A chronic pro-inflammatory environment contributes to the physiopathology of actinic lentigines.

Actinic lentigines (AL) or age spots, are skin hyperpigmented lesions associated with age and chronic sun exposure. To better understand the physiopathology of AL, we have characterized the inflammation response in AL of European and Japanese volunteers. Gene expression profile showed that in both populations, 10% of the modulated genes in AL versus adjacent non lesional skin (NL), i.e. 31 genes, are associated with inflammation/immune process. A pro-inflammatory environment in AL is strongly suggested by the activation of the arachidonic acid cascade and the plasmin pathway leading to prostaglandin production, along with the decrease of anti-inflammatory cytokines and the identification of inflammatory upstream regulators. Furthermore, in line with the over-expression of genes associated with the recruitment and activation of immune cells, immunostaining on skin sections revealed a significant infiltration of CD68+ macrophages and CD4+ T-cells in the dermis of AL. Strikingly, investigation of infiltrated macrophage subsets evidenced a significant increase of pro-inflammatory CD80+/CD68+ M1 macrophages in AL compared to NL. In conclusion, a chronic inflammation, sustained by pro-inflammatory mediators and infiltration of immune cells, particularly pro-inflammatory M1 macrophages, takes place in AL. This pro-inflammatory loop should be thus broken to normalize skin and improve the efficacy of age spot treatment.

Investigation of Rare Earth Element Binding to a Surface-Bound Affinity Peptide Derived from EF-Hand Loop I of Lanmodulin.

Bioinspired strategies have been given extensive attention for the recovery of rare earth elements (REEs) from waste streams because of their high selectivity, regeneration potential, and sustainability as well as low cost. Lanmodulin protein is an emerging biotechnology that is highly selective for REE binding. Mimicking lanmodulin with shorter peptides is advantageous because they are simpler and potentially easier to manipulate and optimize. Lanmodulin-derived peptides have been found to bind REEs, but their properties have not been explored when immobilized on solid substrates, which is required for many advanced separation technologies. Here, two peptides, LanM1 and scrambled LanM1, are designed from the EF-hand loop 1 of lanmodulin and investigated for their binding affinity toward different REEs when surface-bound. First, the ability of LanM1 to bind REEs was confirmed and characterized in solution using circular dichroism (CD), nuclear magnetic resonance (NMR), and molecular dynamics (MD) simulations for Ce(III) ions. Isothermal titration calorimetry (ITC) was used to further analyze the binding of the LanM1 to Ce(III), Nd(III), Eu(III), and Y(III) ions and in low-pH conditions. The performance of the immobilized peptides on a model gold surface was examined using a quartz crystal microbalance with dissipation (QCM-D). The studies show that the LanM1 peptide has a stronger REE binding affinity than that of scrambled LanM1 when in solution and when immobilized on a gold surface. QCM-D data were fit to the Langmuir adsorption model to estimate the surface-bound dissociation constant (Kd) of LanM1 with Ce(III) and Nd(III). The results indicate that LanM1 peptides maintain a high affinity for REEs when immobilized, and surface-bound LanM1 has no affinity for potential competitor calcium and copper ions. The utility of surface-bound LanM1 peptides was further demonstrated by immobilizing them to gold nanoparticles (GNPs) and capturing REEs from solution in experiments utilizing an Arsenazo III-based colorimetric dye displacement assay and ultraviolet-visible (UV-vis) spectrophotometry. The saturated adsorption capacity of GNPs was estimated to be around 3.5 µmol REE/g for Ce(III), Nd(III), Eu(III), and Y(III) ions, with no binding of non-REE Ca(II) ions observed.

Chemically Stable Styrenic Electrospun Membranes with Tailorable Surface Chemistry.

Membranes with tailorable surface chemistry have applications in a wide range of industries. Synthesizing membranes from poly(chloromethyl styrene) directly incorporates an alkyl halide surface-bound initiator which can be used to install functional groups via SN2 chemistry or graft polymerization techniques. In this work, poly(chloromethyl styrene) membranes were synthesized through electrospinning. After fabrication, membranes were crosslinked with a diamine, and the chemical resistance of the membranes was evaluated by exposure to 10 M nitric acid, ethanol, or tetrahydrofuran for 24 h. The resulting membranes had diameters on the order of 2-5 microns, porosities of >80%, and permeance on the order of 10,000 L/m2/h/bar. Crosslinking the membranes generally increased the chemical stability. The degree of crosslinking was approximated using elemental analysis for nitrogen and ranged from 0.5 to 0.9 N%. The poly(chloromethyl styrene) membrane with the highest degree of crosslinking did not dissolve in THF after 24 h and retained its high permeance after solvent exposure. The presented chemically resistant membranes can serve as a platform technology due to their versatile surface chemistry and can be used in membrane manufacturing techniques that require the membrane to be contacted with organic solvents or monomers. They can also serve as a platform for separations that are performed in strong acids.

An electrochemical technique for sensing uranium adsorption and desorption.

Uranium is a toxic, heavy metal that can pose elevated health risks if leached into the environment. Uranium mobility is dependent on many factors, including speciation, solution pH, ligands in solution, and presence of surfaces. Surface adsorption is one phenomenon that inhibits uranium mobility in the environment and is studied as a naturally occurring phenomenon as well an intentional tool for environmental remediation. This work presents and validates a potentiometric, electrochemical technique for sensing uranium adsorption on and desorption from an electrochemically active surface solely through changes of the electrode potential. This novel electrochemical technique presents a new lens to study adsorption that complements external techniques (e.g., spectroscopy). Indication of adsorption and desorption via the electrochemical technique are gravimetrically validated using an electrochemical quartz crystal microbalance. This work contributes a unique, complementary technique that corroborates the adsorption of uranium on an electrode surface.

The identification of economically relevant health and social care services for mental disorders in the PECUNIA project.

BACKGROUND: Health economic research is still facing significant problems regarding the standardization and international comparability of health care services. As a result, comparative effectiveness studies and cost-effectiveness analyses are often not comparable. This study is part of the PECUNIA project, which aimed to improve the comparability of economic evaluations by developing instruments for the internationally standardized measurement and valuation of health care services for mental disorders. The aim of this study was to identify internationally relevant services in the health and social care sectors relevant for health economic studies for mental disorders. METHODS: A systematic literature review on cost-of-illness studies and economic evaluations was conducted to identify relevant services, complemented by an additional grey literature search and a search of resource use measurement (RUM) questionnaires. A preliminary long-list of identified services was explored and reduced to a short-list by multiple consolidation rounds within the international research team and an external international expert survey in six European countries. RESULTS: After duplicate removal, the systematic search yielded 15,218 hits. From these 295 potential services could be identified. The grey literature search led to 368 and the RUM search to 36 additional potential services. The consolidation process resulted in a preliminary list of 186 health and social care services which underwent an external expert survey. A final consolidation step led to a basic list of 56 services grouped into residential care, daycare, outpatient care, information for care, accessibility to care, and self-help and voluntary care. CONCLUSIONS: The initial literature searches led to an extensive number of potential service items for health and social care. Many of these items turned out to be procedures, interventions or providing professionals rather than services and were removed from further analysis. The resulting list was used as a basis for typological coding, the development of RUM questionnaires and corresponding unit costs for international mental health economic studies in the PECUNIA project.

Clickable polymer scaffolds enable Ce recovery with peptide ligands.

Rare earth elements (REEs) are a vital part of many technologies with particular importance to the renewable energy sector and there is a pressing need for environmentally friendly and sustainable processes to recover and recycle them from waste streams. Functionalized polymer scaffolds are a promising means to recover REEs due to the ability to engineer both transport properties of the porous material and specificity for target ions. In this work, REE adsorbing polymer scaffolds were synthesized by first introducing poly(glycidyl methacrylate) (GMA) brushes onto porous polyvinylidene fluoride (PVDF) surface through activator generated electron transfer atom transfer radical polymerization (AGET ATRP). Azide moieties were then introduced through a ring opening reaction of GMA. Subsequently, REE-binding peptides were conjugated to the polymer surface through copper catalyzed azide alkyne cycloaddition (CuAAC) click chemistry. The presence of GMA, azide, and peptide was confirmed through Fourier transform infrared spectroscopy. Polymer scaffolds functionalized with the REE-binding peptide bound cerium, while polymer scaffolds functionalized with a scrambled control peptide bound significantly less cerium. Importantly, this study shows that the REE binding peptide retains its functionality when bound to a polymer surface. The conjugation strategy employed in this work can be used to introduce peptides onto other polymeric surfaces and tailor surface specificity for a wide variety of ions and small molecules.

Actinic lentigines from Japanese and European volunteers share similar impaired biological functions.

BACKGROUND: Hyperpigmented spots develop earlier and with a higher incidence in Asian individuals compared with Europeans. Although actinic lentigines (AL) are very common, the biological events underlying their formation remain ill-defined. OBJECTIVE: AL from Japanese volunteers were characterized through morphological and gene expression analyses. Data were then compared with published data on European volunteers. METHODS: AL on hands were selected through dermoscopic imaging and pattern scoring in Japanese women. Skin biopsies of AL and adjacent non-lesional (NL) skin were processed for histology and gene expression profiling. Japanese and European studies were compared after harmonizing the data using the same mathematical and statistical methods. RESULTS: Histologically, AL from Japanese individuals revealed deep epidermal invaginations with melanin accumulation in the depth of epidermal rete ridges. Transcriptomic data identified 245 genes differentially expressed in AL versus NL skin samples, associated with the different skin compartments and multiple functional families and biological processes, such as epidermal homeostasis, extracellular matrix organization and ion binding/transmembrane transport. Strikingly, melanogenesis-related genes were not significantly modulated in AL compared with NL skin. Comparison of the molecular profiles of Japanese and European AL showed that a huge majority of genes were modulated in the same way, recapitulating the overall biological alterations. CONCLUSION: AL from Japanese volunteers exhibited morphological and molecular alterations of the whole skin structure with impairment of multiple biological functions similar to that found in European women. These findings will contribute to the development of efficient treatments of AL lesions.

A Lysine-Modified Polyethersulfone (PES) Membrane for the Recovery of Lanthanides.

Rare-earth elements (which include all lanthanides, scandium, and yttrium) play a key role in many fields including oil refining, metallurgy, electronics manufacturing, and other high-technology applications. Although the available lanthanide resources are enough for current levels of manufacturing, increased future demand for lanthanides will require new, efficient recovery methods to provide a sustainable supply. Membrane adsorbers are promising separation materials to recover lanthanides from high volumes of wastewater due to their tailorable surface chemistry, high binding capacity and high throughput. In this work, membrane adsorbers were synthesized by first using ultraviolet-initiated free radical polymerization to graft a poly(glycidyl methacrylate) (p-GMA) layer to the surface of polyethersulfone membranes. Then, the reactive epoxy groups of the grafted p-GMA were used for the covalent attachment of lysine molecules via a zinc perchlorate-catalyzed, epoxide ring-opening reaction at 35°C. Changes in membrane surface chemistry throughout the functionalization process were monitored with Fourier Transform Infrared Spectroscopy. The degree of grafting for the p-GMA film was quantified gravimetrically and increased with increasing polymerization time. Equilibrium adsorption experiments were performed for single specie solutions of La3+, Ce3+, Nd3+, Na+, Ca2+, and Mg2+ at pH 5.25 ± 0.25. Lysine-modified membranes showed negligible uptake of Na+, Ca2+, and Mg2+. The maximum capacities modeled by the Langmuir isotherm for La3+ and Ce3+ were 6.11 ± 0.58 and 6.45 ± 1.29 mg/g adsorbent, respectively. Nd3+ adsorbed to the membrane; however, the fit of the Langmuir model was not significant and it adsorbed to a lower extent than La3+ and Ce3+. Lower adsorption of the higher charge density species indicates that the primary binding mode is through the amine moieties of lysine and not the carboxylic acid. Dynamic adsorption experiments were conducted with 1 ppm La3+ feed solutions at different flow rates using either a single membrane or three membranes in series. The dynamic binding capacity at 50% breakthrough was independent of flowrate within the tested range. The low-temperature membrane functionalization methodology presented in this work can be used to immobilize biomolecules with even higher specificity, like engineered peptides or proteins, on membrane surfaces.

Keratinocytic Malfunction as a Trigger for the Development of Solar Lentigines.

INTRODUCTION: Solar lentigines (SL) affect chronically UV-radiated skin. Treatment is often refractory. Deeper knowledge on its pathogenesis might improve therapeutic effects. MATERIAL AND METHODS: Morphological characterization of 190 SL was performed and epidermal thickness, pigment distribution, dendricity, and cornification grade were measured. Immunoreactivity was investigated using Melan A, Tyrosinase, MITF, p53, and CD20, as well as Notch1 using immunofluorescence. RESULTS: We found 2 groups of histological patterns, i.e., either acanthotic or atrophic epidermis. Lesions with basket-woven cornification and atrophic epidermis were observed in 6 out of 9 and 14 out of 16 cases from the face, respectively. Consistency of areas with a high pigmentation was observed in 96-97% of the cases. Hyperpigmentation grade and acanthosis or cornification disorders correlated positively in 88.5% of the cases. Overexpressed of p53 was found in 19 out of 20 lesions, presenting in a scattered distribution. A significant correlation of p53 and acanthosis (p = 0.003) and cornification grade (p = 0.0008) was observed. Notch1 was expressed in all SL, with the highest immunoreactivity in atrophic facial lesions. Lesions from the hands expressed Notch1 mainly in acanthotic areas with elongated rete ridges and less compact cornification. DISCUSSION: We suggest that Notch1-dependent keratinocytic malfunction causes the development of SL. Consequently, hyperpigmentation would be a result and not the primary cause of the pathogenesis. Confirmation of these findings might have clinical implications as hitherto treatment has mainly focused on melanocytes and pigmentation and not on the proliferation/differentiation balance of keratinocytes.

Clinical and Biological Characterization of Skin Pigmentation Diversity and Its Consequences on UV Impact.

Skin color diversity is the most variable and noticeable phenotypic trait in humans resulting from constitutive pigmentation variability. This paper will review the characterization of skin pigmentation diversity with a focus on the most recent data on the genetic basis of skin pigmentation, and the various methodologies for skin color assessment. Then, melanocyte activity and amount, type and distribution of melanins, which are the main drivers for skin pigmentation, are described. Paracrine regulators of melanocyte microenvironment are also discussed. Skin response to sun exposure is also highly dependent on color diversity. Thus, sensitivity to solar wavelengths is examined in terms of acute effects such as sunburn/erythema or induced-pigmentation but also long-term consequences such as skin cancers, photoageing and pigmentary disorders. More pronounced sun-sensitivity in lighter or darker skin types depending on the detrimental effects and involved wavelengths is reviewed.

Rapid Sample Preparation for Alpha Spectroscopy with Ultrafiltration Membranes.

This contribution describes a rapid, fieldable alpha spectroscopy sample preparation technique that minimizes consumables and decreases the nuclear forensics timeline. Functional ultrafiltration membranes are presented that selectively concentrate uranium directly from pH 6 groundwater and serve as the alpha spectroscopy substrate. Membranes were prepared by ultraviolet grafting of uranium-selective polymer chains from the membrane surface. Membranes were characterized by Fourier-transform infrared spectroscopy before and after modification to support functionalization. Membrane performance was evaluated using uranium-233 or depleted uranium in both deionized and simulated groundwater at pH 6. Functionalized membranes achieved peak energy resolutions of 31 ± 2 keV and recoveries of 81 ± 4% when prepared directly from pH 6 simulated groundwater. For simulated groundwater spiked with depleted uranium, baseline energy resolution was achieved for both isotopes (uranium-238 and uranium-234). The porous, uranium-selective substrate designs can process liters per hour of uranium-contaminated groundwater using low-pressure (<150 kPa) filtration and a 45 mm diameter membrane filter, leading to a high-throughput, one-step concentration, purification, and sample mounting process.

Melanosome Distribution in Keratinocytes in Different Skin Types: Melanosome Clusters Are Not Degradative Organelles.

The melanosome pattern was characterized systematically in keratinocytes in situ in highly, moderately, and lightly pigmented human skin, classified according to the individual typological angle, a colorimetric measure of skin color phenotype. Electron microscopy of skin samples showed qualitatively and quantitatively that in highly pigmented skin, although melanosomes are mostly isolated and distributed throughout the entire epidermis, clusters are also observed in the basal layer. In moderately and lightly pigmented skin, melanosomes are concentrated in the first layer of the epidermis, isolated-but for most of them, grouped as clusters of melanocores delimited by a single membrane. Electron tomography resolving intracellular three-dimensional organization of organelles showed that clustered melanocores depict contacts with other cellular compartments, such as endoplasmic reticulum and mitochondria. Additionally, immunogold labelling showed that clusters of melanocores do not correspond to autophagosomes or melanophagosomes but that they present, similarly to melanosomes in melanocytes, features of nonacidic, nondegradative organelles. Overall, these observations suggest that melanocore clusters do not correspond to autophagic organelles but represent reservoirs or protective structures for melanosome integrity and function. These results open avenues for understanding the basis of skin pigmentation in different skin color phenotypes.

Lixisenatide Therapy in Older Patients With Type 2 Diabetes Inadequately Controlled on Their Current Antidiabetic Treatment: The GetGoal-O Randomized Trial.

OBJECTIVE: To evaluate the efficacy and safety of lixisenatide versus placebo on glycemic control in older patients with type 2 diabetes uncontrolled on their current antidiabetic treatment. RESEARCH DESIGN AND METHODS: In this phase III, double-blind, randomized, placebo-controlled, two-arm, parallel-group, multicenter trial, patients aged ≥70 years were randomized to receive once-daily lixisenatide 20 µg or placebo before breakfast concomitantly with their existing antidiabetic therapy (including insulin) for 24 weeks. Patients at risk for malnutrition or with moderate to severe cognitive impairment were excluded. The primary end point was absolute change in HbA1c from baseline to week 24. Secondary end points included change from baseline to week 24 in 2-h postprandial plasma glucose (PPG) and body weight. RESULTS: A total of 350 patients were randomized. HbA1c decreased substantially with lixisenatide (-0.57% [6.2 mmol/mol]) compared with placebo (+0.06% [0.7 mmol/mol]) from baseline to week 24 (P < 0.0001). Mean reduction in 2-h PPG was significantly greater with lixisenatide (-5.12 mmol/L) than with placebo (-0.07 mmol/L; P < 0.0001). A greater decrease in body weight was observed with lixisenatide (-1.47 kg) versus placebo (-0.16 kg; P < 0.0001). The safety profile of lixisenatide in this older population, including rates of nausea and vomiting, was consistent with that observed in other lixisenatide studies. Hypoglycemia was reported in 17.6% of patients with lixisenatide versus 10.3% with placebo. CONCLUSIONS: In nonfrail older patients uncontrolled on their current antidiabetic treatment, lixisenatide was superior to placebo in HbA1c reduction and in targeting postprandial hyperglycemia, with no unexpected safety findings.

Differential effects of glucagon-like peptide-1 receptor agonists on heart rate.

While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N = 202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1-12 h) mean placebo- and baseline-adjusted 24-h HR increase of 1-3 beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6-10 bpm compared with dulaglutide and exenatide LAR at 3-4 bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24 h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained increase during the day and night. Findings from recently completed trials indicate that a GLP-1 RA-induced increase in HR, regardless of magnitude, does not present an increased cardiovascular risk for subjects with T2DM, although a pronounced increase in HR may be associated with adverse clinical outcomes in those with advanced heart failure.

Extractive scintillating polymer sensors for trace-level detection of uranium in contaminated ground water.

This contribution describes the synthesis of robust extractive scintillating resin and its use in a flow-cell detector for the direct detection of uranium in environmental waters. The base poly[(4-methyl styrene)-co-(4-vinylbenzyl chloride)-co-(divinylbenzene)-co-(2-(1-napthyl)-4-vinyl-5-phenyloxazole)] resin contains covalently bound fluorophores. Uranium-binding functionality was added to the resin by an Arbuzov reaction followed by hydrolysis via strong acid or trimethylsilyl bromide (TMSBr)-mediated methanolysis. The resin was characterized by Fourier-transform infrared spectroscopy and spectrofluorometry. Fluorophore degradation was observed in the resin hydrolyzed by strong acid, while the resin hydrolyzed by TMSBr-mediated methanolysis maintained luminosity and showed hydrogen bonding-induced Stokes' shift of ∼100 nm. The flow cell detection efficiency for uranium of the TMSBr-mediated methanolysis resin was evaluated at pH 4, 5 and 6 in DI water containing 500 Bq L-1 uranium-233 and demonstrated flow cell detection efficiencies of 23%, 16% and 7%. Experiments with pH 4, synthetic groundwater with 50 Bq L-1 uranium-233 exhibited a flow cell detection efficiency of 17%. The groundwater measurements show that the resins can concentrate the uranyl cation from waters with high concentrations of competitor ions at near-neutral pH. Findings from this research will lay the groundwork for development of materials for real-time environmental sensing of alpha- and beta-emitting radionuclides.

Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal-Plus or Basal-Bolus in Type 2 Diabetes: The GetGoal Duo-2 Trial.

OBJECTIVE: To provide evidence-based options on how to intensify basal insulin, we explored head-to-head prandial interventions in overweight patients with type 2 diabetes inadequately controlled on basal insulin glargine with or without 1-3 oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS: Patients were randomized to lixisenatide once daily or insulin glulisine given once or thrice daily, added to glargine, with or without metformin, if HbA1c remained ≥7 to ≤9% (≥53 to ≤75 mmol/mol) after 12 weeks of glargine optimization with OADs other than metformin stopped at the start of optimization. Coprimary end points at 26 weeks were 1) noninferiority (95% CI upper bound <0.4% [<4.4 mmol/mol]) in HbA1c reduction with lixisenatide versus glulisine once daily, and either 2a) noninferiority in HbA1c reduction for lixisenatide versus glulisine thrice daily or 2b) superiority in body weight change for lixisenatide versus glulisine thrice daily. Fasting and postprandial plasma glucose, composite efficacy/safety end points, and adverse events were also assessed. RESULTS: Baseline characteristics were similar between arms (n = 298, diabetes and basal insulin duration of 12.2 and 3.2 years, respectively; BMI 32.2 kg/m(2)). HbA1c improved from 8.5% to 7.9% (69 to 63 mmol/mol) with glargine optimization and further to 7.2%, 7.2%, and 7.0% (55, 55, and 53 mmol/mol) with lixisenatide and glulisine once daily and thrice daily, respectively; all coprimary end points were met. Symptomatic hypoglycemia and body weight were lower in lixisenatide versus glulisine patients. More gastrointestinal events occurred with lixisenatide. CONCLUSIONS: Short-acting glucagon-like peptide-1 receptor agonists as add-on to basal insulin may become a preferred treatment intensification option, attaining meaningful glycemic targets with fewer hypoglycemic events without weight gain versus basal-plus or basal-bolus in uncontrolled basal insulin-treated type 2 diabetes.

Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A Randomized, Open-Label Trial.

OBJECTIVE: This mechanistic trial compared the pharmacodynamics and safety of lixisenatide and liraglutide in combination with optimized insulin glargine with/without metformin in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: This was a multicenter, randomized, open-label, three-arm trial comparing lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg once daily for 8 weeks in combination with insulin glargine after optimized titration. The primary end point was change from baseline to week 8 in incremental area under the postprandial plasma glucose curve for 4 h after a standardized solid breakfast (AUC PPG0030-0430 h). Changes from baseline in gastric emptying, 24-h plasma glucose profile, HbA1c, fasting plasma glucose (FPG), 24-h ambulatory heart rate and blood pressure, amylase and lipase levels, and adverse events (AEs) were also assessed. RESULTS: In total, 142 patients were randomized and treated. Lixisenatide 20 µg achieved greater reductions of AUC PPG0030-0430 h compared with liraglutide (marginal mean [95% one-sided CI] treatment difference, -6.0 [-7.8] h ⋅ mmol/L [-108.3 (-140.0) h ⋅ mg/dL] vs. liraglutide 1.2 mg and -4.6 [-6.3] h ⋅ mmol/L [-83.0 (-114.2) h ⋅ mg/dL] vs. liraglutide 1.8 mg; P < 0.001 for both), and gastric emptying was delayed to a greater extent than with liraglutide 1.2 and 1.8 mg (P < 0.001 for treatment comparisons). FPG was unchanged in all treatment arms. At week 8, mean ± SD HbA1c was 6.2 ± 0.4% (44 ± 5 mmol/mol), 6.1 ± 0.3% (44 ± 4 mmol/mol), and 6.1 ± 0.3% (44 ± 4 mmol/mol) for lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg, respectively. At week 8, both liraglutide doses increased marginal mean ± SE 24-h heart rate from baseline by 9 ± 1 bpm vs. 3 ± 1 bpm with lixisenatide (P < 0.001). Occurrence of symptomatic hypoglycemia was higher with lixisenatide; gastrointestinal AEs were more common with liraglutide. Lipase levels were significantly increased from baseline with liraglutide 1.2 and 1.8 mg (marginal mean ± SE increase 21 ± 7 IU/L for both; P < 0.05). CONCLUSIONS: Lixisenatide and liraglutide improved glycemic control in optimized insulin glargine-treated T2D albeit with contrasting mechanisms of action and differing safety profiles.

Key regulatory role of dermal fibroblasts in pigmentation as demonstrated using a reconstructed skin model: impact of photo-aging.

To study cutaneous pigmentation in a physiological context, we have previously developed a functional pigmented reconstructed skin model composed of a melanocyte-containing epidermis grown on a dermal equivalent comprising living fibroblasts. The present studies, using the same model, aimed to demonstrate that dermal fibroblasts influence skin pigmentation up to the macroscopic level. The proof of principle was performed with pigmented skins differing only in the fibroblast component. First, the in vitro system was reconstructed with or without fibroblasts in order to test the global influence of the presence of this cell type. We then assessed the impact of the origin of the fibroblast strain on the degree of pigmentation using fetal versus adult fibroblasts. In both experiments, impressive variation in skin pigmentation at the macroscopic level was observed and confirmed by quantitative parameters related to skin color, melanin content and melanocyte numbers. These data confirmed the responsiveness of the model and demonstrated that dermal fibroblasts do indeed impact the degree of skin pigmentation. We then hypothesized that a physiological state associated with pigmentary alterations such as photo-aging could be linked to dermal fibroblasts modifications that accumulate over time. Pigmentation of skin reconstructed using young unexposed fibroblasts (n = 3) was compared to that of tissues containing natural photo-aged fibroblasts (n = 3) which express a senescent phenotype. A stimulation of pigmentation in the presence of the natural photo-aged fibroblasts was revealed by a significant increase in the skin color (decrease in Luminance) and an increase in both epidermal melanin content and melanogenic gene expression, thus confirming our hypothesis. Altogether, these data demonstrate that the level of pigmentation of the skin model is influenced by dermal fibroblasts and that natural photo-aged fibroblasts can contribute to the hyperpigmentation that is associated with photo-aging.

Solar ultraviolet radiation induces biological alterations in human skin in vitro: relevance of a well-balanced UVA/UVB protection.

Cutaneous damages such as sunburn, pigmentation, and photoaging are known to be induced by acute as well as repetitive sun exposure. Not only for basic research, but also for the design of the most efficient photoprotection, it is crucial to understand and identify the early biological events occurring after ultraviolet (UV) exposure. Reconstructed human skin models provide excellent and reliable in vitro tools to study the UV-induced alterations of the different skin cell types, keratinocytes, fibroblasts, and melanocytes in a dose- and time-dependent manner. Using different in vitro human skin models, the effects of UV light (UVB and UVA) were investigated. UVB-induced damages are essentially epidermal, with the typical sunburn cells and DNA lesions, whereas UVA radiation-induced damages are mostly located within the dermal compartment. Pigmentation can also be obtained after solar simulated radiation exposure of pigmented reconstructed skin model. Those models are also highly adequate to assess the potential of sunscreens to protect the skin from UV-associated damage, sunburn reaction, photoaging, and pigmentation. The results showed that an effective photoprotection is provided by broad-spectrum sunscreens with a potent absorption in both UVB and UVA ranges.