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Background For several variants of quasi-moyamoya disease, cerebral revascularization treatment is as effective as it is for the more typical cases of moyamoya disease. Here, we examined a case of moyamoya disease with concurrent congenital rubella syndrome (CRS). On the basis of concurrent underlying disease, the patient was considered to have quasi-moyamoya disease and was treated with cerebral revascularization. Case Description A 36-year-old female presented with a large cerebral infarction. She was diagnosed with quasi-moyamoya disease on the basis of clinical and imaging features. The ischemic symptoms and cognitive dysfunction improved after combined direct and indirect revascularization. Conclusions To our knowledge, this is the first known report of moyamoya disease with concurrent CRS. We treated this patient with revascularization as typical for other quasi-moyamoya conditions including Down syndrome. This case emphasizes the effectiveness of revascularization treatment for moyamoya disease with concurrent CRS for the prevention of ischemic stroke and improvement of cognitive function, despite existing cerebral infarction.

Background Fibromyalgia is characterized by chronic widespread pain, and more than half of patients with fibromyalgia report that weather-related variables aggravate their symptoms. However, the differences in actual symptoms have not been measured between those with and without weather sensitivity. The present study aimed to investigate whether weather sensitivity associated with the minimal clinically important difference values of quality of life in patients with fibromyalgia, between those with and without weather sensitivity. Methods Sixty-four consecutive outpatients with fibromyalgia on their first visit to our tertiary center were included. Weather sensitivity was measured using self-perceived symptoms. Pain intensity was measured using the 0–10 Numerical Rating Scale (NRS). Quality of life was measured using the Euro Quality of life-5 Dimensions-3 level (EQ-5D-3L) scale. The variables were subjected to univariable and multivariable analysis using the EQ-5D-3L scale. Results The mean age of the patients was 50 years. Forty-eight patients (75%) were women. The mean EQ-5D-3L score was 0.55. Thirty-seven patients (58%) reported weather sensitivity. In univariable analysis, the welfare recipient, weather sensitivity, and NRS values were associated with EQ-5D-3L scale scores. In multivariable analysis, NRS value and weather sensitivity were independently associated with EQ-5D-3L scale scores. The NRS and EQ-5D-3L scale scores were significantly worse in those with weather sensitivity than those without weather sensitivity. The difference in NRS values was less than 1.5 points between groups. The differences in EQ-5D-3L scale scores were 0.16 points between groups. Conclusions Weather sensitivity was significantly associated with quality of life in patients with fibromyalgia. There was an association with weather sensitivity and the minimal clinically important difference values of quality of life in patients with fibromyalgia. The presence of weather sensitivity could have a key role in the quality of life in patients with fibromyalgia.

Introduction Inappropriate antidiuretic hormone secretion syndrome can be a serious adverse event of cisplatin-based chemotherapy. Cisplatin had to be changed to other drugs or chemotherapy completely discontinued in earlier reported cases. Case presentation Three cycles of bleomycin, etoposide, and cisplatin chemotherapy were planned for a 40-year-old man with a diagnosis of lymph node recurrence of testicular cancer. On day 9, he suffered from vomiting and mental disturbance. Severe hyponatremia (110 mEq/L) with low plasma osmolality led to a diagnosis of a syndrome of inappropriate antidiuretic hormone secretion, and infusions of hypertonic saline and salt intake were prescribed. Second and third courses of bleomycin, etoposide, and cisplatin chemotherapy could then be given with careful electrolyte management. Conclusion Continuation of cisplatin administration with precise electrolyte adjustment can be a treatment option in regimens where cisplatin is essential for achieving optimal antitumor efficacy.

Background The incidence of penetrating intracranial foreign bodies is rare, and to date, not many relevant studies have been published worldwide. In particular, a nail penetrating intracranially, just near the superior sagittal sinus (SSS), is extremely rare. We treated the case of a large nail that penetrated the middle of the head and strategized its removal. Case Description A 70-year-old man had experienced headache lasting a day. Computed tomography of the brain revealed a nail penetrating the middle of his head; in particular, the tip of the nail had penetrated the right ventricle, causing a slight subarachnoid hemorrhage. Angiography showed that the nail was very close to the SSS and that the venous flow was normal. However, there was a risk of the nail penetrating through the SSS or injuring other arteries, and we removed the nail directly from the intracranial view to stop bleeding from the SSS or other vessels. Fortunately, there was no bleeding, and we washed the hole created by the nail penetration and concluded the surgery. Conclusions Our technique is useful and safe for removing large nails penetrating the head.

Background Chronic subdural hematoma (CSDH) is the most common disease encountered in neurosurgery. Diagnoses of CSDH are usually made on the basis of computed tomography (CT) images. In this report, we discuss the case of a patient with meningioma whose findings instead suggested CSDH. Case Description A 91-year-old woman complained of dizziness. Brain CT imaging revealed a low-density subdural space, following which we diagnosed her with CSDH. On the same day, we performed burr hole surgery. However, when opening the burr hole and cutting the dura, a light yellowish tumor was observed under the dura. After the operation, her condition deteriorated and she died 2 days later. After 10 days, pathologic examination of the tumor specimen led to a diagnosis of atypical meningioma. Conclusions In almost all cases, CSDH can be diagnosed using CT images only. However, our patient's true diagnosis was meningioma, rather than CSDH. We rouse attention not to take it for CSDH with a CT image easily.

Studies have indicated that chronic low back pain (LBP) should be approached according to its morphological basis and in consideration of biopsychosocial interventions. This study presents an updated review on available psychological assessments and interventions for patients with chronic LBP. Psychosocial factors, including fear-avoidance behavior, low mood/withdrawal, expectation of passive treatment, and negative pain beliefs, are known as risk factors for the development of chronic LBP. The Örebro Musculoskeletal Pain Questionnaire, STarT Back Screening Tool, and Brief Scale for Psychiatric Problems in Orthopaedic Patients have been used as screening tools to assess the development of chronicity or identify possible psychiatric problems. The Pain Catastrophizing Scale, Pain Self-Efficacy Questionnaire, and Injustice Experience Questionnaire are also widely used to assess psychosocial factors in patients with chronic pain. With regard to interventions, the placebo effect can be enhanced by preferable patient-clinician relationship. Reassurance to patients with non-specific pain is advised by many guidelines. Cognitive behavioral therapy focuses on restructuring the negative cognition of the patient into realistic appraisal. Mindfulness may help improve pain acceptance. Self-management strategies with appropriate goal setting and pacing theory have proved to improve long-term pain-related outcomes in patients with chronic pain.

[Abstract] Background: To evaluate if early improvements in pain and function with subcuta-neous tanezumab are meaningful and sustained over 24 weeks. Methods: Patients with moderate- to- severe osteoarthritis (hip or knee) in Europe and Japan were randomized to placebo, tanezumab 2.5 mg or tanezumab 5 mg (baseline, Week 8 and Week 16). Outcomes included: average daily index joint pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales, rescue medication use, WOMAC responders (within- patient ≥30% reduction in WOMAC Pain or Physical Function), Outcome Measures in Rheumatology- Osteoarthritis Research Society International (OMERACT- OARSI) responders (within- patient) and Patient- reported Treatment Impact Assessment- Modified questionnaire. Results: Patients received placebo (n = 282), tanezumab 2.5 mg (n = 283) or tanezumab 5 mg (n = 284). Changes from baseline in average daily index joint pain (within the first week) and WOMAC subscales (Week 2 through Week 24) were greater for each tanezumab group versus placebo (least squares [LS] mean, unadjusted p ≤ .05). Rescue medication use (days/week) was lower for each tan-ezumab group versus placebo from Week 2 through Week 12 (LS mean, unad-justed p ≤ .05) but not at Week 16 or 24. A higher proportion of each tanezumab group than placebo achieved ≥30% reduction from baseline in WOMAC Pain or Physical Function, or OMERACT- OARSI response (Week 2 through Week 24, unadjusted p ≤ .05), or were satisfied with treatment at Week 24 (unadjusted p ≤ .05). Conclusions: Subcutaneous tanezumab, compared with placebo, reduced pain within the first week, and pain and function were improved throughout 24 weeks. The propor-tions of responders and patients satisfied were higher with tanezumab than placebo. ClinicalTrials.gov:NCT02709486. Significance: This exploratory analysis of data from a placebo- controlled, Phase 3 study of patients with moderate- to- severe osteoarthritis of the hip or knee for whom standard analgesics were not effective or could not be taken, found that onset of efficacy of subcutaneous tanezumab was within the first week, and efficacy was maintained through the 24- week treatment period. Tanezumab was effective in those patients with the most radiologically severe osteoarthritis.

PURPOSE The abdominal procedure of ventriculoperitoneal or lumboperitoneal shunt is difficult because of a deep and narrow operative view, especially for obese patients. We have developed the 'Hoisting method,' which enables us to make abdominal procedures easy and safe. MATERIAL AND METHODS We report our experience with five cases between April 2020 and March 2021. RESULTS The placement of the shunt was easy and safe in all patients without any complications. CONCLUSION The shunt method is very effective and easy without requiring additional devices.

Background: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of renal complications. Resolution of renal side effects following NSAID administration has been observed following short-term use. Thus, the aim of the present study was to investigate a series of patients with chronic musculoskeletal pain who underwent long-term NSAIDs administration followed by switching to TA combination tablets to study the impact of NSAID-induced renal side effects.Methods: This was a longitudinal retrospective study of 99 patients with chronic musculoskeletal pain. The patients were administrated NSAIDs daily during the first 12 months followed by daily TA combination tablets for 12 months. Estimated glomerular filtration rate (eGFR) and serum levels of aspartate aminotransferase and alanine transaminase were measured at baseline, after NSAIDs administration, and after TA administration.Results: eGFR was significantly reduced following 12-month NSAIDs administration (median, from 84.0 mL/min/1.73 m2 to 72.8 mL/min/1.73 m2), and the reduction was not shown following the subsequent 12-month TA administration (median, 71.5 mL/min/1.73 m2). Reduction in eGFR was less in patients who received celecoxib (median, -1.8 mL/min/1.73 m2) during the first 12 months. There was no significant difference in aspartate aminotransferase and alanine transaminase in each period.Conclusions: Thus, patients receiving NSAIDs for 12 months displayed both reversible and irreversible reduction of eGFR upon cessation of NSAIDs and switching to TA. Our data highlights the potential safety benefit of utilizing multimodal analgesic therapies to minimize the chronic administration of NSAIDs.

Introduction This study aimed to investigate the differences in the Injustice Experience Questionnaire (IEQ) scores during the early period after the diagnosis of Whiplash-associated disorder (WAD) between Japanese and Canadian samples, and the associations between the IEQ scores and treatment terms in Japanese patients with acute WAD. Methods We used secondary data for the IEQ scores of Canadian patients with acute WAD. In Japan, we collected data from 85 consecutively enrolled patients with acute WAD, and their treatment terms were collected; these referred to the number of days between the date of injury and the closure date of the insurance claim and the number of treatment visits. Before treatment, the Numeric Rating Scale, Neck Disability Index, Hospital Anxiety and Depression Scale, IEQ, and Euro Quality of Life five-dimensional questionnaire were administered. The variables were subjected to multivariate analysis with each treatment term. Results The IEQ scores were higher in Japan than in Canada. Through multiple regression analysis, IEQ scores were independently correlated with treatment terms. The optimal cutoff point of the IEQ scores for a prolonged treatment term was 21 and 22 points, respectively. Conclusions The IEQ scores were associated with treatment terms in patients with acute WAD in Japan.

ObjectiveTanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up.MethodsThis double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient’s Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study.ResultsFrom March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE –0.62±0.18, p=0.0006), WOMAC Physical Function (–0.71±0.17, pConclusionTanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups.Trial registration numberNCT02709486.

Objectives: In the diagnosis of nonconvulsive status epilepticus (NCSE), the use of ongoing ictal electroencephalographic (EEG) findings is the gold standard. However, this is difficult without the availability of continuous EEG monitoring facilities. Given this, a small telemetry EEG amplifier (Headset-EEG; AE-120A EEG Headset™) was introduced for use in simple EEG monitoring facilities. In this study, we examined the diagnostic performance of the Headset-EEG for NCSE in a neuroemergency setting.Methods: We retrospectively selected five patients who were diagnosed with NCSE using Headset-EEG by attending physicians between October 2017 and July 2018. Reevaluation with Headset-EEG was performed, and the findings were compared with the initial diagnosis. Results: In Case 1, Headset-EEG clearly revealed repeated ictal discharges associated with acute subdural hematoma. However, in Cases 2 and 3, the initial EEG diagnosis was incorrectly made because of an EEG interpretation error. In Cases 4 and 5, various artifacts, caused by unstable electrode placement, resulted in an initial diagnosis of ongoing seizure activity. Nevertheless, the initial diagnoses and subsequent treatment of Cases 2–5 did not directly affect the patients' outcomes.Conclusion: The present study indicates that Headset-EEG is a possible tool for use in NCSE screening. However, considerable knowledge of EEG interpretation is needed to establish a correct NCSE diagnosis. When NCSE is suspected per Headset-EEG, a subsequent routine EEG with a full montage of 10–20 EEG electrodes should be performed in collaboration with an epileptologist or electroencephalographer. Keywords: Triphasic waves, Metabolic encephalopathy, Artifact

Aim To explore the characteristics of psychiatric morbidity in chronic pain patients who present with or without fibromyalgia. Methods Patients are referred to our chronic pain clinic from primary medical institutions, as we are a secondary medical institution. Although some patients have chronic pain, they have no clear organic disorder such as rheumatoid arthritis to account for the pain. Among the 367 new patients seen during the period from March 2009 to August 2012, 347 patients underwent psychiatric evaluation in face‐to‐face interviews with mental health specialists before a physical examination. Results Of the 347 patients examined, at least one psychiatric diagnosis was made for 94.6%. The average number of DSM‐IV‐TR diagnoses was 1.46 in the 330 chronic pain patients who had at least one psychiatric diagnosis. The breakdown of the number of psychodiagnoses was one in 60.8%, two in 27.1%, three in 4.9%, and more than three in 2.3% chronic pain patients with or without fibromyalgia. In fibromyalgia patients, the highest relative frequencies were found for somatoform disorders (76%), followed by dysthymic disorder (17%) and major depressive disorder (15%). In patients without fibromyalgia, the highest relative frequencies were found for somatoform disorders (64%), followed by major depressive disorder (15%) and dysthymic disorder (14%). Psychiatric disorders were found in 96.9% of fibromyalgia patients, and in 93.5% of chronic pain patients without fibromyalgia in Japan (no significant difference using chi‐square test). Conclusion Results show that chronic pain patients with or without fibromyalgia are extremely likely to be diagnosed with a psychiatric disorder., Psychodiagnoses of fibromyalgia patients and chronic pain patients without fibromyalgia.

Background. Spur cell anemia (SCA) is a cause of hemolytic anemia in patients with alcoholic liver cirrhosis. Because dyslipidemia is related to the development of spur cells, SCA was previously treated with plasmapheresis.Case Report. A 52-year-old Japanese man with SCA associated with alcoholic liver cirrhosis (Child–Pugh C) underwent two rounds of plasmapheresis. Clinical features and serum lipid concentrations were compared before and after plasmapheresis. Although indirect hyperbilirubinemia and SCA persisted after plasmapheresis, reticulocyte counts significantly decreased from 22.4% to 4.5%, and Hb levels improved without red cell transfusions. Analysis of lipids showed that total and free cholesterol, HDL cholesterol, phospholipid, and apo-AI concentrations, all of which were reduced before plasmapheresis, had improved after treatment, while LDL cholesterol, lipoprotein (a), and apo-AII concentrations, which were also reduced before plasmapheresis, remained unchanged.Conclusions. Despite plasmapheresis partially ameliorating the degree of hemolysis, the persistence of SCA may have been linked with the lack of improvement in certain types of lipid metabolism.

Background Current worldwide clinical practice guidelines recommend acetaminophen as the first option for the treatment of acute low back pain. However, there is no concrete evidence regarding whether acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) is more effective for treating acute low back pain (LBP) in Japan. The present study aimed to investigate whether acetaminophen treatment for acute musculoskeletal pain was comparable with loxoprofen (a traditional NSAID in Japan) treatment. Methods Of the 140 patients with acute LBP who visited out-patient hospitals, 127 were considered eligible and were randomly allocated to a group taking acetaminophen or one taking loxoprofen. As primary outcome measure, pain intensity was measured using a 0–10-numeric rating scale (NRS). Moreover, pain disability, pain catastrophizing, anxiety, depression, and quality of life, as well as adverse events, were assessed as secondary outcomes. The primary outcome was tested with a noninferiority margin (0.84 on changes in pain-NRS), and the secondary outcomes were compared using conventional statistical methods at week 2 and week 4. Results Seventy patients completed the study (acetaminophen: 35, loxoprofen: 35). The dropout rates showed no significant difference between the two medication-groups. We found that the mean differences of changes in pain-NRS from baseline to week 2 or 4 between the two medication groups were not statistically beyond the noninferiority margin (mean [95% confidence interval]: −0.51 [−1.70, 0.67], at week 2 and −0.80 [−2.08, 0.48] at week 4). There were no consistent differences between the two medication groups in terms of secondary outcomes. Conclusions The results suggest that acetaminophen has comparable analgesic effects on acute LBP, based on at least a noninferiority margin, compared with loxoprofen at 4 weeks. Acetaminophen seems to be a reasonable first-line option for patients with acute LBP in Japan.

Tissue diagnosis of brain tumours in eloquent is often done via needle biopsy but this method yields small samples that may not be representative of the whole tumour. The Neuroport® system enables a larger tumour biopsy to be taken via a burr hole. We report our experience on 5 cases October 2017 and June 2018. Brainlab® navigation was used. The diagnosis in all patients was made without worsening of their modified Rankin scale scores.

Objectives This study aimed to determine the optimal cutoff score of the 9-item short version of the CSI, the CSI-9, by comparing patients with central sensitivity syndrome (CSS) not only to healthy volunteers as with the original version, but also to patients with musculoskeletal (MSK) disorders. Methods All participants filled out the CSI, EuroQol 5-dimension, Brief Pain Inventory, and Pain Catastrophizing Scale questionnaires. To identify a clinically relevant cutoff score, receiver operating characteristic analyses were conducted. The area under the curve was used to examine the ability of the CSI-9 to distinguish patients with fibromyalgia (FM) from patients with MSK disorders and healthy individuals. Results Twenty-six participants with FM, 30 patients with MSK disorders, and 28 healthy individuals were included. We determined 2 cutoff scores: 20 for distinguishing patients with FM from patients with MSK disorders and 17 for distinguishing patients with FM from healthy individuals. These cutoff scores had good sensitivity (patients with MSK disorders, 92.3%; healthy individuals, 96.2%) and specificity (patients with MSK disorders, 93.3%; healthy individuals, 100%). In addition, the patients who scored above the cutoff of 20 points exhibited worse clinical symptoms (higher pain intensity, higher pain interference, higher Pain Catastrophizing Scale scores, and lower EuroQol 5-dimension scores) than those who scored below it. Furthermore, a significantly higher number of subjects who scored more than 20 on the CSI-9 had a history of 2 or more diagnoses of CSS. Conclusion The optimal CSI-9 cutoff score of 20 is beneficial to clinicians in the evaluation of central sensitization-related symptoms. The cutoff score helps to identify patients who need additional treatments, such as pain neuroscience education and cognitive behavioral therapy.

Objectives Existing treatments for fibromyalgia have limited efficacy, and only a minority of individuals clinically respond to any single intervention. This study was a prospective, multicenter, randomized, double-blind, controlled clinical trial to evaluate the feasibility of alternating magnetic field therapy in fibromyalgia patients by comparing the Angel Touch device (AT-02) with a sham control (S-01). Methods Two sites enrolled 44 subjects with diagnosed fibromyalgia. After informed consent, subjects taking prohibited concomitant drugs underwent a washout period of two or more weeks. All subjects then began a one-week run-in period. Numerical rating scale (NRS) pain scores were collected without device intervention for one day, followed by S-01 application to four or more painful sites for 10 minutes at each site, twice daily for six days. Subjects were then randomized to AT-02 or S-01, applied to four or more painful sites for 10 minutes at each site, twice daily for eight weeks. NRS scores were obtained twice daily during the entire treatment period. Results The primary end point (change in NRS ± SD at week 8 vs baseline) was –0.94 ± 1.33 in the AT-02 group and –0.22 ± 1.38 in the S-01 group. A trend toward a between-group difference in eight-week NRS scores favored the AT-02 group (–0.73, 95% confidence interval = –1.56 to 0.11, P = 0.086). An adjusted repeated measure analysis detected a significant difference in NRS scores (P = 0.039). Conclusions The reduction in NRS scores for AT-02 relative to sham was comparable to reductions observed in meta-analyses of fibromyalgia drug therapy. The unadjusted results and the persistence of the pain score reductions remain encouraging.

Background Tanezumab, a monoclonal antibody against nerve growth factor, is in development for treatment of osteoarthritis (OA) pain. Objectives To assess efficacy and safety of tanezumab in patients with moderate to severe OA pain who have not responded to or cannot tolerate standard of care analgesics. Methods A randomized, double-blind, placebo-controlled study (24 week treatment; 24 week follow-up) was conducted in patients in Europe and Japan with moderate to severe OA pain of the knee or hip and history of insufficient pain relief or intolerance to acetaminophen, oral nonsteroidal anti-inflammatory drug, and either tramadol or opioids (or unwilling to take opioids). Patients received subcutaneous tanezumab (2.5 or 5 mg) or placebo at baseline, week 8, and week 16. Co-primary endpoints were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, and Patient Global Assessment of OA (PGA-OA) scores at week 24. Safety, including independent adjudication of joint safety events, was assessed. Results Tanezumab 5 mg met all co-primary endpoints (Fig. 1). Tanezumab 2.5 mg met WOMAC Pain and Physical Function endpoints but not the PGA-OA endpoint; thus, this dose did not meet pre-specified efficacy criteria. The occurrence of adverse events (AEs) and discontinuations due to AEs were similar across groups, though serious AEs occurred more frequently in both tanezumab groups relative to placebo. Two deaths in the 5 mg tanezumab group were deemed unrelated to treatment. The only AE occurring in =3% of patients in any group, and more frequently (>1% difference) in both tanezumab groups relative to placebo, was OA. Total joint replacements (TJR) occurred in 6.7%, 7.8%, and 7.0% of patients in the placebo, tanezumab 2.5 mg, and tanezumab 5 mg groups, respectively. Joint safety events, including TJRs, were mostly adjudicated as normal progression of OA (58/79; 73.4%). Pre-specified joint safety events occurred in 0% and 2.5% (n = 14) of patients in the placebo and tanezumab (2.5 mg = 1.8%; 5 mg = 3.2%) groups, respectively. These 14 events in the tanezumab groups included rapidly progressive OA (2.5 mg n = 4; 5 mg n = 8), subchondral insufficiency fracture (2.5 mg n = 1), and primary osteonecrosis (5 mg n = 1). Conclusion Tanezumab 5 mg significantly improved all co-primary endpoints of pain, physical function, and PGA-OA. Tanezumab 2.5 mg significantly improved pain and physical function, but did not reach significance on PGA-OA. AEs are consistent with previous studies of tanezumab in OA. A similar number of TJRs were reported across groups, though overall joint safety events were more frequent with tanezumab than placebo. Disclosure of Interests Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (throughinstitution), Consultant for: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Francisco J. Blanco Grant/research support from: Galapagos NV, Abbvie, Sanofi, Bristol MS, UCB, Novartis, Genentech Inc., Regeneron, Lilly, Celgene, Amgen, Janssen, kiniksa Pharmaceuticals, Ltd., Tedec Meiji., Consultant for: Pfizer, Gebro, Bioiberica, Sanofi., Ali Guermazi Consultant for: AstraZeneca, Pfizer, TissueGene, Galapagos, Roche and MerckSerono., Eric Vignon Consultant for: Pfizer/Eli Lilly, Kenji Miki Speakers bureau: Pfizer, Janssen, Ayumi, Hisamitsu, Takaharu Yamabe Shareholder of: Pfizer, Employee of: Pfizer, Lars Viktrup Shareholder of: Eli Lilly & Company, Grant/research support from: Astella, Lundbeck, Coloplast, Employee of: Ciba Geigy, Eli Lilly and Company (currently), Rod Junor Shareholder of: Pfizer, Employee of: Pfizer, William Carey Shareholder of: Pfizer, Employee of: J&J, Pfizer (currently), Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ken Verburg Shareholder of: Pfizer, Employee of: Pfizer, Christine West Shareholder of: Pfizer, Employee of: Pfizer

Background: Many known risk factors, including hypertension and hyperlipidemia cause intracerebral hemorrhage (ICH). Recently, microbleeds have been identified as one of the factors leading to ICH. While some patients have been found to have recurrent ICH, risk factors for recurrent ICH are scarcely reported. We conducted an observational study on the risk-factors of recurrent ICH, comparing stroke patients with a single hemorrhagic episode and those with recurrent ICH. Methods: A retrospective analysis of a single-center database was performed to analyze the clinical presentation and characteristics of patients with a single and recurrent ICH. From January 2016 to December 2017, a total of 317 patients were analyzed based on suspected factors including patients’ sex, age, medical history, antiplatelet therapy use, and presence of microbleeds on images. Results: Of the 317 patients, 36 patients (11.4%) developed a second episode of cerebral hemorrhage. Brain magnetic resonance imaging (MRI) of the patients without microbleeds, predicted reduced risk of recurrence. This is the first report strongly associating the presence of microbleeds with the possibility of a recurrent ICH. Other factors under study did not show an apparent association with recurrent ICH probably because of the high statistical significance obtained with the presence of microbleeds. Conclusion: Our findings revealed that the absence of microbleeds on images is a factor that strongly predicts a reduced risk for recurrent ICH and that the detection of microbleeds on MRI performed in patients with a single hemorrhagic episode, is useful in defining further therapeutic management. These findings may benefit physicians treating stroke patients.

BACKGROUND Acquired factor V deficiency (AFVD) caused by Factor V (FV) inhibition is a rare event, characterized by prolonged prothrombin time and activated partial thromboplastin time. To date, various factors were reported as triggers for developing FV inhibitor. Clinical symptoms range from asymptomatic to life-threatening bleeding. Case Report and Conclusions: Here, we report an 84-year-old Japanese male on hemodialysis due to renal failure who developed subcutaneous hemorrhage after administration of cefepime (CFPM) to treat bacteremia. Deficient FV activity (< 1.0%) was identified and AFVD with FV inhibitor titer of 9 BU/mL was diagnosed. Although the patient had multiple risks for developing FV inhibitor, CFPM was thought to be the major culprit in this case. After the diagnosis, oral prednisolone (30 mg/day) was initiated, but the patient died of respiratory/cardiac failure, unrelated to AFVD.

Disseminated intravascular coagulation (DIC) is a systemic life-threatening process that can cause thrombosis and hemorrhage. Chronic DIC has been associated with aortic aneurysm/dissection. Aortic aneurysm/dissection should be included in the differential diagnosis of elderly patients with hemorrhagic diathesis due to DIC of uncertain etiology. Treatment depends on various factors, including the severity of underlying disease, extent of DIC, and patient comorbidities, as well as the ability of the patient to maintain activities of daily living once discharged from the hospital. This report describes the clinical characteristics of four elderly patients with chronic DIC associated with aortic aneurysm/dissection who were treated in our institution. We also offer the recommendations around most appropriate nonsurgical treatment of these patients.

Aim Intracranial metastases from uterine leiomyosarcoma, particularly solitary skull metastases, are very rare, with only five cases reported to date. In this study, we present our experience with the treatment of these lesions, along with a review of the previously reported cases. To the best of our knowledge, this represents the first review of cases of skull metastasis from uterine leiomyosarcoma. Material and Methods We examined three patients with skull metastases from uterine leiomyosarcomas. Planning their treatment was challenging because of the lack of literature on such cases. Results Gross tumor resection with a 1-cm surgical margin was performed in all three cases. One of the patients also received postoperative radiation therapy. In two cases, there was no recurrence until the 15-month follow-up. The third patient developed two recurrences within a short period, and after two operations, she was treated with nivolumab. Genomic analysis was also performed in one case. Conclusions Due to the lack of effective chemotherapy, skull metastasis from uterine leiomyosarcoma has a poor prognosis. However, in cases where genomic analysis does not indicate a poor prognosis, surgical treatment may be effective and is recommended.

Background The financial burden of medical insurance on the government of Japan has recently become severe, which has led to the control of outpatient orthopedic reimbursements for common procedures. On the other hand, the overall disease burden for total hip or knee arthroplasty, decompression for cervical myelopathy or lumbar spinal canal stenosis, and new surgical technologies to treat other painful conditions and the post-surgical care related to these procedures has been reduced. Methods Medical insurance systems in Japan are generally influenced by budget-balancing action. Consequently, the further development of interventional evaluation methods should be promoted. From the viewpoint of health economics, the value (meaning) of medical intervention can partly be explained by its cost-effectiveness. In order for appropriate medical reimbursement levels to be set for orthopedic surgery, the financial status of medical institutions needs to be concurrently reviewed. In particular, the relationship between the expense structure and medical reimbursement must be discussed to evaluate its role in community medicine system. Results Over the past 10 years, medical expenditures have increased by 9.6% in all fields, whereas the monthly medical reimbursements per patient have dropped by an average of 17.5%. Remarkably, surgery-related costs have increased by 36.5%, while other medical costs have decreased by 19.8%. There are a few reports of cost-utility analyses which investigate interventions such as total hip arthroplasty for hip osteoarthritis patients (US$ 4,600–70,500/QALY) and laminectomy for patients with spinal canal stenosis. Interventions may be an inevitable part of relative expense control under the current trend; however, there has been a slight increase in other parameters in response to changes in medical reimbursement evaluations - specifically, in the total income of medical institutions. Conclusions If medical professionals such as orthopedic surgeons contribute to the economic value of orthopedic surgery, it is crucial to clearly establish interventions among the different performances of medical reimbursement to motivate the increased allocation of management resources. To further develop this concept, discussions between stakeholders should involve the value of medicine based on cost and benefit.

We thank Riddle and Perera1 for their interest in our publication.2 In our article, we adhered to recognised statistical methods and appropriate association with meaningfulness. We agree with the American Statistical Association guidance that a statistically significant effect does not inform its size or importance,3 and therefore, a change needs to be associated with clinical impact. In this study (ClinicalTrials.gov: NCT02709486), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale and Physical Function subscale were measured using an 11-point numeric rating scale (specifically, the WOMAC NRS3.1 V5 US). As specified in the WOMAC User Guide, each WOMAC subscale is to be summed and can be normalised on a 0–10 scale for the numeric rating scale. Therefore, in this study, the five questions for the Pain subscale and the 17 questions for the Physical Function subscale were summed and averaged, respectively, to determine each mean subscale score. This differs from subscale scores that are not normalised …

We report here two cases of Waldenstrom’s macroglobulinemia (WM), one with central nervous system (CNS) symptoms and severe retinopathy and one with renal failure. In both cases, the serum IgM levels exceeded 3,000 mg/dL and monoclonal IgM-kappa was observed in the blood. At onset, Case 1, a 63-year-old female, developed CNS symptoms—namely, drowsiness and syncope. Case 2, a 58-year-old male, had nausea and dysgeusia on admission associated with renal failure, which is quite rare in patients with WM. Both patients exhibited hyperviscosity-related retinopathy, but it was particularly severe in Case 1: she suddenly lost her vision after admission. However, her vision recovered completely during treatment. Case 2 required hemodialysis immediately after admission. Needle biopsy of his kidney revealed tubulointerstitial nephritis with marked infiltration with CD20-positive lymphoplasmacytic lymphoma cells. After treatment, Case 1 has been in a remission longer than 8 years, but Case 2 died of pneumonia in 6 months. Since the initial symptoms of WM are ambiguous and vary significantly and hyperviscosity-related ophthalmological problems or severe renal dysfunction can arise, it is essential to promptly measure serum IgM levels and to institute appropriate care immediately when WM is confirmed in a patient.

Background Although extracranial-intracranial (EC-IC) bypass is an effective treatment strategy for symptomatic moyamoya disease, surgeons need to be cautious regarding the possibility of postoperative hemorrhagic complications in patients with a concurrent coagulation disorder. Here, we describe a case of EC-IC bypass for moyamoya disease concurrent with von Willebrand disease type 1. Case Description Following perioperative replacement of the von Willebrand factor, the patient showed an uneventful and uncomplicated clinical course. Conclusion This is the first reported case of EC-IC bypass being performed for moyamoya disease in a patient with concurrent von Willebrand disease. We emphasize the importance of appropriate management with replacement of the von Willebrand factor during the perioperative period to avoid hemorrhagic complications.

Background Ecchordosis physaliphora (EP) is a benign notochordal remnant that is usually asymptomatic. We report a case of a symptomatic large EP mimicking an epidermoid cyst. Case Description A 44-year-old woman presented with right facial dysesthesia. Brain magnetic resonance imaging showed a mass with a diameter of 3.2 cm that was hypointense on T1-weighted imaging, hyperintense on T2-weighted imaging, isointense to hyperintense on diffusion-weighted imaging, and hyperintense on apparent diffusion coefficient map (1.2–1.6 × 10 −3 mm 2 /second). There was no apparent contrast enhancement. Differential diagnoses included epidermoid cyst, dermoid cyst, EP, chordoma, chondrosarcoma, neurenteric cyst, and arachnoid cyst. Clinicopathologic examination revealed that the mass was an EP. Conclusions EP in the prepontine cistern should be considered in the differential diagnosis of epidermoid cyst.

Transplant of human induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) cell-sheet is a promising approach for treating ischemic cardiomyopathy (ICM). However, poor blood supply to the transplanted cell-sheet is a concern related to the effectiveness and durability of the treatment. Herein, we hypothesized that the combined the omentum flap might enhance survival and the therapeutic effects of hiPS-CM cell-sheet transplant for ICM treatment. Treatment by Wnt signaling molecules in hiPS cells produced hiPS-CMs, which were magnetically labeled by superparamagnetic iron oxide (SPIO), followed by culture in the thermoresponsive dishes to generate hiPS-CMs cell-sheets. A porcine ICM model included 4 groups; sham operation, omentum flap only, cell-sheet only, or combination therapy. Ejection fraction (EF) was significantly greater in the cell-sheet only and combination group compared to the other groups during the follow-up period. At 3 months, the EF of the combination group was significantly greater than that of the cell-sheet only group. Consistently, the survival rate of the SPIO-labeled hiPS-CMs, as assessed by MRI, was significantly greater in the combination group than in the cell-sheet only group. This cell delivery system would be useful in optimizing the hiPS-CM cell-sheet transplant for treating severe heart failure.

Background: Pain is regarded as one of the most common nonmotor symptoms in Parkinson's disease (PD). In particular, musculoskeletal pain has been reported as the most common type of PD-associated pain. Crowned dens syndrome (CDS), related to microcrystalline deposition in the periodontoid process, is the main cause of acute or chronic cervical pain. Case Presentation: This report describes the case of an 87-year-old woman who had severe bradykinesia, muscle rigidity, gait disturbance and neck pain. Laboratory examination revealed marked elevations of white blood cells (10,100/µl) and C-reactive protein (CRP; 8.63 mg/dl). She was primarily diagnosed with severe and untreated PD, corresponding to Hoehn and Yahr scale score IV, with musculoskeletal pain and urinary tract infection. The patient was treated with antiparkinsonism drugs, antibiotic agents and nonsteroidal anti-inflammatory drugs, but they had only limited effects. Cervical plain computed tomography (CT) scanning detected remarkable crown-like calcification surrounding the odontoid process. Based on CT findings, the patient was diagnosed as having CDS with PD, and was immediately treated with corticosteroid. The severe neck rigidity with pain and the serum CRP level (0.83 mg/dl) of the patient were drastically improved within a week by the additional corticosteroid therapy. Conclusion: Severe neck rigidity and bradykinesia in this patient might have strengthened the chondrocalcinosis around the odontoid process. Cervical plain CT scan is necessary and useful for the definitive diagnosis of CDS. CDS should be considered as a differential diagnosis of a possible etiology for musculoskeletal pain related to rigidity and bradykinesia in PD.

Background: Brain metastasis from undifferentiated pleomorphic sarcoma (UPS) is a rare occurrence, and its clinical course is little known. In this report, we investigate a case of a rapidly growing brain metastasis from gastric UPS. Case Description: An 82-year-old man with a known gastric tumor, pathologically compatible with UPS, underwent partial gastrectomy at an outside facility. 3 months later, a 4-cm brain tumor was detected, which was completely resected. The patient was diagnosed with metastatic tumor from previously treated gastric UPS. Within 2 months of the initial resection, a large recurrent mass was detected in the same location, which was again removed. Although the patient underwent radiotherapy and chemotherapy for other metastatic tumors, he died 5 months after the second craniotomy. Conclusions: Brain metastasis from gastric UPS is rare and difficult to treat. Although aggressive treatment, such as surgical intervention, may improve patient survival in some cases, the timing of treatment is challenging because cerebral metastasis rapidly grows and and patients frequently suffer from synchronous systematic metastasis. Therefore, early detection and close follow-up of rapidly progressing brain metastasis are important to improve treatment outcomes.

Background: Myelitis is one of the rarest neurological complications of the varicella zoster virus (VZV) infection. Focal muscle weakness with or without sensory disturbance occurs in approximately 5% of the cases after acute VZV infection, with complete recovery in 50-70%. Case Presentation: This report describes two rare cases of elderly patients with VZV myelitis secondary to dermatomal zoster rash. Patient 1 was a 79-year-old woman who developed paraplegia, numbness and decreased sensation in the left arm and below thoracic (Th)-10 after sacral zoster. Spinal cord MRI showed a high-signal-intensity lesion at the cervical spinal nerve 2 on a T2-weighted image. Patient 2 was a 73-year-old man who developed right flaccid leg weakness and urinary retention after right dorsal Th 5-8 zoster. Spinal cord MRI showed a high-signal-intensity lesion at Th 3-4 on a T2-weighted image. In both cases, although the conventional single polymerase chain reaction (PCR) assays all showed negative results, the original nested PCR assay detected VZV DNA in the cerebrospinal fluid (CSF) specimen collected on admission. In addition, the anti-VZV IgG antibody by enzyme immunoassay and antibody index were elevated in the CSF specimens during the clinical courses of both patients. On the basis of these findings, both patients were diagnosed with VZV myelitis and were treated with high-dose acyclovir and corticosteroid. This combined treatment was appropriate and effective for the improvement of their functional outcomes. Conclusion: The detection of VZV DNA in CSF by nested PCR assay and the evaluation of the antibody index to VZV had significant diagnostic value.

Pancreaticoduodenectomy (PD) is the only potential treatment for pancreatic head adenocarcinomas, which are sometimes located close to or invade the portal-superior mesenteric vein (PSMV). Surgeons often attempt to obtain a negative resectional margin after resection of the PSMV. This attempt requires PSMV reconstruction through graft replacements or end-to-end anastomosis; however, possible complications should be concerned including anastomosis stenosis, damage to some of the PSMV branches, prosthetic graft infection, and that associated with autologous graft harvesting. The first jejunal artery and vein are often resected in PD with the intent of lymphadenectomy. In this study, jejunal vein flap was used for PSMV reconstruction without causing damage to any of the PSMV branches in two patients. Here, we describe the new methods of PSMV reconstruction using first jejunal vein flap in PD.

Background: Few studies have investigated whether the Glasgow Prognostic Score (GPS), an inflammation-based prognostic score measured before resection of colorectal liver metastasis (CRLM), can predict postoperative survival. Patients and Methods: Sixty-three consecutive patients who underwent curative resection for CRLM were investigated. GPS was calculated on the basis of admission data as follows: patients with both an elevated C-reactive protein (>10 mg/l) and hypoalbuminemia (Results: Significant factors concerning survival were the number of liver metastases (p = 0.0044), carcinoembryonic antigen level (p = 0.0191), GPS (p = 0.0029), grade of liver metastasis (p = 0.0033), and the number of lymph node metastases around the primary cancer (p = 0.0087). Multivariate analysis showed the two independent prognostic variables: liver metastases ≧3 (relative risk 2.83) and GPS1/2 (relative risk 3.07). Conclusions: GPS measured before operation and the number of liver metastases may be used as novel predictors of postoperative outcomes in patients who underwent curative resection for CRLM.

Background Recent studies have revealed that Glasgow prognostic score (GPS), an inflammation-based prognostic score, is associated with poor outcome in a variety of tumors. However, few studies have investigated whether GPS measured prior to neoadjuvant chemoradiotherapy (nCRT) is useful for postoperative prognosis of patients with advanced esophageal squamous cell carcinoma (ESCC). Methods GPS was calculated on the basis of admission data as follows: patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminaemia (

A 44-year-old woman with mitochondrial encephalomyopathy noticed weakness of the lower extremities at the age of 30 years. She also has type 2 diabetes mellitus, posterior subcapsular cataracts in both eyes, and corpus callosum atrophy. Family history showed that a maternal cousin had a myopathy, 3 maternal aunts had diabetes mellitus, and her mother and 2 maternal aunts had cataracts. External ophthalmoplegia, proximal myopathy, and absent deep tendon reflexes were noted. The mitochondrial DNA 3243 point mutation was negative. Muscle biopsy showed ragged-red fibers, cytochrome c oxidase (COX)-positive fibers, and COX-negative fibers.

We determined the relationship between the serum concentrations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) in 33 patients with subacute sclerosing panencephalitis (SSPE) to investigate the function of the blood-brain-barrier (BBB) in SSPE. Serum MMP-9 and TIMP-1 levels were measured by ELISA. Serum MMP-9 levels and MMP-9/TIMP-1 ratios of SSPE patients in Papua New Guinea (n = 24), and those in Japan (n = 9) were significantly higher than the each control (MMP-9, p = 0.0390, and p = 0.0023, respectively; MMP-9/TIMP-1, p = 0.0319, and p = 0.0009, respectively). Serum MMP-9 levels and MMP-9/TIMP-1 ratios of SSPE patients with Jabbour stage III (n = 13) were significantly higher than those with Jabbour stage II (n = 18) (p = 0.003, and p = 0.0412, respectively). There were no significant differences of serum TIMP-1 levels between the SSPE patients and controls. High serum MMP-9 and MMP-9/TIMP-1 levels will promote brain invasion through the BBB by immunocompetent cells in the blood. Our findings suggest that the balance of serum MMP-9 and TIMP-1 levels modulate the inflammatory cascade of SSPE.

Low-threshold sensory pathways have been suggested to have an important role in the formation and maintenance of sensory abnormalities which are observed after peripheral nerve injury. Fos-like immunoreactive (Fos-LI) neurons are expressed in spinal cord laminae III–IV and the gracile nucleus by electrically stimulating the injured nerves at Aβ strength after sciatic nerve transection in rats. This suggests that the excitability of these neurons is increased by nerve injury. In this study, we investigated which receptors are involved in the regulation of the increased excitability in spinal and gracile nucleus neurons. The sciatic nerve of Sprague–Dawley rats (150 g) was transected 7 days before the experiment day. The rats were administered morphine, muscimol, baclofen, MK-801, CNQX, NG-nitro- l -arginine methyl ester hydrochloride ( l -NAME) or clonidine i.p., and then electrically stimulated at 0.1 mA to the proximal region to the nerve injury site under urethane anesthesia. Two hours after the stimulation, Fos-LI expression was increased in the spinal cord dorsal horn and the gracile nucleus in control rats. Baclofen inhibited the Fos-LI expression both in the spinal cord and the gracile nucleus. Morphine inhibited only the Fos-LI expression in the posterior cutaneous (PC) nerve territory of laminae I–II, but not in the sciatic nerve (SC) territory, laminae III–IV nor the gracile nucleus. MK-801 had an inhibitory but complicated effect in laminae I–II and the gracile nucleus. The other drugs were not effective on Fos-LI expression. It is suggested that the GABAB receptor has a pivotal role in the regulation of Fos-LI expression after electrical stimulation to the injured low-threshold sensory fibers, and other receptors have little effect on the Fos-LI expression.

Spinal and cranial motoneurons express alpha- and beta-calcitonin gene-related peptide (CGRP) mRNAs constitutively at variable ratios, and these two mRNAs are differentially regulated following axotomy in spinal, facial, and hypoglossal motoneurons. The purpose of this study was to investigate the change in CGRP mRNA expression following nerve injury in oculomotor, trochlear, abducens, and trigeminal motor nuclei in which beta-CGRP mRNA is predominantly expressed under normal conditions. Using male Sprague-Dawley rats, either the left eyeball and the orbital contents including the bulbar muscles were removed, or the left masseter nerve was ligated and transected. The rats were allowed to survive for 1, 3, 7, 14, 28, 56 days following these procedures. The levels of mRNAs for alpha- and beta-CGRP and growth-associated protein (GAP)-43 were analyzed by in situ hybridization histochemistry using 35S-labeled oligonucleotide probes. Following nerve injury, the expression of alpha-CGRP mRNA rapidly increased on the directly-injured side in all of these nuclei. Thereafter, it gradually decreased and returned to about the control level at postoperative day 56 within oculomotor, trochlear, and abducens motoneurons, but it sustained at a high level within trigeminal motoneurons. The expression of beta-CGRP was quite variable among these nuclei, and significant changes were also seen on the side contralateral to the directly-injured side. These data indicate that the up-regulation of alpha-CGRP mRNA may be a common response of cranial motor neurons following axotomy even if the constitutive expression of beta-CGRP mRNA exceeds that of alpha-CGRP mRNA in these neurons.

Peripheral tissue injury is known to induce changes in gene expression in spinal neurons and result in a prolonged alteration of neuronal excitability. The purpose of this study was to examine the effect of halothane on the dynorphin mRNA expression in spinal dorsal horn neurons after peripheral tissue injury by formalin injection and compare the effect to that of ketamine and nitrous oxide. Male Sprague–Dawley rats were anesthetized with 1.3% halothane, ketamine, or 67% nitrous oxide. Fifteen minutes after induction of anesthesia, rats received an intraplantar injection of 150 μl 5% formalin into the unilateral hindpaw. General anesthesia was maintained for 8 h, and the expression of preprodynorphin (PPD) and preproenkephalin (PPE) mRNAs in the spinal cord (L4-5) was examined by in situ hybridization. The degree of edema of the inflamed foot was not different among the three anesthesia groups and the control (no anesthesia) group. The number of neurons expressing PPD mRNA dramatically increased in the superficial dorsal horn ipsilateral to the formalin injection in the control group compared to the contralateral side. The number of neurons labeled for PPD mRNA in the halothane group was significantly less than the control group. However, the number of PPD mRNA-expressing neurons in both the ketamine and nitrous oxide groups was significantly less than the halothane group. The expression of PPE mRNA was not influenced by these anesthetics. These data indicate that the suppressive effect of halothane anesthesia on the induction of PPD mRNA in dorsal horn neurons was smaller than those of ketamine and nitrous oxide, suggesting an important supplemental way to control the alteration of gene expression in spinal neurons for clinical settings.

We examined two possible mechanisms of neuropathic pain: contribution of adjacent intact nerves and decrease in presynaptic inhibition at the central terminal of the injured primary afferent. To this end, we examined the effects of unilateral L5 spinal nerve ligation, which causes mechanical allodynia and heat hyperalgesia in the ipsilateral hind paw, on gene expression in L4 and L5 dorsal root ganglion (DRG) neurons using in situ hybridization (ISH). Specifically, we examined changes in the expression of messenger RNAs (mRNAs) for neuropeptides which have been reported to be up- or down-regulated in the axotomized DRG neurons and for gamma-aminobutyric acid (GABA)A receptor (GABA(A)-R) subunits which contribute to presynaptic inhibition at the primary afferent terminals. Seven days following ligation, ISH demonstrated an increase in signal intensity for calcitonin gene-related peptide (CGRP) mRNA in the subpopulation of small-to medium-sized L4 DRG neurons ipsilateral to the ligation which were not directly injured as compared to the contralateral side, although the overall percentages and the size distribution of positively labelled neurons for CGRP mRNA were not different between the bilateral L4 DRGs. This suggests that the L4 DRG neurons which express CGRP mRNA constitutively up-regulated the gene expression and the functional importance of these neurons has increased following L5 spinal nerve ligation. However, the mRNAs for other neuropeptides such as preprotachykinin (PPT), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), and galanin (GAL), were not different between the bilateral L4 DRGs. The mRNA for the GABA(A)-Rgamma2 subunit was significantly down-regulated in the medium- to large-sized L5 DRG neurons ipsilateral to the ligation as compared to the contralateral side. GABA(A)-Ralpha2 subunit mRNA also decreased in the ipsilateral L5 DRG neurons but did not reach statistical significance. There was no difference in mRNAs between the bilateral L4 DRGs. These data suggest that the presynaptic disinhibition of the ipsilateral L5 primary afferent terminals may be explained at least partly by the down-regulation of GABA(A)-R following L5 spinal nerve ligation. Thus, both the up-regulation of CGRP in adjacent intact nerves and the decrease in presynaptic inhibition at the central terminal of the injured primary afferent could cause the hyper-excitability of dorsal horn neurons and contribute to the molecular mechanisms of this neuropathic pain model.

Dynorphin, an endogenous opioid, may contribute to secondary nervous tissue damage following spinal cord injury. The temporal and spatial distribution of preprodynorphin (PPD) mRNA expression in the injured rat spinal cord was examined by in situ hybridization. Rats were subjected to traumatic spinal cord injury at the T13 spinal segment using the weight-drop method. Motor function of these rats was evaluated by their ability to maintain their position on an inclined plane. Two double-labeling experiments revealed that increased PPD mRNA and dynorphin peptide expression were found exclusively in dorsal horn neurons. Neurons exhibiting an increase in the level of PPD mRNA were concentrated in the superficial laminae and the neck of dorsal horn within several spinal segments from the epicenter of the injury at 24 and 48 h after injury. A number of neurons showing increased PPD mRNA were found in gray matter adjacent to the injury areas. Segments caudal to the injury site exhibited a long-lasting elevation of PPD mRNA in neurons, compared to the rostral segments. The number of neurons expressing PPD mRNA in each rat was significantly positively correlated with its motor dysfunction. These findings suggest that increased expression of dynorphin mRNA and peptide in dorsal horn neurons occurs after traumatic spinal cord injury. This also supports the hypothesis that the dynorphin has a pathological role in secondary tissue damage and neurological dysfunction after spinal cord injury.