The primary purpose of the Japanese myasthenia gravis registry (JAMG-R) has been to research and promote high-quality medical care for MG patients in Japan. We reviewed the findings of surveys performed by JAMG-R over an ~10-y period. The first goal for favorable quality of life (QOL) is a status of minimal manifestations (MM) or better with an oral prednisolone (PSL) dose of 5 mg/d or less (MM-5 mg). Early and aggressive use of nonoral fast-acting treatment together with low-dose oral PSL (the “EFT strategy”) is recommended to reduce disease severity with minimal oral steroid use so that the MM-5 mg target can be met as soon as possible. We conducted the fourth largest multicenter survey ever in 2021, obtaining detailed clinical information from 1710 consecutive MG patients all over Japan, and compared the 2021 surveys with those from 2012 and 2015. The frequency of patients treated with EFT strategies showed a gradual increase, reaching 39% of the total MG patients in the 2021 survey. The current and maximum dose of PSL and the number of days at high-dose (>20 mg/d) PSL showed decreases. Survey results indicate that as EFT strategies have spread, the percentage of patients on MM-5 mg has increased. We again confirmed that MM-5 mg was associated with favorable QOL in the 2021 survey. Recent data regarding COVID-19 suggests that it did not seriously impact the MG population in Japan; unfortunately, refractory MG, observed in 21% of patients, is still an unresolved problem.
{"title":"Japan MG registry: Chronological surveys over 10 years","authors":"Shigeaki Suzuki, Masayuki Masuda, Akiyuki Uzawa, Yuriko Nagane, Shingo Konno, Yasushi Suzuki, Tomoya Kubota, Takamichi Sugimoto, Makoto Samukawa, Genya Watanabe, Kei Ishizuchi, Hiroyuki Akamine, Yosuke Onishi, Kazuki Yoshizumi, Takafumi Uchi, Itaru Amino, Yuki Ueta, Naoya Minami, Naoki Kawaguchi, Takashi Kimura, Masanori P. Takahashi, Hiroyuki Murai, Kimiaki Utsugisawa","doi":"10.1111/cen3.12731","DOIUrl":"10.1111/cen3.12731","url":null,"abstract":"<p>The primary purpose of the Japanese myasthenia gravis registry (JAMG-R) has been to research and promote high-quality medical care for MG patients in Japan. We reviewed the findings of surveys performed by JAMG-R over an ~10-y period. The first goal for favorable quality of life (QOL) is a status of minimal manifestations (MM) or better with an oral prednisolone (PSL) dose of 5 mg/d or less (MM-5 mg). <span>E</span>arly and aggressive use of nonoral <span>f</span>ast-acting <span>t</span>reatment together with low-dose oral PSL (the “EFT strategy”) is recommended to reduce disease severity with minimal oral steroid use so that the MM-5 mg target can be met as soon as possible. We conducted the fourth largest multicenter survey ever in 2021, obtaining detailed clinical information from 1710 consecutive MG patients all over Japan, and compared the 2021 surveys with those from 2012 and 2015. The frequency of patients treated with EFT strategies showed a gradual increase, reaching 39% of the total MG patients in the 2021 survey. The current and maximum dose of PSL and the number of days at high-dose (>20 mg/d) PSL showed decreases. Survey results indicate that as EFT strategies have spread, the percentage of patients on MM-5 mg has increased. We again confirmed that MM-5 mg was associated with favorable QOL in the 2021 survey. Recent data regarding COVID-19 suggests that it did not seriously impact the MG population in Japan; unfortunately, refractory MG, observed in 21% of patients, is still an unresolved problem.</p>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"14 1","pages":"5-12"},"PeriodicalIF":0.0,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cen3.12731","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43187886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The mechanisms underlying therapeutic hypothermia, which protects neurons following severe brain damage, are only partially understood. We previously demonstrated that hypothermia reduced, whereas hyperthermia augmented, the release of tumor necrosis factor (TNF)-α and interleukin (IL)-17. Cerebral ischemia causes the loss of the blood–brain barrier (BBB) integrity, thereby increasing cerebral vascular permeability, which directly contributes to vasogenic edema, hemorrhagic transformation, and increased mortality. Brain microvascular endothelial cells (BMVECs) are a major component of BBB and tight junction proteins (TJPs) in these cells maintain the BBB integrity. In this study we determined the mechanisms underlying this treatment by measuring the effects of TNF-α and IL-17 on BMVEC barrier function and TJP expression in BMVECs, and by evaluating the effects of hypothermia and hyperthermia on TJP expression.
Methods
The barrier function of BMVECs was evaluated by measuring transepithelial electrical resistance (TEER). The expression of several TJPs, such as claudin-5 and junctional adhesion molecule (JAM)-B, was measured at the mRNA and protein levels using real-time polymerase chain reaction and immunocytochemistry, respectively.
Results
TNF-α and IL-17 decreased TEER values, and TNF-α decreased claudin-5 and JAM-B mRNA and protein levels, whereas IL-17 decreased JAM-B mRNA and protein levels, and all of these effects were concentration-dependent. Compared with normothermia, claudin-5 and JAM-B proteins were not affected by hypothermia, whereas JAM-B protein was reduced by hyperthermia.
Conclusion
The hypothermic suppression of TNF-α and IL-17 release may contribute to the maintenance of BBB function by ameliorating the decrease of TJP(s). In contrast, hyperthermia may decrease barrier function through a decrease in JAM-B expression. However, the contribution of changes in the JAM-B expression to the barrier function of BMVECs remains to be clarified.
{"title":"Concentration-dependent effects of proinflammatory cytokines on barrier function and tight junction protein expression in brain microvascular endothelial cells and the hypothermic and hyperthermic effects on tight junction protein expression","authors":"Tomohiro Matsui, Yuji Mochiduki, Yusuke Yoshida, Takenori Nitta","doi":"10.1111/cen3.12730","DOIUrl":"10.1111/cen3.12730","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The mechanisms underlying therapeutic hypothermia, which protects neurons following severe brain damage, are only partially understood. We previously demonstrated that hypothermia reduced, whereas hyperthermia augmented, the release of tumor necrosis factor (TNF)-α and interleukin (IL)-17. Cerebral ischemia causes the loss of the blood–brain barrier (BBB) integrity, thereby increasing cerebral vascular permeability, which directly contributes to vasogenic edema, hemorrhagic transformation, and increased mortality. Brain microvascular endothelial cells (BMVECs) are a major component of BBB and tight junction proteins (TJPs) in these cells maintain the BBB integrity. In this study we determined the mechanisms underlying this treatment by measuring the effects of TNF-α and IL-17 on BMVEC barrier function and TJP expression in BMVECs, and by evaluating the effects of hypothermia and hyperthermia on TJP expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The barrier function of BMVECs was evaluated by measuring transepithelial electrical resistance (TEER). The expression of several TJPs, such as claudin-5 and junctional adhesion molecule (JAM)-B, was measured at the mRNA and protein levels using real-time polymerase chain reaction and immunocytochemistry, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TNF-α and IL-17 decreased TEER values, and TNF-α decreased claudin-5 and JAM-B mRNA and protein levels, whereas IL-17 decreased JAM-B mRNA and protein levels, and all of these effects were concentration-dependent. Compared with normothermia, claudin-5 and JAM-B proteins were not affected by hypothermia, whereas JAM-B protein was reduced by hyperthermia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The hypothermic suppression of TNF-α and IL-17 release may contribute to the maintenance of BBB function by ameliorating the decrease of TJP(s). In contrast, hyperthermia may decrease barrier function through a decrease in JAM-B expression. However, the contribution of changes in the JAM-B expression to the barrier function of BMVECs remains to be clarified.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"14 1","pages":"52-60"},"PeriodicalIF":0.0,"publicationDate":"2022-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46200519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shingo Konno, Takafumi Uchi, Jun Isonishi, Mari Matsushima, Hideo Kihara, Hideki Sugimoto, Toshiki Fujioka
Objectives
Evidence on factors contributing to the development of infections in myasthenia gravis (MG) patients on immunotherapy is scarce.
Methods
We studied 192 MG patients attending our hospital between April 2000 and May 2021. We examined the data of patients who had undergone immunotherapy and developed an infection and analyzed factors influencing infectious events including MG severity, antibody type, thymoma, thymectomy, treatment regimens and duration, and status of MG.
Results
A total of 148/192 (77%) patients (52 men, mean onset 43 y) underwent immunotherapy. Of these, 22/148 (14.8%) patients developed an infection-related hospitalization within 10 y of starting immunotherapy. Respiratory infections occurred in 14/22 (63.6%) of patients. The infections were fatal in 6/22 (27.2%) of patients. Infection-associated myasthenic crisis developed in 4/22 (18.1%) patients. Age at MG onset was the only variable associated with the development of infection (hazard ratio [HR]; 1.056, 95% confidence interval (95% CI): 1.0291.085, P < .001). The infection-free rate within 10 y of starting immunotherapy by MG subtype was 83.5% (95% CI: 61.4–93.5%) in ocular-MG (n = 29), and 87.5% (95% CI: 72.3–94.7%) in generalized early-onset MG (n = 55), 46.1% (95% CI: 21.7–67.6%) in generalized late-onset MG (n = 22), 87.7% (95% CI; 66.3–95.9%) in thymoma-associated MG (n = 29). Patients with muscle-specific tyrosine kinase antibody-positive MG (n = 2) and antibodies-negative MG (n = 11) did not experience infections.
Conclusion
Age at onset of MG was a significant contributor to the development of infection. Generalized late-onset MG is the most susceptible to infection and should be carefully monitored during immunotherapy.
关于重症肌无力（MG）患者在免疫治疗中导致感染发展的因素的证据很少。
{"title":"Development of infections among patients with myasthenia gravis undergoing immunotherapy","authors":"Shingo Konno, Takafumi Uchi, Jun Isonishi, Mari Matsushima, Hideo Kihara, Hideki Sugimoto, Toshiki Fujioka","doi":"10.1111/cen3.12723","DOIUrl":"10.1111/cen3.12723","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Evidence on factors contributing to the development of infections in myasthenia gravis (MG) patients on immunotherapy is scarce.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We studied 192 MG patients attending our hospital between April 2000 and May 2021. We examined the data of patients who had undergone immunotherapy and developed an infection and analyzed factors influencing infectious events including MG severity, antibody type, thymoma, thymectomy, treatment regimens and duration, and status of MG.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 148/192 (77%) patients (52 men, mean onset 43 y) underwent immunotherapy. Of these, 22/148 (14.8%) patients developed an infection-related hospitalization within 10 y of starting immunotherapy. Respiratory infections occurred in 14/22 (63.6%) of patients. The infections were fatal in 6/22 (27.2%) of patients. Infection-associated myasthenic crisis developed in 4/22 (18.1%) patients. Age at MG onset was the only variable associated with the development of infection (hazard ratio [HR]; 1.056, 95% confidence interval (95% CI): 1.0291.085, <i>P <</i> .001). The infection-free rate within 10 y of starting immunotherapy by MG subtype was 83.5% (95% CI: 61.4–93.5%) in ocular-MG (<i>n</i> = 29), and 87.5% (95% CI: 72.3–94.7%) in generalized early-onset MG (<i>n</i> = 55), 46.1% (95% CI: 21.7–67.6%) in generalized late-onset MG (<i>n</i> = 22), 87.7% (95% CI; 66.3–95.9%) in thymoma-associated MG (<i>n</i> = 29). Patients with muscle-specific tyrosine kinase antibody-positive MG (<i>n</i> = 2) and antibodies-negative MG (<i>n</i> = 11) did not experience infections.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Age at onset of MG was a significant contributor to the development of infection. Generalized late-onset MG is the most susceptible to infection and should be carefully monitored during immunotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"14 1","pages":"34-43"},"PeriodicalIF":0.0,"publicationDate":"2022-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49276937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ana Rita Silva, Helena Felgueiras, Ana Isabel Gonçalves, Andreia Fernandes, Bruna Meira, Diana Melância, José Rosa, Maria Teresa Silvério, Ana Macedo
Objective
There is little research on the relationship between self-concept, psychiatric symptoms and quality of life among multiple sclerosis (MS) patients. We assessed the impact of disease perception (expectation and knowledge) on these metrics according to time from diagnosis.
Methods
This was an observational, cross-sectional, multicenter study. Group 1 included patients up to 3 months from MS diagnosis, whereas group 2 included patients with MS diagnosis established for >12 months and <36 months. A 19-item true/false questionnaire developed by the investigators to assess disease perception, Hospital Anxiety and Depression Scale (HADS), Fatigue Severity Scale and three-level level version of EQ-5D questionnaires were used.
Results
A total of 90 patients from six centers were included (38 in group 1). A total of 80% had a good disease knowledge, whereas just 48% reported positive expectations. There were no differences in disease knowledge, disease expectations, HADS, Fatigue Severity Scale and EQ-5D. We found an inverse correlation between disease knowledge and problems in self-care (P = 0.018) and fatigue (P = 0.032). Patients with the worst expectations about the disease were more anxious (P = 0.012 on HADS and P < 0.001 on EQ-5D). They also reported more problems in mobility (P = 0.002), self-care (P = 0.005), usual activities (p = 0.009) and pain (P = 0.001), and a worst health status compared with the past 12 months (P < 0.001) and with the best imaginable status (P < 0.001).
Conclusions
Our study showed no association between disease duration and disease perception. Patients with less disease knowledge reported more problems in self-care and higher fatigue scores. Patients with the worst disease expectations were more anxious and reported a worse health status. More attention should be paid to perceived health status in MS patients.
{"title":"Disease perception impacts quality of life and fatigue in relapsing–remitting multiple sclerosis patients","authors":"Ana Rita Silva, Helena Felgueiras, Ana Isabel Gonçalves, Andreia Fernandes, Bruna Meira, Diana Melância, José Rosa, Maria Teresa Silvério, Ana Macedo","doi":"10.1111/cen3.12720","DOIUrl":"10.1111/cen3.12720","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>There is little research on the relationship between self-concept, psychiatric symptoms and quality of life among multiple sclerosis (MS) patients. We assessed the impact of disease perception (expectation and knowledge) on these metrics according to time from diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This was an observational, cross-sectional, multicenter study. Group 1 included patients up to 3 months from MS diagnosis, whereas group 2 included patients with MS diagnosis established for >12 months and <36 months. A 19-item true/false questionnaire developed by the investigators to assess disease perception, Hospital Anxiety and Depression Scale (HADS), Fatigue Severity Scale and three-level level version of EQ-5D questionnaires were used.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 90 patients from six centers were included (38 in group 1). A total of 80% had a good disease knowledge, whereas just 48% reported positive expectations. There were no differences in disease knowledge, disease expectations, HADS, Fatigue Severity Scale and EQ-5D. We found an inverse correlation between disease knowledge and problems in self-care (<i>P</i> = 0.018) and fatigue (<i>P</i> = 0.032). Patients with the worst expectations about the disease were more anxious (<i>P</i> = 0.012 on HADS and <i>P</i> < 0.001 on EQ-5D). They also reported more problems in mobility (<i>P</i> = 0.002), self-care (<i>P</i> = 0.005), usual activities (<i>p</i> = 0.009) and pain (<i>P</i> = 0.001), and a worst health status compared with the past 12 months (<i>P</i> < 0.001) and with the best imaginable status (<i>P</i> < 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study showed no association between disease duration and disease perception. Patients with less disease knowledge reported more problems in self-care and higher fatigue scores. Patients with the worst disease expectations were more anxious and reported a worse health status. More attention should be paid to perceived health status in MS patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"14 1","pages":"28-33"},"PeriodicalIF":0.0,"publicationDate":"2022-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48953080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
It is well established that adult neurogenesis occurs in the subventricular zone and the subgranular zone, but a controversy remains about adult neurogenesis in other regions. The cerebral cortex is the most controversial site and has long been of interest to not only neuroscientists, but also scientists with broad backgrounds and medical doctors since the late 19th century. However, recent studies have been gradually clarifying that neurogenesis in the adult cerebral cortex occurs, especially under pathological conditions. These studies suggest that endogenous neural stem cells and/or progenitor cells might exist in or around the cerebral cortex, and be useful for regenerative cell therapy in cases of brain insults and diseases. In this review, recent literature regarding neurogenesis in the adult cerebral cortex is summarized, and the possibility of cell therapy for cortex-related disorders is discussed.
{"title":"Cortical adult neurogenesis and its biological implication","authors":"Koji Ohira","doi":"10.1111/cen3.12652","DOIUrl":"10.1111/cen3.12652","url":null,"abstract":"<p>It is well established that adult neurogenesis occurs in the subventricular zone and the subgranular zone, but a controversy remains about adult neurogenesis in other regions. The cerebral cortex is the most controversial site and has long been of interest to not only neuroscientists, but also scientists with broad backgrounds and medical doctors since the late 19th century. However, recent studies have been gradually clarifying that neurogenesis in the adult cerebral cortex occurs, especially under pathological conditions. These studies suggest that endogenous neural stem cells and/or progenitor cells might exist in or around the cerebral cortex, and be useful for regenerative cell therapy in cases of brain insults and diseases. In this review, recent literature regarding neurogenesis in the adult cerebral cortex is summarized, and the possibility of cell therapy for cortex-related disorders is discussed.</p>","PeriodicalId":10193,"journal":{"name":"Clinical and Experimental Neuroimmunology","volume":"14 1","pages":"44-51"},"PeriodicalIF":0.0,"publicationDate":"2021-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/cen3.12652","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46205287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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