Wound healing is a well-tuned biological process, which is achieved via consecutive and overlapping phases including hemostasis, inflammatory-related events, cell proliferation and tissue remodeling. Several factors can impair wound healing such as oxygenation defects, aging, and stress as well as deleterious health conditions such as infection, diabetes, alcohol overuse, smoking and impaired nutritional status. Growing evidence suggests that reactive oxygen species (ROS) are crucial regulators of several phases of healing processes. ROS are centrally involved in all wound healing processes as low concentrations of ROS generation are required for the fight against invading microorganisms and cell survival signaling. Excessive production of ROS or impaired ROS detoxification causes oxidative damage, which is the main cause of non-healing chronic wounds. In this context, experimental and clinical studies have revealed that antioxidant and anti-inflammatory strategies have proven beneficial in the non-healing state. Among available antioxidant strategies, treatments using mitochondrial-targeted antioxidants are of particular interest. Specifically, mitochondrial-targeted peptides such as elamipretide have the potential to mitigate mitochondrial dysfunction and aberrant inflammatory response through activation of nucleotide-binding oligomerization domain (NOD)-like family receptors, such as the pyrin domain containing 3 (NLRP3) inflammasome, nuclear factor-kappa B (NF-κB) signaling pathway inhibition, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2).

Bart Staels and his colleagues show that the transcription factor Rev-erb-α is highly expressed in oxidative muscle and, via loss- and gain-of-function experiments, including pharmacological activation, that it plays a key partin regulating the oxidative capacity of the muscle and exercise endurance. The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1–Ppargc-1α signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In complementary experiments, Rev-erb-α overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-α in vivo increased exercise capacity. This study identifies Rev-erb-α as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.

Background—: Obesity and diabetes mellitus are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance, and diabetes mellitus on the intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy. Methods and Results—: Right atrial myocardium was obtained from 141 consecutive patients presenting no sign of cardiomyopathy. We investigated ex vivo isometric contraction, mitochondrial respiration and calcium retention capacity, and respiratory chain complex activities and oxidative stress status. Diabetes mellitus was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction, and increased myocardial oxidative stress, regardless of weight status. In contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated hemoglobin A _1C , but neither body mass index nor the insulin resistance index (homeostasis model assessment–insulin resistance), was independently associated with cardiac mitochondrial function. Furthermore, diabetes mellitus was associated with cardiac mitochondrial network fragmentation and significantly decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to hemoglobin A _1C . Conclusion—: Worsening of intrinsic myocardial contraction in the transition from obesity to diabetes mellitus is likely related to worsening of cardiac mitochondrial function because impaired mitochondrial function and dynamics and contractile dysfunction are observed in diabetic patients but not in “metabolically healthy” obese patients at early stage in insulin resistance.

The diagnostic accuracy of protected-specimen brush (PSB), bronchoalveolar lavage (BAL), and endotracheal aspirates (EA) was prospectively evaluated in a series of 28 mechanically ventilated patients (MV patients) who died within 3 d of the bronchoscopic procedure, using postmortem lung examination as the gold standard for establishing the diagnosis of pneumonia. The entire fixed lungs were carefully dissected along the bronchovascular axes and each segment was cut into 5- to 10-mm thick sections, enabling gross examination of the lung parenchyma. Two tissue blocks were taken from each segment, including grossly abnormal areas whenever present. In several cases, two peripheral (subpleural) lung-tissue blocks were also taken from each lobe prior to systematic dissection of the lungs. Quantitative cultures (QC) and direct cytologic and microbiologic examination (DE) was performed on respiratory samples obtained within 72 h before death. Values of 10(3) cfu/ml of Ringer's solution, 10(4) cfu/ml of retrieved fluid, and 10(6) cfu/ml of respiratory secretions were used as cutoff points for quantitative PSB, BAL, and EA cultures, respectively. The main findings in this study were that: (1) Pneumonia was present in 67% of the patients. (2) Histologic lesions of pneumonia were mainly bilateral and predominated in the dependent lung segments. (3) Coexistence of a variety of noninfectious processes was a common finding in patients with pneumonia. (4) In several cases pneumonia was absent from peripheral lung samples while more central areas of the same segment displayed typical foci of pneumonia. (5) The sensitivity of quantitative cultures was 55%, 57%, and 47% for EA, PSB, and BAL, respectively, and the specificity was 85%, 88%, and 100%, respectively. Reducing the diagnostic threshold of EA to 10(5) cfu/ml of respiratory secretions instead of 10(6) cfu/ml resulted in a sensitivity of 63.1% and a specificity of 75% for EA. The sensitivity of direct examination (DE) was 50%, 47%, and 47%, respectively, and the specificity was 75%, 88%, and 87%. (6) The presence of intracellular organisms (ICO) in BAL had a 36.8% sensitivity and 100% specificity in establishing the diagnosis of pneumonia regardless of their percentage. (7) Although 15 patients (53%) were not on antibiotics or were off antibiotics for more than 48 h before testing, no relationship could be established between the patients' antibiotic status and the result of any diagnostic test. By using a recommended methodology for respiratory sampling techniques together with complete postmortem lung examination as a diagnostic "gold standard," this study provides a realistic insight into the diagnostic values of EA, PSB, and BAL in MV patients with suspected pneumonia.

To determine whether correction of acidemia using bicarbonate improves hemodynamic variables and tissue oxygenation in patients with lactic acidosis. Prospective, randomized, blinded, cross over study. Each patient sequentially received sodium bicarbonate and sodium chloride. The order of the infusions was randomized. Ten patients with metabolic acidosis, increased arterial plasma lactate concentrations (greater than 2.45 mmol/L), and no severe renal failure (creatinine less than 250 mumol/L [less than 2.3 mg/dL]). Sodium bicarbonate (1 mmol/kg body weight) or equal volume of sodium chloride was injected iv at the beginning of two successive 1-hr study periods. Period order was randomized. Arterial and venous blood gas measurements, plasma electrolytes (sodium, potassium, chloride), osmolality and lactate, 2,3-diphosphoglycerate (DPG), and oxygen hemoglobin affinity, hemodynamic variables, oxygen delivery, and oxygen consumption measurements were obtained before and repeatedly during the 1-hr period after the injection of bicarbonate or sodium chloride. Sodium bicarbonate administration increased arterial and venous pH, serum bicarbonate, and the partial pressure of CO2 in arterial and venous blood. Hemodynamic responses to sodium bicarbonate and sodium chloride were similar. Tissue oxygenation (as estimated by oxygen delivery, oxygen consumption, oxygen extraction ratio, and transcutaneous oxygen pressure) was not modified. No changes in serum sodium concentration, osmolality, arterial and venous lactate, red cell 2,3-DPG levels, or hemoglobin affinity for oxygen were observed. Administration of sodium bicarbonate did not improve hemodynamic variables in patients with lactic acidosis, but did not worsen tissue oxygenation.

To test the hypothesis whether or not dobutamine or dopamine infusion increases gastric mucosal perfusion, a prospective randomized crossover trial was conducted on 10 septic patients in the intensive care unit of a university hospital. Systemic hemodynamic, oxygen transport, and gastric perfusion assessed by gastric intramucosal pH and laser Doppler flowmetry were measured at baseline and after administration of dobutamine or dopamine (5 micrograms/kg/min). Both increased oxygen transport. In response to dobutamine, gastric mucosal blood flow increased (+32 +/- 14% from baseline; p < 0.05), gastric tonometered PCO2 and gastric arterial PCO2 difference decreased (58 +/- 7 versus 52 +/- 7 mm Hg; p < 0.05; 16.8 +/- 7.0 versus 10.5 +/- 7.2 mm Hg; p < 0.05), and intramucosal pH increased (7.23 +/- 0.05 versus 7.29 +/- 0.06; p < 0.05). In response to dopamine, gastric mucosal blood flow decreased (-28 +/- 8% from baseline; p < 0.05), gastric tonometered PCO2, gastric-arterial PCO2 difference, and calculated intramucosal pH were unchanged (58 +/- 7 versus 61 +/- 9 mm Hg, ns; 16.8 +/- 7.0 versus 18.9 +/- 8.4 mm Hg, ns; 7.24 +/- 0.05 versus 7.21 +/- 0.06, ns). We speculated that despite an oxygen transport increase, dobutamine and dopamine have affected differently gastric mucosal perfusion in septic patients.