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.     

Critical role of Frizzled1 in age‐related alterations of Wnt/β‐catenin signal in myogenic cells during differentiation

Activation of Wnt/β‐catenin signal in muscle satellite cells (mSCs) of aged mice during myogenic differentiation has been appreciated as an important age‐related feature of the skeletal muscles, resulting in impairment of their regenerative ability following muscle injury. However, it remains elusive about molecules involved in this age‐related alteration of Wnt/β‐catenin signal in myogenic cells. To clarify this issue, we carried out expression analyses of Wnt receptor genes using real‐time RT‐PCR in mSCs isolated from the skeletal muscles of young and aged mice. Here, we show that expression of Frizzled1 (Fzd1) was detected at high levels in mSCs of aged mice. Higher expression levels of Fzd1 were also detected in mSC‐derived myogenic cells from aged mice and associated with activation of Wnt/β‐catenin signal during their myogenic differentiation in vitro. We also provide evidence that suppressed expression of Fzd1 in myogenic cells from aged mice results in a significant increase in myogenic differentiation, and its forced expression in those from young mice results in its drastic inhibition. These findings indicate the critical role of Fzd1 in altered myogenic differentiation associated with aging.     

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.

     

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

Journal of Neurology - The original version of this article unfortunately contained a mistake.     

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.     

Adding coronary artery bypass grafting to aortic valve replacement increases operative mortality for elderly (70 years and older) patients with aortic stenosis

Objective

This retrospective study aimed to determine the effect of simultaneous aortic valve replacement (AVR) and coronary artery bypass grafting (CABG) on operative outcomes and long-term survival in elderly patients with a high prevalence of comorbidity.

Methods

One hundred and fifty-seven elderly patients (70 years old or older) undergoing isolated AVR (n = 120) or combined AVR/CABG (n = 37) were evaluated. Operative outcomes were compared between the two surgical groups. Long-term survival was also compared between the groups using the Kaplan–Meier method and long-rank (Mantel–Cox) test.

Results

Operative mortality was 0.8 % for the isolated AVR group and 5.4 % for the combined AVR/CABG group (p = 0.076). The length of the intensive care unit stay for the combined AVR/CABG group was significantly longer than that for the isolated AVR group (median: 40 vs. 21 h, p = 0.008). However, the occurrence rate of hospital complications, such as reoperation for bleeding, deep sternal infection, supra-ventricular arrhythmia, and neurological complications, was similar between the two groups. Actuarial survival at 3 and 5 years was 82.3 and 80.9 % for the isolated AVR group, and 88.3 and 73.0 % for the combined AVR/CABG group, respectively (p = 0.637).

Conclusions

The satisfactory operative and long-term results in our study support a more aggressive simultaneous coronary revascularization combined with AVR for aortic valve stenosis in elderly patients.     

Athermal ω Phase and Lattice Modulation in Binary Zr-Nb Alloys

To further explore the potential of Zr-based alloys as a biomaterial that will not interfere with magnetic resonance imaging (MRI), the microstructural characteristics of Zr-xat.% Nb alloys (10 ≤ x ≤ 18), particularly the athermal ω phase and lattice modulation, were investigated by conducting electrical resistivity and magnetic susceptibility measurements and transmission electron microscopy observations. The 10 Nb alloy and 12 Nb alloys had a positive temperature coefficient of electrical resistivity. The athermal ω phase existed in 10 Nb and 12 Nb alloys at room temperature. Alternatively, the 14 Nb and 18 Nb alloys had an anomalous negative temperature coefficient of the resistivity. The selected area diffraction pattern of the 14 Nb alloy revealed the co-occurrence of ω phase diffraction and diffuse satellites. These diffuse satellites were represented by g_β + q when the zone axis was [001] or [113], but not [110]. These results imply that these diffuse satellites appeared because the transverse waves consistent with the propagation and displacement vectors were q = <ζ ζ¯ 0>* for the ζ~1/2 and <110> directions. It is possible that the resistivity anomaly was caused by the formation of the athermal ω phase and transverse wave. Moreover, control of the athermal ω-phase transformation and occurrence of lattice modulation led to reduced magnetic susceptibility, superior deformation properties, and a low Young’s modulus in the Zr-Nb alloys. Thus, Zr-Nb alloys are promising MRI-compatible metallic biomaterials.