Effect of Serum Perampanel Concentration on Sporadic Amyotrophic Lateral Sclerosis Progression.

BACKGROUND AND PURPOSE: To clarify the effect of perampanel (PER) on sporadic amyotrophic lateral sclerosis (sALS) progression, the relationship between the changes in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores and serum PER concentrations was investigated. METHODS: 12 patients with sALS from our hospital who agreed to participate and completed the PER for sALS randomized phase 2 study were included. After completing the study, we retrospectively obtained serum PER concentration data from the patients. Based on their mean PER concentrations, we divided the patients who had been taking PER into two groups: four patients with a mean PER concentration of ≥400 ng/mL were assigned to the H group, and three with a mean PER concentration of <400 ng/mL were assigned to the L group. The control group consisted of five patients who had been taking a placebo. We obtained the ALSFRS-R scores of each patient at 36 and 48 weeks after randomization. The differences in ALSFRS-R scores at baseline (0 weeks) and each subsequent week were used in the analysis. RESULTS: At 48 weeks, there were no differences in the degree of deterioration of the bulbar, upper and lower limb, and respiratory ALSFRS-R subscores and total ALSFRS-R score. However, at 36 weeks, the bulbar subscore was significantly lower in the H group than in the control group (p=0.032). CONCLUSIONS: Because high PER concentrations may exacerbate bulbar symptoms in patients with sALS, serum PER measurements may be beneficial when patients with sALS are taking PER.

Pathological features of glial cells and motor neurons in the anterior horn of the spinal cord in sporadic ALS using ADAR2 conditional knockout mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective degeneration of motor neurons (MNs). In the MNs of patients with ALS, adenosine deaminase acting on RNA 2 (ADAR2)-mediated RNA editing of GluA2 mRNA at the Q/R site is profoundly deficient. In genetically modified mice (ADAR2flox/flox/VAChT-Cre.Fast; AR2), the selective knockout of ADAR2 in cholinergic neurons induced progressive loss of lower MNs. MNs exhibiting an age-related increase in abnormal TDP-43 localization and reduced ADAR2 immunoreactivity are localized in the lateral areas of the anterior horns (AHs) in aged wild-type mice. However, the patterns in the AHs of AR2 mice remain unknown. In this study, we investigated whether similar degeneration is observed in AR2 mice. We compared the number of astrocytes and MNs in the lateral and medial AHs of the lumbar spinal cord of 12-month-old AR2 mice with age-matched wild-type mice. The number of MNs significantly decreased in both the lateral and medial areas in AR2 mice AHs, particularly in the former. The number of reactive astrocytes increased significantly in the lateral areas of the AHs of AR2 mice. In conclusion, stronger activation of astrocytes with reduction of MNs in the ADAR2 deficiency-related lateral area increases in AR2 mice AHs. Fast fatigable MNs are expected to be present in the lateral area of the AHs. We found that MN death is more common in the lateral area of AHs associated with FF MNs due to differences in vulnerability to MN under ADAR2 deficiency.

Position of meristems and the angles of the cell division plane regulate the uniqueness of lateral organ shape.

Leaf meristem is a cell proliferative zone present in the lateral organ primordia. In this study, we examined how cell proliferative zones in primordia of planar floral organs and polar auxin transport inhibitor (PATI)-treated leaf organs differ from those of non-treated foliage leaves of Arabidopsis thaliana, with a focus on the accumulation pattern of ANGUSTIFOLIA3 (AN3) protein, a key element for leaf meristem positioning. We found that PATI-induced leaf shape changes were correlated with cell division angle but not with meristem positioning/size or AN3 localisation. In contrast, different shapes between sepals and petals compared with foliage leaves were associated with both altered meristem position, due to altered AN3 expression patterns, and different distributions of cell division angles. A numerical simulation showed that meristem position majorly affected the final shape but biased cell division angles had a minor effect. Taken together, these results suggest that the unique shapes of different lateral organs depend on the position of the meristem in the case of floral organs and cell division angles in the case of leaf organs with different auxin flow.

Prolyl Isomerase Pin1 Expression in the Spinal Motor Neurons of Patients With Sporadic Amyotrophic Lateral Sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Selective deficiency of edited adenosine deaminase acting on RNA 2 (ADAR2), a key molecule in the acquisition of Ca2+ resistance in motor neurons, has been reported in sporadic ALS (sALS) spinal motor neurons. Since ADAR2 activity is positively regulated by prolyl isomerase Protein never in mitosis gene A interacting-1 (Pin1), a known phosphorylation-dependent peptidyl-prolyl cis/trans isomerase, we investigated Pin1 expression in spinal motor neurons in sALS. METHODS: Specimens of the spinal cord were obtained from the lumbar region in eight sALS patients and age-matched five controls after postmortem examinations. The specimens were double stained with anti-Pin1 and anti-TAR DNA-binding protein of 43 kDa (TDP-43) antibodies, and examined under a fluorescence microscope. RESULTS: This study analyzed 254 and 422 spinal motor neurons from 8 sALS patients and 5 control subjects, respectively. The frequency of motor neurons with high cytoplasmic Pin1 expression from the spinal cord did not differ significantly between sALS specimens without cytoplasmic TDP-43 inclusions and control specimens. However, in sALS specimens, neurons for which the Pin1 immunoluminescence intensity in the cytoplasm was at least twice that in the background were more common in specimens with cytoplasmic TDP-43 inclusions (p<0.05 in χ² test). CONCLUSIONS: In sALS, neurons with higher expression levels of Pin1 levels had more TDP-43 inclusions. Despite the feedback mechanism between Pin1 and ADAR2 being unclear, since Pin1 positively regulates ADAR2, our results suggest that higher Pin1 expression levels in motor neurons with TDP-43 pathology from sALS patients represent a compensatory mechanism.

Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

Persistent Hemichorea as a Preceding Symptom of Cerebral Infarction Due to Middle Cerebral Artery Stenosis.

We herein report an 84-year-old woman with right middle cerebral artery (MCA) stenosis who presented with persistent left hemichorea preceding cerebral infarction. She visited our hospital on day 9 after the hemichorea onset. Magnetic resonance imaging (MRI) showed no acute cerebral infarction. Magnetic resonance angiography revealed right MCA stenosis. Her hemichorea persisted for 19 days and subsequently disappeared. On day 21, she developed left hemiplegia. Repeat MRI revealed a cerebral infarction in the right putamen. MCA stenosis can present with persistent hemichorea, even in the absence of cerebral infarction. Persistent hemichorea with MCA stenosis may presage cerebral infarction.

VISUAL-CC system uncovers the role of GSK3 as an orchestrator of vascular cell type ratio in plants.

The phloem transports photosynthetic assimilates and signalling molecules. It mainly consists of sieve elements (SEs), which act as "highways" for transport, and companion cells (CCs), which serve as "gates" to load/unload cargos. Though SEs and CCs function together, it remains unknown what determines the ratio of SE/CC in the phloem. Here we develop a new culture system for CC differentiation in Arabidopsis named VISUAL-CC, which almost mimics the process of the SE-CC complex formation. Comparative expression analysis in VISUAL-CC reveals that SE and CC differentiation tends to show negative correlation, while total phloem differentiation is unchanged. This varying SE/CC ratio is largely dependent on GSK3 kinase activity. Indeed, gsk3 hextuple mutants possess many more SEs and fewer CCs, whereas gsk3 gain-of-function mutants partially increase the CC number. Taken together, GSK3 activity appears to function as a cell-fate switch in the phloem, thereby balancing the SE/CC ratio.

Gait analysis in Down syndrome pediatric patients using a sheet-type gait analyzer: Pilot study.

BACKGROUND: Children with Down syndrome (DS), who are likely to suffer from a large number of musculoskeletal problems, tend to have a unique pattern of walking in clinical settings. Despite such apparent uniqueness, few studies have empirically investigated gait development pattern in DS children, especially at an earlier age. We therefore conducted gait analysis in young DS children who are prescribed insoles, to explore how their gait patterns develop, using the gait parameters identified by Sutherland et al. as determinants of gait maturity of typical children. METHODS: Participants consisted of 63 DS children (31 boys) aged 1-6 years (mean, 4 years 1 month) with a diagnosis of flat feet who were prescribed orthotic insoles. A 2.4 m sheet-type gait analyzer was used to analyze gait pattern. We measured the following variables: walking velocity (cm/min), cadence (steps/min), step length (cm), and single-limb stance phase ratio (%), and examined their relationship with age on regression analysis. RESULTS: Walking velocity and step length were significantly and positively related to age. Cadence was also significantly, but negatively associated with age. In contrast, SLS phase ratio did not have a statistically significant relationship with age. CONCLUSION: Down syndrome children have unique gait development patterns. Although walking velocity, cadence, and step length were found to develop with age, as in typical children, SLS phase ratio did not change with age in DS children. Further studies with a larger sample are necessary to replicate these findings.

Transgenic Arabidopsis plants expressing the rice dehydroascorbate reductase gene are resistant to salt stress.

Vitamin C (l-ascorbate) is important for antioxidative and metabolic functions in both plants and humans. Ascorbate itself is oxidized to dehydroascorbate during the process of antioxidation, and dehydroascorbate reductase (DHAR, EC 1.8.5.1) re-reduces the oxidized ascorbate. Therefore, this enzyme is assumed to be critical for ascorbate recycling. Here we show that the expression of rice DHAR in transgenic Arabidopsis thaliana enhanced resistance to salt stress. Salt tolerance was remarkably improved despite slight increases in DHAR activity and total ascorbate. This study provides direct evidence for the importance of DHAR in salt tolerance.