One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) ...receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In recent years, social differences in overweight and obesity (OWOB) have become more pronounced. Health impact assessments provide population-level scenario evaluations of changes in disease ...prevalence and risk factors. The objective of this study was to simulate the health effects of reducing the prevalence of overweight and obesity in populations with short and medium education.
The DYNAMO-HIA tool was used to conduct a health inequality impact assessment of the future reduced disease prevalence (ischemic heart disease (IHD), diabetes, stroke, and multi-morbidity) and changes in life expectancy for the 2040-population of Copenhagen, Denmark (n = 742,130). We simulated an equalized weight scenario where the prevalence of OWOB in the population with short and medium education was reduced to the levels of the population with long education.
A higher proportion of the population with short and medium education were OWOB relative to the population with long education. They also had a higher prevalence of cardiometabolic diseases. In the equalized weight scenario, the prevalence of diabetes in the population with short education was reduced by 8-10% for men and 12-13% for women. Life expectancy increased by one year among women with short education. Only small changes in prevalence and life expectancy related to stroke and IHD were observed.
Reducing the prevalence of OWOB in populations with short and medium education will reduce the future prevalence of cardiometabolic diseases, increase life expectancy, and reduce the social inequality in health. These simulations serve as reference points for public health debates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple steatosis (NAFL), over nonalcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis with ...end-stage disease. The hepatic molecular events underlying the development of NAFLD and transition to NASH are poorly understood. The present study aimed to determine hepatic transcriptome dynamics in patients with NAFL or NASH compared with healthy normal-weight and obese individuals. RNA sequencing and quantitative histomorphometry of liver fat, inflammation and fibrosis were performed on liver biopsies obtained from healthy normal-weight ( n = 14) and obese ( n = 12) individuals, NAFL ( n = 15) and NASH ( n = 16) patients. Normal-weight and obese subjects showed normal liver histology and comparable gene expression profiles. Liver transcriptome signatures were largely overlapping in NAFL and NASH patients, however, clearly separated from healthy normal-weight and obese controls. Most marked pathway perturbations identified in both NAFL and NASH were associated with markers of lipid metabolism, immunomodulation, extracellular matrix remodeling, and cell cycle control. Interestingly, NASH patients with positive Sonic hedgehog hepatocyte staining showed distinct transcriptome and histomorphometric changes compared with NAFL. In conclusion, application of immunohistochemical markers of hepatocyte injury may serve as a more objective tool for distinguishing NASH from NAFL, facilitating improved resolution of hepatic molecular changes associated with progression of NAFLD. NEW & NOTEWORTHY Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. NAFLD is associated with the metabolic syndrome and can progress to the more serious form, nonalcoholic steatohepatitis (NASH), and ultimately lead to irreversible liver damage. Using gold standard molecular and histological techniques, this study demonstrates that the currently used diagnostic tools are problematic for differentiating mild NAFLD from NASH and emphasizes the marked need for developing improved histological markers of NAFLD progression.
OBJECTIVES
Video-assisted thoracoscopic anatomical resections are increasingly used in Europe to manage primary lung cancer. The purpose of this study was to compare the outcome following ...thoracoscopic versus open lobectomy in case-matched groups of patients from the European Society of Thoracic Surgeon (ESTS) database.
METHODS
All patients having lobectomy as the primary procedure via thoracoscopy video-assisted thoracoscopic surgery (VATS)-L) or thoracotomy (TH-L) were identified in the ESTS database (January 2007 to December 2013). A propensity score was constructed using several patients' baseline characteristics. The matching using the propensity score was responsible for the minimization of selection bias. A propensity score-matched analysis was performed to compare the incidence of postoperative major complications (according to the ESTS database definitions) and mortality at hospital discharge between the matched groups. After exclusions, 28 771 patients were identified: 26 050 having thoracotomy and 2721 having thoracoscopy. Propensity score yielded two well-matched groups of 2721 patients. Numeric variables were compared by Student's t-tests and categorical variables were compared by McNemar's tests.
RESULTS
Compared with TH-L, VATS-L was associated with a lower incidence of total complications n = 792 (29.1%) vs 863 (31.7%), P = 0.0357, major cardiopulmonary complications n = 316 (15.9%) vs 435 (19.6%), P = 0.0094, atelectasis requiring bronchoscopy n = 65 (2.4%) vs 150 (5.5%), P < 0.0001, initial ventilation >48 h n = 18 (0.7%) vs 38 (1.4%), P = 0.0075 and wound infection n = 6 (0.2%) vs 17 (0.6%), P = 0.0218. There was no difference in the incidence of postoperative atrial fibrillation between the two groups (P = 0.14). Postoperative hospital stay was 2 days shorter in the VATS-L patients (mean: 7.8 vs 9.8 days; P = 0.0003). In terms of outcome at hospital discharge, there were 27 deaths in the VATS-L group (1%) versus 50 in the TH-L group (1.9%, P = 0.0201).
CONCLUSIONS
Data from the ESTS database confirmed that lobectomy performed through VATS is associated with a lower incidence of complications compared with thoracotomy.
The high organic matter content in agricultural soils tends to complex and retain contaminants such as heavy metals. Electrokinetic remediation was tested in an agricultural soil contaminated with Co
...+2
, Zn
+2
, Cd
+2
, Cu
+2
, Cr(VI), Pb
+2
and Hg
+2
. The unenhanced electrokinetic treatment was not able to remove heavy metals from the soil due to the formation of precipitates in the alkaline environment in the soil section close to the cathode. Moreover, the interaction between metals and organic matter probably limited metal transportation under the effect of the electric field. Citric acid and ethylenediaminetetraacetic acid (EDTA) were used in the catholyte as complexing agents in order to enhance the extractability and removal of heavy metals from soil. These complexing agents formed negatively charged complexes that migrated towards the anode. The acid front electrogenerated at the anode favored the dissolution of heavy metals that were transported towards the cathode. The combined effect of the soil pH and the complexing agents resulted in the accumulation of heavy metals in the center of the soil specimen.
Maintaining nanoparticle properties when scaling up a chemical synthesis is challenging due to the complex interplay between reducing agents and precursors. A sonochemical synthesis route does not ...require the addition of reducing agents as they are instead being continuously generated in-situ by ultrasonic cavitation throughout the reactor volume. To optimize the sonochemical synthesis of nanoparticles, understanding the role of radical scavengers is paramount. In this work we demonstrate that optimum scavenger concentrations exist at which the rate of Ag-nanoparticle formation is maximized. Titanyl dosimetry experiments were used in conjunction with Ag-nanoparticle formation rates to determine these optimum scavenger concentrations. It was found that more hydrophobic scavengers require lower optimum concentrations with 1-butanol < 2-propanol < ethanol < methanol < ethylene glycol. However, the optimum concentration is shifted by an order of magnitude towards higher concentrations when pyrolytic decomposition products contribute to the reduction. The reduction rate is also enhanced considerably.
Aims/hypothesis
High prevalence of coexisting morbidity in people with type 2 diabetes highlights the need to include interactions with education and comorbidity in the assessments of societal ...consequences of type 2 diabetes. The purpose of this study was to estimate the joint effects of education, type 2 diabetes and six frequent comorbidities.
Methods
Nationwide administrative register data on type 2 diabetes diagnosis, hospital admissions, education and disability pension were grouped at the individual level by means of a unique personal identification number. Included were all people (
N
= 2,281,599) in the age span of 40–59 years living in Denmark in the period 2005 to 2017, covering a total of 17,754,788 person-years. We used both Cox proportional hazards and Aalen additive hazards models to estimate relative and absolute joint effects of type 2 diabetes, educational attainment and six common comorbidities (CVD, cancer and cerebrovascular, respiratory, musculoskeletal and psychiatric diseases). We decomposed the joint effects of educational level, type 2 diabetes and comorbidities into main effects and the interaction effect, measured as extra cases of disability pension.
Results
Lower level of educational attainment, type 2 diabetes and comorbidities independently contributed to additional granted disability pensions. The joint number of cases of disability pension exceeded the sum of the three exposures, which is explained by a synergistic effect of lower educational level, type 2 diabetes and comorbidity.
Conclusions/interpretation
In this population study, the joint effects of type 2 diabetes, lower education and comorbidity were associated with larger than additive rates of disability pension. An integrated approach that takes into account socioeconomic barriers to type 2 diabetes rehabilitation may slow down disease progression and increase the working ability of socially disadvantaged people.
Graphical abstract
Fibroblast growth factor 21 (FGF21) plays a key role in hepatic lipid metabolism and long-acting FGF21 analogs have emerged as promising drug candidates for the treatment of nonalcoholic ...steatohepatitis (NASH). It remains to characterize this drug class in translational animal models that recapitulate the etiology and hallmarks of human disease. To this end, we evaluated the long-acting FGF21 analog PF-05231023 in the GAN (Gubra Amylin NASH) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. Male C57BL/6J mice were fed the GAN diet high in fat, fructose, and cholesterol for 34 wk before the start of the study. GAN DIO-NASH mice with biopsy-confirmed NAFLD Activity Score (NAS ≥5) and fibrosis (stage ≥F1) were biweekly administered with PF-05231023 (10 mg/kg sc) or vehicle (sc) for 12 wk. Vehicle-dosed chow-fed C57BL/6J mice served as healthy controls. Pre-to-post liver biopsy histopathological scoring was performed for within-subject evaluation of NAFLD Activity Score (NAS) and fibrosis stage. Terminal endpoints included quantitative liver histology and transcriptome signatures as well as blood and liver biochemistry. PF-05231023 significantly reduced body weight, hepatomegaly, plasma transaminases, and plasma/liver lipids in GAN DIO-NASH mice. Notably, PF-05231023 reduced both NAS (≥2-point improvement) and fibrosis stage (1-point improvement). Improvements in NASH and fibrosis severity were supported by reduced quantitative histological markers of steatosis, inflammation, and fibrogenesis as well as improvements in disease-associated liver transcriptome signatures. In conclusion, PF-05231023 reduces NASH and fibrosis severity in a translational biopsy-confirmed mouse model of NASH, supporting development of FGF21 analogs for the treatment of NASH.
It is unclear if long-acting FGF21 analogs have antifibrotic efficacy in NASH. We therefore profiled the clinically relevant FGF21 analog PF-05231023 in a translational diet-induced obese and biopsy-confirmed mouse model of NASH. We found PF-05231023 to exert hepatoprotective effects as indicated by notable improvements in plasma markers and histological hallmarks of NASH, including improved fibrosis stage. Collectively, the present study supports the continued exploration of long-acting FGF21 analogs for the treatment of NASH and other fibrotic diseases.
BackgroundWe compared mortality inequalities by occupational class in Japan and South Korea with those in European countries, in order to determine whether patterns are similar.MethodsNational ...register-based data from Japan, South Korea and eight European countries (Finland, Denmark, England/Wales, France, Switzerland, Italy (Turin), Estonia, Lithuania) covering the period between 1990 and 2015 were collected and harmonised. We calculated age-standardised all-cause and cause-specific mortality among men aged 35–64 by occupational class and measured the magnitude of inequality with rate differences, rate ratios and the average inter-group difference.ResultsClear gradients in mortality were found in all European countries throughout the study period: manual workers had 1.6–2.5 times higher mortality than upper non-manual workers. However, in the most recent time-period, upper non-manual workers had higher mortality than manual workers in Japan and South Korea. This pattern emerged as a result of a rise in mortality among the upper non-manual group in Japan during the late 1990s, and in South Korea during the late 2000s, due to rising mortality from cancer and external causes (including suicide), in addition to strong mortality declines among lower non-manual and manual workers.ConclusionPatterns of mortality by occupational class are remarkably different between European countries and Japan and South Korea. The recently observed patterns in the latter two countries may be related to a larger impact on the higher occupational classes of the economic crisis of the late 1990s and the late 2000s, respectively, and show that a high socioeconomic position does not guarantee better health.
The organic matter content of marine sediments is often used to infer past changes in ocean conditions. However, the organic carbon pool preserved in coastal sediments is a complex mixture derived ...from different sources and may not reflect
in situ
processes. In this study, we combine taxonomic identification of reworked palynomorphs with pyrolysis organic geochemistry and reflected‐light organic petrographic microscopy to investigate the provenance, composition and preservation of organic matter in a marine sediment core retrieved from the NE Greenland shelf. Our study reveals continuous yet variable input of land‐derived organic carbon to the marine environment throughout the late Younger Dryas–Holocene, with the highest input of inert carbon in the late Younger Dryas. Although the sediments contain some recent marine palynomorphs, there is no other evidence of fresh marine organic carbon. In contrast, our results indicate that these shelf sediments represent a significant sink of recycled organic carbon. The results of pyrolysis geochemistry revealed that ~90% of the total organic carbon in the sediments is inert. The organic petrography analyses revealed that >70–84% of the organic carbon in the sediment core is terrigenous. Reworked dinoflagellate cysts showed a continuous provenance of Cretaceous land‐derived material, most likely from the nearby Clavering Island. Our study points to the importance of constraining the organic matter origin, composition and preservation in marine sediments to achieve more accurate palaeoenvironmental reconstructions based on organic proxies.
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