High-dose fasudil preserves postconditioning against myocardial infarction under hyperglycemia in rats: Role of mitochondrial KATP channels

Background: The current study was carried out to determine whether fasudil hydrochloride (fasudil), a Rho-kinase inhibitor, has myocardial postconditioning (PostC) activity under hyperglycemia as well as normoglycemia, and if so, whether the effects could be mediated by mitochondrial ATP-sensitive potassium (m-KATP) channels.Methods: Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. After opening the chest, all rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received low-dose (0.15 mg/kg) or high-dose (0.5 mg/kg) fasudil or diazoxide, an m-KATP channel opener, at 10 mg/kg, just before reperfusion under normoglycemic or hyperglycemic conditions. In another group, rats received 5-hydroxydecanoic acid (5HD), an m-KATP channel blocker, at 10 mg/kg, before high-dose fasudil. Myocardial infarct size was expressed as a percentage of area at risk (AAR).Results: Under normoglycemia, low-dose and high-dose fasudil and diazoxide reduced myocardial infarct size (23 ± 8%, 21 ± 9% and 21 ± 10% of AAR, respectively) compared with that in the control (42 ± 7%). Under hyperglycemia, low-dose fasudil (40 ± 11%) and diazoxide (44 ± 14%) could not exert this beneficial effect, but high-dose fasudil reduced myocardial infarct size in the same manner as under normoglycemia (21 ± 13%). 5HD prevented fasudil-induced reduction of myocardial infarct size (42 ± 13%).Conclusion: Fasudil induces PostC against myocardial infarction via activation of m-KATP channels in the rat. Although hyperglycemia attenuates the PostC, high-dose fasudil can restore cardioprotection

Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice

Mitochondria play a crucial role in Alzheimer's disease (AD) onset and progression. Traditional transgenic AD mouse models which were widely used in the past decades share a common limitation: The overexpression of APP and overproduction of amyloid-beta (Aβ) are accompanied by other APP peptide fragments, which could introduce artificial and non-clinically relevant phenotypes. Here, we performed an in-depth and time-resolved behavioral and metabolic characterization of a clinically relevant AD mouse model engineered to express normal physiological levels of APP harboring humanized Swedish (K670N/M671L), Beyreuther/Iberian (I716F), and Arctic (E693G) mutations (AppNL−G−F/NL−G−F), termed APP knock-in (APPKI) mice. Our result showed that APPKI mice exhibited fear learning deficits at 6-m age and contextual memory deficit at 12-m age. Histopathological analysis revealed mild amyloidosis (6E10) accompanied by microgliosis (Iba1) as early as 3 months, which progressed significantly together with significant astrocytosis at 6 and 12 m. We further analyzed hippocampal mitochondrial dysfunction by multiple assays, while 3-m APPKI mice brain mitochondrial function remains a similar level as WT mice. Significant mitochondrial dysfunction characterized by decreased ATP production and higher membrane potential with subsequent overproduction of reactive oxygen species (ROS) was observed in mitochondria isolated from 7-m APPKI mice hippocampal tissue. Morphologically, these mitochondria were larger in volume with a decreased level of mitochondrial fusion protein mitofusin-2 (MFN2). At 12 months, APPKI mice exhibit a significantly decreased total mitochondrial oxygen consumption rate (OCR) in isolated hippocampal mitochondria detected by high-resolution respirometry. These data indicate early mitochondrial dysfunction in the brain at pre-symptomatic age in the AppNL−G−F/NL−G−mice, which may play a key role in the progression of the disease. Moreover, the identified behavioral and bioenergetic alterations in this clinically relevant AD mouse model provide a valuable tool to optimize the temporal component for therapeutic interventions to treat AD

Postoperative coagulation profiles of patients undergoing adult-to-adult living donor liver transplantation?A single-center experience

Objective: To characterize the pre- and postoperative coagulation profiles of patients undergoing adult-to-adult living donor liver transplantation (LDLT), using various coagulation tests and rotational thromboelastometry (ROTEM). Methods: This single-center observational study evaluated the various coagulation profiles of 22 patients (13 men and 9 women). Blood samples were obtained immediately after the induction of anesthesia (PRE) and on postoperative days (PODs) 1, 3, 5, and 7 after LDLT surgery. Results: Most procoagulant factors (fibrinogen, platelet, and coagulation factors II, VII, VIII, and IX) improved to levels equal to or greater than the PRE levels on POD 7. The levels of von Willebrand factor significantly increased after surgery, whereas those of disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13 decreased. Although the thrombin-antithrombin III complex increased immediately after surgery, the plasmin-α 2 plasmin inhibitor complex increased only on POD 7. The level of plasminogen activator inhibitor-1 increased on POD 1, returning to PRE levels on POD 3. Almost all ROTEM parameters were decreased or prolonged, compared to the PRE levels, on POD 7. Conclusions: The values of most coagulation tests showed the improvement or acceleration of coagulability on POD 7 than at PRE, with almost all the ROTEM parameters decreased or prolonged. Therefore, it cannot be concluded whether ROTEM reflects the net effect of hemostatic balance after liver transplantation

Association between enterocyte injury and fluid balance in patients with septic shock: a post hoc exploratory analysis of a prospective observational study

Background: The required fluid volume differs among patients with septic shock. Enterocyte injury caused by shock may increase the need for fluid by triggering a systematic inflammatory response or an ischemia-reperfusion injury in the presence of intestinal ischemia/necrosis. This study aimed to evaluate the association between enterocyte injury and positive fluid balance in patients with septic shock.Methods: This study was a post hoc exploratory analysis of a prospective observational study that assessed the association between serum intestinal fatty acid-binding protein, a biomarker of enterocyte injury, and mortality in patients with septic shock. Intestinal fatty acid-binding protein levels were recorded on intensive care unit admission, and fluid balance was monitored from intensive care unit admission to Day 7. The association between intestinal fatty acid-binding protein levels at admission and the infusion balance during the early period after intensive care unit admission was evaluated. Multiple linear regression analysis, with adjustments for severity score and renal function, was performed.Results: Overall, data of 57 patients were analyzed. Logarithmically transformed intestinal fatty acid-binding protein levels were significantly associated with cumulative fluid balance per body weight at 24 and 72 h post-intensive care unit admission both before (Pearson’s r = 0.490 [95% confidence interval: 0.263–0.666]; P < 0.001 and r = 0.479 [95% confidence interval: 0.240–0.664]; P < 0.001, respectively) and after (estimate, 14.4 [95% confidence interval: 4.1–24.7]; P = 0.007 and estimate, 26.9 [95% confidence interval: 11.0–42.7]; P = 0.001, respectively) adjusting for severity score and renal function.Conclusions: Enterocyte injury was significantly associated with cumulative fluid balance at 24 and 72 h post-intensive care unit admission. Enterocyte injury in patients with septic shock may be related to excessive fluid accumulation during the early period after intensive care unit admissio

Successful vaginal delivery in a parturient with long QT syndrome type 2 using double-catheter epidural analgesia

Rationale: Congenital long QT syndrome (LQTS) can cause syncope or sudden death due to ventricular arrhythmia. Congenital LQTS has 3 major types, 1, 2, and 3. Life-threatening arrhythmias are triggered by emotion in patients with LQTS type 2. As patients with LQTS type 2 have a higher incidence of postnatal cardiac events, careful perinatal management especially during delivery is required. To the best of our knowledge, perinatal management of a patient with LQTS type 2 has not been properly described with consideration to its type-specific risk factors for ventricular tachyarrhythmia.Patient concerns: A 36-year-old pregnant woman, gravida 1, para 0, with LQTS type 2 was scheduled to undergo vaginal delivery under epidural labor analgesia in the 38th week of pregnancy. No fainting episodes were reported since she began to take 40 mg of propranolol once daily at the age of 25. Despite this, we instituted maximum preventive measures for the safety of both the parturient and the fetus to minimize the risk of maternal cardiac events throughout the perinatal period.Diagnoses: She was diagnosed with LQTS type 2 by genetic testing at the age of 25.Interventions: Two epidural catheters were placed at levels T11–T12 and L5–S1. Injection of 0.2% ropivacaine and subsequent infusion of ropivacaine 0.1% with fentanyl (2 μg/mL) was directed through each catheter according to the stage of labor. Concurrently, landiolol, a selective and short-acting β1 receptor antagonist, was infused intravenously at a dose of 1 to 7 μg/kg/min.Outcomes: The delivery proceeded uneventfully without pain. No adverse cardiac events were observed during the perinatal period.Lessons: Vaginal delivery under epidural labor analgesia using 2 catheters might be a viable option for maternal perinatal care and delivery of patients with LQTS type 2

Effects of programmed intermittent thoracic paravertebral bolus of levobupivacaine on the spread of sensory block: a randomized, controlled, double-blind study.

Background and objectivesThis randomized, controlled, double-blind trial compared the effectiveness of levobupivacaine delivery of a programmed intermittent paravertebral bolus with a continuous paravertebral infusion.MethodsThirty-two consecutively enrolled patients who underwent unilateral video-assisted thoracic surgery were randomized to receive either a programmed intermittent paravertebral bolus of 10 mL of 0.2% levobupivacaine every 2 hours (Bolus group, n=16) or a continuous paravertebral infusion of 0.2% levobupivacaine at 5 mL/hour (Infusion group, n=16) after the operation. Postoperatively, after injection of 20 mL of 0.25% levobupivacaine through the paravertebral catheter, a mechanical infusion pump was set depending on the assigned group. The primary efficacy outcome was the number of anesthetized dermatomes 24 hours after the initial bolus of levobupivacaine. The secondary efficacy outcomes included the number of anesthetized dermatomes at other time points, pain at rest and coughing, additional analgesic use and patient acceptance of the analgesic technique. Arterial levobupivacaine concentration was measured to ensure safety. P&lt;0.05 was considered statistically significant.ResultsThe mean (95% CI) number of anesthetized dermatomes 24 hours after the initial bolus of levobupivacaine was significantly larger among subjects receiving programmed intermittent bolus (n=16) compared with those receiving continuous infusion (n=16; 6.8 (5.7-7.9) vs 3.1 (2.0-4.2); p&lt;0.001). The arterial levobupivacaine concentration did not reach a toxic level.ConclusionsThe programmed intermittent paravertebral bolus of levobupivacaine provided a wider dermatomal spread of sensory block than continuous paravertebral infusion with an identical hourly dose of levobupivacaine.Trial registration numberUMIN000022532

Effect of perioperative acetaminophen on body temperature after cardiovascular surgery with cardiopulmonary bypass: A single-center retrospective study

Context: Postoperative hyperthermia, which may lead to cognitive decline, is a common complication of cardiovascular surgery with cardiopulmonary bypass (CPB).Aims: The aim of this study was to examine the effectiveness of perioperative intravenous acetaminophen on body temperature in adult patients after cardiovascular surgery with CPB.Settings and Design: This was a single-center retrospective study focusing on adult patients who underwent elective cardiovascular surgery with CPB at a university hospital in Japan.Subjects and Methods: Patients were divided into two groups based on whether they received acetaminophen perioperatively. In the acetaminophen group, 15 mg/kg intravenous acetaminophen solution was infused at 30 min after discontinuation of CPB and every 6 h after intensive care unit (ICU) admission.Statistical Analysis Used: The primary outcome was the maximum axillary temperature within 12 h after ICU admission. The effects of acetaminophen on postoperative body temperature were estimated by the standardization and inverse probability weighting using propensity scores.Results: A total of 201 patients were included in the final analysis (acetaminophen group, n = 101; non-acetaminophen group, n = 100). The maximum axillary temperature within 12 h after ICU admission was 37.20 ± 0.54°C in the acetaminophen group and 37.78 ± 0.59°C in the non-acetaminophen group. Acetaminophen lowered the standardized mean of primary endpoint (?0.54°C, 95% confidence interval, ?0.69 to ?0.38) compared to non-acetaminophen.Conclusions: Perioperative intravenous acetaminophen inhibited body temperature elevation after cardiovascular surgery with CPB, compared with the non-acetaminophen group