Electrical Stimulation-Based Twitch Exercise Suppresses Progression of Immobilization-Induced Muscle Fibrosis via Downregulation of PGC-1?/VEGF Pathway.

This study aimed to determine whether electrical stimulation-based twitch exercise is effective in inhibiting the progression of immobilization-induced muscle fibrosis. 19 Wistar rats were randomly divided into a control group (n=6), an immobilization group (n=6; with immobilization only), and a Belt group (n=7; with immobilization and twitch exercise through the belt electrode device, beginning 2 weeks after immobilization). The bilateral soleus muscles were harvested after the experimental period. The right soleus muscles were used for histological analysis, and the left soleus muscles were used for biochemical and molecular biological analysis. As a result, in the picrosirius red images, the perimysium and endomysium were thicker in both the immobilization and Belt groups compared to the control group. However, the perimysium and endomysium thickening were suppressed in the Belt group. The hydroxyproline content and alpha-SMA, TGF-beta1, and HIF-1alpha mRNA expressions were significantly higher in the immobilization and belt groups than in the control group. These expressions were significantly lower in the Belt group than in the immobilization group. The capillary-to-myofiber ratio and the mRNA expressions of VEGF and PGC-1alpha were significantly lower in the immobilization and belt groups than in the control group, these were significantly higher in the Belt group than in the immobilization group. From these results, Electrical stimulation-based twitch exercise using the belt electrode device may prevent the progression of immobilization-induced muscle fibrosis caused by downregulating PGC-1alpha/VEGF pathway, we surmised that this intervention strategy might be effective against the progression of muscle contracture. Keywords: Immobilization, Skeletal muscle, Fibrosis, Electrical stimulation-based twitch exercise, PGC-1alpha/VEGF pathway.

Skeletal Muscle Electrical Stimulation Prevents Progression of Disuse Muscle Atrophy via Forkhead Box O Dynamics Mediated by Phosphorylated Protein Kinase B and Peroxisome Proliferator-Activated Receptor gamma Coactivator-1alpha.

Although electrical muscle stimulation (EMS) of skeletal muscle effectively prevents muscle atrophy, its effect on the breakdown of muscle component proteins is unknown. In this study, we investigated the biological mechanisms by which EMS-induced muscle contraction inhibits disuse muscle atrophy progression. Experimental animals were divided into a control group and three experimental groups: immobilized (Im; immobilization treatment), low-frequency (LF; immobilization treatment and low-frequency muscle contraction exercise), and high-frequency (HF; immobilization treatment and high-frequency muscle contraction exercise). Following the experimental period, bilateral soleus muscles were collected and analyzed. Atrogin-1 and Muscle RING finger 1 (MuRF-1) mRNA expression levels were significantly higher for the experimental groups than for the control group but were significantly lower for the HF group than for the Im group. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNA and protein expression levels in the HF group were significantly higher than those in the Im group, with no significant differences compared to the Con group. Both the Forkhead box O (FoxO)/phosphorylated FoxO and protein kinase B (AKT)/phosphorylated AKT ratios were significantly lower for the Im group than for the control group and significantly higher for the HF group than for the Im group. These results, the suppression of atrogin-1 and MuRF-1 expression for the HF group may be due to decreased nuclear expression of FoxO by AKT phosphorylation and suppression of FoxO transcriptional activity by PGC-1alpha. Furthermore, the number of muscle contractions might be important for effective EMS.

Comparison of short-term outcomes of robotic and laparoscopic transabdominal peritoneal repair for unilateral inguinal hernia: a propensity-score matched analysis.

PURPOSE: This study aimed to compare perioperative outcomes of robotic and laparoscopic transabdominal peritoneal repair (TAPP) for unilateral inguinal hernia. METHODS: This single institutional retrospective cohort study used de-identified data of patients who underwent robotic TAPP (R-TAPP) or laparoscopic TAPP (L-TAPP) for unilateral inguinal hernia between January 1, 2016 and October 31, 2021. Two cohorts were propensity matched, and data were analyzed. The learning curve was evaluated in the R-TAPP group. RESULTS: Among 938 patients analyzed, 704 were included. After propensity-score matching, 80 patients were included in each group. The difference in operative time between R-TAPP and L-TAPP groups was 10 min (99.5 and 89.5 min, p = 0.087); however, console/laparoscopic time was similar (67 and 66 min, p = 0.71). The dissection time for medial-type hernia in the R-TAPP group was marginally shorter than that in the L-TAPP group (17 and 27 min, p = 0.056); however, there was no difference for lateral-type hernia (38.5 and 40 min p = 0.37). Perioperative variables, including estimated blood loss, postoperative hospital stay, and postoperative pain, had no significant difference, and chronic pain, which needed medication or intervention, was not observed in each group. The number of cases needed to achieve plateau performance was 7-10 in the R-TAPP group. CONCLUSION: This study suggests that R-TAPP was safely introduced, and its perioperative outcomes were not inferior to those of L-TAPP. A shorter dissection time for medial-type hernia might be due to the robot's advantages, and a fast-learning curve could help with the early standardization of the procedure.

Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

The effects of wheel-running using the upper limbs following immobilization after inducing arthritis in the knees of rats.

This study investigated the effects of wheel-running using the upper limbs following immobilization after inducing arthritis in the knees of rats. Forty male Wistar rats (aged 8 weeks) divided into four groups randomly: arthritis (AR), immobilization after arthritis (Im), wheel-running exercise with the upper limbs following immobilization after arthritis induction (Im+Ex) and sham arthritis induction (Con). The knee joints of the Im and Im+Ex groups were immobilized with a cast for 4 weeks. In the Im+Ex group, wheel-running exercise was administered for 60 min/day (5 times/week). The swelling and the pressure pain threshold (PPT) of the knee joint were evaluated for observing the condition of inflammatory symptoms in affected area, and the paw withdraw response (PWR) was evaluated for observing the condition of secondary hyperalgesia in distant area. Especially, in order to evaluate histological inflammation in the knee joint, the number of macrophage (CD68-positive cells) in the synovium was examined. The expression of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn (L2-3 and L4-5) was examined to evaluate central sensitization. The Im+Ex group showed a significantly better recovery than the Im group in the swelling, PPTs, and PWRs. Additionally, CGRP expression of the spinal dorsal horn (L2-3 and L4-5) in the Im+Ex group was significantly decreased compared with the Im group. According to the results, upper limb exercise can decrease pain in the affected area, reduce hyperalgesia in distant areas, and suppress the central sensitization in the spinal dorsal horn by triggering exercise-induced hypoalgesia (EIH).

Active site rearrangement and structural divergence in prokaryotic respiratory oxidases.

Cytochrome bd-type quinol oxidases catalyze the reduction of molecular oxygen to water in the respiratory chain of many human-pathogenic bacteria. They are structurally unrelated to mitochondrial cytochrome c oxidases and are therefore a prime target for the development of antimicrobial drugs. We determined the structure of the Escherichia coli cytochrome bd-I oxidase by single-particle cryo-electron microscopy to a resolution of 2.7 angstroms. Our structure contains a previously unknown accessory subunit CydH, the L-subfamily-specific Q-loop domain, a structural ubiquinone-8 cofactor, an active-site density interpreted as dioxygen, distinct water-filled proton channels, and an oxygen-conducting pathway. Comparison with another cytochrome bd oxidase reveals structural divergence in the family, including rearrangement of high-spin hemes and conformational adaption of a transmembrane helix to generate a distinct oxygen-binding site.

SAPPHIRE: a randomised phase II study of planned discontinuation or continuous treatment of oxaliplatin after six cycles of modified FOLFOX6 plus panitumumab in patients with colorectal cancer.

BACKGROUND: Fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) plus panitumumab therapy is a commonly used first-line chemotherapy for metastatic colorectal cancer (mCRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). We investigated whether the planned discontinuation of oxaliplatin after FOLFOX plus panitumumab therapy can maintain efficacy and reduce PN incidence. PATIENTS AND METHODS: Chemotherapy-naive patients with RAS wild-type mCRC, aged ≥20 years, were enrolled and received six cycles of modified FOLFOX6 (mFOLFOX6) plus panitumumab as induction therapy. Patients who completed induction therapy without progression were randomised to mFOLFOX6 plus panitumumab (group A) or to 5-FU/LV plus panitumumab (group B). The primary end-point was the progression-free survival (PFS) rate at 9 months after randomisation. The secondary end-points were PFS, overall survival (OS), time to treatment failure (TTF), response rate (RR) and safety. RESULTS: In total, 164 patients were enrolled; of whom, 113 patients were then randomised (group A, n = 56; group B, n = 57). The median follow-up after randomisation was 19.6 months. The PFS rates at 9 months and median PFS were 46.4% (80% confidence interval [CI], 38.1-54.9) and 9.1 months (95% CI, 8.6-11.1) in group A, compared with 47.4% (80% CI, 39.1-55.8) and 9.3 months (95% CI, 6.0-13.0) in group B, respectively. RR, OS and TTF were also similar in both groups. Grade ≥2 PN incidence was lower in group B (9.3%) than in group A (35.7%). CONCLUSION: Planned discontinuation of oxaliplatin after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC, achieving similar efficacy while reducing oxaliplatin-associated PN compared with mFOLFOX6 plus panitumumab. TRIAL REGISTRATION NUMBER: NCT02337946.

Engineering a platform for nerve regeneration with direct application to nerve repair technology.

The development of effective treatment options for repair of peripheral nerves is complicated by lack of knowledge concerning the interactions between cells and implants. A promising device, the multichannel scaffold, incorporates microporous channels, aligning glia and directing axonal growth across a nerve gap. To enhance clinical outcomes of nerve repair, a platform, representative of current implant technology, was engineered which 1) recapitulated key device features (porosity and linearity) and 2) demonstrated remyelination of adult neurons. The in vitro platform began with the study of Schwann cells on porous polycaprolactone (PCL) and poly(lactide co-glycolide) (PLGA) substrates. Surface roughness determined glial cell attachment, and an additional layer of topography, 40 µm linear features, aligned Schwann cells and axons. In addition, direct co-culture of sensory neurons with Schwann cells significantly increased neurite outgrowth, compared to neurons cultured alone (naive or pre-conditioned). In contrast to the control substrate (glass), on porous PCL substrates, Schwann cells differentiated into a mature myelinating phenotype, expressing Oct-6, MPZ and MBP. The direct applicability of this platform to nerve implants, including its response to physiological cues, allows for optimization of cell-material interactions, close observation of the regeneration process, and the study of therapeutics, necessary to advance peripheral nerve repair technology.

Changes in penile length after radical prostatectomy: effect of neoadjuvant androgen deprivation therapy.

Although reports have shown evidence for penile length (PL) shortening after radical prostatectomy (RP), the association between neoadjuvant androgen deprivation therapy (NADT) and PL after RP has yet to be determined. This study evaluates chronological changes in PL after NADT and RP. Stretched PLs (SPLs) of 143 patients, 41 of whom had undergone NADT, were measured before, 10 days after, and 1, 3, 6, 9, 12, 18, and 24 months after RP. Chronological erectile function and testosterone levels were then evaluated. SPL was shortest 10 days after RP in both the NADT (-) and NADT (+) groups and gradually recovered in length thereafter. SPL in the NADT (-) group was significantly longer than that in the NADT (+) group before RP. However, no significant differences in SPLs were found between both groups 6 months after RP. Although all subjects in the NADT (+) group had testosterone levels of <50 ng/dL before RP, such levels increased after RP. Before RP, the NADT (-) group was found to have significantly better erectile function than the NADT (+) group. However, differences in erectile function between the NADT (-) and NADT (+) groups after RP were not significant. This report is the first to show that among patients with prostate cancer, those who underwent NADT had greater PL recovery after RP than those who did not. Data regarding PL recovery after NADT and RP obtained in this study could be useful for patients with prostate cancer who plan to undergo such procedures.

Potential biological control of Erwinia tracheiphila by internal alimentary canal interactions in Acalymma vittatum with Pseudomonas fluorescens.

AIMS: We aim to determine if Pseudomonas fluorescens is a viable biological control for Erwinia tracheiphila within the insect vector, Acalymma vittatum. METHODS AND RESULTS: Pseudomonas fluorescens secreted fluorescein and inhibited growth of E. tracheiphila in disc diffusion assays. To determine if this antagonism was conserved within the insect vector, we performed in vivo assays by orally injecting beetles with bacterial treatments and fluorescent in situ hybridization to determine bacterial presence within the alimentary canal. CONCLUSIONS: Pseudomonas fluorescens inhibited the growth of E. tracheiphila on a nutrient-limiting medium. In situ experiments demonstrated that P. fluorescens is maintained within the alimentary canal of the beetle for at least 4 days, and co-occurred with E. tracheiphila. When beetles were first presented with Pseudomonas and then challenged with E. tracheiphila, E. tracheiphila was not recovered via FISH after 4 days. These data suggest that P. fluorescens has potential as a biological control agent to limit E. tracheiphila within the insect vector. SIGNIFICANCE AND IMPACT OF THE STUDY: This is a novel approach for controlling E. tracheiphila that has the potential to decrease reliance on insecticides, providing a safer environment for pollinators and growers.

Microstructure and in vivo characterization of multi-channel nerve guidance scaffolds.

In a previous study, we demonstrated a novel manufacturing approach to fabricate multi-channel scaffolds (MCS) for use in spinal cord injuries (SCI). In the present study, we extended similar materials processing technology to fabricate significantly longer (5X) porous poly caprolactone (PCL) MCS and evaluated their efficacy in 1 cm sciatic peripheral nerve injury (PNI) model. Due to the increase in MCS dimensions and the challenges that may arise in a longer nerve gap model, microstructural characterization involved MCS wall permeability to assess nutrient flow, topography, and microstructural uniformity to evaluate the potential for homogeneous linear axon guidance. It was determined that the wall permeability dramatically varied from 0.02 ± 0.01 × 10-13 to 21.7 ± 11.4 × 10-13 m2 for 50% and 70% porous PCL, respectively. Using interferometry, the porous PCL surface roughness was determined to be 10.7 ± 1.2 µm, which is believed to be sufficient to promote cell integration. Using micro computed tomography, the 3D MCS microstructure was determined to be uniform over 1 cm with an open lumen volume of 44.6% ± 3.6%. In vivo implantation, in the rat sciatic nerve model, over 4 weeks, demonstrated that MCS scaffolds maintained structural integrity, were biocompatible, and supported linear axon guidance and distal end egress over 1 cm. Taken together, this study demonstrated that MCS technology previously developed for the SCI is also relevant to longer nerve gap PNI.

Effects of a psychosocial intervention programme combined with exercise in community-dwelling older adults with chronic pain: A randomized controlled trial.

BACKGROUND: Although researchers have recommended exercise training and psychosocial intervention to manage chronic pain, an effective intervention for Japanese community-dwelling older adults with chronic pain has not been established. This randomized controlled trial examined whether exercise training combined with psychosocial intervention more effectively improves pain, psychological status and physical activity than does exercise training alone in this population. METHODS: We randomized 128 older adults with chronic pain to either an intervention group (n = 64) involving exercise training combined with psychosocial intervention, or a control group (n = 64) involving only exercise training. Exercise training comprised weekly 60-min sessions for 12 weeks. Psychosocial intervention involved changing participants' focus on pain using self-management education and cognitive behavioural therapy, and participants recorded their daily pain intensity and step counts. Pain intensity, psychological status and physical activity were assessed before and 12 weeks after the intervention. RESULTS: A time-by-group interaction emerged for psychological status (p = 0.003) and physical activity (p < 0.001), both favouring the intervention group. The intervention group also showed greater improvement in pain intensity at 12 weeks than did the control group (p = 0.007). CONCLUSIONS: Exercise training combined with psychosocial intervention improves key outcome indicators more effectively than does exercise training alone in older adults with chronic pain. SIGNIFICANCE: Although research has shown that combined exercise and psychosocial intervention is optimal for managing chronic pain, our study is the first, to the best of our knowledge, to test a specific intervention of this type in community-dwelling older adults with chronic pain in Japan.

The influence of aging on the effectiveness of heat stress in preventing disuse muscle atrophy.

This study examined the aging effect on disuse muscle atrophy prevention using heat stress. Wistar rats aged 7 and 60 weeks were divided into three groups as follows: control, immobilized (Im), and immobilized and heat stressed (ImH). Heat stress was given by immersing the hindlimbs in hot water (42 °C) for 60 min, once in every 3 days and the gastrocnemius (GAS) and soleus (SOL) muscles were extracted after 14 days. Muscle-fiber types were classified using ATPase staining. Heat shock protein 70 (HSP70) was assessed through Western blotting. In GAS muscle of both groups and SOL muscle of 7-week-old rats, the fiber diameter of each muscle type in the ImH group significantly increased compared with that in the Im group. However, this could not be observed in the SOL muscle of the 60-week-old rats. The increased percentage of type-I fibers and variability of types I and II muscle-fiber diameter were evident in the SOL muscle of the 60-week rats. HSP70 was significantly elevated in the ImH group compared with in the Im group in both muscle types of both age groups. Thus, effectiveness of heat stress in the prevention of disuse muscle atrophy appears unsatisfactory in aging muscle fibers.

Effects of peripheral administration of a Neuromedin U receptor 2-selective agonist on food intake and body weight in obese mice.

BACKGROUND: Neuromedin U (NMU) is a neuropeptide with various physiological functions, including regulation of smooth-muscle contraction, blood pressure, stress responses and feeding behaviors. NMU activates two distinct receptors, NMUR1 and NMUR2, which are predominantly expressed in peripheral tissues and the central nervous system (CNS), respectively. It is reported that the NMU signaling system regulates food intake (FI) and body weight (BW) via NMUR2, suggesting that an NMUR2 agonist exhibiting anorectic effects would be a potential therapy for obesity. METHODS: Antiobesity effects of NMUR2 activation were assessed using a recently developed, novel NMUR2-selective agonist, NMU-7005 (a polyethylene glycolated octapeptide). Here we assessed cumulative FI and BW loss after peripheral administration of NMU-7005 in NMUR2 knockout and diet-induced obese mice. To gain mechanistic insights, we performed immunohistochemical analysis of c-Fos-like protein expression in the brain. RESULTS: We found that NMU-7005 was a NMUR2-selective agonist with little activity toward NMUR1. The anorectic effect of NMU-7005 was completely abrogated in NMUR2 knockout mice. Repeated subcutaneous administration of NMU-7005 showed a potent antiobesity effect with FI inhibition (P<0.025) in diet-induced obese mice. NMU-7005 in combination with the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide showed an additive antiobesity effect, suggesting that NMUR2-mediated anorectic action is different from that of GLP-1R agonists. NMU-7005 also elicited a minimal conditioned taste-aversive effect, while the effect of liraglutide was significant. As c-Fos expression was upregulated in the hypothalamus and the medulla oblongata in NMU-7005-administered mice, the pharmacological effects of NMU-7005 appeared to be mediated via activation of the CNS. CONCLUSION: Our results demonstrated that a novel NMUR2-selective agonist, NMU-7005, is a beneficial tool for the elucidation of NMUR2-mediated physiological functions, which is a promising therapeutic strategy for treating obesity.

Myeloperoxidase in blood neutrophils during normal and abnormal menstrual cycles in women of reproductive age.

INTRODUCTION: We previously reported that granulocyte colony-stimulating factor (G-CSF) plays a critical role in ovulation, suggesting that neutrophils may maintain ovulation. We assessed myeloperoxidase (MPO), a major and specific enzyme of neutrophils, in women with abnormal and normal menstrual cycles to clarify the relationship between MPO and ovulation. METHODS: We analyzed MPO activity in blood neutrophils of women with abnormal menstrual cycles (indicative of anovulation, n = 12) and age- and body mass index-matched normal menstrual cycles (indicative of ovulation, n = 24) using two parameters as a marker of MPO, Neut X and mean peroxidase index (MPXI). RESULTS: MPO of women with abnormal menstrual cycles was significantly lower than that of women with normal menstrual cycles [Neut X: 62.6 ± 1.1 (mean ± standard error of the mean) vs. 66.2 ± 0.3, P = 0.009; MPXI: -0.54 ± 1.66 vs. 4.91 ± 0.53, P = 0.008]. Among women with normal menstrual cycles, MPO was highest in the follicular phase (Neut X: 67.0 ± 0.3; P = 0.033). CONCLUSION: The difference in MPO between women with abnormal and normal menstrual cycles and the upregulation of MPO before ovulation suggest that neutrophils and MPO are closely related to ovulation.

Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

Effect of continuous passive motion initiated after the onset of arthritis on inflammation and secondary hyperalgesia in rats.

This study investigated the effect of continuous passive motion (CPM) initiated after the onset of arthritis in rats. Rats were injected with 3 % kaolin/carrageenan in the knee joint and randomized to the control, immobilization (IM), or CPM group. The knee joints of the IM and CPM groups were immobilized with a cast for 56 days. In the CPM group, CPM exercise was administered for 60 min/day (6 times/week). Joint transverse diameter and pressure pain threshold (PPT) were assessed as indicators of inflammation, and paw withdrawal response (PWR) was assessed as indicator of secondary hyperalgesia. Central sensitization was analyzed by measuring calcitonin gene-related peptide (CGRP) expression levels in the spinal dorsal horn. In the CPM group, the PPT was significantly increased compared with the IM group from 14 to 35 days, and PWR was significantly decreased from 14 to 56 days. Additionally, CGRP expression in the super facial layer (I-II) of the spinal dorsal horn (L4-5) in the CPM group was significantly decreased compared with the IM group. Our study found the CPM initiated after the onset of arthritis promoted the recovery of inflammation and mitigated secondary hyperalgesia.

Heat treatment inhibits skeletal muscle atrophy of glucocorticoid-induced myopathy in rats.

The purpose of this study was to investigate the influence of heat treatment on glucocorticoid (GC)-induced myopathy. Eight-week-old Wistar rats were randomly assigned to the control, Dex, and Dex + Heat groups. Dexamethasone (2 mg/kg) was injected subcutaneously 6 days per week for 2 weeks in the Dex and Dex + Heat group. In the Dex + Heat group, heat treatment was performed by immersing hindlimbs in water at 42 °C for 60 min, once every 3 days for 2 weeks. The extensor digitorum longus muscle was extracted following 2 weeks of experimentation. In the Dex + Heat group, muscle fiber diameter, capillary/muscle fiber ratio, and level of heat shock protein 72 were significantly higher and atrogene expression levels were significantly lower than in the Dex group. Our results suggest that heat treatment inhibits the development of GC-induced myopathy by decreasing atrogene expression and increasing angiogenesis.

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study.

BACKGROUND: A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety. RESULTS: Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups. CONCLUSION: Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment. CLINICAL TRIAL IDENTIFIER: UMIN000002557.

Differentiating benign and malignant salivary gland tumours: diagnostic criteria and the accuracy of dynamic contrast-enhanced MRI with high temporal resolution.

OBJECTIVE: To determine the optimal diagnostic criterion of dynamic contrast-enhanced MRI (DCE-MRI) for predicting salivary gland malignancy using a dynamic sequence with high temporal resolution, as well as the accuracy of this technique. METHODS: The DCE-MRI findings of 98 salivary gland tumours (74 benign and 24 malignant) were reviewed. MR images were sequentially obtained at 5-s intervals for 370 s. Two parameters, peak time and washout ratio (WR) were determined from the time-signal intensity curve. The optimal thresholds of these parameters for differentiating benign and malignant tumours were determined, along with the diagnostic accuracy of the criterion using these thresholds. RESULTS: A peak time of 150 s and a WR of 30% were identified as optimal thresholds. As the criterion for malignancy, the combination of peak time <150 s and WR <30% provided a sensitivity of 79% (19/24), specificity of 95% (70/74) and an overall accuracy of 91% (89/98). Three of the five false-negative cases were malignant lymphomas of the parotid gland. CONCLUSION: Peak time <150 s with WR <30% comprised the optimal diagnostic criterion in predicting salivary gland malignancy, providing a sensitivity of 79% and specificity of 95%. The use of high temporal resolution might improve the accuracy of DCE-MRI. ADVANCES IN KNOWLEDGE: Although several studies have reported the usefulness of DCE-MRI in the differential diagnosis of salivary gland tumours, the specific diagnostic criteria employed have differed widely. We determined the optimal criterion and its accuracy using a dynamic sequence with high temporal resolution.