Association analyses between the variants of SNAP25, SV2C and ST3GAL2 and the efficacy of botulinum toxin A in the treatment of the primary Meige syndrome.

Objective: Individual differences were observed in the clinical efficacy of Botulinum toxin A (BoNT-A) in the treatment of the primary Meige syndrome. Our study aimed to explore the potential associations between the clinical efficacy of BoNT-A in the treatment of the primary Meige syndrome and variants of SNAP25, SV2C and ST3GAL2, which are involving in the translocation of the BoNT-A in vivo. Methods: Patients with the primary Meige syndrome treated with BoNT-A were enrolled. Clinical efficacy was evaluated by the maximum improvement rate of motor symptoms and the duration of efficacy. Variants of SNAP25, SV2C and ST3GAL2 were obtained by Sanger sequencing. Another cohort diagnosed with primary cervical dystonia was also enrolled in the replication stage. Results: Among the 104 primary Meige syndrome patients, 80 patients (76.9%) had a good efficacy (the maximum improvement rate of motor symptoms ≥30%) and 24 (23. 1%) had a poor (the maximum improvement rate of motor symptoms <30%). As to the duration of efficacy, 52 patients (50.0%) had a long duration of efficacy (≥4 months), and 52 (50.0%) had a short (<4 months). In terms of primary Meige syndrome, SNAP25 rs6104571 was found associating with the maximum improvement rate of motor symptoms (Genotype: P = 0.02, OR = 0.26; Allele: P = 0.013, OR = 0.29), and SV2C rs31244 was found associating with the duration of efficacy (Genotype: P = 0.024, OR = 0.13; Allele: P = 0.012, OR = 0.13). Besides, we also conducted the association analyses between the variants and BoNT-A-related adverse reactions. Although, there was no statistical difference between the allele of SV2C rs31244 and BoNT-A-related adverse reactions, there was a trend (P = 0.077, OR = 2.56). In the replication stage, we included 39 patients with primary cervical dystonia to further expanding the samples' size. Among the 39 primary cervical dystonia patients, 25 patients (64.1%) had a good efficacy (the maximum improvement rate of motor symptoms ≥50%) and 14 (35.9%) had a poor (the maximum improvement rate of motor symptoms <50%). As to the duration of efficacy, 32 patients (82.1%) had a long duration of efficacy (≥6 months), and 7 (17.9%) had a short (<6 months). Integrating primary Meige syndrome and primary cervical dystonia, SV2C rs31244 was still found associating with the duration of efficacy (Genotype: P = 0.002, OR = 0. 23; Allele: P = 0.001, OR = 0. 25). Conclusion: In our study, SNAP25 rs6104571 was associated with the maximum improvement rate of motor symptoms in patients with primary Meige syndrome treated with BoNT-A, and patients carrying this variant had a lower improvement rate of motor symptoms. SV2C rs31244 was associated with duration of treatment in patients with primary Meige syndrome treated with BoNT-A and patients carrying this variant had a shorter duration of treatment. Patients with primary Meige syndrome carrying SV2C rs31244 G allele have an increase likelihood of BoNT-A-related adverse reactions. Involving 39 patients with primary cervical dystonia, the results further verify that SV2C rs31244 was associated with duration of treatment and patients carrying this variant had a shorter duration of treatment.

Targeting epigenetic and post-translational modifications regulating pyroptosis for the treatment of inflammatory diseases.

Inflammatory diseases, including infectious diseases, diabetes-related diseases, arthritis-related diseases, neurological diseases, digestive diseases, and tumor, continue to threaten human health and impose a significant financial burden despite advancements in clinical treatment. Pyroptosis, a pro-inflammatory programmed cell death pathway, plays an important role in the regulation of inflammation. Moderate pyroptosis contributes to the activation of native immunity, whereas excessive pyroptosis is associated with the occurrence and progression of inflammation. Pyroptosis is complicated and tightly controlled by various factors. Accumulating evidence has confirmed that epigenetic modifications and post-translational modifications (PTMs) play vital roles in the regulation of pyroptosis. Epigenetic modifications, which include DNA methylation and histone modifications (such as methylation and acetylation), and post-translational modifications (such as ubiquitination, phosphorylation, and acetylation) precisely manipulate gene expression and protein functions at the transcriptional and post-translational levels, respectively. In this review, we summarize the major pathways of pyroptosis and focus on the regulatory roles and mechanisms of epigenetic and post-translational modifications of pyroptotic components. We also illustrate these within pyroptosis-associated inflammatory diseases. In addition, we discuss the effects of novel therapeutic strategies targeting epigenetic and post-translational modifications on pyroptosis, and provide prospective insight into the regulation of pyroptosis for the treatment of inflammatory diseases.

Melatonin MT1 receptors regulate the Sirt1/Nrf2/Ho-1/Gpx4 pathway to prevent α-synuclein-induced ferroptosis in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons and aggregation of α-synuclein (α-syn). Ferroptosis, a form of cell death induced by iron accumulation and lipid peroxidation, is involved in the pathogenesis of PD. It is unknown whether melatonin receptor 1 (MT1) modulates α-syn and ferroptosis in PD. Here, we used α-syn preformed fibrils (PFFs) to induce PD models in vivo and in vitro. In PD mice, α-syn aggregation led to increased iron deposition and ferroptosis. MT1 knockout exacerbated these changes and resulted in more DA neuronal loss and severe motor impairment. MT1 knockout also suppressed the Sirt1/Nrf2/Ho1/Gpx4 pathway, reducing resistance to ferroptosis, and inhibited expression of ferritin Fth1, leading to more release of ferrous ions. In vitro experiments confirmed these findings. Knockdown of MT1 enhanced α-syn PFF-induced intracellular α-syn aggregation and suppressed expression of the Sirt1/Nrf2/Ho1/Gpx4 pathway and Fth1 protein, thereby aggravating ferroptosis. Conversely, overexpression of MT1 reversed these effects. Our findings reveal a novel mechanism by which MT1 activation prevents α-syn-induced ferroptosis in PD, highlighting the neuroprotective role of MT1 in PD.

Unraveling the interplay between dyskinesia and overactive bladder symptoms in Parkinson's disease: a comprehensive cohort study based on the long-term follow-up database of Parkinson's disease.

OBJECTIVES: Overactive bladder (OAB) and dyskinesia are frequent complications in patients with Parkinson's disease (PD). However, the correlation between OAB and dyskinesia has been insufficiently explored. The purpose of this study was to examine the relationship between dyskinesia, OAB, and clinical characteristics among individuals with PD. METHODS: 1338 PD patients were included in the present study. Demographic features were compared between patients with or without dyskinesia and OAB symptoms. Logistic regression was conducted on dyskinesia to screen clinically relevant factors. Overactive Bladder Symptom Score (OABSS) was further used to stratify the association between the severity of OAB and the occurrence of dyskinesia. RESULTS: This study indicates that both dyskinesia and OAB are significantly related to disease severity and cognitive status. PD patients with dyskinesia and OAB having higher UPDRS scores (p < 0.001), H-Y scores (p < 0.001), NMSQ (p < 0.001) and MoCA scores (p < 0.001), and lower MMSE scores (p < 0.001) are identified. The multivariate logistic regression confirms that disease duration (p = 0.041), LEDD (p < 0.001), UPDRSII (p < 0.001), MoCA (p = 0.024), urgency (p < 0.001), frequency (p < 0.001), and nocturia (p = 0.002) are independent risk factors for dyskinesia. Trend analysis indicates that the risk of dyskinesia significantly increases when patients exhibit moderate to severe OAB symptoms (OABSS > 5) (p < 0.001). No significant interactions were found between OABSS and age, gender, disease duration, LEDD, and NMSQ scores in different subgroups, indicating that dyskinesia is more pronounced in patients with OABSS > 5. DISCUSSION: This study provides compelling evidence supporting the strong correlation between OAB and dyskinesia in PD patients, emphasizing the presence of shared pathogenic mechanisms between these two conditions. Our findings underscore the importance of considering both OAB and dyskinesia in the clinical management of PD, investigating the intricate connections between OAB and dyskinesia could unveil valuable insights into the complex pathophysiology of PD and potentially identify novel therapeutic targets for more effective PD treatment strategies.

Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson's disease.

Parkinson's disease (PD) is a ubiquitous brain cell degeneration disease and presents a significant therapeutic challenge. By injecting 6-hydroxydopamine (6-OHDA) into the left medial forebrain bundle, rats were made to exhibit PD-like symptoms and treated by intranasal administration of a low-dose (2 × 105) or high-dose (1 × 106) human neural stem cells (hNSCs). Apomorphine-induced rotation test, stepping test, and open field test were implemented to evaluate the motor behavior and high-performance liquid chromatography was carried out to detect dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin, and 5-hydroxyindole-3-acetic acid in the striatum of rats. Animals injected with 6-OHDA showed significant motor function deficits and damaged dopaminergic system compared to the control group, which can be restored by hNSCs treatment. Treatment with hNSCs significantly increased the tyrosine hydroxylase-immunoreactive cell count in the substantia nigra of PD animals. Moreover, the levels of neurotransmitters exhibited a significant decline in the striatum tissue of animals injected with 6-OHDA when compared to that of the control group. However, transplantation of hNSCs significantly elevated the concentration of DA and DOPAC in the injured side of the striatum. Our study offered experimental evidence to support prospects of hNSCs for clinical application as a cell-based therapy for PD.

Life and disease status of patients with Parkinson's disease during and after zero-COVID in China: an online survey.

BACKGROUND: Little is known about the impact of the COVID-19 pandemic on patients with Parkinson's disease (PD) at different stages of the pandemic. This study aims to assess the lives and disease status of PD patients during the zero-COVID policy period and after ending the zero-COVID policy. METHODS: This multicenter cross-sectional study included two online surveys among PD patients in China, from May 30 to June 30 in 2022 and from January 1 to February 28 in 2023, respectively. The survey questionnaires contained four sections: (1) status of COVID-19 infection; (2) impact on motor and non-motor symptoms; (3) impact on daily and social lives; and (4) impact on PD disease management. RESULTS: A total of 1764 PD patients participated in the first online survey, with 200 patients having lockdown experience and 3 being COVID-19-positive (0.17%). In addition, 537 patients participated in the second online survey, with 467 patients having COVID-19 infection (86.96%). (1) During zero-COVID, all of the COVID-19-positive patients had mild symptoms of COVID-19 and no death was reported. After zero-COVID, 83.51% of the COVID-19-positive patients had mild symptoms. The overall death rate and inpatient mortality rate of COVID-19-positive PD patients were 3.21% and 30.00%, respectively. (2) During zero-COVID, 49.43% of PD patients reported worsening of PD-related symptoms (lockdown vs. unlockdown, 60.50% vs. 48.02%, P = 0.0009). After zero-COVID, 54.93% of PD patients reported worsening of PD-related symptoms (COVID-19 positive vs. COVID-19 negative, 59.31% vs. 25.71%, P < 0.0001). (3) During zero-COVID, 62.36% of patients felt worried, and 'limited outdoor activities' (55.39%) was the top reason for mental health problems. After zero-COVID, 59.03% of patients felt worried, with 'poor health' (58.10%) being the top reason. The PD patients tended to change their daily activities from offline to online, and their economic and caregiver burdens increased both during and after zero-COVID. (4) Most PD patients would like to choose online rehabilitation during (69.56%) and after zero-COVID (69.27%). The demand for online medication purchasing also increased during (47.00%) and after zero-COVID (26.63%). CONCLUSIONS: The COVID-19 pandemic aggravated the motor and non-motor symptoms of PD patients either during or after the zero-COVID policy period. The PD patients also experienced prominent mental health problems, changes in daily activities, and increases in economic and caregiver burdens. The COVID-19 pandemic has changed ways of PD management with increasing demands for online medication purchasing and rehabilitation.

Slow-wave sleep and REM sleep without atonia predict motor progression in Parkinson's disease.

BACKGROUND: Growing evidence supports the potential role of sleep in the motor progression of Parkinson's disease (PD). Slow-wave sleep (SWS) and rapid eye movement (REM) sleep without atonia (RWA) are important sleep parameters. The association between SWS and RWA with PD motor progression and their predictive value have not yet been elucidated. METHODS: We retro-prospectively analyzed clinical and polysomnographic data of 136 patients with PD. The motor symptoms were assessed using Unified Parkinson's Disease Rating Scale Part III (UPDRS III) at baseline and follow-up to determine its progression. Partial correlation analysis was used to explore the cross-sectional associations between slow-wave energy (SWE), RWA and clinical symptoms. Longitudinal analyses were performed using Cox regression and linear mixed-effects models. RESULTS: Among 136 PD participants, cross-sectional partial correlation analysis showed SWE decreased with the prolongation of the disease course (P = 0.046), RWA density was positively correlated with Hoehn & Yahr (H-Y) stage (tonic RWA, P < 0.001; phasic RWA, P = 0.002). Cox regression analysis confirmed that low SWE (HR = 1.739, 95% CI = 1.038-2.914; P = 0.036; FDR-P = 0.036) and high tonic RWA (HR = 0.575, 95% CI = 0.343-0.963; P = 0.032; FDR-P = 0.036) were predictors of motor symptom progression. Furthermore, we found that lower SWE predicted faster rate of axial motor progression (P < 0.001; FDR-P < 0.001) while higher tonic RWA density was associated with faster rate of rigidity progression (P = 0.006; FDR-P = 0.024) using linear mixed-effects models. CONCLUSIONS: These findings suggest that SWS and RWA might represent markers of different motor subtypes progression in PD.

Clinical and electroencephalogram characteristics of methylmalonic acidemia with MMACHC and MUT gene mutations.

OBJECTIVE: This study investigated the clinical, imaging, and electroencephalogram (EEG) characteristics of methylmalonic acidemia (MMA) with nervous system damage as the primary manifestation. METHODS: From January 2017 to November 2022, patients with nervous system injury as the main clinical manifestation, diagnosed with methylmalonic acidemia by metabolic and genetic testing, were enrolled and analyzed. Their clinical, imaging, and electroencephalogram data were analyzed. RESULTS: A total of 18 patients were enrolled, including 15 males and 3 females. The clinical symptoms were convulsions, poor feeding, growth retardation, disorder of consciousness, developmental delay, hypotonia, and blood system changes. There were 6 cases (33%) of hydrocephalus, 9 (50%) of extracerebral space widened, 5 (27%) of corpus callosum thinning, 3 (17%) of ventricular dilation, 3 (17%) of abnormal signals in the brain parenchyma (frontal lobe, basal ganglia region, and brain stem), and 3 (17%) of abnormal signals in the lateral paraventricular. In addition, there were 3 cases (17%) of cerebral white matter atrophy and 1 (5%) of cytotoxic edema in the basal ganglia and cerebral peduncle. EEG data displayed 2 cases (11%) of hypsarrhythmia, 3 (17%) of voltage reduction, 12(67%) of abnormal discharge, 13 (72%) of abnormal sleep physiological waves or abnormal sleep structure, 1 (5%) of immature (delayed) EEG development, and 8 (44%) of slow background. There were 2 cases (11%) of spasms, 1 (5%) of atonic seizures, and 1 (5%) of myoclonic seizures. There were 16 patients (89%) with hyperhomocysteinemia. During follow-up, 1 patient was lost to follow-up, and 1 died. In total, 87.5% (14/16) of the children had varying developmental delays. EEG was re-examined in 11 cases, of which 8 were normal, and 3 were abnormal. Treatments included intramuscular injections of vitamin B12, L-carnitine, betaine, folic acid, and oral antiepileptic therapy. Acute treatment included anti-infective, blood transfusion, fluid replacement, and correcting acidosis. The other treatments included low-protein diets and special formula milk powder. CONCLUSION: Methylmalonic acidemia can affect the central nervous system, leading to structural changes or abnormal signals on brain MRI. Metabolic screening and genetic testing help clarify the diagnosis. EEG can reflect changes in brain waves during the acute phase.

Inhibition of GluN2D-Containing NMDA Receptors Protects Dopaminergic Neurons against 6-OHDA-Induced Neurotoxicity via Activating ERK/NRF2/HO-1 Signaling.

Abnormal glutamate signaling is implicated in the heightened vulnerability of dopaminergic neurons in Parkinson's disease (PD). NMDA receptors are ion-gated glutamate receptors with high calcium permeability, and their GluN2D subunits are prominently distributed in the basal ganglia and brainstem nuclei. Previous studies have reported that dopamine depletion led to the dysfunctions of GluN2D-containing NMDA receptors in PD animal models. However, it remains unknown whether selective modulation of GluN2D could protect dopaminergic neurons against neurotoxicity in PD. In this study, we found that allosteric activation of GluN2D-containing NMDA receptors decreased the cell viability of MES23.5 dopaminergic cells and the GluN2D inhibitor, QNZ46, showed antioxidant effects and significantly relieved apoptosis in 6-OHDA-treated cells. Meanwhile, we demonstrated that QNZ46 might act via activation of the ERK/NRF2/HO-1 pathway. We also verified that QNZ46 could rescue abnormal behaviors and attenuate dopaminergic cell loss in a 6-OHDA-lesioned rat model of PD. Although the precise mechanisms underlying the efficacy of QNZ46 in vivo remain elusive, the inhibition of the GluN2D subunit should be a considerable way to treat PD. More GluN2D-selective drugs, which present minimal side effects and broad therapeutic windows, need to be developed for PD treatment in future studies.

Gut microbiota dysbiosis contributes to α-synuclein-related pathology associated with C/EBPß/AEP signaling activation in a mouse model of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202409000-00042/figure1/v/2024-01-16T170235Z/r/image-tiff Parkinson's disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction. Gastrointestinal dysfunction can precede the onset of motor symptoms by several years. Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson's disease, whether it plays a causal role in motor dysfunction, and the mechanism underlying this potential effect, remain unknown. CCAAT/enhancer binding protein ß/asparagine endopeptidase (C/EBPß/AEP) signaling, activated by bacterial endotoxin, can promote α-synuclein transcription, thereby contributing to Parkinson's disease pathology. In this study, we aimed to investigate the role of the gut microbiota in C/EBPß/AEP signaling, α-synuclein-related pathology, and motor symptoms using a rotenone-induced mouse model of Parkinson's disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation. We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier, as well as activation of the C/EBP/AEP pathway, α-synuclein aggregation, and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits. However, treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics. Importantly, we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits, intestinal inflammation, and endotoxemia. Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits, intestinal inflammation, endotoxemia, and intestinal barrier impairment. These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits, C/EBPß/AEP signaling activation, and α-synuclein-related pathology in a rotenone-induced mouse model of Parkinson's disease. Additionally, our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson's disease.

Bridging Reduced Grip Strength and Altered Executive Function: Specific Brain White Matter Structural Changes in Patients with Alzheimer's Disease.

Objective: To investigate the correlation between specific fiber tracts and grip strength and cognitive function in patients with Alzheimer's disease (AD) by fixel-based analysis (FBA). Methods: AD patients were divided into AD with low grip strength (AD-LGS, n=29) and AD without low grip strength (AD-nLGS, n=25), along with 31 normal controls (NC). General data, neuropsychological tests, grip strength and cranial magnetic resonance imaging (MRI) scans were collected. FBA evaluated white matter (WM) fiber metrics, including fiber density (FD), fiber cross-sectional (FC), and fiber density and cross-sectional area (FDC). The mean fiber indicators of the fiber tracts of interest (TOI) were extracted in cerebral region of significant statistical differences in FBA to further compare the differences between groups and analyze the correlation between fiber properties and neuropsychological test scores. Results: Compared to AD-nLGS group, AD-LGS group showed significant reductions in FDC in several cerebral regions. In AD patients, FDC values of bilateral uncinate fasciculus and left superior longitudinal fasciculus were positively correlated with Clock Drawing Test scores, while FDC of splenium of corpus callosum, bilateral anterior cingulate tracts, forceps major, and bilateral inferior longitudinal fasciculus were positively correlated with the Executive Factor Score of Memory and Executive Screening scale scores. Conclusion: Reduced grip strength in AD patients is associated with extensive impairment of WM structural integrity. Changes in FDC of specific WM fiber tracts related to executive function play a significant mediating role in the reduction of grip strength in AD patients.

The association between plasma GPNMB and Parkinson's disease and multiple system atrophy.

AIMS: Parkinson's disease (PD), as the second most common neurodegenerative disorder, often presents diagnostic challenges in differentiation from other forms of Parkinsonism. Recent studies have reported an association between plasma glycoprotein nonmetastatic melanoma protein B (pGPNMB) and PD. METHODS: A retrospective study was conducted, comprising 401 PD patients, 111 multiple system atrophy (MSA) patients, 13 progressive supranuclear palsy (PSP) patients and 461 healthy controls from the Chinese Han population, with an assessment of pGPNMB levels. RESULTS: The study revealed that pGPNMB concentrations were significantly lower in PD and MSA patients compared to controls (area under the receiver operating characteristics curve (AUC) 0.62 and 0.74, respectively, P < 0.0001 for both), but no difference was found in PSP patients compared to controls (P > 0.05). Interestingly, the level of pGPNMB was significantly higher in PD patients than in MSA patients (AUC = 0.63, P < 0.0001). Furthermore, the study explored the association between pGPNMB levels and disease severity in PD and MSA patients, revealing a positive correlation in PD patients but not in MSA patients with both disease severity and cognitive impairment. CONCLUSION: This study successfully replicated prior findings, demonstrating an association between pGPNMB levels and disease severity, and also identified a correlation with cognitive impairment in PD patients of the Chinese Han population. Additionally, this study is the first to identify a significant difference in pGPNMB levels between MSA, PD, and normal controls. The data provide new evidence supporting the potential role of pGPNMB in the diagnosis and differential diagnosis of Parkinsonism.

Safinamide alleviates hyperalgesia via inhibiting hyperexcitability of DRG neurons in a mouse model of Parkinson's disease.

Pain is a widespread non-motor symptom that presents significant treatment challenges in patients with Parkinson's disease (PD). Safinamide, a new drug recently introduced for PD treatment, has demonstrated analgesic effects on pain in PD patients, though the underlying mechanisms remain unclear. To investigate the analgesic and anti-PD effect of safinamide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model was used, and rasagiline as positive control on motor symptoms. Notably, only safinamide alleviated hyperalgesia in MPTP mice. Whole-cell patch-clamp recordings of dorsal root ganglion (DRG) neurons revealed hyperexcitability in MPTP mice, which safinamide counteracted in a concentration-dependent manner. The voltage clamp further demonstrated that sodium current in DRG neurons of MPTP mice was enhanced and safinamide reduced sodium current density. RT-qPCR identified upregulated Nav1.7 and Nav1.8 transcripts (Scn9a and Scn10a) in DRG neurons of MPTP mice. Our results suggest that safinamide could relieve hyperalgesia by inhibiting DRG neuron hyperexcitability in MPTP mice.

Optimum Baseline Clinical Severity Scale Cut Points for Prognosticating Intracerebral Hemorrhage: INTERACT Studies.

BACKGROUND: The optimal cut point of baseline National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale scores for prognosticating acute intracerebral hemorrhage (ICH) is unknown. METHODS: Secondary analyses of participant data are from the INTERACT (Intensive Blood Pressure Reduction in Acute Intracerebral Hemorrhage Trials) 1 and 2 studies. Receiver operating characteristic analyses were used to compare the predictive performance of baseline NIHSS and Glasgow Coma Scale scores, ICH score, and max-ICH score. Optimal cut points for predicting 90-day clinical outcomes (death or major disability [defined as modified Rankin Scale scores 3-6], major disability [defined as modified Rankin Scale scores 3-5], and death alone) were determined using the Youden index. Logistic regression models were adjusted for age, sex, hematoma volume, and other known risk factors for poor prognosis. We validated our findings in the INTERACT1 database. RESULTS: There were 2829 INTERACT2 patients (age, 63.5±12.9 years; male, 62.9%; ICH volume, 10.96 [5.77-19.49] mL) included in the main analyses. The baseline NIHSS score (area under the curve, 0.796) had better prognostic utility for predicting death or major disability than the Glasgow Coma Scale score (area under the curve, 0.650) and ICH score (area under the curve, 0.674) and was comparable to max-ICH score (area under the curve, 0.789). Similar findings were observed when assessing the outcome of major disability. A cut point of 10 on baseline NIHSS optimally (sensitivity, 77.5%; specificity, 69.2%) predicted death or major disability (adjusted odds ratio, 4.50 [95% CI, 3.60-5.63]). The baseline NIHSS cut points that optimally predicted major disability and death alone were 10 and 12, respectively. The predictive effect of NIHSS≥10 for poor functional outcomes was consistent in all subgroups including age and baseline hematoma volume. Results were consistent when analyzed in the independent INTERACT1 validation database. CONCLUSIONS: In patients with mild-to-moderate ICH, a baseline NIHSS score of ≥10 was optimal for predicting poor outcomes at 90 days. Prediction based on baseline NIHSS is better than baseline Glasgow Coma Scale score. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00226096 and NCT00716079.

Circadian Rhythm Disturbance in Acute Ischemic Stroke Patients and Its Effect on Prognosis.

INTRODUCTION: Poststroke sleep disturbances are common and can affect stroke outcomes, but the clinical studies mainly focus on breathing-related sleep disorders, while the bidirectional impact of circadian rhythm dysfunction in ischemic stroke remains unknown. This study observed the characteristics of melatonin secretion in acute ischemic stroke patients and evaluated whether melatonin rhythm impacts the prognosis after stroke by assessing the neurological function, cognition, emotion, and quality of life 3 months after stroke. METHODS: Acute ischemic stroke patients were selected from the Department of Neurology Inpatients of the Second Hospital affiliated with Soochow University from October 2019 to July 2021. Healthy control subjects were recruited at the same time. Demographic and clinical data were collected, and relevant scale scores (including neurological function, cognition, emotion, and sleep) were assessed within 2 weeks of onset and followed up 3 months later. All participants collected salivary melatonin samples on the 4th day of hospitalization and dim light melatonin onset (DLMO) was calculated according to melatonin concentration. Stroke patients were then divided into three groups based on their DLMO values. RESULTS: A total of 74 stroke patients and 33 control subjects were included in this analysis. Compared with healthy controls, stroke patients exhibited a delayed melatonin rhythm during the acute phase of stroke (21:36 vs. 20:38, p = 0.004). Stroke patients were then divided into three groups, namely normal (n = 36), delayed (n = 28), or advanced DLMO (n = 10), based on their DLMO values. A χ2 test showed that there were significant differences in the rate of poor prognosis (p = 0.011) and depression tendency (p = 0.028) among the three groups. A further pairwise comparison revealed that stroke patients with delayed DLMO were more likely to experience poor short-term outcomes than normal DLMO group (p = 0.003). The average melatonin concentration of stroke patients at 5 time points was significantly lower than that of the control group (3.145 vs. 7.065 pg/mL, p < 0.001). Accordingly, we split stroke patients into three groups, namely low melatonin level (n = 14), normal melatonin level (n = 54), or high melatonin level (n = 6). Unfortunately, there were no great differences in the clinical characteristics, cognition, emotion, sleep quality, and short-term outcome among groups. CONCLUSIONS: This is a preliminary study, and our results indicate that changes in melatonin secretion phase of stroke patients may have effect on their short-term prognosis.

Integration of transcriptomic, proteomic, and metabolomic data to identify lncRNA rPvt1 associations in lipopolysaccharide-treated H9C2 cardiomyocytes.

Background: Recent evidence has shown that the long non-coding RNA (lncRNA) rPvt1 is elevated in septic myocardial tissues and that its knockdown attenuates sepsis-induced myocardial injury. However, the mechanism underlying the role of rPvt1 in septic myocardial dysfunction has not been elucidated. Methods: In this study, we performed transcriptomic, proteomic, and metabolomic assays and conducted an integrated multi-omics analysis to explore the association between rPvt1 and lipopolysaccharide (Lipopolysaccharide)-induced H9C2 cardiomyocyte injury. LncRNA rPvt1 silencing was achieved using a lentiviral transduction system. Results: Compared to those with the negative control, rPvt1 knockdown led to large changes in the transcriptome, proteome, and metabolome. Specifically, 2,385 differentially expressed genes (DEGs), 272 differentially abundant proteins and 75 differentially expressed metabolites (DEMs) were identified through each omics analysis, respectively. Gene Ontology functional annotation, Kyoto Encyclopedia of Genes and Genomes, Nr, eukaryotic orthologous groups, and Clusters of Orthologous Groups of Proteins pathway analyses were performed on these differentially expressed/abundant factors. The results suggested that mitochondrial energy metabolism might be closely related to the mechanism through which Pvt1 functions. Conclusion: These genes, proteins, metabolites, and their related dysregulated pathways could thus be promising targets for studies investigating the rPvt1-regluatory mechanisms involved in septic myocardial dysfunction, which is important for formulating novel strategies for the prevention, diagnosis and treatment of septic myocardial injury.

Albumin-Globulin Ratio and Common Carotid Artery Intima-Media Thickness in Patients with Ischemic Stroke.

BACKGROUND: The relationships between serum albumin, albumin-globulin (A/G) ratio, globulin and atherosclerosis in acute ischemic stroke (AIS) remain uncertain. We investigated the associations between serum albumin, A/G ratio, globulin levels and carotid atherosclerosis in patients with AIS. METHODS: A total of 1,339 AIS patients were enrolled. Admission A/G ratio was divided into quartiles, and serum albumin and globulin levels were also categorized. Carotid atherosclerosis was detected through the assessment of common carotid artery intima-media thickness (cIMT), and abnormal cIMT was characterized by mean and maximum cIMT values of ≥1 mm. We evaluated the relationships between A/G ratio, albumin, globulin and abnormal cIMT, using multivariable logistic regression models. RESULTS: In the multivariable-adjusted analysis, the highest A/G ratio quartile (Q4) was linked to a 59% decreased risk of abnormal mean cIMT (OR 0.41; 95% CI 0.29-0.60) and a 58% decreased risk of abnormal maximum cIMT (OR 0.42; 95% CI 0.30-0.60) when compared to the lowest quartile (Q1), respectively. Moreover, decreased albumin and elevated globulin levels were also associated with abnormal mean cIMT and maximum cIMT. In addition, the A/G ratio provided supplementary predictive capability beyond the already established risk factors, and the C-statistic of the A/G ratio for abnormal cIMT is larger than globulin (P <0.01). CONCLUSION: Decreased serum A/G ratio, albumin and elevated serum globulin were independently associated with abnormal cIMT in AIS patients. Moreover, the A/G ratio appeared to be a better predictor of abnormal cIMT.

Prediction of Parkinson's disease by transcranial sonography-based deep learning.

OBJECTIVES: Transcranial sonography has been used as a valid neuroimaging tool to diagnose Parkinson's disease (PD). This study aimed to develop a modified transcranial sonography (TCS) technique based on a deep convolutional neural network (DCNN) model to predict Parkinson's disease. METHODS: This retrospective diagnostic study was conducted using 1529 transcranial sonography images collected from 854 patients with PD and 775 normal controls admitted to the Second Affiliated Hospital of Soochow University (Suzhou, Jiangsu, China) between September 2019 and May 2022. The data set was divided into training cohorts (570 PD patients and 541 normal controls), and the validation set (184 PD patients and 234 normal controls). Using these datasets, we developed four different DCNN models (ResNet18, ResNet50, ResNet152, and DenseNet121). We then assessed their diagnostic performance, including the area under the receiver operating characteristic (AUROC) curve, specificity, sensitivity, positive predictive value (PPV), negative predictive value (NPV), and F1 score and compared with traditional diagnostic criteria. RESULTS: Among the 1529 TCS images, 570 PD patients and 541 normal controls from 4 of 6 sonographers of the TCS team were selected as the training cohort, and 184 PD patients and 234 normal controls from the other 2 sonographers were chosen as the validation cohort. There were no sex and age differences between PD patients and normal control subjects in the training and validation cohorts (P values > 0.05). All DCNN models achieved good performance in distinguishing PD patients from normal control subjects on the validation datasets, with diagnostic AUROCs and accuracy of 0.949 (95% CI 0.925, 0.965) and 86.60 for the RestNet18 model, 0.949 (95% CI 0.929, 0.971) and 87.56 for ResNet50, 0.945 (95% CI 0.931, 0.969) and 88.04 for ResNet152, 0.953 (95% CI 0.935, 0.971) and 87.80 for DenseNet121, respectively. On the other hand, the diagnostic accuracy of the traditional diagnostic method was 82.30. The accuracy of all DCNN models was higher than that of traditional diagnostic method. Moreover, the 5k-fold cross-validation results in train datasets showed that these DCNN models are robust. CONCLUSION: The developed transcranial sonography-based DCNN models performed better than traditional diagnostic criteria, thus improving the sonographer's accuracy in diagnosing PD.

Children with severe neurological symptoms associated with SARS-CoV-2 infection during Omicron pandemic in China.

BACKGROUND: To analyze the clinical characteristics and outcomes of children with severe neurological symptoms associated with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection during the Omicron pandemic in China. METHODS: This study used a questionnaire to obtain data from pediatric intensive care unit (PICU) centers in seven tertiary hospitals in Northeast China from December 1, 2022, to January 31, 2023. RESULTS: A total of 255 patients were confirmed to have SARS-CoV-2 infection, and 45 patients (17.65 %) were included in this study. Of these, seven (15.6%) patients died, and the median time from admission to death was 35 h (IQR, 14-120 h). Twenty (52.6%) survivors experienced neurological sequelae. Patients with platelet counts lower than 100 × 109/L had a higher incidence of complications such as multiple organ dysfunction, mechanical ventilation rate, and mortality. Cranial magnetic resonance imaging (MRI) always reveals cerebral tissue edema, with some severe lesions forming a softening site. CONCLUSION: Children infected with SARS-CoV-2 often exhibit severe neurological symptoms, and in some cases, they may rapidly develop malignant cerebral edema or herniation, leading to a fatal outcome. An early decrease in platelet count may associated with an unfavorable prognosis. IMPACT: Since early December 2022, China has gradually adjusted its prevention and control policy of SARS-CoV-2; Omicron outbreaks have occurred in some areas for a relatively short period. Due to the differences in ethnicity, endemic strains and vaccination status, there was a little difference from what has been reported about children with SARS-CoV-2 infection with severe neurological symptoms in abroad. This is the first multicenter clinical study in children with nervous system involvement after acute SARS-CoV-2 infection in China, and helpful for pediatricians to have a more comprehensive understanding of the clinical symptoms and prognosis of such disease.