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Red blood cells (RBCs) mediate cardioprotection via nitric oxide-like bioactivity, but the signaling and the identity of any mediator released by the RBCs remains unknown. We investigated whether RBCs exposed to hypoxia release a cardioprotective mediator and explored the nature of this mediator. Perfusion of isolated hearts subjected to ischemiareperfusion with extracellular supernatant from mouse RBCs exposed to hypoxia resulted in improved postischemic cardiac function and reduced infarct size. Hypoxia increased extracellular export of cyclic guanosine monophosphate (cGMP) from mouse RBCs, and exogenous cGMP mimicked the cardioprotection induced by the supernatant. The protection induced by hypoxic RBCs was dependent on RBC-soluble guanylate cyclase and cGMP transport and was sensitive to phosphodiesterase 5 and activated cardiomyocyte protein kinase G. Oral administration of nitrate to mice to increase nitric oxide bioactivity further enhanced the cardioprotective effect of hypoxic RBCs. In a placebo- controlled clinical trial, a clear cardioprotective, soluble guanylate cyclase-dependent effect was induced by RBCs collected from patients randomized to 5 weeks nitrate-rich diet. It is concluded that RBCs generate and export cGMP as a response to hypoxia, mediating cardioprotection via a paracrine effect. This effect can be further augmented by a simple dietary intervention, suggesting preventive and therapeutic opportunities in ischemic heart disease., Introduction There are several lines of evidence suggesting that red blood cells (RBCs), in addition to their fundamental role as transporters of oxygen, are involved in the regulation of cardiovascular [...]

This non-randomized controlled trial aimed to compare the effect of the 5:2 diet on insulin levels as a primary outcome and markers of insulin secretion (connecting peptide (C-peptide) and insulin-like growth factor binding protein-1 (IGFBP-1)) and sensitivity (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)), as well as body composition as secondary outcomes in overweight/obese individuals with and without type 2 diabetes (T2D). Ninety-seven participants (62% women), 35 with T2D and 62 BMI- and waist-matched controls without T2D, followed the 5:2 diet (two days per week of fasting) for six months with a 12-month follow-up. At six months, there was no loss to follow-up in the T2D group, whereas four controls discontinued this study. Overall, 82% attended the 12-month follow-up. After the intervention, insulin levels decreased in the control group and glucose decreased in the T2D group, while C-peptide, HOMA-IR, waist circumference, BMI, trunk, and total fat% decreased in both groups. Furthermore, low IGFBP-1, indicating hyperinsulinemia, improved in the T2D group. The changes in fasting glucose and waist measurement were significantly more improved in the T2D group than in the controls. Persistent positive effects were observed at the 12-month follow-up. The 5:2 diet for six months was feasible and efficient to reduce markers of insulin secretion and resistance and therefore holds promise as management of overweight/obesity in subjects with and without T2D. [ABSTRACT FROM AUTHOR]

Background: Charcot neuro‐osteoarthropathy (CNO) is a rare but devastating complication of diabetes associated with high rates of morbidity; yet, many nonfoot specialists are unaware of it, resulting in missed and delayed diagnosis. Clinical practice guidelines (CPGs) have proven useful in improving quality of care and standardizing practice in diabetes and diabetic foot care. However, little is known about the consistency in recommendations for identification and management of active CNO. Aim: The aim of this study is to review European national diabetes CPGs for the diagnosis and management of active CNO and to assess their methodological rigor and transparency. Methods: A systematic search was performed to identify diabetes national CPGs across Europe. Guidelines in any language were reviewed to explore whether they provided a definition for active CNO and recommendations for diagnosis, monitoring, and management. Methodological rigor and transparency were assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE‐II) tool, which comprises 23 key items organized within six domains with an overall guideline assessment score of ≥ 60% considered to be of adequate quality to recommend use. Each guideline was assessed by two reviewers, and inter‐rater agreement (Kendall's W) was calculated for AGREE‐II scores. Results: Seventeen CPGs met the inclusion criteria. Breadth of CNO content varied across guidelines (median (IQR) word count: 327; Q1 = 151; Q3 = 790), and 53% provided a definition for active CNO. Recommendations for diagnosis and monitoring were provided by 82% and 53%, respectively, with offloading being the most common management recommendation (88%). Four guidelines (24%) reached threshold for recommendation for use in clinical practice (≥ 60%) with the scope and purpose domain scoring highest (mean (SD): 67%, ± 23%). The remaining domains had average scores ranging between 19% and 53%. Inter‐rater agreement was strong (W = 0.882; p < 0.001). Conclusions: European national CPGs for diabetes provide limited recommendations on active CNO. All guidelines showcased deficits in their methodology, suggesting that more rigorous methods should be employed for diabetes CPG development across Europe. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the effect of four isocaloric meals with different macronutrient compositions on postprandial blood glucose, lipids, and glucagon in adults with type 1 diabetes (T1D). Seventeen subjects tested four isocaloric meals in a randomized crossover design. The meal compositions were as follows: high-carbohydrate (HC); high-carbohydrate with extra fiber (HC-fiber); low-carbohydrate high-protein (HP); and low-carbohydrate high-fat (HF). Blood glucose and lipid measurements were collected up to 4 h and glucagon up to 3 h postprandially. Mean postprandial glucose excursions were lower after the HP compared to the HC (p = 0.036) and HC-fiber meals (p = 0.002). There were no differences in mean glucose excursions after the HF meal compared to the HC and HP meals. The HF meal resulted in higher triglyceride excursions compared to the HP meal (p < 0.001) but not compared to the HC or HC-fiber meals. Glucagon excursions were higher at 180 min after the HP meal compared to the HC and HF meals. In conclusion, the low-carbohydrate HP meal showed the most favorable glycemic and metabolic effects during a 4 h postprandial period in subjects with T1D. [ABSTRACT FROM AUTHOR]

Background: A few prospective trials and case series have suggested that hyperbaric oxygen therapy (HBOT) may be efficacious for the treatment of severe COVID-19, but safety is a concern for critically ill patients. We present an interim analysis of the safety of HBOT via a randomized controlled trial (COVID-19-HBO). Methods: A randomized controlled, open-label, clinical trial was conducted in compliance with good clinical practice to explore the safety and efficacy of HBOT for severe COVID-19 in critically ill patients with moderate acute respiratory distress syndrome (ARDS). Between 3 June 2020, and 17 May 2021, 31 patients with severe COVID-19 and moderate-to-severe ARDS, a ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) < 26.7 kPa (200 mmHg), and at least two defined risk factors for intensive care unit (ICU) admission and/or mortality were enrolled in the trial and randomized 1:1 to best practice, or HBOT in addition to best practice. The subjects allocated to HBOT received a maximum of five treatments at 2.4 atmospheres absolute (ATA) for 80 min over seven days. The subjects were followed up for 30 days. The safety endpoints were analyzed. Results: Adverse events (AEs) were common. Hypoxia was the most common adverse event reported. There was no statistically significant difference between the groups. Numerically, serious adverse events (SAEs) and barotrauma were more frequent in the control group, and the differences between groups were in favor of the HBOT in PaO2/FiO2 (PFI) and the national early warning score (NEWS); statistically, however, the differences were not significant at day 7, and no difference was observed for the total oxygen burden and cumulative pulmonary oxygen toxicity dose (CPTD). Conclusion: HBOT appears to be safe as an intervention for critically ill patients with moderate-to-severe ARDS induced by COVID-19. Clinical trial registration: NCT04327505 (31 March 2020) and EudraCT 2020-001349-37 (24 April 2020). [ABSTRACT FROM AUTHOR]

Wound healing is a complex process that is characterized by an initial inflammatory phase followed by a proliferative phase. This transition is a critical regulatory point; however, the factors that mediate this process are not fully understood. Here, we evaluated microRNAs (miRs) in skin wound healing and characterized the dynamic change of the miRNome in human skin wounds. miR-132 was highly upregulated during the inflammatory phase of wound repair, predominantly expressed in epidermal keratinocytes, and peaked in the subsequent proliferative phase. TGF-β1 and TGF-β2 induced miR-132 expression in keratinocytes, and transcriptome analysis of these cells revealed that miR-132 regulates a large number of immune response- and cell cycle-related genes. In keratinocytes, miR-132 decreased the production of chemokines and the capability to attract leukocytes by suppressing the NF-κB pathway. Conversely, miR-132 increased activity of the STAT3 and ERK pathways, thereby promoting keratinocyte growth. Silencing of the miR-132 target heparin-binding EGF-like growth factor (HB-EGF) phenocopied miR-132 overexpression in keratinocytes. Using mouse and human ex vivo wound models, we found that miR-132 blockade delayed healing, which was accompanied by severe inflammation and deficient keratinocyte proliferation. Together, our results indicate that miR-132 is a critical regulator of skin wound healing that facilitates the transition from the inflammatory to the proliferative phase., Introduction Wound healing is a fundamental physiological process that maintains the integrity of the skin and includes a series of well-orchestrated biological and molecular events (1). The first stage of [...]