Long-Term Safety and Efficacy of Tacrolimus in Myasthenia Gravis.

PURPOSE: Myasthenia gravis (MG) is a lifelong autoimmune disorder that affects neuromuscular transmission. The long-term treatment plan should include immunotherapy. We investigated the long-term safety and efficacy of tacrolimus for the treatment of MG in real-world clinical practice. MATERIALS AND METHODS: We retrospectively reviewed 160 MG patients treated with tacrolimus from 2005 to 2015. Myasthenia Gravis Foundation of America (MGFA) clinical classification, MGFA post-intervention status, myasthenic functional score, and dose of oral prednisolone were investigated. RESULTS: Adverse events occurred in 68 patients (42.5%), most of which were minor and well-managed. Clinical severity scales improved after administration of tacrolimus, compared to the baseline. Compared to 6 months before administration of tacrolimus, prednisolone dose significantly decreased at 12 months after treatment (2.85±0.92 mg/day, p=0.002), 18 months after treatment (3.36±0.99 mg/day, p=0.001), and 24 months after treatment (3.71±0.93 mg/day, p<0.001). CONCLUSION: Tacrolimus may be effective in reducing the severity of MG and may permit a reduction in the steroid dose prescribed to the patients. Adverse events due to tacrolimus treatment were not serious.

Using the Region of Interest from Time-of-Flight Magnetic Resonance Angiography to Differentiate Between Intracranial Arterial Dissection and True Atherosclerotic Stenosis.

BACKGROUND: Noncontrast three-dimensional time-of-flight magnetic resonance angiography (3D TOF MRA) is commonly used to examine intracranial arterial stenosis, although it can be difficult to identify the etiology of the stenosis. Our aim was to determine the effectiveness of 3D TOF MRA in differentiating an intracranial arterial dissection from atherosclerosis. METHODS: During 2015-2017, 356 patients had confirmed intracranial arterial stenosis based on high resolution-magnetic resonance imaging. This study ultimately included 51 patients with severe focal stenosis that was caused by dissection and atherosclerosis. We compared the dissection group with the atherosclerotic narrowing group by measuring the region-of-interest (ROI) values 3 mm proximal and 3 mm distal from sites of severe focal stenosis. RESULTS: A significant difference was observed between the median ROI difference values in the dissection group (n = 18) and the atherosclerosis group (n = 33; 35.6 [20.9-78.4] vs. 165.5 [99.8-328.5]; p < 0.001). A receiver operating characteristic curve was prepared to distinguish between dissection and atherosclerosis using the ROI difference values. The area under the curve was 0.919 (sensitivity 75.8%, specificity 94.4%). The optimal cutoff value for using ROI to distinguish between dissection and atherosclerosis was found to be 99.0 based on the Youden's index. CONCLUSION: The ROI difference value from 3D TOF MRA could help distinguish between dissection and atherosclerosis. If the ROI difference value from 3D TOF MRA is small (< 99.0), detailed testing should be performed to identify dissection.

Quantitative evaluation of hand motor function using a gyrosensor in mild and moderate carpal tunnel syndrome.

INTRODUCTION: The objective of this study was to determine whether patients with carpal tunnel syndrome (CTS) manifest changes in early-stage motor function and to investigate the utility of a gyrosensor for quantitative evaluation of motor function. METHODS: Angular velocity signal was measured during finger tapping in 52 patients with mild-to-moderate CTS and 45 controls. Four finger-tapping performance (FTP) values-root-mean-squared (RMS) velocity, RMS angle, peak power, and total power-were derived from the signal. RESULTS: All FTP values were significantly lower in patients with CTS than in controls (P = 0.001 or P < 0.001). There were no significant differences between the mild and moderate CTS subgroups. DISCUSSION: FTP measurement with a gyrosensor represents a valuable tool for the evaluation of median nerve motor function in patients with CTS. It facilitates the detection of subclinical motor dysfunction in patients with early stage CTS. Muscle Nerve 59:465-469, 2019.

Method development, matrix effect, and risk assessment of 49 multiclass pesticides in kiwifruit using liquid chromatography coupled to tandem mass spectrometry.

In the present study, a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method with a minimal matrix effect (ME) was developed and validated for simultaneous determination of a diverse range of pesticides (49) in kiwifruit. Samples extracted by the quick, easy, cheap, effective, rugged, and safe (QuEChERS) citrate-buffered method were analyzed either without purification or following purification (with primary secondary amine (PSA) or PSA + graphitized carbon black (GCB)). With the addition of a clean-up step, the suppression of the ME decreased, with a higher number of pesticides determined by the application of PSA + GCB. The method exhibited good linearity with coefficients of determination (R2) ≥ 0.9972 and satisfactory recoveries (70-120%) with a relative standard deviations (RSDs) <10%. The limits of quantification (LOQ) were lower than the maximum residue limits (MRLs) set by the Korean Ministry of Food and Drug Safety (MFDS) and the CODEX Alimentarius. The developed method was applied to the real samples and the results indicated that the quantitated levels of all pesticides, except for pyraclostrobin and carbendazim, are lower than the MRLs set by the regulatory authorities. The percentage of the acceptable daily intake was <20%, suggesting that there is no risk associated with the intake of residual pesticides through kiwifruit.

Clinical Significance of Repetitive Compound Muscle Action Potentials in Patients with Myasthenia Gravis: A Predictor for Cholinergic Side Effects of Acetylcholinesterase Inhibitors.

BACKGROUND AND PURPOSE: Acetylcholinesterase inhibitors (AChEIs) are widely used to treat myasthenia gravis (MG). Although AChEIs are usually tolerated well, some MG patients suffer from side effects. Furthermore, a small proportion of MG patients show cholinergic hypersensitivity and cannot tolerate AChEIs. Because repetitive compound muscle action potentials (R-CMAPs) are an electrophysiologic feature of cholinergic neuromuscular hyperactivity, we investigated the clinical characteristics of MG patients with R-CMAPs to identify their clinical usefulness in therapeutic decision-making. METHODS: We retrospectively reviewed the clinical records and electrodiagnostic findings of MG patients who underwent electrodiagnostic studies and diagnostic neostigmine testing (NT). RESULTS: Among 71 MG patients, 9 could not tolerate oral pyridostigmine bromide (PB) and 17 experienced side effects of PB. R-CMAPs developed in 24 patients after NT. The highest daily dose of PB was lower in the patients with R-CMAPs (240 mg/day vs. 480 mg/day, p<0.001). The frequencies of PB intolerance and side effects were higher in the patients with R-CMAPs than in those without R-CMAPs [37.5% vs. 0% (p<0.001) and 45.8% vs. 12.8% (p=0.002), respectively]. The MG Foundation of America postintervention status did not differ significantly between MG patients with and without R-CMAPs, and the response to immunotherapy was also good in both groups. CONCLUSIONS: Side effects of and intolerance to AChEIs are more common in MG patients with R-CMAPs than in those without R-CMAPs. AChEIs should be used carefully in MG patients with R-CMAPs. The presence of R-CMAPs after NT may be a good indicator of the risks of PB side effects and intolerance.

Utility of the Midbrain Tegmentum Diameter in the Differential Diagnosis of Progressive Supranuclear Palsy from Idiopathic Parkinson's Disease.

BACKGROUND AND PURPOSE: Various magnetic resonance (MR) measurements have been proposed to aid in differentiating between progressive supranuclear palsy (PSP) and idiopathic Parkinson's disease (IPD); however, these methods have not been compared directly. The aim of this study was to determine which measurement method exhibits the highest power to differentiate between PSP and IPD. METHODS: Brain MR images from 82 IPD and 29 PSP patients were analyzed retrospectively. T1-weighted 3D volumetric axial images, or sagittal images reconstructed from those axial images were examined. MR measurements included the length from the interpeduncular fossa to the center of the cerebral aqueduct at the mid-mammillary-body level, adjusted according to the anterior commissure-posterior commissure length (MB(Tegm)), the ratio of the midbrain area to the pons area (M/P ratio) as measured by both Oba's method (Oba M/P) and Cosottini's method (Cosottini M/P), and a modified MR parkinsonism index (mMRPI). RESULTS: Receiver operating characteristic (ROC) analysis indicated that the areas under the ROC curves (AUCs) exceeded 0.70, with a high intrarater reliability for all MR measurement methods. ROC analyses of four MR measurements yielded AUCs of 0.69-0.76. At the cutoff value with the highest Youden index, mMRPI had the highest sensitivity, while Oba M/P offered the highest specificity. A comparison of the ROC analyses revealed that MB(Tegm) was superior to mMRPI in differentiating PSP from IPD (p=0.049). There was no difference in discriminating power among Oba M/P, Cosottini M/P, and MB(Tegm). CONCLUSIONS: Simple measurements of MB(Tegm) on axial MR images at the mid-mammillary-body level are comparable to measurements of the M/P ratio with regard to their ability to discriminate PSP from IPD.

Miller Fisher syndrome related to Orientia tsutsugamushi infection.

Miller Fisher syndrome is typically associated with a preceding infection, especially with Campylobacter jejuni. We describe a patient with Miller Fisher syndrome following Orientia tsutsugamushi infection, which to our knowledge has not been previously reported.

Development of NC1 and NC2 domains of type VII collagen ELISA for the diagnosis and analysis of the time course of epidermolysis bullosa acquisita patients.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is an acquired autoimmune mechanobullous disease. EBA patients possess autoantibodies against type VII collagen which is composed of a collagenous domain flanked by non-collagenous NC1 and NC2 domains. It was reported that major epitopes reside within the NC1 domain and minor epitopes reside within NC2 domain. OBJECTIVE: The aim of this study is to develop a sensitive and specific ELISA to facilitate the diagnosis of EBA. METHODS: We developed ELISAs using recombinant NC1 domain produced by mammalian expression system and recombinant NC2 domain produced by mammalian or bacterial expression system to characterize autoantibodies in EBA. Next, we developed an ELISA using a combination of the NC1 (mammalian expression) and NC2 (bacterial expression). We tested the ELISAs with 49 EBA sera, 55 normal control sera, 20 pemphigus vulgaris and 20 bullous pemphigoid sera. RESULTS: When we evaluated the 49 EBA sera using the NC1 and NC2 ELISAs, 38 (77.5%) reacted with NC1 domain only, 7 sera (14.2%) reacted with both NC1 and NC2 domains, and one serum (2%) reacted with NC2 domain only. Therefore, to increase the sensitivity of the assay, we developed an ELISA coated with a mixture of recombinant NC1 and NC2 domains, resulting in 93.8% sensitivity and 98.1% specificity. By analyzing the time course of two EBA patients, ELISA scores fluctuated in parallel with their disease activity. CONCLUSION: We conclude that the NC1+NC2 ELISA can be a practical assay for the diagnosis and follow up of the antibody titers of EBA patients.

Multilevel nonvolatile small-molecule memory cell embedded with Ni nanocrystals surrounded by a NiO tunneling barrier.

Four-level nonvolatile small-molecule 4F(2) memory cells were developed with a sandwiched device structure consisting of an upper Al electrode, upper small-molecule layer (Alq(3), aluminum tris(8-hydroxyquinoline)), Ni nanocrystals surrounded by NiO tunneling barrier, lower small-molecule layer, and bottom Al electrode. In particular, an in situ O(2)-plasma oxidation process following Ni evaporation was developed to produce uniformly stable 10 nm Ni nanocrystals surrounded by a NiO tunneling barrier embedded in the small-molecule layer. They presented a memory margin (I(on)/I(off) ratio) of approximately 1 x 10(3), a retention time of more than 10(5) s, an endurance of more than 5 x 10(2) erase-and-program cycles, and multilevel cell (MLC) operation, being a terabit nonvolatile memory-cell. A vertically double-stacked 4F(2) multilevel nonvolatile memory cell was also developed, showing a memory margin of approximately 1 x 10(3) in both the top and bottom memory cells and eight-level cell operation.

Novel function of C5 protein as a metabolic stabilizer of M1 RNA.

Escherichia coli RNase P is a ribonucleoprotein composed of a large RNA subunit (M1 RNA) and a small protein subunit (C5 protein). We examined if C5 protein plays a role in maintaining metabolic stability of M1 RNA. The sequestration of C5 protein available for M1 RNA binding reduced M1 RNA stability in vivo, and its reduced stability was recovered via overexpression of C5 protein. In addition, M1 RNA was rapidly degraded in a temperature-sensitive C5 protein mutant strain at non-permissive temperatures. Collectively, our results demonstrate that the C5 protein metabolically stabilizes M1 RNA in the cell.

Dual function of RNase E for control of M1 RNA biosynthesis in Escherichia coli.

M1 RNA, the gene product of rnpB, is the catalytic subunit of RNase P in Escherichia coli. M1 RNA is transcribed from a proximal promoter as pM1 RNA, a precursor M1 RNA, and then is processed at its 3' end by RNase E. In addition to pM1 RNA, large rnpB-containing transcripts are produced from unknown upstream promoters. However, it is not known yet how these large transcripts contribute to M1 RNA biosynthesis. To examine their biological relevance to M1 RNA biosynthesis, we constructed a model upstream transcript, upRNA, and analyzed its cellular metabolism. We found that upRNA was primarily degraded rather than processed to M1 RNA in the cell and that this degradation occurred in RNase E-dependent manner. The in vitro cleavage assay with the N-terminal catalytic fraction of RNase E showed that the M1 RNA structural sequence in upRNA was much more vulnerable to the enzyme than the sequence in pM1 RNA. Considering that RNase E is a processing enzyme involved in 3' end formation of M1 RNA, our results imply that this enzyme plays a dual role in processing and degradation to achieve tight control of M1 RNA biosynthesis.