[Multifocal Motor Neuropathy].

Multifocal motor neuropathy (MMN), an acquired chronic progressive immune-mediated motor neuropathy, is characterized by asymmetrical distal upper limb muscle weakness and muscle atrophy without sensory impairment. Differentiation from amyotrophic lateral sclerosis is usually challenging, and electrophysiological studies show multifocal conduction blocks. Immunoglobulin (Ig)M GM1 antibodies are detected in approximately 50% of patients. In contrast to chronic inflammatory demyelinating polyneuropathy, corticosteroids are ineffective for management of MMN, and IVIg is the sole established treatment.

Duration of atrial fibrillation persistence: implications for recurrence risk after catheter ablation and efficacy of additional substrate ablation.

BACKGROUND: The optimal duration of atrial fibrillation (AF) persistence for predicting poor outcomes after catheter ablation of long-standing AF (LsAF) and the best ablation strategy for these patients remain unclear. OBJECTIVE: We aimed to assess the impact of the duration of AF persistence on outcomes after catheter ablation of AF. METHODS: We analyzed the Efficacy of Pulmonary Vein Isolation Alone in Patients with Persistent Atrial Fibrillation (EARNEST-PVI) trial data comparing pulmonary vein isolation (PVI) alone (PVI-alone) with additional linear ablation or defragmentation (PVI-plus) in persistent AF (PerAF). Patients who received catheter ablation by contact force-sensing catheter were enrolled in the study. In patients with LsAF, the optimal cutoff duration of AF persistence was evaluated. With use of the threshold, patients with LsAF were divided into 2 groups and compared with PerAF <1 year for arrhythmia-free survival after a 3-month blanking period. RESULTS: The optimal cutoff duration was 2.4 years. Of 458 patients, arrhythmia-free survival rates for LsAF 1-2.4 years were comparable to those of PerAF (hazard ratio [HR], 1.01; 95% CI, 0.67-1.52). However, LsAF >2.4 years had a higher recurrence risk than PerAF (HR, 2.22; 95% CI, 1.42-3.47). In LsAF >2.4 years, the PVI-plus strategy showed advantages over the PVI-alone strategy (HR, 0.36; 95% CI, 0.14-0.89). However, the interaction effect between LsAF 1-2.4 years and LsAF >2.4 years did not reach statistical significance (P = .116). CONCLUSION: Whereas LsAF 1-2.4 years has similar outcomes to those of PerAF, LsAF >2.4 years was linked to higher arrhythmia recurrence risks. For LsAF >2.4 years, the PVI-plus strategy showed a potential to be superior to the PVI-alone strategy.

Endoscopic view of the vertebra during laser balloon ablation of paroxysmal atrial fibrillation.

Key Clinical Message: Left atrial posterior wall on the vertebra is often difficult to obtain stable tissue contact with ablation-catheter. Laser balloon ablation is effective because the compression from the vertebra can be visualized through endoscopy. Abstract: When performing pulmonary vein isolation (PVI) with radiofrequency, left atrial posterior wall on the vertebra is often difficult to obtain stable tissue contact with ablation-catheter because of the movement of the ablation point. Laser balloon ablation is effective for the achievement of durable PVI in cases with such anatomical characteristics because the compression from the vertebra can be visualized through endoscopy.

Uplift modeling to identify patients who require extensive catheter ablation procedures among patients with persistent atrial fibrillation.

Identifying patients who would benefit from extensive catheter ablation along with pulmonary vein isolation (PVI) among those with persistent atrial fibrillation (AF) has been a subject of controversy. The objective of this study was to apply uplift modeling, a machine learning method for analyzing individual causal effect, to identify such patients in the EARNEST-PVI trial, a randomized trial in patients with persistent AF. We developed 16 uplift models using different machine learning algorithms, and determined that the best performing model was adaptive boosting using Qini coefficients. The optimal uplift score threshold was 0.0124. Among patients with an uplift score ≥ 0.0124, those who underwent extensive catheter ablation (PVI-plus) showed a significantly lower recurrence rate of AF compared to those who received only PVI (PVI-alone) (HR 0.40; 95% CI 0.19-0.84; P-value = 0.015). In contrast, among patients with an uplift score < 0.0124, recurrence of AF did not significantly differ between PVI-plus and PVI-alone (HR 1.17; 95% CI 0.57-2.39; P-value = 0.661). By employing uplift modeling, we could effectively identify a subset of patients with persistent AF who would benefit from PVI-plus. This model could be valuable in stratifying patients with persistent AF who need extensive catheter ablation before the procedure.

ProNGF promotes brain metastasis through TrkA/EphA2 induced Src activation in triple negative breast cancer cells.

BACKGROUND: Triple-Negative Breast Cancer is particularly aggressive, and its metastasis to the brain has a significant psychological impact on patients' quality of life, in addition to reducing survival. The development of brain metastases is particularly harmful in triple-negative breast cancer (TNBC). To date, the mechanisms that induce brain metastasis in TNBC are poorly understood. METHODS: Using a human blood-brain barrier (BBB) in vitro model, an in vitro 3D organotypic extracellular matrix, an ex vivo mouse brain slices co-culture and in an in vivo xenograft experiment, key step of brain metastasis were recapitulated to study TNBC behaviors. RESULTS: In this study, we demonstrated for the first time the involvement of the precursor of Nerve Growth Factor (proNGF) in the development of brain metastasis. More importantly, our results showed that proNGF acts through TrkA independent of its phosphorylation to induce brain metastasis in TNBC. In addition, we found that proNGF induces BBB transmigration through the TrkA/EphA2 signaling complex. More importantly, our results showed that combinatorial inhibition of TrkA and EphA2 decreased TBNC brain metastasis in a preclinical model. CONCLUSIONS: These disruptive findings provide new insights into the mechanisms underlying brain metastasis with proNGF as a driver of brain metastasis of TNBC and identify TrkA/EphA2 complex as a potential therapeutic target.

[Arsenic Poisoning, in Murder is Easy].

Agatha Christie's detective novel Murder is Easy has the title with the message that the perpetrator of a serial murder in the English countryside was actually an unimaginable individual, and that murder is easy unless it is imagined. In the novel, arsenic is used as a murder tool. Therefore, and this essay aims to educate the readers about the neurological symptoms of arsenic poisoning. In the future, criminal acts using arsenic may appear before us. For reliable diagnosis, it is a major premise to have the basic knowledge written here; simultaneously, this novel shows that flexible thinking that is not bound by common sense is also required.

Effects of biochar application depth on nitrate leaching and soil water conditions.

Nitrate leaching from farmland pollutes the surrounding environment, such as groundwater, causing health hazards to inhabitants. To mitigate the leaching, biochar can be applied. The effect of biochar application differs depending on the application depth; however, the effect of the application depth remains unclear. To evaluate the effect, we conducted a pipe experiment with no plant using bagasse biochar with four treatments: no biochar application, surface application (0-5 cm), plow layer application (0-30 cm), and subsurface application (25-30 cm). The results showed that surface and plow layer applications reduced nitrate leaching, whereas subsurface application did not affect leaching. This difference was due to changes in the soil water movement and water budget. Surface application reduced evaporation, inducing increases in both drainage and the amount of water in the pipe. The increased amount of water might contribute to an increase in the amount of nitrogen in the pipe, reducing the leaching. Plow layer application increased evaporation, leading to decreased drainage and nitrate leaching. Subsurface application did not affect drainage and nitrate leaching; however, the change in the volumetric water content at a depth of 10 cm was the most significant among the treatments. Our study indicated that, although the same amount of biochar was applied, the effect of biochar application differs depending on the application depth.

Lead Encephalopathy in a 73-year-old Man Manifesting as Acute Disturbance of Consciousness with a Unique Magnetic Resonance Imaging Appearance.

A 73-year-old man was admitted with Cheyne-Stokes respiration and progressive disturbance of consciousness over the course of a month. Cranial magnetic resonance imaging revealed signs suggestive of angioedema in the posterior limb of the internal capsule, external capsule, and subcortical white matter. Acute lead encephalopathy was diagnosed based on abnormally high plasma lead levels. After methylprednisolone pulse therapy followed by chelation therapy, the patient fully recovered. In this case, the angioedema with a distinctive magnetic resonance imaging appearance was attributed to the cytotoxic effects of lead on the nervous system, which responded well to methylprednisolone pulse therapy.

Antineutrophil cytoplasmic antibody-associated vasculitis with predominant truncal muscle weakness: a retrospective case series.

Introduction: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) frequently leads to mononeuritis multiplex, which are characterized by distal weakness associated with sensory disturbances. Although AAV has also been reported to be associated with myopathy, the pathogenesis and characteristics remain unclear. We aimed to show the clinical and laboratory findings in AAV-associated myopathy. Methods: This retrospective single-center study included patients with the diagnosis of AAV who had been admitted to the neurology department and had biopsy specimens of muscle and/or nerve tissue. Results: We identified four patients with a distinct clinical presentation of muscle weakness in the trunk and proximal limbs. The weakness resembled that of inflammatory muscle disease. These patients denied symptoms associated with neuropathy, and had normal serum creatine kinase (CK) levels. Needle electromyography (needle EMG) showed spontaneous electrical activity at rest, and results of magnetic resonance imaging (MRI) suggested inflammatory myopathy. Muscle biopsy specimens from all four patients revealed vasculitis and inflammation in proximity to the affected vessels, without any discernible characteristics of other myopathies. The patients also complained of symptoms affecting other organs, such as the ears and kidneys, which is typical of AAV cases. Remission induction therapy, such as cyclophosphamide pulse therapy in addition to oral prednisolone, were effective for all four patients. However, relapses occurred in two patients during maintenance therapy and two patients died of aspiration pneumonia. Discussion: The clinical course of our patients might represent a subtype of AAV that is characterized by muscle weakness of the trunk and proximal extremities and arises from vasculitis within the muscles. The clinical manifestations of our patients were similar to those of patients with inflammatory myopathy with regard to the distribution of muscle weakness, MRI and needle EMG findings. However, there are notable differences between AAV associated myopathy vs. inflammatory myositis like dermatomyositis; (1) the absence of elevated CK levels, (2) the presence of complications in other organs, (3) distinct pathological findings, and (4) severe outcomes. Awareness that AAV patients with muscle involvement could have a subtype of AAV that seriously affects various organs is critical for an accurate diagnosis and effective therapeutic management.

Long-Term Impact of Additional Ablation After Pulmonary Vein Isolation: Results From EARNEST-PVI Trial.

Background An optimal strategy for left atrial ablation in addition to pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (AF) has not been determined. Methods and Results We conducted an extended follow-up of the multicenter randomized controlled EARNEST-PVI (Efficacy of Pulmonary Vein Isolation Alone in Patients With Persistent Atrial Fibrillation) trial, which compared 12-month rhythm outcomes in patients with persistent AF between patients randomized to a PVI-alone strategy (n=248) or PVI-plus strategy (n=248; PVI followed by left atrial additional ablation, including linear ablation or ablation targeting areas with complex fractionated electrograms). The present study extended the follow-up period to 3 years after enrollment. Outcomes were compared not only between randomly allocated groups but also between on-treatment groups categorized by actually created ablation lesions. Recurrence rate of AF or atrial tachycardia (AT) was lower in the randomly allocated to PVI-plus group than the PVI-alone group (29.0% versus 37.5%, P=0.036). On-treatment analysis revealed that patients with PVI+linear ablation (n=205) demonstrated a lower AF/AT recurrence rate than those with PVI only (26.3% versus 37.8%, P=0.007). In contrast, patients with PVI+complex fractionated electrograms ablation (n=37) had an AF/AT recurrence rate comparable to that of patients with PVI only (40.5% versus 37.8%, P=0.76). At second ablation in 126 patients with AF/AT recurrence, ATs excluding common atrial flutter were more frequent in patients with PVI+linear ablation than in those with PVI only (32.6% versus 5.7%, P<0.0001). Conclusions Left atrial ablation in addition to PVI was efficacious during 3-year follow-up. Linear ablation was superior to other ablation strategies but may increase iatrogenic ATs. Registration URL: http://www.umin.ac.jp/ctr/index-j.htm; Unique identifier: UMIN000019449.

[Therapeutic Strategies for Inflammatory Neuropathy].

Most cases of inflammatory neuropathy can be treated. It is important to treat patients before axonal degeneration can cause irreversible damage. Conventional treatments include corticosteroids, intravenous immunoglobulin (IVIg), and plasma exchange. Recently, the efficacy of various immunosuppressive and biological agents has increased. Drug efficacy varies depending on the disease and the underlying pathomechanisms. In addition, patients often respond differently to each treatment; therefore, selecting the most appropriate treatment for each patient by assessing the severity of the disease and the efficacy of drugs at appropriate time points is necessary.

Jo-1 Antibodies From Myositis Induce Complement-Dependent Cytotoxicity and TREM-1 Upregulation in Muscle Endothelial Cells.

BACKGROUND AND OBJECTIVES: Muscle microangiopathy due to dysfunction of endothelial cells because of inflammation is a critical hallmark of dermatomyositis (DM); however, its pathomechanism remains unclear. The aim of this study was to evaluate the effect of immunogloblin G (IgG) from patients with idiopathic inflammatory myopathies (IIM) on muscle endothelial cells in vitro. METHODS: Using a high-content imaging system, we analyzed whether IgG purified from sera from patients with IIM (n = 15), disease controls (DCs: n = 7), and healthy controls (HCs: n = 7) can bind to muscle endothelial cells and induce complement-dependent cellular cytotoxicity. RESULTS: IgGs from Jo-1 antibody myositis could bind to muscle endothelial cells and caused complement-dependent cell cytotoxicity. RNA-seq demonstrated the upregulation of genes associated with tumor necrosis factor (TNF)-α, triggering receptor expressed on myeloid cells-1 (TREM-1), CD25, and mitochondria pathways after exposure to IgG from the Jo-1, signal recognition particle (SRP), and polymyositis (PM) groups. The high-content imaging system showed that TREM-1 expression in the Jo-1, SRP, and PM groups was increased in comparison with DCs and HCs and that the TNF-α expression in the Jo-1 group was higher in comparison with the SRP, PM, DC, and HC groups. The expression of TREM-1 was observed in biopsied capillaries and the muscle membrane from patients with Jo-1 and in biopsied muscle fiber and capillaries from patients with DM and SRP. The depletion of Jo-1 antibodies by IgG of patients with Jo-1 antibody myositis reduced the Jo-1 antibody-induced complement-dependent cellular cytotoxicity in muscle endothelial cells. DISCUSSION: Jo-1 antibodies from Jo-1 antibody myositis show complement-dependent cellular cytotoxicity in muscle endothelial cells. IgGs from patients with Jo-1, SRP, and DM increase the TREM-1 expression in endothelial cells and muscles.

Highlighting In Vitro the Role of Brain-like Endothelial Cells on the Maturation and Metabolism of Brain Pericytes by SWATH Proteomics.

Within the neurovascular unit, brain pericytes (BPs) are of major importance for the induction and maintenance of the properties of the blood-brain barrier (BBB) carried by the brain microvessel endothelial cells (ECs). Throughout barriergenesis, ECs take advantage of soluble elements or contact with BPs to maintain BBB integrity and the regulation of their cellular homeostasis. However, very few studies have focused on the role of ECs in the maturation of BPs. The aim of this study is to shed light on the proteome of BPs solocultured (hBP-solo) or cocultured with ECs (hBP-coc) to model the human BBB in a non-contact manner. We first generated protein libraries for each condition and identified 2233 proteins in hBP-solo versus 2492 in hBP-coc and 2035 common proteins. We performed a quantification of the enriched proteins in each condition by sequential window acquisition of all theoretical mass spectra (SWATH) analysis. We found 51 proteins enriched in hBP-solo related to cell proliferation, contractility, adhesion and extracellular matrix element production, a protein pattern related to an immature cell. In contrast, 90 proteins are enriched in hBP-coc associated with a reduction in contractile activities as observed in vivo in 'mature' BPs, and a significant gain in different metabolic functions, particularly related to mitochondrial activities and sterol metabolism. This study highlights that BPs take advantage of ECs during barriergenesis to make a metabolic switch in favor of BBB homeostasis in vitro.

[Clinical features of 8 patients with multifocal motor neuropathy in the long-term follow-up].

OBJECTIVE: To clarify the clinical and long-term characteristics of multifocal motor neuropathy (MMN). METHODS: We retrospectively evaluated data from 8 consecutive MMN patients in Yamaguchi University Hospital from 2005 to 2020. Clinical information including dominant hand, occupations, hobbies, nerve conduction data, protein level in cerebrospinal fluid (CSF), responsiveness to intravenous immunoglobulin (IVIg) therapy as initial therapy as well as maintenance therapy were collected. RESULTS: Unilateral upper limb was initially affected in all patients and a dominant upper extremity was affected in six of them. Seven patients had occupations or hobbies which were associated with overuse of their dominant upper extremity. CSF protein level was normal or slightly elevated. Nerve conduction studies showed conduction blocks in 4 cases. Effectiveness of IVIg treatment as initial therapy was observed in all patients. Maintenance therapy was not needed in 2 patients because of mild symptoms with stable clinical course. Long-term maintenance therapy with immunoglobulin was effective in 5 patients during the follow-up period. CONCLUSION: Dominant upper extremity was frequently affected and most patients had job or habit associated with its overuse, suggesting that physical overload induces inflammation or demyelination in MMN. IVIg was commonly effective as both introduction and long-term maintenance therapies. Complete remission was achieved after several IVIg treatments in some patients.

TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1.

Neuroinflammation and brain lipid imbalances are observed in Alzheimer's disease (AD). Tumor necrosis factor-α (TNFα) and the liver X receptor (LXR) signaling pathways are involved in both processes. However, limited information is currently available regarding their relationships in human brain pericytes (HBP) of the neurovascular unit. In cultivated HBP, TNFα activates the LXR pathway and increases the expression of one of its target genes, the transporter ATP-binding cassette family A member 1 (ABCA1), while ABCG1 is not expressed. Apolipoprotein E (APOE) synthesis and release are diminished. The cholesterol efflux is promoted, but is not inhibited, when ABCA1 or LXR are blocked. Moreover, as for TNFα, direct LXR activation by the agonist (T0901317) increases ABCA1 expression and the associated cholesterol efflux. However, this process is abolished when LXR/ABCA1 are both inhibited. Neither the other ABC transporters nor the SR-BI are involved in this TNFα-mediated lipid efflux regulation. We also report that inflammation increases ABCB1 expression and function. In conclusion, our data suggest that inflammation increases HBP protection against xenobiotics and triggers an LXR/ABCA1 independent cholesterol release. Understanding the molecular mechanisms regulating this efflux at the level of the neurovascular unit remains fundamental to the characterization of links between neuroinflammation, cholesterol and HBP function in neurodegenerative disorders.

Autocrine TNF-α Increases Penetration of Myelin-Associated Glycoprotein Antibodies Across the Blood-Nerve Barrier in Anti-MAG Neuropathy.

BACKGROUND AND OBJECTIVES: Deposition of myelin-associated glycoprotein (MAG) immunoglobulin M (IgM) antibodies in the sural nerve is a key feature in anti-MAG neuropathy. Whether the blood-nerve barrier (BNB) is disrupted in anti-MAG neuropathy remains elusive.We aimed to evaluate the effect of sera from anti-MAG neuropathy at the molecular level using our in vitro human BNB model and observe the change of BNB endothelial cells in the sural nerve of anti-MAG neuropathy. METHODS: Diluted sera from patients with anti-MAG neuropathy (n = 16), monoclonal gammopathies of undetermined significance (MGUS) neuropathy (n = 7), amyotrophic lateral sclerosis (ALS, n = 10), and healthy controls (HCs, n = 10) incubated with human BNB endothelial cells to identify the key molecule of BNB activation using RNA-seq and a high-content imaging system, and exposed with a BNB coculture model to evaluate small molecule/IgG/IgM/anti-MAG antibody permeability. RESULTS: RNA-seq and the high-content imaging system showed the significant upregulation of tumor necrosis factor (TNF-α) and nuclear factor-kappa B (NF-κB) in BNB endothelial cells after exposure to sera from patients with anti-MAG neuropathy, whereas the serum TNF-α concentration was not changed among the MAG/MGUS/ALS/HC groups. Sera from patients with anti-MAG neuropathy did not increase 10-kDa dextran or IgG permeability but enhanced IgM and anti-MAG antibody permeability. Sural nerve biopsy specimens from patients with anti-MAG neuropathy showed higher TNF-α expression levels in BNB endothelial cells and preservation of the structural integrity of the tight junctions and the presence of more vesicles in BNB endothelial cells. Neutralization of TNF-α reduces IgM/anti-MAG antibody permeability. DISCUSSION: Sera from individuals with anti-MAG neuropathy increased transcellular IgM/anti-MAG antibody permeability via autocrine TNF-α secretion and NF-κB signaling in the BNB.

Paraneoplastic Neuromyelitis Optica Spectrum Disorder Related to Glucose-regulated Protein 78 (GRP78) Autoantibodies in a Patient with Lynch Syndrome-associated Colorectal Cancer.

Neuromyelitis optica spectrum disorders have been previously reported in a paraneoplastic context, although there is no clear consensus on their pathogenesis. We herein report a case of aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder in a 64-year-old woman with colorectal cancer. She underwent tumor resection, resulting in serum aquaporin-4 antibody titers subsequently becoming negative. Serum samples were also positive for glucose-regulated protein 78 antibody, which has recently been suggested to be a novel factor in the disruption of the blood-brain barrier. Serological and pathological investigations in this case highlight the role and involvement of aquaporin-4 and glucose-regulated protein 78 antibodies in paraneoplastic conditions.