Effects of n-3 polyunsaturated fatty acid supplementation on quadriceps weakness immediately after total knee arthroplasty: a pilot, randomized, open-label clinical trial.

[Purpose] Severe quadriceps weakness immediately after total knee arthroplasty can be problematic. The n-3 long-chain polyunsaturated fatty acids have antioxidant and anti-inflammatory effects against ischemia-reperfusion injury, whereas n-6 long-chain polyunsaturated fatty acids exert pro-inflammatory effects, thereby promoting ischemia-reperfusion injury. [Participants and Methods] We explored the efficacy of preoperative n-3 long-chain polyunsaturated fatty acid supplementation against early quadriceps weakness among 20 patients scheduled for total knee arthroplasty (intervention group, n=10; control group, n=10). The intervention group received 645 mg of eicosapentaenoic acid) and 215 mg of docosahexaenoic acid daily for 30 days preoperatively. Serum eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels were measured preoperatively. We compared serum derivatives of reactive oxygen metabolites as oxidative stress biomarkers, knee circumference, thigh volume, knee pain during the quadriceps strength test, and quadriceps strength preoperatively and 4 days postoperatively to quantify the change. [Results] Preoperative n-3 long-chain polyunsaturated fatty acid supplementation significantly increased the (eicosapentaenoic acid+docosahexaenoic acid)/arachidonic acid ratio in the intervention group. A significantly lower increase in quadriceps weakness was exhibited in the intervention group than in the control group. However, changes in oxidative stress, knee/thigh swelling, and knee pain during strength testing did not significantly differ between the two groups. [Conclusion] Preoperative n-3 long-chain polyunsaturated fatty acid supplementation exhibited beneficial effects on quadriceps weakness immediately after total knee arthroplasty.

Synthesis of 6-Amino- and 6-Arylazoazulenes via Nucleophilic Aromatic Substitution and Their Reactivity and Properties.

The nucleophilic aromatic substitution (SNAr) reaction of diethyl 6-bromoazulene-1,3-dicarboxylate (1) with a variety of amines afforded the corresponding 6-aminoazulene derivatives 2a-2j in good-to-excellent yields. 6-Aminoazulene derivatives 3a-3f without the 1,3-diethoxycarbonyl functions were obtained by the deesterification of 2a-2f with 100% H3PO4. The reactivity of 6-aminoazulenes toward the bromination, SNAr, and palladium-catalyzed cross-coupling reactions was also clarified. 6-Arylazoazulenes 13a-13c were also prepared via the SNAr reaction of 1 with arylhydrazines, followed by oxidation with Pb(OAc)4 in the presence of N2H4. The structural, optical, and electrochemical properties of the 6-amino- and 6-arylazoazulenes were revealed by single-crystal X-ray structure analysis, UV/vis spectroscopy, voltammetry analysis, spectroelectrochemistry, and theoretical calculations.

Synthesis of 2-Azulenyltetrathiafulvalenes by Palladium-Catalyzed Direct Arylation of 2-Chloroazulenes with Tetrathiafulvalene and Their Optical and Electrochemical Properties.

Tetrathiafulvalene (TTF) derivatives with 2-azulenyl substituents 5-11 were prepared by the palladium-catalyzed direct arylation reaction of 2-chloroazulenes with TTF in good yield. Photophysical properties of these compounds were investigated by UV-vis spectroscopy and theoretical calculations. Redox behavior of the novel azulene-substituted TTFs was examined by using cyclic voltammetry and differential pulse voltammetry, which revealed their multistep electrochemical oxidation and/or reduction properties. Moreover, these TTF derivatives showed significant spectral change in the visible region under the redox conditions.

Synthesis of 2-amino- and 2-arylazoazulenes via nucleophilic aromatic substitution of 2-chloroazulenes with amines and arylhydrazines.

The SNAr reaction of 2-chloroazulene derivative 1 with ethoxycarbonyl groups at the 1,3-positions of the azulene ring with several amines afforded the corresponding 2-aminoazulenes 3-9 in excellent yields. 2-Chloroazulene (2) without the electron-withdrawing groups reacted with highly nucleophilic cyclic amines (i.e., morpholine, piperidine and pyrrolidine) under the high-temperature conditions in a sealed tube to produce the corresponding 2-aminoazulenes 10-12 in good yields. 2-Aminoazulenes 10-14 without the electron-withdrawing groups were also obtained in good yields by the treatment of compounds 3-7 with 100% H3PO4, but in the cases of the reaction of 8 and 9 with a secondary amine function, the decomposition of the products resulted. The synthesis of 2-arylazoazulenes 15-18 was also established via the SNAr reaction of 1 with arylhydrazines. The optical and electrochemical properties of the 2-arylazoazulene derivatives were examined by UV/Vis spectroscopy, theoretical calculations and voltammetric experiments.

Quadriceps Strength Loss Following Total Knee Arthroplasty as a Predictor of Three-Month Strength Recovery: A Secondary Analysis of a Randomized Controlled Trial.

Background and objectives Patients often experience significant quadriceps muscle weakness immediately after total knee arthroplasty (TKA), which can persist and lead to reduced physical function, increased risk of falls, and reduced patient satisfaction. Immediate postoperative quadriceps weakness is commonly caused by several factors, such as preoperative quadriceps weakness related to knee osteoarthritis (OA) and TKA-induced quadriceps weakness. Although many interventions have focused on addressing knee OA-related quadriceps weakness, there may be fewer studies specifically investigating TKA-induced quadriceps weakness. This study aimed to clarify whether TKA-induced quadriceps weakness is a significant predictor of quadriceps strength at three months postoperatively, highlighting the clinical importance of preoperative interventions targeting this specific weakness. Methods This secondary analysis of a randomized controlled trial included patients aged 60-79 years with advanced knee OA who underwent unilateral TKA. The study used pooled data from two groups of 11 participants each: those receiving preoperative low-intensity resistance training with blood flow restriction and those performing low-intensity resistance training with slow movement and tonic force generation. Quadriceps strength was assessed using a pull-type handheld dynamometer preoperatively at six weeks and one week as well as postoperatively at four days, one month, and three months. TKA-induced quadriceps weakness was defined as a change in strength from one week preoperatively to four days postoperatively. Postoperative quadriceps strength gain, reflecting postoperative recovery, was defined as the strength change from four days to three months postoperatively. Correlation and multiple regression analyses were used to identify the predictors of postoperative quadriceps strength at three months. Statistical significance was set at p < 0.05. Results The analysis included 22 participants. The median preoperative quadriceps strength was 1.1 Nm/kg (IQR: 0.9-1.4) at six weeks and 1.3 Nm/kg (IQR: 1.1-1.4) at one week. Quadriceps strength significantly decreased immediately after TKA (median quadriceps strength dropped to 0.4 Nm/kg (IQR: 0.3-0.4) at four days postoperatively) and gradually improved over three months (median three-month postoperative quadriceps strength was 0.9 Nm/kg (IQR: 0.8-1.0)). TKA-induced quadriceps weakness was -72% (SD: 11%), and postoperative quadriceps strength gain was 210% (IQR: 98-324%). TKA-induced quadriceps weakness was strongly correlated with quadriceps strength at four days (r = 0.84, p < 0.01). The postoperative quadriceps strength at four days was significantly correlated with the quadriceps strength at three months (r = 0.51, p = 0.02). Regression analysis showed that one-week preoperative quadriceps strength, TKA-induced quadriceps weakness, and postoperative quadriceps strength gain significantly predicted quadriceps strength at three months (R² = 0.77, p < 0.001). Conclusions This study highlights TKA-induced quadriceps weakness as a key predictor of postoperative quadriceps strength at three months. Preoperative interventions targeting TKA-induced weakness may improve postoperative recovery of quadriceps strength and functional outcomes.

Safety and Effects of a Four-Week Preoperative Low-Load Resistance Training With Blood Flow Restriction on Pre- and Postoperative Quadriceps Strength in Patients Undergoing Total Knee Arthroplasty: A Single-Blind Randomized Controlled Trial.

Background/Objectives Enhancing preoperative quadriceps strength and mitigating quadriceps strength loss due to total knee arthroplasty (TKA) is crucial for post-TKA recovery. This study compared the safety and effect of a four-week preoperative regimen of low-load resistance training with blood flow restriction (LLRT-BFR) with those of low-intensity resistance training with slow movement and tonic force generation (LST) on the pre- and postoperative quadriceps strength in patients undergoing TKA. Methods In this randomized controlled trial, 22 patients were assigned to either the LLRT-BFR (n=11) or LST (n=11) group. Primary outcomes included changes in quadriceps strength before and after the intervention and surgery. To assess safety, we monitored D-dimer and high-sensitivity C-reactive protein levels pre- and post-intervention. Statistical analysis involved independent samples t-tests and Mann-Whitney U tests for group comparisons of quadriceps strength changes. Additionally, a two-way repeated-measures analysis of variance was used to assess safety parameters. Results No significant differences were observed between the BFR and LST groups in terms of the rate of increase in quadriceps strength pre- and post-intervention (BFR: median 12.1%, interquartile range -0.8% to 19.5%; LST: median 6.2%, interquartile range 2.7% to 14.7%; p>0.99) or in the rate of reduction in quadriceps strength pre- and post-surgery (BFR: mean -72.4%, standard deviation ±11.2%; LST: mean -75.3%, standard deviation ±12.2%; p=0.57). Safety assessments showed no significant main effects of time, group, or interaction on the safety parameters (all p>0.05). Conclusions LLRT-BFR and LST demonstrated comparable effects on quadriceps strength before and after intervention and surgery in patients undergoing TKA. The lack of significant changes in the safety parameters supports the safety profile of both interventions, indicating their suitability for preoperative conditioning in patients scheduled for TKA.

Association between Preoperative Long-Chain Polyunsaturated Fatty Acids and Oxidative Stress Immediately after Total Knee Arthroplasty: A Pilot Study.

Quadriceps muscle atrophy following total knee arthroplasty (TKA) can be caused by tourniquet-induced ischemia-reperfusion (IR) injury, which is often accompanied by oxidative stress and inflammatory responses. n-3 long-chain polyunsaturated fatty acids (LCPUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert antioxidant and anti-inflammatory effects against IR injury, whereas n-6 LCPUFAs, particularly arachidonic acid (AA), exhibit pro-inflammatory effects and promote IR injury. This study aimed to examine whether preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio are associated with oxidative stress immediately after TKA. Fourteen eligible patients with knee osteoarthritis scheduled for unilateral TKA participated in this study. The levels of serum EPA, DHA, and AA were measured immediately before surgery. Derivatives of reactive oxygen metabolites (d-ROMs) were used as biomarkers for oxidative stress. The preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio were found to be significantly negatively correlated with the serum d-ROM levels at 96 h after surgery, and the rate of increase in serum d-ROM levels between baseline and 96 h postoperatively. This study suggested the preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio can be negatively associated with oxidative stress immediately after TKA.

Effects of preoperative low-intensity training with slow movement on early quadriceps weakness after total knee arthroplasty in patients with knee osteoarthritis: a retrospective propensity score-matched study.

BACKGROUND: Severe and early quadriceps weakness (QW) after total knee arthroplasty (TKA), which is caused by acute inflammation resulting from surgical trauma and tourniquet-induced ischemia-reperfusion (IR) injury, can be especially problematic. We focused on tourniquet-induced IR injury, because it has been shown to be preventable through ischemic and exercise preconditioning. Low-intensity resistance exercise with slow movement and tonic force generation (LST) share some similarities with ischemic and exercise preconditioning. The present study primarily aimed to clarify the efficacy of preoperative LST program as prehabilitation for early QW among patients with TKA using propensity score matching analysis. METHODS: This single-center retrospective observational study used data from patients with knee osteoarthritis (n = 277) who were scheduled to undergo unilateral TKA between August 2015 and January 2017. Those with missing outcome data due to their inability to perform tests were excluded. The LST group included participants who performed LST and aerobic exercise (LST session) more than seven times for three months prior to surgery. The control group included participants who performed less than eight LST sessions, a general and light exercise or had no exercise for three months prior to surgery. Knee circumference, thigh volume, knee pain during quadriceps strength test (QST) and timed up and go test (TUG), quadriceps strength, and TUG were measured before and 4 days after surgery. Knee swelling, thigh swelling, Δknee pain, QW, and ΔTUG were determined by comparing pre- and postoperative measurements. RESULTS: Propensity score matching generated 41 matched pairs who had nearly balanced characteristics. The LST group had a significantly lower knee and thigh swelling, QW, and ΔTUG compared to the control group (all, p < 0.05). No significant differences in Δknee pain during the QST and TUG were observed between both groups (both, p > 0.05). CONCLUSIONS: The present study demonstrated the beneficial effects of preoperative LST program on knee swelling, thigh swelling, QW, and walking disability immediately after TKA.

Direct synthesis of 2-arylazulenes by [8+2] cycloaddition of 2H-cyclohepta[b]furan-2-ones with silyl enol ethers.

We developed a procedure for the direct synthesis of 2-arylazulenes, which were obtained in moderate to excellent yields, by [8+2] cycloaddition of 2H-cyclohepta[b]furan-2-ones with aryl-substituted silyl enol ethers. The structures of some 2-arylazulenes were clarified by single-crystal X-ray analysis. The 2-phenylazulene derivatives obtained by this study showed noticeable fluorescence in acidic media.

Association between serum n-3 polyunsaturated fatty acids and quadriceps weakness immediately after total knee arthroplasty.

OBJECTIVES: Quadriceps weakness (QW) following total knee arthroplasty (TKA) can be elicited by tourniquet-induced ischaemia reperfusion (IR), which causes a vigorous acute inflammatory response. Dietary n-3 polyunsaturated fatty acids (PUFA) are important determinants of organ and tissue protection from IR. This study aimed to examine the association between serum n-3 PUFA levels and QW, knee pain, and knee swelling immediately after TKA. METHODS: A total of 32 patients who underwent unilateral TKA participated in this prospective study. On Postoperative Day 1, serum n-3 PUFA (eicosapentaenoic acid and docosahexaenoic acid) levels were measured. Preoperatively and on Postoperative Day 4, quadriceps strength, knee pain during quadriceps testing, and knee circumference were measured. QW, knee pain, and knee swelling were defined as changes in quadriceps strength, knee pain during quadriceps testing, and knee circumference, respectively, between the preoperative to the postoperative measurement. RESULTS: Mean serum n-3 PUFA levels were 192 µg/mL (standard deviation, 58 µg/mL) on Postoperative Day 1. All measured variables changed significantly between the preoperative and the postoperative measurement time-points (P <0.01). Quadriceps strength decreased from 1.2 to 0.4 Nm/kg (QW = -65%). Knee pain during quadriceps testing increased from 1.1 to 6.0 (knee pain = 4.0). Knee circumference increased from 40 to 44 cm (knee swelling = 10%). Multivariate analysis showed that lower serum n-3 PUFA levels were independently associated with an increased QW after adjusting for the Kellgren-Lawrence grade and the tourniquet time (P = 0.04). No significant relationship was observed between serum n-3 PUFA levels and knee pain or knee swelling. CONCLUSION: Higher serum n-3 PUFA are independently associated with a lower increase in the QW immediately after TKA.

Pulmonary oxygen uptake on-kinetics can predict acute physiological responses to resistance exercise training in healthy young men.

PURPOSE: To clarify whether pulmonary oxygen uptake kinetics ( τ V ˙ O 2 p ) at the onset of moderate-intensity exercise can predict acute physiological responses to resistance exercise training (RET). METHODS: We investigated the relationship between τ V ˙ O 2 p and acute metabolic and hemodynamic responses to a single RET session in 27 healthy young adult men. Cardiopulmonary exercise was on a cycle ergometer, and a single RET at 30% or 60% of one-repetition maximum was on a bilateral leg-extension machine. We measured the anaerobic threshold, peak V ˙ O 2 and τ V ˙ O 2 p while cardiopulmonary exercising, and the rates of increase in blood lactate (Bla), heart rate (HR), systolic blood pressure (SBP) and rate pressure product (RPP) for a single RET. RESULTS: There were significant positive associations between τ V ˙ O 2 p and the rates of increase in Bla, HR, SBP and RPP during a single RET session (P<0·05). However, the anaerobic threshold and peak V ˙ O 2 did not significantly affect these parameters. CONCLUSION: The τ V ˙ O 2 p is a useful evaluation index for predicting acute physiological responses to RET.

Sensitisation of Cancer Cells to MLN8237, an Aurora-A Inhibitor, by YAP/TAZ Inactivation.

BACKGROUND: Transcriptional co-activators YES-associated protein (YAP) and transcriptional coactivator with PDZ-motif (TAZ) stimulate the expression of cell cycle-related genes to permit for tumour cell growth. MLN8237 is a potent aurora-A kinase inhibitor; however, patients responding to MLN8237 are limited. Therefore, rational combination therapy could enhance their response. MATERIALS AND METHODS: YAP and TAZ were depleted using siRNA and then treated with MLN8237 in YAP/TAZ-dependent OVCAR-8 and MDA-MB-231 cell lines. MLN8237 was combined with fluvastatin, an agent constraining nuclear localisation of YAP/TAZ for potential combination therapy in vitro. RESULTS: Depletion of either YAP or TAZ sensitised these cell lines to MLN8237, resulting in apoptosis and reduction in aurora-A. MLN8237 reduced YAP/TAZ expression. A combination of MLN8237 with fluvastatin effectively reduced the cell viability of OVCAR-8 and MDA-MB-231 cell lines. CONCLUSION: A combination of MLN8237 and small-molecule agents inactivating YAP/TAZ, such as statins, could be a novel therapeutic strategy for YAP/TAZ-dependent cancer.