Short-term and long-term prognoses in AChR-Ab positive very-late-onset myasthenia gravis patients.

Background: Very-late-onset myasthenia gravis (VLOMG) refers to myasthenia gravis (MG) with onset at age 65 or older. Current research on VLOMG prognosis remains limited, especially regarding factors influencing outcomes.

Objectives: To identify the clinical factors that affect the short- and long-term prognosis of MG patients with an onset age ⩾65 years.

Diisodecyl phenyl phosphate promotes foam cell formation by antagonizing Liver X receptor alpha.

While the cardiovascular system is a primary target of organophosphorus flame retardants (OPFRs), particularly aryl-OPFRs, it is still exclusive whether the diisodecyl phenyl phosphate (DIDPP), widely used and broadly present in the environment at high concentrations, elicits atherosclerosis effects. Liver X receptors (LXRs) play a direct role in regulating the formation of atherosclerotic lesions. This study was the first to demonstrate that DIDPP acts as an LXRα ligand and functions as an LXRα antagonist with a half-maximal inhibitory concentration of 16.

Ckip-1 3'UTR alleviates prolonged sleep deprivation induced cardiac dysfunction by activating CaMKK2/AMPK/cTNI pathway.

Sleep deprivation (SD) has emerged as a critical concern impacting human health, leading to significant damage to the cardiovascular system. However, the underlying mechanisms are still unclear, and the development of targeted drugs is lagging. Here, we used mice to explore the effects of prolonged SD on cardiac structure and function.

Advancing the Understanding of Vesicle-Associated Membrane Protein 1-Related Congenital Myasthenic Syndrome: Phenotypic Insights, Favorable Response to 3,4-Diaminopyridine, and Clinical Characterization of Five New Cases.

Background: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS.

Methods: This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype.

Relationships of Liver X Receptor Antagonists and Atherosclerosis in Drinking Water from Six Chinese Major Cities.

While environmental factors have been considered contributors to atherosclerosis, it remains unclear whether drinking water promotes foam cell formation, the initial event of atherosclerosis. This study revealed that drinking water from six major cities in China, namely, Harbin, Jinan, Shanghai, Wuhan, Chongqing, and Zhuhai, significantly promoted foam cell formation in an in vitro macrophage model at a minimum concentration fold of 2. Moreover, cholesterol efflux was significantly impeded by all samples at 2-16-fold, while cholesterol influx was induced only by samples from Jinan and Chongqing at 16-fold, suggesting the dominant role of efflux in foam cell formation.

Discovery of Three Organothiophosphate Esters in River Water Using High-Resolution Mass Spectrometry.

Records of the environmental occurrence of organothiophosphate esters (OTPEs), which are used as flame retardants and food and industrial additives, are unavailable. In this study, we discovered three OTPEs, namely ,,-tris(2,4-di--butylphenyl) phosphorothioate (AO168═S), -butyl -(butyl-methylphenyl) -(di-butylphenyl) phosphorothioate (BBMDBPt)/,-bis(dibutylphenyl) -methyl phosphorothioate (BDBPMPt), and -butyl -ethyl -hydrogen phosphorothioate (BEHPt), in the surface water of the Yangtze River Basin by applying a characteristic phosphorothioate fragment-directed high-resolution mass spectrometry method. Among the 17 water samples tested, the detection frequencies of AO168═S and BEHPt were 100% and that of BBMDBPt/BDBPMPt was 29%.

Impaired gating of γ- and ε-AChR respectively causes Escobar syndrome and fast-channel myasthenia.

Objective: To dissect the kinetic defects of acetylcholine receptor (AChR) γ subunit variant in an incomplete form of the Escobar syndrome without pterygium and compare it with those of a variant of corresponding residue in the AChR ε subunit in a congenital myasthenic syndrome (CMS).

Methods: Whole exome sequencing, α-bungarotoxin binding assay, single channel patch-clamp recordings, and maximum likelihood analysis of channel kinetics.

Results: We identified compound heterozygous variants in AChR γ and ε subunits in three Escobar syndrome (1-3) and three CMS patients (4-6), respectively.

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients.

Comparison between mono-tacrolimus and mono-glucocorticoid in the treatment of myasthenia gravis.

Objective: Use of tacrolimus in mild to moderate myasthenia gravis (MG) is generally limited to glucocorticoid-refractory cases; the advantage of mono-tacrolimus over mono-glucocorticoids is unknown.

Methods: We included mild to moderate MG patients treated with mono-tacrolimus (mono-TAC) or mono-glucocorticoids (mono-GC). The correlation between the immunotherapy options and the treatment efficacy and side effects were examined in 1:1 propensity-score matching.

Benzotriazole ultraviolet stabilizer UV-234 promotes foam cell formation in RAW264.7 macrophages.

Benzotriazole ultraviolet stabilizers (BUVSs) have been reported to induce inflammatory responses which may promote cholesterol accumulation and to downregulate the expression of genes involved in cholesterol biosynthesis; hence, we speculated whether BUVSs promote foam cell formation, which plays a key role in all stages of atherosclerosis. Herein, we used high-content imaging to screen all available BUVSs; of all the 17 candidates, 6 of them could promote foam cell formation at 10 μM. Further analyses showed that one BUVS UV-234 markedly increased the foam cell staining intensity by 15.

Exposure assessment of aryl-organophosphate esters based on specific urinary biomarkers and their associations with reproductive hormone homeostasis disruption in women of childbearing age.

The effects of aryl-organophosphate esters (aryl-OPEs) on female reproduction health are still unclear owing to the lack of specific exposure biomarkers. Here, we analyzed the hydroxylated metabolites of three aryl-OPEs (phenyl diphenyl phosphate [TPhP], 2-ethylhexyl diphenyl phosphate [EHDPP], and tricresyl phosphate [TCrP]) and diphenyl phosphate (DPhP) in urine samples from 913 women of childbearing age, and explored the association between exposure to the aryl-OPEs and reproductive hormone levels. The detection frequencies of 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-OH-EHDPP), phenyl di-p-tolyl phosphate (4-OH-MDTP), and 4-hydroxyphenyl diphenyl phosphate (4-OH-TPhP) were 94.

Missense Mutations of Codon 116 in the Gene Cause Rapid Progressive Familial ALS and Predict Short Viability With PMA Phenotype.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, characterized by a great variety of both clinical presentations and genetic causes. Previous studies had identified two different missense mutations in (p.R116C and p.

Charcot-Marie-Tooth Disease With Episodic Rhabdomyolysis Due to Two Novel Mutations in the β Subunit of Mitochondrial Trifunctional Protein and Effective Response to Modified Diet Therapy.

A 29-year-old female experienced chronic progressive peripheral neuropathy since childhood and was diagnosed with Charcot-Marie-Tooth disease (CMT) at age 15. She developed recurrent, fever-induced rhabdomyolysis (RM) at age 24. EMG studies showed decreased amplitude of compound muscle action potential, declined motor conductive velocity, and absence of sensor nerve action potential.

CYP3A5*3 polymorphism and age affect tacrolimus blood trough concentration in myasthenia gravis patients.

The study aims to identify clinical factors affecting tacrolimus blood trough concentration (C0) in myasthenia gravis (MG) patients and to optimize the initial dose of tacrolimus in MG treatment. A total of 103 MG patients participated in this study, and their clinical factors, medication regimens, C0 values and CYP3A5*3 polymorphisms were collected in detail. We used a linear mixed model to analyze the effect of multiple factors on the dosage-weighted C0 (C0:D) and performed subgroup analyses to investigate the consistency of correlations between influencing factors and the C0:D ratios.

Determinants of the repetitive-CMAP occurrence and therapy efficacy in slow-channel myasthenia.

Objective: To find determinants of the occurrence of repetitive compound muscle action potential (R-CMAP) and to assess the efficacy of channel blocker therapy in slow-channel congenital myasthenic syndrome (SCCMS).

Methods: Neurologic examination, EMG study, laboratory test, muscle biopsy, and next-generation and Sanger sequencing; literature review of reported patients with SCCMS, including EMG, kinetics of mutant acetylcholine receptors (AChRs), and response to therapy; and simulation of the decay phase of endplate potential (EPP) were performed.

Results: Three newly characterized and 57 reported patients with SCCMS with mutations of AChR subunits were included.

A novel fast-channel myasthenia caused by mutation in β subunit of AChR reveals subunit-specific contribution of the intracellular M1-M2 linker to channel gating.

Genetic variants causing the fast-channel congenital myasthenic syndrome (CMS) have been identified in the α, δ, and ε but not the β subunit of acetylcholine receptor (AChR). A 16-year-old girl with severe myasthenia had low-amplitude and fast-decaying miniature endplate potentials. Mutation analysis revealed two heteroallelic variants in CHRNB1 encoding the AChR β subunit: a novel c.

Congenital myasthenic syndrome-associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner.

Congenital myasthenic syndromes (CMS) are caused by mutations in molecules expressed at the neuromuscular junction. We report clinical, structural, ultrastructural, and electrophysiologic features of 4 CMS patients with 6 heteroallelic variants in AGRN, encoding agrin. One was a 7.

Bisphenol A and polychlorinated biphenyls enhance the cancer stem cell properties of human ovarian cancer cells by activating the WNT signaling pathway.

Cancer stem cells (CSCs) are a very small subpopulation that have stem-cell qualities, such as exhibiting self-renewal, immortality, and pluripotency, and the capability to differentiate into different tumor cell subtypes. CSCs contribute to tumor onset, expansion, metastasis, resistance and recurrence. Meanwhile, organic pollutants, including nonpersistent pollutants, such as bisphenol A (BPA), and persistent pollutants, such as polychlorinated biphenyls (PCBs), are toxic chemicals that can be readily ingested via dietary exposure and other exposure routes and can accumulate through the food chain.

Slow-channel myasthenia due to novel mutation in M2 domain of AChR delta subunit.

Objective: To characterize the molecular and phenotypic basis of a severe slow-channel congenital myasthenic syndrome (SCCMS).

Methods: Intracellular and single-channel recordings from patient endplates; alpha-bungarotoxin binding studies; direct sequencing of AChR genes; microsatellite analysis; kinetic analysis of AChR activation; homology modeling of adult human AChR structure.

Results: Among 24 variants reported to cause SCCMS only two appear in the AChR δ-subunit.

A homozygous mutation in GMPPB leads to centronuclear myopathy with combined pre- and postsynaptic defects of neuromuscular transmission.

Mutations in GMPPB cause a wide spectrum of neuromuscular syndromes, including muscular dystrophies and congenital myasthenic syndrome. The mechanisms by which GMPPB mutations impair neuromuscular transmission however remain incompletely understood. We expand here upon a previous report of one such patient presenting with a myopathy-congenital myasthenic syndrome overlap phenotype.

Presence of antibodies against low-density lipoprotein receptor-related protein 4 and impairment of neuromuscular junction in a Chinese cohort of amyotrophic lateral sclerosis.

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Radial extracorporeal shock wave promotes the enhanced permeability and retention effect to reinforce cancer nanothermotherapeutics.

Since most cancer nanomedicine relies on the enhanced permeability and retention (EPR) effect to eradicate tumors, strategies that are able to promote nanoparticle (NP) delivery and extravasation are presupposed to elevate the EPR effect for more effective cancer therapeutics. However, nanothermotherapeutics still suffers from limited drug delivery into tumor sites, for even though numerous efforts have been made to enhance the selective tumor targeting of NPs. In this study, we uncovered that radial extracorporeal shock wave therapy (rESWT), an important approach in physical therapy that has been overlooked in cancer treatment in the past, can largely improve the EPR-dependent tumor uptake of NPs.

Diagnostic significance of metallothionein members in recognizing cadmium exposure in various organs under low-dose exposure.

Metallothioneins (MTs) are known to protect cells against oxidative stress, especially providing protection against cadmium (Cd) toxicity. To date, besides liver and kidney, the expression profiles of MT members have not been thoroughly determined in a full-spectrum of organs, especially under low-dose exposure settings. Furthermore, their diagnostic value has not been evaluated in reflecting the Cd exposure in diverse organs.

Low-dose PCB126 compromises circadian rhythms associated with disordered glucose and lipid metabolism in mice.

It has been documented that 3, 3', 4, 4', 5-pentachlorobiphenyl (PCB126) elicits diverse detrimental effects on human health including metabolic syndrome and non-alcoholic fatty-liver disease (NAFLD), through a wide array of non-carcinogenic mechanisms, which require further detailed investigations. The circadian clock system consists of central clock machinery (located in the suprachiasmatic nucleus in the hypothalamus) and the peripheral clocks (located in nearly all peripheral tissues). Peripheral clocks in the liver play fundamental roles in maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes that fine-tune the absorption and metabolism of xenobiotics.