Search

Objective To determine whether autonomic dysfunction in neurosarcoidosis is associated with anti-ganglionic acetylcholine receptor (gAChR) antibodies, which are detected in autoimmune autonomic ganglionopathy. Methods We retrospectively extracted cases of sarcoidosis from 1787 serum samples of 1,381 patients between 2012 and 2018. Anti-gAChR antibodies against the α3 and β4 subunit were measured by luciferase immunoprecipitation to confirm the clinical features of each case. We summarized literature reviews of neurosarcoidosis with severe dysautonomia to identify relevant clinical features and outcomes. Results We extracted three new cases of neurosarcoidosis with severe dysautonomia, among which two were positive for anti-gAChR antibodies: Case 1 was positive for antibodies against the β4 subunit, and Case 2 was positive for antibodies against both the α3 and β4 subunits. We reviewed the cases of 15 patients with neurosarcoidosis and severe dysautonomia, including the three cases presented herein. Orthostatic hypotension and orthostatic intolerance were the most common symptoms. Among the various types of neuropathy, small fiber neuropathy (SFN) was the most prevalent, with seven of nine cases exhibiting definite SFN. Six of eight cases had impaired postganglionic fibers, of which the present three cases revealed abnormality of 123I-MIBG myocardial scintigraphy. Of the 11 cases, 10 were responsive to immunotherapy, except one seropositive case (Case 2). Conclusions The presence of gAChR antibodies may constitute one of the mechanisms by which dysautonomia arises in neurosarcoidosis.

Objective Patients with acquired autonomic dysfunction may have antibodies specific to the ganglionic nicotinic acetylcholine receptor (gAChR). However, the clinical features of children and adolescents with acquired autonomic dysfunction (AAD) remain unclear. This study aimed to determine the clinical features of pediatric patients with acquired autonomic dysfunction. Methods This study retrospectively examined a series of patients of AAD with serum gAChR antibodies who were referred to our laboratory for antibody testing between January 2012 and April 2019. The study included 200 patients (

Plasmapheresis is a well-recognized treatment for autoimmune neurological diseases in Japan. However, the practice varies depending on the facility, and the actual treatment conditions are unclear.To clarify real-world conditions, a prospective observational study was conducted on patients with neurological diseases who were scheduled to receive plasmapheresis. A dataset was analyzed that included 887 treatments from 210 patients with myasthenia gravis (MG), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and other diseases for 82, 30, 24, and 74 patients, respectively.The types of plasmapheresis performed included immunoadsorption plasmapheresis, plasma exchange, and double filtration plasmapheresis with 620, 213, and 54 treatments, respectively. Approximately, 60% of the treatments were performed using peripheral blood access alone. Non-serious adverse events were observed in 10 patients.A statistically significant improvement was observed after plasmapheresis in patients with MG, MS, and NMOSD. These were evaluated using the modified Rankin Scale.

Introduction The majority of patients with myasthenia gravis (MG) initially present with ocular symptoms, but it is difficult to predict which cases will remain as ocular MG (OMG) or will progress to generalized MG. Herein we evaluated the serologic profile of Japanese OMG and its relationship with clinical features. Methods Seventy‐three patients with OMG from five Japanese myasthenia gravis (MG) centers were enrolled. Live cell‐based assays (CBAs) were used to determine the presence of autoantibodies (Abs) to clustered adult (2α, β, δ, ε) and fetal (2α, β, δ, γ) acetylcholine receptor (AChR) isoforms, muscle‐specific receptor tyrosine kinase (MuSK), and lipoprotein receptor–related protein‐4 (LRP4). Results Thirty‐four of 73 (46.5%) serum samples were positive for Abs against both the adult‐type and fetal‐type AChR, as expected, but 7 (9.6%) and 2 (2.7%) were positive only for fetal or adult AChR‐Abs, respectively. Four (5.4%) samples were positive for MuSK‐Abs, but two of these also contained antibodies to fetal AChR or LRP4. Twenty‐six (35.6%) samples were seronegative. Discussion Abs against fetal‐specific AChR, MuSK, and LRP4 are found in some patients with OMG. Future studies attempting to predict conversion from ocular symptoms to generalized MG may benefit from measurement of these antibodies.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.

Immunosuppressive agents (cytotoxic agents) may be effective in cases of central nervous system autoimmune/inflammatory diseases that do not respond to steroids, plasmapheresis, or intravenous immunoglobulin therapy. Cytotoxic drugs can cause serious side effects. Therefore, it is important to obtain adequate informed consent after a timely decision based on the indication has been made. It is important to be prepared in advance for opportunistic infections and adverse events and to closely monitor the subsequent course.

BACKGROUND AND PURPOSE Neuromyelitis optica spectrum disorder (NMOSD) often presents in the elderly with an insidious onset of symptoms and aggressive progression. There have been anecdotal cases of very late onset (VLO)-NMOSD, but case series reports are rare. The aim of this retrospective study was to clarify the clinical features of VLO-NMOSD. METHODS According to the age at onset, we classified patients with NMOSD into three subgroups: ≤49 years, early onset NMOSD (EO-NMOSD); 50-69 years, late onset NMOSD (LO-NMOSD); and ≥70 years, VLO-NMOSD. We evaluated the clinical characteristics, magnetic resonance imaging (MRI) findings, laboratory data, and immunotherapies of the groups. RESULTS Overall, 12 men and 64 women with a median (interquartile range) age at onset and duration of disease of 42.0 (29.0-55.8) years and 70.0 (16.3-143.0) months, respectively, were included. Eight (11%) patients had VLO-NMOSD, 22 (29%) had LO-NMOSD, and 46 (61%) had EO-NMOSD. Patients with EO-NMOSD had a significantly longer interval between episodes as well as time between the first symptom and diagnosis of NMOSD than did those with VLO-NMOSD and LO-NMOSD (p = 0.046). Optic neuritis and nerve lesions on MRI were significantly less frequent in patients with VLO-NMOSD than in those with LO-NMOSD and EO-NMOSD (p = 0.002 and p = 0.028, respectively). In contrast, patients with VLO-NMOSD had higher nadir Expanded Disability Status Scale and Nurick scale scores and a significantly longer spinal lesion length than did those with LO-NMOSD and EO-NMOSD (p = 0.029, p = 0.049, and p = 0.032, respectively). CONCLUSIONS Patients with VLO-NMOSD tend to develop severe myelitis with long cord lesions but not optic neuritis.

There has been a growing demand of laser welding for copper materials to manufacture industrial products with high electrical and thermal conductivities. The high thermal conductivity characteristic generates rapid thermal diffusion at a welding spot and hence reduces the power efficiency of laser welding. To overcome this issue, we propose to combine a blue laser beam performing a high absorptivity for copper materials, with a 1070-nm high power laser beam, launched from a single mode fiber laser. The blue laser beam can be focused at the welding spot with a sufficiently narrow beam waist, and the absorption of the blue light for copper materials is much higher than that of infrared light. Therefore, the focused blue laser beam causes rapid and highly efficient heat generation at the welding spot, and this localized heat is expected to improve the quality of laser welding. To generate the high-power blue laser beam efficiently, we fabricated a high power blue LD-integrated SLP which achieves an optical output power of 11.7 W at 10.5 A. We also fabricated a blue-DDL module using multiple SLPs and a stepped structure package adopted with a water-cooling system. The blue- DDL module can output a high fiber-coupled optical power exceeding 150 W. Next, we built a blue-NIR hybrid laser equipment which exhibits the excellent quality of laser welding by accurately controlled optical output power and beam spot diameters of both blue and NIR laser beams. In this paper, we describe the design and performance of blue LDintegrated SLP and blue-DDL module. We also report how the blue-NIR hybrid laser equipment contributes to improve the quality of the laser welding.

The glial cells in the central nervous system express diverse inward rectifying potassium channels (Kir). They express multiple Kir channel subtypes that are likely to have distinct functional roles related to their differences in conductance, and sensitivity to intracellular and extracellular factors. Dysfunction in a major astrocyte potassium channel, Kir4.1, appears as an early pathological event underlying neuronal phenotypes in several neurological diseases. The autoimmune effects on the potassium channel have not yet been fully described in the literature. However, several research groups have reported that the potassium channels are an immune target in patients with various neurological disorders. In 2012, Srivastava et al. reported about Kir4.1, a new immune target for autoantibodies in patients with multiple sclerosis (MS). Follow-up studies have been conducted by several research groups, but no clear conclusion has been reached. Most follow-up studies, including ours, have reported that the prevalence of Kir4.1-seropositive patients with MS was lower than that in the initial study. Therefore, we extensively review studies on the method of antibody testing, seroprevalence of MS, and other neurological diseases in patients with MS. Finally, based on the role of Kir4.1 in MS, we consider whether it could be an immune target in this disease.

In ultra-dense RAN consisting of a large number of distributed antennas, the coverage and the capacity can be improved by forming a number of user clusters (also called virtual small cells) with each cluster consisting of neighbor users and by executing cluster-wise small-scale MIMO in parallel using the same radio resource. However, a straightforward clustering produces a severe inter-cluster interference (ICI) and the capacity improvement is much smaller than expected. In this paper, we propose a joint multilayered user clustering and scheduling. This approach is based on user clustering using the user location information, user-cluster layering based on the interference-offset-distance (IOD), antenna assignment on each layer, simple layer-by-layer round-robin-type scheduling and cluster-wise MIMO. We evaluate by computer simulation the user capacity, the sum capacity, and the fairness to show the effectiveness of the proposed joint multilayered user clustering and scheduling.

Ultra-densification of radio access network (RAN) is necessary to handle ever-increasing mobile data traffic even after starting of 5G services. Dense reuse of the same radio resource produces severe interference. Furthermore, when extremely high frequency band like mmWave band is utilized, the radio link may be frequently blocked by obstacles placed between transmitter and receiver according to user movement. To realize highly reliable communications in such a severe radio link environment, an enhanced interference coordination (eIC) and radio resource management (RRM) needs to be introduced. In this paper, we will present the concept of an eIC and RRM for 5G advanced ultra-dense RAN using distributed MIMO, which integrates a classification of user-equipments (UEs) into inner-cell and cell-edge groups, UE clustering, cluster-antenna association, distributed MIMO cooperative transmission & reception (CTR), and scheduling. Then, we will present some preliminary results obtained by numerical computation.

Background: Patients with systemic sclerosis (SSc) complicated by gastrointestinal dysmotility are difficult to treat and have high mortality. To clarify the pathogenesis of gastrointestinal manifestations, we aimed to demonstrate the association among the clinical features of SSc, the serological markers, the autoantibodies against nicotinic acetylcholine receptor at autonomic ganglia (gAChR). Methods: Fifty patients were enrolled and divided into two groups according to the presence or absence of gastrointestinal manifestations, and the characteristics were analyzed between these two groups. We measured biomarkers and the autoantibodies against two gAChRα3 and β4 subunits to test sera samples. Furthermore, patients were classified based on the presence or absence of anti-gAChR autoantibodies, and their clinical features were compared. Results: In patients with SSc and gastrointestinal manifestations, digital ulcers were more frequent (p = 0.050) and VEGF expression was significantly higher (p = 0.038). Seven subjects with SSc were seropositive for α3 subunit, whereas one patient was seropositive for β4 subunit. The mean level of anti-gAChRα3 autoantibodies in SSc patients with gastrointestinal manifestations was significantly higher than that in SSc patients without gastrointestinal manifestations (p = 0.001). The group of patients with SSc and gAChR autoantibodies had significantly higher endostatin levels (p = 0.046). Conclusions: This study is the first to demonstrate that clinical characteristics of SSc patients with seropositivity for gAChR autoantibodies. Patients with SSc have circulating autoantibodies against gAChR, which may contribute to gastrointestinal manifestations associated with this disease, suggesting that gAChR-mediated autonomic neurotransmission may provide a pathomechanism for gastrointestinal dysmotility in SSc., Arthritis Research and Therapy, 22(1), art.no.32; 2020

Autonomic neuropathy has been reported in autoimmune rheumatic diseases (ARD) including Sjögren’s syndrome, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, the pathophysiological mechanism underlying autonomic dysfunction remains unknown to researchers. On the other hand, autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder, which causes dysautonomia that is mediated by autoantibodies against ganglionic acetylcholine receptors (gAChRs). The purpose of this review was to describe the characteristics of autonomic disturbance through previous case reports and the functional tests used in these studies and address the importance of anti-gAChR antibodies. We have established luciferase immunoprecipitation systems to detect antibodies against gAChR in the past and determined the prevalence of gAChR antibodies in various autoimmune diseases including AAG and rheumatic diseases. Autonomic dysfunction, which affects lower parasympathetic and higher sympathetic activity, is usually observed in ARD. The anti-gAChR antibodies may play a crucial role in autonomic dysfunction observed in ARD. Further studies are necessary to determine whether anti-gAChR antibody levels are correlated with the severity of autonomic dysfunction in ARD.

The β-D-Mannuronic acid (M2000) as a novel immunosuppressive drug, patented (PCT/EP2017/067920), has shown positive effects in experimental model of multiple sclerosis (MS). In this study, our aim was to assess efficacy and safety outcomes in MS treated patients with mannuronic acid compared to the conventional drug. In a 6-month, randomized controlled, phase II trial, we enrolled patients who had secondary progressive multiple sclerosis (SPMS), were 21–54 years of age, with a score of 1–7 on the Expanded Disability Status Scale (EDSS), and who had at least one relapse in the previous 6 months. Patients were administered orally 1000 mg/day (two 500 mg/capsule daily) of M2000. Endpoints included changes in brain magnetic resonance imaging (MRI) measures and the EDSS score, as compared to the conventional drug (interferon beta-1a, interferon beta-1b). A total of 25 (92.5%) of the M2000 treated patients and 25 conventionally treated patients completed the study. M2000 had better performance compared to the conventional drug regarding to MRI-related measurements, however, the differences between groups were not statistically significant. M2000 decreased the disability progression over the 6-month period. The EDSS score was decreased in the M2000 treated group in the sixth month versus the conventional drug (p As compared with the conventional drug, mannuronic acid (M2000) improved the rate of disability progression. This clinical trial demonstrated the efficacy and safety of mannuronic acid in patients with SPMS. (Registered Clinical Trials number, IRCT2016111313739N6).

An 82-year-old woman developed neck weakness and dysarthria with antibodies against acetylcholine receptor (AChR) and low-density lipoprotein receptor-related protein 4 (LRP4). Myasthenia gravis (MG) was diagnosed by edrophonium and repetitive nerve stimulation tests. Her symptoms resolved completely by immunotherapy. One year later, she presented with muscle weakness and bulbar palsy accompanied by atrophy and fasciculation. Her tendon reflexes were brisk, and Babinski’s sign was positive. She was diagnosed with probable amyotrophic lateral sclerosis (ALS). Immunotherapy did not improve her symptoms, and she ultimately died of respiratory failure. MG and ALS may share a pathophysiology, including anti-LRP4 antibodies at the neuromuscular junction.

Background To explore the effects of β- d -mannuronic acid (M2000) on levels of Th17, regulatory T (Treg) cells and their related cytokines in patients with ankylosing spondylitis (AS). Methods 30 AS patients and 15 age and sex-matched healthy individuals were enrolled in this study. The frequencies of Th17 and Treg cells and serum levels of related cytokines were measured by flow cytometry analysis and ELISA respectively, before (baseline) and 3 months after M2000 therapy. Results Significantly higher baseline Th17 cells and serum IL-17, TNF-α and IL-6 were observed in AS patients than in normal controls, whereas baseline levels of Treg cells and serum IL-10 were not significantly different between AS patients and healthy controls. After M2000 therapy, frequencies of Th17 and serum levels of IL-17 and IL-6 significantly decreased in AS patients. The frequencies of Treg cells and serum level of IL-10 were not significantly changed, in comparison to before therapy. Moreover, the correlation analysis showed that frequencies of Th17 and levels of IL-17, TNF-α and IL-6 were positively correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scores, whereas Treg cells were revealed to be negatively correlated with BASDAI and BASFI scores. Conclusions It can be concluded that the oral administration of M2000 as a novel NSAID with the immunosuppressive property that down-regulates Th17 and Th17-related cytokines and facilitates the correction of the Th17/Treg imbalance can be effective in the process of AS treatment.

The aim of this study was to evaluate the association between postural orthostatic tachycardia syndrome (POTS) and circulating antiganglionic acetylcholine receptor (gAChR) antibodies. We reviewed clinical assessments of Japanese patients with POTS, and determined the presence of gAChR antibodies in serum samples from those patients. Luciferase immunoprecipitation systems detected anti‐gAChR α3 and β4 antibodies in the sera from POTS (29%). Antecedent infections were frequently reported in patients in POTS patients. Moreover, autoimmune markers and comorbid autoimmune diseases were also frequent in seropositive POTS patients. Anti‐gAChR antibodies were detectable in significant number of patients with POTS, and POTS entailed the element of autoimmune basis.

Objective To evaluate the efficacy, safety and tolerability of β- d -mannuronic acid (M2000) in the treatment of ankylosing spondylitis (AS). Methods The study was a 12-week randomized, double-blind, placebo-controlled, phase I/II clinical trial with 3 treatment arms: placebo, β- d -mannuronic acid and naproxen. Patients who had AS according to the modified New York criteria, with active disease at baseline were eligible for study. Primary outcome measure was the Assessment of SpondyloArthritis international Society (ASAS) 20 response rate at week 12. Results Of the 85 randomized patients, 27 were allocated to receive placebo, 28 naproxen, and 30 β- d -mannuronic acid. There were no statistically significant differences between treatment groups at baseline. Of the patients receiving β- d -mannuronic acid, 57.7% achieved an ASAS20 response at week 12, compared with 59% of the patients in the naproxen group (P > 0.05) and 19% of the patients in the placebo group (P = 0.007). In comparison with patients receiving placebo over the 12-week treatment period, those receiving β- d -mannuronic acid and naproxen demonstrated statistically significantly greater improvement in all secondary endpoints. Interestingly, β- d -mannuronic acid reduced some parameters associated with inflammation more effectively than naproxen and placebo. The incidence of gastrointestinal and other adverse events were higher on naproxen than on β- d -mannuronic acid and placebo. Conclusion The present study demonstrated similar efficacy, but with a more favorable safety profile for β- d -mannuronic acid than naproxen and, therefore, suggest that β- d -mannuronic acid is suitable for the management of AS. Trial registration Iranian registry of clinical trials; www.irct.ir ; IRCT2013062213739N1.

Background : Marburg type multiple sclerosis (MS) is diagnosed with its “acute and fulminant” clinical course. Case reports of “Marburg MS” include variety of patients with radiological findings and heterogeneous clinical courses. Case description : We present a case diagnosed with Marburg MS with frequent relapses of tumefactive lesions successfully treated with mitoxantrone. The patient was followed up for 8 years, and is almost independent in daily life. Conclusions : Mitoxantrone is one of the treatment options for Marburg MS. Here we review the previous reports of Marburg MS and propose a treatment strategy.

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.

Objective Patients with perihilar malignancy often develop recurrence of infectious cholangitis, which makes further transpapillary intervention extremely difficult. As endoscopic ultrasound (EUS)-guided biliary drainage (EUS-BD) of an intrahepatic bile duct is a possible option for additional intervention, the aim of this study was to estimate the feasibility of such intervention. Methods and Patients Patients who had undergone EUS-BD after further transpapillary intervention was deemed impossible or ineffective were investigated in this study. Those who had not received previous interventions via the papilla were excluded. Procedure-related adverse events, clinical efficacy, and time to recurrence of jaundice or infectious cholangitis transthyretin (TTR) were evaluated. Results Seven patients were eligible for the study between 2007 and 2016 (7 men; mean age, 77 years; 4 with perihilar cholangiocarcinoma and 3 with intrahepatic cholangiocarcinoma). No procedure-related adverse events were observed. EUS-BD was clinically effective and enabled hospital discharge in 4 patients (57%). The TTR in these 4 clinically effective patients was 43, 105, 118, and 147 days after the procedure (median, 112 days). Conclusion EUS-BD was found to be safe and often effective in patients in whom additional transpapillary intervention had become difficult, although its efficacy was limited to a short period.

Ankylosing spondylitis (AS) is a debilitating chronic inflammatory disease with genetic predisposition, which is characterized by the involvement of spine and sacroiliac joints. Due to the relatively unsuccessful treatments, we designed β-D-mannuronic (M2000) with the beneficial effects in various experimental models as a novel non-steroidal anti-inflammatory drug (NSAID). The aims of our present study were: first, to compare the therapeutic effects of M2000, as a novel designed NSAID, with naproxen and placebo in Iranian patients with AS during 12 weeks; second, to evaluate the effect of M2000 on gene expression of cyclooxygenase enzyme (COX-1/COX-2), a key enzyme in the initiation of inflammatory pathways in AS patients; and third, to assess the activity of COX-1 and COX-2 enzymes in the presence/absence of M2000 at the different doses in the murine macrophage, J774 cell line. This was a sub-study of phase II, randomized, placebo-controlled trial with three treatment arms: M2000, naproxen, and placebo. The outcome measures were the mean changes from baseline to week 12. The gene expression was assessed by real-time PCR. The COX-1 and COX-2 activities were evaluated by ELISA in J774 cell line induced by LPS and arachidonic acid (AA). Our findings demonstrated that M2000 had beneficial therapeutic effects on pain, stiffness, and inflammation, whereas no adverse effects were observed following the use of M2000 after 12 weeks. The analysis of gene expression showed that M2000 could effectively reduce the expression levels of COX-1 and COX-2 in comparison with untreated patients. In addition, the enzymatic activities in the presence of M2000 were significantly less than LPS- and AA-treated groups. Our results indicate that M2000, as a novel designed NSAID with immunosuppressive properties, can be considered as one of the therapeutic options for the treatment of inflammatory diseases without adverse events. Clinical trial identifier IRCT2013062213739N1/ http://www.IRCT.ir .

The discovery of hematologic improvement and bone marrow modification by the drug β-D mannuronic acid (M2000) during treatment of rheumatoid arthritis in phase 1/2/3 clinical trials prompted us to design a new trial to target hematologic deficits in myelodysplastic syndromes (MDS). In this open-label, randomized phase 2 clinical trial, the potential effect and tolerability of drug M2000 was assessed in patients with low- and intermediate-1-risk MDS. The primary efficacy end point was hematologic improvement after 12 weeks of β-D-mannuronic acid therapy. Among 34 enrolled patients, half received their conventional therapy plus β-D-mannuronic acid, and the other half received only conventional drugs. In the conventional + β-D mannuronic acid treatment group, hematologic improvement and development of transfusion independence and/or reduction in transfusion requirements were seen in 12 patients (92.3%) and 1 patient (7.7%), respectively. Moreover, 5 patients (38.5%), 2 patients (15.4%), and 1 patient (7.7%) in the β-D-mannuronic acid-treated group showed hematologic improvement of the major parameters of erythroid, neutrophil, and platelet responses, respectively, based on the International Working Group criteria), whereas in the conventional treatment group as control, no hematologic improvements including erythroid, neutrophil, and platelet response was seen. In this trial, the addition of β-D mannuronic acid to conventional treatment showed promising results in MDS patients with low and intermediate-1 risk with effects on hematologic improvements without significant adverse effect.

The clinical importance of autoantibodies against the ganglionic acetylcholine receptor (gAChR) remains to be fully elucidated. We aimed to identify the clinical characteristics of autoimmune autonomic ganglionopathy (AAG) in patients with gAChR autoantibodies. For this cohort investigation, serum samples were obtained from patients with AAG between 2012 and 2018 in Japan. We measured the levels of autoantibodies against gAChRα3 and gAChRβ4 and evaluated clinical features, as well as assessing the laboratory investigation results among the included patients. A total of 179 patients tested positive for antibodies, including 116 gAChRα3-positive, 13 gAChRβ4-positive, and 50 double antibody-positive patients. Seropositive AAG patients exhibited widespread autonomic dysfunction. Extra-autonomic manifestations including sensory disturbance, central nervous system involvement, endocrine disorders, autoimmune diseases, and tumours were present in 118 patients (83%). We observed significant differences in the frequencies of several autonomic and extra-autonomic symptoms among the three groups. Our 123I-metaiodobenzylguanidine myocardial scintigraphy analysis of the entire cohort revealed that the heart-to-mediastinum ratio had decreased by 80%. The present study is the first to demonstrate that patients with AAG who are seropositive for anti-gAChRβ4 autoantibodies exhibit unique autonomic and extra-autonomic signs. Decreased cardiac uptake occurred in most cases, indicating that 123I- metaiodobenzylguanidine myocardial scintigraphy may be useful for monitoring AAG. Therefore, our findings indicate that gAChRα3 and gAChRβ4 autoantibodies cause functional changes in postganglionic fibres in the autonomic nervous system and extra-autonomic manifestations in seropositive patients with AAG.

To determine the usefulness of MRI measurements in patients with pure akinesia with gait freezing (PAGF), Richardson’s syndrome, and Parkinson’s disease for diagnosis. We obtained MRI measurements for patients with PAGF, Richardson’s syndrome, or Parkinson’s disease: 9 patients with PAGF, 26 with Richardson’s syndrome, and 93 with Parkinson’s disease. We measured the area of the pons and midbrain on midsagittal MRIs and the midbrain width on axial MRIs. We also calculated the mean values of the superior cerebellar peduncle, middle cerebellar peduncle, and cerebral crus width; the pons area-to-midbrain area ratio; the middle cerebellar peduncle width-to-superior cerebellar peduncle width ratio; and the magnetic resonance (MR) Parkinsonism index. The Richardson’s syndrome group had the highest pons area-to-midbrain area ratio and MR Parkinsonism index; the Parkinson’s disease group had the lowest values. The Parkinson’s disease group also had the highest midbrain width and cerebral crus width, with the lowest values being seen in the Richardson’s syndrome group. The PAGF group had the intermediate values of the pons area-to-midbrain area ratio and MR Parkinsonism index between the Richardson’s syndrome group and the Parkinson’s disease group, whereas significant differences were found only in the pons area-to-midbrain area ratio. Results from receiver operating characteristic curve analyses showed that the pons area-to-midbrain area ratio has a higher sensitivity, specificity, and accuracy than the MR Parkinsonism index. The pons area-to-midbrain area ratio is more useful to distinguish PAGF from Richardson’s syndrome and Parkinson’s disease than the MR Parkinsonism index.