Abstract Chronic wounds are a common complication in patients with diabetes that often lead to amputation. These non-healing wounds are described as being stuck in a persistent inflammatory state ...characterized by accumulation of pro-inflammatory macrophages, cytokines and proteases. Some medications approved for management of type 2 diabetes have demonstrated anti-inflammatory properties independent of their marketed insulinotropic effects and thus have underappreciated potential to promote wound healing. In this review, the potential for insulin, metformin, specific sulfonylureas, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors to promote healing is evaluated by reviewing human and animal studies on inflammation and wound healing. The available evidence indicates that diabetic medications have potential to prevent wounds from becoming arrested in the inflammatory stage of healing and to promote wound healing by downregulating pro-inflammatory cytokines, upregulating growth factors, lowering matrix metalloproteinases, stimulating angiogenesis, and increasing epithelization. However, no clinical recommendations currently exist on the potential for specific diabetic medications to impact healing of chronic wounds. Thus, we encourage further research that may guide physicians on providing personalized diabetes treatments that achieve glycemic goals while promoting healing in patients with chronic wounds.
Chronic wounds represent a significant health problem, especially in diabetic patients. In the current study, we investigated a novel therapeutic approach to wound healing--whole body low-intensity ...vibration (LIV). LIV is anabolic for bone, by stimulating the release of growth factors, and modulating stem cell proliferation and differentiation. We hypothesized that LIV improves the delayed wound healing in diabetic mice by promoting a pro-healing wound environment. Diabetic db/db mice received excisional cutaneous wounds and were subjected to LIV (0.4 g at 45 Hz) for 30 min/d or a non-vibrated sham treatment (controls). Wound tissue was collected at 7 and 15 d post-wounding and wound healing, angiogenesis, growth factor levels and wound cell phenotypes were assessed. LIV increased angiogenesis and granulation tissue formation at day 7, and accelerated wound closure and re-epithelialization over days 7 and 15. LIV also reduced neutrophil accumulation and increased macrophage accumulation. In addition, LIV increased expression of pro-healing growth factors and chemokines (insulin-like growth factor-1, vascular endothelial growth factor and monocyte chemotactic protein-1) in wounds. Despite no evidence of a change in the phenotype of CD11b+ macrophages in wounds, LIV resulted in trends towards a less inflammatory phenotype in the CD11b- cells. Our findings indicate that LIV may exert beneficial effects on wound healing by enhancing angiogenesis and granulation tissue formation, and these changes are associated with increases in pro-angiogenic growth factors.
The hypothesis of this study was that sustained activity of the Nod-like receptor protein (NLRP)-3 inflammasome in wounds of diabetic humans and mice contributes to the persistent inflammatory ...response and impaired healing characteristic of these wounds. Macrophages (Mp) isolated from wounds on diabetic humans and db/db mice exhibited sustained inflammasome activity associated with low level of expression of endogenous inflammasome inhibitors. Soluble factors in the biochemical milieu of these wounds are sufficient to activate the inflammasome, as wound-conditioned medium activates caspase-1 and induces release of interleukin (IL)-1β and IL-18 in cultured Mp via a reactive oxygen species-mediated pathway. Importantly, inhibiting inflammasome activity in wounds of db/db mice using topical application of pharmacological inhibitors improved healing of these wounds, induced a switch from proinflammatory to healing-associated Mp phenotypes, and increased levels of prohealing growth factors. Furthermore, data generated from bone marrow-transfer experiments from NLRP-3 or caspase-1 knockout to db/db mice indicated that blocking inflammasome activity in bone marrow cells is sufficient to improve healing. Our findings indicate that sustained inflammasome activity in wound Mp contributes to impaired early healing responses of diabetic wounds and that the inflammasome may represent a new therapeutic target for improving healing in diabetic individuals.
We performed Spitzer Infrared Spectrograph mapping observations covering nearly the entire extent of the Cassiopeia A supernova remnant (SNR), producing mid-infrared (5.5-35 mu m) spectra every 5" ...-10". Gas lines of Ar, Ne, O, Si, S, and Fe, and dust continua were strong for most positions. We identify three distinct ejecta dust populations based on their continuum shapes. The dominant dust continuum shape exhibits a strong peak at 21 mu m. A line-free map of 21 mu m peak dust made from the 19-23 mu m range closely resembles the Ar II, O IV, and Ne II ejecta-line maps, implying that dust is freshly formed in the ejecta. Spectral fitting implies the presence of SiO sub(2), Mg protosilicates, and FeO grains in these regions. The second dust type exhibits a rising continuum up to 21 mu m and then flattens thereafter. This "weak 21 mu m" dust is likely composed of Al sub(2)O sub(3) and C grains. The third dust continuum shape is featureless with a gently rising spectrum and is likely composed of MgSiO sub(3) and either Al sub(2)O sub(3) or Fe grains. Using the least massive composition for each of the three dust classes yields a total mass of 0.020 M unk. Using the most massive composition yields a total mass of 0.054 M unk. The primary uncertainty in the total dust mass stems from the selection of the dust composition necessary for fitting the featureless dust as well as 70 mu m flux. The freshly formed dust mass derived from Cas A is sufficient from SNe to explain the lower limit on the dust masses in high-redshift galaxies.
Similarity between percepts and concepts is used to accomplish many everyday tasks, e.g., object identification; so this similarity is widely used to construct geometrical spaces that represent ...stimulus qualities, but the intrinsic validity of the geometry, i.e., whether similarity operations support a particular geometry, is almost never tested critically. We introduce an experimental approach for equating relative similarities by setting perceived midpoints between pairs of stimuli. Midpoint settings are used with Varignon's Theorem to test the intrinsic geometry of a representation space, and its mapping to a physical space of stimuli. For perceptual color space, we demonstrate that geometrical structure depends on the mental representation used in judging similarity: An affine geometry was valid when observers used an opponent-color mental representation. Similarities based on a conceptual space of complementary colors thus power a geometric coordinate system. An affine geometry implies that similarity can be judged within straight lines and across parallel lines, and its neural coding could involve ratios of responses. We show that this perceptual space is invariant to changes in illumination color, providing a formal justification to generalize color constancy results measured for color categories, to all of color space. The midpoint measurements deviate significantly from midpoints in the extensively used "uniform" color spaces CIELAB and CIELUV, showing that these spaces do not provide adequate metric representation of perceived colors. Our paradigm can thus test for intrinsic geometrical assumptions underlying the representation space for many perceptual modalities, and for the extrinsic perceptual geometry of the space of physical stimuli.
In this paper, we trace the compounding and escalation of frames to try and encompass the reality of climate change. These frames capture significant aspects, revealing new contours and extreme ...organizational challenges. However, what if climate change is unframeable? We locate three ontological dimensions of climate change – its unboundedness, incalculability and unthinkability – that make this case. This means that climate change is not a problem that organizations can encompass, divide or draw lines around – some ‘thing’ that can be recuperated into existing institutional, infrastructural and interpersonal frameworks. Instead, it is calling forth forms of organization without any precedent. We argue that the philosophy of speculative realism, specifically the work of Quentin Meillassoux, reveals climate change as a new World for which we do not have categories. We deploy Meillassoux’s concepts which are non-human and rational to think through what climate change is ontologically. Meillassoux’s work is characterized as the reintroduction of the old philosophical idea of the absolute, and we use it as a possible way to overcome the equivocal status of climate change without succumbing to despondency and passivity. Rather than a negative, overwhelming threat, climate change gives us what we call a bleak optimism: the realization that climate change has already happened, and that human civilization must learn how to die in a way that is a creative and just foreclosure of the Earth’s organizational forms.
High-Cr ferritic model steels containing various additions of the refractory elements Nb and/or W were studied with respect to oxidation behaviour (hot) tensile properties, creep behaviour and ...high-temperature electrical conductivity of the surface oxide scales. Whereas W additions of around 2
wt.% had hardly any effect on the oxidation rates at 800 and 900
°C, Nb additions of 1% led to a substantially enhanced growth rate of the protective surface oxide scale. It was found that this adverse effect can be alleviated by suitable Si additions. This is related to the incorporation of Si and Nb into Laves phase precipitates which also contribute to increased creep and hot tensile strength. The dispersion of Laves phase precipitates was greatly refined by combined additions of Nb and W. The high-temperature electrical conductivity of the surface oxide scales was similar to that of the Nb/W-free alloys. Thus the combined additions of Nb, W and Si resulted in an alloy with oxidation resistance, ASR contribution and thermal expansion comparable to the commercial alloy Crofer 22 APU, but with creep strength far greater than that of Crofer 22 APU.
Glutamatergic neurotransmission mediated by N -methyl- d -aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric ...illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain’s global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate’s role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.
Discrete porous coordination cages are attractive as a solution processable material whose porosity is not predicated on a network structure. Here, we leverage the peripheral functionalization of ...these cage structures to obtain 12 novel, solution processable, porous coordination cages that afford crystalline and amorphous single-phase millimeter-scale monolithic bulk structures (six of each) upon solidification. These structures are based upon prototypal metal–organic polyhedra Cu24(5-x-isophthalate)24 (where x = NH2, OH), wherein meta-substitution of linker ligands with acyl chloride or isocyanate moieties afforded amide and urethane functional groups, respectively. These porous cage structures were obtainable via direct synthesis between a metal salt and a ligand as well as postsynthetic modification of the cage and formed monoliths following centrifugation and drying of the product. We rationalize their self-assembly as colloidal packing of nanoscale cuboctahedral cages through weak interactions between their hydrophobic alkyl/aromatic surfaces. In general, amorphous solids were obtained via rapid precipitation from the mother liquor upon methanol addition, while crystalline solids could be obtained only following further chloroform and pyridine additions. The structure of the materials is confirmed via gas sorption and spectroscopic methods, while powder X-ray diffraction and transmission electron microscopy are used to determine the nature of these bulk solids.
PDF
