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.

IRAK-M Plays A Role in the Pathology of Amyotrophic Lateral Sclerosis Through Suppressing the Activation of Microglia.

Microglial activation plays a crucial role in the disease progression in amyotrophic lateral sclerosis (ALS). Interleukin receptor-associated kinases-M (IRAK-M) is an important negative regulatory factor in the Toll-like receptor 4 (TLR4) pathway during microglia activation, and its mechanism in this process is still unclear. In the present study, we aimed to investigate the dynamic changes of IRAK-M and its protective effects for motor neurons in SOD1-G93A mouse model of ALS. qPCR (Real-time Quantitative PCR Detecting System) were used to examine the mRNA levels of IRAK-M in the spinal cord in both SOD1-G93A mice and their age-matched wild type (WT) littermates at 60, 100 and 140 days of age. We established an adeno-associated virus 9 (AAV9)-based platform by which IRAK-M was targeted mostly to microglial cells to investigate whether this approach could provide a protection in the SOD1-G93A mouse. Compared with age-matched WT mice, IRAK-M mRNA level was elevated at 100 and 140 days in the anterior horn region of spinal cords in the SOD1-G93A mouse. AAV9-IRAK-M treated SOD1-G93A mice showed reduction of IL-1ß mRNA levels and significant improvements in the numbers of spinal motor neurons in spinal cord. Mice also showed previously reduction of muscle atrophy. Our data revealed the dynamic changes of IRAK-M during ALS pathological progression and demonstrated that an AAV9-IRAK-M delivery was an effective and translatable therapeutic approach for ALS. These findings may help identify potential molecular targets for ALS therapy.

Low Expression of PALB2 is Associated With Poor Survival in Chinese Women With Primary Breast Cancer.

BACKGROUND: PALB2 plays a crucial role in genome stability and the DNA repair process, and its mutation is associated with a moderate to high risk of breast cancer. However, the status and prognostic role of PALB2 expression in breast cancer are still unclear. MATERIALS AND METHODS: The expression level of PALB2 mRNA was evaluated by using quantitative real-time polymerase chain reaction in core biopsy samples from 563 primary breast cancer tissues. RESULTS: In the entire cohort, low expression of PALB2 mRNA was significantly associated with poor survival (low vs. intermediate: DFS, adjusted HR = 1.79, 95% CI = 1.21-2.65, P = .003; DDFS, adjusted HR = 2.07, 95% CI = 1.34-3.20, P = .001; DSS, adjusted HR = 2.59, 95% CI = 1.45-4.64, P = .001; OS, adjusted HR = 2.77, 95% CI = 1.56-4.92, P = .001; low vs. high: DFS, adjusted HR = 1.57, 95% CI = 1.06-2.35, P = .026; DDFS, adjusted HR = 1.66, 95% CI = 1.08-2.55, P = .020; DSS, adjusted HR = 1.74, 95% CI = 1.00-3.03, P = .048; OS, adjusted HR = 1.59, 95% CI = 0.95-2.67, P = .08). Notably, among hormone receptor (HR)-positive/HER2-negative subtype, patients with low PALB2 expression also had significantly worse outcomes (low vs. intermediate: DFS, adjusted HR = 2.33, 95% CI = 1.32-4.13, P = .004; DDFS, adjusted HR = 2.78, 95% CI = 1.47-5.27, P < .001; DSS, adjusted HR = 3.08, 95% CI = 1.27-7.43, P = .013; OS, adjusted HR = 3.15, 95% CI = 1.32-7.50, P = .010; low vs. high: DFS, adjusted HR = 1.84, 95% CI = 1.04-3.28, P = .04; DDFS, adjusted HR = 1.82, 95% CI = 0.99-3.36, P = .05; DSS, adjusted HR = 2.06, 95% CI = 0.87-4.86, P = .10; OS, adjusted HR = 1.54, 95% CI = 0.71-3.33, P = .28). CONCLUSION: Breast cancer patients with low expression of mRNA have a poor survival, suggesting that patients with PALB2 low expression may be the potential beneficiaries for PARP inhibitors therapy.

Spontaneous ventilation anesthesia combined with uniportal and tubeless thoracoscopic sympathectomy in selected patients with primary palmar hyperhidrosis.

BACKGROUND: To assess the feasibility and safety of tubeless video-assisted thoracoscopic sympathectomy (VATS) with a single 5 mm port under nonintubated, intravenous anesthesia with spontaneous ventilation in selected patients with primary palmar hyperhidrosis (PPH). METHODS: Adults (aged between 18 and 60 years) with moderate or severe PPH symptoms were enrolled. Demographic information and clinical data were obtained from 172 consecutive patients undergoing thoracoscopic surgery for PPH from March 2014 to December 2020. The primary outcomes were the rate of complications, including death, and the intraoperative conversion rate to 3-port VATS. The secondary outcomes were the conversion rate to intubated anesthesia during the operation and the surgical duration and pain score of postoperative day 0. RESULTS: In total, 172 patients were included with 88 males and 84 females. The median age was was 25 years (IQR:21-30 years). No mortalities or major morbidities occurred in any patient. The overall median surgical duration was 53 min (IQR:37-72 min). The median length of postoperative hospital stay was one day (IQR:one-one day). The median pain score of POD0 was 2 (IQR:2-2). Intraoperative conversion to 3-port VATS followed by drainage tube insertion occurred in one (0.6%) patient due to extensive pleural adhesions. No patients required conversion to intubated anesthesia during surgery. No postoperative mechanical ventilation was noted in any patient. CONCLUSIONS: For selected patients with PPH, tubeless VATS with a single 5 mm port using spontaneous ventilation anesthesia can be considered a feasible and safe operation. The surgical wound is extremely small and the operation time is shorter than the conventional technique. Trial registration This study was in conformity with the Declaration of Helsinki, and was approved by the National Ethics Committee of the University of the Hong Kong-Shenzhen Hospital (Approval number: [2020]70). We registered the study in the Chinese Clinical Trial Registry (Registration number: ChiCTR2100049063) in 2021.Informed consent was collected from all the participants of this study. URL for this clinical trial registration is: https://www.chictr.org.cn/index.aspx .

Predictors of Primary Functional Maturation of Autogenous Radiocephalic Arteriovenous Fistula in a Cohort of Asian Patients.

BACKGROUND: The aim of this study was to investigate the predictors of autogenous radiocephalic arteriovenous fistula (RCAVF) maturation. METHODS: This was a retrospective analysis of patients undergoing RCAVF creation from June 2013 to December 2018 at a single medical center. Comparison of the variables between the matured and nonmatured group was performed. RESULTS: A total of 277 patients (men, 173; 62.5%) with a mean age of 56.6 ± 16.9 years underwent primary RCAVF creation during the study period. The mean diameter of the cephalic vein and radial artery were 2.4 ± 0.6 mm (range 1.5 to 4.3 mm) and 2.3 ± 0.5 mm (range 1.5 to 4.0 mm), respectively. Primary functional maturation was achieved in 236 patients (236/277, 85%). There was no statistical significance between the matured and nonmatured group in terms of age (56.4 ± 14.8 vs. 58.1 ± 15.1, respectively; P = 0.498), coronary arterial disease (12% vs. 17%, respectively; P = 0.449), diabetes mellitus (42% vs. 39%, respectively; P = 0.864), smoking (26% vs. 22%, respectively; P = 0.699), or antiplatelet therapy (23% vs. 24%, respectively; P = 0.844). However, female gender (35% vs. 54%, respectively; P = 0.024), peripheral arterial disease (9% vs. 22%, respectively; P = 0.025), and small vein (2.4 ± 0.5 mm vs. 2.0 ± 0.5 mm, respectively; P < 0.01) and artery (2.4 ± 0.5 vs. 2.1 ± 0.4, respectively; P < 0.01) diameter were associated with the failure of maturation. The best cutoff diameter for the cephalic vein and radial artery was 1.85 mm and 2.05 mm, respectively. CONCLUSIONS: In this cohort of patients undergoing RCAVF creation, vein and artery diameter on preoperative ultrasound mapping was the predictor of functional maturation. Female gender and presence of peripheral arterial disease were associated with failure of maturation.

Laparoscopic sphincter-saving surgery for low rectal cancer through marker meeting approach.

Laparoscopic low anterior resection (LAR) with sphincter preservation for ultra-low rectal cancer is always a challenging operation in colorectal surgery. To achieve negative margins, reducing the difficulty and risks of the procedure are major goals for us. The marker meeting approach we reported can help to accomplish this goal. The key technique for the marker meeting approach is to ensure a clear distal margin in a low resection of the rectum by transanal dissection. This procedure allows access to the space around the distal rectum and mesorectum and to pack the gauzes in the distal part of the space as a landmark. Routine laparoscopic LAR was performed to dissect the space until reaching the gauzes packed above and achieve complete mobilization of the rectum and mesorectum. This surgical procedure is simpler and reduces the difficulty of the operation. Therefore, it is expected to reduce the risk of surgery-related complications and positive margins and is suitable to be widely applied and extended in clinical practice. The short-term and long-term clinical outcomes of the marker meeting approach need more research in large samples.

Laparoscopic repair of multiple incisional hernias in a single midline incision by double composite mesh.

Laparoscopic repair of ventral incisional hernia with intraperitoneal onlay mesh (IPOM) technique by anti-adhesion mesh has been widely adopted. Due to clinical heterogenicity in location, quantity and size of abdominal incisional hernia, strategy of such repair can be challenging. We hereby present the video of a patient with multiple swiss-cheese hernias in a single long midline incision repaired with double anti-adhesion mesh by IPOM technique. Patient demographics, technical details and clinical tips & tricks are discussed.