Inhibitory Effect of a Tankyrase Inhibitor on Mechanical Stress-Induced Protease Expression in Human Articular Chondrocytes.

We investigated the effects of a Tankyrase (TNKS-1/2) inhibitor on mechanical stress-induced gene expression in human chondrocytes and examined TNKS-1/2 expression in human osteoarthritis (OA) cartilage. Cells were seeded onto stretch chambers and incubated with or without a TNKS-1/2 inhibitor (XAV939) for 12 h. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 8% elongation, 30 min) was applied and the gene expression of type II collagen a1 chain (COL2A1), aggrecan (ACAN), SRY-box9 (SOX9), TNKS-1/2, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and matrix metalloproteinase-13 (MMP-13) were examined by real-time PCR. The expression of ADAMTS-5, MMP-13, nuclear translocation of nuclear factor-κB (NF-κB), and ß-catenin were examined by immunocytochemistry and Western blotting. The concentration of IL-1ß in the supernatant was examined by enzyme-linked immunosorbent assay (ELISA). TNKS-1/2 expression was assessed by immunohistochemistry in human OA cartilage obtained at the total knee arthroplasty. TNKS-1/2 expression was increased after CTS. The expression of anabolic factors were decreased by CTS, however, these declines were abrogated by XAV939. XAV939 suppressed the CTS-induced expression of catabolic factors, the release of IL-1ß, as well as the nuclear translocation of NF-κB and ß-catenin. TNKS-1/2 expression increased in mild and moderate OA cartilage. Our results demonstrated that XAV939 suppressed mechanical stress-induced expression of catabolic proteases by the inhibition of NF-κB and activation of ß-catenin, indicating that TNKS-1/2 expression might be associated with OA pathogenesis.

Influence of Janus kinase inhibitors on early postoperative complications in patients with rheumatoid arthritis undergoing orthopaedic surgeries.

OBJECTIVE: We retrospectively reviewed the records of rheumatoid arthritis (RA) patients who underwent orthopaedic surgery to examine the influence of the perioperative use of Janus kinase (JAK) inhibitors on early postoperative complications. PATIENTS AND METHODS: Thirty-two patients with RA under disease control with JAK inhibitors who underwent 49 orthopaedic procedures were included in the study. Patient records after surgery were investigated for surgical site infection (SSI), delayed wound healing (DWH), a flare-up of the disease, preoperative and postoperative absolute lymphocyte counts (ALCs), venous thromboembolism, and other postoperative complications. RESULTS: JAK inhibitors were continued during the perioperative period in 31 procedures. In the remaining 18 procedures, JAK inhibitors were discontinued perioperatively with a mean discontinuation period of 2.4 days. No instances of SSI were identified in any patient during at least 90 days' follow-up, while DWH was seen in one patient. Disease flare-up was noted in two patients after 3 and 9 days of discontinuation of JAK inhibitors, respectively. The ALCs significantly decreased on postoperative Day 1 (P < .0001), and there was a significant correlation between pre- and post-one-day ALCs (r = 0.75, P < .0001). CONCLUSION: JAK inhibitors seem to be safe during the perioperative period of orthopaedic surgery.

Feeding Rhythm-Induced Hypothalamic Agouti-Related Protein Elevation via Glucocorticoids Leads to Insulin Resistance in Skeletal Muscle.

Circadian phase shifts in peripheral clocks induced by changes in feeding rhythm often result in insulin resistance. However, whether the hypothalamic control system for energy metabolism is involved in the feeding rhythm-related development of insulin resistance is unknown. Here, we show the physiological significance and mechanism of the involvement of the agouti-related protein (AgRP) in evening feeding-associated alterations in insulin sensitivity. Evening feeding during the active dark period increased hypothalamic AgRP expression and skeletal muscle insulin resistance in mice. Inhibiting AgRP expression by administering an antisense oligo or a glucocorticoid receptor antagonist mitigated these effects. AgRP-producing neuron-specific glucocorticoid receptor-knockout (AgRP-GR-KO) mice had normal skeletal muscle insulin sensitivity even under evening feeding schedules. Hepatic vagotomy enhanced AgRP expression in the hypothalamus even during ad-lib feeding in wild-type mice but not in AgRP-GR-KO mice. The findings of this study indicate that feeding in the late active period may affect hypothalamic AgRP expression via glucocorticoids and induce skeletal muscle insulin resistance.

[Rapid transition from purulent to constrictive pericarditis].

A 48-year-old woman experienced a high fever and precordial pain. Computed tomography revealed pericardial fluid, and she was diagnosed with viral pericarditis. The pericardial fluid gradually increased, and she experienced pre-shock. Pericardial drainage was therefore performed, and the fluid was found to be purulent on the 11th day. Pleural effusion and ascites retention, then increased, and she was diagnosed with constrictive pericarditis on the 21st day by the date of the right ventricular pressure. Excision of the pericardium was performed through median sternotomy on the 27th day after the onset. As the ventricular diastolic function improved, the heart swelled, and sternal closure became impossible. It was finally closed 5 days after the surgery. The patient had no recurring infection, and was discharged on the 36th postoperative day. Although purulent pericarditis is a rare disease, you should keep in mind that it may progress rapidly to constrictive pericarditis.

Chronic exposure to an extremely low-frequency magnetic field induces depression-like behavior and corticosterone secretion without enhancement of the hypothalamic-pituitary-adrenal axis in mice.

An extremely low-frequency magnetic field (ELF-MF) is generated by power lines and household electrical devices. Many studies have suggested an association between chronic ELF-MF exposure and anxiety and/or depression. The mechanism of these effects is assumed to be a stress response induced by ELF-MF exposure. However, this mechanism remains controversial. In the present study, we investigated whether chronic ELF-MF exposure (intensity, 1.5 mT; [corrected] total exposure, 200 h) affected emotional behavior and corticosterone synthesis in mice. ELF-MF-treated mice showed a significant increase in total immobility time in a forced swim test and showed latency to enter the light box in a light-dark transition test, compared with sham-treated (control) mice. Corticosterone secretion was significantly high in the ELF-MF-exposed mice; however, no changes were observed in the amount of the adrenocorticotropic hormone and the expression of genes related to stress response. Quantification of the mRNA levels of adrenal corticosteroid synthesis enzymes revealed a significant reduction in Cyp17a1 mRNA in the ELF-MF-exposed mice. Our findings suggest the possibility that high intensity and chronic exposure to ELF-MF induces an increase in corticosterone secretion, along with depression- and/or anxiety-like behavior, without enhancement of the hypothalamic-pituitary-adrenal axis.

[Sleep regulatory mechanisms].

The fact that resting wakefulness does not satisfy the need for sleep suggests that sleep has a critical role for the brain, probably for its maintenance or repair. Neuronal oxidative stress, neuroinflammation, or energy insufficiency in the brain is now considered to be a trigger or cause for sleep induction. And the timing for sleep is controlled by circadian clock which also exists in the brain. Sleep is occurred in the brain, which is regulated by the brain itself. "Why do we sleep ?" Although everyone wants to know the answer for this issue, scientists should still question that "How do we sleep"?

Dual orexin receptor antagonist drug suvorexant can help in amelioration of predictable chronic mild stress-induced hyperalgesia.

AIMS: This study aimed to evaluate the involvement of the orexin system in predictable chronic mild stress (PCMS) and the effects of suvorexant, a dual orexin receptor antagonist, on nociceptive behavior in PCMS. MATERIALS AND METHODS: Male C57BL/6 J mice were separated into various PCMS groups: a control group with sawdust on the floor of the rearing cage (C), a group with mesh wire on the floor (M), and a group with water just below the mesh wire (W). Activation of lateral hypothalamic orexin neurons was assessed using immunofluorescence. In another experiment, half of the mice in each group were administered an intraperitoneal injection of suvorexant (10 mg/kg), and the remaining mice were injected with the same amount of vehicle (normal saline). Thermal hyperalgesia was examined using tail immersion and hot plate tests, while mechanical hyperalgesia was investigated using the tail pinch test after 21 days of PCMS. KEY FINDINGS: Animals subjected to PCMS showed an increased percentage of activated orexin neurons in the lateral hypothalamic region after 21 days. Mice raised in the PCMS environment showed increased pain sensitivity in several pain tests; however, the symptoms were significantly reduced by suvorexant administration. SIGNIFICANCE: The findings revealed that PCMS activates hypothalamic orexin neuronal activity, and the use of suvorexant can help attenuate PCMS-induced thermal and mechanical hyperalgesia.

Superiority of MRI for Evaluation of Sacral Insufficiency Fracture.

STUDY DESIGN: Retrospective observational study. BACKGROUND: Sacral insufficiency fractures (SIF) are relatively rare fractures and difficult to diagnose on plain radiographs. The primary objective of the present study was to evaluate the role of lumbar magnetic resonance imaging (MRI) for the diagnosis of SIF. The secondary objective was to identify the classification of SIF by computed tomography (CT). METHODS: A total of 77 (Male 11, female 66, mean 80.3 years) people were included in this study. Inclusion criteria for this study were: age ≥ 60 years and no history of high energy trauma. Exclusion criteria were high energy trauma and a current history of malignancy. Differences in the fracture detection and description in the various radiologic procedures were evaluated. Fracture patterns were evaluated with CT. The detection rates of additional pathologies in the MRI of the pelvis and lumbar spine were also recorded. RESULTS: The sensitivities for SIF were 28.5% in radiographs and 94.2% in CT, and all fractures were detected in MRI. MRI showed a more complex fracture pattern compared with CT in 65% of the cases. We observed 71.4% of single SIFs, 9.1% with other spinal fractures, 13.0% with other pelvic fractures, and 7.8% with other fractures. According to the SIF fracture pattern, the H/U type was 40.2%, transverse type was 33.7%, λ/T type was 24.7%, unilateral vertical type was 1.3%, and bilateral vertical type was 0%. CONCLUSIONS: an MRI of the lumbar spine including the sacrum with a coronal fat-suppressed T2-weighted image is useful for elderly patients with suddenly increasing low back pain at an early stage. This procedure improves an early SIF detection, recognition of concomitant pathologies, and adequate treatment for the patients.

Intracranial mast cells contribute to the control of social behavior in male mice.

Mast cells (MCs) exist intracranially and have been reported to affect higher brain functions in rodents. However, the role of MCs in the regulation of emotionality and social behavior is unclear. In the present study, using male mice, we examined the relationship between MCs and social behavior and investigated the underlying mechanisms. Wild-type male mice intraventricularly injected with a degranulator of MCs exhibited a marked increase in a three-chamber sociability test. In addition, removal of MCs in Mast cell-specific Toxin Receptor-mediated Conditional cell Knock out (Mas-TRECK) male mice showed reduced social preference levels in a three-chamber sociability test without other behavioral changes, such as anxiety-like and depression-like behavior. Mas-TRECK male mice also had reduced serotonin content and serotonin receptor expression and increased oxytocin receptor expression in the brain. These results suggested that MCs may contribute to the regulation of social behavior in male mice. This effect may be partially mediated by serotonin derived from MCs in the brain.

Pain sensitivity increases with sleep disturbance under predictable chronic mild stress in mice.

Even though it has been well documented that stress can lead to the development of sleep disorders and the intensification of pain, their relationships have not been fully understood. The present study was aimed at investigating the effects of predictable chronic mild stress (PCMS) on sleep-wake states and pain threshold, using the PCMS rearing conditions of mesh wire (MW) and water (W) for 21 days. Exposure to PCMS decreased the amount of non-rapid eye movement (NREM) sleep during the dark phase. Moreover, the chronicity of PCMS decreased slow-wave activity (SWA) during NREM sleep in the MW and W groups in both the light and dark phases. Mechanical and aversively hot thermal hyperalgesia were more intensified in the PCMS groups than the control. Higher plasma corticosterone levels were seen in mice subjected to PCMS, whereas TNF-α expression was found higher in the hypothalamus in the W and the trigeminal ganglion in the MW group. The W group had higher expression levels of IL-6 in the thalamus as well. The PCMS paradigm decreased SWA and may have intensified mechanical and thermal hyperalgesia. The current study also suggests that rearing under PCMS may cause impaired sleep quality and heightened pain sensation to painful mechanical and aversively hot thermal stimuli.

[Spinal cord infarction due to aortic dissection during coronary artery bypass grafting under percutaneous cardiopulmonary support].

We report a case of aortic dissection due to improper position of a percutaneous cardiopulmonary support (PCPS) cannula into the femoral artery during coronary artery bypass grafting (CABG). A 77-year-old man with 3-vessel disease underwent off-pump CABG (OPCAB). Blood pressure suddenly lowered during bypass grafting to the right coronary artery. PCPS was performed between the left femoral artery and the right atrium. Bradycardia occurred 37 min after initiation of PCPS, and transesophageal echocardiography revealed Stanford type A aortic dissection. By converting the perfusion site from the femoral artery to the right axillar artery, the false lumen disappeared and did not reccur after cessation of PCPS. Therefore, the aorta was not replaced. He had however, bilateral leg paralysis after surgery. Magnetic resonance imaging (MRI) revealed spinal cord infarction caused by aortic dissection. Computed tomography (CT) confirmed disappearance of the false lumen and no expansion of the aorta 1 month after surgery. Meticulous care should be taken of the site and size of the arterial cannula in the extracorporeal circuit in such cases.

Sleep profile during fasting in PPAR-alpha knockout mice.

Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that belongs to the nuclear receptor family and plays an important role in regulating gene expression associated with lipid metabolism. PPARα promotes hepatic fatty acid oxidation and ketogenesis in response to fasting. Because energy metabolism is known to affect sleep regulation, manipulations that change PPARα are likely to affect sleep and other physiological phenotypes. In this study, we examined the role of PPARα in sleep/wake regulation using PPARα knockout (KO) mice. Sleep, body temperature (BT), locomotor activity, arterial pressure (AP) and heart rate (HR) were recorded in KO mice and wild-type (WT) controls under ad libitum-fed conditions and 24-hour food deprivation (FD). KO and WT mice were identical in basal sleep amount, BT, mean AP and HR, although KO mice showed enhanced sleepiness (enhanced EEG slow-wave activity). In response to FD, KO mice showed a large drop in wakefulness and locomotor activity at the end of the dark phase, whereas WT mice did not. Similarly, AP and HR, which were suppressed by FD, decreased more in KO than in WT mice. Compared to WT mice, KO mice showed a reduced concentration of plasma ketone bodies and decreased mRNA expression of the ketogenic enzyme gene Hmgcs2 in the liver and brain under FD conditions. These results suggest that PPARα and/or lipid metabolism is involved in the maintenance of wakefulness and locomotor activity during fasting in mice.

Dopamine stimulation of the septum enhances exercise efficiency during complicated treadmill running in mice.

We aimed to identify the neurotransmitters and brain regions involved in exercise efficiency in mice during continuous complicated exercises. Male C57BL/6J mice practiced treadmill running with intermittent obstacles on a treadmill for 8 days. Oxygen uptake (VO2) during treadmill running was measured as exercise efficiency. After obstacle exercise training, the VO2 measured during treadmill running with obstacles decreased significantly. Obstacle exercise-induced c-Fos expressions and dopamine turnover (DOPAC/dopamine) in the septum after obstacle exercise training were significantly higher than that before training. The dopamine turnover was correlated with exercise efficiency on the 3rd day after exercise training. Furthermore, the training effect on exercise efficiency was significantly decreased by injection of dopamine receptor antagonists into the septum and was associated with decreased c-Fos expressions in the septum and hippocampus of the mice. These results suggest that dopaminergic function in the septum is involved in exercise efficiency during continuous complicated exercises.

Rotigotine suppresses sleep-related muscle activity augmented by injection of dialysis patients' sera in a mouse model of restless legs syndrome.

Idiopathic restless legs syndrome (RLS) has a genetic basis wherein BTBD9 is associated with a higher risk of RLS. Hemodialysis patients also exhibit higher rates of RLS compared with the healthy population. However, little is known about the relationship of BTBD9 and end-stage renal disease to RLS pathophysiology. Here we evaluated sleep and leg muscle activity of Btbd9 mutant (MT) mice after administration of serum from patients with either idiopathic or RLS due to end-stage renal disease (renal RLS) and investigated the efficacy of treatment with the dopamine agonist rotigotine. At baseline, the amount of rapid eye movement (REM) sleep was decreased and leg muscle activity during non-REM (NREM) sleep was increased in MT mice compared to wild-type (WT) mice. Wake-promoting effects of rotigotine were attenuated by injection of serum from RLS patients in both WT and MT mice. Leg muscle activity during NREM sleep was increased only in MT mice injected with serum from RLS patients of ideiopatic and renal RLS. Subsequent treatment with rotigotine ameliorated this altered leg muscle activity. Together these results support previous reports showing a relationship between the Btbd9/dopamine system and RLS, and elucidate in part the pathophysiology of RLS.

Sufficient intake of high-fat food attenuates stress-induced social avoidance behavior.

AIMS: Psychosocial stress is a form of mental stress associated with human relationships that underlies the pathogenesis of mental disorders such as depression. Previous studies have suggested that intake of energy-dense foods, also known as "palatable foods," can relieve psychosocial stress. However, it remains unclear whether the volume of palatable food affects abnormal behavior induced by psychosocial stress. In the present study, we aimed to determine whether levels of high-fat food intake significantly influence psychosocial stress using the social-defeat stress (SDS) paradigm. MAIN METHODS: Mice subjected to SDS ate either a high-fat or normal chow diet for 10 days. Behavioral tests were conducted following the completion of the SDS paradigm. The hypothalamus, liver, and blood were examined post-mortem. KEY FINDINGS: Mice with sufficient intake of high-fat chow immediately following exposure to SDS did not exhibit social avoidance behavior, suggesting that a high-fat diet may improve social behavior. However, inadequate intake of high-fat food, which did not alter cholesterol metabolism or hypothalamic-pituitary-adrenal axis activity, was not associated with such benefits, instead increased anxiety-like behavior. SIGNIFICANCE: The results of the present study demonstrate that eating a high-fat diet may attenuate stress, but that this benefit disappears with insufficient intake of high-fat foods. The benefits of a high-fat diet under SDS may be related to cholesterol metabolism in the liver.

Enhancement of fear learning in PPARα knockout mice.

Peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear receptor superfamily and regulates fatty acid oxidation. Although PPARα is expressed not only in the peripheral tissues but also in the brain, its role in higher brain function is unclear. In this study, we investigated the role of PPARα in the control of behavior, including memory/learning and mood change, using PPARα knockout (KO) mice. A significant difference between wild-type (WT) and KO mice was seen in the passive avoidance test, demonstrating that KO mice showed enhanced fear leaning. In the amygdala of KO mice, the levels of dopamine and its metabolites were increased, and the mRNA expression of dopamine degrading enzyme was decreased. When dopamine D1 receptor antagonist was administered, the enhanced fear learning observed in KO mice was attenuated. These results suggest that PPARα is involved in the regulation of emotional memory via the dopamine pathway in the amygdala.

Mast cell involvement in glucose tolerance impairment caused by chronic mild stress with sleep disturbance.

We have developed a chronic mild stress (MS) mouse model by simply rearing mice on a wire net for 3 weeks and investigated the effects of MS on glucose homeostasis and sleep. MS mice showed impaired glucose tolerance and disturbed sleep. One-week treatment with a histamine H1 receptor antagonist (H1RA) ameliorated the glucose intolerance and improved sleep quality in MS mice. MS mice showed an increased number of mast cells in both adipose tissue and the brain. Inhibition of mast cell function ameliorated the impairment in both glucose tolerance and sleep. Together, these findings indicate that mast cells may represent an important pathophysiological mediator in sleep and energy homeostasis.

Late feeding in the active period decreases slow-wave activity.

AIMS: Sleep and feeding behaviors closely interact to maintain energy homeostasis. While it is known that sleep disorders can lead to various metabolic issues such as insulin resistance, the mechanism for this effect is poorly understood. We thus investigated whether different feeding rhythms during the active period affect sleep-wake regulation. MAIN METHODS: For 2weeks, mice were randomly assigned to 1 of 3 feeding schedules as follows: free access to lab chow during the active period (ZT12-24, Ad-lib group), free access to lab chow during the first half of the active period (ZT12-18; Morning group), or free access to lab chow during the second half of the active period (ZT18-24, Evening group). Food intake, body weight, body temperature, locomotor activity, and sleep were evaluated. The hypothalamus and cerebral cortex were examined post-mortem. KEY FINDINGS: No alterations in food intake or body weight were observed among the 3 groups. The Evening group showed lower slow-wave activity (SWA) than the other 2 groups, in addition to higher expression of orexin mRNA in the hypothalamus and higher concentrations of dopamine and its metabolites in the cerebral cortex. AMPK phosphorylation was increased in the hypothalamus of mice in the Evening group; however, AMPK inhibition had no effect on SWA. SIGNIFICANCE: We concluded that late feeding reduces SWA in NREM sleep via a mechanism that involves orexin-mediated arousal in the hypothalamus and elevated monoamines in the cerebral cortex. These data have important implications for the relationship between sleep-wake disturbances and metabolic disorders.

Voluntary exercise and increased food intake after mild chronic stress improve social avoidance behavior in mice.

It is well-established that exercise can influence psychological conditions, cognitive function, and energy metabolism in peripheral tissues including the skeletal muscle. However, it is not clear whether exercise can influence social interaction with others and alleviate defeat stress. This study investigated the effect of voluntary wheel running on impaired social interaction induced by chronic social defeat stress (SDS) using the resident-intruder social defeat model. Mice were divided into three groups: control, stress alone, and stress+exercise. SDS was performed by exposing C57BL/6 mice to retired ICR mice for 2.5 min. The C57BL/6 mice were continuously defeated by these resident (aggressor) mice and, following 5 days of SDS, experienced 2 days of rest with no SDS. Mice in the stress+exercise group were allowed to voluntarily run on a wheel for 2h after every SDS exposure. Two weeks later, compared to the control group, the stress group showed a higher ratio of time spent in the corner zone of a social interaction paradigm even though SDS did not elicit depressive- and anxiety-like behaviors. We also observed that voluntary exercise, which did not affect muscle weight and gene expression, decreased social avoidance behavior of stressed mice without clear changes in brain monoamine levels. Interestingly, food intake in the stress+exercise group was the greatest among the three groups. To test the effect of the exercise-induced increase in food intake on social behavior, we set up a pair-fed group where food intake was restricted. We then compared these mice to mice in the stress alone group. We found that the ratio of time spent in the corner zone of the social interaction test was not different between ad libitum- and pair-fed groups, although pair-fed mice spent more time in the corner zone when an aggressor mouse was present than when it was absent. In addition, pair-feeding did not show exercise-induced reductions of adrenal gland weight and enhanced the loss of body fat. Our findings indicate that voluntary exercise reduces social avoidance behavior induced by SDS. Further, we determined that SDS and exercise-induced increases in food intake partially influence energy metabolism and social avoidance behavior.

Emergent operation for aneurysm of the left main coronary artery presenting acute myocardial infarction.

We report an emergent operation on a 37-year-old man presenting with acute myocardial infarction with an aneurysm of the left main coronary artery. A preoperative coronary angiogram revealed a large saccular aneurysm of the left main coronary artery and complete occlusion of the left anterior descending artery. Emergent coronary artery bypass graftings to the left anterior descending artery with the left internal thoracic artery and the circumflex artery with the saphenous vein were performed, followed by the ligation and exclusion of the aneurysm of the left main coronary artery. The postoperative course was uncomplicated and the patient did well. Although the etiology of the aneurysm was not investigated, it was suspected to be a congenital aneurysm.