The mechanism of multistep progression of the transcriptional cascade in activated microglia as approached by a proteome approach.

The ocular cytokine network plays pivotal roles in terms of the initiation and progression of retinal degeneration. Several types of immunocompetent cells such as microglia participate in inflammation, and a temporal transition in the molecular events of inflammation has been hypothesized. We previously found that the Csf2 gene was induced in the early phase of retinal degeneration. CSF2 participates in the transcriptional activation of several cytokines expressed by microglia; however, whether CSF2 is essential in this context is not known. In this work, we approach this question by using anti-CSF2 neutralizing bntibody and the protein synthesis inhibitor cycloheximide (CHX). We first revealed that CSF2 positively regulated the cytokine induction cascade using a CSF2-neutralizing antibody (anti-CSF2) to treat the microglial cell line that were activated by lipopolysaccharide (LPS). LPS or Lipid A stimulation in the presence of the protein synthesis inhibitor cycloheximide (CHX) led to cytokine superinduction, but suppression of the expression of a few cytokines was also noted in MG5 cells. To examine transitions of the molecular events within LPS-activated microglia, we next performed proteome analysis of MG5 cells stimulated with LPS for 0, 4, and 9 h. The Database for Annotation, Visualization, and Integrated Discovery analysis of differentially expressed proteins showed that various mRNA-modifying molecules were induced after LPS stimulation, in addition to molecules involved in inflammation. However, the numbers of common proteins founded in the comparison between the induced proteins of 4 and 9 h were only one-third and one-half of induced proteins at 4 and 9 h, respectively, suggesting dynamic transition of the induced proteins. LPS-induced mRNA-modifying proteins were almost completely suppressed by CHX, as expected, suggesting that transient induction of transcription-editing proteins plays an important role in terms of the phenotype of inflammation that develops in microglia after LPS stimulation.

High prevalence of severe pain is associated with low opioid availability in patients with advanced cancer: Combined database study and nationwide questionnaire survey in Japan.

OBJECTIVES: Opioid availability for the palliative care of patients with advanced cancer is increasing globally. However, opioid availability remains extremely low in Japan. We investigated whether pain is appropriately controlled by low-dose opioid prescriptions in patients with advanced cancer in Japan. METHODS: A web-based nationwide survey for caregivers from 2000 community comprehensive support care centers was performed in Japan to assess details about pain in the 30 days before patients died of end-stage cancer. Separately, the data for opioid prescription doses and medical services in the 90 days before the death of patients with cancer were extracted from a health insurance claim database. RESULTS: Responses from 1034 responders were retrieved and 665 patients were included. In total, 254 patients (38.2%) complained of severe-to-intolerable cancer-related pain. The median cumulative prescription dose of opioids in the 90 days before patient death was 311.0 mg by oral morphine equivalent doses. Multiple regression analyses across prefectures revealed that the proportion of patients with severe-to-intolerable cancer-related pain was negatively associated with the cumulative opioid consumption expressed as morphine-equivalent doses within 90 days before death. CONCLUSIONS: The very low availability of opioids for patients with end-stage cancer could result in high rate of severe-to-intolerable cancer-related pain patients. There were several limitations in this study, and the interpretations of the findings should be carefully. However, the increase in the absolute dose of opioids could improve the palliative care framework to the pain control levels of the global standard.

Case Report: Guanfacine and methylphenidate improved chronic lower back pain in autosomal dominant polycystic kidney disease with comorbid attention deficit hyperactivity disorder and autism spectrum disorder.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by the bilateral development of multiple cysts in the kidneys. Pain management is a clinically important issue, especially because approximately 60% of patients with ADPKD experience chronic pain related to hemorrhage from renal cysts, which significantly reduces their daily life. The cystic fibrosis transmembrane conductance regulator, the molecule responsible for cyst formation in ADPKD, is also the cause of cystic fibrosis. Since attention deficit hyperactivity disorder (ADHD) is known to occur frequently in conjunction with cystic fibrosis, ADPKD may be associated with ADHD. However, to our knowledge, no study has investigated 1) ADHD or autism spectrum disorder (ASD) as comorbidities with ADPKD, 2) the effects of ADHD medications on chronic pain in ADPKD, or 3) cerebral blood flow corresponding to guanfacine (GF) or methylphenidate (MP) treatment for chronic pain. We report the case of a 15-year-old girl with ADPKD, who had chronic back pain associated with ADPKD and had to withdraw from high school because the pain interfered with her daily life. Although she took antihypertensive medications to prevent bleeding, they did not provide adequate blood pressure control. The patient was referred to a child psychiatrist and diagnosed with ASD; however, the pain did not improve. Subsequently, she was referred to our pain center. The diagnosis of ADHD was confirmed and treatment with ADHD medications was initiated. Monotherapy with MP, atomoxetine, and GF resulted in hypertension and hypotension as side effects; however, a combination of MP 18 mg and GF 4 mg provided pain relief and moderate blood pressure control, and the patient was able to go on to college. During the course of treatment, there was an improvement in the distribution of cerebral blood flow in the prefrontal and insular cortices. Confirmation of an ADHD diagnosis comorbid with ASD enabled the use of ADHD medications. The combination of MP and GF improved chronic back pain and high blood pressure due to ADPKD and cerebral blood flow. Screening for ADHD is important in the treatment of ADPKD.

Case report: Atomoxetine improves chronic pain with comorbid post-traumatic stress disorder and attention deficit hyperactivity disorder.

Background: It is known that patients reporting chronic pain often experience trauma or post-traumatic stress disorder (PTSD) and tend to be more difficult to treat. Attention deficit hyperactivity disorder (ADHD), a neurodevelopmental disorder, is frequently associated with chronic pain. Furthermore, patients diagnosed with ADHD are more likely to encounter trauma and develop PTSD because of their inattentive and impulsive tendencies. There are reports stating that atomoxetine (ATX), a selective noradrenaline reuptake inhibitor for ADHD, is effective in patients diagnosed with PTSD and ADHD. However, there have been no reports on cases of comorbid PTSD and ADHD with chronic pain, and ATX's potential in improving chronic pain coexisting PTSD. Furthermore, no reports have evaluated patient cerebral blood flow in conjunction with the course of treatment with ATX for chronic pain. Case report: In this study, we reported a case where ATX improved chronic pain with PTSD and improved cerebral blood flow. The patient was a 56-year-old woman exhibiting chronic pain with PTSD, resulting from 6 years of severe domestic violence from her common-law husband. She had no history of ADHD diagnosis, but through aggressive screening, comorbid ADHD was diagnosed. When treated with ATX, there were significant improvements in her pain, quality of life, anxiety, depression, catastrophic thoughts, and cerebral blood flow. As a result, she could resume work after 11 years. Conclusion: The study showed that chronic pain with PTSD may be comorbid with ADHD. Moreover, we found that ATX can improve chronic pain with PTSD and cerebral blood flow. Aggressive screening of ADHD is important because once the diagnosis of comorbidity is confirmed, an ideal ADHD treatment can be selected. Therefore, based on the results of this study, ATX may be a candidate for treatment for cases of chronic pain with PTSD and ADHD.

Secondary analysis of preoperative predictors for acute postoperative exacerbation in interstitial lung disease.

This study assessed whether perioperative management is associated with postoperative acute exacerbations (AEs) in interstitial lung disease (ILD) patients. Using secondary data from the study "Postoperative acute exacerbation of interstitial lung disease: a case-control study," we compared the perioperative clinical management of the AE and non-AE groups (1:4 case-control matching) selected by sex, year of surgery (2009-2011, 2012-2014, and 2015-2017), and multiple surgeries within 30 days. We compared 27 and 108 patients with and without AEs, respectively. Rates of one lung ventilation (OLV) cases (70 vs. 29%; OR, 5.9; 95%CI, 2.34-14.88; p < 0.001) and intraoperative steroid administration (48 vs. 26%; OR, 2.65; 95%CI, 1.11-6.33; p = 0.028), and average mean inspiratory pressure (9.2 [1.8] vs. 8.3 [1.7] cmH2O; OR, 1.36; 95%CI, 1.04-1.79; p = 0.026), were significantly higher in the AE group. There was a significant difference in OLV between the groups (OR, 4.99; 95%CI, 1.90-13.06; p = 0.001). However, the fraction of inspired oxygen > 0.8 lasting > 1 min (63 vs. 73%, p = 0.296) was not significantly different between the groups. OLV was significantly associated with postoperative AEs in patients with ILD undergoing both pulmonary and non-pulmonary surgeries. Thus, preoperative risk considerations are more important in patients who require OLV.

Improvement in persistent idiopathic facial pain with comorbid ADHD using the combination of a dopamine system stabilizer and psychostimulant: A case report.

Key Clinical Message: Persistent idiopathic facial pain (PIFP) and attention-deficit/hyperactivity disorder (ADHD) may coexist and can be improved with ADHD medications. Thus, clinicians should screen for ADHD by a multidisciplinary approach when treating PIFP and differentiate between other odontogenic disorders. Abstract: We report a case of a woman with persistent idiopathic facial pain (PIFP) and attention-deficit/hyperactivity disorder (ADHD) that markedly improved with the administration of a combination of aripiprazole (APZ) and methylphenidate (MP) treatment. Screening for ADHD and administration of APZ and/or MP may be considered in treating PIFP.

Case report: Remission of chronic low back pain and oral dysesthesia comorbid with attention deficit/hyperactivity disorder by treatment with atomoxetine and pramipexole.

Introduction: Oral dysesthesia is a disease characterized by pain and/or abnormal sensations in the oral region, without any organic abnormality. Its symptoms include pain, and it is considered to be a disorder associated with idiopathic oral-facial pain. It is also known that idiopathic oral-facial pain tends to coexist with chronic musculoskeletal pain, including low back pain, even before its onset. Such coexisting idiopathic pain conditions are also called chronic overlapping pain conditions (COPCs). In general, COPCs are often refractory to treatment. Recently, it has been reported that attention deficit hyperactivity disorder (ADHD) is associated with many COPCs, such as pain in the facial and lower back regions and so on. However, there are no reports of (1) ADHD as a comorbidity with oral dysesthesia (OD) or (2) of the therapeutic effects of ADHD medications or dopamine agonists on low back pain and OD or an (3) evaluation of cerebral blood flow over time after treatment with these medications for OD and low back pain. Case Presentation: In this study, we report the case of an 80-year-old man with OD and chronic low back pain that persisted for more than 25 years. His OD and chronic back pain were refractory to standard treatment, prevented him from continuing work, and tended to be exacerbated by conflicts in his relationship with his son. In recent years, ADHD has often been found to be comorbid with chronic pain, and ADHD medications have been reported to improve chronic pain as well. The patient was confirmed to have undiagnosed ADHD and was treated with the ADHD medication atomoxetine and dopamine agonist pramipexole, which dramatically improved his OD, chronic back pain, and cognitive function. Furthermore, along the course of treatment, there was improvement in cerebral blood flow in his prefrontal cortex, which was thought to reflect improved function in the region. Consequently, he was able to resume work and improve his family relationships. Conclusion: Therefore, in the cases of ODs and COPCs, screening for ADHD and, if ADHD is diagnosed, ADHD medications or dopamine agonists may be considered.

Allergic reactions to propofol in adult patients with egg or soybean allergy: a retrospective cohort study from a large database of a single institute.

BACKGROUND: In recent years, many reports have indicated that propofol is safe to administer to patients with egg/soybean allergy in Western countries. Egg allergy is more frequent in Asia, but there are limited reports regarding allergic reactions to propofol use among adults. This study aimed to determine whether propofol causes allergic reactions in patients with egg/soybean allergy. METHODS: Adult patients who underwent surgery involving anesthesiologists from 2018 to 2021 were included. In all patients, we reviewed food allergy information in their electronic medical record and extracted anesthetics. Patients with egg/soybean allergy were subdivided into two groups on the basis of intraoperative use of propofol. We evaluated each group for allergic reactions within 24 h after the induction of anesthesia. The primary outcome was a relative risk of allergic reactions after propofol use for patients with egg/soybean allergy. RESULTS: In total, 22,111 patients with 28,710 anesthesia records were identified. Among patients with egg/soybean allergy, 173 (0.8%) patients and 237 (0.8%) anesthesia records were included in the study. Among the records of egg-/soybean-allergic patients, 151 were administered propofol, and 86 were not. The relative risk of allergic reactions after propofol use for patients with egg/soybean allergy was 1.14 (95% confidence interval, 0.10-12.4; p = 0.74). CONCLUSION: The use of propofol in patients with egg/soybean allergy does not significantly increase the relative risk of allergic reactions. Therefore, anesthesiologists can appropriately determine the indication for propofol, even in patients with egg/soybean allergy. TRIAL REGISTRATION: UMIN-CTN, UMIN000049321 registered 26 October 2022 - retrospectively registered, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000056167.

Diagnosis and treatment of intractable idiopathic orofacial pain with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with primary chronic pain syndromes, such as fibromyalgia, migraine, and chronic low back pain. Although idiopathic orofacial pain (IOP) is classified as burning mouth syndrome or persistent idiopathic facial or dentoalveolar pain and as a primary chronic pain, the association between IOP and ADHD has not been investigated. This retrospective cohort study investigated the severity of ADHD symptoms measured using the ADHD scale and the effects of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole. The participants were 25 consecutive patients with refractory IOP referred to a psychiatrist and diagnosed with coexisting ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5. The ADHD scale scores were higher in patients with intractable IOP than those in the general population. Pharmacotherapy used in this study led to clinically significant improvements in pain, anxiety/depression, and pain catastrophizing. Intractable IOP and ADHD were shown to be associated. In the future, screening and pharmacotherapy for ADHD should be considered in the treatment of intractable IOP.

Reviewing COVID-19 from an anesthesiologist's perspective in 2022: JA symposium.

The COVID-19 pandemic is ongoing as of September 2022. Since January 2020 when the first case was reported in Japan, the medical community faced a variety of problems both domestically and internationally. It is meaningful to review the impact of COVID-19 from an anesthesiologist's perspective to clarify our policy for future infectious disease outbreaks. In this year's Journal of Anesthesia (JA) symposium, five experts who were deeply involved in the COVID-19 response reviewed the past 2.5 years and made recommendations for potential future pandemics. Anesthesiologists are specialists in airway management and their role in intubating patients with COVID-19 has received much attention. However, they have also played an important backup role in intensive care as critical care physicians and must be more involved in critical care in regular (non-pandemic) times to properly fulfill this role. It is especially important for the Japan Society of Anesthesiologists and JA to quickly disseminate accurate information on unknown infectious diseases to the medical community and wider society. Therefore, it is important to promptly publish papers that are quality-assured through peer review.

Quantitative relationship between anteriorization of alpha oscillations and level of general anesthesia.

A typical electroencephalogram (EEG) change induced by general anesthesia is anteriorization-disappearance of occipital alpha oscillations followed by the development of frontal alpha oscillations. Investigating the quantitative relationship between such a specific EEG change and the level of anesthesia has academic and clinical importance. We quantified the degree of anteriorization and investigated its detailed relationship with the level of anesthesia. We acquired 21-electrode EEG data and bispectral index (BIS) values of 50 patients undergoing surgery from before anesthesia induction until after patient arousal. For each epoch of a 10.24-s window with 1-s offsets, we calculated frontal alpha power [Formula: see text], occipital alpha power [Formula: see text], and their difference [Formula: see text] to quantify anteriorization. We calculated Spearman's rank correlation coefficients between these values and the BIS value. We used locally weighted regression to estimate [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] at each BIS value. Thirty-six patients (26 females and 10 males aged 24-85 years) were analyzed. The 95% confidence intervals for the mean of Fisher transformations of Spearman's rank correlation coefficients between [Formula: see text], [Formula: see text], and [Formula: see text] and BIS value were [- 0.68, - 0.26], [0.02, 0.62], and [- 1.11, - 0.91], respectively. The change in [Formula: see text] and [Formula: see text] with BIS value showed different patterns by the type of anesthetic agent, whereas that in [Formula: see text] was more consistent with smaller individual variance. Anteriorization, quantified by the difference between frontal and occipital alpha powers, continuously developed in conjunction with general anesthesia. Quantifying anteriorization may provide an objective indicator of the level of anesthesia.

Different Profiles of the Triad of Lysophosphatidylcholine, Lysophosphatidic Acid, and Autotaxin in Patients with Neuropathic Pain Diseases: a Preliminary Observational Study.

The mechanisms underlying neuropathic pain remain unclear. Lysophosphatidic acid (LPA) is a bioactive phospholipid derived mainly from lysophosphatidylcholine (LPC) by extracellular autotaxin (ATX), and has attracted attention as a candidate biomarker of neuropathic pain. We aimed to investigate the levels of LPA, LPC, and ATX in patients with lumbar spinal canal stenosis (LSCS) or other neuropathic pain diseases, and to distinguish the underlying mechanism of LSCS from other neuropathic pain conditions. Furthermore, the levels of phosphorylated neurofilament heavy chain (pNF-H), an objective surrogate marker of axonal damage, were also measured. Cerebrospinal fluid (CSF) samples were obtained from 56 patients with LSCS (n = 31) and various etiologies other than LSCS (n = 25). Patients with LSCS complained of pain intensity comparable to that of patients without LSCS. The LPA levels were significantly higher in patients with LSCS than in non-LSCS patients, while the ATX levels were significantly lower. However, the differences in LPC and pNF-H levels between the two patient groups were not significant. The LPA/LPC ratio was significantly higher in the LSCS group. Notably, the difference in LPA between the two groups diminished in the analysis of covariance (ANCOVA) with ATX as a covariate. Thus, it helped to reveal that LPA synthesis in patients with LSCS depends more efficiently on ATX than in non-LSCS neuropathic pain patients with other etiologies. Our findings further suggest that the triad of LPA, LPC, and ATX in LSCS may contribute to the development and maintenance of neuropathic pain in a manner different from non-LSCS neuropathic conditions.

A dried blood spot test for diagnosis of autoimmune pulmonary alveolar proteinosis.

Granulocyte/macrophage colony-stimulating factor autoantibodies (GMAbs) mediate the pathogenesis of autoimmune pulmonary alveolar proteinosis (autoimmune PAP) and their quantification in serum by enzyme-linked immunosorbent assay (ELISA) - the serum GMAb test - is the 'gold standard' for diagnosis of autoimmune PAP. Because GMAbs are high in autoimmune PAP and low or undetectable in healthy people, we hypothesized that the ELISA could be adapted for evaluation of blood obtained from the fingertip using a dried blood spot card (DBSC) for specimen collection. Here, we report development of such a method - the DBSC GMAb test - and evaluate its ability to measure GMAb concentration in blood and to diagnose autoimmune PAP. Fresh, heparinized whole blood was obtained from 60 autoimmune PAP patients and 19 healthy people and used to measure the GMAb concentration in blood (by the DBSC GMAb test). After optimization, the DBSC GMAb test was evaluated for accuracy, precision, reliability, sensitivity, specificity, and ruggedness. The coefficient of variation among repeated measurements was low with regard to well-to-well, plate-to-plate, day-to-day, and inter-operator variation, and results were unaffected by exposure of prepared DBSC specimens to a wide range of temperatures (from -80 °C to 65 °C), repeated freeze-thaw cycles, or storage for up to 2.5 months before testing. The limit of blank (LoB), limit of detection (LoD), and lower limit of quantification (LLoQ), were 0.01, 0.21, and 3.5 µg/ml of GMAb in the blood, respectively. Receiver operating curve characteristic analysis identified 2.7 µg/ml as the optimal GMAb concentration cutoff value to distinguish autoimmune PAP from healthy people. This cutoff value was less than the LLoQ and the ranges of GMAb results for autoimmune PAP patients and healthy people were widely separated (median (interquartile range): 22.6 (13.3-43.8) and 0.23 (0.20-0.30) µg/ml, respectively). Consequently, the LLoQ is recommended as the lower limit of the range indicating a positive test result (i.e., that autoimmune PAP is present); lower values indicate a negative test result (i.e., autoimmune PAP is not present). Among the 30 autoimmune PAP patients and 19 healthy people evaluated, the sensitivity and specificity of the DBSC GMAb test were both 100% for a diagnosis of autoimmune PAP. Results demonstrate the DBSC GMAb test reliably measures GMAbs in blood and performs well in the diagnosis of autoimmune PAP.

Elevation of serum plasminogen activator inhibitor-1 predicts postoperative delirium independent of neural damage: a sequential analysis.

Older adult surgical patients are susceptible to developing delirium. Early intervention can be initiated if a potential biomarker associated with delirium can be identified during the acute phase of surgery. Therefore, we investigated the changes in the levels of serum inflammatory mediators responsible for delirium. Serum biomarkers were measured preoperatively to postoperative day 3 in 96 patients who underwent esophageal cancer surgery and compared between patients who did and did not develop delirium. Serum concentrations of the brain-derived phosphorylated neurofilament heavy subunit remained at higher levels throughout the entire perioperative period in patients with delirium (n = 15) than in those without delirium (n = 81). The interaction between delirium and non-delirium was significant for plasminogen activator inhibitor-1 (including age as a covariate, F = 13.360, p < 0.0001, η2 p = 0.134, observed power 1.000) during the perioperative periods. Plasminogen activator inhibitor-1 level discriminated between patients with and without clinically diagnosed delirium with significantly high accuracy (area under curve, 0.864; sensitivity, 1.00: negative predictive value, 1.000; p = 0.002). Rapid increases in the levels of serum plasminogen activator inhibitor-1 may enable clinicians to identify patients at risk of developing postoperative delirium and initiate early prevention and intervention.

Genetic polymorphism of pleiotrophin is associated with pain experience in Japanese adults: Case-control study.

Genetic factors play a role in individual differences in pain experience. Here, we performed a genome-wide association study (GWAS) to identify novel loci regulating pain processing. We conducted a 2-stage GWAS and the candidate single-nucleotide polymorphisms (SNPs) association study on pain experience using an exploratory cohort of patients with cancer pain. The confirmatory cohort comprised of participants from the general population with and without habitual use of analgesic medication. In the exploratory cohort, we evaluated pain intensity using a numerical rating scale, recorded daily opioid dosages, and calculated pain reduction rate. In the confirmatory cohort, pain experience was defined as habitual nonsteroidal anti-inflammatory drug usage. Using linear regression models, we identified candidate SNP in the exploratory samples, and tested the association between phenotype and experienced pain in the confirmatory samples. We found 1 novel SNP (rs11764598)-located on the gene encoding for pleiotrophin on chromosome 7-that passed the genome-wide suggestive significance at 20% false discovery rate (FDR) correction in the exploratory samples of patients with cancer pain (P = 1.31 × 10-7, FDR = 0.101). We confirmed its significant association with daily analgesic usage in the confirmatory cohort (P = .028), although the minor allele affected pain experience in an opposite manner. We identified a novel genetic variant associated with pain experience. Further studies are required to validate the role of pleiotrophin in pain processing.

Case report: Treatment of persistent atypical odontalgia with attention deficit hyperactivity disorder and autism spectrum disorder with risperidone and atomoxetine.

Chronic pain has recently been associated with developmental disorders [autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD)]. Regarding chronic pain in adulthood, fibromyalgia, migraine, and chronic low back pain have been associated with ADHD. The ICD-11 disease classification categorizes these pain diseases as chronic primary pain, suggesting high comorbidity with developmental disorders in chronic primary pain. Atypical odontalgia (AO) is a persistent tooth pain that occurs in the absence of any of the usual dental causes, most of which are triggered by dental treatment. Conditions characterized by tooth pain with no apparent cause are also classified as chronic primary pain. Approximately half the patients with AO are diagnosed with psychiatric disorders; the most common are depression (15.4%) and anxiety disorders (10.1%). However, there are no reports on neurodevelopmental disorders comorbid with AO. In the present study, we report a case of a 46-year-old man with numerous complaints (e.g., occlusal instability, difficulty eating, difficulty speaking), who took work leave due to worsening of his symptoms after periodontal scaling ("gingival recession" and "aggressive periodontal treatment") and frequently expressed dissatisfaction and anger at the hospital, making the dental treatment difficult. After a referral to a psychiatrist specializing in chronic pain, AO and previously undiagnosed comorbidity of ASD and ADHD were confirmed. Atypical antipsychotic risperidone for ASD irritability and an ADHD medication, atomoxetine dramatically reduced anger, pain, anxiety, depression, and pain catastrophizing thoughts, leading to reduced obsession with his symptoms and less frequent complaints. After risperidone (1 mg/day) + atomoxetine (120 mg/day) were ultimately prescribed after adjustment, he was able to return to work 226 days after initiation of psychiatric treatment. Recent studies show that comorbidity of developmental disorders in patients with chronic pain is likely to be undetected. Clinicians should include screening for ASD and ADHD not only in cases of fibromyalgia, migraine, and chronic low back pain, but also in orofacial pain such as AO and other treatments for chronic primary pain. For patients diagnosed with ASD or ADHD, an effective drug therapy for ASD and ADHD should be considered.

Roles of CSF2 as a modulator of inflammation during retinal degeneration.

Colony-stimulating factor 2 (CSF2) is a potent cytokine that stimulates myeloid cells, such as dendritic cells and macrophages. We have been analyzing the roles of microglia in retinal degeneration through the modulation of inflammation in the eye, and examined the roles of CSF2 in this process. Both subunits of the CSF2 receptor are expressed in microglia, but no evidence suggesting the involvement of CSF2 in inflammation in the degenerating eye has been reported. We found that Csf2 transcripts were induced in the early phase of in vitro mouse adult retina culture, used as degeneration models, suggesting that CSF2 induction is one of the earliest events occurring in the pathology of retinal degeneration. The administration of CSF2 into the retina after systemic NaIO3 treatment increased the number of microglia. To examine the roles of CSF2 in retinal inflammation, we overexpressed CSF2 in retinal explants. Induction of CSF2 activated microglia and Müller glia, and the layer structure of the retina was severely perturbed. CC motif chemokine ligand 2 (Ccl2) and C-X-C motif chemokine ligand 10 (Cxcl10), both of which are expressed in activated microglia, were strongly induced by the expression of CSF2 in the retina. The addition of CSF2 to primary retinal microglia and the microglial cell lines MG5 and BV2 showed statistically significant increase in Ccl2 and Il1b transcripts. Furthermore, CSF2 induced proliferation, migration, and phagocytosis in MG5 and/or BV2. The effects of CSF2 on microglia were mild, suggesting that CSF2 induced strong inflammation in the context of the retinal environment.