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Diabetic Foot Ulcer Beyond Wound Closure: Clinical Practice Guideline
No full textA total of 37.3 million Americans have diabetes, and 96 million more have prediabetes. Hyperglycemia, the hallmark of diabetes, increases the risk for diabetes-related complications, including skin breakdown and cardiovascular disease. Many clinical practice guidelines exist, but there are gaps regarding the best approaches to assess physical fitness and mobility in adults with diabetes; incorporate exercise into the care plan; and reload the diabetic foot after ulcer closure has occurred to avoid ulcer reoccurrence. The purpose of this clinical practice guideline was to review and assess previously published guidelines and address gaps within the guidelines specific to the following: best screening tools/tests and interventions to prevent a future reulceration, best screening tools and interventions to assess and address mobility impairments, best tools to measure and interventions to address reduced physical fitness and activity, best approach to reloading the foot after ulceration closure and, finally, whether improvement in physical fitness will positively change quality of life and health care costs. The Guidelines Development Group performed a systematic literature search and review of the literature. A total of 701 studies were identified. Following duplicate removal and exclusion for irrelevance, 125 studies underwent full-text review, and 38 studies were included. Recommendations were developed using a software assistant created specifically for guideline recommendation development. Recommendations resulted for physical fitness and activity inclusion and measurement for adults with diabetes and with or without foot ulceration. Exercise and physical activity should be prescribed according to the physiologic response of an adult with diabetes to exercise and preferences for optimizing long-term quality of life and reduce health care costs. Reloading following diabetic foot ulcer closure should include maximal offloading, especially during the first 3 months; loading should be titrated using a footwear schedule. Further research is necessary in the areas of exercise in the wound healing process and the assessment of methods to reload a newly reepithelialized ulcer to prevent recurrence
Elucidating the Role of Ref-1 in Retinal Neovascularization
No full textIUIRetinal neovascularization in retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR) impairs vision. Current treatments of intravitreal (IVT) antivascular endothelial growth factor (VEGF) injections are accompanied by high treatment burden and resistance. Also, VEGF alone is not sufficient for induction of neovascularization, suggesting that targeting multiple disease-relevant pathways may increase therapeutic response. Thus, there is a critical need to develop novel therapies that modulate multiple disease-relevant pathways. APE1/Ref-1, a multifunctional protein with both endonuclease (APE1) and redox regulatory activity (Ref-1), activates multiple transcription factors linked to retinal neovascularization. However, the precise molecular mechanisms of Ref-1 in retinal neovascularization remain unclear. To investigate this, I examined the expression of Ref- 1 in two mouse models of retinal neovascularization – the oxygen-induced retinopathy (OIR) and the Vldlr-/- model – and observed elevated Ref-1 expression at sites of neovascularization. Further, I observed heightened expression of Ref-1 in endothelial cells in human PDR tissue compared to normal eyes. Through cell-based and biochemical approaches, I identified that Ref-1 redox activity modulates canonical Wnt signaling, and inhibition of Ref-1 redox activity blocks Wnt signaling activation. I found that Ref-1 redox activity regulates HIF-1a transcriptional activation in hypoxic human retinal endothelial cells. Hypoxia-induced activation of Wnt signaling was regulated by Ref-1, suggesting a dynamic Ref-1-HIF-1a-Wnt signaling axis. Finally, inhibition of Ref-1 redox activity decreased retinal neovascularization and downregulated expression of Wnt- and angiogenesis-related genes at sites of neovascularization in a mouse model of retinal neovascularization. These findings suggest that Ref-1 redox activity promotes ischemic retinal neovascularization via Wnt signaling activation. This study advanced our understanding of Ref-1’s role in neovascular eye diseases, and targeting Ref-1 with a redox inhibitor could offer a novel therapeutic strategy for retinal neovascularization
Chikamatsu, Mori, and the uncanny valley
No full textIn Japan, robotics projects like Geminoid, modeled after Hiroshi Ishiguro, exhibit a fascination with creating human doubles. Yet, warnings against this also thread through Japanese thought, from the Edo-period playwright Chikamatsu Monzaemon (1653-1724) to the robotics professor Mori Masahiro (1927-2025). Though centuries apart, they describe the same uncanny valley phenomenon-eerie, cold, repellent feelings that arise when confronting the imperfectly human. In an interview with Hozumi Ikan, translated here, Chikamatsu presents a theory of realism exemplified through puppet theater and kabuki. He divides realism into four zones: the unreal, conceptual realism, surface realism, and the real. The unreal lacks authenticity, surface realism lacks soul, and the real lacks expressiveness. For Chikamatsu, it is conceptual realism that captivates an audience. A play's unfolding events evoke empathy and emotion through their meaning for the characters. Similarly, Mori divides realism into four zones: industrial, humanoid, and android robots, and real people. Industrial robots evoke little affinity, and androids risk appearing eerie. Though real people evoke the most affinity, androids cannot become indistinguishable from them. For Mori, only humanoid robots evoke affinity without risking uncanniness. By exploring anthropomorphism, both Chikamatsu and Mori illuminate principles for designing robots that do not unsettle but delight
Posterior cingulate cortex microRNA dysregulation differentiates cognitive resilience, mild cognitive impairment, and Alzheimer's disease
Get PDFIntroduction: MicroRNA (miRNA) activity is increasingly appreciated as a key regulator of pathophysiologic pathways in Alzheimer's disease (AD). However, the role of miRNAs during the progression of AD, including resilience and prodromal syndromes such as mild cognitive impairment (MCI), remains underexplored.
Methods: We performed miRNA-sequencing on samples of posterior cingulate cortex (PCC) obtained post mortem from Rush Religious Orders Study participants diagnosed ante mortem with no cognitive impairment (NCI), MCI, or AD. NCI subjects were subdivided as low pathology (Braak stage I/II) or high pathology (Braak stage III/IV), suggestive of resilience. Bioinformatics approaches included differential expression, messenger RNA (mRNA) target prediction, interactome modeling, functional enrichment, and AD risk modeling.
Results: We identified specific miRNA groups, mRNA targets, and signaling pathways distinguishing AD, MCI, resilience, ante mortem neuropsychological test performance, post mortem neuropathological burden, and AD risk.
Discussion: These findings highlight the potential of harnessing miRNA activity to manipulate disease-modifying pathways in AD, with implications for precision medicine.
Highlights: MicroRNA (MiRNA) dysregulation is a well-established feature of Alzheimer's disease (AD). Novel miRNAs also distinguish subjects with mild cognitive impairment and putative resilience. MiRNAs correlate with cognitive performance and neuropathological burden. Select miRNAs are associated with AD risk with age as a significant covariate. MiRNA pathways include insulin, prolactin, kinases, and neurite plasticity
Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine
No full textPancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G). PH potentiates the effects of G in in vitro, orthotopic mouse models, and a patient-derived xenograft model of PDAC. Proteomic and single-cell RNA sequencing (RNA-seq) analyses reveal that GPH treatment upregulates autophagy and endoplasmic reticulum (ER) stress-related transcripts. GPH treatment decreases the number of Ki67, fibroblast-associated protein (FAP), and alpha-smooth muscle actin (SMA)-expressing fibroblasts with a decrease in autophagy-related transcripts. The GPH treatment increases M1 polarization and CD4+ and CD8+ T cells and reduces CD4+ and CD8+ regulatory T cells (Tregs). These effects of GPH were confirmed in paired biopsies obtained from patients treated in a clinical trial
Age-dependent phenotypes of cognitive impairment as sequelae of SARS-CoV-2 infection
No full textCognitive changes associated with PASC may not be uniform across populations. We conducted individual-level pooled analyses and meta-analyses of cognitive assessments from eight prospective cohorts, comprising 2,105 patients and 1,432 controls from Argentina, Canada, Chile, Greece, India, Italy, Russia, and the UK. The meta-analysis found no differences by country of origin. The profile and severity of cognitive impairment varied by age, with mild attentional impairment observed in young and middle-aged adults, but memory, language, and executive function impairment in older adults. The risk of moderate to severe impairment doubled in older adults. Moderately severe or severe impairment was significantly associated with infection diagnoses (chi-square = 26.57, p ≤ 0.0001) and the severity of anosmia (chi-square = 31.81, p ≤ 0.0001). We found distinct age-related phenotypes of cognitive impairment in patients recovering from COVID-19. We identified the severity of acute illness and the presence of olfactory dysfunction as the primary predictors of dementia-like impairment in older adults
The Impact of Low Serum Magnesium Levels on COVID-19 Severity and Potential Therapeutic Benefits of Magnesium Supplementation: A Systematic Review
No full textIn this review, our objective was to analyze the association between serum magnesium (Mg) levels, Mg supplementation, and coronavirus disease 2019 (COVID-19) outcomes. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching major databases until February 2023. Twenty-six studies (11,363 patients) were included: 22 examining serum Mg levels (8474 patients) and four investigating Mg supplementations (2889 patients). Most studies indicated an association between lower serum Mg levels and increased COVID-19 severity, including higher mortality rates and prolonged recovery periods. Critical patients demonstrated significantly lower Mg levels compared to moderate/severe cases. However, some studies reported conflicting findings, with hypermagnesemia also associated with poor outcomes in specific patient populations. Regarding supplementation, higher dietary Mg intake correlated with shorter hospitalization duration and faster recovery. Mg supplementation exceeding 450 mg showed potential benefits, including increased antibody titers in pregnant women and reduced oxygen support requirements in elderly patients when combined with vitamins D and B12. While evidence suggests a potential relationship between Mg status and COVID-19 outcomes, findings are heterogeneous. Further investigation through well-designed clinical trials is required to gain deeper insights into the role of Mg in COVID-19 pathophysiology and the therapeutic potential of Mg supplementation
Optimizing Confocal Imaging Protocols for Muscle Fiber Typing in the Mouse Masseter Muscle
Get PDFThe masseter muscle, a key orofacial muscle, demonstrates unique anatomical and functional properties, including sexual dimorphism in myosin heavy chain (MyHC) expression and complex fiber architecture. Despite its importance in mastication and relevance to various disorders, phenotypic characterization of the masseter remains limited. Conventional fluorescence microscopy has been a cornerstone in muscle fiber typing, reliably identifying MyHC isoforms and measuring fiber cross-sectional areas. Building on this foundation, confocal microscopy offers complementary advantages, such as enhanced resolution, increased flexibility for multiplexing, and the ability to visualize complex structures in three dimensions. This study presents a detailed protocol for using confocal microscopy to achieve high-resolution imaging and molecular characterization of masseter muscle cryosections. By leveraging advanced technologies such as white light lasers and extended z-length imaging, this method ensures precise spectral separation, simultaneous multichannel fluorescence detection, and the ability to capture muscle architecture in three dimensions. The protocol includes tissue preparation, immunostaining for MyHC isoforms, and postprocessing for fiber segmentation and quantification. The imaging setup was optimized for minimizing signal bleed through, improving the signal-to-noise ratio, and enabling detailed visualization of muscle fibers and molecular markers. Image postprocessing allows for quantification of the cross-sectional area of individual fibers, nuclei location measurements, and identification of MyHC isoforms within each fiber. This confocal microscopy-based protocol provides similar resolution and contrast compared to conventional techniques, enabling robust multiplexed imaging and 3D reconstruction of muscle structures. These advantages make it a valuable tool for studying complex muscle architecture, offering broad applications in muscle physiology and pathology research. Key features • Enables high-resolution imaging of muscle fiber architecture, capturing detailed spatial relationships using extended z-length and advanced spectral separation techniques. • Supports simultaneous detection of multiple molecular markers for robust muscle fiber typing and molecular localization. • Allows for the generation of three-dimensional models to analyze muscle structures such as neuromuscular junctions, extracellular matrix, and mitochondrial organization. • Adaptable to various skeletal muscles and species, providing valuable insights into muscle physiology, regeneration, and disease processes. Graphical overview Analyzing muscle fiber composition and morphology in mice's masseter muscle using confocal microscopy. Workflow for characterizing rodent masseter muscle fibers using advanced confocal microscopy. Confocal microscopy, equipped with white light laser technology and optimized z-stack imaging, allows precise spectral unmixing to reduce bleed through and enhance signal detection. The z-length is extended beyond the physical thickness of the sample to account for potential variations in tissue flatness and ensure complete imaging of all focal planes. The resulting high-resolution images provide detailed insights into fiber architecture, molecular composition, and cross-sectional areas, ensuring robust and reproducible data for analyzing the complex phenotypic characteristics of the masseter and other muscles
The Role of TREM2 and the Responses Mediated by Galectin-3 During Age-Related Myelin Degeneration
Get PDFIUIAging is the greatest known risk factor for various neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and normal part of aging; albeit, to a lesser extent. Despite this, little is known about how age-related degeneration could contribute to and impact development of neurodegenerative disease. Microglia participate in a variety of white matter events from demyelination to remyelination. The microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated in regulating (de)myelination.
We found in response to demyelination, TREM2 is required for large volumes of myelin debris and during extended periods of phagocytosis. In addition to lysosomal regulation, we showed TREM2 can modify the ER stress response prior to overt myelin debris preventing early microglial dysfunction. We found TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. One of the signaling factors involved, the β-galactosidase-binding protein galectin-3 (gal-3), was recently identified as a ligand for TREM2, however little is known about this interaction in the context of aging or neurodegenerative disease.
Treating microglia with a pharmacological gal-3 inhibitor, we found overlapping functional deficits with Trem2-deficient microglia during myelin phagocytosis. These shared deficits included impaired myelin uptake, altered lysosomal function, ER stress, and lipid droplet accumulation that were rescued inTrem2-deficient microglia with the addition of recombinant gal-3. RNA-seq analyses revealed common genes and pathways affected that importantly included genes associated with the integrated stress response.
Taken together, these data suggest Gal-3 mediates and throttles the TREM2-dependent stress response during age-related myelin degeneration. Further, it provides support for targeting TREM2 function early to augment reparative signaling preventing overt debris accumulation and/or promoting gal-3 to alleviate stress pathways that can lead to premature microglial dysfunction and onset of pathology