EVOLUTION: Of Mice . . .

There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

Why most published research findings are false

Mitochondria play an important role in cell death and cardioprotection. During ischemia, when ATP is progressively depleted, ion pumps cannot function resulting in a rise in calcium (Ca2+), which f...

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Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury

Skeletal muscle architecture is the structural property of whole muscles that dominates their function. This review describes the basic architectural properties of human upper and lower extremity muscles. The designs of various muscle groups in humans and other species are analyzed from the point of view of optimizing function. Muscle fiber arrangement and motor unit arrangement is discussed in terms of the control of movement. Finally, the ability of muscles to change their architecture in response to immobilization, eccentric exercise, and surgical tendon transfer is reviewed. Future integrative physiological studies will provide insights into the mechanisms by which such adaptations occur. It is likely that muscle fibers transduce both stress and strain and respond by modifying sarcomere number in a way more suited to the new biomechanical environment.

http://billnordt.com/COREANATOMYFUNCTION/FUNCTIONALANDCLINICALSIGNIFICANCE.pdf

Functional and clinical significance of skeletal muscle architecture.

Context The American Diabetes Association and Surviving Sepsis Campaign recommend tight glucose control in critically ill patients based largely on 1 trial that shows decreased mortality in a surgical intensive care unit. Because similar studies report conflicting results and tight glucose control can cause dangerous hypoglycemia, the data underlying this recommendation should be critically evaluated. Objective To evaluate benefits and risks of tight glucose control vs usual care in critically ill adult patients. Data Sources MEDLINE (1950-2008), the Cochrane Library, clinical trial registries, reference lists, and abstracts from conferences from both the American Thoracic Society (2001-2008) and the Society of Critical Care Medicine (2004-2008). Study Selection We searched for studies in any language in which adult intensive care patients were randomly assigned to tight vs usual glucose control. Of 1358 identified studies, 34 randomized trials (23 full publications, 9 abstracts, 2 unpublished studies) met inclusion criteria. Data Extraction and Analysis Two reviewers independently extracted information using a prespecified protocol and evaluated methodological quality with a standardized scale. Study investigators were contacted for missing details. We used both random- and fixed-effects models to estimate relative risks (RRs). Results Twenty-nine randomized controlled trials totaling 8432 patients contributed data for this meta-analysis. Hospital mortality did not differ between tight glucose control and usual care overall (21.6% vs 23.3%; RR, 0.93; 95% confidence interval [CI], 0.85-1.03). There was also no significant difference in mortality when stratified by glucose goal ([1] very tight: ≤110 mg/dL; 23% vs 25.2%; RR, 0.90; 95% CI, 0.77-1.04; or [2] moderately tight: Conclusion In critically ill adult patients, tight glucose control is not associated with significantly reduced hospital mortality but is associated with an increased risk of hypoglycemia.

https://jamanetwork.com/journals/jama/articlepdf/182432/jce80007_933_944.pdf

Benefits and Risks of Tight Glucose Control in Critically Ill Adults: A Meta-analysis

Aims/hypothesis
Empagliflozin (EMPA), an inhibitor of the renal sodium–glucose cotransporter (SGLT) 2, reduces the risk of cardiovascular death in patients with type 2 diabetes. The underlying mechanism of this effect is unknown. Elevated cardiac cytoplasmic Na+ ([Na+]c) and Ca2+ ([Ca2+]c) concentrations and decreased mitochondrial Ca2+ concentration ([Ca2+]m) are drivers of heart failure and cardiac death. We therefore hypothesised that EMPA would directly modify [Na+]c, [Ca2+]c and [Ca2+]m in cardiomyocytes.

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Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits

Sodium–glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) constitute a novel class of glucose-lowering (type 2) kidney-targeted agents. We recently reported that the SGLT2i empagliflozin (EMPA) reduced cardiac cytosolic Na+ ([Na+]c) and cytosolic Ca2+ ([Ca2+]c) concentrations through inhibition of Na+/H+ exchanger (NHE). Here, we examine (1) whether the SGLT2i dapagliflozin (DAPA) and canagliflozin (CANA) also inhibit NHE and reduce [Na+]c; (2) a structural model for the interaction of SGLT2i to NHE; (3) to what extent SGLT2i affect the haemodynamic and metabolic performance of isolated hearts of healthy mice. Cardiac NHE activity and [Na+]c in mouse cardiomyocytes were measured in the presence of clinically relevant concentrations of EMPA (1 μmol/l), DAPA (1 μmol/l), CANA (3 μmol/l) or vehicle. NHE docking simulation studies were applied to explore potential binding sites for SGTL2i. Constant-flow Langendorff-perfused mouse hearts were subjected to SGLT2i for 30 min, and cardiovascular function, O2 consumption and energetics (phosphocreatine (PCr)/ATP) were determined. EMPA, DAPA and CANA inhibited NHE activity (measured through low pH recovery after NH4
 + pulse: EMPA 6.69 ± 0.09, DAPA 6.77 ± 0.12 and CANA 6.80 ± 0.18 vs vehicle 7.09 ± 0.09; p < 0.001 for all three comparisons) and reduced [Na+]c (in mmol/l: EMPA 10.0 ± 0.5, DAPA 10.7 ± 0.7 and CANA 11.0 ± 0.9 vs vehicle 12.7 ± 0.7; p < 0.001). Docking studies provided high binding affinity of all three SGLT2i with the extracellular Na+-binding site of NHE. EMPA and CANA, but not DAPA, induced coronary vasodilation of the intact heart. PCr/ATP remained unaffected. EMPA, DAPA and CANA directly inhibit cardiac NHE flux and reduce [Na+]c, possibly by binding with the Na+-binding site of NHE-1. Furthermore, EMPA and CANA affect the healthy heart by inducing vasodilation. The [Na+]c-lowering class effect of SGLT2i is a potential approach to combat elevated [Na+]c that is known to occur in heart failure and diabetes.

/pdf/class-effects-of-sglt2-inhibitors-in-mouse-cardiomyocytes-38b2q5n55j.pdf

Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.

Hyperglycemia is becoming recognized as an important risk factor for microvascular dysfunction. We hypothesized that short-term hyperglycemia, either on the scale of hours or weeks, alters the barrier function and the volume of the endothelial glycocalyx and decreases functional capillary density and deformability of the red blood cells (RBCs). All experiments were performed in anesthetized, mechanically ventilated, C57BL/6 mice that were either normoglycemic, acutely hyperglycemic (25 mM) for 60 min due to infusion of glucose, or hyperglycemic (25 mM) for 2-4 wk (db/db mice). The glycocalyx was probed using 40-kDa Texas red dextran, which is known to permeate the glycocalyx, and 70-kDa FITC dextran, which has impaired access to the glycocalyx in healthy animals. Clearance of the dye from the blood was measured. An orthogonal polarization spectral imaging technique was used to visualize the number of capillaries with flowing RBCs of the dorsal flexor muscle. The data indicate that short-term hyperglycemia causes a rapid decrease of the ability of the glycocalyx to exclude 70-kDa dextran. No change in the vascular permeation of 40-kDa dextran was observed. Glycocalyx volume was not affected by short-term hyperglycemia. In addition, 1 h of hyperglycemia resulted in a 38% decrease of the lineal density of capillaries with flowing RBCs. This decreased lineal density was not observed in the 2- to 4-wk hyperglycemia model. Short-term hyperglycemia was without any effect on the deformablity of the RBCs. The data indicate that the described increased vascular permeability with hyperglycemia can be ascribed to an increased permeability of the glycocalyx, identifying the glycocalyx as a potential early target of hyperglycemia.

Short-term hyperglycemia increases endothelial glycocalyx permeability and acutely decreases lineal density of capillaries with flowing red blood cells.

This study evaluates the effects of anesthesia and fluid support on hemodynamic parameters of the mechanically ventilated mouse of four different strains. All experiments were performed at a simila...

https://www.physiology.org/doi/pdf/10.1152/ajpheart.01002.2001

Coert J. Zuurbier

Papers

Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits

Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.

Short-term hyperglycemia increases endothelial glycocalyx permeability and acutely decreases lineal density of capillaries with flowing red blood cells.

Hemodynamics of anesthetized ventilated mouse models: aspects of anesthetics, fluid support, and strain

Length-force characteristics of the aponeurosis in the passive and active muscle condition and in the isolated condition.