The adequate formulation of topical vehicles to treat skin diseases is particularly complex. A desirable formulation should enhance the accumulation of the active drugs in the target tissue (the ...skin), while avoiding the penetration enhancement to be so large that the drugs reach the systemic circulation in toxic amounts. We have evaluated the transcutaneous penetration of three drugs chosen for their widely variable physicochemical properties: Amphotericin B, Imiquimod and Indole. We incorporated the drugs in fluid or ultra-flexible liposomes. Ultra-flexible liposomes produced enhancement of drug penetration into/through human skin in all cases in comparison with fluid liposomes without detergent, regardless of drug molecular weight. At the same time, our results indicate that liposomes can impede the transcutaneous penetration of molecules, in particular small ones.
MicroRNA and Metastasis Ma, L
Advances in cancer research,
2016, Volume:
132
Journal Article
Peer reviewed
Noncoding RNAs are important regulatory molecules of cellular processes. MicroRNAs (miRNAs) are small noncoding RNAs that bind to complementary sequences in the 3' untranslated region of target ...mRNAs, leading to degradation of the target mRNAs and/or inhibition of their translation. Some miRNAs are essential for normal animal development; however, many other miRNAs are dispensable for development but play a critical role in pathological conditions, including tumorigenesis and metastasis. miRNA genes often reside at fragile chromosome sites and are deregulated in cancer. Some miRNAs function as oncogenes or tumor suppressors, collectively termed "oncomirs." Specific metastasis-regulating miRNAs, collectively termed "metastamirs," govern molecular processes and pathways in malignant progression in either a tumor cell-autonomous or a cell-nonautonomous manner. Recently, exosome-transferred miRNAs have emerged as mediators of the tumor-stroma cross talk. In this chapter, we focus on the functions, mechanisms of action, and therapeutic potential of miRNAs, particularly oncomirs and metastamirs.
Atmospheric carbonaceous aerosols play an important role in the climate system by influencing the Earth's radiation budgets and modifying the cloud properties. Despite the importance, their ...representations in large-scale atmospheric models are still crude, which can influence model simulated burden, lifetime, physical, chemical and optical properties, and the climate forcing of carbonaceous aerosols. In this study, we improve the current three-mode version of the Modal Aerosol Module (MAM3) in the Community Atmosphere Model version 5 (CAM5) by introducing an additional primary carbon mode to explicitly account for the microphysical ageing of primary carbonaceous aerosols in the atmosphere. Compared to MAM3, the four-mode version of MAM (MAM4) significantly increases the column burdens of primary particulate organic matter (POM) and black carbon (BC) by up to 40 % in many remote regions, where in-cloud scavenging plays an important role in determining the aerosol concentrations. Differences in the column burdens for other types of aerosol (e.g., sulfate, secondary organic aerosols, mineral dust, sea salt) are less than 1 %. Evaluating the MAM4 simulation against in situ surface and aircraft observations, we find that MAM4 significantly improves the simulation of seasonal variation of near-surface BC concentrations in the polar regions, by increasing the BC concentrations in all seasons and particularly in cold seasons. However, it exacerbates the overestimation of modeled BC concentrations in the upper troposphere in the Pacific regions. The comparisons suggest that, to address the remaining model POM and BC biases, future improvements are required related to (1) in-cloud scavenging and vertical transport in convective clouds and (2) emissions of anthropogenic and biomass burning aerosols.
Objective
Social frailty is related to adverse health-related outcomes. However, the measurement thereof is controversial and research into the relationship between social frailty and physical ...functioning remains limited. This study aimed to determine social frailty status via developing a simple self-reported screening tool, termed the HALFT scale, and to examine the association between social frailty and physical functioning, cognition, depression, and mortality among community-dwelling older adults.
Design
Prospective cohort study.
Setting
Community.
Participants
1697 community-dwelling adults aged ≥60 years from Beijing Longitudinal Study of Aging were included.
Measurements
The HALFT scale was developed based on 5 items: unhelpful to others, limited social participation, loneliness, financial difficulty, and not having anyone to talk to. Socioeconomic and demographic data were collected, and physical functioning, frailty index, cognition, and depression were assessed.
Results
The prevalence of social frailty was 7.7% (weighted, 4.5%). Participants with physical frailty, low levels of physical activity, and poor physical functioning had a higher prevalence of social frailty. Social frailty was associated with dementia, subjective memory decline, depression, cognitive impairment, and having experienced a recent significant life event. After adjusting for age and sex, the 8-year mortality hazard ratios were 2.5-4.3 and 1.6-2.3, respectively, for those with social frailty or pre-social frailty. Each component of the HALFT scale predicted 8-year mortality.
Conclusion
Social frailty is associated with physical functioning, cognition, and depression, and predicts mortality. The HALFT scale could be a useful screening tool for determining social frailty in older adults. Interventions aimed at preventing or delaying social frailty are warranted.
The Community Atmosphere Model (CAM), version 5, is now coupled to extensive tropospheric and stratospheric chemistry, called CAM5-chem, and is available in addition to CAM4-chem in the Community ...Earth System Model (CESM) version 1.2. The main focus of this paper is to compare the performance of configurations with internally derived "free running" (FR) meteorology and "specified dynamics" (SD) against observations from surface, aircraft, and satellite, as well as understand the origin of the identified differences. We focus on the representation of aerosols and chemistry. All model configurations reproduce tropospheric ozone for most regions based on in situ and satellite observations. However, shortcomings exist in the representation of ozone precursors and aerosols. Tropospheric ozone in all model configurations agrees for the most part with ozonesondes and satellite observations in the tropics and the Northern Hemisphere within the variability of the observations. Southern hemispheric tropospheric ozone is consistently underestimated by up to 25%. Differences in convection and stratosphere to troposphere exchange processes are mostly responsible for differences in ozone in the different model configurations. Carbon monoxide (CO) and other volatile organic compounds are largely underestimated in Northern Hemisphere mid-latitudes based on satellite and aircraft observations. Nitrogen oxides (NOx) are biased low in the free tropical troposphere, whereas peroxyacetyl nitrate (PAN) is overestimated in particular in high northern latitudes. The present-day methane lifetime estimates are compared among the different model configurations. These range between 7.8 years in the SD configuration of CAM5-chem and 8.8 years in the FR configuration of CAM4-chem and are therefore underestimated compared to observational estimations. We find that differences in tropospheric aerosol surface area between CAM4 and CAM5 play an important role in controlling the burden of the tropical tropospheric hydroxyl radical (OH), which causes differences in tropical methane lifetime of about half a year between CAM4-chem and CAM5-chem. In addition, different distributions of NOx from lightning explain about half of the difference between SD and FR model versions in both CAM4-chem and CAM5-chem. Remaining differences in the tropical OH burden are due to enhanced tropical ozone burden in SD configurations compared to the FR versions, which are not only caused by differences in chemical production or loss but also by transport and mixing. For future studies, we recommend the use of CAM5-chem configurations, due to improved aerosol description and inclusion of aerosol–cloud interactions. However, smaller tropospheric surface area density in the current version of CAM5-chem compared to CAM4-chem results in larger oxidizing capacity in the troposphere and therefore a shorter methane lifetime.
Circulating fatty acids (FA) are associated with a multitude of chronic diseases. However, a major gap in establishing such relationships is the lack of accepted fatty acid reference ranges ...representing healthy individuals. Data on validated FA reference ranges would provide a better understanding of study baseline measures and aid in the evaluation and interpretation of pharmaceutical or dietary interventions. Reference ranges for plasma FA levels have been reported in a few small studies and on a limited number of FA. Therefore, we determined the average and percentiles of a broad set of 61 FA (C14 - C24:1) from plasma total lipids from an ethnically diverse population of healthy young Canadian males and females (Total n = 826). Plasma concentrations of some of the major FA ranged from 0.3 to 4.1 mmol/L for palmitic acid, 0.1 to 1.0 mmol/L for stearic acid, 0.03 to 3.2 mmol/L for oleic acid, 0.2 to 5.0 mmol/L for linoleic acid (LA), 12.0 to 186.9 μmol/L for α-linolenic acid, and 7.2 to 237.5 μmol/L for docosahexaenoic acid (DHA). Males had significantly higher plasma concentrations of γ-linolenic acid (GLA) and n-3 docosapentaenoic acid and lower concentrations of palmitoleic acid, LA and DHA than females. Comparison of FA concentrations between Caucasians, East Asians and South Asians revealed that South Asians had significantly lower levels of palmitoleic acid (p < 0.01) and oleic acid (p = 0.01) while East Asians had lower levels of GLA (p = 0.02) and dihomo-γ-linolenic acid (p = 0.03). Overall, these data provide a comprehensive set of quantitative values that profiles a small cohort of Canadians which highlights the utility of establishing validated FA reference ranges that may be used to understand how deficient, suboptimal, or excess amounts of a given FA may be associated with chronic disease.
Summary
Background
Psoriasis is a chronic skin disorder that manifests as epidermal keratinocyte hyperplasia.
Objectives
We examined the effect of oxymatrine treatment on cell proliferation and ...apoptosis in skin lesions of psoriasis.
Patients and methods
Patients with severe plaque psoriasis were treated with oxymatrine or with acitretin. The skin lesions were stained with proliferating cell nuclear antigen (PCNA), Ki‐67 and Bcl‐2, as well as examined by terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling (TUNEL). We performed correlations of the Psoriasis Area and Severity Index (PASI) and the proliferation and apoptosis index.
Results
Oxymatrine significantly reduced the psoriasis lesions as demonstrated by the reduced PASI score after treatment 6·91; 95% confidence interval (CI) 5·00–8·81, P < 0·001. In the oxymatrine group, the mitotic index was 26·15 (95% CI 24·80–27·49) before oxymatrine treatment, decreasing to 14·52 (95% CI 13·82–15·25; P < 0·001) after treatment, but remained higher than the normal group (6·24; 95% CI 5·87–6·61, P < 0·001). Oxymatrine also inhibited the proliferation of epidermal cells in the skin lesion as indicated by the reduced proliferation index after treatment (P < 0·01). In addition, oxymatrine treatment reduced cellular apoptosis as shown by increased Bcl‐2 expression and a decrease in TUNEL‐positive cells. The PASI score was positively correlated with mitotic index, proliferation index and apoptotic index (TUNEL), but negatively correlated with Bcl‐2 expression.
Conclusions
Oxymatrine treatment reduced proliferation but inhibited apoptosis of cells in the skin lesion. The balance between cell proliferation and turnover may contribute to the significant alleviation of psoriasis by oxymatrine.
What's already known about this topic?
Psoriasis manifests as epidermal keratinocyte hyperplasia with proliferation, keratinocyte maturation and turnover rates.
Current drugs for psoriasis may inhibit cell proliferation but could not adjust the balance of cell division, differentiation and apoptosis.
What does this study add?
We studied the efficacy of oxymatrine in the treatment of psoriasis and analysed the correlation of skin lesions, proliferation and apoptosis index before and after oxymatrine treatment.
What is the translational message?
Our study has demonstrated that oxymatrine is effective in the treatment of severe plaque psoriasis.
It has comparable efficacy with acitretin.
Because acitretin treatment was sometimes associated with metabolic abnormalities, our study suggests oxymatrine therapy as an alternative treatment for psoriasis in the context of acitretin allergy or adverse reactions.
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Linked Comment: Groma. Br J Dermatol 2019; 181:891–892.
Summary
Identifying dependency in multivariate data is a common inference task that arises in numerous applications. However, existing nonparametric independence tests typically require computation ...that scales at least quadratically with the sample size, making it difficult to apply them in the presence of massive sample sizes. Moreover, resampling is usually necessary to evaluate the statistical significance of the resulting test statistics at finite sample sizes, further worsening the computational burden. We introduce a scalable, resampling-free approach to testing the independence between two random vectors by breaking down the task into simple univariate tests of independence on a collection of $2\times 2$ contingency tables constructed through sequential coarse-to-fine discretization of the sample , transforming the inference task into a multiple testing problem that can be completed with almost linear complexity with respect to the sample size. To address increasing dimensionality, we introduce a coarse-to-fine sequential adaptive procedure that exploits the spatial features of dependency structures. We derive a finite-sample theory that guarantees the inferential validity of our adaptive procedure at any given sample size. We show that our approach can achieve strong control of the level of the testing procedure at any sample size without resampling or asymptotic approximation and establish its large-sample consistency. We demonstrate through an extensive simulation study its substantial computational advantage in comparison to existing approaches while achieving robust statistical power under various dependency scenarios, and illustrate how its divide-and-conquer nature can be exploited to not just test independence, but to learn the nature of the underlying dependency. Finally, we demonstrate the use of our method through analysing a dataset from a flow cytometry experiment.
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