Case report: Bilateral facial palsy with paresthesias and positive anti-GT1a antibodies.

Bilateral facial palsy with paresthesia (FDP) is a rare variant of GBS, characterized by simultaneous bilateral facial palsy and paresthesia of the distal limbs. Mounting evidence indicates that the presence of anti-GT1a IgG has a pathogenic role as an effector molecule in the development of cranial nerve palsies in certain patients with GBS, whereas anti-GT1a antibody is rarely presented positive in FDP. Here, we report the case of a 33-year-old male diagnosed with FDP presented with acute onset of bilateral facial palsy and slight paresthesias at the feet as the only neurological manifestation. An antecedent infection with no identifiable reason for the fever or skin eruptions was noted in the patient. He also exhibited cerebrospinal fluid albuminocytologic dissociation and abnormal nerve conduction studies. Notably, the testing of specific serum anti-gangliosides showed positive anti-GT1a IgG/IgM Ab. The patient responded well to intravenous immunoglobulin therapy. This case brings awareness to a rare variant of GBS, and provides the first indication that anti-GT1a antibodies play a causative role in the development of FDP. The case also suggests that prompt management with IVIG should be implemented if FDP is diagnosed.

Insights into the anti-Candida albicans properties of natural phytochemicals: An in vitro and in vivo investigation.

Invasive candidiasis, attributed to Candida albicans, has long been a formidable threat to human health. Despite the advent of effective therapeutics in recent decades, the mortality rate in affected patient populations remains discouraging. This is exacerbated by the emergence of multidrug resistance, significantly limiting the utility of conventional antifungals. Consequently, researchers are compelled to continuously explore novel solutions. Natural phytochemicals present a potential adjunct to the existing arsenal of agents. Previous studies have substantiated the efficacy of phytochemicals against C. albicans. Emerging evidence also underscores the promising application of phytochemicals in the realm of antifungal treatment. This review systematically delineates the inhibitory activity of phytochemicals, both in monotherapy and combination therapy, against C. albicans in both in vivo and in vitro settings. Moreover, it elucidates the mechanisms underpinning the antifungal properties, encompassing (i) cell wall and plasma membrane damage, (ii) inhibition of efflux pumps, (iii) induction of mitochondrial dysfunction, and (iv) inhibition of virulence factors. Subsequently, the review introduces the substantial potential of nanotechnology and photodynamic technology in enhancing the bioavailability of phytochemicals. Lastly, it discusses current limitations and outlines future research priorities, emphasizing the need for high-quality research to comprehensively establish the clinical efficacy and safety of phytochemicals in treating fungal infections. This review aims to inspire further contemplation and recommendations for the effective integration of natural phytochemicals in the development of new medicines for patients afflicted with C. albicans.

SARS-CoV-2 may play a direct role in the pathogenesis of posterior reversible encephalopathy syndrome (PRES) associated with COVID-19: A CARE-compliant case report and literature review.

RATIONALE: During the past 3 years of the corona virus disease 2019 (COVID-19) pandemic, COVID-19 has been recognized to cause various neurological complications, including rare posterior reversible encephalopathy syndrome (PRES). In previously reported cases of PRES associated with COVID-19, the majority of patients had severe COVID-19 infection and known predisposing factors for PRES, such as uncontrolled hypertension, renal dysfunction, and use of immunosuppressants. It remains unclear whether these risk factors or infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contributes to the development of PRES in these patients. Here we report a special case of PRES associated with COVID-19 without any known risk factors for PRES, indicating the SARS-CoV-2's direct role in the pathogenesis of PRES associated with COVID-19. PATIENT CONCERNS: An 18-year-old female patient presented to the emergency department with abdominal pain. Preliminary investigations showed no abnormalities, except for positive results in novel coronavirus nucleic acid tests using oropharyngeal swabs. However, the patient subsequently developed tonic-clonic seizures, headaches, and vomiting on the second day. Extensive investigations have been performed, including brain MRI and lumbar puncture. Brain MRI showed hypointense T1-weighted and hyperintense T2-weighted lesions in the bilateral occipital, frontal, and parietal cortices without enhancement effect. Blood and cerebrospinal fluid analyses yielded negative results. The patient had no hypertension, renal insufficiency, autoimmune disease, or the use of immunosuppressants or cytotoxic drugs. DIAGNOSES: PRES was diagnosed based on the clinical features and typical MRI findings of PRES. INTERVENTIONS: Symptomatic treatments such as anticonvulsants were administered to the patients. OUTCOMES: The patient fully recovered within 1 week. The initial MRI abnormalities also disappeared completely on a second MR examination performed 11 days later, supporting the diagnosis of PRES. The patient was followed up for 6 months and remained in a normal state. LESSONS: The current case had no classical risk factors for PRES, indicating that although the cause of PRES in COVID-19 patients may be multifactorial, the infection of SARS-CoV-2 may play a direct role in the pathogenesis of PRES associated with COVID-19.

Signal amplification strategy of DNA self-assembled biosensor and typical applications in pathogenic microorganism detection.

Biosensors have emerged as ideal analytical devices for various bio-applications owing to their low cost, convenience, and portability, which offer great potential for improving global healthcare. DNA self-assembly techniques have been enriched with the development of innovative amplification strategies, such as dispersion-to-localization of catalytic hairpin assembly, and dumbbell hybridization chain reaction, which hold great significance for building biosensors capable of realizing sensitive, rapid and multiplexed detection of pathogenic microorganisms. Here, focusing primarily on the signal amplification strategies based on DNA self-assembly, we concisely summarized the strengths and weaknesses of diverse isothermal nucleic acid amplification techniques. Subsequently, both single-layer and cascade amplification strategies based on traditional catalytic hairpin assembly and hybridization chain reaction were critically explored. Furthermore, a comprehensive overview of the recent advances in DNA self-assembled biosensors for the detection of pathogenic microorganisms is presented to summarize methods for biorecognition and signal amplification. Finally, a brief discussion is provided about the current challenges and future directions of DNA self-assembled biosensors.

Berberine inhibits Candida albicans growth by disrupting mitochondrial function through the reduction of iron absorption.

AIMS: This study aimed to investigate whether berberine (BBR) can inhibit the iron reduction mechanism of Candida albicans, lowering the iron uptake of the yeast and perhaps having antimicrobial effects. METHODS AND RESULTS: We determined that BBR may cause extensive transcriptional remodeling in C. albicans and that iron permease Ftr1 played a crucial role in this process through eukaryotic transcriptome sequencing. Mechanistic research showed that BBR might selectively inhibit the iron reduction pathway to lower the uptake of exogenous iron ions, inhibiting C. albicans from growing and metabolizing. Subsequent research revealed that BBR caused significant mitochondrial dysfunction, which triggered the process of mitochondrial autophagy. Moreover, we discovered that C. albicans redox homeostasis, susceptibility to antifungal drugs, and hyphal growth are all impacted by the suppression of this mechanism by BBR. CONCLUSIONS: The iron reduction mechanism in C. albicans is disrupted by BBR, which disrupts mitochondrial function and inhibits fungal growth. These findings highlight the potential promise of BBR in antifungal applications.

Platelet-Based Nanoparticles with Stimuli-Responsive for Anti-Tumor Therapy.

In addition to hemostasis and coagulation, years of studies have proved that platelets are involved in the whole process of tumor progression, including tumor invasion, intravasation, extravasation, and so on. It means that this property of platelets can be used in anti-tumor therapy. However, traditional platelet-based antitumor drugs often cause autologous platelet damage due to lack of targeting, resulting in serious side effects. Therefore, the researchers designed a variety of anti-tumor drug delivery systems based on platelets by targeting platelets or platelet membrane coating. The drug delivery systems have special response modes, which is crucial in the design of nanoparticles. These modes enhance the targeting and improve the anti-tumor effect. Here, we present a review of recent discoveries in the field of the crosstalk between platelets and tumors and the progress of platelet-based anti-tumor nanoparticles.

Altered gut microbiota in temporal lobe epilepsy with anxiety disorders.

Introduction: Patients with epilepsy are particularly vulnerable to the negative effects of anxiety disorders. In particular, temporal lobe epilepsy with anxiety disorders (TLEA) has attracted more attention in epilepsy research. The link between intestinal dysbiosis and TLEA has not been established yet. To gain deeper insight into the link between gut microbiota dysbiosis and factors affecting TLEA, the composition of the gut microbiome, including bacteria and fungi, has been examined. Methods: The gut microbiota from 51 temporal lobe epilepsy patients has been subjected to sequencing targeting 16S rDNA (Illumina MiSeq) and from 45 temporal lobe epilepsy patients targeting the ITS-1 region (through pyrosequencing). A differential analysis has been conducted on the gut microbiota from the phylum to the genus level. Results: TLEA patients' gut bacteria and fungal microbiota exhibited distinct characteristics and diversity as evidenced by high-throughput sequencing (HTS). TLEA patients showed higher abundances of Escherichia-Shigella (genus), Enterobacterales (order), Enterobacteriaceae (family), Proteobacteria (phylum), Gammaproteobacteria (class), and lower abundances of Clostridia (class), Firmicutes, Lachnospiraceae (family), Lachnospirales (order), and Ruminococcus (genus). Among fungi, Saccharomycetales fam. incertae sedis (family), Saccharomycetales (order), Saccharomycetes (class), and Ascomycota (phylum) were significantly more abundant in TLEA patients than in patients with temporal lobe epilepsy but without anxiety. Adoption and perception of seizure control significantly affected TLEA bacterial community structure, while yearly hospitalization frequency affected fungal community structures in TLEA patients. Conclusion: Here, our study validated the gut microbiota dysbiosis of TLEA. Moreover, the pioneering study of bacterial and fungal microbiota profiles will help in understanding the course of TLEA and drive us toward preventing TLEA gut microbiota dysbiosis.

Electrophysiologic Characteristics of Nitrous-Oxide-Associated Peripheral Neuropathy: A Retrospective Study of 76 Patients.

BACKGROUND AND PURPOSE: The electrophysiologic characteristics of peripheral neuropathy secondary to nitrous oxide (N2O) abuse remain unclear. The paper therefore aimed to summarize the electrophysiologic characteristics of N2O-associated peripheral neuropathy and identify the risk factors of severe nerve injury. METHODS: The electrophysiologic results and clinical data of patients with peripheral neuropathy secondary to N2O abuse at our hospital between 2018 and 2020 were analyzed retrospectively, and their electrophysiologic changes were summarized. RESULTS: Most patients exhibited decreased sensory and motor nerve conduction velocities (75% and 76%), decreased sensory nerve and compound motor action potentials (57% and 59%), and prolonged distal motor latency (59%), while a response was absent in 36%. These findings indicate that N2O abuse can result in generalized injury to sensory and motor nerves. Electrophysiologic results indicated axonal neuropathy in 37 cases (49%), demyelinating peripheral neuropathy in 4 (5%), and mixed neuropathy in 12 (16%). Peripheral nerve injury was more common in the lower limbs (72%) than in the upper limbs (42%, p<0.0001). The upper and lower limbs were primarily affected by sensory nerve demyelination (35%) and motor axonal injury (67%), respectively. Subgroup analysis indicated that longer N2O exposure and longer disease course were associated with more-severe motor axonal injury in the lower limbs. CONCLUSIONS: N2O-associated peripheral neuropathy can lead to sensory and motor nerve injury, with axonal injury being the most common. Injuries were more severe in the lower limbs. Prolonged N2O exposure and disease course increased the severity of motor axonal injury in the lower limbs.

An integrated framework of ground source heat pump utilisation for high-performance buildings.

CO2 emissions from building operations have increased to their highest level globally, moving away from the Paris Agreement goal of below 2 °C. While geothermal is recognised as a promising renewable source, the lack of an integrated framework guiding investigating ground source heat pumps for building operations, along with the incapability of well-known simulation tools in accurately capturing ground thermal performance, hinders its application. This research aims to unlock ground source heat pumps for building operations through an integrated framework, including an overarching improved U.S. National Renewable Energy Laboratory (NREL) monitoring guideline, a sensor-based monitoring prototype, and a g-function-based simulation approach. This research proposes amendments and improvements to the NREL guideline for monitoring geothermal energy by separating Thermal Energy Net Production from Thermal Energy Gross Production. A state-of-the-art case building located in Melbourne, Australia, housing advanced technologies, including ground source heat pump systems, is used to demonstrate and validate the research framework. A typical winter month in the southern hemisphere, July 2021, is monitored for the ground source heat pump systems designed and used for space heating. The findings reveal that the thermal energy generation during working days in July 2021 is close to the simulation results, with a difference of 2.2% in gross thermal energy production and a difference of 0.92% in inlet temperature. This research develops and validates an integrated approach for evaluating ground source heat pump systems, contributing to the utilisation of geothermal energy for building operations.

Antifungal activity and potential mechanism of berberine hydrochloride against fluconazole-resistant Candida albicans.

Introduction. The emergence of resistance to fluconazole in Candida albicans has made the clinical treatment of this microbe difficult. A potential strategy to address this problem involves diminishing fungal resistance to antimicrobial drugs.Hypothesis. Berberine hydrochloride (BH), the primary active ingredient of the traditional Chinese medicine (TCM) Coptis, inhibits the growth of fluconazole-resistant C. albicans through its action on the high-osmolarity glycerol mitogen-activated protein kinase (HOG-MAPK) pathway.Aim. To examine the effect of BH on the HOG-MAPK pathway to assess the potential molecular mechanism by which BH inhibits fluconazole-resistant C. albicans.Methodology. The minimum inhibitory concentration (MIC) of BH to fluconazole-resistant C. albicans was measured using the broth microdilution approach to determine the concentration of effective drug intervention. Changes in physiological functions regulated by the HOG-MAPK pathway in response to BH treatment were measured, as well as the expression of central signalling pathway genes and key downstream factors by qRT-PCR and Western blotting, respectively.Results. BH inhibited fluconazole-resistant C. albicans and the sensitivity to fluconazole increased after BH treatment. At a concentration of 256 and 64 µg ml-1 BH may affect key downstream factors that regulate several physiological functions of C. albicans by upregulating the core genes expression of SLN1, SSK2, HOG1, and PBS2 in the HOG-MAPK pathway. Upregulation of GPD1, the key gene for glycerol synthesis, increased cell osmotic pressure. BH treatment increased the accumulation of reactive oxygen species by upregulating the expression of the key respiratory metabolism gene ATP11 and downregulating the expression of the superoxide dismutase gene SOD2. Furthermore, downregulation of mycelial-specific HWP1 hindered the morphological transformation of C. albicans and inhibition of the chitin synthase gene CHS3 and the ß-(1,3) glucan synthase gene GSC1 impaired cytoderm integrity.Conclusion. BH affects multiple target genes in diminishing the resistance of C. albicans strains to fluconazole. This effect may be related to the action of BH on the HOG-MAPK pathway.

Circ_0000811 acts as a miR-15b sponge and inhibits Prkar2a-mediated JAK2/STAT1 pathway to attenuate cerebral ischemic vertigo.

Circular RNAs (circRNAs) have been noted to express in the brain and thus participate in various diseases related to the central nervous system. However, the potential role of circRNAs in cerebral ischemia (CI)-induced vertigo remains unknown. We initially predicted through bioinformatics analysis the poor expression of circ_0000811 related to CI. A mouse model of CI-induced vertigo was then established, which was validated by measurement of escape latency and medial vestibular nucleus (MVN) blood flow, with NeuN/Annexin counterstaining utilized to detect cell apoptosis in the MVN. An oxygen glucose deprivation (OGD)-exposed neuron-like cell model was further established for in vitro gain- and loss- of function assays, with flow cytometry performed to detect cell apoptosis. The poorly expressed circ_0000811, up-regulated miR-15b expression, and down-regulated Prkar2a expression were observed in both mice with CI-induced vertigo and OGD-exposed cells. Our data then demonstrated that circ_0000811 restoration alleviated CI-induced vertigo in mouse models, and that circ_0000811 acted as a miR-15b sponge to inhibit miR-15b expression. Prkar2a was validated as the target gene of miR-15b. Prkar2a restoration was subsequently revealed to repress OGD-induced neuronal apoptosis through JAK2/STAT1 signaling pathway inactivation. Furthermore, inactivation of the JAK2/STAT1 signaling pathway exerted an anti-apoptotic effect in OGD-induced neurons and an alleviatory effect in mice with CI-induced vertigo with Prkar2a overexpression and circ_0000811 overexpression. Taken together, our work suggests that circ_0000811 is involved in neuronal apoptosis of CI-induced vertigo and may be used as a biomarker for ameliorating CI-induced vertigo.

Analysis of clinical characteristics and prognostic factors in 110 patients with nitrous oxide abuse.

PURPOSE: To review the clinical symptoms, auxiliary examination findings, and outcomes of patients with nitrous oxide (N2 O) abuse, and analyze the factors that affect outcomes. METHODS: Patients with N2 O abuse treated in the Department of Neurology between January 2018 and December 2020 were included. The clinical data of these patients were collected, and follow-up was conducted to determine the outcomes. RESULTS: The average age of the 110 patients with N2 O abuse was 21.4 ± 4.2 years (range: 14-33 years). Clinical presentation primarily included neurological symptoms, such as limb numbness and/or weakness (97%), psychiatric symptoms, changes in appetite, and skin hyperpigmentation. Laboratory test results were characterized by vitamin B12 deficiency (60%, 34 out of 57 cases) and high homocysteine level (69%, 31 out of 45 cases). Electromyography indicated mixed axonal and demyelination injury (92%, 80 out of 87 cases). Motor and sensory nerves were simultaneously involved, and injury primarily involved the lower limbs. One hundred and seven (97%) patients were clinically diagnosed with peripheral neuropathy, of whom 26 (24%) exhibited spinal abnormalities on magnetic resonance imaging, supporting a diagnosis of subacute combined degeneration. Treatment included N2 O withdrawal and vitamin B12 supplementation. Reexamination of six patients indicated that treatment was effective. Follow-up was completed for 51 patients. Thirty-four patients (67%) recovered completely, 17 patients (33%) had residual limb numbness, and only one patient experienced relapse. Sex was an independent prognostic factor; the outcomes of female patients were better than that of male patients. CONCLUSION: The recreational use of N2 O has largely expanded among youth in recent decades, which has become a growing public health concern in China. It highlights the importance of the recognition of various clinical symptoms, particularly limb numbness and/or weakness related to the cases of N2 O abuse. The therapeutic administration of vitamin B12 supplementation and N2 O withdrawal can make the overall prognosis good, especially for female patients.

Overexpressing circ_0000831 is sufficient to inhibit neuroinflammation and vertigo in cerebral ischemia through a miR-16-5p-dependent mechanism.

Circular RNAs (circRNAs) hold potential as stroke-related biomarkers due to involvement in various pathophysiological processes associated with cerebral ischemia and stability in peripheral blood. Differentially expressed circulating circRNAs were identified by preliminary sequencing analysis, through which we identified underexpressed circ_0000831 in ischemic stroke (IS). Validation was performed in peripheral blood of IS patients by quantitative polymerase chain reaction. Microglia was exposed to oxygen-glucose deprivation (OGD), where polarization phenotypes and inflammation were assessed. Middle cerebral artery occlusion was performed in mice to mimic ischemic stroke-induced vertigo, where cerebral blood flow, neurological deficits, vertigo degree, infarct area, inflammation and cell apoptosis were assayed in response to ectopic expression and knockdown of circ_0000831, miR-16-5p, and AdipoR2. Mechanically, circ_0000831 bound to miR-16-5p and downregulated miR-16-5p, and AdipoR2 was targeted by miR-16-5p and increased PPARγ expression in microglia. Furthermore, circ_0000831, AdipoR2, or PPARγ overexpression or miR-16-5p inhibition alleviated neuroinflammation, vertigo, neurological deficit, and cell apoptosis in MCAO mice. Consistently, circ_0000831, AdipoR2, or PPARγ upregulation or miR-16-5p downregulation diminished apoptosis and inflammation of OGD-induced microglia. Consequently, these findings pinpoint the circ_0000831/miR-16-5p/AdipoR2 axis as an essential signaling pathway during ischemia stroke. Thus, the circRNA circ_0000831 may work as a possible target for novel treatment in patients with ischemic stroke.

Clinical characteristics of Lewy body dementia in Chinese memory clinics.

BACKGROUND: Lewy body dementia (LBD), consisting of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is the second most common type of neurodegenerative dementia in older people. The current study aimed to investigate the clinical characteristics of LBD in Chinese memory clinics. METHODS: A total of 8405 dementia medical records were reviewed, revealing 455 patients with LBD. Demographic data, neuropsychological scores, and the scale for Medial Temporal lobe Atrophy (MTA) were then analyzed from nine memory clinics in the China Lewy Body Disease Collaborative Alliance. RESULTS: The clinical proportion of LBD among the subjects and among all dementia types was 5.4% (4.9-5.9%) and 7.3% (6.7-8.0%), respectively, with a mean onset age of 68.6 ± 8.4 years. Patients with DLB comprised 5.6% (n = 348, age of onset 69.1 ± 8.3), while PDD comprised 1.7% (n = 107, age of onset 66.7 ± 8.8) of all dementia cases. There were slightly more males than females with DLB (n = 177, 50.9%) and PDD (n = 62, 57.9%). Patients with DLB had a poorer performance compared to those with PDD on the MMSE (16.8 ± 7.1 vs. 19.5 ± 5.7, p = 0.001), the MoCA (11.4 ± 6.6 vs. 14.0 ± 5.8, p<0.001), the CDR (1.8 ± 0.7 vs. 1.6 ± 0.7, p = 0.002), and the MTA (1.8 ± 0.7 vs. 1.2 ± 0.6, p = 0.002). Diagnostic differences for LBD exist among the centers; their reported proportions of those with DLB ranged from 0.7 to 11.4 and those with PDD ranged from 0.0 to 2.9%. CONCLUSIONS: Variations of diagnoses exists in different regions and the clinical proportion of LBD is likely to be underestimated in China and other regions.

Clinical and MRI Differences Between Patients With Subacute Combined Degeneration of the Spinal Cord Related vs. Unrelated to Recreational Nitrous Oxide Use: A Retrospective Study.

Objective: To explore the clinical and imaging characteristics of subacute combined degeneration of the spinal cord (SCD) related to recreational nitrous oxide (N2O) use. Methods: Clinical and imaging data were retrospectively collected from patients with SCD related to recreational N2O use who were diagnosed and treated at Shengjing Hospital of China Medical University from January 2016 to June 2020. The clinical and imaging features of patients with recreational N2O-related SCD were compared with those of patients with N2O-unrelated SCD, who were diagnosed and treated during the same period of time. Results: The study enrolled 50 patients (male/female: 22/28, age: 21.4 ± 4.7 years) with N2O-related SCD and 48 patients (male/female: 27/21, age: 62.0 ± 11.4 years) with SCD unrelated to N2O use. The most common signs/symptoms of the patients in both groups were limb numbness and weakness and unsteady gait, but the incidence of limb weakness, unsteady gait, disorders of urination and defecation, anorexia, reduced deep sensation in lower limbs, ataxia, and positive Babinski sign were lower in the N2O-related SCD group than those in the N2O-unrelated SCD group (P < 0.05). The functional disability rating score of patients in the N2O-related SCD group (median: 3, IQR: 2-5) was also significantly lower than the score in the N2O-unrelated SCD group (median: 5, IQR: 4-7) (P < 0.05). The serum vitamin B12 level was significantly lower in the N2O-unrelated SCD group (median: 96 pg/mL, IQR: 50-170 pg/mL) than the level in the N2O-related SCD group (median: 218 pg/mL, IQR:121-350 pg/mL) (P < 0.05), while both groups had similarly increased levels of homocysteine (P > 0.05). Compared with the N2O-unrelated SCD patients, more patients with N2O-related SCD had abnormal spinal magnetic resonance imaging (MRI) scans (80.0 vs. 64.2%). The patients with N2O-related SCD also had wider spinal lesions on sagittal MRI (5.3 ± 0.8 mm vs. 4.2 ± 1.0 mm), fewer spinal segments with lesions (median: 5, IQR: 4-6 segments vs. median: 6, IQR: 5-7.5 segments), and a higher incidence of the inverted V sign on axial MRI (72.0 vs. 31.2%) (all P < 0.05). Conclusion: The recreational use of N2O has become an important cause of SCD in young patients. Compared with the N2O-unrelated SCD patients, the N2O-related SCD patients had less severe clinical presentations, less obvious decrease in serum VB12 levels, and more obvious MRI changes.

SQSTM1 variant in disorders of the frontotemporal dementia-amyotrophic lateral sclerosis spectrum: identification of a novel heterozygous variant and a review of the literature.

INTRODUCTION: Accumulating evidence shows that SQSTM1 plays a vital role in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which represent a neurodegenerative disease continuum. Here, we report a novel SQSTM1 variant in a patient presenting with progressive nonfluent aphasia (PNFA) and progressive bulbar palsy (PBP). Relevant literature about FTD and FTD-ALS caused by SQSTM1 mutation was reviewed to better understand its clinical features. METHODS: We collected data from a 66-year-old male patient with a novel heterozygous variant (c.995C > G, p.S332X) in the SQSTM1 gene who was diagnosed with PNFA and PBP and performed a PubMed literature search using the advanced research criteria: [("frontotemporal lobar degeneration") OR ("frontotemporal dementia") OR ("amyotrophic lateral sclerosis") OR ("motor neuron disease")] AND ("SQSTM1"). The clinical features of FTD and FTD-ALS related to SQSTM1 mutation were summarized based on previous cases and our new case. RESULTS: The initial symptom of the current patient was progressive verb finding difficulties and effortful speech output, which developed into dysarthria and dysphagia in subsequent months. The results, including tongue atrophy, fasciculations, neurogenic changes, and mild left dominant hypometabolism of 18F-fluorodeoxyglucose PET in the frontal cortex, suggest the possibility of PNFA and PBP. A novel likely pathogenic heterozygous variant (c.995C > G, p.S332X) in the SQSTM1 gene was identified. The literature search revealed a total of 33 FTD and FTD-ALS cases related to the SQSTM1 mutation with detailed clinical information. The mean age of onset (including our patient) was 63.5 ± 9.7 years. bvFTD was the most common clinical phenotype. The missense mutation in the SQSTM1 gene coding region and the UBA domain involvement are its main genetic characteristics. CONCLUSION: Although rare, mutations in SQSTM1 can lead to various clinical subtypes of FTD and FTD-ALS, including the rare combination of PNFA and PBP. Exon missense mutation is the main type of mutation, which is common in the UBA domain.

Circulating Exosome microRNAs as Diagnostic Biomarkers of Dementia.

Dementia is a syndrome of acquired cognitive impairment that leads to a significant decline in a patient's daily life, ability to learn, and the ability to communicate with others. Dementia occurs in many diseases, including Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia, and Parkinson's disease dementia (PDD). Although the analysis of biomarkers in the cerebrospinal fluid (CSF) and peripheral blood physicochemical analysis can indicate neurological impairment, there are currently no sensitive biomarkers for early clinical diagnosis of dementia or for identifying the cause of dementia. Previous studies have suggested that circulating micro (mi)RNAs may be used as biomarkers for diagnosing neurological disorders. However, miRNAs are susceptible to interference by other components in the peripheral circulation, bringing into question the diagnostic value of circulating miRNAs. Exosomes secreted by most cell types contain proteins, mRNAs, and miRNAs that are closely associated with changes in cellular functions. Exosome miRNAs (ex-miRNAs) are highly stable and resistant to degradation. Therefore, these may serve as useful biomarkers for the early clinical diagnosis of dementia. Here, we review studies of ex-miRNAs that commonly cause clinical dementia and explore whether ex-miRNAs may be used as early diagnostic biomarkers of dementia.

Skin hyperpigmentation: a rare presenting symptom of nitrous oxide abuse.

Context: Recreational nitrogen oxide (N2O) abuse can cause nervous system damage. There was a sharp increase in the number of patients with neurological disorders associated with recreational N2O use in China, as recreational N2O use became popular in young people nationwide. Among cases with neurological disorders caused by N2O abuse, a few showed skin hyperpigmentation, which has rarely been reported. We explored the characteristics of hyperpigmentation in N2O abusers to draw the attention of clinicians to this rare cutaneous symptom related to N2O abuse.Methods: We retrospectively collected data of patients with neurological disorders related to recreational N2O abuse in Shengjing Hospital of China Medical University from January 2014 to June 2019. Detailed clinical data were gathered from patients who manifested skin pigmentation, including the history of N2O abuse and characteristics of neurological lesions and skin pigmentation.Results: In total, 66 patients (average age: 22.7 ± 4.5 years, 36 males) with neurological disorders due to N2O abuse were included; four of them (17-23 years old, 1 male) manifested skin hyperpigmentation. The duration of N2O abuse of the four patients ranged from 2 to 24 months, and they all had peripheral neuropathy; the two patients also had subacute combined degeneration of the spinal cord. One patient exhibited significant hyperpigmentation throughout the body (trunk, limbs, and face), with no abnormalities in cortisol and other biochemical tests. One patient presented with punctuate pigmentation throughout the trunk. Two patients presented with finger skin pigmentation, especially in the distal phalanxes. Pigmentation after N2O use remitted slowly with vitamin B12 supplementation.Conclusion: Skin hyperpigmentation is a rare symptom in N2O abusers, which can distribute locally in hands or diffusely throughout the body. Therefore, attention should be paid to a history of N2O abuse and serum vitamin B12 level should be tested.

The sharp rise of neurological disorders associated with recreational nitrous oxide use in China: a single-center experience and a brief review of Chinese literature.

INTRODUCTION: In recent years, there has been a sharp increase in the number of patients with neurological disorders associated with recreational use of nitrous oxide (N2O) in China. Here, we summarize the clinical characteristics of patients with neurological disorders associated with N2O abuse diagnosed in our Hospital. Further, we conducted a literature search on recent cases reported in mainland China to improve the awareness of the outbreak of neurological disorders associated with N2O abuse. METHODS: We retrospectively collected data of patients diagnosed with neurological disorders associated with recreational use of N2O in Shengjing Hospital of China Medical University from January 2018 to June 2019, and performed a literature search using the "nitrous oxide" and "neurological disorder" as keywords in the Chinese literature databases of WANFANG and CNKI and the English literature databases of Pubmed and Web of Science RESULTS: We enrolled 43 patients (average age: 21.9 ± 3.3 years). The main clinical manifestations were weakness and paresthesia in the four extremities and unsteady gait. Further, most patients showed significantly lower levels of serum vitamin B12 (169.4 ± 79.1 pg/mL) and increased homocysteine levels (78.1 ± 32.2 µmol/L). MRI of the spinal cord showed longitudinal high T2 signal lesions in the dorsal spinal cord in some patients. Moreover, electromyography showed sensory and motor nerve axonal damage combined with demyelination, which was relatively more severe in the lower limbs. There was rapid improvement of the symptoms after treatment with intramuscular injections of vitamin B12 and the overall prognosis was good. The literature search indicated that the number of published papers and related patients showed a rapid annual increase since the first Chinese case reported in 2016 CONCLUSION: Recreational use of N2O is an emerging public health problem in China that needs prompt action from the society and government. Early diagnosis and treatment allow a good overall prognosis.

MicroRNA-217-5p ameliorates endothelial cell apoptosis induced by ox-LDL by targeting CLIC4.

BACKGROUND AND AIMS: Endothelial cell apoptosis plays an essential role in the pathogenesis of atherosclerosis. MicroRNAs and chloride intracellular channels (CLICs) have been verified to participate in the endothelial cell apoptosis process, however, the underlying molecular mechanisms are still unclear. The main aim of this study was to investigate the biological effects of microRNA-217-5p (miR-217-5p) and CLIC4 on endothelial cell apoptosis in atherosclerosis. METHODS AND RESULTS: An atherosclerotic mouse model (n = 18) was constructed by feeding apolipo protein E knockout ApoE(-/-) mice with high-fat diet for 12 weeks. An atherosclerotic cell model was established by treating human aortic endothelial cells with oxidized low-density lipoprotein (ox-LDL; 50 µg/mL) for 24 h. Quantitative real-time polymerase chain reaction and immunofluorescent staining confirmed the downregulation of miR-217-5p and upregulation of CLIC4 in atherosclerotic endothelial cells. Combined with western blot, flow cytometry assay and Hoechst staining, we demonstrated that miR-217-5p upregulation or CLIC4 knockdown regulated the apoptosis-related genes, ameliorated mitochondrial membrane permeability and therefore inhibited the apoptosis of aortic endothelial cells induced by ox-LDL. We further confirmed that miR-217-5p inhibited apoptosis of endothelial cells through targeting CLIC4 using luciferase report assay and rescue experiments. CONCLUSION: We revealed for the first time that miR-217-5p inhibited apoptosis of endothelial cells in atherosclerosis and identified CLIC4 as a novel target of miR-217-5p. Our work provides a potential therapeutic approach for the treatment of atherosclerosis.