Accelerated myocardial metabolic and functional recovery with terminal nicorandil-Mg cardioplegia in heart transplantation

Cardiac reperfusion injury after heart transplantation or cardiopulmonary bypass has been difficult to control due to the variable degree of myocardial damage with respect to the length of ischemia and the complexity of the surgical procedure. Here, we evaluated the myocardial metabolic and functional recovery of hearts infused with a nicorandil vasodilator-magnesium (Mg) solution just prior to reperfusion (terminal cardioplegia). Donor hearts (20 dogs) were removed and immersed in a 4 degrees C water bath containing 20 mEq/l KCL-5% glucose for 6 hours, and then were transplanted to recipient dogs. Orthotopically transplanted dog hearts were either reperfused without any further treatment or received a terminal cardioplegic solution containing 8 mg/l nicorandil, 30 mEq/l Mg, and 50 g/l glucose, which was infused at a pressure of 75 cm H2O for 2 minutes. During the reperfusion period, myocardial tissue PCO2 (t-PCO2) and calcium ion (t-Ca) were continuously monitored by an ISFET (ion-sensitive field effect transistor) sensor. Myocardial oxygen consumption and lactate flux were calculated/monitored at 5, 10, 20 and 40 minutes of reperfusion. Thereafter, myocardial function was evaluated at 45 minutes of reperfusion using LVSWI. Just after reperfusion, the treatment group (group B, n = 10) had a significantly greater coronary flow than the control group (Group A, n = 10, 35.0 +/- 10.1; group B, 47.4 +/- 8.5 ml/100 g/min, p less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dab1‐mediated colocalization of multi‐adaptor protein CIN85 with Reelin receptors,ApoER2 and VLDLR,in neurons

Reelin‐Dab1 signaling is indispensable for proper positioning of neurons in mammalian brain. Reelin is a glycoprotein secreted from Cajal‐Reztuis cells in marginal zone of cerebral cortex, and its receptors are Apolipoprotein E receptor 2 (ApoER2) or very low density lipoprotein receptor (VLDLR) expressed on migrating neurons. When Reelin binds to ApoER2 or VLDLR, an adaptor protein Dab1 bound to the receptors undergoes Tyr phosphorylation that is essential for Reelin signaling. We reported previously that Cdk5‐p35 phosphorylates Dab1 at Ser400 and Ser491 and the phosphorylation regulates its binding to CIN85, which is an SH3‐containing multiadaptor protein involved in endocytic downregulation of receptor‐tyrosine kinases. However, the interaction of CIN85 with Dab1 has not been addressed in neurons. We examined here a possibility that CIN85 has a role in Reelin signaling. We found nonpho‐sphorylated Dab1‐mediated colocalization of CIN85 with ApoER2. The colocalization of CIN85 with ApoER2 was increased in neurons stimulated with Reelin repeats 3‐6, an active Reelin fragment. The stimulation recruited CIN85 to domains in plasma membrane where it colocalized with ApoER2 and Dab1 and then to EEA1‐labeled early endosomes in the cytoplasm. In addition, Tyr phosphorylation of Dab1 strengthened the binding to CIN85. These results suggest that CIN85 participates in Reelin signaling through the binding to Dab1.     

Role of spinal metabotropic glutamate receptors in regulation of lower urinary tract function in the decerebrate unanesthetized rat

Biomarker levels in cerebrospinal fluid (CSF) may serve as surrogate markers for treatment efficacy in clinical trials of disease-modifying drugs against Alzheimer's disease (AD). A prerequisite, however, is that the marker is sufficiently stable over time in individual patients. Here, we tested the stability of the three established CSF biomarkers for AD, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau(181)) and the 42 amino acid isoform of beta-amyloid (Abeta42), over 6 months in a cohort of AD patients on stable treatment with acetylcholinesterase (AChE) inhibitors. Fifty-three patients completed the study, 29 men and 24 women, mean age (+/-S.D.) 76.1+/-7.9 years. Mean levels of CSF biomarkers were very stable between baseline and endpoint, with coefficients of variation (CVs) of 4.4-6.1%. Intra-individual biomarker levels at baseline and endpoint were also highly correlated with Pearson r-values above 0.95 (p<0.0001), for all three markers. We conclude that T-tau, P-tau and Abeta42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients. This suggest that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness as surrogate markers in clinical trials with drug candidates with disease-modifying potential, such as secretase inhibitors, Abeta immunotherapy and tau phosphorylation inhibitors.     

Clinical significance of small, dense LDL cholesterol in patients with hyperlipidemia and type 2 diabetes

We investigated the serum levels of small, dense LDL-cholesterol (sd LDL-C) in patients with hyperlipidemia and type 2 diabetes. An analytical assay was used to determine the levels of sd LDL-C, employing a filter method using a separating agent of polyanion and divalent cation natures. Reference intervals of sd LDL-C in normal healthy subjects (n=113) ranged from 8.0 to 42.0 mg/dl. We found a strong correlation between the levels of sd LDL-C and both the ratio of LDL-C/apolipoprotein B and the LDL migration index. The LDL migration index was analyzed using polyacrylamide gel disk electrophoresis. The levels of sd LDL-C in patients with types IIa, IIb and IV hyperlipidemia were significantly higher than those in normal subjects and in patients with normal lipidemia. The levels of sd LDL-C in patients with type IIb were higher than those with types IIa and VI. Examination of patients with polydisperse LDL showed that the levels of nodular and disrupted type sd LDL-C were higher than the levels of symmetry type sd LDL-C. Moreover, the levels of sd LDL-C in patients with type 2 diabetes were higher than those in normal subjects. A high level of sd LDL-C in patients with type 2 diabetes was found to be an indicator of possible complications of hyperlipidemia and lessly related to glycemic control. Therefore, the determination of sd LDL-C levels can be useful in the diagnosis of patients with hyperlipidemia and polydisperse LDL and in patients with type 2 diabetes with complications of hyperlipidemia and atherosclerosis.     

Analysis of autonomic outcomes in APOLLO,a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, − 7.5; 95% CI: − 11.9, − 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, − 1.1; − 1.8, − 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; − 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, − 0.3; − 0.5, − 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, − 5.3; 95% CI: − 7.9, − 2.7) and individual domains, orthostatic intolerance (− 4.6; − 6.3, − 2.9) and gastrointestinal symptoms (− 0.8; − 1.5, − 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.

     

Comparison of patency of single and sequential radial artery grafting in coronary artery bypass

Open in a separate window OBJECTIVESSequential radial artery (RA) grafting has the potential to enhance arterial revascularization compared to single grafting. Sequential RA grafting was performed predominantly with a single side-to-side anastomosis. The study aimed to assess if sequential RA grafting improved long-term graft patency compared to single RA grafting. In addition, the anastomotic patencies of side-to-side and end-to-side anastomoses in sequential RA grafting were assessed.METHODSTwo hundred nineteen patients underwent isolated coronary artery bypass grafting with skeletonized RA conduits between 2005 and 2016. Of these, 208 patients underwent radiological graft assessment; thus, 125 and 83 patients underwent single and sequential RA grafting, respectively. The graft and anastomotic patency rates were estimated using the Kaplan–Meier method.RESULTSThe median follow-up period was 9.1 years, and the radiological assessment lasted 5.1 years. The overall RA graft patency rates at 1, 5 and 10 years were 99.4%, 92.7% and 88.1%, respectively. The RA graft patency rate for sequential grafting was similar to that for single grafting (88.7% vs 87.4% at 10 years; P = 0.88). In the stratified analysis of anastomotic patency, the patency rate of side-to-side anastomoses of sequential RA grafting was significantly better than that of end-to-side anastomoses (100% vs 88.7% at 10 years; P = 0.01).CONCLUSIONSThe long-term RA graft patencies of sequential and single grafting were equally high. The anastomotic patency of side-to-side anastomoses of sequential RA grafting was remarkably high. Considering these findings, the RA can be effectively used for multiple arterial coronary revascularizations.