Objective:To explore brain MRI features of methylmalonic acidemia (MMA).Methods:This observational study retrospectively analyzed the clinical and imaging data of 123 patients with MMA diagnosed at Shandong Provincial Hospital Affiliated to Shandong First Medical University and Qilu Hospital of Shandong University from January 2010 to November 2022. The 123 patients were divided into 7 stages according to age of onset, neonatal period (0 to<1 month), infancy (1 month to<1 year), early childhood (1 to<4 years), preschool (4 to<7 years), school age (7 to<13 years), adolescent (13 to 17 years) and adult (>17 years). All patients underwent brain MRI scanning. The imaging performances were evaluated, including the number, location, morphology of the lesions.Results:Of the 123 patients, 40 were in the neonatal period, 29 in infancy, 13 in early childhood, 9 in preschool, 6 in school age, 13 in adolescence, and 13 in adulthood. The first symptoms of patients in the neonatal period were mainly digestive system abnormalities, such as difficulty in breastfeeding (37.5%, 15/40) and vomiting (25.0%, 10/40), with neurological symptoms gradually becoming the main manifestations from infancy. Seventy-three cases (59.3%) showed significant abnormalities on cranial MRI, including 17 cases with 33 foci in the neonatal period, 23 cases with 53 foci in infancy, 11 cases with 16 foci in early childhood, 2 cases with 2 foci in preschool, 3 cases with 7 foci in school age, 7 cases with 9 foci in adolescence, and 10 cases with 16 foci in adulthood. In neonatal period, the main manifestations were myelin dysplasia (18%,6/33), dilatation of the lateral ventricular system (18%,6/33), and pallidal bulb infarct foci (18%,6/33); in infancy, the main manifestations were hypoplasia or thinning of the corpus callosum (30%,16/53); in early childhood, the main manifestations were pallidal bulb infarct foci (38%,6/16); and the two MRI abnormalities in preschool were pallidum and thalamic infarct foci; in school age, the main manifestations were infarct foci in the chiasmatic nucleus (29%,2/7) and in the caudate nucleus (29%,2/7); in adolescence, the main manifestation was dilatation of the lateral ventricular system (33%,3/9); and in adulthood, the main manifestation was dilatation of the lateral ventricular system (19%,3/16).Conclusion:By staging the age of onset, it is found that the imaging manifestations of MMA patients show significant differences with age, suggesting that there is a dynamic nature of MMA damage to brain structures at different developmental stages.

Objective To explore the efficacy and action mechanism of a novel phenothiazine derivative,DA414,in rats with intracerebral hemorrhage(ICH).Methods Male Sprague-Dawley(SD)rats(aged 8～10 weeks,weighing 250～300 g)were randomly divided into sham operation,model,and low and high dose DA414 groups[5 and 10 mg/(kg·d)],with 20 animals per group.The size and extent of injury in the ICH area were measured by magnetic resonance imaging(MRI)and histopathological slices.Neurological function was evaluated with a behavioral grading system.Western blotting was used to detect the expression of ferroptosis-related factor,glutathione peroxidase 4(GPX4).Multiplex immunohistochemistry was employed to quantitatively evaluate microglial activation in perihematomal tissue.RT-qPCR was applied to measure the mRNA expression levels of NLRP3 inflammasome components(NLRP3,Caspase-1,IL-1β),pro-inflammatory(IL-18,TLR4,IL-6,TNF-α)and anti-inflammatory cytokines(IL-4,IL-10).The integrity of the blood-brain barrier(BBB)was assessed by Evans blue staining,and the biosafety of DA414 for the liver,kidneys and heart was assessed by HE staining and clinical biochemical tests.Results DA414 significantly promoted the absorption of hematoma,reduced neuronal injury,and improved neurological function scores.DA414 significantly up-regulated the ferroptosis regulatory factor GPX4(P<0.01),and also significantly inhibited the activation of microglia after ICH(P<0.001).RT-qPCR indicated that DA414 treatment resulted in down-regulation of mRNA expression in the inflammasome pathway(NLRP3,Caspase-1,IL-1β,all P<0.01)and pro-inflammatory cytokines(TLR4,IL-6,both P<0.05;IL-18,TNF-α,both P<0.01)and up-regulation of anti-inflammatory cytokines(IL-4,IL-10,both P<0.05),suggesting that DA414 exerts its neuroprotective effect probably by regulating ferroptosis and inflammation.Safety assessment revealed that DA414 had no significant effect on BBB integrity or damage to the liver,kidneys,and heart in rats.Conclusion DA414 exerts significant neuroprotective effects in ICH model by targeted inhibition for ferroptosis and modulating inflammatory response.Our study provides an experimental foundation for ICH treatment.

Objective To develop an endothelialized microfluidic chip model that simulates the spatial architecture and bioactivity of retinal vasculature,enabling thrombosis modeling and thrombolytic efficacy validation.Methods A tri-level microvascular network chip(300/200/100 μm diameters)with bifurcated architecture was fabricated using soft lithography.Human retinal microvascular endothelial cells(HRMECs)were perfused into channels,with endothelial coverage monitored via phase-contrast microscopy and F-actin staining.Cellular bioactivity was assessed using mitochondrial membrane potential probes(5,5,6,6-Tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide,JC-1)and nitric oxide(NO)quantification.Fresh blood samples from 10 healthy donors(Yongchuan Hospital Affiliated to Chongqing Medical University,March to June 2024)were perfused with digital injection pump to mimic blood flow in human body into 3 experimental groups:normal whole blood,and TNF-α-activated endothelium+normal blood,TNF-α-activated endothelium+TNF-α-treated blood.Three inlet blood flow rates of 37.8、11.1 and 3.5 μL/min were set in each group.Two experimental groups,normal saline and recombinant human tissue-type plasminogen activator(rtPA),were established using the endothelialized microfluidic thrombosis model to validate thrombolytic efficacy.Endothelial functional impacts were assessed through integrated DAPI/NO staining and thrombosis model analysis across 3 intervention phases:pre-thrombosis,post-thrombosis,and post-thrombolysis.Results A tri-level microfluidic vascular model(300/200/100 μm diameters)was successfully constructed.In 72 h after endothelial cell perfusion,complete channel coverage was achieved,with phase-contrast microscopy and F-actin staining confirming confluent cellular alignment.JC-1/NO assays validated preserved endothelial bioactivity.Compared with the whole blood group,both TNF-α-activated endothelium+normal blood and TNF-α-activated endothelium+TNF-α-treated blood groups exhibited significantly increased thrombus occupancy rates at identical flow rates(all P<0.001).Notably,TNF-α-activated endothelium+TNF-α-treated blood group demonstrated the highest thrombus ratio at 3.5 μL/min(P<0.001).The rtPA group showed superior thrombolytic efficacy versus saline(P<0.001).Endothelial monolayer integrity was maintained across intervention phases,with thrombosis triggering significant NO elevation(P<0.001).Conclusion Our retinal vasculature-mimetic microfluidic model enables precise thrombosis modeling and drug evaluation,providing new methodology for studying retinal vascular occlusive diseases.

Post-traumatic stress disorder(PTSD)is a severe mental disorder that significantly impacts an indi-vidual's health,with its primary symptom being fear-based memories.In the pathological state of PTSD,fear-based memo-ries are prolonged and intensified by certain physiological mechanisms.Therefore,expediting the extinction of fear-based memories and preventing their excessive consolidation are crucial for successful treatment.Recently,researchers have dis-covered that ketamine,beyond its role as an anesthetic,also plays a substantial part in regulating fear-based memories.This paper aims to elucidate the role of ketamine in modulating conditioned fear-based memories across various time frames and brain regions,as well as the associated molecular mechanisms.Furthermore,it seeks to clarify the specificity of dif-ferent molecular mechanisms in distinct time frames of fear-based memories and assess whether ketamine could be a prima-ry medication for treating PTSD.

Objective To explore the clinical characteristics of immune-related adverse events (irAEs) involving the pituitary gland in malignant tumor patients following the administration of immune checkpoint inhibitors (ICIs), and to compare characteristics of pituitary irAEs with primary hypophysitis. Methods A total of 753 malignant tumor patients who were hospitalized at Sir Run Run Shaw Hospital School of Medicine, Zhejiang University from January 2019 to November 2022 and received ICIs treatment were retrospectively included. The incidence of endocrine irAEs were statistically analyzed. The clinical characteristics of patients with pituitary irAEs were analyzed and compared with those of patients with primary hypophysitis (n＝18). Results Among the 753 patients treated with ICIs, the majority (742, 98.5%) received PD-1/PD-L1 inhibitors. The incidence of endocrine irAEs was 32.0% (241/753), with primary thyroid dysfunction being most common (212, 28.2%), followed by pituitary dysfunction (35, 4.6%). The median time to onset of pituitary irAEs was 5.8 months, with the majority presenting as secondary hypoadrenocorticism (33, 94.3%). Surgery was a protective factor for preventing pituitary irAEs (P＝0.002), whereas higher body mass index (BMI) and dual ICIs combination therapy were recognized as risk factors (P＜0.05). Compared to patients with primary hypophysitis, patients with pituitary irAEs had a higher proportion of males, lower BMI, lower rates of visual field defects and diabetes insipidus, higher rate of secondary hypoadrenocorticism and lower positive rate on MRI (P＜0.05). Conclusions Malignant tumor patients treated with ICIs exhibit a relatively high incidence of endocrine irAEs, with thyroid involvement being most common, followed by the pituitary gland. Pituitary irAEs primarily manifest as secondary hypoadrenocorticism, lacking specific clinical symptoms and exhibiting a low positive rate on MRI. These factors contribute to a high risk of misdiagnosis or missed diagnosis, necessitating heightened clinical vigilance.

Voice biomarkers， as an emerging smart medical technology， are now being used in applications such as assisting in the diagnosis and treatment of diseases， facilitating accurate and personalized medical services for patients. However， it also raises many ethical issues， including informed consent， privacy protection， accuracy and reliability， data security， legal risks， and other issues. This paper systematically sorted out the ethical issues in the applications of voice biomarkers in the medical field， summarized these issues， such as informed consent， privacy protection， accuracy and reliability， data security， and legal risks， as well as explored the corresponding coping strategies. These countermeasures encompassed utilizing new media platforms to raise public awareness of voice biomarkers， strengthening supervision and management to promote the privacy protection of voice biomarkers， reducing algorithm biases to promote the general benefits of voice biomarkers to the public， establishing multidisciplinary teams to protect the data security of voice biomarkers， and encouraging medical professionals and researchers to participate in policy research， with a view to providing references for promoting and regulating the applications of voice biomarkers in the medical field.

Objective:To investigate the effect of age factor on glymphatic function in patients with Parkinson′s disease (PD) and its potential correlation with overall cognitive performance based on diffusion tensor imaging analysis along the perivascular space(DTI-ALPS) index.Methods:The study was cross-sectional. Clinical and imaging data of 77 PD patients (PD group) who attended the Provincial Hospital of Shandong First Medical University from October 2021 to June 2024 were retrospectively analyzed. In the same period, 30 healthy volunteers matched by age and gender were collected as the normal control (NC) group. All subjects underwent MRI scanning and DTI-ALPS index was calculated based on diffusion tensor imaging. Cognitive functions of 46 patients in the PD group were assessed using the mini-mental state examination (MMSE) and montreal cognitive assessment (MoCA) scores. Independent samples t-tests were used to compare the differences in DTI-ALPS index between the PD and NC groups. After adjusting for confounders, the relationship between DTI-ALPS and age was explored using partial correlation analyses, multiple linear regression models. A mediation model was further developed to explore the mediating effect of DTI-ALPS index between age and cognitive function scores. Results:The DTI-ALPS indices of PD and NC groups were 1.66±0.20 and 1.44±0.17, respectively, and the differences were statistically significant ( t=5.27, P<0.001). The age of patients in the PD group was negatively correlated with the DTI-ALPS index ( r=-0.54, P<0.001), and age (β=-0.467, P<0.001) was an independent influencer of DTI-ALPS index. The DTI-ALPS index was positively correlated with MMSE scores ( r=0.53, P<0.001) and positively correlated with MoCA scores ( r=0.56, P<0.001). The mediation model showed that the DTI-ALPS index fully mediated between age and MMSE scores and partially mediated between age and MoCA scores, with an effect share of 33.25%. Conclusion:Age is an independent risk factor for impaired glymphatic pathway in PD patients, and it may induce cognitive decline in PD patients by exacerbating glymphatic pathway impairment.

Objective:To analyze and compare differences in cortical functioning between patients with post-stroke dysphagia (PSD) following a left hemisphere stroke and healthy individuals using functional near-infrared spectroscopy (fNIRS).Methods:Twenty-six patients recovering from post-stroke dysphagia following a left hemisphere stroke formed the study′s PSD group, and 26 age-matched healthy subjects serves as the HC group. A 41-channel infrared spectroscope was used to record any changes in oxyhemoglobin (HbO) concentration while swallowing and at rest. The fNIRS data were statistically analyzed using Nirspark software. The β-values, reflecting the level of cortical activation, and the swallowing-related specific functional connectivity (FC) strength values (ΔFCs), representing task-specific FC strength, were extracted. The β-values and ΔFCs of the two groups were compared.Results:Compared with the HC group, the PSD group showed significantly reduced activation in Brodmann area (BA) 3/4/6/43 and BA4/6 of the left hemisphere during swallowing. Those areas correspond to the left primary motor cortex (M1), primary somatosensory cortex (S1), premotor cortex, and supplementary motor area (PM). Significantly reduced activation was observed in the PSD group in the right hemisphere at BA45/46/47, BA45/38/48, and BA10, corresponding to the right prefrontal cortex (PFC). The ΔFC values between the left PM-left M1, left PM-left S1, left M1-right S1, and left S1-right M1 in the PSD group were significantly lower than those in the HC group.Conclusions:Left hemispheric PSD is associated not only with decreased activation in the ipsilesional sensorimotor cortex (M1, S1, PM) but also with functional decline in the contra-lesional PFC. During swallowing, persons with left hemispheric PSD exhibit extensive impairment in inter-cortical network connectivity, with particularly marked reductions in connectivity between their ipsilesional and contra-lesional sensorimotor cortices.

Renal autotransplantation (RA) offers significant technical advantages for the management of certain complex renal vascular diseases, such as complex renal aneurysms and renal artery malformations. This report describes a case of a 5-year-old child with a complex left renal artery aneurysm combined with multiple aneurysms. The child was admitted to Peking University People's Hospital in December 2023 due to a one-year history of intermittent abdominal pain, with an abdominal mass detected in the past month. Computed tomography angiography(CTA) revealed multiple vascular anomalies, including: (1) a left renal artery aneurysm, (2) an abdominal aortic aneurysm, and (3) a right iliac artery aneurysm. After a comprehensive evaluation of these findings, the surgical team developed a treatment plan that involved the excision of the left renal artery aneurysm, autotransplantation of the left kidney, and resection of the abdominal aortic aneurysm with an artificial vascular catheterization. During surgery, it was discovered that the left renal artery anatomy was highly complex. The artery had two primary branches, along with an additional polar artery located at the lower pole. The aneurysm was identified at the distal end of the renal artery trunk, with a pronounced bulging at the intersection between the main renal artery trunk and its secondary branches. Due to these structural complexities, the team decided to use an ex vivo surgical approach to repair the aneurysm. Ex vivo repair involves temporarily removing the kidney from the body to repair the renal artery aneurysm with enhanced precision, enabling the surgical team to meticulously reconstruct the complex vascular architecture without the constraints of in vivo manipulation. The ex vivo repair of the renal artery aneurysm was successful, allowing for accurate vascular reconstruction and avoiding potential intraoperative complications. Following the reconstruction, the kidney was autotransplanted back into the child's body, and blood flow was effectively restored to the organ. The therapeutic outcome was excellent, with the child experiencing no postoperative complications. The patient recovered well and was discharged from the hospital in stable condition. This case underscores the value of renal autotransplantation combined with ex vivo repair for pediatric patients with complicated renal artery aneurysms. Through this report, we aim to provide insights and considerations for the surgical treatment of similar cases in children with complex renal vascular anatomy.
Child, Preschool ; Humans ; Aneurysm/surgery* ; Aortic Aneurysm, Abdominal/diagnostic imaging* ; Computed Tomography Angiography ; Iliac Aneurysm/surgery* ; Kidney Transplantation/methods* ; Renal Artery/abnormalities* ; Transplantation, Autologous

Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC₅₀ = 0.049 μmol/L, huBuChE IC₅₀ = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.