Microglia sense astrocyte dysfunction and prevent disease progression in an Alexander disease model.

Alexander disease (AxD) is an intractable neurodegenerative disorder caused by GFAP mutations. It is a primary astrocyte disease with a pathological hallmark of Rosenthal fibres within astrocytes. AxD astrocytes show several abnormal phenotypes. Our previous study showed that AxD astrocytes in model mice exhibit aberrant Ca2+ signals that induce AxD aetiology. Here, we show that microglia have unique phenotypes with morphological and functional alterations, which are related to the pathogenesis of AxD. Immunohistochemical studies of 60TM mice (AxD model) showed that AxD microglia exhibited highly ramified morphology. Functional changes in microglia were assessed by Ca2+ imaging using hippocampal brain slices from Iba1-GCaMP6-60TM mice and two-photon microscopy. We found that AxD microglia showed aberrant Ca2+ signals, with high frequency Ca2+ signals in both the processes and cell bodies. These microglial Ca2+ signals were inhibited by pharmacological blockade or genetic knockdown of P2Y12 receptors but not by tetrodotoxin, indicating that these signals are independent of neuronal activity but dependent on extracellular ATP from non-neuronal cells. Our single-cell RNA sequencing data showed that the expression level of Entpd2, an astrocyte-specific gene encoding the ATP-degrading enzyme NTPDase2, was lower in AxD astrocytes than in wild-type astrocytes. In situ ATP imaging using the adeno-associated virus vector GfaABC1D ATP1.0 showed that exogenously applied ATP was present longer in 60TM mice than in wild-type mice. Thus, the increased ATP level caused by the decrease in its metabolizing enzyme in astrocytes could be responsible for the enhancement of microglial Ca2+ signals. To determine whether these P2Y12 receptor-mediated Ca2+ signals in AxD microglia play a significant role in the pathological mechanism, a P2Y12 receptor antagonist, clopidogrel, was administered. Clopidogrel significantly exacerbated pathological markers in AxD model mice and attenuated the morphological features of microglia, suggesting that microglia play a protective role against AxD pathology via P2Y12 receptors. Taken together, we demonstrated that microglia sense AxD astrocyte dysfunction via P2Y12 receptors as an increase in extracellular ATP and alter their morphology and Ca2+ signalling, thereby protecting against AxD pathology. Although AxD is a primary astrocyte disease, our study may facilitate understanding of the role of microglia as a disease modifier, which may contribute to the clinical diversity of AxD.

Comparison of 2-octyl cyanoacrylate with polyester mesh with standard suture and staples in total knee and hip arthroplasty.

OBJECTIVE: The use of 2-octyl cyanoacrylate with polyester mesh (OCA-M) has become common in total hip and knee arthroplasty (THA, TKA). We aimed to compare the safety and cosmetic outcomes between OCA-M and standard suture techniques and staples, and determine whether OCA-M can safely be used for TKA. METHOD: Inclusion criteria were patients who underwent THA or TKA from January 2010 to October 2011 (Suture group), November 2011 to August 2013 (Staple group), March 2017 to September 2018 (OCA-M group). Exclusion criteria was loss of imaging data. Complications during hospitalisation (early complication) and after discharge (late complication) were compared in groups. Plastic and orthopaedic surgeons performed cosmetic evaluations with the modified Vancouver Scar Scale (VSS) and Likert scale at three and six months postoperatively and compared in groups. RESULTS: A total of 249 arthroplasties (suture group=88 patients; staple group=94 patients; OCA-M group=67 patients) were included in the study. The OCA-M group had a significantly lower early complication rate than the suture group (p=0.015). For THA, the OCA-M group had a significantly lower total complication rate than the suture group (p=0.048). For TKA, there was no significant difference among the three groups. The complication rate in the OCA-M group showed no significant difference between THA/TKA. With regards to the VSS, the OCA-M group was significantly better for cosmetic qualities than the suture group (p=<0.001, p=0.021 at three and six months, respectively). For the Likert scale, the OCA-M group was also significantly better for cosmetic qualities than the suture group and staple group (suture-OCA-M, p=0.003 (three months), p=<0.001 (six months); staple-OCA-M, p=0.027 (three months)). CONCLUSION: In this study, the OCA-M complication rate was low compared to suturing and similar to stapling. Moreover, better cosmetic outcomes were achieved compared to suturing and stapling.

Astrocytic NKCC1 inhibits seizures by buffering Cl- and antagonizing neuronal NKCC1 at GABAergic synapses.

OBJECTIVE: A pathological excitatory action of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been observed in epilepsy. Blocking the Cl- importer NKCC1 with bumetanide is expected to reduce the neuronal intracellular Cl- concentration ([Cl- ]i ) and thereby attenuate the excitatory GABA response. Accordingly, several clinical trials of bumetanide for epilepsy were conducted. Although NKCC1 is expressed in both neurons and glial cells, an involvement of glial NKCC1 in seizures has not yet been reported. Astrocytes maintain high [Cl- ]i with NKCC1, and this gradient promotes Cl- efflux via the astrocytic GABAA receptor (GABAA R). This Cl- efflux buffers the synaptic cleft Cl- concentration to maintain the postsynaptic Cl- gradient during intense firing of GABAergic neurons, thereby sustaining its inhibitory action during seizure. In this study, we investigated the function of astrocytic NKCC1 in modulating the postsynaptic action of GABA in acute seizure models. METHODS: We used the astrocyte-specific conditional NKCC1 knockout (AstroNKCC1KO) mice. The seizurelike events (SLEs) in CA1 pyramidal neurons were triggered by tetanic stimulation of stratum radiatum in acute hippocampus slices. The SLE underlying GABAA R-mediated depolarization was evaluated by applying the GABAA R antagonist bicuculline. The pilocarpine-induced seizure in vivo was monitored in adult mice by the Racine scale. The SLE duration and tetanus stimulation intensity threshold and seizure behavior in AstroNKCC1KO mice and wild-type (WT) mice were compared. RESULTS: The AstroNKCC1KO mice were prone to seizures with lower threshold and longer duration of SLEs and larger GABAA R-mediated depolarization underlying the SLEs, accompanied by higher Racine-scored seizures. Bumetanide reduced these indicators of seizure in AstroNKCC1KO mice (which still express neuronal NKCC1), but not in the WT, both in vitro and in vivo. SIGNIFICANCE: Astrocytic NKCC1 inhibits GABA-mediated excitatory action during seizures, whereas neuronal NKCC1 has the converse effect, suggesting opposing actions of bumetanide on these cells.

Association between postoperative delirium and heart rate variability in the intensive care unit and readmissions and mortality in elderly patients with cardiovascular surgery.

This study aimed to investigate the relationship between heart rate variability (HRV), a parameter of the autonomic nervous system activity (ANSA), and postoperative delirium and postoperative events. This retrospective cohort study included elderly patients aged 65 years or older who were admitted to the intensive care unit (ICU) after cardiovascular surgery. ANSA was measured using HRV parameters for 1 h at daytime and 1 h at night-time before ICU discharge. The primary endpoint was the effect of HRV parameters and delirium on mortality and readmission rates within 1 year after discharge, and the secondary endpoint was the association between HRV parameters and delirium. Cox proportional hazards models were used to examine the association between HRV parameters and postoperative events by adjusting for delirium and pre and postoperative information. A total of 71 patients, 39 without delirium and 32 with delirium, met the inclusion criteria. The incidence of death and readmission within 1 year was significantly higher in the delirium group and in the group with higher daytime HF (high frequency power) and r-MSSD (square root of the squared mean of the difference of successive NN intervals), parameters of the parasympathetic nervous system activity (PNSA), than that in other groups. Furthermore, the delirium group had significantly higher HF and r-MSSD than the nondelirium group. Even after adjusting for confounding factors in the multivariate analysis, a trend of higher daytime HF and r-MSSD was observed, indicating a significant effect on the occurrence of combined events within 1 year of discharge. ICU delirium has been associated with higher daytime HF and r-MSSD, parameters of PNSA. ICU delirium was a prognostic factor, and increased daytime PNSA may worsen the prognosis of elderly patients after cardiovascular surgery.

Effect of a new remnant-preserving technique with anatomical double-bundle anterior cruciate ligament reconstruction on MRI-based graft maturity: a comparison cohort study.

PURPOSE: To investigate the effects of a new remnant-preserving double-bundle anterior cruciate ligament reconstruction (ACLR) technique, focused on avoiding remnant damage and preserving continuity of remnants, on graft maturity using magnetic resonance imaging (MRI). METHODS: A total of 169 patients were divided into three groups: 41 in the preservation group, 70 in the resection group, and 58 in the absent group. In the preservation group, rather than passing the graft through the remnant tissue, the graft was reconstructed such that the anteromedial and posterolateral bundles sandwiched the remnant to avoid damage to the remnant and maintain its continuity. Based on 1-year postoperative MRI, the grafts were divided into three regions: distal, middle, and proximal. The signal/noise quotient (SNQ) of each region of interest was calculated to evaluate the signal intensity of the graft and was compared among the three groups. Additionally, to identify factors influencing graft maturity, a multiple regression analysis was performed with SNQ as the dependent variable and patient demographics, bone morphology, and surgical factors as independent variables. RESULTS: In a three-group comparison of mean SNQs, the distal region was 3.3 ± 3.4, 8.9 ± 8.3, and 9.0 ± 8.6 (p < 0.001), the middle region was 5.3 ± 3.7, 10.9 ± 11.1, and 11.3 ± 10.2 (p < 0.001), and the proximal region was 6.8 ± 4.5, 11.1 ± 8.8, and 11.7 ± 10.8 (p = 0.017), in order of the preservation, resection, and absent groups, respectively. That indicated that the remnant-preserving ACLR was more hypointense than ACLR with remnant resection or absent in all three regions. Multiple regression analysis showed that remnant preservation remained the relevant factor affecting SNQ of the graft at the distal and middle levels. CONCLUSION: The new remnant-preserving anatomic double-bundle ACLR had significantly better graft maturity, measured by SNQ on MRI, than the remnant resection and absent groups. The remnant procedure was the relevant factor affecting graft maturity. LEVEL OF EVIDENCE: Level III.

Anatomical implications of the subvastus approach on major vascular injury during a distal femoral osteotomy: a computed tomographic venography study.

PURPOSE: This study evaluated major vascular injury risk in distal femoral osteotomy (DFO) via the subvastus approach and examined the relationship between the posterior border of the vastus medialis (VM) and the superficial femoral artery (SFA) and vein (SFV). METHODS: Eighty limbs from 80 patients were evaluated using lower extremity computed tomographic venography. The positional relationship between the VM, SFA, and SFV was evaluated by measuring the angle between each structure and the horizontal reference point (VMA: VM angle, FAA (femoral arterial angle), FVA (femoral venous angle) and the distance between VM and the SFA and SFV (VMAD: VM-arterial distance, VMVD: VM-venous distance) in each axial slice (0/10/20/30/40 mm) proximal to the level of the superior patellar margin. The proximity of the posterior border of the VM and the SFA/SFV as a vertical distance, measured between the slice of the superior border of the patella and the slice where the posterior border of the VM contacted the SFA was evaluated. Single and multiple regression analyses were performed using the vertical distance as the objective variable. RESULTS: As the slice shifted proximally, the VMA significantly increased (24.9 ± 8.5, 36.3 ± 8.8, 47.4 ± 11.8, 59.9 ± 14, 70.3 ± 13.7 degrees, respectively, p < 0.001 between all slices) and moved posteromedially from a medial direction. FAA (94.2 ± 7, 86.9 ± 9.2, 78.4 ± 9.7, 71.4 ± 9.8, 66.6 ± 10.5 degree, respectively, p < 0.001 between all slices) and FVA (100.6 ± 4.9, 98.3 ± 5.9, 93.7 ± 7.5, 88 ± 9.2, 81.1 ± 10.5 degrees, respectively, p < 0.001 between all slices) decreased and moved from a posterolateral to a posteromedial direction, while VMAD (35.4 ± 7.8, 24.1 ± 7.3, 14.3 ± 6, 8.4 ± 7, 6.2 ± 6.3 mm, respectively, p < 0.001 between all slices) and VMVD significantly decreased (42.7 ± 7.3, 32 ± 7.4, 22.4 ± 6.8, 14.5 ± 10.6, 8.7 ± 7.1 mm, respectively, p < 0.001 between all slices). The average vertical distance was 36 ± 9.3 mm (range 18.6-61.5 mm). The body height and the patellar length significantly affected the vertical distance. CONCLUSION: The posterior border of the VM shifted posteromedially from distal to proximal and contacted the SFA at an average of 36 mm from the suprapatellar border. Surgeons should be aware of the risk of major vascular injury during exposure and osteotomy. LEVEL OF EVIDENCE: Case series, Level IV.

Macroscopic and microscopic findings of multi-folded hamstring grafts of anatomical double-bundle ACL reconstruction 13 years after surgery.

A 49-year-old woman underwent anatomic double-bundle anterior cruciate ligament reconstruction using a hamstring tendon. Due to knee osteoarthritis progression, total knee arthroplasty was performed 13 years after the surgery. The anteromedial (AM) bundle was composed partly of tendon-like tissue and partly of scar-like tissue. In the tendon-like part of the AM bundle, the collagen fibers were slightly loose and showed a low-frequency crimp structure with an ovoid cell shape. In contrast, the collagen arrangement in the scar-like part was irregular, edematous, and sparsely cell-dense, with an ovoid cell shape. The posterolateral bundles were generally composed of spindle-shaped cells, and the collagen was arranged in tight cohesion and had well-demarcated bundles with normal crimping. Within the tibial tunnel, the graft was mainly connected to the surrounding lamellar bone on the posterior sides, with sparser connections on the anterior and medial/lateral side. The findings of this long-term case provide valuable information to enable understanding of multiple-folded hamstring tendons.Level of evidence V.

Myeloid cell dynamics correlating with clinical outcomes of severe COVID-19 in Japan.

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.

Recovery from severe persistent COVID-19 without evidence of an anti-SARS-CoV-2 antibody response in a man with mantle cell lymphoma treated with rituximab.

Lymphoma has been reported to worsen the prognosis of COVID-19 partly because it disturbs the normal production of antibodies. We treated a man with mantle cell lymphoma treated with rituximab, who developed severe COVID-19 with viral shedding that lasted for 78 days. He stayed in the intensive care unit for 28 days and did not respond to any treatment against COVID-19. His increased oxygen demand at rest eventually resolved despite the absence of anti-SARS-CoV-2-IgG. This case illustrates that recovery from COVID-19 can occur without antibody production, and that even patients with an inability to produce antibodies can recover from severe COVID-19. It also illustrates that lymphoma patients who develop severe COVID-19 while on rituximab therapy can recover from a prolonged viral shedding state if the acute lung injury can be overcome.

A new remnant preservation technique reduces bone tunnel enlargement after anatomic double-bundle anterior cruciate ligament reconstruction.

PURPOSE: To investigate the effect of a new remnant preservation technique with a focus on remnant continuity on postoperative femoral and tibial tunnel enlargement after anatomical double-bundle anterior cruciate ligament reconstruction (ACLR). METHODS: A total of 150 knees were divided into three groups: Preservation Group (Group P: 49 knees), wherein the remnant continuity remained after tunnel creation; Resection Group (Group R: 47 knees), wherein the remaining remnant was resected, and Absent Group (Group A: 54 knees), wherein the remnant had no femoral attachment before tunnel creation. In Group P, the remnant maintained continuity, and the anteromedial (AM) and posterolateral (PL) bundles were positioned anterior and posterior to the remnant, respectively. Computed tomographic scans were performed at 1 week and 1 year after surgery, and the cross-sectional area of each tunnel aperture was measured. Tunnel enlargement was compared among the three groups by one-way analysis of variance (ANOVA) and the Bonferroni test. Univariate and multivariate logistic analyses were performed to identify the risk factors for tunnel enlargement in demographic and radiographic data. RESULT: For femoral AM tunnels, the tunnel enlargement of Group P was significantly smaller than Groups R and A (p < 0.001), femoral PL (p < 0.001 vs. R and A), tibial AM (p < 0.001 vs. R, 0.002 vs. A), and tibial PL (p < 0.001 vs. R, 0.002 vs. A). There was no significant difference between Groups R and A. Multivariate logistic analysis showed that remnant preservation was a significant factor in reducing tunnel enlargement in the femoral AM, femoral PL, tibial AM, and tibial PL. CONCLUSION: The new remnant-preserving anatomical double-bundle ACLR, which preserves the continuity of the remnant, prevented all bone tunnel enlargement at 1 year postoperatively. LEVEL OF EVIDENCE: Level III.

Potential risk of medial cortex perforation due to peg position of morphometric tibial component in unicompartmental knee arthroplasty: a computer simulation study.

PURPOSE: The purpose of this study is to evaluate the risk of medial tibial cortical perforation in unicompartmental knee arthroplasty (UKA) due to peg positions on the tibial tray of the Persona Partial Knee (PPK). METHODS: Preoperative CT images of 60 patients and 60 osteoarthritic knees (30 male and 30 female patients) were used. A tibial multiplanar reconstruction (MPR) image was reconstructed in preoperative planning software, and the implant was placed in a virtual osteotomy plane. In addition to PPK, Zimmer Unicompartmental Knee (ZUK) and TRIBRID (TBD) were used for evaluation. The horizontal distances from the medial tibial cortex to the anterior and posterior pegs (APCD/PPCD, respectively) were measured under neutral, 3-degree varus, 3-degree valgus and 2 mm distal positions. The differences between implants under the same positions and between positions using the same implants were compared. The percentage of total cases with APCD/PPCD of less than 3 mm and the perforation risk rate were calculated. RESULTS: The APCD of PPK was significantly shorter at all positions except for the varus position of TBD. The PPCD of PPK was significantly shorter at all positions compared to ZUK and TBD. There were no cases with an APCD of less than 3 mm. Except for varus positions, the perforation risk rate of PPCD was significantly higher for PPK than the other two implants. CONCLUSION: The posterior pegs of the PPK are located more medially than the other two implants, which may result in perforation of the medial tibial cortex during implantation. Surgeons should consider the risk involved in the type of implant used.

Values for the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire in the general elderly population: A Japanese cohort survey randomly sampled from a basic resident registry.

BACKGROUND: Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) is widely used as a patient-based evaluation tool for lumbar spine disease in Japan. However, there are currently few established JOABPEQ reference values for the general population. This study proposes population-based reference values for JOABPEQ using a randomly sampled Japanese cohort. METHODS: Registered citizens of 50-89 years old were targeted for this survey. We established 8 groups based on age (50's, 60's, 70's, and 80's) and gender (male and female) after random sampling from the basic resident registry of Obuse town in 2014. A total of 414 participants (202 males and 212 females) were enrolled for calculations of average JOABPEQ scores for each age and gender group. We also evaluated for correlations between JOABPEQ domain scores and visual analogue scale (VAS) scores for low back pain. RESULTS: Median reference JOABPEQ scores stratified by age and gender were determined in this study. Lumbar function, walking ability, and social life function deteriorated significantly with age in both genders, with remarkable declines for the social life function domain. VAS scores for low back pain were not significantly correlated with JOABPEQ item scores. CONCLUSIONS: This first resident cohort of Japanese individuals determined median JOABPEQ scores by age and gender, which might serve as reference values for future studies.

Early combination treatment with baloxavir and peramivir for hospitalized adults with influenza A in Yokohama, Japan.

Baloxavir marboxil is a new anti-influenza drug, but data on the clinical efficacy of a combination treatment of baloxavir and peramivir is scarce. We conducted a single-center retrospective analysis comparing the mortality of a combination of baloxavir and peramivir (B & P, n = 10) and peramivir without baloxavir (P-mono, n = 132) in hospitalized adults with influenza A between 2011 and 2019 in Yokohama City, Japan. Sequencing analysis was conducted in the B & P group to check the I38 mutation in polymerase acidic protein which is associated with baloxavir resistance. The 30-day mortality rates were 0 (0%) in the B & P group and 6 (4.5%) in the P-mono group, respectively, which was not statistically significant. The I38 mutation was not detected before and after the combination treatment. A combination treatment of baloxavir and peramivir might be more effective than peramivir without baloxavir and prevent the emergence of baloxavir resistance in hospitalized adults with influenza A.

Fragility fractures and delayed wound healing after tooth extraction in Japanese older adults.

INTRODUCTION: Fragility fractures can cause delayed wound healing after tooth extraction, which contributes to an increased risk of osteomyelitis of the jaw. We evaluated whether a history of fragility fracture was associated with increased risk of delayed wound healing after tooth extraction in older adults in Japan. MATERIALS AND METHODS: Of 5352 people aged 50-89 years in the 2014 basic resident registry of the town of Obuse, the present study included 376 subjects (190 men and 186 women) who completed a structured questionnaire and measurement of the bone mineral densities (BMDs) of the bilateral femoral neck. Delayed wound healing after tooth extraction was self-reported. Fragility fractures were confirmed via examination of hospital medical records. Logistic regression analyses adjusted for age and gender were used to evaluate association of clinical variables with delayed would healing after tooth extractions. Odds ratios (ORs) and the 95% confidence intervals (CIs) of all possible associated variables for the presence of delayed wound healing were calculated. RESULTS: Subjects with a history of fragility fractures had a significantly higher risk of delayed wound healing compared with those without previous fragility fractures (OR 2.68; 95% CI 1.11-6.46, p = 0.028). This association still remained after adjusted for all other variables (OR 2.70; 95% CI 1.10-6.60, p = 0.030). Delayed wound healing was not significantly associated with the BMD of the femoral neck. CONCLUSIONS: History of fragility fracture may be associated with increased risk of delayed wound healing after tooth extraction in Japanese men and women aged 50-89 years.

A Japanese case of COVID-19: An autopsy report.

A 93-year-old woman was admitted with a 10-day history of cough and prostration. Thoracic computed tomography revealed extensive ground-glass opacities in both the lungs. The polymerase chain reaction test of sputum for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) was positive. She was treated with antiviral agents and steroid pulse therapy. However, her oxygen saturation gradually declined, and she died 10 days after hospitalization. The most important autopsy finding was fuzzily segmented diffuse alveolar damage (DAD) that expanded from the subpleural to the medial area. No remarkable changes were observed in organs other than the lungs. Therefore, pneumocytes were suggested as the primary target for SARS-CoV-2, which might explain why coronavirus infectious disease-19 is a serious condition. Thus, early treatment is essential to prevent viral replication from reaching a level that triggers DAD.

Clinical characteristics of the coronavirus disease 2019 (COVID-19) outbreak on a cruise ship.

BACKGROUND: A large COVID-19 outbreak occurred on the cruise ship Diamond Princess in February 2020. Little information has been reported about the clinical characteristics of the patients. METHODS: This single-center, retrospective, observational study was conducted in Yokohama, Japan. We included symptomatic patients who were infected on the ship and admitted to our hospital between 5 and 19 February 2020. All the cases were confirmed with SARS-CoV-2 infection by polymerase chain reaction (PCR). RESULTS: We confirmed 17 cases. The average age was 69 years; 10 patients were Asian and 7 were Caucasian. Eleven patients had one or more chronic diseases. The major symptoms were cough and fever. Chest computed tomography (CT) scans found bilateral ground-glass opacities predominantly in the peripheral area, which were similar to reports from cases in China. C-reactive protein (CRP) levels were higher in severe and critical cases than in mild to moderate cases. The moderate to severe cases reached symptomatic resolution; one of the three critical cases resulted in death due to multiple organ failure. SARS-CoV-2 was detected by PCR at an average of 7 days after symptomatic resolution. CONCLUSIONS: Cough and fever, increased blood CRP levels, and CT findings of bilateral ground-glass opacities predominantly in the peripheral lung were characteristic of the COVID-19 cases in this study. These findings were compatible with those of previous reports.

Association between musculoskeletal function deterioration and locomotive syndrome in the general elderly population: a Japanese cohort survey randomly sampled from a basic resident registry.

BACKGROUND: Locomotive syndrome (LoS) is defined as the loss of mobility due to age-related impairment of motor organs. The purpose of this study was to evaluate the prevalence and severity of LoS, muscular strength and balancing ability, and prevalence of sarcopenia in relation to the presence of LoS according to sex and age groups ranging between 50 and 89 years. METHODS: Male and female participants between the ages of 50-89 were randomly selected in the resident registry of a cooperating town. Calls for participation continued until approximately 50 consenting participants were successfully recruited for each age group and sex. A total of 413 participants (203 male and 210 female) were enrolled for undergoing a LoS risk test and measuring their physical function. Physical function was compared to participants with or without LoS. RESULTS: A total of 312 patients (75.5%) were diagnosed as LoS, of which 144 (46.2%) were male and 168 (53.8%) were female. The severity of LoS for the 312 patients were 210 (67.3%) for stage 1 and 102 (32.7%) for stage 2. The prevalence of LoS in males were 37, 59, 91, and 100% in the 50s, 60s, 70s, and 80s age strata, respectively. The prevalence of LoS in females were 71, 62, 89, and 98% in the 50s, 60s, 70s, and 80s age strata, respectively. The prevalence of sarcopenia was significantly higher as the age strata in males grew higher. Knee extension strength was significantly lower for participants in their 50s and females in addition to females in their 60s with LoS. The 31 patients diagnosed as sarcopenia included 29 (93.5%) with LoS, 11 (35.4%) classified as LoS stage 1, and 18 (58.1%) classified as stage 2. CONCLUSIONS: The prevalence of LoS was high in participants over 70 years of age. In males, the prevalence of sarcopenia was higher as the age strata grew higher. Patients with LoS exhibited lower knee extension strength. We believe that some measures to prevent or improve LoS may require exercise to increase the muscle strength of the lower limbs.

Hepatitis A Outbreak Among Men Who Have Sex With Men, Yokohama, Japan, January to May 2018.

Between January and May in 2018, 17 male cases of hepatitis A were reported in Yokohama, Japan. Of these, 14 identified as men who have sex with men. The viral sequence in this outbreak was same as that of the recent European and Taiwanese outbreaks strain.

Changes in the expression of IL-6-Mediated MicroRNAs in the dorsal root ganglion under neuropathic pain in mice.

A multiplex analysis for profiling the expression of candidate microRNAs (miRNAs), which are small noncoding RNAs that function as key post-transcriptional regulators, may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we performed a miRNA array analysis using tissues of the dorsal root ganglion (DRG), a primary site for pain processing, obtained from mice with partial sciatic nerve ligation. Among 1135 total miRNAs, 26 miRNAs showed up-regulation (more than 2-fold change) and only 4 miRNAs showed down-regulation (less than 0.5-fold change) in the DRG of nerve-ligated mice. In a RT-qPCR assay, the levels of miR-21, miR-431, and miR-511-3p were significantly increased on the ipsilateral side of the DRG from 3 to 7 days after sciatic nerve ligation. These elevations were almost absent in IL-6 knockout mice. Furthermore, the expression level of miR-21, but not those of miR-431 or miR511-3p, was significantly increased in exosomes extracted from blood of nerve-ligated mice. These findings suggest that the increased expression of IL-6-regulated miR-21, miR-431, and miR-511-3p in the DRG and increased exosomal miR-21 extracted from blood after sciatic nerve ligation may play at least a partial role in neuropathic pain. Synapse 70:317-324, 2016. © 2016 Wiley Periodicals, Inc.

CCL11 enhances excitotoxic neuronal death by producing reactive oxygen species in microglia.

The chemokine CCL11 (also known as eotaxin-1) is a potent eosinophil chemoattractant that mediates allergic diseases such as asthma, atopic dermatitis, and inflammatory bowel diseases. Previous studies demonstrated that concentrations of CCL11 are elevated in the sera and cerebrospinal fluids (CSF) of patients with neuroinflammatory disorders, including multiple sclerosis. Moreover, the levels of CCL11 in plasma and CSF increase with age, and CCL11 suppresses adult neurogenesis in the central nervous system (CNS), resulting in memory impairment. However, the precise source and function of CCL11 in the CNS are not fully understood. In this study, we found that activated astrocytes release CCL11, whereas microglia predominantly express the CCL11 receptor. CCL11 significantly promoted the migration of microglia, and induced microglial production of reactive oxygen species by upregulating nicotinamide adenine dinucleotide phosphate-oxidase 1 (NOX1), thereby promoting excitotoxic neuronal death. These effects were reversed by inhibition of NOX1. Our findings suggest that CCL11 released from activated astrocytes triggers oxidative stress via microglial NOX1 activation and potentiates glutamate-mediated neurotoxicity, which may be involved in the pathogenesis of various neurological disorders.