Cocoa flavanols, Nrf2 activation, and oxidative stress in peripheral artery disease: mechanistic findings in muscle based on outcomes from a randomized trial.

The pathophysiology of muscle damage in peripheral artery disease (PAD) includes increased oxidant production and impaired antioxidant defenses. Epicatechin (EPI), a naturally occurring flavanol, has antioxidant properties that may mediate the beneficial effects of natural products such as cocoa. In a phase II randomized trial, a cocoa-flavanol-rich beverage significantly improved walking performance compared with a placebo in people with PAD. In the present work, the molecular mechanisms underlying the therapeutic effect of cocoa flavanols were investigated by analyzing baseline and follow-up muscle biopsies from participants. Increases in nuclear factor erythroid 2-related factor 2 (Nrf2) target antioxidants heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) in the cocoa group were significantly associated with reduced accumulation of central nuclei, a myopathy indicator, in type II muscle fibers (P = 0.017 and P = 0.023, respectively). Protein levels of the mitochondrial respiratory complex III subunit, cytochrome b-c1 complex subunit 2 (UQCRC2), were significantly higher in the cocoa group than in the placebo group (P = 0.032), and increases in UQCRC2 were significantly associated with increased levels of Nrf2 target antioxidants HO-1 and NQO1 (P = 0.001 and P = 0.035, respectively). Exposure of non-PAD human myotubes to ex vivo serum from patients with PAD reduced Nrf2 phosphorylation, an indicator of activation, increased hydrogen peroxide production and oxidative stress, and reduced mitochondrial respiration. Treatment of myotubes with EPI in the presence of serum from patients with PAD increased Nrf2 phosphorylation and protected against PAD serum-induced oxidative stress and mitochondrial dysfunction. Overall, these findings suggest that cocoa flavanols may enhance antioxidant capacity in PAD via Nrf2 activation.NEW & NOTEWORTHY The current study supports the hypothesis that in people with PAD, cocoa flavanols activate Nrf2, thereby increasing antioxidant protein levels, protecting against skeletal muscle damage, and increasing mitochondrial protein abundance. These results suggest that Nrf2 activation may be an important therapeutic target for improving walking performance in people with PAD.

ApoE isoform does not influence skeletal muscle regeneration in adult mice.

Introduction: Apolipoprotein E (ApoE) has been shown to be necessary for proper skeletal muscle regeneration. Consistent with this finding, single-cell RNA-sequencing analyses of skeletal muscle stem cells (MuSCs) revealed that Apoe is a top marker of quiescent MuSCs that is downregulated upon activation. The purpose of this study was to determine if muscle regeneration is altered in mice which harbor one of the three common human ApoE isoforms, referred to as ApoE2, E3 and E4. Methods: Histomorphometric analyses were employed to assess muscle regeneration in ApoE2, E3, and E4 mice after 14 days of recovery from barium chloride-induced muscle damage in vivo, and primary MuSCs were isolated to assess proliferation and differentiation of ApoE2, E3, and E4 MuSCs in vitro. Results: There was no difference in the basal skeletal muscle phenotype of ApoE isoforms as evaluated by section area, myofiber cross-sectional area (CSA), and myonuclear and MuSC abundance per fiber. Although there were no differences in fiber-type frequency in the soleus, Type IIa relative frequency was significantly lower in plantaris muscles of ApoE4 mice compared to ApoE3. Moreover, ApoE isoform did not influence muscle regeneration as assessed by fiber frequency, fiber CSA, and myonuclear and MuSC abundance. Finally, there were no differences in the proliferative capacity or myogenic differentiation potential of MuSCs between any ApoE isoform. Discussion: Collectively, these data indicate nominal effects of ApoE isoform on the ability of skeletal muscle to regenerate following injury or the in vitro MuSC phenotype.

Comparative Analysis of Machine Learning Models for Image Detection of Colonic Polyps vs. Resected Polyps.

(1) Background: Colon polyps are common protrusions in the colon's lumen, with potential risks of developing colorectal cancer. Early detection and intervention of these polyps are vital for reducing colorectal cancer incidence and mortality rates. This research aims to evaluate and compare the performance of three machine learning image classification models' performance in detecting and classifying colon polyps. (2) Methods: The performance of three machine learning image classification models, Google Teachable Machine (GTM), Roboflow3 (RF3), and You Only Look Once version 8 (YOLOv8n), in the detection and classification of colon polyps was evaluated using the testing split for each model. The external validity of the test was analyzed using 90 images that were not used to test, train, or validate the model. The study used a dataset of colonoscopy images of normal colon, polyps, and resected polyps. The study assessed the models' ability to correctly classify the images into their respective classes using precision, recall, and F1 score generated from confusion matrix analysis and performance graphs. (3) Results: All three models successfully distinguished between normal colon, polyps, and resected polyps in colonoscopy images. GTM achieved the highest accuracies: 0.99, with consistent precision, recall, and F1 scores of 1.00 for the 'normal' class, 0.97-1.00 for 'polyps', and 0.97-1.00 for 'resected polyps'. While GTM exclusively classified images into these three categories, both YOLOv8n and RF3 were able to detect and specify the location of normal colonic tissue, polyps, and resected polyps, with YOLOv8n and RF3 achieving overall accuracies of 0.84 and 0.87, respectively. (4) Conclusions: Machine learning, particularly models like GTM, shows promising results in ensuring comprehensive detection of polyps during colonoscopies.

Posterior Communicating Artery Aneurysm With Referred Tooth Pain: A Case Report.

Oculomotor nerve (CN III) palsy (ONP) has multiple etiologies, with aneurysms and ischemic injury being the two leading causes. The presentations of these conditions differ, as aneurysms commonly manifest with pupillary involvement, while ischemic-related ONP often leads to a pupil-sparing presentation. We present a 63-year-old African American male with a history of sickle cell trait, ocular sickle cell disease, and untreated hypertension that develops "down and out" left eye with a mid-dilated pupil unresponsive to light. However, the patient developed severe left upper tooth pain after the onset of the eye pain, which progressed to ONP. The patient's dental and radiographic evaluation did not indicate any obvious source for his tooth pain. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the head revealed a 7-mm saccular aneurysm with a 2-mm neck arising from the left posterior communicating artery (PCOM) aneurysm, and neurovascular surgical intervention was initiated. This case highlights the potential of referred tooth pain as an early symptom in patients with PCOM aneurysm, which physicians should be vigilant about and consider as a potential indicator of the condition. Therefore, collaboration between different specialties, including ophthalmology, neurology, neurosurgery, and dental care, is necessary to formulate a comprehensive treatment plan that effectively addresses the patient's specific needs and challenges.

Lessons Learned: A Disruption in Care Leads to Increased Rates of Proximal Amputations.

BACKGROUND: In March 2020, due to the COVID-19 pandemic, hospitalizations in New York state were restricted to emergency purposes. Non-COVID related cases involving lower extremity wounds were only admitted for acute infections and limb salvage. Patients with these conditions were placed at higher risk for eventual limb loss. PURPOSE: To understand the impact of COVID-19 on amputation rates. METHODS: A retrospective review of lower limb institution-wide amputations was conducted at Northwell Health from January 2020 to January 2021. The amputation rates during the COVID-19 shutdown period were compared to the pre-pandemic, post-shutdown, and reopening period. RESULTS: The pre-pandemic period had 179 amputations, of which 8.38 % were proximal. 86 amputations were performed during shutdown, with a greater proportion being proximal (25.58 %, p=0.0009). Following the shutdown period, amputations returned to baseline. The proportion of proximal amputations during post-shutdown was 18.5 % and during reopening was 12.06 %. Patients had 4.89 times higher odds of undergoing a proximal amputation during the shutdown period. CONCLUSIONS: The effect of COVID-19 on amputation rates demonstrates an increase in proximal amputation during the initial shutdown. This study suggests an indirect negative effect of COVID-19 hospital restrictions on surgeries during the initial shutdown period.