Exploring the neuroprotective role of artesunate in mouse models of anti-NMDAR encephalitis: insights from molecular mechanisms and transmission electron microscopy.

BACKGROUND: The pathway involving PTEN-induced putative kinase 1 (PINK1) and PARKIN plays a crucial role in mitophagy, a process activated by artesunate (ART). We propose that patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis exhibit insufficient mitophagy, and ART enhances mitophagy via the PINK1/PARKIN pathway, thereby providing neuroprotection. METHODS: Adult female mice aged 8-10 weeks were selected to create a passive transfer model of anti-NMDAR encephalitis. We conducted behavioral tests on these mice within a set timeframe. Techniques such as immunohistochemistry, immunofluorescence, and western blotting were employed to assess markers including PINK1, PARKIN, LC3B, p62, caspase3, and cleaved caspase3. The TUNEL assay was utilized to detect neuronal apoptosis, while transmission electron microscopy (TEM) was used to examine mitochondrial autophagosomes. Primary hippocampal neurons were cultured, treated, and then analyzed through immunofluorescence for mtDNA, mtROS, TMRM. RESULTS: In comparison to the control group, mitophagy levels in the experimental group were not significantly altered, yet there was a notable increase in apoptotic neurons. Furthermore, markers indicative of mitochondrial leakage and damage were found to be elevated in the experimental group compared to the control group, but these markers showed improvement following ART treatment. ART was effective in activating the PINK1/PARKIN pathway, enhancing mitophagy, and diminishing neuronal apoptosis. Behavioral assessments revealed that ART ameliorated symptoms in mice with anti-NMDAR encephalitis in the passive transfer model (PTM). The knockdown of PINK1 led to a reduction in mitophagy levels, and subsequent ART intervention did not alleviate symptoms in the anti-NMDAR encephalitis PTM mice, indicating that ART's therapeutic efficacy is mediated through the activation of the PINK1/PARKIN pathway. CONCLUSIONS: At the onset of anti-NMDAR encephalitis, mitochondrial damage is observed; however, this damage is mitigated by the activation of mitophagy via the PINK1/PARKIN pathway. This regulatory feedback mechanism facilitates the removal of damaged mitochondria, prevents neuronal apoptosis, and consequently safeguards neural tissue. ART activates the PINK1/PARKIN pathway to enhance mitophagy, thereby exerting neuroprotective effects and may achieve therapeutic goals in treating anti-NMDAR encephalitis.

Association of time spent outdoors with the risk of Parkinson's disease: a prospective cohort study of 329,359 participants.

BACKGROUND: Studies on the association between time spent outdoors and the development of Parkinson's disease (PD) are lacking, and whether this relationship differs in different subgroups (age, sex) remains unclear. OBJECTIVE: We here examined the association between time spent outdoors and the incidence of PD in different seasons. METHODS: This study included 329,359 participants from the UK Biobank. Data regarding hours spent outdoors during a typical day were obtained through questionnaires. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) for the association between exposure to outdoors duration and PD incidence. Restricted cubic spline was used to explore the potential nonlinear relationship between time spent outdoors and PD risk. To explore the potential mechanisms of time spent outdoors effecting the risk of PD incidence, their association with serum vitamin D was further analysed separately. RESULTS: During a median follow-up of 13.57 years, 2,238 participants developed PD. In summer, time spent outdoors > 5.0 h/day was associated with a reduced PD risk compared with ≤ 2.0 h/day (HR = 0.84, 95% CI, 0.74-0.95). In winter too, time spent outdoors > 2.0 h/day was also associated with a reduced PD risk compared with ≤ 1.0 h/day (HR = 0.85, 95% CI, 0.76-0.94). For annual average time spent outdoors, participants who went outdoors for more than 3.5 h/day had a reduced PD risk than those who went outdoors for ≤ 1.5 h/day (HR = 0.85, 95% CI, 0.75-0.96). Additionally, sex and age differences were observed in the association between time spent outdoors and the PD risk. Moreover, Time spent outdoors was observed to be positively associated with serum vitamin D levels. Compared with serum vitamin D-deficient participants, the risk of PD was reduced by 15% in the sufficient participants. CONCLUSION: In the total population, higher time spent outdoors was linked to a reduced PD risk. However, this association may vary among different age or sex groups.

An Analysis and Literature Review of a Family Case of Acute Intermittent Porphyria With Initial Symptoms of Epileptic Seizure.

Acute intermittent porphyria (AIP) is the most common form of acute porphyria and is characterized by acute onset and recurrent episodes. Clinical presentation frequently initiates with gastrointestinal symptoms and is often misdiagnosed or delayed secondary to nonspecific symptoms. Acute porphyria with epilepsy as the primary symptom is a very unusual or unexpected manifestation. This family case found an unexpected association between acute porphyria and seizures. This patient is a 33-year-old woman whose initial symptom was symptomatic epilepsy, followed by significant abdominal pain. After excluding infection, immunity, and other factors, whole exome sequencing analysis showed the presence of c.22dupG mutation in the HMBS gene and the patient was finally diagnosed with AIP. Her symptoms significantly improved after receiving high-glucose and high-carbohydrate load treatment. This case report is rare and suggests that for patients who experience epileptic seizures coupled with complaints related to the abdomen, the possibility of porphyria should be specially considered in the differential diagnosis.

A case report of brainstem hemorrhage due to Rhizopus delemar-induced encephalitis diagnosed by metagenomic next-generation sequencing (mNGS).

BACKGROUND: Rhizopus delemar is an invasive fungal pathogen that can cause fatal mucormycosis in immunodeficient individuals. Encephalitis caused by R. delemar is rare and difficult to diagnose early. Clinical detection methods for R. delemar include blood fungal culture, direct microscopic examination, and histopathological examination, but the detection is often inadequate for clinical diagnosis and can easily lead to missed diagnosis with delayed treatment. CASE PRESENTATION: We report a case of a 47-year-old male with brainstem hemorrhage caused by encephalitis due to R. delemar. The patient had a history of hypertension, type 2 diabetes, and irregular medication. No pathogens were detected in cerebrospinal fluid (CSF) and nasopharyngeal secretion cultures. R. delemar was identified by metagenomic next-generation sequencing (mNGS) in CSF, and in combination with the patient's clinical characteristics, encephalitis caused by R. delemar was diagnosed. Antibiotic treatment using amphotericin B liposome in combination with posaconazole was given immediately. However, due to progressive aggravation of the patient's symptoms, he later died due to brainstem hemorrhage after giving up treatment. CONCLUSIONS: mNGS technique is a potential approach for the early diagnosis of infections, which can help clinicians provide appropriate antibiotic treatments, thus reducing the mortality and disability rate of patients.

Autoimmune Encephalitis With Multiple Auto-Antibodies With Concomitant Human Herpesvirus-7 and Ovarian Teratoma: A Case Report.

Infectious etiologies and tumors are common triggers of autoimmune encephalitis. We herein reported a rare case of autoimmune encephalitis with multiple autoantibodies in cerebrospinal fluid (CSF) and serum, with concomitant human herpesvirus 7 (HHV-7) infection and ovarian teratoma. A 36-year-old woman presented with mental and behavioral changes and gibberish for 13 days, followed by fever for 1 day. Her brain MRI indicated limbic encephalitis. Metagenomic next-generation sequencing (mNGS) of CSF revealed HHV-7. Antibody testing showed positive anti-N-methyl-D-aspartate receptor (NMDAR) and anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibodies in CSF and serum. Ovarian teratoma was considered after pelvic MRI, which was then pathologically confirmed after laparoscopic ovariectomy. Her conditions improved after laparoscopic surgery, intravenous steroids, immunoglobulin, and rituximab therapy. Our findings suggested that the combination of multiple therapies including antiviral, immunotherapy, and resection of tumors were appropriate and improved the prognosis, when HHV-7 infection and ovarian teratoma were concomitant with multiple anti-neuronal antibodies of autoimmune encephalitis.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis Associated With Clear Cell Renal Carcinoma: A Case Report.

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a cause of autoimmune encephalitis and is characterized by epileptic seizures, psychosis, and consciousness impairments. It mostly affects young adults with ovarian cancers. We herein reported a case of anti-NMDAR encephalitis associated with clear cell renal carcinoma. Case Presentation: A 54-year-old male with headache for 1 week and mood and behavioral changes for 3 days was presented, but his clinical presentation and poor response to antiviral treatment did not support a diagnosis of viral encephalitis. Positive anti-NMDAR antibodies in serum and cerebrospinal fluid confirmed autoimmune encephalitis. A subsequent evaluation revealed a paraneoplastic etiology of a renal mass, and this was then resected and pathologically confirmed as clear cell renal carcinoma. The patient's symptoms showed improvement after resection of the mass. The patient relapsed 6 months after discharge, and the symptoms completely disappeared after treatment with corticosteroids and intravenous immunoglobulin. Conclusion: Our findings suggested that NMDAR encephalitis might be associated with clear cell renal carcinoma. When patients present with unexplained seizures, neuropsychiatric disorder, or other brain symptoms, clinicians should be careful with paraneoplastic neurological disorders. Early diagnosis and treatment of primary tumors might show improvement.

Subacute Combined Degeneration of the Spinal Cord and Hydrocephalus Associated with Vitamin B12 Deficiency.

BACKGROUND: This study aimed to report the case of a patient who presented with depression, cognitive impairment, ataxic gait, and urinary incontinence associated with vitamin B12 deficiency. CASE DESCRIPTION: Serum vitamin B12 level was low in this patient, and anti-intrinsic factor antibody was positive. Neuroimaging revealed abnormal hyperintense signals in the cerebellum and dorsal and lateral columns of the spinal cord, and obstructive hydrocephalus. A biopsy of the stomach revealed chronic gastritis, intestinal metaplasia, and atrophy. After 3 months of initiating methylcobalamin therapy, significant improvement was noticed clinically, and brain magnetic resonance imaging was near to normal. CONCLUSIONS: This study was novel in reporting subacute combined degeneration of the spinal cord and hydrocephalus associated with vitamin B12 deficiency in adults.

Clinical and Imaging Characteristics of Cerebral Infarction in Patients with Nonvalvular Atrial Fibrillation Combined with Cerebral Artery Stenosis.

AIMS: Nonvalvular atrial fibrillation often occurs in combination with carotid atherosclerosis, but less is known about it in combination with cerebral artery stenosis. This study investigated the characteristics of cerebral infarction in patients with nonvalvular atrial fibrillation with or without cerebral artery stenosis. METHODS: A retrospective analysis was conducted on 172 cerebral infarction patients with nonvalvular atrial fibrillation hospitalized at the Affiliated Ganzhou Hospital of Nanchang University between December 2011 and January 2016. The patients were divided into two groups (stenosis and non-stenosis groups) based on whether the cerebral infarction was combined with cerebral artery stenosis or not. Clinical characteristics, related supplementary examination, and the imaging characteristics of cerebral infarction lesions were compared between the groups. RESULTS: Mean age [(75.73±8.46) years vs. (63.44±9.95) years], National Institute of Health stroke scale (NIHSS) score [(8.66±6.73) vs. (4.59±3.51)], CHA2DS2-VASc score [(2.93±1.40) vs. (0.96±0.98)], history of hypertension (74.4% vs. 30.0%), and history of stroke/ transient ischemic attack (TIA) (55.8% vs. 13.3%) were higher in the stenosis group (n=107) than in the non-stenosis group (n=65) (P＜0.01). In the stenosis group, there were different types of cerebral infarction lesions, including multiple infarction (multifocal type), massive infarction, watershed infarction, and lacunar infarction; in the non-stenosis group, the 60.0% lesions were multiple infarction (multifocal type), a significantly higher proportion than the stenosis group (26.2%, P＜0.05). NIHSS score was an independent risk factor for worse prognosis at follow-up (OR (95%CI) 1.251-1.674, P＜0.001). CONCLUSIONS: Advanced age, hypertension, and stroke/TIA were increased in patients with cerebral infarction with nonvalvular atrial fibrillation combined with cerebral artery stenosis.