ObjectiveTo investigate the potential mechanism of Danggui Buxuetang （DBT） in the treatment of vascular dementia （VAD）. MethodsSixty male SD rats were randomly assigned to the sham-operated group， model group， DBT low-， medium-， and high-dose groups， and the donepezil group. Except for the sham-operated group， rats in all other groups underwent bilateral common carotid artery ligation. After successful modeling， DBT was administered at doses of 9.2， 18.4， 36.8 g·kg^-1 for the low-， medium-， and high-dose groups， respectively， while the donepezil group received 3 mg·kg^-1 donepezil solution by gavage once daily. After 4 consecutive weeks of drug treatment， rats underwent the Morris water maze test， novel object recognition test， Nissl staining to observe hippocampal neurons， and immunofluorescence staining to detect the expression of neuronal nuclear protein （NeuN） in the hippocampus. Western blot was used to assess the expression of PTEN-induced kinase 1 （PINK1）， Parkin， microtubule-associated protein 1 light chain 3Ⅱ （LC3Ⅱ）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax）. Transmission electron microscopy was used to observe hippocampal neuronal ultrastructure. Real-time PCR was used to detect the expression of NADPH oxidase subunits p22^phox and p47^phox in hippocampal tissues. The levels of malondialdehyde （MDA）， glutathione （GSH）， superoxide dismutase （SOD）， and total antioxidant capacity were measured to evaluate oxidative stress levels. ResultsIn the Morris water maze test， escape latency changed significantly over time in all groups except the model group. Compared with the sham-operated group， the model group showed significantly prolonged escape latency （P<0.01）. Compared with the model group， rats in the DBT groups and the donepezil group exhibited significantly shorter escape latency （P<0.05， P<0.01）. The number of crossings over the original platform was significantly reduced in the model group compared with the sham-operated group （P<0.01）， whereas rats in the DBT and donepezil groups showed significantly increased platform crossings compared with the model group （P<0.05， P<0.01）. Compared with the sham-operated group， exploration time of new objects was significantly reduced in the model group （P<0.01）. Compared with the model group， exploration time of new objects increased significantly in the medium- and high-dose DBT groups and the donepezil group （P<0.05， P<0.01）， while no significant change was observed in the low-dose DBT group. Compared with the high-dose DBT group， rats in the donepezil group had significantly prolonged escape latency and reduced platform crossings and new-object exploration time （P<0.05）. Nissl staining showed decreased density of healthy neurons in the CA1 and CA3 regions of the hippocampus in the model group， with loss of Nissl bodies and nuclear atrophy or disappearance. In the high-dose DBT group， neuronal density in CA1 and CA3 increased， with neurons arranged closely and displaying normal morphology. Immunofluorescence showed that compared with the sham-operated group， the hippocampal NeuN⁺ cell count in the VAD model group was significantly decreased（P<0.01）， compared with the VAD model group， the hippocampal NeuN⁺ cell count in the high-dose DBT group was significantly increased（P<0.01）. Compared with the sham-operated group， the expression of PINK1， Parkin， LC3Ⅱ， and Bax proteins was significantly increased（P<0.01）， while the expression of Bcl-2 was significantly decreased in the VAD model group（P<0.01）. Compared with the VAD model group， the high-dose DBT group showed significantly decreased expression of PINK1， Parkin， LC3Ⅱ， and Bax proteins（P<0.01）and significantly upregulated Bcl-2 expression（P<0.01）. The medium-dose DBT group exhibited significantly reduced expression of Parkin， LC3Ⅱ， and Bax proteins（P<0.05，P<0.01） and significantly increased Bcl-2 expression（P<0.01）， while no statistically significant differences were observed in the low-dose DBT group. Transmission electron microscopy showed mitochondrial pyknosis， thickened cristae， increased electron density， and the presence of mitochondrial autophagy in the model group. In contrast， hippocampal neurons in the high-dose DBT group contained abundant mitochondria with intact morphology， clear cristae， and uniform matrix. Compared with the sham-operated group， total antioxidant capacity， SOD activity， and GSH levels were significantly decreased， while MDA levels were significantly increased in the model group （P<0.01）. Compared with the model group， total antioxidant capacity and antioxidant levels （SOD， GSH） increased significantly， and MDA decreased significantly in the medium- and high-dose DBT groups （P<0.01）， while no significant changes were observed in the low-dose DBT group. Compared with the sham-operated group， mRNA expression of p22^phox and p47^phox was significantly increased in the model group （P<0.01）. Compared with the model group， expression of p22^phox and p47^phox was significantly decreased in the DBT groups （P<0.05， P<0.01）. ConclusionDBT may exert neuroprotective effects by regulating PINK1/Parkin-mediated mitochondrial autophagy， thereby improving learning and memory abilities and treating VAD.

Neuronal intranuclear inclusion disease（NIID）is a rare hereditary neurodegenerative disorder that can affect multiple systems. However，it is uncommon for urinary dysfunction to be the initial symptom. This article reports five cases. The five patients began to experience voiding dysfunction such as frequent urination，weak urination，and incomplete urination at the mean ages of 55.4（47 - 65）years old. Four months to twelve years after urinary onset，neurological symptoms such as headache，memory decline，transient loss of consciousness，and unsteady gait began to appear. Four of the five cases had a family history. Brain MRI revealed the “ribbon sign” or “crest sign” in all cases. Skin biopsy revealed eosinophilic inclusions in the cell nuclei，and NOTCH2NLC gene testing identified abnormal GGC mutations. Three of the five patients underwent cystostomy due to secondary hydronephrosis，while the other two received no special treatment. After a follow-up of 18 to 35 months since diagnosis，the patients who underwent cystostomy had normal renal function. Neurological symptoms in all five patients worsened to varying degrees.

Neuronal intranuclear inclusion disease（NIID）is a rare hereditary neurodegenerative disorder that can affect multiple systems. However，it is uncommon for urinary dysfunction to be the initial symptom. This article reports five cases. The five patients began to experience voiding dysfunction such as frequent urination，weak urination，and incomplete urination at the mean ages of 55.4（47 - 65）years old. Four months to twelve years after urinary onset，neurological symptoms such as headache，memory decline，transient loss of consciousness，and unsteady gait began to appear. Four of the five cases had a family history. Brain MRI revealed the “ribbon sign” or “crest sign” in all cases. Skin biopsy revealed eosinophilic inclusions in the cell nuclei，and NOTCH2NLC gene testing identified abnormal GGC mutations. Three of the five patients underwent cystostomy due to secondary hydronephrosis，while the other two received no special treatment. After a follow-up of 18 to 35 months since diagnosis，the patients who underwent cystostomy had normal renal function. Neurological symptoms in all five patients worsened to varying degrees.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Objective:To analyze the clinicopathological features of histological mixed-type early gastric cancer and to compare the endoscopic pathological features of dominant proportions.Methods:Clinical data of 43 patients with histological mixed-type early gastric cancer who underwent endoscopic submucosal dissection (ESD) at the Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School from January 2015 to December 2020 were retrospectively analyzed. The endoscopic characteristics, coincidence rate of preoperative diagnosis and postoperative pathology of the patients were analyzed. The endoscopic pathological findings of differentiation dominant group and undifferentiation dominant group were compared.Results:Histological mixed-type early gastric cancer was more common in patients over 60 years old (55.81%, 24/43) , male (65.12%, 28/43), and Helicobacter pylori ( HP) infection (69.77%, 30/43). Most lesions were found in atrophic background (79.07%, 34/43), and lower part of stomach (65.12%, 28/43). Redness or mixed redness was the main color (76.74%, 33/43), and 0-Ⅱc was the main type in lesion morphology (58.14%, 25/43). Characteristics of both differentiated and undifferentiated carcinoma could be observed under magnifying endoscopy. Only 16.28% (7/43) of the patients were diagnosed as having histological mixed-type carcinoma by biopsy. Postoperative pathology showed that there were 33 cases in differentiation dominant group and 10 cases in undifferentiation dominant group. There were 15 (34.88%) patients with deep submucosal infiltration, and 3 (6.98%) patients with positive lymphatic vessels. Differentiation dominant group had clearer demarcation line under endoscopy [78.79% (26/33) VS 4/10, χ2=7.753, P=0.012]. There was no significant difference between the two groups in gender, HP infection, background mucosa, lesion location, endoscopic morphology, lesion long diameter, color, or microscopic and microvascular manifestations under magnifying endoscopy ( P>0.05). Tub2+por was the most common pathological type in differentiation dominant group (78.79%, 26/33), and sig+tub2 was the dominant combination in undifferentiation dominant group (6/10). Endoscopic diagnosis of differentiated primary carcinoma was highly sensitive (93.94%, 31/33), and highly specific for undifferentiated primary carcinoma (94.28%, 33/35). Conclusion:Histological mixed-type early gastric cancer can be diagnosed qualitatively by endoscopy. It is difficult to accurately judge the differentiation advantage and the invasion depth before the operation, which is prone to postoperative pathological upgrading. Therefore, the indications should be strictly considered for ESD treatment for mixed-type early gastric cancer.

Objective:To investigate the clinicopathological features of gastric adenocarcinoma of fundic gland type (GA-FG).Methods:A total of 12 patients, including 7 cases treated with endoscopic submucosal dissection (ESD), were diagnosed as having GA-FG in Nanjing Drum Tower Hospital from January 2018 to August 2019. Morphological changes were analyzed by reviewing endoscopic and pathological results. Patients were followed up after definitive diagnosis.Results:The clinical symptoms of patients with GA-FG were nonspecific. No Helicobacter pylori infection was identified. The lesions were found in the non-atrophic gastric mucosa of the upper 1/3 portion in 10 cases and middle 1/3 portion in 2 cases. Endoscopically, the most common features were whitish color (9 cases), and all lesions diameter≤1 cm. Their macroscopic types were classified as 0-Ⅰ (2 cases), 0-Ⅱa (9 cases) and 0-Ⅱc (1 case) respectively. All lesions had sharp boundary, with branching dilated blood vessels on the surface. Five in 7 cases who were treated with ESD showed submucosal invasion. Immunohistochemically, 9 cases were classified as the chief cell type , 3 as the mixed type, 11 MUC6 positive, 4 MUC5AC positive, 2 MUC2 positive, and 3 CD10 positive. P53 was detected in all 12 cases, and 9 cases had low Ki-67 staining index (<10%). The mean time of follow-up was 11 months, and 11 patients survived. Conclusion:GA-FG should be taken into consideration when the polyps are found in the upper part of the stomach, with whitish color, and branch dilated blood vessels on the surface. Excellent clinical outcomes can be achieved for GA-FG patients with ESD.

Objective:To investigate the clinicopathological characteristics and cost-effectiveness of endoscopic resection and surgical resection for gastric schwannomas arising from the muscularis propria layer.Methods:Thirty-eight consecutive cases of gastric schwannomas diagnosed by histopathology between October 2011 and July 2016 were divided into the endoscopy group(including endoscopic submucosal excavation and endoscopic full-thickness resection) and the surgery group. Complications, complete resection rate and cost-effectiveness were analyzed.Results:The age was 52±10 years (range, 41-63 years) with 11(28.9%) males and 27(71.1%) females. The most common site of gastric schwannomas was the body (71.1%) and the antrum (21.1%). All 38(100%) lesions were protruded. The maximum diameter of the lesions was 2.5±1.2 cm (range 0.6-4.5 cm). Under endoscopic ultrasonography (EUS), 60.5% lesions were heterogeneous hypoechoic, and 15 (39.5%) hypoechoic. The complete resection rate of endoscopy group was 100.0% (17/17). The median operation time of the endoscopy group was 54 minutes. Perforations occurred in 11 patients (64.7%, 11/17), and metal clips or the nylon rope combined with metallic clips were used to close the defect in the endoscopy group. Compared with the surgery group, the length of hospital stay was significantly shorter (4.6±0.6 d VS 9.6±4.4 d, P<0.001); the time to the first fluid diet was significantly shorter (1.2±0.4 d VS 2.7±0.7 d, P<0.001), and the costs were significantly lower (21 965.0±9 342.4 yuan VS 34 253.3±10 520.9 yuan, P<0.001) in the endoscopy group. S100 immunoreactivity was present in all tumors. Local recurrence and distant metastasis did not occur during the median 34 months of follow-up. Conclusions:Endoscopic resection appears to be safe and effective for diagnosis and treatment of gastric schwannomas from the muscularis propria layer. The cost-effectiveness of endoscopic resection is significantly higher than surgical resection.

Objective To investigate the clinical characteristics of stroke in young patients with cardiac myxoma.Methods Medical records of young patients (aged between 18-44 years) diagnosed with cardiac myxoma in Beijing Anzhen Hospital affiliated to Capital Medical University from January 2005 to March 2016 were retrospective reviewed.Results A total of 117 cases were included (85 female and 32 male)with the average age (36 ±7)years old.Most myxomas (83.8％) were located in the left atrium,7.7％ were in the right atrium,3.5％ were in the both atriums,2.6％ were in the left ventricle,and a few were in the left atrium plus left ventricle and in the right ventricle.Of all the patients,24 (20.5％) (16 women and 8 men) were complicated with cerebral infarction.Among them,3 patients were with lower extremity arterial embolisms.Two patients were with cerebral hemorrhage.The cerebral infarction mainly involved in the distribution area of the internal carotid artery.Infarctions involving 2 or more cerebral vessels were found in 4 cases.Most subjects (58.3％) manifested with hemiplegia,and some (18.2％) with syncope.The proportion of the left atrial myxoma in patients with cerebral infarction (100.0％) was significantly higher than those in patients without cerebral infarction (85.1％,P =0.044).Subjects with tumor diameter less than 3 cm were more frequently complicated with cerebral infarction (37.5％ vs 13.8％,P =0.009).A logistic analysis showed that the odds ratio of myxoma with tumor diameter less than 3 cm for cerebral infarction was 3.750 (95％ CI 1.343-10.470).Conclusions Cardiac myxoma is more common in young women,and often complicated with cerebral infarction.The infarctions are mainly distributed in internal carotid artery system,and some are involved in multiple vascular systems.The incidence of stroke is associated with the position of the myxoma.Smail-size myxoma cannot be ignored for its risk of stroke.

OBJECTIVETo evaluate the therapeutic effects of VSD combined with irrigation of oxygen loaded fluid on the growth of granulation tissue and macrophage polarization in chronic venous leg ulcers.

METHODSThiry-four patients with chronic venous leg ulcers hospitalized in our department from December 2010 to July 2014 were divided into VSD group ( A, n = 11) , VSD + irrigation group ( B, n = 11) , and VSD + oxygen loaded fluid irrigation group ( C, n = 12) according to the random number table. After admissian, debridement was performed, and granulation tissue in the center of the wound was harvested during the operation. After dehridement, the patients in group A were treated with VSD only (negative pressure from -30 to -25 kPa, the same below) ; the patients in group B were treated with VSD combining irrigation of normal saline; the patients in group C were treated with VSD combining normal saline loaded with oxygen irrigation (flow of 1 L/min) . On post treatment day (PTD) 7, the VSD devices were removed. Cross observation was conducted before debridement and on PTD 7. On PTD 7, the granulation tissue in the center of the wound was harvested for histopathological observation with HE staining and Masson staining, following calculation of granulation tissue coverage rate. After debridement but before the negative pressure therapy (hereinafter referred to as before treatment) and on PTD 7, partial pressure of oxygen of the skin around the wound was measured by transcutaneous tissue oxygen tension survey meter. On PTD 7, expression of vascular endothelial growth factor (VECF) was determined with immunohistochemistry. Before treatment and on PTD 7, cells with double positive expressions of induced nitric oxide synthase plus CD68 ( type I macro- phage) and arginase 1 plus CD68 ( type II macrophage) were observed with immunofluorescence staining and quantified. Data were processed with Fisher's exact test, one-way analysis of variance, covariance analysis, paired test, and LSD test.

RESULTS(1) The gross observation showed that before debridement there was a certain amount of necrotic tissue and little granulation tissue in the wounds of patients in all the 3 groups. On PTD 7, new granulation tissue was found in the wounds of patients in all the 3 groups, and in group C its amount was the largest. (2) On PTD 7, the granulation tissue coverage rate of wounds in pa- tients of group C was higher than that of group A or B ( P <0.05 or P <0.01). (3) On PTD 7, HE staining showed that there appeared more abundant new born microvessels and fibroblasts in the wounds of patients in group C than those in groups A and B; Masson staining showed that there was more abundant fresh collagen distributed orderly in the wounds of patients in group C compared with group A or B. (4) On PTD 7, it was found that partial pressure of oxygen of the skin around the wounds in patients of group C [(40.7 +/- 4.1) mmHg, 1 mmHg = 0.133 kPa] was higher than that of group A [ (35.0 +/- 3.1) mmHg] or B [(35.4 +/- 2.7) mmHg, with P values below 0.01]; the partial pressure of oxygen of the skin around the wounds of patients in all the 3 groups was increased significantly compared with that before treatment (with values from 10.38 to 22.52, P values below 0.01). (5) On PTD 7, the expression of VECF in the wounds of patients in group C was higher than that in group A or B ( P <0.05 or P < 0.01). (6) On PTD 7, the number of type I macrophages in granulation tissue of patients was respectively 14.3 +/- 2.3, 11.5 +/- 3.0, and 10.7 +/- 2.3 per 400 times vision field in groups A , B, and C ( F = 25.14, P < 0.01), while the number in group C was less than that in group A or B ( P < 0.05 or P < 0.01). Compared with that before treatment, the number of type I macrophages was significantly decreased on PTD 7 in all the 3 groups (with values from 14.76 to 23. 73, P values below 0. 01). On PTD 7, the number of type II macrophages in granulation tissue of patients was respectively 32.7 +/- 3.2, 35.1 +/- 3.3 , and 41.3 +/- 3.2 per 400 times vision field in groups A, B, and C ( F = 81.10, P < 0.01), and the number in group C was lager than that in group A or B ( with P values below 0. 01). Compared with that before treatment, the number of type II macrophages in all the 3 groups was significantly increased (with t values from -69.34 to -47.95, P values below 0.01).

CONCLUSIONSVSD combined with irrigation of oxygen loaded fluid can raise the partial pressure of oxygen of the skin around the wounds effectively, promoting the transition of macrophages from type I to type II, thus it may promote the growth of granulation tissue, resulting in a better recipient for skin grafting or epithelization.

Debridement ; Drainage ; Granulation Tissue ; Humans ; Leg Ulcer ; etiology ; surgery ; Macrophages ; Microvessels ; Negative-Pressure Wound Therapy ; methods ; Nitric Oxide Synthase Type II ; Oxygen ; Skin ; Skin Transplantation ; Skin Ulcer ; Surgical Flaps ; Treatment Outcome ; Vacuum ; Vascular Endothelial Growth Factor A ; Veins ; Wound Healing

Objective To investigate the clinical features of stroke in young adults with infective endocarditis (IE).Methods This is a retrospective analysis of clinical data of young patients (aged between 18 and 44 years) diagnosed with IE in Beijing Anzhen Hospital affiliated to Capital Medical University from January 2003 to March 2013.Results Three hundred IE patients (209 male and 91 female) were enrolled with mean age of (31.8 ± 7.8) years old.Fourteen of them were prosthetic valve endocarditis.All of the cases were found vegetations.The vegetations were mainly distributed in the mitral valve and/or aortic valve (262/300 patients).Congenital heart disease and rheumatic valvular disease were most frequently background diseases.Thirty-five cases (11.7％) were complicated with stroke.Among them,21 cases were with cerebral infarction (including 7 subjects with hemorrhagic transformation),9 cases with cerebral hemorrhage,3 cases with subarachnoid hemorrhage,and 2 with reasons unknown.Within the 21 cerebral infarction cases,the infarction sites were mainly distributed in internal carotid artery system with 5 cases involving bilateral internal carotid artery systems and 2 vertebro-basilar artery systems.As to the cerebral hemorrhage,lobar were the bleeding sites in all cases,and mainly distributed in internal carotid artery system.The proportions of left-sided endocarditis and rheumatic valvular disease were significantly higher in patients with stroke than those without [100.0％ (35/35) vs 86.4％ (229/265),P =0.02;22.8％ (8/35) vs 6.4％ (17/265),P =0.001,respectively].Regression analysis showed that the OR of the rheumatic valvular disease for stroke in young IE patients was 4.950 (95％ CI 1.626-15.072),and the OR of stroke for death was 8.387 (95％ CI 1.997-35.225),respectively.Conclusions Stroke is common in young patients with IE.Cerebral infarction often involves multiple vascular systems,and is prone to hemorrhagic transformation.Intracerebral hemorrhage often occurs in lobar.Rheumatic valvular disease might be a risk factor for stroke in young patients with IE,which is an independent risk factor for death of these patients.