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Purpose: The aim of this study was to evaluate the accuracy of prostate volume estimates calculated from the ellipsoid formula using the anteroposterior (AP) diameter measured on axial and sagittal images obtained through ultrasonography (US) and magnetic resonance imaging (MRI).Methods: This retrospective study included 456 patients with transrectal US and MRI from two university hospitals. Two radiologists independently measured the prostate gland diameters on US and MRI: AP diameters on axial and sagittal images, transverse, and longitudinal diameters on midsagittal images. The volume estimates, volumeax and volumesag, were calculated from the ellipsoid formula by using the AP diameter on axial and sagittal images, respectively. The prostate volume extracted from MRI-based whole-gland segmentation was considered the gold standard. The intraclass correlation coefficient (ICC) was used to evaluate the inter-method agreement between volumeax and volumesag, and agreement with the gold standard. The Wilcoxon signedrank test was used to analyze the differences between the volume estimates and the gold standard.Results: The prostate gland volume estimates showed excellent inter-method agreement, and excellent agreement with the gold standard (ICCs >0.9). Compared with the gold standard, the volume estimates were significantly larger on MRI and significantly smaller on US (P

Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.

IntroductionTo investigate the effects of different strategies and cognitive load we explored brain hemodynamic responses associated with the use of different strategies to solve subtraction of fractions. We focused on those born extremely preterm (EPT; MethodsFunctional MRI was acquired while the participants mentally solved fraction equations using either a strategy based on improper or mixed fractions. Different fraction item types were given, which affected respective required cognitive loads per strategy. Diffusion and T1-weighted structural images were also acquired.ResultsThe EPT and FT groups differed in terms of task-related hemodynamic responses. Functional group differences were greatest when strategies were applied to item types that result in high cognitive load. Other findings showed reduced white and grey matter volume and reduced white matter connectivity in widespread areas in the EPT group compared to the FT group.ConclusionThe understanding of function and structure presented here may help inform pedagogical practices by allowing for tailoring of mathematical education through identifying suitable strategy adoption that depends on item type, to circumvent weaknesses in cognitive skills.

The evident genetic, pathological and clinical heterogeneity of Alzheimer’s disease (AD) poses challenges for traditional drug development. We conducted a computational drug-repurposing screen for drugs to treat apolipoprotein E4 (APOE4)-related AD. We first established APOE genotype-dependent transcriptomic signatures of AD by analyzing publicly available human brain databases. We then queried these signatures against the Connectivity Map database, which contains transcriptomic perturbations of more than 1,300 drugs, to identify those that best reverse APOE genotype-specific AD signatures. Bumetanide was identified as a top drug for APOE4-related AD. Treatment of APOE4-knock-in mice without or with amyloid β (Aβ) accumulation using bumetanide rescued electrophysiological, pathological or cognitive deficits. Single-nucleus RNA sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in APOE4 induced pluripotent stem cell (iPSC)-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 years in two electronic health record databases, suggesting the effectiveness of bumetanide in preventing AD. Through computational drug repurposing, Taubes et al. identified bumetanide as a potential drug for APOE4-related Alzheimer’s disease (AD). The effectiveness of bumetanide was validated in AD mouse models and via real-world health record databases.

The evident genetic, pathological, and clinical heterogeneity of Alzheimer’s disease (AD) poses challenges for traditional drug development. We conducted a computational drug repurposing screen for drugs to treat apolipoprotein (apo) E4-related AD. We first established apoE-genotype-dependent transcriptomic signatures of AD by analyzing publicly-available human brain database. We then queried these signatures against the Connectivity Map database containing transcriptomic perturbations of >1300 drugs to identify those that best reverse apoE-genotype-specific AD signatures. Bumetanide was identified as a top drug for apoE4 AD. Bumetanide treatment of apoE4 mice without or with Aβ accumulation rescued electrophysiological, pathological, or cognitive deficits. Single-nucleus RNA-sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in apoE4-iPSC-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 in two electronic health record databases, suggesting effectiveness of bumetanide in preventing AD.

The objective of this study was to evaluate the effects of diabetes mellitus (DM) on the rate of carpal tunnel release (CTR) using a large nationwide cohort in Korea and to identify risk factors, including comorbidities and socioeconomic status (SES), associated with CTR. Patients with a primary or secondary diagnosis of carpal tunnel syndrome (CTS; ICD-10 code: G560) were selected and divided into two groups according to the presence of DM. A Cox proportional hazard model was used to assess the rate of CTR between the two groups. To evaluate the influence of demographic factors, comorbidities, and SES on CTR, multivariate Cox proportional hazard regression models were used to adjust for confounding variables. In total, 12,419 patients with CTS were included in the study: 2487 in DM cohort and 9932 in non-DM cohort. DM duration was negatively related with the rate of CTR (HR = 0.89, 95% CI 0.87–0.91) in CTS patients with DM. The rate of CTR was decreased in patients with DM compared to those without DM in the unadjusted model; however, after adjusting for comorbidities, DM had no significant effect on the rate of CTR. Female sex (HR = 1.50, 95% CI 1.36–1.67) correlated with the rate of CTR, and an inverse relationship between the number of comorbidities and CTR was found (p

Apolipoprotein E4 (APOE4) genotype and aging are critical risk factors for Alzheimer’s disease (AD). Aged APOE4 knock-in (APOE4-KI) mice have phenotypes reflecting features of AD. We conducted a large-scale single nucleus RNA-sequencing study to identify cell-type-specific effects of APOE4 on hippocampal gene expression during aging. APOE4-KI mice showed prominent alterations, relative to APOE3-KI mice, in neuronal transcriptome related to synaptic function, calcium signaling, and MAPK/Rap1/Pld signal transduction, starting by 5 months and persisting during aging. Mice with the APOE4 gene removed specifically from neurons failed to show most of these neuronal transcriptomic changes, suggesting a specific effect of neuron-derived APOE4 on the transcriptome. APOE4 affects similar cellular pathways in induced pluripotent stem cell-derived human neurons transplanted into APOE4-KI mouse hippocampus and in cortical neurons from aged human brains. Thus, neuronal APOE4 has early and persistent effects on neuronal transcriptomes, suggesting the requirement of early interventions for successfully treating APOE4-related AD.

Selective neurodegeneration is a critical causal factor in Alzheimer's disease (AD); however, the mechanisms that lead some neurons to perish, whereas others remain resilient, are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that ApoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of ApoE-which has a robust genetic linkage to AD-correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wild-type mice, human ApoE knock-in mice and humans with or without AD. Elimination or over-expression of neuronal ApoE revealed a causal relationship among ApoE expression, neuronal MHC-I expression, tau pathology and neurodegeneration. Functional reduction of MHC-I ameliorated tau pathology in ApoE4-expressing primary neurons and in mouse hippocampi expressing pathological tau. These findings suggest a mechanism linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration.

The analgesic effect of alpha-2 adrenergic receptor (α2AR) agonists, which relieve chronic neuropathic pain, is highly variable among individuals. Here, we used a mouse model of spared nerve injury (SNI) to show that treatment time after the establishment of neuropathic pain was important for the variability in the analgesic efficacy of α2AR agonists, which was related to the activity of regulator of G-protein signaling protein 4 (RGS4). Intrathecal treatment with α2AR agonists, clonidine (0.1–1 nmol) or dexmedetomidine (0.3–1 nmol), relieved mechanical allodynia and thermal hyperalgesia on postoperative day (POD) 14, but their efficacy was weaker on POD28 and absent on POD56. The RGS4 level of plasma membrane was increased on POD56 compared to that on POD14. Moreover, in RGS4-deficient or RGS4 inhibitor (CCG50014)-treated mice, the analgesic effect of the α2AR agonists was conserved even on POD56. The increased plasma membrane RGS4 expression and the reduced level of active Gαi after clonidine injection on POD56 were completely restored by CCG50014. Higher doses of clonidine (10 nmol) and dexmedetomidine (3 nmol) relieved neuropathic pain on POD56 but were accompanied with serious side effects. Whereas, the coadministration of CCG50014 with clonidine (1 nmol) or dexmedetomidine (1 nmol) did not cause side effects. These findings demonstrated that SNI-induced increase in plasma membrane RGS4 expression was associated with low efficacy of α2AR agonists in a model of persistent, chronic neuropathic pain. Furthermore, α2AR agonist administration together with RGS4-targeted intervention represents a novel strategy for the treatment of neuropathic pain to overcome dose-limiting side effects.

Introduction: Patients with Parkinson’s disease (PD) are prone to falls, thereby increasing the risk of fractures and mortality. This population-based study investigated the risk of hip fractures and their effect on mortality in patients with PD in Korea. Methods: National Health Insurance Service-National Sample Cohort data were used. Patients newly diagnosed with PD between 2006 and 2015 and age- and sex-matched individuals were classified into the PD group and the comparison group, respectively, with a 1:9 ratio. The Cox proportional hazards model was used to calculate hazard ratios (HRs), and the Kaplan-Meier method to identify survivorship. Results: In total, 26,570 individuals were enrolled in the study: 2,657 in the PD cohort and 23,913 in the matched comparison cohort. The PD group had about a 2 times higher risk of hip fracture than the comparison group (3.95 vs. 1.94%, p < 0.001). According to sex, the difference between the PD and comparison groups for the risk of hip fracture was greater in males than in females. The highest difference in HR for hip fracture between the PD and comparison groups was found in individuals aged between 60 and 69 years. Regarding post-fracture mortality in patients with PD, the mortality risk was twice as high in the patients with hip fracture than in those without. The effect of hip fracture on mortality between these 2 groups was also the highest in individuals aged between 60 and 69 years. Conclusion: The PD group showed an approximately 2 times higher risk of hip fracture compared with the comparison group, and the post-fracture mortality rate was 2 times higher in the patients with PD with hip fracture than in those without. Those aged 60–69 years were associated with the highest risk of hip fracture and post-hip fracture mortality among patients with PD.

Although weight loss is a frequent symptom in Parkinson disease (PD), there have been few studies on the association between body mass index (BMI) and mortality. The objective of this study was to investigate the association between BMI and change in BMI at diagnosis in patients with PD and all-cause mortality.Cohort study using Korean National Health Insurance Service-Elderly Cohort data.Patients with new-onset PD were selected using the International Classification of Diseases 10th edition code (G20). Then, patients who were diagnosed more than 3 times with PD and had been prescribed anti-parkinsonian medication for ≥30 days were included. Those with a combined diagnosis of atypical parkinsonism and secondary parkinsonism were excluded.The primary outcome was all-cause mortality. Anthropometric data, including height and weight, were obtained from the health screening data to calculate BMI. The Cox proportional hazards model was used to assess mortality risk by BMI.Among the 2703 patients with PD, 492 (18.20%) died during the 11-year follow-up period. There was a significant inverse dose-response relationship between baseline BMI and mortality [18.5 kg/mWe demonstrated an inverse dose-response association between BMI at diagnosis and mortality in patients with PD, especially in women. Early detection of PD before weight loss progression and proper management might improve mortality. The small number of obese PD participants in our study should be considered when interpreting and generalizing results.

Background previous studies on mortality of Parkinson’s disease (PD) enrolled a relatively small number of participants and were conducted in western countries. The objective of this study was to evaluate mortality rate of PD using a large nationwide cohort in Korea and to evaluate effects comorbidities have on mortality in PD. Methods the nationwide population-based cohort study was conducted using the Korean National Health Insurance Service—National Sample Cohort data. Patients with a primary diagnosis of PD were selected from the database. A matched cohort without PD was enrolled through randomly matching patients by sex, age, year of diagnosis, residential area and income level to the PD group with a ratio of 1:9. The Cox proportional hazard model was used to assess mortality risk between the two cohorts. A logistic regression analysis was used to identify mortality risk factors in PD cohort. Results in total, 25,620 patients were enrolled. The Cox proportional regression model had an adjusted hazard ratio of 2.479 [95% confidence interval (CI), 2.272-2.704] for mortality in PD cohort. Comorbidities, such as ischaemic stroke [odds ratios (OR) = 2.314, 95% CI, 1.895-2.824], haemorrhagic stroke (OR = 2.281, 95% CI, 1.466-3.550) and chronic obstructive pulmonary disease (OR = 1.307, 95% CI, 1.048-1.630) were associated with increased mortality, whereas dyslipidemia (OR = 0.285, 95% CI, 0.227-0.358) was negatively correlated with mortality. Conclusion over the 10 year follow-up period, the PD cohort’s mortality rate was 2.5 times higher than the comparison cohort. Understanding the effects that comorbidities have on morality in PD would be useful for predicting mortality in patients with PD.

Introduction To evaluate the mortality rate and impact of SES on mortality in PD using a nationwide cohort in Korea. Methods We selected patients diagnosed with PD (ICD-10 code: G20) and registration code for PD (V124) in the program for rare intractable diseases between 2004 and 2015. After that, atypical parkinsonism was excluded. A matched cohort of individuals without PD were enrolled by randomly matching patients by sex, age, and year of diagnosis to the PD group with a ratio of 1:9. Cox proportional hazard models were used to identify the effects of SES on mortality using Hazard Ratios and 95% confidence intervals. Results In total, 26,570 participants were enrolled. The mortality rate was 30.37% in PD cohort and 16.69% in the comparison cohort. According to income level, PD patients in low-middle group revealed significantly decreased HRs of 0.704 (95% CI, 0.533–0.930) compared to those in the lowest group. The medical aid group showed an increased mortality rate (HR = 1.552, 95% CI, 1.191–2.021) compared to the national health insurance group. In the subgroup analyses, medical aid was associated with mortality only in PD with female (HR = 1.740, 95% CI, 1.242–2.438) or aged 60–79 years (HR = 1.434, 95% CI 1.005–2.045). There was no significant difference in mortality rate according to residential area in PD. Conclusions In Korea, individual level low SES including income level and insurance type were significantly associated with increased mortality, whereas regional level SES (residential area) was not related with mortality on PD.

Objective To compare postural balance ability in patients with low back pain between groups with and without lumbosacral radiculopathy.Methods Patients who were referred for electromyography because of low back pain during the period from April 2017 through June 2018 were chosen as subjects. They were divided into groups with and without lumbosacral radiculopathy based on the results of electromyography. We used Tetrax (Sunlight Medical Ltd., Ramat Gan, Israel) to objectively evaluate postural balance ability, and to measure the fall risk, stability index, weight distribution index, and Fourier index.Results Patients in the lumbosacral radiculopathy group showed significantly higher fall risk (73.25 vs. 38.00; p

Background We investigated the risk of carpal tunnel syndrome (CTS) in diabetic polyneuropathy (DPN). Methods This study was conducted using records from the National Health Insurance System (NHIS). We divided patients diagnosed with diabetes mellitus (DM) into those with and without DPN. We assessed the effect of DPN on the risk of CTS using Cox proportional hazards regression analyses. Results DPN was associated with an increased risk of CTS (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.12-1.58). In sub-analyses, female gender (HR, 1.45; 95% CI, 1.20-1.76), presence of type 2 DM (HR, 1.36; 95% CI, 1.11-1.64), and age 35 to 64 years (HR 1.35; 95% CI, 1.11-1.64) were significantly associated with an increased risk of CTS. Conclusions Patients with DPN had an increased risk of CTS compared with the non-DPN group, particularly females, those with type 2 DM, and those aged 35 to 64 years.

Background Extracorporeal shock wave therapy (ESWT) has been used in various musculoskeletal disorders, including lateral epicondylitis. However, in 2005, a meta-analysis of randomized controlled trials showed that ESWT provides minimal or no benefit in terms of pain and function in patients with lateral epicondylitis. Since the review, several randomized controlled trials including different types of ESWT such as radial type for lateral epicondylitis have been published. Investigations of the effect modifiers such as symptom and follow-up duration on the effects of ESWT on lateral epicondylitis have not been performed. Questions/purposes (1) Does ESWT reduce pain and improve grip strength in patients with lateral epicondylitis? (2) Which type of ESWT, radial or focused, is more effective? (3) Is the duration of symptoms associated with the efficacy of ESWT for lateral epicondylitis? (4) Do improvements in pain scores remain in patients with longer follow-up? Methods The PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched up to July 2019 for articles published in English or Korean. Studies were included if patient allocation was randomized, the sample was composed of patients with lateral epicondylitis, interventions were ESWT (focused or radial), comparison group only received sham stimulation or no additional treatment, and the study outcome was pain intensity or grip strength. The quality of the evidence was assessed using the Cochrane risk of bias tool. Twelve studies including 1104 participants fulfilled the inclusion criteria and were included in the meta-analysis. The mean difference for pain reduction and improvement in grip strength was calculated. Results The meta-analysis showed no clinically important difference in the VAS score (2.48 ± 7.55 versus 3.17 ± 9.78, mean difference -0.68 [95% confidence interval -1.17 to -0.19]; p = 0.006) and grip strength (38.02 ± 70.56 versus 34.85 ± 108.26, mean difference 3.33 [95% CI 0.93 to 5.73]; p = 0.007) after ESWT relative to the comparison group's score. Even though radial ESWT showed more improvement than focused, the mean difference for VAS did not exceed the minimal clinically important differences threshold. There were no clinically important effects on the VAS scores of patients with lateral epicondylitis (2.78 ± 5.57 versus 3.92 ± 6.29, mean difference -1.13 [95% CI -1.84 to -0.42]; p = 0.002) and focused ESWT did not improve pain in patients with lateral epicondylitis. In the subgroup analysis, ESWT was effective in patients with a symptom duration of more than 6 months (2.28 ± 8.48 versus 3.31 ± 11.81, mean difference -0.95 [95% CI -1.75 to -0.15]; p = 0.02) but not for those with shorter symptom duration. The effects did not last beyond 24 weeks (2.52 ± 9.19 versus 3.34 ± 5.93, mean difference -0.82 [95% CI -2.57 to 0.93]; p = 0.36). Conclusions ESWT did not show clinically important improvement in pain reduction and grip strength. Radial ESWT, symptom duration of longer than 6 months, and short follow-up duration (less than 24 weeks) were related to better effects. Further studies are needed to determine the appropriate protocol and elucidate the effects according to the intervention type and specific disease condition. Level of evidence Level I, therapeutic study.

Poststroke complex regional pain syndrome (CRPS) is characterized by swelling, pain, and changes in the skin that appear on the affected wrist and hand. In this retrospective study, we analyzed the relationship between poststroke CRPS and the location of stroke lesion. From all patients admitted to our hospital from 2009 to 2019, we recruited 80 patients affected by their first unilateral stroke who met the inclusion/exclusion criteria. Thirty-eight patients diagnosed with CRPS after stroke were assigned to the experimental group according to the "Budapest criteria" adopted by the International Association for the Study of Pain, and 42 patients without CRPS were included as controls. Regions of interest were manually drawn on T1-weighted magnetic resonance images, and data were normalized to a standard brain template. In the poststroke CRPS group, the relationship between the location of brain lesion and pain severity was analyzed using Freedman-Lane multivariable regression adjusting for Medication Quantification Scale rating, which was the only parameter to show a statistically significant correlation with pain intensity. A threshold of P < 0.01 was considered statistically significant for all voxel-based lesion symptom mapping tests, corrected for multiple comparisons with 5000 permutations. Analyses using voxel-wise subtraction and Liebermeister statistics indicated that the corticospinal tract (CST) was associated with the development of poststroke CRPS. Statistically significant correlations were found between pain intensity and the CST and the adjacent lentiform nucleus. Our results suggest that the CST may be a relevant neural structure for development of poststroke CRPS and the intensity of pain caused by the syndrome.

To investigate gait characteristics in patients with freezing of gait (FOG) after hypoxic-ischemic brain injury (HIBI) and to elucidate neural correlates for FOG using F-18 fluoro-2-deoxy-d-glucose positron emission tomography.We enrolled 12 patients with FOG after HIBI and 17 patients without FOG after HIBI. We performed three-dimensional gait analyses and compared each parameter and gait variability. Brain metabolism was measured, and we compared regional brain metabolism using a voxel-by-voxel-based statistical mapping analysis.The FOG group revealed a significantly decreased joint range of motion (ROM), particularly in the sagittal plane for three-joint summated ROM (p 0.0025). Spatiotemporal results demonstrated that stride length and step length were decreased in the with FOG group (p 0.005). FOG severity was negatively correlated with brain metabolism in the left thalamus, and three-joint summated ROM in the sagittal plane was positively associated with brain metabolism in the left thalamus and midbrain (p 0.05).Central organizational level amplitude disorder may play an important role in the pathophysiology, and disturbance in the cholinergic pathway might contribute to the development of FOG in patients with HIBI.These findings contribute to understanding FOG in HIBI.

Prominin-1 (PROM1), also known as CD133, is expressed in hepatic progenitor cells (HPCs) and cholangiocytes of the fibrotic liver. In this study, we show that PROM1 is upregulated in the plasma membrane of fibrotic hepatocytes. Hepatocellular expression of PROM1 was also demonstrated in mice (Prom1CreER; R26TdTom) in which cells expressed TdTom under control of the Prom1 promoter. To understand the role of hepatocellular PROM1 in liver fibrosis, global and liver-specific Prom1-deficient mice were analyzed after bile duct ligation (BDL). BDL-induced liver fibrosis was aggravated with increased phosphorylation of SMAD2/3 and decreased levels of SMAD7 by global or liver-specific Prom1 deficiency but not by cholangiocyte-specific Prom1 deficiency. Indeed, PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that hepatocyte-specific overexpression of SMAD7 ameliorated BDL-induced liver fibrosis in liver-specific Prom1-deficient mice. Thus, we conclude that PROM1 is necessary for the negative regulation of TGFβ signaling during liver fibrosis.

The protective effects of physical activity (PA) against Parkinson disease (PD) development have been suggested; however, the association of PA with mortality in PD has rarely been investigated.To evaluate the association between PA and mortality in individuals with PD and determine how the amount and maintenance of PA are associated with mortality.This nationwide population-based cohort study used Korean National Health Insurance System data. Participants were included from January 1, 2010, and December 31, 2013, and were followed up until December 31, 2017. Data were analyzed from September 2020 to March 2021. Individuals who were newly diagnosed with PD were selected using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code G20 and registration code V124 in the program for rare intractable diseases in 2010 through 2013. Individuals who underwent health checkups within 2 years before and after the PD diagnosis were enrolled. Those aged younger than 40 years or with missing data were excluded.Physical activity levels were collected using self-reported questionnaires.All-cause mortality.A total of 45 923 individuals were identified; 10 987 were enrolled, and 34 individuals younger than 40 years and 254 with missing data were excluded. A total of 10 699 individuals with PD were included; 4925 (46%) were male and 5774 (54%) were female, and the mean (SD) age was 69.2 (8.8) years. During the 8-year follow-up period, there were 1823 deaths (17%). The mortality rate was lower among individuals who were physically active vs inactive at all PA intensities (vigorous: hazard ratio [HR], 0.80 [95% CI, 0.69-0.93]; moderate: HR, 0.66 [95% CI, 0.55-0.78]; light: HR, 0.81 [95% CI, 0.73-0.90]). There was a significant inverse dose-response association between the total amount of PA and mortality (HRs: vigorous, 0.80 [95% CI, 0.69-0.93]; moderate, 0.66 [95% CI, 0.55-0.78]; light, 0.81 [95% CI, 0.73-0.90]; P .001). Moreover, maintenance of PA was associated with the mortality rate. Individuals with PD who were physically active both before and after the PD diagnosis had the greatest reduction in mortality rate across all PA intensities (HRs: vigorous, 0.66 [95% CI, 0.50-0.88]; moderate, 0.49 [95% CI, 0.32-0.75]; light, 0.76 [95% CI, 0.66-0.89]). Individuals who started PA after receiving the PD diagnosis had a lower mortality rate than those who remained physically inactive (HRs: vigorous, 0.82 [95% CI, 0.70-0.97]; moderate, 0.69 [95% CI, 0.57-0.83]; light, 0.86 [95% CI, 0.78-0.98]).This analysis found a dose-response association between PA and all-cause mortality in PD. Reverse causality may exist, and future prospective randomized clinical trials are warranted to determine the effect of PA on mortality in PD.

Background: Ankylosing spondylitis (AS) is an immune-mediated, chronic inflammatory rheumatic disorder. The etiology of Parkinson’s disease (PD) is multifactorial; however, inflammation is receiving an increasing amount of attention as an underlying cause of the neurodegenerative process of PD. Objective: We performed a nationwide longitudinal, population-based matched cohort study to assess the association with the later development of parkinsonism in Korea. Methods: This study was conducted using records from the Health Insurance Review and Assessment Service database. The cumulative incidence rate of PD was estimated. Fine–Gray subdistribution hazard models were used to identify hazards associated with PD development based on the presence of AS. Exposure to anti-inflammatory drugs was measured and analyzed to determine the protective effect of these medications. Additionally, the hazard ratio (HR) for atypical parkinsonism was estimated. Results: The results of the Fine–Gray subdistribution hazard model revealed that the HR for PD development in the AS group was 1.82 (95%confidence interval [CI], 1.38–2.39, p

Few studies have investigated the factors associated with assisted ventilation use in amyotrophic lateral sclerosis (ALS) in western countries with a relatively small number of participants. This study aimed to evaluate the factors associated with assisted ventilation use using a large nationwide cohort covering the entire Korean population. We selected patients with primary or secondary diagnoses of ALS (ICD-10 code: G12.21) and a registration code for ALS (V123) in the rare intractable disease registration program. Covariates included in the analyses were age, sex, socioeconomic status and medical condition. Factors associated with non-invasive ventilation (NIV) and tracheostomy invasive ventilation (TIV) were evaluated. Logistic regression analyses were performed using odds ratios and 95% confidence intervals. In total, 3057 patients with ALS were enrolled. During the 6-year follow-up period, 1228 (40%) patients started using assisted ventilation: 956 with NIV and 272 with TIV. There was no significant difference in the assisted ventilation use according to sex, whereas different patterns of discrepancies were noted between the sexes: Females living in non-metropolitan areas showed decreased use of assisted ventilation, whereas high income levels showed a positive relationship with assisted ventilation use only in males. Patients aged ≥ 70 years showed decreased use of NIV. NIV use was more affected by socioeconomic status than TIV, whereas TIV showed a significant relationship with medical conditions such as nasogastric tube insertion and gastrostomy. We found that various factors, including age, socioeconomic status, and medical condition, were related with assisted ventilation use. Understanding the pattern of assisted ventilation use would help set optimal management strategies in patients with ALS.

Our recent study demonstrated that the CC-chemokine ligand 2 (CCL2) present in primary afferent fibers (PAFs) plays an important role in the microglia-dependent neuronal activation associated with zymosan-induced inflammatory pain. The present study was aimed to evaluate whether BD1047 (a prototypical sigma-1 receptor (Sig-1R) antagonist) is capable of modifying elevated levels of inflammation-evoked CCL2 as a peripheral antinociceptive mechanism. In DRG primary culture, zymosan dose-dependently increased CCL2 release from isolectin B4 (IB4)-positive DRG neurons, a process that was inhibited by co-culture with BD1047. Single treatment of BD1047 before intraplantar injection of zymosan in rats significantly reduced thermal hyperalgesia and mechanical hyperalgesia, as well as CCL2 expression in DRG neurons and microglia activation in the spinal dorsal horn. In the Complete Freund’s adjuvant (CFA)-induced inflammation model, repeated administration of BD1047 dramatically attenuated thermal hyperalgesia and mechanical hyperalgesia, and significantly diminished CCL2 immunoreactivity and microglia activation. Notably, CFA-induced inflammation significantly increased Sig-1R immunoreactivity in DRG neurons, which was co-localized with CCL2 and IB4, respectively. Taken together, our results suggest that BD1047′s anti-nociceptive property was substantially mediated by the inhibition of CCL2 release in unmyelinated PAFs and that this may, in turn, have attenuated the spinal microglia activation that is associated with inflammatory pain.

A predominant trigger and driver of sporadic Alzheimer’s disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences have remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind Aβ1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that Aβ1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.

As a first-line treatment for lateral elbow tendinopathy (LET), eccentric exercise has been suggested as a conservative treatment method. This study aimed to investigate the impact of eccentric exercise on LET with regard to pain reduction, and strength and functional improvement. The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched, and studies up to May 2021 were included if (1) randomization was used for patient allocation, (2) the study comprised patients with LET, (3) the intervention was eccentric exercise, and (4) the primary outcomes included improvement in pain intensity, muscle strength, or function. The meta-analysis comprised of six studies, totaling 429 participants. Additional eccentric exercise with underlying adjuvant therapy significantly improved the visual analog scale (VAS) scores (standardized mean difference [SMD], −0.63; 95% confidence interval [CI], −0.90–−0.36) and muscle strength (SMD, 1.05; 95% CI, 0.78–1.33) compared with adjuvant therapy alone. Compared with the concentric or isotonic exercise group, the eccentric exercise group showed significantly improved VAS scores (SMD, −0.30; 95% CI, −0.58–−0.02). However, no differences in muscle strength and function were observed between the two groups. Eccentric exercise can improve pain and muscle strength in patients with LET. The limited number of included studies and heterogeneous exercise parameters are important when interpreting these findings.

OBJECTIVES Patients with acquired brain injury show decreased pulmonary function and diaphragm excursion (DE), which can affect functional outcomes. This study aimed to compare ultrasonography (US) and fluoroscopy for DE assessment and to determine how the relationship between pulmonary function test results and DE differs according to the paralytic condition. METHODS From September 2017 to April 2018, we prospectively enrolled patients with acquired brain injury. The patients underwent a pulmonary function test, including the functional vital capacity, forced expiratory volume at 1 second, forced expiratory volume at 1 second-to-functional vital capacity ratio, peak cough flow, and respiratory muscle strength such as the maximal inspiratory pressure and maximal expiratory pressure. Diaphragm excursion was measured with M-mode US and fluoroscopy on admission. A partial correlation analysis was used to assess the correlation between US and fluoroscopy for DE assessment. RESULTS During the study period, 50 patients with acquired brain injury were enrolled. After adjusting for age, sex, height, and weight, the correlation coefficients between US and fluoroscopy were 0.744 for the right side (P