Benefits of Robot-Assisted Upper-Limb Rehabilitation from the Subacute Stage after a Stroke of Varying Severity: A Multicenter Randomized Controlled Trial.

BACKGROUND: The aim of this study was to compare the clinical effectiveness of robot-assisted therapy with that of conventional occupational therapy according to the onset and severity of stroke. METHODS: In this multicenter randomized controlled trial, stroke patients were randomized (1:1) to receive robot-assisted therapy or conventional occupational therapy. The robot-assisted training group received 30 min of robot-assisted therapy twice and 30 min of conventional occupational therapy daily, while the conventional therapy group received 90 min of occupational therapy. Therapy was conducted 5 days/week for 4 weeks. The primary outcome was the Wolf Motor Function Test (WMFT) score after 4 and 8 weeks of therapy. RESULTS: Overall, 113 and 115 patients received robot-assisted and conventional therapy, respectively. The WMFT score after robot-assisted therapy was not significantly better than that after conventional therapy, but there were significant improvements in the Motricity Index (trunk) and the Fugl-Meyer Assessment. After robot-assisted therapy, wrist strength significantly improved in the subacute or moderate-severity group of stroke patients. CONCLUSIONS: Robot-assisted therapy improved the upper-limb functions and activities of daily living (ADL) performance as much as conventional occupational therapy. In particular, it showed signs of more therapeutic effectiveness in the subacute stage or moderate-severity group.

Electric field simulation and appropriate electrode positioning for optimized transcranial direct current stimulation of stroke patients: an in Silico model.

Transcranial Direct Current Stimulation (tDCS) has benefits for motor rehabilitation in stroke patients, but its clinical application is limited due to inter-individual heterogeneous effects. Recently, optimized tDCS that considers individual brain structure has been proposed, but the utility thereof has not been studied in detail. We explored whether optimized tDCS provides unique electrode positions for each patient and creates a higher target electric field than the conventional approach. A comparative within-subject simulation study was conducted using data collected for a randomized controlled study evaluating the effect of optimized tDCS on upper extremity function in stroke patients. Using Neurophet tES LAB 3.0 software, individual brain models were created based on magnetic resonance images and tDCS simulations were performed for each of the conventional and optimized configurations. A comparison of electrode positions between conventional tDCS and optimized tDCS was quantified by calculation of Euclidean distances. A total of 21 stroke patients were studied. Optimized tDCS produced a higher electric field in the hand motor region than conventional tDCS, with an average improvement of 20% and a maximum of 52%. The electrode montage for optimized tDCS was unique to each patient and exhibited various configurations that differed from electrode placement of conventional tDCS. Optimized tDCS afforded a higher electric field in the target of a stroke patient compared to conventional tDCS, which was made possible by appropriately positioning the electrodes. Our findings may encourage further trials on optimized tDCS for motor rehabilitation after stroke.

Clinical Practice Guideline for Stroke Rehabilitation in Korea-Part 1: Rehabilitation for Motor Function (2022).

This clinical practice guideline (CPG) is the fourth edition of the Korean guideline for stroke rehabilitation, which was last updated in 2016. The development approach has been changed from a consensus-based approach to an evidence-based approach using the Grading of Recommendations Assessment Development and Evaluation (GRADE) method. This change ensures that the guidelines are based on the latest and strongest evidence available. The aim is to provide the most accurate and effective guidance to stroke rehabilitation teams, and to improve the outcomes for stroke patients in Korea. Fifty-five specialists in stroke rehabilitation and one CPG development methodology expert participated in this development. The scope of the previous clinical guidelines was very extensive, making it difficult to revise at once. Therefore, it was decided that the scope of this revised CPG would be limited to Part 1: Rehabilitation for Motor Function. The key questions were selected by considering the preferences of the target population and referring to foreign guidelines for stroke rehabilitation, and the recommendations were completed through systematic literature review and the GRADE method. The draft recommendations, which were agreed upon through an official consensus process, were refined after evaluation by a public hearing and external expert evaluation.

Safety and therapeutic effects of personalized transcranial direct current stimulation based on electrical field simulation for prolonged disorders of consciousness: study protocol for a multi-center, double-blind, randomized controlled trial.

Background: Disorders of consciousness (DOC) resulting from acquired brain injury (ABI) increase the mortality rate of patients, complicate rehabilitation, and increase the physical and economic burden that DOC imposes on patients and their families. Thus, treatment to promote early awakening from DOC is vital. Transcranial direct current stimulation (tDCS) has shown great potential for promoting neuro-electrochemical activity. However, previous tDCS studies did not consider structural damage or head and brain lesions, so the applicability of the results to all DOC patients was limited. In this study, to establish a patient-specific tDCS treatment plan considering the brain lesions of and damage sustained by DOC patients, we considered the electric field calculated by a the "finite electric" three-dimensional brain model based on magnetic resonance images. This protocol was developed to aid tDCS treatment of actual patients, and to verify its safety and effectiveness. Methods/design: Twenty-four patients with DOC after ABI will be enrolled in this cross-over trial. All participants will receive typical rehabilitation combined with sham tDCS and typical rehabilitation plus personalized tDCS (P-tDCS). Each interventional period will last 2 weeks (30 min/day, 5 days/week). The primary outcome [score on the Korean version of the Coma Recovery Scale-Revised (K-CRS-R)] will be assessed at baseline and the end of the first day of the intervention. Secondary outcomes (K-CRS-R at 1 week and 2 weeks after experimental session and quantitative EEG changes quantitative electroencephalography changes) will be measured at baseline and the end of week 4. Adverse events will be recorded during each treatment session. Discussion: For patients with neurological disorders, tDCS has served as a painless, non-invasive, easily applied, and effective therapy for several decades, and there is some evidence that it can improve the level of consciousness of patients with DOC. However, variability in the effects on consciousness among subjects have been reported and personalized strategies are lacking. This protocol is for a randomized controlled trial designed to validate the effectiveness and safety of P-tDCS combined with typical rehabilitation for DOC. Clinical trial registration: https://cris.nih.go.kr, identifier KCT0007157.

MRI-Based Personalized Transcranial Direct Current Stimulation to Enhance the Upper Limb Function in Patients with Stroke: Study Protocol for a Double-Blind Randomized Controlled Trial.

Transcranial direct current stimulation (tDCS) has been shown to have the potential to improve the motor recovery of the affected upper limbs in patients with stroke, and recently, several optimized tDCS methods have been proposed to magnify its effectiveness. This study aims to determine the effectiveness of personalized tDCS using brain MRI-based electrical field simulation and optimization, to enhance motor recovery of the upper limbs in the patients. This trial is a double-blind, randomized controlled trial in the subacute to chronic rehabilitation phase. Forty-two adult stroke patients with unilateral upper limb involvement will be randomly allocated to three groups: (1) personalized tDCS with MRI-based electrical field simulation and optimized stimulation, (2) conventional tDCS with bihemispheric stimulation of the primary motor cortex, and (3) sham tDCS. All three groups will undergo 10 intervention sessions with 30 min of 2-mA intensity stimulation, during a regular upper limb rehabilitation program over two weeks. The primary outcome measure for the motor recovery of the upper limb impairment is the Fugl-Meyer assessment for the upper extremity score at the end of the intervention, and the secondary measures include changes in the motor evoked potentials, the frequency power and coherence of the electroencephalography, performance in activities of daily living, and adverse events with a 1-month follow-up assessment. The primary outcome will be analyzed on the intention-to-treat principle. There is a paucity of studies regarding the effectiveness of personalized and optimized tDCS that considers individual brain lesions and electrical field characteristics in the real world. No feasibility or pivotal studies have been performed in stroke patients using brain MRI, to determine a lesion-specific tDCS simulation and optimization that considers obstacles in the segmentation and analysis of the affected brain tissue, such as ischemic and hemorrhagic lesions. This trial will contribute to addressing the effectiveness and safety of personalized tDCS, using brain MRI-based electrical field simulation and optimization, to enhance the motor recovery of the upper limbs in patients with stroke.

Single Nucleotide Polymorphisms May Increase the Risk of Aspiration Pneumonia in Post-Stroke Patients with Dysphagia.

This study aimed to evaluate whether genetic polymorphism is associated with an increased risk of infection, specifically post-stroke aspiration pneumonia. Blood samples were obtained from a total of 206 post-stroke participants (males, n = 136; mean age, 63.8 years). Genotyping was performed for catechol-O-methyltransferase (rs4680, rs165599), dopamine receptors (DRD1; rs4532, DRD2; rs1800497, DRD3; rs6280), brain-derived neurotrophic factor (rs6265), apolipoprotein E (rs429358, rs7412), and the interleukin-1 receptor antagonist gene (rs4251961). The subjects were stratified into two groups, aged < 65 (young) and ≥ 65 (elderly). Functional parameters and swallowing outcomes were measured at enrollment and at 3 months post-onset. The primary outcome was the incidence of aspiration pneumonia. Analysis of the association between genetic polymorphisms and aspiration pneumonia history showed that a minor C rs429358 allele was associated with the occurrence of aspiration pneumonia in the young group, both in the additive and the dominant models (odds ratio: 4.53; 95% CI: 1.60−12.84, p = 0.004). In the multivariable analysis, the minor C rs429358 allele increased the risk of post-stroke aspiration pneumonia in young stroke patients by 5.35 (95% CI: 1.64−20.88). In contrast, no such association was observed in the elderly group. Apolipoprotein E polymorphism may affect the risk of post-stroke aspiration pneumonia.

Potential Prognostic Impact of Dopamine Receptor D1 (rs4532) Polymorphism in Post-stroke Outcome in the Elderly.

Background: Single-nucleotide polymorphisms (SNPs) may affect post-stroke motor recovery, and some SNPs have been implicated in swallowing disturbances after stroke. Certain SNPs may also have altered influences according to different age. Objective: This post-hoc study investigated whether SNPs have different effects on dysphagia recovery between the elderly vs. young stroke patients. Methods: Analysis was conducted from a previous study including 218 stroke subjects with dysphagia. They were stratified into two groups, aged <65 and aged ≥65 years. The primary outcome was persistence of nil per mouth (NPM) at 3 months post-stroke onset. Association between outcome and nine different SNPs were investigated. Results: The elderly group (50%, n = 103) showed poorer swallowing outcomes than the young group. The minor allele of the dopamine receptor D1 (DRD1, rs4532) polymorphism showed potential association (p = 0.022) with an increased risk of NPM at 12 weeks post-stroke in the elderly, both in the additive (OR, 2.94; 95% CI, 1.17-7.37) and dominant models (OR, 2.93; 95% CI, 1.04-8.23) but did not reach statistical significance after Bonferonni correction. Logistic regression analysis showed that in those aged ≥65 years, models including the minor allele of rs4532 predicted the risk of the poor outcome with good accuracies even after adjustment of clinical factors, such as previous pneumonia episodes (AUROC, 0.86; 95% CI, 0.79-0.93) or the National Institutes of Health Stroke Scale (AUROC, 0.82; 95% CI, 0.67-0.92). In contrast, those aged <65 years seemed not to be affected by the presence of the rs4532 polymorphism, and models that included intubation history (AUROC, 0.81; 95% CI, 0.73-0.90) or previous pneumonia episodes (AUROC, 0.77; 95% CI, 0.68-0.87) showed modest levels of accuracies in predicting NPM at 12 weeks poststroke. Conclusions: Our study suggests a possible association between the rs4532 and post-stroke swallowing recovery, primarily in those aged ≥65 years. Certain SNPs may lead to less favorable outcomes in the elderly. The gene-age interaction should be considered in post-stroke swallowing recovery. Clinical Trial Registration: https://www.clinicaltrials.gov, Unique identifier [NCT03577444].

Role of rs6265 BDNF polymorphisms and post-stroke dysphagia recovery-A prospective cohort study.

BACKGROUND: Previous studies suggest that specific genes may predispose some to increased risk of dysphagia in the geriatric population, but whether these genes may affect swallowing recovery after a stroke is unknown. This study investigated whether single-nucleotide polymorphisms (SNP) of the brain-derived neurotrophic factor (BDNF), catechol-O-methyl transferase, apolipoprotein E, interleukin-1 receptor antagonist, and dopamine, which have been linked to swallowing, could adversely affect the prognosis of post-stroke dysphagia. METHODS: In this study, 218 subjects with confirmed post-stroke dysphagia were enrolled. The primary endpoint was failed recovery from nil per mouth (NPM) status with the first 3 months post-stroke. KEY RESULTS: The Val/Val group from the rs6265, BDNF, showed higher score changes on the Functional Oral Intake Scale at 1 month. The proportion of patients with recovery from NPM status within the first 1 month was 60.8% in the Val/Val group, which was statistically higher than those in the Met allele groups (38.1%, P = .017). At 3 months, the BDNF rs6265 showed significant group differences in Modified Barium Swallow Impairment Profile© score changes with the Val/Val allele leading to greater improvement. However, no single SNP was associated with increased risk of poor recovery with persistence of NPM at 3 months post-stroke. CONCLUSIONS AND INFERENCES: Those with the dominant Val/Val phenotype of BDNF manifested with faster and greater improvement than the Met-phenotypes. Based on our results, the BDNF Val allele may play a positive role with faster score improvement and rapid recovery from NPM than the Met allele. Clinical Trials gov: NCT03577444 (https://clinicaltrials.gov/ct2/show/study/NCT03577444).

KSNR Clinical Consensus Statements: Rehabilitation of Patients with Parkinson's Disease.

Clinical consensus statements (CCSs) aim to improve care for patients with Parkinson's disease (PD) and reduce the variability of rehabilitation methods in clinical practice. A literature search was conducted to find available evidence on the rehabilitation of patients with PD and to determine the scope of CCSs. The selection of PD rehabilitation domains and key questions was done using the modified Delphi method in 43 expert panels. These panels achieved a consensus on 11 key questions regarding rehabilitation assessment and goal setting, gait and balance, activities of daily living, and swallowing and communication disorders. After the completion of an agreement procedure, 11 key consensus statements were developed by the consensus panel. These statements addressed the needs of rehabilitation as a continuum in patients with PD. They included the appropriate rehabilitation initiation time, assessment items, rehabilitation contents, and complication management. This agreement can be used by physiatrists, rehabilitation therapists, and other practitioners who take care of patients with PD. The consensus panel also highlighted areas where a consensus could not be reached. The development of more focused CCS or clinical practice guidelines that target specific rehabilitation approaches is considered the next needed step.

Usefulness of comprehensive targeted multigene panel sequencing for neuromuscular disorders in Korean patients.

BACKGROUND: Multigene panel sequencing (MGPS) is the first-line option in diagnostic testing for genetically heterogeneous but clinically similar conditions, such as neuromuscular disorders (NMDs). In this study, we aimed to assess the utility of comprehensive NMD MGPS and the need for updated panels. METHODS: All patients were analyzed by either of two versions of the NMD MGPS and by chromosomal microarray and karyotype testing. Four patients with negative NMD MGPS results underwent whole exome sequencing. RESULTS: In total, 91 patients were enrolled, and a genetic diagnosis was made in 36 (39.6%); of these, 33 were diagnosed by the comprehensive NMD MGPS, two were confirmed by chromosomal microarray, and one was diagnosed by whole exome sequencing. For MGPS, the diagnostic yield of Version 2 (19/52; 36.5%) was a little higher than that of Version 1 (14/39; 35.9%), and one gene identified in Version 2 was not included in Version 1. A total of 36 definitive and nine possible causative variants were identified, of which 17 were novel. CONCLUSION: A more comprehensive panel for NMD MGPS can improve the diagnostic efficiency in genetic testing. The rapid discovery of new disease-causing genes over recent years necessitates updates to existing gene panels.

Calcimimetic restores diabetic peripheral neuropathy by ameliorating apoptosis and improving autophagy.

Decreased AMPK-eNOS bioavailability mediates the development of diabetic peripheral neuropathy (DPN) through increased apoptosis and decreased autophagy activity in relation to oxidative stress. Schwann cells are responsible for maintaining structural and functional integrity of neurons and for repairing damaged nerves. We evaluated the neuro-protective effect of cinacalcet on DPN by activating the AMPK-eNOS pathway using db/db mice and human Schwann cells (HSCs). Sciatic nerve of db/db mice was characterized by disorganized myelin, axonal shrinkage, and degeneration that were accompanied by marked fibrosis, inflammation, and apoptosis. These phenotypical alterations were significantly improved by cinacalcet treatment along with improvement in sensorimotor functional parameters. Cinacalcet demonstrated favorable effects through increased expression and activation of calcium-sensing receptor (CaSR)-CaMKKß and phosphorylation of AMPK-eNOS signaling in diabetic sciatic nerve. Cinacalcet decreased apoptosis and increased autophagy activity in relation to decreased oxidative stress in HSCs cultured in high-glucose medium as well. This was accompanied by increased expression of the CaSR, intracellular Ca++ ([Ca++]i) levels, and CaMKKß-LKB1-AMPK signaling pathway, resulting in the net effect of increased eNOS phosphorylation, NOx concentration, Bcl-2/Bax ratio, beclin 1, and LC3-II/LC3-I ratio. These results demonstrated that cinacalcet treatment ameliorates inflammation, apoptosis, and autophagy through increased expression of the CaSR, [Ca++]i levels and subsequent activation of CaMKKß-LKB-1-AMPK-eNOS pathway in the sciatic nerve and HSCs under diabetic condition. Therefore, cinacalcet may play an important role in the restoration and amelioration of DPN by ameliorating apoptosis and improving autophagy.

The Effects of Botulinum Toxin Injections on Plantar Flexor Spasticity in Different Phases After Stroke: A Secondary Analysis From a Double-Blind, Randomized Trial.

BACKGROUND: There are no guidelines on the ideal time to inject botulinum toxin type A (BT-A) for lower leg spasticity in stroke patients. An early injection may produce unwanted weakness, interfering with gait recovery. OBJECTIVE: To evaluate whether the outcomes after BT-A injection for plantarflexion spasticity can be different according to stroke chronicity. DESIGN: A secondary analysis study from a double-blinded, randomized trial with group reclassification according to stroke chronicity. SETTING: Two rehabilitation centers. PARTICIPANTS: Stroke participants (n = 40) with plantar flexor spasticity, treated with BT-A (200 units) into the gastrocnemius muscle. METHODS: Outcome parameters were reanalyzed serially using 2-way repeated measures of analysis of variance (ANOVA), at baseline and 2, 4, and 8 weeks postinjection. Subjects were reclassified into 3 groups: early, within 6 months (n = 12); middle, between 6 months and 1 year (n = 14); and late, between 1 and 2 years from stroke onset (n = 12). MAIN OUTCOME MEASURES: The Modified Ashworth Scale, clonus scale, 10-m walking test, ABILOCO, and the Functional Ambulation Category. RESULTS: The 2-way repeated measures of ANOVA showed improvement in gait and spasticity after injection in the 3 groups. Significant improvement in the Modified Ashworth Scale (P < .001) was observed, starting from the post-2 week injection period. Improvement of gait as assessed by the functional measurement ABILOCO and the Functional Ambulation Category (P < .001) were observed in all 3 groups, mostly at the post-8 week injection period. CONCLUSIONS: Our serial measurements of the outcome parameters indicated that BT-A could be expected to lead to consistent improvement in both the muscle tone and gait quality in those with plantar flexor spasticity regardless of stroke chronicity, including those injected as early as within the first 6 months. LEVEL OF EVIDENCE: I.

Methyllucidone inhibits STAT3 activity by regulating the expression of the protein tyrosine phosphatase MEG2 in DU145 prostate carcinoma cells.

During the search for signal transducer and activator of transcription 3 (STAT3) inhibitors from natural products, methyllucidone, isolated from Lindera species (Lauraceae), was identified as a STAT3 inhibitor. Methyllucidone inhibited STAT3 phosphorylation at tyrosine 705 in a dose- and time dependent manner in DU145 prostate cancer cells and suppressed IL-6-induced STAT3 phosphorylation at Tyr-705 in LNCaP cells. Methyllucidone decreased the expression levels of STAT3 target genes, such as cyclin D1, cyclin A, Bcl-2, Mcl-1, and survivin. Methyllucidone inhibited DU145 cell growth and induced apoptosis by arresting the cell cycle at G1 phase. Notably, knockdown of the MEG2 gene by small interfering RNA suppressed the ability of methyllucidone to inhibit STAT3 activation. Methyllucidone regulates STAT3 activity by modulating MEG2 expression, and our results suggest that this compound is a novel inhibitor of the STAT3 pathway and may be a useful lead molecule for the development of a therapeutic STAT3 inhibitor.

Anatomical Localization of Motor Points of the Abductor Hallucis Muscle: A Cadaveric Study.

OBJECTIVE: To identify the anatomical motor points of the abductor hallucis muscle in cadavers. METHODS: Motor nerve branches to the abductor hallucis muscles were examined in eight Korean cadaver feet. The motor point was defined as the site where the intramuscular nerve penetrates the muscle belly. The reference line connects the metatarsal base of the hallux (H) to the medial tubercle of the calcaneus (C). The x coordinate was the horizontal distance from the motor point to the point where the perpendicular line from the navicular tuberosity crossed the reference line. The y coordinate was the perpendicular distance from the motor point to the navicular tuberosity. RESULTS: Most of the medial plantar nerves to the abductor hallucis muscles divide into multiple branches before entering the muscles. One, two, and three motor branches were observed in 37.5%, 37.5%, and 25% of the feet, respectively. The ratios of the main motor point from the H with respect to the H-C line were: main motor point, 68.79%±5.69%; second motor point, 73.45%±3.25%. The mean x coordinate value from the main motor point was 0.65±0.49 cm. The mean value of the y coordinate was 1.43±0.35 cm. All of the motor points of the abductor hallucis were consistently found inferior and posterior to the navicular tuberosity. CONCLUSION: This study identified accurate locations of anatomical motor points of the abductor hallucis muscle by means of cadaveric dissection, which can be helpful for electrophysiological studies in order to correctly diagnose the various neuropathies associated with tibial nerve components.

The Korean Version of the Cognitive Assessment Scale for Stroke Patients (K-CASP): A Reliability and Validity Study.

OBJECTIVE: To develop the Korean version of the Cognitive Assessment Scale for Stroke Patients (K-CASP) and to evaluate the test reliability and validity of the K-CASP in stroke patients. METHODS: The original CASP was translated into Korean, back-translated into English, then reviewed and compared with the original version. Thirty-three stroke patients were assessed independently by two examiners using the K-CASP twice, with a one-day interval, for a total of four test results. To evaluate the reliability of the K-CASP, intra-class correlation coefficients were used. Pearson correlations were calculated and simple regression analyses performed with the Korean version of Mini-Mental State Examination (K-MMSE) and the aphasia quotient (AQ) to assess the validity. RESULTS: The mean score was 24.42±9.47 (total score 36) for the K-CASP and 21.50±7.01 (total score 30) for the K-MMSE. The inter-rater correlation coefficients of the K-CASP were 0.992 on the first day and 0.995 on the second day. The intra-rater correlation coefficients of the K-CASP were 0.997 for examiner 1 and 0.996 for examiner 2. In the Pearson correlation analysis, the K-CASP score significantly correlated with the K-MMSE score (r=0.825, p<0.001). The coefficients of determination (r2) of the AQ were 0.586 for the K-MMSE and 0.513 for the K-CASP in the simple regression analysis. CONCLUSION: The K-CASP is a reliable and valid instrument for cognitive dysfunction screening in post-stroke patients. It is more applicable than other cognitive assessment tools in stroke patients with aphasia.

Botulinum toxin type A for neuropathic pain in patients with spinal cord injury.

OBJECTIVE: To evaluate the analgesic effect of botulinum toxin type A (BTX-A) on patients with spinal cord injury-associated neuropathic pain. METHODS: The effect of BTX-A on 40 patients with spinal cord injury-associated neuropathic pain was investigated using a randomized, double-blind, placebo-controlled design. A 1-time subcutaneous BTX-A (200U) injection was administered to the painful area. Visual analogue scale (VAS) scores (0-100mm), the Korean version of the short-form McGill Pain Questionnaire, and the World Health Organization WHOQOL-BREF quality of life assessment were evaluated prior to treatment and at 4 and 8 weeks after the injection. RESULTS: At 4 and 8 weeks after injection, the VAS score for pain was significantly reduced by 18.6 ± 16.8 and 21.3 ± 26.8, respectively, in the BTX-A group, whereas it was reduced by 2.6 ± 14.6 and 0.3 ± 19.5, respectively, in the placebo group. The pain relief was associated with preservation of motor or sensory function below the neurological level of injury. Among the responders in the BTX-A group, 55% and 45% reported pain relief of 20% or greater at 4 and 8 weeks, respectively, after the injection, whereas only 15% and 10% of the responders in the placebo group reported a similar level of pain relief. Improvements in the score for the physical health domain of the WHOQOL-BREF in the BTX-A group showed a marginal trend toward significance (p = 0.0521) at 4 weeks after the injection. INTERPRETATION: These results indicate that BTX-A may reduce intractable chronic neuropathic pain in patients with spinal cord injury.

Substitution of Heavy Complementarity Determining Region 3 (CDR-H3) Residues Can Synergistically Enhance Functional Activity of Antibody and Its Binding Affinity to HER2 Antigen.

To generate a biobetter that has improved therapeutic activity, we constructed scFv libraries via random mutagenesis of several residues of CDR-H3 and -L3 of hu4D5. The scFv clones were isolated from the phage display libraries by stringent panning, and their anti-proliferative activity against HER2-positive cancer cells was evaluated as a primary selection criterion. Consequently, we selected AH06 as a biobetter antibody that had a 7.2-fold increase in anti-proliferative activity (IC50: 0.81 nM) against the gastric cancer cell line NCI-N87 and a 7.4-fold increase in binding affinity (KD: 60 pM) to HER2 compared to hu4D5. The binding energy calculation and molecular modeling suggest that the substitution of residues of CDR-H3 to W98, F100c, A101 and L102 could stabilize binding of the antibody to HER2 and there could be direct hydrophobic interactions between the aromatic ring of W98 and the aliphatic group of I613 within HER2 domain IV as well as the heavy and light chain hydrophobic interactions by residues F100c, A101 and L102 of CDR-H3. Therefore, we speculate that two such interactions were exerted by the residues W98 and F100c. A101 and L102 may have a synergistic effect on the increase in the binding affinity to HER2. AH06 specifically binds to domain IV of HER2, and it decreased the phosphorylation level of HER2 and AKT. Above all, it highly increased the overall level of p27 compared to hu4D5 in the gastric cancer cell line NCI-N82, suggesting that AH06 could potentially be a more efficient therapeutic agent than hu4D5.

Efficacy and Safety of a New Botulinum Toxin Type A Free of Complexing Proteins.

MT10107 is botulinum neurotoxin type A derived drug which utilizes the 150 kDa portion without complexing proteins and human serum albumin contents. To evaluate the efficacy and the safety of MT10107, it was compared with onabotulinumtoxinA in this double-blind, randomized controlled trial. Twenty-five healthy males received a randomly selected dose of MT10107 into the extensor digitorum brevis (EDB) muscle of one foot, and an equivalent dose of onabotulinumtoxinA (BOTOX) was injected into the contralateral EDB muscle. While efficacy of the administered substance was determined by measuring paretic effects on the EDB, the local spread of toxin effects was evaluated by the paretic effects on the nearby abductor hallucis (AH) and abductor digiti quinti (ADQ) muscles. Paretic effects were defined as the percentage of reduction of the compound muscle action potential (CMAP) amplitudes, measured at 14, 30, 90 days after the injection, compared to the baseline value. Intergroup (MT10107 and onabotulinumtoxinA) differences were not significant in the percentage reduction of the amplitudes in the EDB muscles. In this study, there was no significant difference in efficacy and safety between the two test drugs. MT10107 may be effective and safe as much as onabotulinumtoxinA to produce the desired paretic effect.

Multiple Lower Extremity Mononeuropathies by Segmental Schwannomatosis: A Case Report.

Schwannoma is an encapsulated nerve sheath tumor that is distinct from neurofibromatosis. It is defined as the occurrence of multiple schwannomas without any bilateral vestibular schwannomas. A 46-year-old man with multiple schwannomas involving peripheral nerves of the ipsilateral lower extremity presented with neurologic symptoms. Electrodiagnostic studies revealed multiple mononeuropathies involving the left sciatic, common peroneal, tibial, femoral and superior gluteal nerves. Histologic findings confirmed the diagnosis of schwannoma. We reported this rare case of segmental schwannomatosis that presented with neurologic symptoms including motor weakness, which was confirmed as multiple mononeuropathies by electrodiagnostic studies.