Association between smoking and central sensitization pain: a web-based cross-sectional study.

PURPOSE: This study aimed to investigate whether smoking is an independent risk factor for central sensitization syndrome (CSS) in individuals with pain as measured by the Central Sensitization Inventory (CSI). METHODS: In 2020, we conducted an Internet survey targeting 2000 ordinary residents of Japan (aged 20-69 years) who had pain symptoms from October to November 2020. A multiple regression analysis was performed on the association between smoking status (nonsmokers and current smokers; Brinkman index) and CSI values. Moreover, compared to nonsmokers, the relative risk (RR) of the CSI cut-off score of 40 points or higher among current smokers was calculated using a modified Poisson regression model. Covariates included age, sex, body mass index, marital status, equivalized income, exercise habits, history of hypertension, history of hyperlipidemia, history of diabetes, pain chronicity, and Pain Catastrophizing Scale score. RESULTS: This study analyzed 1,822 individuals (1,041 men and 781 women). Among those experiencing pain, current smoking was associated with the increase in CSI values (ß = 0.07). The Brinkman index was also significantly associated with the increase in CSI values (ß = 0.06). Current smoking also increased the risk of being over the CSI cut-off score, with a relative risk (RR) of 1.29 (95% confidence intervals, 1.04-1.60). Younger age, being women, experiencing chronic pain, and higher pain catastrophizing thinking were also significantly associated with increased CSS severity, independent of smoking status. CONCLUSION: Smoking is an independent risk factor for CSS. This indicates that smoking may be an important factor in the management of central pain disorders.

A Case Report of Respiratory Syncytial Virus-Infected 8p Inverted Duplication Deletion Syndrome with Low Natural Killer Cell Activity.

The 8p inverted duplication deletion [inv dup del(8p)] is a complex structural rearrangement in chromosome 8. Patients with this chromosomal abnormality exhibit developmental delay, facial dysmorphism, central nervous abnormalities, hypotonia, orthopedic abnormalities, and congenital heart defects. However, cellular immune function in inv dup del(8p) syndrome has never been reported. We present the case of a 1-month-old boy with inv dup del(8p) syndrome who had severe respiratory syncytial (RS) virus bronchiolitis. Natural killer (NK) cells are recruited to airway epithelium in the early phase of RS viral infection. A cluster of defensin genes (DEFs), which are deleted in inv dup del(8p), are located in 8p23.1. Human defensins are involved in antiviral activity through the NK cell-mediated cytotoxic pathway and envelope disruption in the normal immune response. This patient showed lower NK cell activity and α-defensin level compared with healthy controls. These results suggest that decreased NK cell activity can result from DEF haploinsufficiency. In addition to a skeletal deformity with chromosomal abnormality, NK cell-mediated immune deficiency may account for the exacerbation of RS virus bronchiolitis.

Switching From Pregabalin to Mirogabalin in Patients with Peripheral Neuropathic Pain: A Multi-Center, Prospective, Single-Arm, Open-Label Study (MIROP Study).

INTRODUCTION: Mirogabalin, which is a selective ligand of the α2δ subunit of voltage-gated Ca2+ channels, was recently approved in Japan for peripheral neuropathic pain. The α2δ ligands, including mirogabalin and pregabalin, are associated with significant risk of adverse events (AEs) such as somnolence or dizziness, leading to poor compliance and subsequent inefficacy. Safety and efficacy data for switching patients from pregabalin to mirogabalin are scarce. METHODS: This prospective, single-arm, open-label study involving ten participating centers in Japan recruited patients aged ≥ 20 years with peripheral neuropathic pain [visual analog scale (VAS) score ≥ 40 mm]. Where necessary, patients underwent a 1-week tapering period to reduce their pregabalin dose, after which pregabalin was stopped and mirogabalin dose was increased using a step-wise dose titration. Patients underwent dose increases after the first and second weeks if there were no tolerability issues, followed by the effective doses until the end of the study (4 weeks). The primary endpoint was the incidence of somnolence, dizziness, and peripheral edema; secondary endpoints included changes in VAS score. AEs were monitored for safety. RESULTS: Of 157 patients who provided informed consent, 152 patients were enrolled; 136 (89.5%) patients completed the study. The overall incidences of somnolence, dizziness, and peripheral edema were 41.4, 15.8, and 2.6%, respectively. Most patients (> 70%) experienced mild AEs, and one patient experienced a severe AE (dizziness). Most patients (> 70%) were able to achieve dose titration to an effective dose. Overall mean VAS score significantly decreased (Δ15.7 mm, p < 0.0001) by the end of the study. CONCLUSIONS: Mirogabalin switching from pregabalin is well tolerated and effective in pain management for peripheral neuropathic pain using a step-wise titration. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031190113).

Sex-Specific Impact of Pain Severity, Insomnia, and Psychosocial Factors on Disability due to Spinal Degenerative Disease.

Purpose: Pain experience due to spinal degenerative disease decreases activity of daily living and quality of life. The present cross-sectional study was aimed at examining the sex-specific impact of pain severity, psychosocial factors, and insomnia on the disability due to chronic pain arising from spinal degenerative disease. Methods: In total, 111 outpatients with chronic spinal degenerative on initial diagnosis were analyzed. The definition of chronic spinal degenerative disease was (1) pain duration ≥3 months, (2) findings of nerve root compression on neurological examination and imaging, and (3) localized neck or lower back pain (not widespread, upper or lower limb pain). We used Numerical Rating Scale (NRS), Pain Disability Assessment Scale (PDAS), Hospital Anxiety and Depression Scale (HADS), Pain Catastrophizing Scale (PCS), and Athens Insomnia Scale (AIS) to assess patients. Univariate regression analysis was performed to investigate whether sex influences the PDAS score, and sex-stratified multivariate regression analysis was conducted to identify the variables associated with the PDAS score. Results: Sex was identified as a predictor of the PDAS score (standardized coefficient (ß) = 0.28; 95% confidence interval (CI), 0.10-0.46; p=0.003). In men, the AIS score was associated with PDAS (ß = 0.36, 95% CI 0.09-0.63). Age (ß = 0.31, 95% CI 0.06-0.55) and NRS (ß = 0.40, 95% CI 0.14-0.67) were associated with PDAS in women. HADS-A, HADS-D, and PCS were not associated with PDAS in both sexes. Conclusion: Insomnia was associated with disability in men, whereas aging and pain severity were associated with disability in women. Catastrophic thinking was not associated with disability in both sexes.

Insomnia and caregiver burden in chronic pain patients: A cross-sectional clinical study.

Insomnia is a major comorbid symptom of chronic pain and is likely to affect caregiver burden. This cross-sectional study investigated the association between insomnia in chronic pain patients and family caregiver burden. Participants were 60 patients with chronic pain of ≥3 months duration. Demographic and clinical information were collected using the Athens Insomnia Scale (AIS), the Pain Disability Assessment Scale (PDAS), the Hospital Anxiety and Depression Scale (HADS), and a pain intensity numerical rating scale (NRS). Family members who accompanied chronic pain patients to hospital completed the Zarit Burden Interview (ZBI). Univariate regression analysis and multiple regression analysis were conducted to clarify the associations between ZBI scores and total/subscale AIS scores. Covariates were age; sex; pain duration; and scores on the PDAS, HADS anxiety subscale, HADS depression subscale, and NRS. Insomnia was independently associated with ZBI scores [ß: 0.27, 95% confidence interval (CI): 0.07-0.52, p = 0.001]. Scores on the AIS subscale of physical and mental functioning during the day were significantly associated with ZBI scores (ß: 0.32, 95% CI: 0.05-0.59, p = 0.007). In conclusion, the findings suggest that in chronic pain patients, comorbid insomnia and physical and mental daytime functioning is associated with family caregiver burden independently of pain duration, pain-related disability, and pain intensity.

Aureobasidium pullulans-cultured fluid induces IL-18 production, leading to Th1-polarization during influenza A virus infection.

Several microbial molecules with pathogen-associated molecular patterns stimulate host innate immune responses. The innate immune system plays a crucial role in activating acquired immune response via cytokine production and antigen presentation. Previous studies have shown that Aureobasidium pullulans-cultured fluid (AP-CF), which contains ß-glucan, exhibits adjuvant activity and renders mice resistance to influenza A virus infection; however, the underlying mechanism remains elusive. In this study, we investigated the innate immune response to AP-CF. We found that intraperitoneal administration of AP-CF increased the serum level of IL-18 and the number of splenic IFN-γ producing CD4+ cells during influenza A virus infection. The adjuvant effect of AP-CF was distinct from that of alum, which is known to have the ability to stimulate a Th2 immune response. In addition, AP-CF injection barely increased the number of peritoneal neutrophils and inflammatory macrophages, whereas alum injection markedly increased the number of neutrophils and inflammatory macrophages, suggesting that AP-CF is a weak inducer of inflammation compared to alum. AP-CF induced IL-18 production by DC2.4 cells, a dendritic cell line, and by peritoneal exudate cells that include peritoneal macrophages. Collectively, our findings indicate that AP-CF is an adjuvant that promotes the Th1 response during influenza A virus infection.

Death receptor 6 contributes to autoimmunity in lupus-prone mice.

Expansion of autoreactive follicular helper T (Tfh) cells is tightly restricted to prevent induction of autoantibody-dependent immunological diseases, such as systemic lupus erythematosus (SLE). Here we show expression of an orphan immune regulator, death receptor 6 (DR6/TNFRSF21), on a population of Tfh cells that are highly expanded in lupus-like disease progression in mice. Genome-wide screening reveals an interaction between syndecan-1 and DR6 resulting in immunosuppressive functions. Importantly, syndecan-1 is expressed specifically on autoreactive germinal centre (GC) B cells that are critical for maintenance of Tfh cells. Syndecan-1 expression level on GC B cells is associated with Tfh cell expansion and disease progression in lupus-prone mouse strains. In addition, Tfh cell suppression by DR6-specific monoclonal antibody delays disease progression in lupus-prone mice. These findings suggest that the DR6/syndecan-1 axis regulates aberrant GC reactions and could be a therapeutic target for autoimmune diseases such as SLE.

[A Case of Cesarean Section Preceded by Coil Embolization for Subarachnoid Hemorrhage under General Anesthesia].

We report a case of subarachnoid hemorrhage due to rupture of a cerebral aneurysm in a 29-year-old woman in the 34th week of pregnancy. The aneurysm at the anterior communicating artery was up to 10 mm in diameter on magnetic resonance imaging and scheduled for emergent coil embolization. Simultaneously, obstetricians determined that cesarean section should be performed. Maintaining anesthesia by propofol and remifentanil, coil embolization was first performed to avoid aneurism re-rupture, and the patient was then transferred from an angiography room to an operating room where a cesarean section was performed. After delivery, fentanyl 600 µg was intravenously administered, and the patient was extubated immediately after the operation without any complaints. The neonate (weighing 1,882 g, Apgar score 4 at 1 min and 5 at 5 min) also recovered with no complications after 24 hr artificial ventilation. In conclusion, intravenous anesthesia mainly with remifentanil is adequate for a pregnant patient receiving cesarean section preceded by neurosurgery.

Type-I interferon is critical for FasL expression on lung cells to determine the severity of influenza.

Infection of influenza A virus in mammals induces hyper lung pneumonia, which often causes lethal diseases. FasL is a specific ligand of Fas, which is a type-I transmembrane protein to induce cell death. Previously, it has been reported that the hyper induction of gene expression associated with Fas signal is observed in lethal influenza A virus infection. More importantly, it was also reported that functional mutation of the FasL gene protects the host against influenza A virus infection. These observations suggest that induction of FasL signal is functionally associated with the severity of influenza. However, regulation of the induction of FasL or Fas by influenza A virus infection is still unknown. Here, we demonstrated that FasL is induced after the viral infection, and inhibition of the Fas/FasL signal by treatment with a recombinant decoy receptor for FasL (Fas-Fc) increases the survival rate of mice after lethal infection of influenza A virus as well as functional mutation of the FasL gene in gld/gld mice. In addition, the induction level of FasL gene expression in the lung was correlated with the severity of influenza. We also showed that a variety of types of cells in the lung express FasL after the viral infection. Furthermore, type-I interferon induced by the viral infection was shown to be critical for induction of FasL protein expression in the lung. These findings suggested that expression of FasL protein induced by type-I IFN on the lung cell surface is critical to determine the severity of influenza.

Critical function of death-associated protein 3 in T cell receptor-mediated apoptosis induction.

Death-associated protein 3 (DAP3) is crucial for promoting apoptosis induced by various stimulations. This report demonstrates that DAP3 is also important for T cell receptor (TCR)-mediated apoptosis induction in immature thymocytes. Enforced expression of DAP3 accelerated the negative selection in developing thymocytes, using the reaggregate thymus organ culture system. In addition, expression of DAP3 accelerated TCR-mediated apoptosis induction in DO11.10 cells. We also demonstrated that DAP3 translocates into the nucleus during TCR-mediated apoptosis in a Nur77 dependent manner. It is concluded that DAP3 is critical for TCR-mediated induction of apoptosis at the downstream of Nur77.

LKB1 is crucial for TRAIL-mediated apoptosis induction in osteosarcoma.

BACKGROUND: Despite improvements in chemotherapy and surgery in the treatment of osteosarcoma, satisfactory results are still difficult to achieve. New therapeutic modalities need to be developed for the improvement of these treatments. TRAIL (TNF-related apoptosis inducing ligand) is known as a selective apoptosis inducer in most tumor cells, but not in normal cells. Therefore, TRAIL is a good candidate target for the treatment of tumors. However, sensitivity of osteosarcoma cells to TRAIL-induced apoptosis is lower than that of other types of tumor cells. Recently, DAP3 (death associated protein 3) was demonstrated to play a critical role in TRAIL-mediated apoptosis through activation of pro-caspase-8. Here, we found that LKB1, a serine/threonine kinase, expressed in bone and soft tissue sarcoma cells, associated with DAP3. We also demonstrated that expression of DAP3 induced apoptosis in osteosarcoma cells. Furthermore, expression of LKB1 induced apoptosis and co-expression of LKB1 with DAP3 strongly induced apoptosis in osteosarcoma cells. In addition, expression of LKB1 kinase dead mutant, LKB1 (K78M), inhibited DAP3-induced apoptosis in these cells. These results suggest that LKB1 is critical for TRAIL-induced apoptosis induction, cooperating with DAP3 in osteosarcoma cells. It is predicted that LKB1 and DAP3 could be critical target molecules for the treatment of osteosarcomas.

Quantitative liquid chromatography-tandem mass spectrometric analysis of 11-dehydro TXB2 in urine.

A simple and selective determination method of 11-dehydrothromboxane B2 (11-dehydroTXB2), which is urinary metabolite of TXA2, has been developed employing liquid chromatography-tandem mass spectrometry (LC-MS-MS). 11-DehydroTXB2 and its deuterium-labeled analogue as an internal standard were extracted from urine by simple solid-phase extraction (SPE). These compounds were analyzed using LC-MS-MS in the selected reaction monitoring (SRM) mode, by monitoring the transitions from m/z 367 to m/z 161 for 11-dehydroTXB2 and from m/z 371 to m/z 165 for its internal standard. A good linear response over the range 50 pg-10 ng per tube was demonstrated. The values determined by LC-MS-MS were well validated and closely corresponded to the values determined by gas chromatography-mass spectrometry (GC-MS). The mean concentration of 11-dehydroTXB2 in urine of healthy adults was 635 +/- 427 pg/mg creatinine (mean +/- S.D., n = 13). This simple, accurate and selective determination method described in this study should greatly aid in evaluating the role of TXA2 in vivo.

Naloxone reversal of opioid anesthesia revisited: clinical evaluation and plasma concentration analysis of continuous naloxone infusion after anesthesia with high-dose fentanyl.

PURPOSE: In spite of several advantages, the need for postoperative ventilatory support limits the use of high-dose opioid anesthesia. We prospectively evaluated the effectiveness of naloxone infusion for the reversal of high-dose fentanyl anesthesia. METHODS: Anesthesia was maintained with fentanyl in patients undergoing major abdominal surgery. After anesthesia, the trachea was extubated when intravenous naloxone, which was titrated in separate 50- micro g doses, established an acceptable level of consciousness and arterial blood gas (ABG) status under spontaneous respiration; this was followed by continuous infusion started at the rate of the sum of the bolus doses per hour. The naloxone infusion was terminated based on evaluation of the level of consciousness, ABG, and acute abstinence symptoms. Postoperative pain was evaluated using self-reported four-step categorical terms (none, mild, moderate, and severe). Plasma concentrations of fentanyl and naloxone were analyzed in 12 patients, using high-performance liquid chromatography. RESULTS: Fifty-seven out of 59 eligible patients were successfully extubated at 34 +/- 14 min after termination of fentanyl (total dose, 127 +/- 64 micro g.kg(-1); mean +/- SD) with naloxone (total bolus, 3.4 +/- 2.6 micro g.kg(-1)). All these patients recovered fully without ventilatory support under the naloxone infusion, which was terminated at 11 +/- 7 h. The reduction of the naloxone infusion rate effectively relieved the increased pain, and no supplemental analgesic was used in any patients during the naloxone infusion. Pharmacokinetic analysis did not indicate any correlations between plasma fentanyl and naloxone concentrations. CONCLUSION: The results suggest that naloxone infusion with individual dose titration facilitates the use of high-dose opioid anesthesia, maintaining the advantager of this anesthesia.

[Effect of propofol on sevoflurane agitation in children].

BACKGROUND: Sevoflurane may be associated with a high incidence of agitation during recovery from anesthesia in children. We tested the hypothesis that bolus administration of propofol after sevoflurane anesthesia would reduce the incidence of recovery agitation compared with sevoflurane anesthesia alone. METHODS: We conducted a randomized, double-blinded study in 90 children, 1-7 yr of age, undergoing short general anesthesia. They were divided into three groups; 2 mg.kg-1 propofol (group P2), 1 mg.kg-1 propofol (group P1) and intralipid 0.2 ml.kg-1 as control (group C). After sevoflurane induction and maintenance and 5 minutes before the end of operation, propofol or intralipid was administered. We compared the speed and quality of each recovery. We made a new scoring system for the assessment of agitation. Each child received a point from -4 to 10 with this system. RESULTS: Recovery score was similar among the three groups (group P2 had point 4, group P1, point 5, and group C point 4). Recovery time in group P2 was significantly longer than that in group C (about 6 minutes). CONCLUSIONS: Bolus administration of propofol after sevoflurane anesthesia prolonged recovery time, but did not inhibit sevoflurane agitation compared with sevoflurane anesthesia alone.