Compound muscle action potential of whole-forearm flexors: A clinical biomarker for inclusion body myositis.

Objective: This study aimed to investigate the potential of whole-forearm flexor muscle (WFFM) compound muscle action potential (CMAP) as a quantitative biomarker for inclusion body myositis (IBM) pathology. Methods: We prospectively enrolled 14 consecutive patients (10 men and 4 women) diagnosed with IBM based on muscle biopsies. We evaluated the baseline-to-peak amplitude of the WFFM CMAP and other quantitative parameters, including grip and pinch strength, Inclusion Body Myositis Functional Rating Scale (IBMFRS) score, and other routine muscle CMAP amplitudes. Results: The WFFM CMAP was strongly correlated with disease duration and the IBMFRS score. The WFFM CMAP on the more affected side was lower than that on the less affected side. Furthermore, grip power was strongly correlated with the WFFM CMAP, whereas lateral pinch strength was strongly correlated with the WFFM and first dorsal interosseous CMAPs. The 3-point pinch strength was also correlated with the WFFM CMAP. Conclusions: This study demonstrates that the WFFM CMAP may serve as a biomarker of severity in IBM. Significance: Identification of this biomarker can support drug development, diagnosis, prognosis, and treatment options for patients with IBM.

Challenges in evaluating forearm muscle activity based on the compound muscle action potential of the flexors of the whole forearm.

Objective: Muscle strength, which correlates with the compound muscle action potential (CMAP), can also be estimated by measuring the CMAP. Therefore, we evaluated the CMAP of the flexor muscles of the whole forearm to identify their muscle strength. Methods: Fourteen healthy volunteers were enrolled. The elbow was determined to be the stimulation point, and the recording site for the flexor muscles of the whole forearm was set at approximately 8 cm distal to the elbow. We prospectively evaluated the baseline-to-peak amplitude of the CMAP of the whole forearm flexor muscles (WFFM), including that obtained from the median nerve stimulation (WFFMm), ulnar nerve stimulation (WFFMu), and their sum (WFFMsum). Additionally, we analyzed the relationships between WFFMm and WFFMu amplitudes with other quantitative parameters, including grip strength and routine CMAP amplitudes. Results: The CMAP's test-retest analysis revealed high reliability. Grip power was significantly correlated with WFFMm and WFFMsum and mildly correlated with WFFMu. Tip-pinch strength with WFFMm and flexor pollicis longus (FPL) measurements correlated significantly. Lateral-pinch strength was significantly correlated with the first dorsal interosseous muscle (FDI) measurements but not with WFFM. The abductor digiti minimi (ADM) and abductor pollicis brevis (APB) were not correlated with grip power or pinch strength. Conclusions: By electrophysiology examination, this study demonstrated that WFFMm is involved in grip power and other pinch strengths. This method may serve as a novel tool for measurement of distal muscle strengths. Significance: This is the first study to attempt to evaluate the muscle strength of forearm flexor muscles by measuring the CMAP.

An Ultrasonographic Evaluation for the Early Detection of Nerve Root Changes in Herpes Zoster-associated Motor Paresis.

We herein report a case of herpes zoster complicated by right-arm paralysis, wherein cervical nerve root ultrasonography enabled the early diagnosis and a therapeutic efficacy evaluation. A 71-year-old man developed progressive weakness in the muscles innervated by the right C5-6 nerve root following the appearance of a painful rash. Cervical nerve root ultrasonography revealed C5-6 nerve root inflammatory swelling. Methylprednisolone pulse therapy and subsequent oral prednisolone therapy gradually improved the muscle weakness. At three weeks following admission, ultrasonography revealed C5-6 nerve root inflammatory swelling improvement. Ultrasonography may aid in the early detection of nerve root inflammatory swelling and help monitor treatment efficacy.

Electromyography varies by stage in inclusion body myositis.

Introduction: Inclusion body myositis (IBM) is a chronic inflammatory muscle disease that is characterized by mixed myogenic and neurogenic electromyography (EMG) findings. We investigated the association between EMG findings and the IBM stage. Methods: We included consecutive patients diagnosed with IBM based on muscle biopsy and had needle EMG performed within 1 month of biopsy. Motor unit potential waveform (MUP) in EMG and pathological findings were compared between patients in early and late phases. Results: In total, 30 patients with biopsy-confirmed IBM and 254 muscles were included. The rate of abnormal discharge did not differ according to disease stage. There was a difference in the frequency of occurrence between myogenic suggestive MUP and neurogenic of biceps and flexor digitorum profundus in the late phase. Abnormal MUP was observed even in muscles without muscle weakness, and myogenic changes were predominant in biceps and gastrocnemius with muscle weakness. The biopsy findings on the contralateral side of the muscle where electromyography was performed revealed a tendency for muscles that exhibited myogenic origin to have more inflammatory cells and RV; however, the difference was not significant. Conclusion: The target muscles for EMG must be selected considering the disease stage as well. In the early stages of IBM, EMG results should be interpreted cautiously, as neurogenic suggestive pattern of MUP might also be exhibited. Contralateral electromyography findings may be helpful in selecting muscles for muscle biopsies, such as biceps and quadriceps.

[A case of Guillain-Barré syndrome with unilateral diaphragmatic nerve palsy that was longitudinally evaluated using multiple examinations].

The patient, a 50-year-old woman, presented with fever and diarrhea in early July, X. One week later, she noticed muscle weakness in both lower extremities, which upon examination was found to be dominant in the distal muscles, with associated loss of tendon reflexes. We diagnosed the case as Guillain-Barré syndrome. After admission, the patient experienced decreased oxygenation, and a chest X-ray indicated elevation of the left hemidiaphragm. The phrenic nerve conduction studies revealed laterality of the amplitude of compound muscle action potential, and diaphragmatic ultrasonographic examination revealed decreased left diaphragmatic wall motion. We diagnosed the patient with unilateral diaphragmatic nerve palsy and initiated intravenous immunoglobulin and methylprednisolone treatment. After 2 weeks, the patient demonstrated good clinical recovery, increased diaphragmatic nerve amplitude, and improved diaphragmatic movement. We evaluated the longitudinal clinical course of unilateral diaphragmatic nerve palsy in the patient using nerve conduction tests and diaphragmatic echocardiography. The longitudinal evaluation allowed us to assess the pathological condition more sensitively so that the prognosis could be predicted accurately.

[A case of the palatal tremor that disappeared during swallowing, thought to be caused by microbleeds of bilateral dentate nucleus].

A 72-year-old female presented with slowly progressive dysphonia, which was a syllable-separated utterance, for three years. She had the rhythmic continues contraction of palatal and uvula muscles during speech with a frequency of about 2 Hz. The videoendoscopy showed that the rhythmic contraction, which synchronized in the nasopharynx and the larynx, did not disappear during vocalization. The swallowing videofluorography showed that the rhythmic contraction disappeared transiently during the swallowing reflex, and there was no aspiration. The MRI revealed olivary pseudohypertrophy and multiple microbleedings including the bilateral dentate nucleus. The degeneration of olivary nucleus secondary to the bilateral asymptomatic dentate nucleus microbleedings within the dentato-rubro-olivary pathway was thought to be a cause of palatal tremor. This is a first report that a dynamic relation between vocalization and swallowing in palatal tremor.

Thoracic Excursion Is a Biomarker for Evaluating Respiratory Function in Amyotrophic Lateral Sclerosis.

Objective: To evaluate the usefulness of thoracic excursion as a biomarker in patients with amyotrophic lateral sclerosis (ALS). Methods: We measured the forced the vital capacity (FVC), thoracic excursion, baseline-to-peak diaphragmatic compound muscle action potential (DCMAP) amplitude, diaphragm thickness at full inspiration (DTfi), Medical Research Council (MRC) sum score for muscle strength, and arterial partial pressures of oxygen and carbon dioxide and administered the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and modified Medical Research Council (mMRC) Dyspnea Scale. The test-retest reliability of thoracic excursion was determined. Results and Conclusions: Thirty-four patients with ALS and 26 age- and sex-matched healthy participants were enrolled. Thoracic excursion measurement had excellent test-retest reliability (intraclass coefficient: 0.974). Thoracic excursion was more strongly correlated with FVC (r = 0.678, p < 0.001) than DCMAP amplitude (r = 0.501, p = 0.003) and DTfi (r = 0.597, p < 0.001). It was also correlated with ALSFRS-R score (r = 0.610, p < 0.001), MRC sum score (r = 0.470, p = 0.005), and mMRC Dyspnea Scale score (r = -0.446, p = 0.008) and was the most sensitive parameter for assessing dyspnea and FVC. Thoracic excursion decreased as FVC declined in the early and late stages, there were no differences in DCMAP amplitude and DTfi between the early and late stages, and ALSFRS-R score and MRC sum score decreased only in the late stage. Thoracic excursion was well correlated with respiratory function and is useful for predicting respiratory and general dysfunction in patients with ALS regardless of stage.

Serum Alkaline Phosphatase in Cryptogenic Stroke Cases with Active Cancer.

Objective We assessed the relationship between the levels of serum alkaline phosphatase, which is often increased with biliary obstruction and bone metastasis, and active cancer in patients with cryptogenic stroke. Methods Serum alkaline phosphatase levels in patients with cryptogenic stroke sampled upon admission were measured using the Japan Society of Clinical Chemistry method used in Japan. Active cancer was defined as a new diagnosis, treatment, progression, or recurrence within six months before admission or metastatic cancer. Multivariate logistic regression analyses were performed to explore the relationship between serum alkaline phosphatase and active cancer in these patients. Results Among the 249 patients classified as having cryptogenic stroke, 64 had active cancer. Patients with cryptogenic stroke with active cancer had significantly higher serum alkaline phosphatase levels (486±497 vs. 259±88.2 U/L; p<0.001) than those without cancer. Multivariate logistic analysis revealed that serum alkaline phosphatase levels ≥286 U/L were associated with cryptogenic stroke with active cancer [odds ratio (OR), 2.669, 95% confidence interval (CI), 1.291-5.517; p=0.008] independent of age ≤70 years old (OR, 3.303, 95% CI, 1.569-6.994; p=0.002), male sex (OR, 0.806, 95% CI, 0.380-1.710; p=0.573), and serum D-dimer levels ≥2.6 µg/mL (OR, 18.78, 95% CI, 8.130-43.40; p<0.001). Conclusion In patients with cryptogenic stroke, high serum alkaline phosphatase levels may be related to active cancer.

Improvement of peripheral neuropathy in a patient with antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis by additional mepolizumab.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by abnormally high eosinophils and frequent peripheral neuropathy. Mepolizumab is an approved therapy for EGPA, but its efficacy against peripheral neuropathy remains unknown. CASE PRESENTATION: A 41-year-old woman was admitted in the hospital with dyspnea and neuropathy. Ground glass opacity and infiltrative shadow in the bilateral lungs were evident on chest computed tomography images. Eosinophils were increased in serum, in bronchoalveolar lavage fluid (BALF), and in transbronchial lung biopsy, and bacteria were not detected in BALF. EGPA resulting in severe eosinophilic asthma, sinusitis, pulmonary infiltrates, and peripheral neuropathy was diagnosed. Prednisolone (50 mg/day) caused remission of eosinophilic pneumonia and sinusitis, but not peripheral neuropathy. During prednisolone tapering (7 mg/day, 10 months after treatment), eosinophils were increased, and peripheral neuropathy relapsed. The humanized anti-IL-5 antibody mepolizumab (300 mg) was initially administered, followed by prednisolone. Mepolizumab caused sustained peripheral neuropathy remission and effective prednisolone tapering. CONCLUSIONS: Introduction of mepolizumab combined with prednisolone may improve peripheral neuropathy.

C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers.

Nuclear import receptors (NIRs) not only transport RNA-binding proteins (RBPs) but also modify phase transitions of RBPs by recognizing nuclear localization signals (NLSs). Toxic arginine-rich poly-dipeptides from C9orf72 interact with NIRs and cause nucleocytoplasmic transport deficit. However, the molecular basis for the toxicity of arginine-rich poly-dipeptides toward NIRs function as phase modifiers of RBPs remains unidentified. Here we show that arginine-rich poly-dipeptides impede the ability of NIRs to modify phase transitions of RBPs. Isothermal titration calorimetry and size-exclusion chromatography revealed that proline:arginine (PR) poly-dipeptides tightly bind karyopherin-ß2 (Kapß2) at 1:1 ratio. The nuclear magnetic resonances of Kapß2 perturbed by PR poly-dipeptides partially overlapped with those perturbed by the designed NLS peptide, suggesting that PR poly-dipeptides target the NLS binding site of Kapß2. The findings offer mechanistic insights into how phase transitions of RBPs are disabled in C9orf72-related neurodegeneration.

Gene Expression Profiles of Human Cerebral Organoids Identify PPAR Pathway and PKM2 as Key Markers for Oxygen-Glucose Deprivation and Reoxygenation.

Ischemic stroke is one of the most common neurological diseases. However, the impact of ischemic stroke on human cerebral tissue remains largely unknown due to a lack of ischemic human brain samples. In this study, we applied cerebral organoids derived from human induced pluripotent stem cells to evaluate the effect of oxygen-glucose deprivation/reoxygenation (OGD/R). Pathway analysis showed the relationships between vitamin digestion and absorption, fat digestion and absorption, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and complement and coagulation cascades. Combinational verification with transcriptome and gene expression analysis of different cell types revealed fatty acids-related PPAR signaling pathway and pyruvate kinase isoform M2 (PKM2) as key markers of neuronal cells in response to OGD/R. These findings suggest that, although there remain some limitations to be improved, our ischemic stroke model using human cerebral organoids would be a potentially useful tool when combined with other conventional two-dimensional (2D) mono-culture systems.

Brainstem Organoids From Human Pluripotent Stem Cells.

The brainstem is a posterior region of the brain, composed of three parts, midbrain, pons, and medulla oblongata. It is critical in controlling heartbeat, blood pressure, and respiration, all of which are life-sustaining functions, and therefore, damages to or disorders of the brainstem can be lethal. Brain organoids derived from human pluripotent stem cells (hPSCs) recapitulate the course of human brain development and are expected to be useful for medical research on central nervous system disorders. However, existing organoid models are limited in the extent hPSCs recapitulate human brain development and hence are not able to fully elucidate the diseases affecting various components of the brain such as brainstem. Here, we developed a method to generate human brainstem organoids (hBSOs), containing midbrain/hindbrain progenitors, noradrenergic and cholinergic neurons, dopaminergic neurons, and neural crest lineage cells. Single-cell RNA sequence (scRNA-seq) analysis, together with evidence from proteomics and electrophysiology, revealed that the cellular population in these organoids was similar to that of the human brainstem, which raises the possibility of making use of hBSOs in investigating central nervous system disorders affecting brainstem and in efficient drug screenings.

Low Serum Eicosapentaenoic Acid Levels in Cryptogenic Stroke with Active Cancer.

BACKGROUND AND PURPOSE: The increased prevalence of cancer has led to it being considered an important factor in the cause of cryptogenic stroke. In recent years, polyunsaturated fatty acids, particularly omega-3 polyunsaturated fatty acids, have been shown to prevent cancer development and progression. This study aimed to clarify the characteristics of serum polyunsaturated fatty acids in cryptogenic stroke with active cancer. METHODS: The serum levels polyunsaturated fatty acid fractions (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA; dihomo-gamma-linolenic acid, DHLA; and arachidonic acid, AA) in cases of cryptogenic stroke, sampled within 5 days after admission, were measured. Active cancer was defined as a new diagnosis, treatment, progression or recurrence within 6 months before admission, or metastatic cancer. Multivariate logistic regression analyses were performed to explore the relationship between serum polyunsaturated fatty acids and cryptogenic stroke with active cancer. RESULTS: Among 123 cases classified as cryptogenic stroke, 27 had active cancer. The serum EPA levels (1.26 ± 0.72 versus 1.89 ± 1.27 umol/l; P = 0.02) were significantly lower in cryptogenic stroke with active cancer, whereas the serum DHA, DHLA and AA levels did not significantly differ. Multivariate logistic analysis revealed that the serum EPA levels were associated with cryptogenic stroke with active cancer independently of age and serum D-dimer levels (odds ratio, 0.974; 95% confidence interval, 0.949-0.999; P = 0.04). CONCLUSIONS: In our study, low serum EPA levels were associated with cryptogenic stroke with active cancer. This suggests that low serum EPA levels may have some involvement in the pathogenesis of cryptogenic stroke with active cancer.

Apraxia of eyelid opening might be critical for levodopa-carbidopa intestinal gel treatment.

Apraxia of eyelid opening (AEO) has been associated with levodopa. It has also been linked to impaired function of the frontal lobe, with the dopaminergic neuron projected to the frontal lobe. However, dopaminergic treatment for AEO is still controversial. Here we describe two patients with both Parkinson's disease (PD) and AEO, who responded differently to a continuous intrajejunal levodopa-carbidopa intestinal gel (LCIG) infusion. One of the patients manifested a deterioration of AEO after LCIG infusion, and off-periods were shortened by the decrease in the severity of dyskinesia. After discontinuing the use of LCIG, there was an improvement in the patient's ability to open her eyelids. The other patient had AEO prior to LCIG treatment, and this treatment spontaneously elevated her eyelids. These two PD patients raised the concern as to whether AEO may be a critical symptom for the indication of LCIG treatment. The different responses to LCIG might have been due to the fluctuation in brain dopamine levels during LCIG treatment.

Retrospective analysis of the clinical response of palmoplantar pustulosis after dental infection control and dental metal removal.

Both metal allergy and dental focal infection have been considered as causative factors for palmoplantar pustulosis, and several case reports described that the skin lesions were ameliorated after dental metal removal or dental infection control. However, limited data are available to evaluate the association of these factors with disease severity of palmoplantar pustulosis. This study is designed to analyze the clinical outcome of 85 palmoplantar pustulosis patients after dental infection control (n = 70), tonsillectomy (n = 6) and dental metal removal (n = 9). More than half of the patients (63%, 44/70) showed positive clinical outcome after dental infection control. The skin lesions of all patients with tonsillitis were improved after tonsillectomy (100%, 6/6). On the other hand, one-third of patients (33%, 3/9) showed positive response after dental metal removal. These results suggest that focal infection is more closely associated with palmoplantar pustulosis than dental metal allergy. According to our findings, palmoplantar pustulosis patients should be preferentially examined for focal infections.

The antihistamine olopatadine regulates T cell activation in palladium allergy.

Because of its corrosion resistance palladium (Pd) has been widely used in many consumer products ranging from fashion accessories to dental materials. Recently, however, an increase in Pd allergy cases has been reported. Metal allergy is categorized as a Type IV allergy, which is characterized as a delayed-type hypersensitivity reaction in which T cells are known to play an important role; however, the precise mechanism of their action remains unclear. Here we defined the relationship between histamine and the Pd allergic reaction specifically with respect to T cell responses. To verify the effects of histamine on T cells, we examined whether there is a change in IFN-γ production following stimulation of histamine or the antihistamine, olopatadine hydrochloride (OLP), in vitro. In addition, we assessed whether OLP administration affected the degree of footpad swelling or IFN-γ production during the Pd allergy response in mice. We found that histamine stimulation increased IFN-γ production in T cells, specifically enhancing IFN-γ production in CD8(+) T cells compared with CD4(+) T cells. Interestingly, OLP suppressed the production of IFN-γ in CD8(+) T cells, and this compound inhibited footpad swelling and IFN-γ production in mice with Pd allergy. These results suggest that histamine promotes the Type IV allergic reaction and thus, the histamine 1 receptor (H1R) might be useful therapeutic target for treatment of metal allergy.

The minimum endpoint variance trajectory depends on the profile of the signal-dependent noise.

It has been proposed that the central nervous system determines reaching movement trajectories so as to minimize the positional variance of the endpoint in the presence of signal-dependent noise. The hypothesis well reproduces the empirical movement trajectories for noise to the control signal whose variance is proportional to the second power of the amplitude of the control signal. However, empirical studies do not necessarily exhibit such a simple signal-noise relationship. The studies exhibit a wide distribution of estimates of the value of the exponent. This discrepancy raises the question of how the minimum endpoint variance trajectory depends on the value of the exponent. To address this question, we calculated minimum endpoint variance trajectories in simulations in which the value of the exponent was varied from 0 to 3. We found that the optimal trajectories differed according to the value of the exponent, and the profiles of optimal trajectories gradually diverged from the empirical ones as the value approached 0, though this change was not remarkable for larger values. Moreover, the optimal trajectories failed to replicate Fitts' law when the value was not equal to 2. These results suggest that the acceptability of the minimum endpoint variance theory depends on the value of the exponent in our motor system.