Rejected

Tobacco smoking is the largest risk factor for developing chronic obstructive pulmonary disease (COPD), and is associated with hyperresponsiveness of airway smooth muscle (ASM). Chronic exposure to cigarette smoke (CS) leads to airway inflammation and remodelling. However, the direct effect of gaseous CS or CS extract (CSE) on human airway smooth muscle cell (hASMC) function remains poorly understood. This study investigated the acute effect of CS/CSE on calcium homeostasis, a key regulator of ASM physiology and pathophysiology. Primary hASMC were isolated from non-smoking donor lungs, and subjected to Ca imaging studies. We found that both CS, and CSE, rapidly elevated cytosolic Ca in hASMC through stimulation of plasmalemmal Ca influx, but excluded store-operated and L-type Ca channels as mediators of this effect. Using a specific pharmacological inhibitor, or shRNA-driven knockdown, we established that both CS and CSE stimulated Ca influx in hASMC through the neurogenic pain receptor channel, transient receptor potential ankyrin 1 (TRPA1). CS/CSE-dependent, TRPA1-mediated Ca influx led to myosin light-chain phosphorylation, a key process regulating ASM contractility. We conclude that TRPA1 is likely an important link between CS/CSE exposure and airway hyperresponsiveness, and speculate that acute CS/CSE-induced Ca influx could lead to exacerbated ASM contraction and potentially initiate further chronic pathological effects of tobacco smoke.

Chronic ketamine abuse is associated with bladder dysfunction and cystitis. However, the effects of ketamine abuse on the urinary proteome profile and the correlations among urinary proteins, urinary ketamine (and metabolites) and clinicopathological features of ketamine-induced bladder dysfunction remain to be established. Here, we recruited 56 ketamine abusers (KA) and 40 age-matched healthy controls (HC) and applied the iTRAQ-based proteomics approach to unravel quantitative changes in the urine proteome profile between the two groups. Many of the differentially regulated proteins are involved in the complement and coagulation cascades and/or fibrotic disease. Among them, a significant increase in APOA1 levels in KA relative to control samples (392.1 ± 59.9 ng/ml vs. 13.7 ± 32.6 ng/ml, p < 0.0001) was detected via ELISA. Moreover, urinary ketamine, norketamine and dehydronorketamine contents (measured via LC-SRM-MS) were found to be positively correlated with overactive bladder syndrome score (OABSS) and APOA1 levels with urinary RBC, WBC, OABSS and numeric pain rating scale in KA. Collectively, our results may aid in developing new molecular tool(s) for management of ketamine-induced bladder dysfunction. Moreover, information regarding the differentially regulated proteins in urine of KA provides valuable clues to establish the molecular mechanisms underlying ketamine-induced cystitis.

Opioid inhibition of nociceptive stimuli varies in individuals and is difficult to titrate. We have reported the vascular stiffness value (K) as a standard monitor to quantify sympathetic response with high accuracy. On the contrary, among individuals, a considerable variation in the rate of change in K for constant pain has been observed. In this study, we proposed a new index, the minimum stimulus intensity value that evoked the response on K (MEC: Minimum Evoked Current of K), and evaluated its accuracy in predicting sympathetic response to nociceptive stimuli under constant opioid administration. Thirty patients undergoing open surgery under general anesthesia were included. After anesthetic induction, remifentanil was administered at a constant concentration of 2 ng/ml at the effect site followed by tetanus stimulation. MEC was defined as the minimal current needed to produce a change in K. MEC significantly (P < 0.001) correlated with the rate of change of systolic blood pressure during skin incision (ROC). Bland-Altman plot analysis using the predicted ROC calculated from MEC and the measured ROC showed that the prediction equation for ROC was highly accurate. This study showed the potential of MEC to predict blood pressure change during surgical incision under opioid analgesia.Clinical trial registration Registry: University hospital medical information network; Registration number: UMIN000041816; Principal investigator's name: Satoshi Kamiya; Date of registration: July 9th, 2019.

Osteoarthritis (OA) is the most common chronic joint disease in the elderly population. Growing evidence indicates that a balance between autophagy and apoptosis in chondrocytes plays a key role in OA's cartilage degradation. Thus, drugs targeting the balance between apoptosis and autophagy are potential therapeutic approaches for OA treatment. In previous studies, we found that the activation of α7 nicotinic acetylcholine receptors (α7-nAChRs) alleviated monosodium iodoacetate (MIA)-induced joint degradation and osteoarthritis pain. To explore the potential functions of α7-nAChRs in autophagy and apoptosis signaling in knee OA, we compared the expression of α7-nAChRs in human knee articular cartilage tissues from normal humans and OA patients. We found that knee joint cartilage tissues of OA patients showed decreased α7-nAChRs and an imbalance between autophagy and apoptosis. Next, we observed that α7-nAChRs deficiency did not affect cartilage degradation in OA development but reversed the beneficial effects of nicotine on mechanical allodynia, cartilage degradation, and an MIA-induced switch from autophagy to apoptosis. Unlike in vivo studies, we found that primary chondrocytes from α7-nAChRs knockout (KO) mice showed decreased LC3 levels under normal conditions and were more sensitive toward MIA-induced apoptosis. Finally, we found that α7-nAChRs deficiency increased the phosphorylation of mTOR after MIA treatment, which can also be observed in OA patients' tissues. Thus, our findings not only confirmed that nicotine alleviated MIA-induced pain behavior and cartilage degradation via stimulating the α7-nAChRs/mTOR signal pathway but found the potential role of α7-nAChRs in mediating the balance between apoptosis and autophagy.

Clinical Scenario: Patellofemoral pain (PFP) is characterized by general anterior knee pain around the patella and is one of the most prevalent knee conditions. PFP is challenging to treat due to a wide range of contributing factors and often has chronic, reoccurring symptoms. Traditional treatment focuses on quadriceps and gluteal strengthening with minimal emphasis on deep trunk musculature. Recently, there has been a growing body of literature supporting the beneficial effects of core stability exercises as a treatment option for PFP. Clinical Question: Are core stability exercises coupled with traditional rehabilitation more effective than only traditional rehabilitation techniques for decreasing pain in patients with PFP? Summary of Key Findings: Three articles met the inclusion criteria and investigated core strengthening exercises as a treatment for PFP. Two studies investigated a 4-week exercise protocol and demonstrated a greater decrease in pain when compared to the control group. The third study examined the effects of a 6-week program where both the intervention and control groups resulted in similar reduction of pain. All articles included received a minimum of 6 on the PEDro scale. Clinical Bottom Line: There is evidence that supports core stability exercise protocols coupled with traditional rehabilitation as being more effective in reducing pain in patients with PFP when compared to traditional rehabilitation alone. Strength of Recommendation: The grade of A is recommended based on the Strength of Recommendation Taxonomy.

The objective of this study was to evaluate the association between (1) different types of ACEs and migraine, and (2) the number of ACEs and migraine among adolescent mothers in Lima, Peru.

Physically active individuals are less likely to develop chronic pain, and physical exercise is an established strategy to control inflammatory diseases. Here, we hypothesized that 1) peripheral pro-inflammatory macrophages phenotype contribute to predisposition of the musculoskeletal to chronic pain, and that 2) activation of PPARγ receptors, modulation of macrophage phenotypes and cytokines through physical exercise would prevent persistent muscle pain. We tested these hypotheses using swimming exercise, pharmacological and immunochemical techniques in a rodent model of persistent muscle hyperalgesia. Swimming prevented the persistent mechanical muscle hyperalgesia most likely through activation of PPARγ receptors, as well as activation of PPARγ receptors by 15d-PGJ and depletion of muscle macrophages in sedentary animals. Acute and persistent muscle hyperalgesia were characterized by an increase in pro-inflammatory macrophages phenotype, and swimming and the 15d-PGJ prevented this increase and increased anti-inflammatory macrophages phenotype. Finally, IL-1β concentration in muscle increased in the acute phase, which was also prevented by PPARγ receptors activation through swimming. Besides, swimming increased muscle concentration of IL-10 in both acute and chronic phases, but only in the persistent phase through PPARγ receptors. Our findings suggest physical exercise activates PPARγ receptors and increases anti-inflammatory responses in the muscle tissue by modulating macrophages phenotypes and cytokines, thereby preventing the establishment of persistent muscle hyperalgesia. These results further highlight the potential of physical exercise to prevent chronic muscle pain.

Although regional analgesia is considered an important component of optimal pain management, use of peripheral nerve blocks for total hip arthroplasty remains controversial. Since the obturator nerve innervates the anteromedial part of the joint capsule, we hypothesized that an obturator nerve block would decrease the opioid consumption after total hip arthroplasty.

Surgery is the treatment of choice for symptomatic disc herniation after conservative management. Several studies have suggested the potential utility of intradiscal ozone infiltration in this pathology. The aim of this trial was to compare intradiscal ozone infiltration vs. oxygen infiltration vs. surgery.