytes expressing interferon-γ (IFNγ), cytotoxicity molecules and other pro-inflammatory cytokines/chemokines. This pre-clinical model of CPI-colitis could be attenuated following blockade of the IL23/IFNγ axis. Therapeutic targeting of IFNγ-producing lymphocytes or regulatory networks, may hold the key to reversing CPI-colitis.
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Colitis , Interferón gamma , Animales , Ratones , Colitis/inducido químicamente , Citocinas , Inhibidores de Puntos de Control Inmunológico , Interferón gamma/genética , LinfocitosRESUMEN
AIMS: The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) is the histological tool used to assess disease severity based on steatosis, inflammation and hepatocyte ballooning. As steatosis contributes up to three of a potential eight points to NAS, it is important to quantify steatosis accurately. We sought to determine the optimum histological technique for identifying fat in tissue. METHODS AND RESULTS: Using tissue from a mouse model of NAFLD, with validation in human liver biopsies, the percentage steatosis and fat droplet size were assessed in haematoxylin and eosin (H&E)- and Oil Red-O (ORO)-stained sections by light microscopy and digital image analysis (DIA). Results were compared to biochemical tissue triglyceride content and MRI assessment of hepatic lipid content. H&E steatosis assessment correlated poorly with tissue triglyceride concentration. However, ORO DIA exhibited much higher sensitivity and specificity for steatosis and correlated very well with triglyceride concentration in mouse and human liver (R = 0.706, P = 0.001 and R = 0.894, P =0.041, respectively). MRI-based assessment of steatosis was inaccurate. CONCLUSIONS: ORO DIA is the most accurate method for detecting and quantifying steatosis. Although H&E-based NAS remains clinically valid in both clinical research and experimental situations, ORO DIA is a more robust technique to assess liver steatosis accurately for NAS scoring.
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Tejido Adiposo/patología , Hígado Graso/patología , Hígado/patología , Tejido Adiposo/química , Tejido Adiposo/metabolismo , Animales , Compuestos Azo/química , Peso Corporal/fisiología , Colorantes/química , Modelos Animales de Enfermedad , Hígado Graso/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Hígado/química , Hígado/metabolismo , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Triglicéridos/análisisRESUMEN
It has been demonstrated that the exaggeration of male sexual ornaments and the intensity of female mate preferences of a wild guppy population change over a period of several months. However, the factors that determine the short-term changes in male ornaments and female preferences remained unclear. In this study, we examined the effect of season on these short-term changes by measuring these traits in the same seasons of different years for a wild guppy population in Okinawa, Japan. We also compared the characteristics of the offspring in each collection term, as female guppies are known to have the ability to control offspring characteristics, such as brood size and sex ratios, depending on their mates' attractiveness. Results showed that the total lengths of the males changed seasonally; males in the summer were larger than those in the spring. In contrast, the size of orange spots in males and the intensity of female mating preferences differed in the same seasons of different years. Brood size and offspring body size in each term showed seasonal changes. However, offspring sex ratios exhibited different patterns in the same seasons of different years. Females produced female-biased broods when attractive males with large orange spots were rare. These results suggest that short-term changes in some traits of adult male and female guppies as well as offspring sex ratios may be not determined by seasonal factors, and that these traits may be interrelated.
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Poecilia/fisiología , Razón de Masculinidad , Conducta Sexual Animal/fisiología , Animales , Femenino , Masculino , Reproducción/fisiología , Estaciones del AñoRESUMEN
Wnt signaling through beta-catenin and TCF maintains preadipocytes in an un-differentiated proliferative state; however, the molecular pathway has not been completely defined. By integrating gene expression microarray, chromatin immunoprecipitation-chip, and cell-based experimental approaches, we show that Wnt/beta-catenin signaling activates the expression of COUP-TFII which recruits the SMRT corepressor complex to the first introns located downstream from the first exons of both PPARgamma1 and gamma2 mRNAs. This maintains the local chromatin in a hypoacetylated state and represses PPARgamma gene expression to inhibit adipogenesis. Our experiments define the COUP-TFII/SMRT complex as a previously unappreciated component of the linear pathway that directly links Wnt/beta-catenin signaling to repression of PPARgamma gene expression and the inhibition of adipogenesis.
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Adipogénesis/genética , Factor de Transcripción COUP I/fisiología , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/fisiología , PPAR gamma/genética , Proteínas Represoras/metabolismo , Transducción de Señal/fisiología , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Acetilación , Animales , Factor de Transcripción COUP I/genética , Cromatina , Ratones , Co-Represor 2 de Receptor Nuclear , ARN Mensajero/genética , RatasRESUMEN
Fixation of samples is broadly used prior to the histological evaluation of tissue samples. Though recent reports demonstrated the ability to use fixed tissues for mass spectrometry imaging (MSI) based proteomics, glycomics and tumor classification studies, to date comprehensive evaluation of fixation-related effects for spatially resolved metabolomics and drug disposition studies is still missing. In this study we used matrix assisted laser desorption/ionization (MALDI) and desorption electrospray ionization (DESI) MSI to investigate the effect of formalin-fixation and formalin-fixation combined with paraffin embedding on the detectable metabolome including xenobiotics. Formalin fixation was found to cause significant washout of polar molecular species, including inorganic salts, amino acids, organic acids and carnitine species, oxidation of endogenous lipids and formation of reaction products between lipids and fixative ingredients. The slow fixation kinetics under ambient conditions resulted in increased lipid hydrolysis in the tissue core, correlating with the time-dependent progression of the fixation. Paraffin embedding resulted in subsequent partial removal of structural lipids resulting in the distortion of the elucidated biodistributions.
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Introduction: Delays in the diagnosis and treatment of endometrial cancer negatively impact patient survival. The aim of this study was to establish whether rapid evaporative ionisation mass spectrometry using the iKnife can accurately distinguish between normal and malignant endometrial biopsy tissue samples in real time, enabling point-of-care (POC) diagnoses. Methods: Pipelle biopsy samples were obtained from consecutive women needing biopsies for clinical reasons. A Waters G2-XS Xevo Q-Tof mass spectrometer was used in conjunction with a modified handheld diathermy (collectively called the 'iKnife'). Each tissue sample was processed with diathermy, and the resultant surgical aerosol containing ionic lipid species was then analysed, producing spectra. Principal component analyses and linear discriminant analyses were performed to determine variance in spectral signatures. Leave-one-patient-out cross-validation was used to test the diagnostic accuracy. Results: One hundred and fifty patients provided Pipelle biopsy samples (85 normal, 59 malignant, 4 hyperplasia and 2 insufficient), yielding 453 spectra. The iKnife differentiated between normal and malignant endometrial tissues on the basis of differential phospholipid spectra. Cross-validation revealed a diagnostic accuracy of 89% with sensitivity, specificity, positive predictive value and negative predictive value of 85%, 93%, 94% and 85%, respectively. Conclusions: This study is the first to use the iKnife to identify cancer in endometrial Pipelle biopsy samples. These results are highly encouraging and suggest that the iKnife could be used in the clinic to provide a POC diagnosis.
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OBJECTIVE: The spread of COVID-19 has made it difficult to provide training in medical treatment in a radiation disaster. In this study, we will examine the effects and challenges of using a hybrid approach that combines online and face-to-face components. METHODS: A total of 5 face-to face and 25 online medical staff participated in the training program. This program was conducted by using multiple cameras for live coverage, while protective clothing and decontamination kits had been sent in advance to the participants so that they could experience face-to-face and online learning at the same time. RESULTS: Participants reported a high level of satisfaction and achievement with the style of delivery. They also experienced problems such as fatigue due to long hours, and dissatisfaction with the debriefing. CONCLUSIONS: In designing new online training, it is necessary to consider the quantity and content of the program, and to take participant fatigue into consideration.
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COVID-19 , Desastres , Educación a Distancia , Humanos , COVID-19/epidemiología , Pandemias/prevención & controlRESUMEN
High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.
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Resistencia a la Insulina , Receptor IGF Tipo 1 , Tejido Adiposo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Anticuerpos Monoclonales Humanizados , Dieta Alta en Grasa/efectos adversos , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lípidos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/metabolismo , Receptor IGF Tipo 1/antagonistas & inhibidoresRESUMEN
BACKGROUND AND OBJECTIVES: The increasing incidence of non-alcoholic fatty liver diseases (NAFLD) and the consequent progression to cirrhosis is expected to become a major cause of liver transplantation. This will exacerbate the organ donor shortage and mean that 'marginal' fatty liver grafts are more frequently used. Autofluorescence spectroscopy is a fast, objective, and non-destructive method to detect change in the endogenous fluorophores distribution and could prove to be a valuable tool for NAFLD diagnosis and transplant graft assessment. MATERIALS AND METHODS: A system was constructed consisting of a fibre probe with two laser diodes that provided excitation light at 375 and 405 nm, and an imaging spectrograph system. This was used to distinguish fluorescence spectra acquired from the harvested livers from mice with NAFLD of differing severity (healthy, mild steatotic and steatohepatitic). The fluorescence data were entered into a sparse multiclass probabilistic algorithm for disease classification. Histopathology, thiobarbituric acid reactive substances (TBARS) and alanine transaminase (ALT) assays were conducted in addition to the fluorescence measurements RESULTS: TBARS and ALT assays enabled differentiation of the steatohepatitic group from the mild steatosis and control groups (P ≤ 0.028) but failed to separate the mild steatotic group from the control group. The three groups were all clearly differentiated from each other using fluorescence spectroscopy, and classification accuracy was found to be 95%. CONCLUSION: Fluorescence spectroscopy appears to be a promising approach for the analysis of diseased liver tissue.
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Hígado Graso/diagnóstico , Láseres de Semiconductores , Espectrometría de Fluorescencia/métodos , Alanina Transaminasa/sangre , Animales , Hígado Graso/patología , Hígado/patología , Modelos Logísticos , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico , Espectrometría de Fluorescencia/instrumentación , Sustancias Reactivas al Ácido Tiobarbitúrico/análisisRESUMEN
Although the epidemiological studies provide evidence for an increased risk of lung cancer risk associated with residential radon, an issue of radon-thoron discrimination remains to be solved. In this study, an updated evaluation of lung cancer risk among the residents in Gansu, China was performed where one of the major epidemiological studies on indoor radon demonstrated an increased risk of lung cancer. We analyzed data from a hospital-based case-control study that included 30 lung cancer cases and 39 controls with special attention to internal exposure assessment based on the discriminative measurement technique of radon isotopes. Results from the analyses showed non-significant increased lung cancer risks; odds ratios (ORs) adjusted for age, smoking, and total income were 0.35 (95% CI: 0.07-1.74) and 0.27 (95% CI: 0.04-1.74) for groups living in residences with indoor radon concentrations of 50-100 Bq m-3 and over 100 Bq m-3, respectively, compared with those with < 50 Bq m-3 indoor radon concentrations. Although the small sample size hampers the usefulness of present analyses, our study suggests that reevaluation of lung cancer risk associated with residential radon in the epidemiological studies will be required on the basis of precise exposure assessment.
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Contaminantes Radiactivos del Aire , Contaminación del Aire Interior , Neoplasias Pulmonares , Monitoreo de Radiación , Radón , Contaminantes Radiactivos del Aire/análisis , Contaminación del Aire Interior/análisis , Estudios de Casos y Controles , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/etiología , Radón/análisisRESUMEN
This paper does not necessarily reflect the views of the International Commission on Radiological Protection.Several radiation monitoring research projects are underway on dose assessment, biological analysis, and risk communication under an agreement with Namie Town. Indoor radon and thoron progeny concentrations have been measured using passive-type monitors to estimate internal doses due to inhalation. In addition, airborne radiocaesium concentrations at five points in Namie Town have been analysed using a high-purity germanium detector to estimate internal doses for comparison with radon. External radiation doses from natural and artificial radionuclides have also been estimated using an in-situ gamma-ray spectrometer. Other support activities are mentioned briefly in this article.