Recently, nanocarriers that transport bioactive substances to a target site in the body have attracted considerable attention and undergone rapid progression in terms of the state of the art. ...However, few nanocarriers can enter the brain via a systemic route through the blood-brain barrier (BBB) to efficiently reach neurons. Here we prepare a self-assembled supramolecular nanocarrier with a surface featuring properly configured glucose. The BBB crossing and brain accumulation of this nanocarrier are boosted by the rapid glycaemic increase after fasting and by the putative phenomenon of the highly expressed glucose transporter-1 (GLUT1) in brain capillary endothelial cells migrating from the luminal to the abluminal plasma membrane. The precisely controlled glucose density on the surface of the nanocarrier enables the regulation of its distribution within the brain, and thus is successfully optimized to increase the number of nanocarriers accumulating in neurons.There are only a few examples of nanocarriers that can transport bioactive substances across the blood-brain barrier. Here the authors show that by rapid glycaemic increase the accumulation of a glucosylated nanocarrier in the brain can be controlled.
Background and purpose
Idiopathic normal pressure hydrocephalus (iNPH) is a clinical entity without established pathological hallmarks. Previous autopsy studies reported that patients with an ...antemortem diagnosis of iNPH had a different postmortem diagnosis, commonly progressive supranuclear palsy (PSP). Disproportionately enlarged subarachnoid space hydrocephalus (DESH) has been reported as a characteristic feature of iNPH on magnetic resonance imaging (MRI). In addition, periventricular white matter hyperintensities (PVHs) are noted in most patients with iNPH; these PVHs are supposed to reflect transependymal movement of ventricular cerebrospinal fluid. It is hypothesized that PSP develops more iNPH‐like MRI features than other neurodegenerative disorders.
Methods
Thirty‐eight patients with a clinical diagnosis of PSP, 42 with Parkinson’s disease (PD) without dementia, 30 with PD with dementia (PDD) and 29 with Alzheimer’s disease (AD) were enrolled. The DESH score and PVH grade were measured using the conventional MRI sequence and were compared amongst the patient groups.
Results
Disproportionately enlarged subarachnoid space hydrocephalus score was significantly higher in patients with PSP than PD without dementia, and there was a trend that the DESH score was higher in patients with PSP than PDD or Alzheimer’s disease. PVH grade was significantly larger in patients with PSP than PD without dementia. In the components of the DESH score, callosal angle was significantly smaller in patients with PSP than in PD without dementia or PDD.
Conclusions
This study demonstrated that some PSP patients develop iNPH‐like MRI features, suggesting the presence of iNPH‐like features in the clinical spectrum of PSP. A clinical phenotype of PSP with hydrocephalus is proposed, which should be further investigated in future studies.
Activating mutation of KRAS and BRAF are focused on as potential prognostic and predictive biomarkers in patients with colorectal cancer (CRC) treated with anti-EGFR therapies. This study ...investigated the clinicopathological features and prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC patients.
Patients with advanced and recurrent CRC treated with systemic chemotherapy (n=229) were analysed for KRAS/BRAF genotypes by cycleave PCR. Prognostic factors associated with survival were identified by univariate and multivariate analyses using the Cox proportional hazards model.
KRAS and BRAF mutations were present in 34.5% and 6.5% of patients, respectively. BRAF mutated tumours were more likely to develop on the right of the colon, and to be of the poorly differentiated adenocarcinoma or mucinous carcinoma, and peritoneal metastasis. The median overall survival (OS) for BRAF mutation-positive and KRAS 13 mutation-positive patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for patients with wild-type (wt) KRAS and BRAF (40.6 months) (BRAF; HR=4.25, P<0.001, KRAS13; HR=2.03, P=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor OS (HR=4.23, P=0.019).
Presence of mutated BRAF is one of the most powerful prognostic factors for advanced and recurrent CRC. The KRAS13 mutation showed a trend towards poor OS in patients with advanced and recurrent CRC.
GALI or Global Activity Limitation Indicator is a global survey instrument measuring participation restriction. GALI is the measure underlying the European indicator Healthy Life Years (HLY). Gali ...has a substantial policy use within the EU and its Member States. The objective of current paper is to bring together what is known from published manuscripts on the validity and the reliability of GALI.
Following the PRISMA guidelines, two search strategies (PUBMED, Google Scholar) were combined to identify manuscripts published in English with publication date 2000 or beyond. Articles were classified as reliability studies, concurrent or predictive validity studies, in national or international populations.
Four cross-sectional studies (of which 2 international) studied how GALI relates to other health measures (concurrent validity). A dose-response effect by GALI severity level on the association with the other health status measures was observed in the national studies. The 2 international studies (SHARE, EHIS) concluded that the odds of reporting participation restriction was higher in subjects with self-reported or observed functional limitations. In SHARE, the size of the Odds Ratio's (ORs) in the different countries was homogeneous, while in EHIS the size of the ORs varied more strongly. For the predictive validity, subjects were followed over time (4 studies of which one international). GALI proved, both in national and international data, to be a consistent predictor of future health outcomes both in terms of mortality and health care expenditure. As predictors of mortality, the two distinct health concepts, self-rated health and GALI, acted independently and complementary of each other. The one reliability study identified reported a sufficient reliability of GALI.
GALI as inclusive one question instrument fits all conceptual characteristics specified for a global measure on participation restriction. In none of the studies, included in the review, there was evidence of a failing validity. The review shows that GALI has a good and sufficient concurrent and predictive validity, and reliability.
The Greenhouse gases Observing SATellite (GOSAT) was launched on 23 January 2009 to monitor the global distributions of carbon dioxide and methane from space. It has operated continuously since then. ...Here, we describe a retrieval algorithm for column abundances of these gases from the short-wavelength infrared spectra obtained by the Thermal And Near infrared Sensor for carbon Observation-Fourier Transform Spectrometer (TANSO-FTS). The algorithm consists of three steps. First, cloud-free observational scenes are selected by several cloud-detection methods. Then, column abundances of carbon dioxide and methane are retrieved based on the optimal estimation method. Finally, the retrieval quality is examined to exclude low-quality and/or aerosol-contaminated results. Most of the retrieval random errors come from instrumental noise. The interferences due to auxiliary parameters retrieved simultaneously with gas abundances are small. The evaluated precisions of the retrieved column abundances for single observations are less than 1% in most cases. The interhemispherical differences and temporal variation patterns of the retrieved column abundances show features similar to those of an atmospheric transport model.
Purpose
Health-related quality of life outcomes are increasingly used to monitor population health and health inequalities and to assess the (cost-) effectiveness of health interventions. The ...EQ-5D-5L has been included in the Belgian Health Interview Survey, providing a new source of population-based self-perceived health status information. This study aims to estimate Belgian population norms for the EQ-5D-5L by sex, age, and region and to analyze its association with educational attainment.
Methods
The BHIS 2018 provided EQ-5D-5L data for a nationally representative sample of the Belgian population. The dimension scores and index values were analyzed using logistic and linear regressions, respectively, accounting for the survey design.
Results
More than half of respondents reported problems of pain/discomfort, while over a quarter reported problems of anxiety/depression. The average index value was 0.84. Women reported more problems on all dimensions, but particularly on anxiety/depression and pain/discomfort, resulting in significantly lower index values. Problems with mobility, self-care, and usual activities showed a sharp increase after the age of 80 years. Consequently, index values decreased significantly by age. Lower education was associated with a higher prevalence of problems for all dimensions except anxiety/depression and with a significantly lower index value.
Conclusion
This paper presents the first nationally representative Belgian population norms using the EQ-5D-5L. Inclusion of the EQ-5D in future surveys will allow monitoring over time of self-reported health, disease burden, and health inequalities.
SUMMARY
We have developed a new method for introducing the effects of pore water distribution into the interpretation of P-wave velocity (VP) dispersion in a partially saturated rock. Pore water in ...an unsaturated rock is distributed as patches, and mesoscopic-scale wave-induced fluid flow (WIFF) from saturated patches to empty patches is known as a key mechanism for interpreting P-wave dispersion. Mesoscopic WIFF depends on permeability and the scale of the saturated patch, thus evaluating their influences is important for estimating the relationship between water saturation (${S_{\rm{w}}}$) and VP. The simplest and conventional law for simulating the ${S_{\rm{w}}} - {V_{{P}}}$ relation considering the mesoscopic WIFF is White's model, which describes the patch size changes proportional to the saturation. However, White's model assumes homogeneity in the size and distribution of pores, and does not consider the effects of pore water distribution in a partially saturated rock. In the rock, pore water is distributed heterogeneously according to the pore radius, causing non-linear changes in the permeability and size of the saturated patches against the water saturation. In this study, we modified White's model by introducing relative permeability and a new coefficient describing the nonlinear change of the patch size into the conventional version, and applied the modified model to better interpret our experimental ${S_{\rm{w}}} - {V_{{P}}}$ relations, which were measured by an ultrasonic technique at 200 and 500 kHz for two types of Berea sandstone samples with different permeabilities as their water saturation was decreased by evaporative drying. The relative permeabilities were determined by applying the Mualem–van Genuchten model into the capillary pressure curves from mercury intrusion porosimetry. Furthermore, we proposed a calculation method for the new coefficient using tortuosity, which corresponds to the pore water connection. The modified White's model could reproduce the experimental ${S_{\rm{w}}} - {V_{{P}}}$ relations better than other conventional models. Consequently, our modification, considering the effect of pore water distribution, would be useful for more quantitative interpretation of P-wave velocity and attenuation under coexisting multifluid conditions.
The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). ...However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN.
Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3weeks for up to 6 cycles; and cetuximab at an initial dose of 400mg/m2, followed by 250mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients.
Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7months and progression-free survival was 5.2months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia.
The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population.
UMIN000010507.
We present the application of a global carbon cycle modeling system to the estimation of monthly regional CO2 fluxes from the column-averaged mole fractions of CO2 (XCO2 ) retrieved from spectral ...observations made by the Greenhouse gases Observing SATellite (GOSAT). The regional flux estimates are to be publicly disseminated as the GOSAT Level 4 data product. The forward modeling components of the system include an atmospheric tracer transport model, an anthropogenic emissions inventory, a terrestrial biosphere exchange model, and an oceanic flux model. The atmospheric tracer transport was simulated using isentropic coordinates in the stratosphere and was tuned to reproduce the age of air. We used a fossil fuel emission inventory based on large point source data and observations of nighttime lights. The terrestrial biospheric model was optimized by fitting model parameters to observed atmospheric CO2 seasonal cycle, net primary production data, and a biomass distribution map. The oceanic surface pCO2 distribution was estimated with a 4-D variational data assimilation system based on reanalyzed ocean currents. Monthly CO2 fluxes of 64 sub-continental regions, between June 2009 and May 2010, were estimated from GOSAT FTS SWIR Level 2 XCO2 retrievals (ver. 02.00) gridded to 5° × 5° cells and averaged on a monthly basis and monthly-mean GLOBALVIEW-CO2 data. Our result indicated that adding the GOSAT XCO2 retrievals to the GLOBALVIEW data in the flux estimation brings changes to fluxes of tropics and other remote regions where the surface-based data are sparse. The uncertainties of these remote fluxes were reduced by as much as 60% through such addition. Optimized fluxes estimated for many of these regions, were brought closer to the prior fluxes by the addition of the GOSAT retrievals. In most of the regions and seasons considered here, the estimated fluxes fell within the range of natural flux variabilities estimated with the component models.
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