Health-Related Quality of Life is Associated With Pain, Kinesiophobia, and Physical Activity in Individuals Who Underwent Cervical Spine Surgery.

OBJECTIVE: To determine the association between health-related quality of life (HRQOL) and neck pain, kinesiophobia, and modalities of physical activity in individuals with postoperative degenerative cervical myelopathy and radiculopathy (DCM/R) because postoperative pain after cervical spine surgery is likely to persist, causing kinesiophobia and avoidance of physical activity. METHODS: A questionnaire was distributed to 280 individuals with DCM/R. The questionnaire comprised the following four items: HRQOL (EuroQol 5-dimensions 5-level), neck pain (numerical rating scale [NRS]), kinesiophobia (11-item Tampa Scale for Kinesiophobia [TSK-11]), and physical activity (paid work, light exercise, walking, strength training, and gardening). Hierarchical multiple regression analysis was performed using the NRS, TSK-11, and physical activity as independent variables. RESULTS: In total, 126 individuals provided analyzable responses (45.0%). After including the NRS score as an independent variable to the multiple regression equation for participants' background, the independent rate of the regression equation significantly improved by only 4.1% (R2=0.153). The addition of the TSK-11 score significantly improved this effect by 11.1% (R2=0.264). Finally, the addition of physical activity also significantly improved the explanatory rate by 9.9% (R2=0.363). CONCLUSION: Neck pain, kinesiophobia, and physical activity (specifically paid work and walking) were independently associated with HRQOL in individuals with postoperative DCM/R.

Relationship Between Central Sensitization-Related Symptoms and Pain-Related Disability After Cervical Spine Surgery: A Structural Equation Model.

BACKGROUND: It is unknown if central sensitization (CS)-related symptoms have an intermediate role that might explain how disability develops from pain after cervical spinal surgery. AIMS: The study aim was to investigate the role of CS-related symptoms in the relationship between pain and disability reported after cervical spinal surgery. DESIGN: Cross-sectional study. SETTINGS: Tertiary care spinal surgery center. PARTICIPANTS/SUBJECTS: The participants included individuals with a cervical degenerative condition who had undergone surgery. METHODS: The following patient-reported outcome measures were evaluated: (1) Numerical Rating Scale; (2) Neck Disability Index; and (3) Short Form of the Central Sensitization Inventory. A hypothesized model containing the CS-related symptoms and the relationships between pain and disability was constructed and tested by structural equation modeling. RESULTS: Questionnaires were mailed to 280 individuals, and responses were obtained from 145 participants. Of these respondents, 99 (68.3%) were males and 46 (31.7%) were females, with a mean age of 64.4 ± 12.3 years. The latent variable for pain, represented by the neck (coefficient: 0.856, p < .001) and upper limb pain (0.568, p < .001), influenced CS-related symptoms (coefficient: 0.504, p < .001). Pain directly affected disability (coefficient: 0.497, p < .001) and indirectly through CS-related symptoms. Bootstrap analysis confirmed this indirect effect (point estimate: 2.85, 95% confidence interval: 1.04 to 6.30, p = .04). CONCLUSIONS: The results revealed that neck and upper limb pain affected disabilities both directly and through CS-related symptoms. Future research should focus on the efficacy of biopsychosocial approaches for patients after cervical spine surgery with a high risk of disability due to CS-related symptoms.

Influence of Pain Self-Efficacy and Gender on Disability in Postoperative Cervical Myelopathy.

BACKGROUND: Pain self-efficacy and gender may influence disability in patients with musculoskeletal disorders. The direct and interactive influence of pain self-efficacy and gender on postoperative disability with degenerative cervical myelopathy (DCM) is unclear. AIM: This study aimed to determine the effects of age, pain, and pain self-efficacy on disability postoperatively in patients with DCM, and explore whether these effects differ by gender. METHOD: A total of 180 participants who underwent DCM surgery were consecutively recruited. The following were evaluated: (1) demographic/descriptive data (age, gender, diagnosis, surgery date, procedure); (2) numerical rating scale pain and dysesthesia intensity; (3) Neck Disability Index; and (4) Pain Self-Efficacy Questionnaire. Hierarchical multiple regression analysis and simple slope analysis determined the effect of patients' biologic and psychosocial factors, and their interaction in terms of disability. RESULTS: The responses of 82 participants were analyzed. The hierarchical multiple regression final model analysis determined 57.1% participant disability variance; gender (B = 3.388; p < .01); pain (B = 3.574; p < .01); pain self-efficacy (B = -0.229; p < .01); age and gender (B = -0.201; p < .05); pain and gender (B = -3.749; p < .01); pain self-efficacy and gender (B = -0.304; p < .01) were significantly associated with disability. Simple slope test indicated that women showed weaker pain associations and stronger age and pain self-efficacy associations with disability than men. CONCLUSIONS: Pain self-efficacy improvement should be focused on after surgery in patients with DCM, especially women.

Increased Tropism of Extracellular Vesicles Derived from Palmitic Acid-Treated Hepatocytes to Activated Hepatic Stellate Cells.

Myofibroblast-like activated hepatic stellate cells (aHSCs), which produce collagen, a major cause of liver fibrosis, are specific target cells for antifibrotic treatment. Recently, several reports have indicated that extracellular vesicles (EVs) play important roles in cell-to-cell communication through their tropism for specific cells or organs. Therefore, the present study aimed to identify aHSC-directed EVs by focusing on cell-to-cell interactions in the liver under pathological conditions. EVs were derived from the hepatocyte cell line AML12 treated with or without palmitic acid (PA) and evaluated for their physical properties and uptake by the aHSC cell line LX-2. AML12-derived EVs had a mean particle diameter of 110-130 nm, negative charge, and expressed the exosomal makers CD9 and CD63. PA-treated AML12 cells released larger EVs with higher protein levels than those without PA treatment. The intracellular uptake efficacy of EVs derived from PA-treated AML12 cells into activated LX-2 cells was significantly higher than those without PA treatment. Our study revealed that PA treatment induces hepatocytes to release EVs with aHSC-tropism. These findings may contribute to the development of an EV-based drug delivery system (DDS) for aHSC-targeted therapy and provide new insights into the role of steatotic hepatocyte-derived EVs in physiological or pathophysiological functions.

[Association between Post-marketing Safety-related Regulatory Actions and Characteristics of New Drugs Approved in Japan between 2005 and 2016].

The pharmacovigilance activities of new drugs are usually planned and conducted based on the clinical safety information obtained at approval. Revealing pre- and post-marketing drug characteristics associated with post-marketing safety-related regulatory actions (PSRAs) would help facilitate pharmacovigilance activities as these activities are not sufficient for early detection of safety signals that require warning. Therefore, we investigated the association between PSRAs and characteristics of new drugs in Japan. New active substances approved in Japan between fiscal year 2005 and 2015 were analyzed. PSRAs were defined as "revisions of precautions in drug package insert" instructed by the regulatory authority within the first 5 years after the initial approval (up to 2021). Drug characteristics included therapeutic area, number of Japanese subjects in clinical trials, dose-response study in Japanese subjects, approval lag between Japan and the United States or Europe (US/EU), novelty of the drug, estimated number of target patients, and number of supplemental approvals. Negative binomial regression and path analyses were performed to investigate the association between PSRAs and drug characteristics. PSRAs were more common among antineoplastic agents and drugs with a larger estimated number of target patients and were less common among drugs with a longer approval lag between Japan and the US/EU. Supplemental approval was more common among antineoplastic agents, and there were fewer target patients for novel drugs. For new drugs with the characteristics identified in the present study, it is important to proactively collect post-market safety information by intensifying patient monitoring.

Sex Differences in the Mediating Effect of Kinesiophobia on Chronic Pain, Dysesthesia, and Health-Related Quality of Life in Japanese Individuals Aged 65 Years Old and Older Treated with Surgery for Lumbar Spinal Stenosis.

Purpose: This study aimed to determine whether kinesiophobia mediates the relationship between low back pain (LBP), leg pain (LP), and leg dysesthesia (LD) and health-related quality of life (HRQOL) among Japanese individuals aged 65 years old and older treated with surgery for lumbar spinal stenosis (LSS). Patients and Methods: Data collection for this study took place between October 2019 and August 2020 at two Japanese medical facilities. Eligibility criteria for participants in this study were individuals aged 65 years or older and those who had undergone surgery for LSS at least more than one year ago. A self-administered questionnaire assessed the intensity of LBP, LP, and LD (numerical rating scale: NRS), HRQOL (EuroQol-5 Dimension-5 Levels: EQ-5D-5L), and kinesiophobia (Tampa Scale for Kinesiophobia-17 items: TSK-17). Mediation analysis using sex as a control variable was conducted. Results: Complete responses were obtained from 238 of 431 individuals (73.1 ± 5.1 years; 135 males and 103 females). The mediating effect of NRS scores for LBP, LP, and LD to EQ-5D-5L index on TSK-17 score was significant, respectively (LBP: -0.007 [95% confidence interval -0.012, -0.004], p = 0.000; LP and LD: -0.007 [-0.011, -0.004], p = 0.000). The strength of the association between NRS scores and EQ-5D-5L index decreased when the mediating effect of TSK-17 score (LBP: ß = -0.698 [-0.792, -0.603], p = 0.000 to ß = -0.616 [-0.707, -0.524], p = 0.000; LP: ß = -0.629 [-0.729, -0.529], p = 0.000 to ß = -0.539 [-0.638, -0.440], p = 0.000; LD: ß = -0.568 [-0.675, -0.460], p = 0.000 to ß = -0.482 [-0.586, -0.378], p = 0.000). The mediating effect of TSK score was greater in females than males. Conclusion: Kinophobia partially mediated the relationship between LBP, LP and LD, and HRQOL in Japanese aged 65 years and older after lumbar surgery. The mediating effect differed by sex.

Validation of a Model Predicting That Physical Activities Improve Health-Related Quality of Life in Older Japanese Adults with Pain, Dysesthesia, and Kinesiophobia after Lumbar Surgery: Structural Equation Modeling.

Objectives: This study assessed the validity of a hypothesized model predicting that physical activity improves health-related quality of life (HRQOL) in older Japanese adults with pain, dysesthesia, and kinesiophobia following lumbar surgery. Methods: We included 431 elderly patients who underwent surgery for lumbar spinal stenosis at two hospitals. The frequency of physical activity, pain, dysesthesia, kinesiophobia (somatic focus and activity avoidance), and HRQOL were investigated using a questionnaire. Missing values were complemented by the stochastic regression imputation. We constructed the following model. (i) physical activity affects pain, dysesthesia, and kinesiophobia. (ii) pain, dysesthesia, and kinesiophobia separately affect HRQOL. This hypothetical model was tested by structural equation modeling. The model was improved based on a modified index. Results: Of the 431 respondents, 297 (median age 72 years, range 65-91 years; 158 men and 139 women) were analyzed (68.9%). The fit of the model improved based on the modification index and was acceptable comparative fit index, 0.948; Tucker-Lewis index, 0.919; root mean square error of approximation, 0.048 (90% confidence interval, 0.026-0.069), and standardized root mean square residual (0.046). The paths by which physical activities reduced pain or dysesthesia (standardized pass coefficients, -0.406) and somatic focus (-0.301) and consequently improved HRQOL were significant (pain/dysesthesia, -0.684; somatic focus, -0.218). Discussion. Our hypothesized model predicting that physical activity improves HRQOL in terms of pain, dysesthesia, and kinesiophobia in older Japanese adults after lumbar surgery was validated using cross-sectional data. Interventional studies on physical activity based on this model are required to establish the model.

Identification of Aerotaxis Receptor Proteins Involved in Host Plant Infection by Pseudomonas syringae pv. tabaci 6605.

Pseudomonas syringae pv. tabaci 6605 (Pta6605) is a foliar plant pathogen that causes wildfire disease on tobacco plants. It requires chemotaxis to enter plants and establish infection. While chemotactic signals appear to be the main mechanism by which Pta6605 performs directional movement, the involvement of aerotaxis or energy taxis by this foliar pathogen is currently unknown. Based on domain structures and similarity with more than 50 previously identified putative methyl-accepting chemotaxis proteins (MCPs), the genome of Pta6605 encodes three potential aerotaxis transducers. We identified AerA as the main aerotaxis transducer and found that it possesses a taxis-to-serine-and-repellent (Tsr)-like domain structure that supports a periplasmic 4HB-type ligand-binding domain (LBD). The secondary aerotaxis transducer, AerB, possesses a cytosolic PAS-type LBD, similar to the Aer of Escherichia coli and Pseudomonas aeruginosa. Aerotaxis ability by single and double mutant strains of aerA and aerB was weaker than that by wild-type Pta6605. On the other hand, another cytosolic PAS-type LBD containing MCP did not make a major contribution to Pta6605 aerotaxis in our assay system. Furthermore, mutations in aerotaxis transducer genes did not affect surface motility or chemotactic attraction to yeast extract. Single and double mutant strains of aerA and aerB showed less colonization in the early stage of host plant infection and lower biofilm production than wild-type Pta6605. These results demonstrate the presence of aerotaxis transducers and their contribution to host plant infection by Pta6605.

Vanishing Cardiac Tumor by Chemotherapy in a Patient With Diffuse Large B-Cell Lymphoma.

A 70-year-old Japanese man presented with a massive cardiac tumor associated with diffuse large B-cell lymphoma. Standard chemotherapy resulted in complete remission and the cardiac tumor disappeared. (Level of Difficulty: Intermediate.).

New Factor Structure of the Tampa Scale for Kinesiophobia in Older Japanese Adults After Lumbar Surgery.

PURPOSE: The Tampa Scale for Kinesiophobia (TSK) has been used worldwide as a measure of kinesiophobia, but its factor structure in older Japanese adults after lumbar surgery is unknown. The purpose of this study was to fill this research gap by identifying the factors that comprise TSK in older Japanese adults after lumbar surgery. PATIENTS AND METHODS: Participants were older Japanese adults who had undergone surgery for lumbar spinal stenosis. Clinicodemographic data, TSK, intensity of low back pain and leg pain, dysesthesia (using an 11-point numerical rating scale), and HRQOL (using the EQ-5D-5L) were collected. After supplementing the missing values by the multiple assignment method, the hypothetical model of TSK was developed by categorical exploratory factor analysis (weighted least squares method, promax rotation). Confirmatory factor analysis (WLSMV method, promax rotation) was used to compare the hypothetical model and the traditional one-factor and two-factor models. Furthermore, we confirmed the relationship between factors extracted from the hypothetical model and HRQOL, pain, and dysesthesia. RESULTS: Questionnaires were mailed to 302 individuals, and responses were obtained from 211 (72.4±4.2 years [range: 65-88]; 115 men and 96 women; 804±343.1 [380-1531] days after surgery; 137 who had undergone decompression and fixation surgery, 74 who had undergone decompression surgery) (response rate: 69.9%). The hypothesized model consisted of "somatic focus," "activity avoidance," and "efficacy of physical activities," all of which were highly consistent. The fit of the hypothetical model was slightly inferior to that of the traditional two-factor model, but the hypothetical model met the criteria for fit. Somatic focus in the hypothetical model was significantly associated with HRQOL, pain, and dysesthesia. CONCLUSION: In older Japanese adults after lumbar surgery, the goodness of fit of the TSK model was maintained by adding efficacy of physical activities as a third factor to the traditional two factors.

[Autoimmune Hepatitis in Small Cell Lung Cancer-A Case Report].

A 64-year-old female presented to our hospital with a chronic cough. She was diagnosed with cStage ⅢA small cell lung cancer(cT2aN2M0, limited disease). On admission for chemoradiation therapy, laboratory data incidentally revealed liver dysfunction. Further examination resulted in the patient being diagnosed with autoimmune hepatitis. Oral prednisolone therapy was started, and after the improvement of liver function tests, consecutive chemoradiation therapy with cisplatin and etoposide was administered. To the best of our knowledge, this is the first report of a patient with autoimmune hepatitis and small cell lung cancer. Autoimmune hepatitis might arise as a paraneoplastic syndrome.

[A Case of Pulmonary Enteric Adenocarcinoma with Soleus Muscle Metastasis].

Pulmonary enteric adenocarcinoma is a unique pulmonary adenocarcinoma subtype and has histopathological findings that are similar to those of colorectal adenocarcinoma. A man in his 50s visited our hospital because of discomfort in his right lower leg for the last 9 months. Imaging studies revealed a mass in his right soleus muscle, and needle biopsy was performed. Histological findings revealed adenocarcinoma, and immunohistochemical staining showed that the tumor cells were positive for CK20 and CDX-2. The tumor was first suspected to be metastasis of gastrointestinal malignant tumors. FDG-PET/CT showed increased FDG uptake in the right soleus muscle mass and presented with increased FDG uptake in a right upper lobe mass and right mediastinum lymphadenopathy. There were no findings in other organs. Scraping cytology of a transbronchial biopsy indicated adenocarcinoma. Upper and lower gastrointestinal endoscopy showed no findings of malignancy. He was finally diagnosed with pulmonary enteric adenocarcinoma(cT3N2M1b, Stage ⅣA). Treatment with cisplatin(CDDP), pemetrexed( PEM), and bevacizumab(BEV) was initiated. After 4 courses of the regimen, the tumor was partially reduced, and the patient showed stable disease(SD).

Dual role of the active-center cysteine in human peroxiredoxin 1: Peroxidase activity and heme binding.

HBP23, a 23-kDa heme-binding protein identified in rats, is a member of the peroxiredoxin (Prx) family, the primary peroxidases involved in hydrogen peroxide catabolism. Although HBP23 has a characteristic Cys-Pro heme-binding motif, the significance of heme binding to Prx family proteins remains to be elucidated. Here, we examined the effect of heme binding to human peroxiredoxin-1 (PRX1), which has 97% amino acid identity to HBP23. PRX1 was expressed in Escherichia coli and purified to homogeneity. Spectroscopic titration demonstrated that PRX1 binds heme with a 1:1 stoichiometry and a dissociation constant of 0.17 µM. UV-vis spectra of heme-PRX1 suggested that Cys52 is the axial ligand of ferric heme. PRX1 peroxidase activity was lost upon heme binding, reflecting the fact that Cys52 is not only the heme-binding site but also the active center of peroxidase activity. Interestingly, heme binding to PRX1 caused a decrease in the toxicity and degradation of heme, significantly suppressing H2O2-dependent heme peroxidase activity and degradation of PRX1-bound heme compared with that of free hemin. By virtue of its cytosolic abundance (∼20 µM), PRX1 thus functions as a scavenger of cytosolic hemin (<1 µM). Collectively, our results indicate that PRX1 has a dual role; Cys-dependent peroxidase activity and cytosolic heme scavenger.

GXXXG-Mediated Parallel and Antiparallel Dimerization of Transmembrane Helices and Its Inhibition by Cholesterol: Single-Pair FRET and 2D IR Studies.

Small-residue-mediated interhelical packings are ubiquitously found in helical membrane proteins, although their interaction dynamics and lipid dependence remain mostly uncharacterized. We used a single-pair FRET technique to examine the effect of a GXXXG motif on the association of de novo designed (AALALAA)3 helices in liposomes. Dimerization occurred with sub-second lifetimes, which was abolished by cholesterol. Utilizing the nearly instantaneous time-resolution of 2D IR spectroscopy, parallel and antiparallel helix associations were identified by vibrational couplings across helices at their interface. Taken together, the data illustrate that the GXXXG motif controls helix packing but still allows for a dynamic and lipid-regulated oligomeric state.

Pulmonary Hypertension as a Possible Cause of Paradoxical Low-Flow, Low-Gradient Aortic Stenosis.

Paradoxical low-flow, low-gradient aortic stenosis (LFLG AS) is recognized as a subtype of aortic stenosis. A small left ventricular (LV) cavity with marked LV concentric remodeling leads to a reduced stroke volume in this condition. The case is reported of a paradoxical LFLG AS patient who was undergoing treatment for pulmonary hypertension (PH) and interstitial pneumonia associated with scleroderma. Echocardiography demonstrated enlargement of the right ventricle and a diminished LV cavity. Moreover, the aortic valve opening was restricted despite a preserved LV ejection fraction (61%). The patient's aortic valve area (obtained with the continuity equation) was 0.57 cm2 (indexed AVA was 0.39 cm2/m2), and the mean gradient was 16 mmHg. Multi-detector computed tomography findings confirmed that the aortic valve calcification was not severe. The main mechanism responsible for LFLG AS was considered to be a reduced LV cavity secondary to PH, rather than a sclerotic aortic valve. Thus, a decision was taken to treat the patient with additional medical management prior to performing any invasive procedures. It should be borne in mind that PH can lead to paradoxical LFLG AS, and that appropriate treatment should be contemplated depending on the underlying mechanisms. Video 1: Transthoracic echocardiography in the parasternal long-axis view showing right ventricular dilatation and a diminished left ventricular cavity. Video 2: Transthoracic echocardiography in the shortaxis view showing enlargement of the right ventricle and septal flattening due to pulmonary hypertension. Video 3: Transesophageal echocardiography clearly demonstrates an insufficient valve opening.

Lignin-rich enzyme lignin (LREL), a cellulase-treated lignin-carbohydrate derived from plants, activates myeloid dendritic cells via Toll-like receptor 4 (TLR4).

Lignin-carbohydrates, one of the major cell wall components, are believed to be the structures that form chemical linkage between lignin and cell wall polysaccharides. Due to the molecular complexity of lignin-containing substances, their isolation and the assignment of their biological activities have so far remained a difficult task. Here, we extracted two lignin-containing carbohydrates, lignin-rich enzyme lignin (LREL) and pure enzyme lignin (PEL), from barley husk and demonstrated that they act as immune stimulators of dendritic cells (DCs), which are particularly important in linking innate and adaptive immunity. Thioacidolysis, acid hydrolysis, and mild alkali hydrolysis of both LREL and PEL revealed that their immunostimulatory activities depended on the lignin structure and/or content, neutral sugar content (especially the characteristic distribution of galactose and mannose), and presence of an ester bond. Furthermore, we showed that the immunostimulatory potency of the lignin-carbohydrate depended on its molecular weight and degree of polymerization. We also demonstrated that the LREL-induced activation of DCs was mediated via TLR4. Thus, LREL-induced increases in the expression levels of several cell surface marker proteins, production of inflammatory cytokines IL-12p40 and TNF-α, and activation and nuclear translocation of transcription factors, as was observed in the WT DCs, were completely abrogated in DCs derived from the TLR4(-/-) mice but not in DCs derived from the TLR2(-/-), TLR7(-/-), and TLR9(-/-) mice. We further demonstrated that LRELs isolated from other plant tissues also activated DCs. These immunostimulatory activities of lignin-carbohydrates, extracted from edible plant tissues, could have potential relevance in anti-infectious immunity and vaccine adjuvants.