Japanese translation and validation of the 12-item Multiple Sclerosis Walking Scale version 2.

BACKGROUND: Disability in ambulation has a critical impact on activities of daily living in patients with multiple sclerosis (MS). The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a self-reported instrument developed to assess the impact of MS on walking. The scale's 12 items assess various aspects of walking-related tasks during the past 2 weeks. MSWS-12 has been used in multiple clinical studies and translated into several languages. In the present study, we translated the MSWS-12 into Japanese and evaluated its psychometric properties in a cross-sectional study. METHODS: The original English MSWS-12 version 2 (v2) was translated into Japanese through a standard procedure. Sixty consecutive Japanese MS patients completed the newly prepared Japanese MSWS-12v2 questionnaire and repeated the test 14 days later. Physical disability was assessed by the Expanded Disability Status Scale (EDSS), Timed 25-foot Walk (T25FW), and 9-hole Peg Test (9HPT). Cognitive performance was evaluated using the Processing Speed Test (PST). Fatigue and health-related quality of life were assessed using the Japanese versions of the Fatigue Severity Scale (FSS) and the Functional Assessment of MS (FAMS). RESULTS: The mean age of the patients was 42.5 years, with median disease duration of 10 years, and median EDSS of 2.0 (range 0, 6.5). Forty-seven patients (78.3 %) had relapsing-remitting, 9 (15.0 %) had secondary-progressive, and 4 (6.7 %) had primary-progressive phenotypes. The median score of the MSWS-12v2 was 5.95 (interquartile range 0, 50.6). Twenty-seven patients (45 %) scored the lowest possible score (0 points), while one (1.7 %) scored the highest possible score (100 points). Cronbach's alpha was 0.98 (95 % confidence interval [CI] 0.97, 0.98), and the test-retest intraclass correlation was 0.95 (95%CI 0.94, 0.96). MSWS-12v2 score was strongly correlated with EDSS (Spearman's ρ = 0.73 [95%CI 0.58, 0.83]), T25FW (ρ = 0.70 [95%CI 0.55, 0.81]), and total FAMS score (ρ = -0.80 [95%CI -0.88, -0.69]), and moderately correlated with 9HPT (ρ = 0.65 [95%CI 0.47, 0.77] for the dominant hand; ρ = 0.62 [95%CI 0.43, 0.75] for the non-dominant hand), PST (ρ = -0.65 [95%CI -0.78, -0.47]), and FSS (ρ = 0.68 [95%CI 0.52, 0.80]). Among the subcomponents of FAMS, the mobility subcomponent showed the most robust correlation with MSWS-12v2 score (ρ = -0.91 [95%CI -0.94, -0.81]). In patients with minimal or no objective disability (EDSS < 3.0, n = 40), only the mobility subcomponent of FAMS was strongly correlated with MSWS-12v2 score (ρ = -0.76 [95% CI -0.87, -0.58]). In contrast, correlations of MSWS-12v2 score with EDSS and T25FW were weak in this subgroup (ρ = 0.28 [95%CI -0.03, 0.55] for EDSS; ρ = 0.25 [95%CI -0.06, 0.52] for T25FW). Response patterns for the single items showed that 32.5 % of the patients with EDSS below 3.0 reported having problems with balance, followed by climbing stairs and standing while doing things (both 25 %). CONCLUSION: The Japanese version of the MSWS-12v2 developed in this study is reliable, valid, and helpful for screening walking disability in Japanese MS patients, including those with minimal objective disability.

Differences in walking and running parameters in elementary school students with and without backpacks.

BACKGROUND: Backpack syndrome (BS) is a term used to describe symptoms such as shoulder and back pain that are believed to be caused by carrying a backpack. Few studies have investigated the changes in walking and running parameters with and without backpacks. OBJECTIVE: The present study aimed to investigate the differences in walking and running parameters with and without backpacks in primary school children with and without BS. METHODS: This cross-sectional study included 51 children (average age 9.3 years, 6- 12 years). Two questions were asked beforehand: whether the respondents had shoulder or back pain when going to school and present; those who answered that they had pain in both cases were defined as the BS group, while the others were the control group. Walking and running at comfortable speeds and walking and running with a 6 kg backpack on their backs were measured. RESULTS: During walking, there were main effects for speed, cadence, and strike angle with and without the backpack, but no interactions were identified for any of the parameters. In running, however, there were main effects for speed, stride length, strike angle, and lift-off angle, and an interaction effect was observed for speed and stride length. CONCLUSIONS: During walking, carrying a 6 kg backpack increased cadence and walking speed. During running, carrying a backpack caused a decrease in stride length and running speed in the BS group, whereas there was no change in the control group, suggesting that the control and BS groups may respond differently.

Trabeculotomy Using the Kahook Dual Blade for Exfoliation Glaucoma and Primary Open Angle Glaucoma: Comparison of Outcomes According to Incision Range.

PRCIS: Large amount of trabeculotomy with Kahook Dual Blade (KDB) confers better intraocular pressure (IOP) lowering. PURPOSE: We compared the postoperative outcomes of trabeculotomy using the KDB in patients with exfoliation glaucoma (EXG) and primary open angle glaucoma between the 120-degree incision and the 210- to 240-degree incision groups. PATIENTS AND METHODS: We retrospectively analyzed the postoperative outcomes of trabeculotomy performed using the KDB in 101 eyes with EXG and primary open angle glaucoma, who received 120- and 210- to 240-degree incisions at Kumamoto University Hospital between April 25, 2018, and August 11, 2021. Kaplan-Meyer survival curves were used to assess the outcomes. Surgical failure was defined as IOP ≥21 mm Hg (criterion A) and ≥19 mm Hg (criterion B), or an IOP ≤4 mm Hg in either criterion and the need for additional glaucoma surgery. RESULTS: In total, 64 and 37 eyes were included in the 120 and 210- to 240-degree groups, respectively. The 210- to 240-degree group had a higher 1-year success rate compared with the 120-degree group, both when considering all eyes and when considering only those with EXG (P<0.05). CONCLUSIONS: In trabeculotomy with KDB, a 210- to 240-degree incision was more effective than a 120-degree incision in lowering IOP in EXG cases.

Injury-induced cooperation of InhibinßA and JunB is essential for cell proliferation in Xenopus tadpole tail regeneration.

In animal species that have the capability of regenerating tissues and limbs, cell proliferation is enhanced after wound healing and is essential for the reconstruction of injured tissue. Although the ability to induce cell proliferation is a common feature of such species, the molecular mechanisms that regulate the transition from wound healing to regenerative cell proliferation remain unclear. Here, we show that upon injury, InhibinßA and JunB cooperatively function for this transition during Xenopus tadpole tail regeneration. We found that the expression of inhibin subunit beta A (inhba) and junB proto-oncogene (junb) is induced by injury-activated TGF-ß/Smad and MEK/ERK signaling in regenerating tails. Similarly to junb knockout (KO) tadpoles, inhba KO tadpoles show a delay in tail regeneration, and inhba/junb double KO (DKO) tadpoles exhibit severe impairment of tail regeneration compared with either inhba KO or junb KO tadpoles. Importantly, this impairment is associated with a significant reduction of cell proliferation in regenerating tissue. Moreover, JunB regulates tail regeneration via FGF signaling, while InhibinßA likely acts through different mechanisms. These results demonstrate that the cooperation of injury-induced InhibinßA and JunB is critical for regenerative cell proliferation, which is necessary for re-outgrowth of regenerating Xenopus tadpole tails.

Silencing of ocular transthyretin, a gene responsible for hereditary transthyretin amyloidosis, by intravitreal injection of an siRNA conjugate into rabbit eyes.

The first small interfering RNA (siRNA) therapeutic received approval for hereditary transthyretin (ATTRv) amyloidosis, and the patients' lifespan extension by specific inhibition of hepatic synthesis of transthyretin (TTR) is expected. However, ocular amyloidosis in these patients has been a crucial issue. This study aims to evaluate the efficacy and safety of intravitreal TTR siRNA conjugate injection into rabbit eyes. Rabbit (r) TTR siRNA is a screened TTR siRNA conjugate from 53 candidates. The intraocular pressure (IOP) immediately after injection was high despite the 65.9 % decrease of aqueous humor TTR protein levels in the rTTR siRNA group compared with those in the Control siRNA group 2 weeks after the 50 µL siRNA injection. The IOP spike was milder after the 30 µL siRNA injection, and aqueous humor TTR levels decreased by ∼50 % in the rTTR siRNA group, which is consistent with the mRNA levels in the retina. The parameters of dark-adapted, light-adapted, and light-adapted 30 Hz electroretinogram and the thickness of each retinal layer in histological analysis demonstrated no significant differences between the groups. In conclusion, we developed TTR siRNA conjugates for rabbit eyes, and the results indicate that intravitreal TTR siRNA conjugate injection could be a therapeutic option for ocular amyloidosis caused by ATTRv amyloidosis.

Exercise habits and perception of physical exercise among residents of an island in the Western Pacific Region.

[Purpose] The current study aimed to validate the exercise habits and perception of physical exercise among residents of an island in the Western Pacific Region, where the high prevalence of noncommunicable diseases is a serious health issue. [Participants and Methods] Semi-structured interviews were conducted with one doctor, three nurses, and six patients from a noncommunicable disease clinic on one island of the Kingdom of Tonga. The questions focused on the patients' exercise habits and perception of physical exercise. Their comments were structured using the KJ method. [Results] Structuring of the comments revealed that the exercise habits of the island residents had three unique features: variations in thinking and behavior toward exercise, variations in the amount of daily exercise, and the presence of key persons in the community who affect their exercise habits. [Conclusion] Exercise programs suitable for countries in the Western Pacific Region that consider environmental and cultural factors should be developed and disseminated in the future.

Risk factors for Baerveldt glaucoma drainage implantation for uveitic glaucoma.

Uveitic glaucoma (UG) is sometimes intractable, including intricate interaction between intraocular pressure (IOP) elevation associated with inflammation and side effects of steroids. Based on the Tube Versus Trabeculectomy study in refractory glaucoma results in 2012, tube shunt surgeries have been performed for UG, but few reports have focused on UG. We retrospectively examined the surgical efficacy, complications, and risk factors in 62 eyes with UG that underwent Baerveldt glaucoma drainage device (BGD) implantation at Kumamoto University. The IOPs significantly dropped, and the mean number of glaucoma medications was reduced by more than two. Kaplan‒Meier survival curves were presented under 2 conditions: an IOP reduction of 20% and 6 ≤ IOP ≤ 18 mmHg (criterion A) or 6 ≤ IOP ≤ 15 mmHg (criterion B). In criterion A, the median survival times (MST) were 124 days (complete) and 997 days (qualified). In criterion B, the MST was 129 days (complete) and 867 days (qualified). The Cox hazard proportional model found that the hazard ratio was 0.170 for a history of cataract surgery (95% CI 0.0303-0.950) and 8.669 for systemic immunosuppressive therapy (95% CI 1.810-41.51). BGD implantation is effective for treating UG, but the presence of systemic treatment and the lens status should be considered.

Outcomes and risk factors for ab interno trabeculotomy with a Kahook Dual Blade.

PURPOSE: To verify the surgical results and risk factors for ab interno trabeculotomy using a Kahook Dual Blade (KDB-LOT) in patients with various glaucoma types. METHODS: This study was a retrospective case series of 205 eyes that underwent KDB-LOT. For Kaplan-Meier survival analysis, criterion A was defined as a ≤ 20% reduction in intraocular pressure (IOP) from baseline. Criteria B, C, and D were IOPs of ≤ 21, 18, and 15 mmHg, respectively. The Cox proportional hazard (CPH) model investigated prognostic factors. RESULTS: The mean (SD) IOP decreased from 24.7 (7.98) to 17.6 (4.80) mmHg in all cases, from 21.3 (6.88) to 17.8 (3.52) mmHg in primary open-angle glaucoma (POAG), from 25.4 (7.32) to 17.1 (4.65) mmHg in exfoliation glaucoma, from 30.6 (8.88) to 17.8 (8.29) mmHg in uveitic glaucoma, and from 30.8 (7.29) to 17.3 (0.83) mmHg in steroid-induced glaucoma at 1 year after KDB-LOT. The Kaplan-Meier survival analysis showed that patients with POAG had the best prognosis under criteria B and C, and the 1-year survival rate in patients under criterion D was less than 35% for any disease type. CPH analysis revealed that age and KDB-LOT with phacoemulsification were good prognostic factors. Risk factors for surgical failure were previous cataract surgery, selective laser trabeculoplasty, and postoperative peripheral anterior synechiae. CONCLUSION: KDB-LOT was effective in treating patients with several glaucoma types but showed difficulty in pushing IOP below 15 mmHg. Prognostic factors should be considered when making decisions regarding surgical indications.

Smoking and younger age at onset in anti-acetylcholine receptor antibody-positive myasthenia gravis.

Smoking is a known risk factor for the development and progression of several autoimmune diseases. Previous studies have pointed out the association of smoking with the development and worsening of symptoms in myasthenia gravis (MG), but further investigation is necessary to confirm this association. Smoking history was investigated in a cross-sectional study of 139 patients with anti-acetylcholine receptor antibody-positive MG, and the association of smoking history with the age at the onset of MG was analyzed. Patients who had been smoking at the onset of MG were significantly younger compared with those who had never smoked or had quit before the onset of MG. A linear regression analysis adjusting for sex and the presence/absence of thymoma showed a significant association between smoking at onset and younger age at onset (regression coefficient -9.05; 95% confidence interval, -17.6, -0.51; p = 0.039). Among patients with smoking exposure within 10 years prior to or at the onset of MG, women were significantly younger at the onset of MG compared with men. Our results suggest that smoking is an independent risk factor for the earlier development of anti-acetylcholine receptor antibody-positive MG and further support the putative link between smoking and MG.

Health-related quality of life in Japanese patients with multiple sclerosis.

OBJECTIVES: Neurological disabilities, especially physical issues, can adversely affect the daily lives of people with multiple sclerosis (MS) and negatively impact their health-related quality of life (HRQOL). On the other hand, physical and psychiatric symptoms are variable in people with MS, and QOL can be influenced by cultural and educational background. This study aimed to evaluate the association of HRQOL with disabilities, fatigue, and depression in Japanese subjects with MS. METHODS: Evaluation of HRQOL, fatigue, and depression was performed in 184 Japanese individuals with MS, using the Functional Assessment of MS (FAMS), Fatigue Severity Scale (FSS), and Beck Depression Inventory-Second Edition (BDI-II), respectively. RESULTS: Multiple linear regression analysis demonstrated negative correlations of the Expanded Disability Status Scale (EDSS) with scores on the FAMS subscales of mobility, symptoms, thinking and fatigue, total FAMS, and additional concerns. The FSS score had negative correlations with mobility, symptoms, emotional well-being, thinking and fatigue, total FAMS, and additional concerns. There were negative correlations between BDI-II scores and all items of FAMS. CONCLUSIONS: HRQOL had relatively close correlations with disabilities and fatigue, and depression had an especially close relationship with HRQOL.

Developing Topics.

BACKGROUND: E2814 is a human IgG1 antibody that binds to microtubule binding region of tau (MTBR-tau), a critical domain for the seeding and spreading of tau pathology in Alzheimer's Disease (AD). It is being developed for the treatment of AD by stopping tau propagation and slowing the associated cognitive decline. E2814 has been evaluated in healthy and Dominantly Inherited Alzheimer's Disease (DIAD) participants for safety, pharmacokinetics (PK), and cerebrospinal fluid (CSF) target engagement. METHOD: Seventy-two healthy participants were enrolled in single and multiple ascending dose cohorts of Study 001 (NCT04231513) and received randomized, double-blind, placebo-controlled treatment of E2814. Intravenous infusion of single and multiple doses (once every 4 weeks for three times) were administered. In Study 103 (NCT04971733), 7 DIAD participants with confirmed mutations and mild to moderate cognitive impairment were enrolled and received open-label treatment of E2814. Four sequential doses were evaluated as intravenous infusion every 4 weeks. Serum and CSF PK, and CSF target engagement (by analyzing both bound and unbound MTBR-tau299 and MTBR-tau354 [containing the epitopes of E2814]) were measured in both healthy and DIAD participants, as well as safety assessments. CSF MTBR-tau243 recapitulating AD tau pathology was also measured in DIAD participants using methods previously described (Horie et al., J Prev Alz Dis 2022). RESULT: E2814 was safe and well-tolerated over a wide dose range. No infusion-related reactions or other clinically significant safety signals were observed with single or repeated dose administration for up to 15 months. E2814 showed a dose-related increase in serum and CSF exposure with CSF-to-serum ratio of ∼0.2%, comparable between healthy and DIAD participants. CSF target engagement was demonstrated by concentration-related and sustained MTBR-tau299 and MTBR-tau354 binding in healthy and DIAD participants. More importantly, E2814 elicited a rapid and robust reduction on MTBR-tau243, a neurofibrillary tangle-specific biomarker, in DIAD participants. CONCLUSION: E2814 demonstrated promising safety, PK and CSF target engagement profile in DIAD participants, and showed evidence of downstream effects on tangle-specific biomarker MTBR-tau243. Data supports further evaluation in the ongoing Ph2/3 DIAN-TU Tau NexGen Platform Study in DIAD (NCT05269394) and future exploration in sporadic AD.

Stages of brain volume loss and performance in the Brief International Cognitive Assessment for Multiple Sclerosis.

BACKGROUND: Cognitive dysfunction occurs in a substantial proportion of patients with multiple sclerosis (MS), negatively affects their daily activities, and is associated with poor prognosis. Cognitive dysfunction in MS can extend across multiple cognitive domains, depending on the patterns and extent of the brain regions affected. Therefore, a combination of tests, including the Brief International Cognitive Assessment for MS (BICAMS), that assess different aspects of cognition is recommended to capture the full picture of cognitive impairment in each patient. However, the temporal relationships between the progression of the MS brain pathology and the performances in different cognitive tests remain unclear. METHODS: Global and regional brain volume data were obtained based on T1-weighted magnetic resonance imaging from 61 patients with MS, and hierarchical cluster analysis was performed using these brain volume data. Cognitive function was assessed using the three subcomponents of the BICAMS: the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test Second Edition (CVLT2), and Brief Visuospatial Memory Test-Revised (BVMTR). Clinical characteristics, patterns of regional brain volume loss, and cognitive test scores were compared among clusters. RESULTS: Cluster analysis of the global and regional brain volume data classified patients into three clusters (Clusters 1, 2, and 3) in order of decreasing global brain volume. A comparison of the clinical profiles of the patients suggested that those in Clusters 1, 2, and 3 are in the early, intermediate, and advanced stages of MS, respectively. Pair-wise analysis of regional brain volume among the three clusters suggested brain regions where volume loss starts early and continues throughout the disease course, occurs preferentially at the early phase, or evolves relatively slowly. SDMT scores differed significantly among the three clusters, with a decrease from Clusters 1 to 3. BVMTR scores also declined in this order, whereas the CVLT2 was significantly impaired only in Cluster 3. CONCLUSION: Our results suggest that SDMT performance declines in conjunction with brain volume loss throughout the disease course of MS. Performance in the BVMTR also declines in line with the brain volume loss, but impairment in the CVLT2 becomes particularly apparent at the late phase of MS.

Risk factors for intraocular pressure elevation in a six-month period after ab interno trabeculotomy using a Kahook Dual Blade.

BACKGROUND: To examine the risk factors for an early postoperative intraocular pressure (IOP) increase after ab interno trabeculotomy using a Kahook Dual Blade (KDB trabeculotomy). METHODS: A retrospective study was performed in 76 exfoliation glaucoma (EXG) eyes and 56 primary open angle glaucoma (POAG) eyes that underwent KDB trabeculotomy, with or without cataract surgery at Kumamoto University Hospital. Postoperative high IOP was classified as IOP≥20 mmHg (within three months after surgery, whether persistent or temporary), transient IOP≥20 mmHg (IOP≥20 mmHg after surgery, then dropped below 20 mmHg), and the presence of IOP spikes (≥ 10 mmHg from baseline). Risk factors were examined using logistic regression analysis. RESULTS: The preoperative mean IOP (SD) was 24.98 (7.23) mmHg in patients with EXG and 21.28 (6.58) mmHg in patients with POAG. IOP was reduced by 32.1% in patients with EXG and by 17.7% in patients with POAG at 6 months after surgery. Postoperative IOP≥20 mmHg was observed in 56.6% of EXG patients and in 51.8% of POAG patients. IOP spikes occurred in 15.8% of EXG patients and in 14.3% of POAG patients. Logistic regression analysis showed that factors with significant odds ratios (ORs) were age (OR = 0.866, 95% CI = 0.793-0.945), preoperative medication use (OR = 2.02, 95% CI = 1.17-3.49), trabeculotomy in combination with cataract surgery (OR = 0.0674, 95% CI = 0.015-0.303), and IOP at day 1 (OR = 1.41, 95% CI = 1.18-1.68) for postoperative IOP≥20 mmHg, the IOP at day 1 (OR = 1.1, 95% CI = 1.03-1.17) for transient IOP≥20 mmHg, and age (OR = 0.948, 95% CI = 0.901-0.997) and preoperative IOP (OR = 0.83, 95% CI = 0.736-0.936) for IOP spikes. CONCLUSION: Although KDB trabeculotomy is an effective treatment for patients with EXG and POAG, patients who take multiple preoperative medications and have a high IOP on day 1 require careful follow-up to prevent postoperative IOP elevation.

Factors associated with the surgical outcomes of Baerveldt glaucoma implant for open-angle glaucoma, an age-related eye disease.

To identify the factors associated with the surgical outcomes of Baerveldt glaucoma implant (BGI) for open-angle glaucoma (OAG), the medical records of 51 consecutive OAG patients (age, 43-91 years) who underwent BGI were retrospectively reviewed (median follow-up, 21.7 months). Surgical success was defined as the following postoperative intraocular pressures (IOPs, mmHg): (A) 6 ≤ IOP ≤ 21; (B) 6 ≤ IOP ≤ 18; and (C) 6 ≤ IOP ≤ 15 without loss of light perception or additional glaucoma surgery. Univariate analysis showed that age (all criteria), glaucoma type (criterion C), and preoperative IOP (criteria A and B) were the candidate factors (P < 0.20). When the patients were divided into two groups according to median age (72 years), the success probability was higher in the older group for criteria B (P = 0.047) and C (P = 0.02), and the postoperative IOP was lower in the older group 1-year post-surgery (P = 0.002). Furthermore, the multivariate Cox proportional hazards model revealed that older age was independently associated with surgical success for criteria B (relative risk [RR], 0.94; P = 0.02) and C (RR, 0.94; P = 0.01). In conclusion, older age is a factor associated with the surgical success of BGI for OAG.

Correlation of the symbol digit modalities test with the quality of life and depression in Japanese patients with multiple sclerosis.

BACKGROUND: This study aimed to evaluate the association between cognitive impairment and health-related quality of life (HRQOL), fatigue, and depression in Japanese patients with multiple sclerosis (MS). METHODS: The Brief International Cognitive Assessment for MS (BICAMS) was performed in 184 Japanese patients with MS. The Functional Assessment of MS (FAMS), Fatigue Severity Scale (FSS), and Beck Depression Inventory-Second Edition (BDI-II) were used to evaluate HRQOL, fatigue, and depression, respectively. RESULTS: Multiple linear regression analysis demonstrated positive correlations of the Symbol Digit Modalities Test (SDMT) with the scores on the FAMS subscales of mobility, symptoms, emotional well-being, and additional concerns and with the total FAMS score even after controlling for the Expanded Disability Status Scale score, age at examination, and duration of education. The SDMT score in the BICAMS battery had negative correlations with the BDI-II score, as revealed by multiple linear regression analysis. None of the three tests in the BICAMS had any correlation with the FSS score. CONCLUSION: The SDMT has a significant relationship with HRQOL and depression in Japanese patients with MS.

Association of Smoking and Generalized Manifestations of Myasthenia Gravis.

Objective Smoking is a known risk factor for the development and progression of autoimmune diseases. Previous studies in ocular myasthenia gravis (MG) patients showed that smoking is associated with the severity of symptoms and progression to generalized MG. However, whether smoking affects MG symptoms in patients with a broader clinical spectrum of presentations is unknown. Therefore, in this study, the associations of smoking with the clinical characteristics of MG were analyzed in a cohort of patients including those with generalized, seronegative, and thymoma-associated MG. Methods The smoking history was investigated in a cross-sectional study of 187 patients with MG followed in a referral hospital for neurology. The association of smoking with MG-activities of daily living score at survey, the presence of generalized manifestations, and the age of onset was assessed using multiple regression models. Results Neither current nor prior smoking habit was associated with the MG-activities of daily living score at survey. However, smoking exposure after MG onset was significantly associated with the presence of generalized manifestations during the disease course (odds ratio, 3.57; 95% confidence interval, 1.04, 12.3). The smoking history before or at onset of MG was not associated with the age of onset. Conclusion Smoking exposure after the onset is associated with generalized manifestations of MG in our cohort of patients with a broad clinical spectrum of presentations.

Eleven new C19-diterpenoid alkaloids from Delphinium elatum cv. Pacific Giant.

Diterpenoid alkaloids, the main components of plants of the genera Aconitum, Delphinium, and Garrya, are a group of natural products with notable chemical properties and biological activities. Several C19-diterpenoid alkaloid components from Delphinium elatum cv. Pacific Giant, as well as their derivatives, exhibited cytotoxic activity against lung, prostate, cervical, and vincristine-resistant cervical cancer cell lines. In the current phytochemical investigation on the seeds of D. elatum cv. Pacific Giant, eleven new C19-diterpenoid alkaloids, elapaciline (1), meladine (2), melapacitine (3), iminoeladine (4), 19-oxopaciline (5), 19-oxopacinine (6), N-deethyldelpheline (7), N-deethylpacinine (8), N-deethyl-19-oxoeladine (9), N-deethyl-N-formyleladine (10), and N-deethyl-N-formyldelpheline (11), together with 15 known C19-diterpenoid alkaloids were isolated. Their structures were elucidated by extensive spectroscopic methods including NMR (1D and 2D), IR, and MS (HRMS). Three known diterpenoid alkaloids, 6-dehydrodelcorine (12), delelatine (23), and 6-dehydroeldelidine (24), were isolated for the first time from this plant. Six of the new C19-diterpenoid alkaloids (2, 4-7, and 11) and three of the known diterpenoid alkaloids (18, 23, and 24) were evaluated for cytotoxic activity against five human tumor cell lines.

The effects of exosomes derived from trabecular meshwork cells on Schlemm's canal endothelial cells.

Trabecular meshwork (TM) and Schlemm's canal (SC) are the main structures within the conventional outflow pathway, and TM cells and SC endothelial (SCE) cells are essential for controlling intraocular pressure. To examine the interaction between TM cells and SCE cells, we investigated whether exosomes contribute to intercellular communication. Additionally, TM cells in glaucoma acquire mesenchymal characteristics in response to transforming growth factor (TGF)-ß2 and extracellular matrix proteins such as collagen type 1 (Col-1); these changes result in increased resistance of aqueous outflow. In this study, we stimulated TM cells with TGF-ß2 and Col-1 and characterized the exosomal miRNAs (exomiRs) released in response to each stimulus. Isolated exosomes were rich in miRNAs, with downregulated miR-23a-5p and upregulated miR-3942-5p and miR-7515 levels following Col-1 or TGF-ß2 stimulation. Next, a miRNA-mRNA network under TGF-ß2 stimulation was constructed. There were no connections among the 3 miRNAs and predicted genes under Col-1 stimulation. GO and KEGG analyses revealed that the identified miRNAs were associated with various signaling pathways, including the inflammatory response. Interestingly, SCE cells treated with miR-7515 mimic showed increased VEGFA, VEGFR2, PECAM, and Tie2 expression. Ultrastructures typical of exosomes and positive staining for exosomal markers were observed in human TM cells. Our data showed that TM cells may communicate with SCE cells via exomiRs and that miR-7515 may be important for SCE cell reprogramming.

Relationships between Gross Motor Abilities and Sensory Processing in Children Aged 18 to 36 Months.

OBJECTIVE: We investigated the relationship between gross motor abilities and sensory processing in typically developing children. METHOD: Participants included children aged 18 to 36 months (N = 48). All participants were full-term infants. We assessed gross motor abilities based on the Gross Motor Function Measure (GMFM), and sensory processing characteristics based on the Infant/Toddler Sensory Profile (ITSP). The gross motor ability index was calculated using GMFM score which was estimated from the age. Pearson's product moment correlation coefficients were used to examine the relationships between the gross motor ability indexes and ITSP section scores. RESULTS: Our findings showed that gross motor ability may be related to oral sensory processing. The children who were more responsive to oral sensory processing tended to exhibit gross motor abilities below the standard for that age. CONCLUSION: Gross motor abilities were related with sensory processing, especially oral sensory processing, in children aged 18 to 36 months.

Potential roles of the IL-6 family in conjunctival fibrosis.

Elevated intraocular pressure (IOP) is a significant risk factor for vision loss due to glaucoma, which is a major cause of blindness worldwide. Glaucoma filtration surgery (GFS) is an important method to reduce IOP by guidance of aqueous humor into a newly built filtration bleb in the conjunctiva; management of the wound healing mechanism is essential for the success of GFS. Here, we investigated the roles of interleukin (IL)-6 family members during the wound healing process after GFS. At the surgical site, the expression levels of genes encoding IL-6, oncostatin M (OSM), their receptors, and collagen I were elevated at 3 h after GFS, whereas the levels of genes encoding transforming growth factor (TGF)-ß, α-smooth muscle actin (SMA), type IV collagen, and fibronectin were elevated at 3 days after GFS. IL-6 trans-signaling and OSM signaling suppressed TGF-ß-induced expression of α-SMA and collagen IV, as well as activation of the non-canonical TGF-ß pathway, suggesting that IL-6 and OSM may aid in controlling the phase transition from inflammation to proliferation and remodeling. The suppressive effects of OSM were accompanied by STAT3 activation, such that STAT1 function was complementary to STAT3. Taken together, these observations indicated that IL-6 family members constitute early response genes after GFS, which can suppress TGF-ß-induced expression of late response genes at the surgical site after GFS.