The Object of the Study: The author of the given paper describes an unusual combination of two diseases: extramammary Paget’s disease manifested by intraepithelial adenocarcinoma of the vulva and anus combined with i...The Object of the Study: The author of the given paper describes an unusual combination of two diseases: extramammary Paget’s disease manifested by intraepithelial adenocarcinoma of the vulva and anus combined with invasive adenocarcinoma of the ampullary part of the rectum and describes the atypical manifestations of these diseases. The Content: The content of this research paper includes a description of the patient, an analysis of the clinical picture, diagnostic methods and therapeutic interventions used, a report of the following disease, and the result of the presented case. The Result of the Research Work: The result of the research work is the analysis of a clinical case with two different tumors, where such a combination of tumors is rarely described in the literature. Moreover, no large specific sample with this combination of diseases is available. Patient Characteristics: The given case report describes a patient of the Palliative Care Unit of the Gerontology Clinic with a primary diagnosis of C20-rectal adenocarcinoma in the background of the anal canal, perineal skin Paget’s disease, stage IV. The presented complications of the patient’s primary diagnosis are multiple metastases in the liver;status post palliative chemotherapy;hepatomegaly;metastases to abdominal lymph nodes, inguinal lymph nodes;metastases at Th12, L4 level;pain syndrome. The presented above combination of diagnosed diseases is very rare. Applied Diagnostics: In October 2021, it was performed diagnostic manipulation: biopsy and the pathologist have provided a microscopic description. The first tissue fragment had a pronounced electrothermal lesion and the epithelial structures were not valuable. The second skin tissue fragment was covered with hyperplastic and acanthotic epithelium;its basal and middle layers contained multiple large cells proliferates extending into the medial epidermis, and the cytoplasm of these cells reacted positively with PAS (Periodic Acid Schiff reaction). It needs to be noted that the patient had previously had several years of biopsies from the perineal and anal epidermis, where Paget’s disease had also been diagnosed. The performed immunohistochemistry showed these cells to be CK20 positive, CK7 rare positive and p16 negative. The following pathohistological findings were made: morphological and immunohistochemical picture is consistent with Paget’s disease. According to the ICD-10, the patient was diagnosed with C51 malignant neoplasm of the female external genitalia. Using imaging diagnostics, it became clear that the patient’s rectal adenocarcinoma had progressed to metastatic stage with distant liver metastases in the background of anal canal, perineal skin Paget’s disease. Therapeutic Plan of the Patient: Based on the patient’s main diagnoses, the complications of the principal diagnosis, the patient’s overall severe condition, pain syndrome, age and comorbidities, palliative chemotherapy was approved as a therapeutic option in council of doctors. Monitoring and Outcome of the Patient: The patient’s general condition was becoming worse over time, and she was diagnosed with exitus latalis in December 2022. At that time, the patient was discharged from hospital and was on palliative care at home under the control of her family physician.展开更多
The perianal disease affects up to one-third of individuals with Crohn's disease(CD),causing disabling symptoms and significant impairment in quality of life,particularly for those with perianal fistulising CD(PFC...The perianal disease affects up to one-third of individuals with Crohn's disease(CD),causing disabling symptoms and significant impairment in quality of life,particularly for those with perianal fistulising CD(PFCD).The collaborative effort between gastroenterologists and surgeons is essential for addressing PFCD to achieve fistula closure and promote luminal healing.Limited fistula healing rates with conventional therapies have prompted the emergence of new biological agents,endoscopic procedures and surgical techniques that show promising results.Among these,mesenchymal stem cells injection is a particularly hopeful therapy.In addition to the burden of fistulas,individuals with perianal CD may face an increased risk of developing anal cancer.This underscores the importance of surveillance programmes and timely interventions to prevent late diagnoses and poor outcomes.Currently,there is no established formal anal screening programme.In this review,we provide an overview of the current state of the art in managing PFCD,including novel medical,endoscopic and surgical approaches.The discussion also focuses on the relevance of establishing an anal cancer screening programme in CD,intending to propose a risk-based surveillance algorithm.The validation of this surveillance programme would be a significant step forward in improving patient care and outcomes.展开更多
BACKGROUND Stem cell transplantation is a promising therapeutic option for curing perianal fistula in Crohn’s disease(CD).Anti-tumor necrotic factor(TNF)therapy combined with drainage procedure is effective as well.H...BACKGROUND Stem cell transplantation is a promising therapeutic option for curing perianal fistula in Crohn’s disease(CD).Anti-tumor necrotic factor(TNF)therapy combined with drainage procedure is effective as well.However,previous studies are limited to proving whether the combination treatment of biologics and stem cell transplantation improves the effect of fistula closure.AIM This study aimed to evaluate the long-term outcomes of stem cell transplantation and compare Crohn’s perianal fistula(CPF)closure rates after stem cell transplantation with and without anti-TNF therapy,and to identify the factors affecting CPF closure and recurrence.METHODS The patients with CD who underwent stem cell transplantation for treating perianal fistula in our institution between Jun 2014 and December 2022 were enrolled.Clinical data were compared according to anti-TNF therapy and CPF closure.RESULTS A total of 65 patients were included.The median age of females was 26 years(range:21-31)and that of males was 29(44.6%).The mean follow-up duration was 65.88±32.65 months,and complete closure was observed in 50(76.9%)patients.The closure rates were similar after stem cell transplantation with and without anti-TNF therapy(66.7%vs 81.6%at 3 year,P=0.098).The patients with fistula closure had short fistulous tract and infrequent proctitis and anorectal stricture(P=0.027,0.002,and 0.008,respectively).Clinical factors such as complexity,number of fistulas,presence of concurrent abscess,and medication were not significant for closure.The cumulative 1-,2-,and 3-year closure rates were 66.2%,73.8%,and 75.4%,respectively.CONCLUSION Anti-TNF therapy does not increase CPF closure rates in patients with stem cell transplantation.However,both refractory and non-refractory CPF have similar closure rates after additional anti-TNF therapy.Fistulous tract length,proctitis,and anal stricture are risk factors for non-closure in patients with CPF after stem cell transplantation.展开更多
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ?-peptide (A?) produced by the cleavage of a transmembrane p...Alzheimer’s disease (AD) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ?-peptide (A?) produced by the cleavage of a transmembrane protein termed Amyloid Precursor Protein (APP). The amyloidogenic cleavage of APP is performed by γ-secretase complex and ?-site APP cleaving enzyme 1 (BACE1), a key enzyme in AD that can be activated by different noxious stimuli. Interestingly, some viruses could activate double-stranded RNA-activated protein kinase (PKR), which phosphorylates Eukaryotic Initiation Factor 2 alpha (eIF2α). This phosphorylation stops global translation to avoid any synthesis of viral infective proteins, but paradoxically up-regulates BACE1 translation. One of the viral mechanisms to circumvent eIF2α phosphorylation is the recruitment of protein phosphatase 1 (PP1), to fully dephosphorylate eIF2α and allow viral protein synthesis. Due to the functional relationship between BACE1, PKR, PP1 and AD we have performed a large (1122 cases and 1191 control individuals) case-control genetic analysis using two biallelic polymorphisms rs2254958 and rs7480390, located within the genes coding for PKR and the catalytic unit A of PP1, respectively. Although a trend to association of the rs2254958 TT genotype with AD risk was found, our results show that neither rs7480390 nor rs2254958 are associated with AD susceptibility.展开更多
AIM:Pelvic magnetic resonance imaging(MRI)and endoanal ultrasound which are established imaging methods for perianal inflammatory lesions in patients with Crohn's disease require expensive specialized equipments a...AIM:Pelvic magnetic resonance imaging(MRI)and endoanal ultrasound which are established imaging methods for perianal inflammatory lesions in patients with Crohn's disease require expensive specialized equipments and expertise.We investigated the feasibility and sensitivity of transcutaneous perianal ultrasound(PAUS)using regular ultrasound probes in the imaging of perianal inflammatory lesions.The sonographic findings were correlated to pelvic MR]-scans. METHODS:We performed PAUS in 25 patients with Crohn's disease and clinical signs of perianal inflammatory disease. Wibhin a median of 10 d(range 0-75)these patients underwent MRI of the pelvis.Regular convex and linear high resolution probes were used for PAUS.The sonographic findings were correlated to the MRI findings by blinded investigators. RESULTS:The sonographic investigations were well tolerated by all patients.Fistulae typically presented as hypoechoic tracks.Twenty-nine fistulae were detected in 22 patients.Abscesses were detected in 7 patients and presented as hypo-or anechoic formations.Twenty-six of 29 fistulae and 6 of 7 abscesses could be confirmed by MRI.Kappa statistics showed an excellent agreement (kappa>0.83)between the two imaging methods. CONCLUSION:PAUS is a simple,painless,feasible,real- time method that can be performed without specific patient preparation which is comparable in its sensitivity to pelvic MRI in the detection of perianal fistulae and/or abscesses. PAUS can especially be recommended as a screening tool in acute perianal disorders such as perianal abscess and for follow-up studies of perianal inflammatory disease.展开更多
To evaluate the imaging course of Crohn’s disease (CD) patients with perianal fistulas on long-term maintenance anti-tumor necrosis factor (TNF)-α therapy and identify predictors of deep remission.METHODSAll patient...To evaluate the imaging course of Crohn’s disease (CD) patients with perianal fistulas on long-term maintenance anti-tumor necrosis factor (TNF)-α therapy and identify predictors of deep remission.METHODSAll patients with perianal CD treated with anti-TNF-α therapy at our tertiary care center were evaluated by magnetic resonance imaging (MRI) and clinical assessment. Two MR examinations were performed: at initiation of anti-TNF-α treatment and then at least 2 years after. Clinical assessment (remission, response and non-response) was based on Present’s criteria. Rectoscopic patterns, MRI Van Assche score, and MRI fistula activity signs (T2 signal and contrast enhancement) were collected for the two MR examinations. Fistula healing was defined as the absence of T2 hyperintensity and contrast enhancement on MRI. Deep remission was defined as the association of both clinical remission, absence of anal canal ulcers and healing on MRI. Characteristics and imaging patterns of patients with and without deep remission were compared by univariate and multivariate analyses.RESULTSForty-nine consecutive patients (31 females and 18 males) were included. They ranged in age from 14-70 years (mean, 33 years). MRI and clinical assessment were performed after a mean period of exposure to anti-TNF-α therapy of 40 ± 3.7 mo. Clinical remission, response and non-response were observed in 53.1%, 20.4%, and 26.5% of patients, respectively. Deep remission was observed in 32.7% of patients. Among the 26 patients in clinical remission, 10 had persisting inflammation of fistulas on MRI (T2 hyperintensity, n = 7; contrast enhancement, n = 10). Univariate analysis showed that deep remission was associated with the absence of rectal involvement and the absence of switch of anti-TNF-α treatment or surgery requirement. Multivariate analysis demonstrated that only the absence of rectal involvement (OR = 4.6; 95%CI: 1.03-20.5) was associated with deep remission.CONCLUSIONDeep remission is achieved in approximately one third of patients on maintenance anti-TNF-α therapy. Absence of rectal involvement is predictive of deep remission.展开更多
Decreased expression of brain-derived neurotrophic factor(BDNF) plays an important role in the pathogenesis of Alzheimer's disease, and a typical pathological change in Alzheimer's disease is neurofibrillary tangl...Decreased expression of brain-derived neurotrophic factor(BDNF) plays an important role in the pathogenesis of Alzheimer's disease, and a typical pathological change in Alzheimer's disease is neurofibrillary tangles caused by hyperphosphorylation of tau. An in vivo model of Alzheimer's disease was developed by injecting okadaic acid(2 μL) and exogenous BDNF(2 μL) into the hippocampi of adult male Wister rats. Spatial learning and memory abilities were assessed using the Morris water maze. The expression levels of protein phosphatase 2 A(PP2 A), PP2 Ac-Yp307, p-tau(Thr231), and p-tau(Ser396/404) were detected by western blot assay. The expression levels of BDNF, TrkB, and synaptophysin mRNA were measured by quantitative real-time polymerase chain reaction. Our results indicated that BDNF expression was suppressed in the hippocampus of OA-treated rats, which resulted in learning and memory deficits. Intra-hippocampal injection of BDNF attenuated this OA-induced cognitive impairment. Finally, our findings indicated an involvement of the PI3 K/GSK-3β/AKT pathway in the mechanism of BDNF in regulating cognitive function. These results indicate that BDNF has beneficial effect on Alzheimer's disease, and highlight the potential of BDNF as a drug target for treatment of Alzheimer's disease.展开更多
[Objectives] To explore the inhibitory effects of flavonoids from Scutellaria baicalensis Georgi stems and leaves against abnormal formation of PHF and regulation mechanism of protein phosphatase(PP) in okadaic acid(O...[Objectives] To explore the inhibitory effects of flavonoids from Scutellaria baicalensis Georgi stems and leaves against abnormal formation of PHF and regulation mechanism of protein phosphatase(PP) in okadaic acid(OA) induced brain injury in rats.[Methods]Male Sprague-Dawley rats were treated with OA(200 ng/kg) in the lateral ventricle to establish a memory impairment model,and Morris water maze was used to screen the memory impairment model.Rats were intragastrically administered with 25,50 and 100 mg/kg SSF daily for 36 d.The protein expressions of PHF,PP1,PP2A-Cα,PP2A-Cβ,PP2 CA and PP2 CB in rat cortex and hippocampus were determined by Western blot.Ginkgo biloba leaf flavonoids were used as positive control drugs.[Results]Compared with the sham-operated rats,the expression of PHF protein in the cortex and hippocampus of the model group was significantly increased(P < 0.01);protein expression of PP2A-Cα and PP2A-Cβin the cortex and hippocampus,and PP2 CB in the hippocampus were significantly decreased(P < 0.05);protein expression of PP2 CA and PP2 CB in the cortex was significantly increased(P < 0.01);protein expression of PP1 in the cortex was significantly decreased(P < 0.01).Compared with the model rats,25,50 and 100 mg/kg SSF 36 d reversed the protein expression of PHF,PP2A-Cα and PP2ACβ in rat cortex and hippocampus and expression of PP1 in rat cortex induced by OA,but had no significant effect on the protein expression of PP2 CA and PP2 CB,G.biloba flavonoids also showed similar results to SSF.[Conclusions] SSF can significantly inhibit the abnormal formation of PHF in rat brain induced by OA.The inhibitory effect may be related to the regulation of PP1,PP2A-Cα and PP2A-Cβ protein expression in cerebral cortex and hippocampus by SSF,but less related to the regulation of PP2 CA and PP2 CB.展开更多
OBJECTIVE PP2Ac demethyl⁃ation is regulated by LCMT(a specific leucine carboxyl methyltransferase catalyzing methyla⁃tion of PP2A)and PME(a specific methylester⁃ase catalyzing demethylation of PP2A.This study was to i...OBJECTIVE PP2Ac demethyl⁃ation is regulated by LCMT(a specific leucine carboxyl methyltransferase catalyzing methyla⁃tion of PP2A)and PME(a specific methylester⁃ase catalyzing demethylation of PP2A.This study was to investigate the mechanism of Cor⁃nel iridoid glycoside(CIG)on PP2A catalytic sub⁃unit C(PP2Ac).METHODS Recombined lentivi⁃rus vector was used to deliver PME-1 genetic materials into N2a cells or transfected LCMT-1 siRNA into N2a cells to block the expression of LCMT-1.Twenty-four hours later,cells were rinsed twice with cold PBS(pH 7.4)and CIG at different concentrations(50,100 and 200 g·L^(-1),respectively)were added for 24 h.Western blotting was used to PP2Ac,demethylaion/methylation PP2Ac,LCMT-1 and PME-1.The ac⁃tivity of PP2A was detected by a biochemical as⁃say.RESULTS①Lentivirus transferred PME-1 was expressed at high level in the N2a cells after transduction.Correspondingly,the demethylation of PP2Ac was increasing and PP2A activity was decreasing after transduction.Treatment with CIG for 24 h reversed the increase of PME-1 and demethylation of PP2Ac without influencing LCMT-1 expression.PP2A activity was also sig⁃nificantly enhanced in CIG treatment group,compared with the cells after PME-1 transduc⁃tion.②LCMT-1 siRNA significantly decreased LCMT-1 expression.CIG did not affect LCMT-1expression.however,demethylation of PP2Ac is increased in siRNA-transfected cells and CIG could reversed the high demethylation of PP2Ac and PP2A activity.CONLUSION CIG increases methylation of PP2A subunit C by inhibiting PME-1.展开更多
为提高小麦病害检测精度,实现将模型方便快速部署到移动端,该研究提出了一种基于改进YOLOv8的轻量化小麦病害检测方法。首先,使用PP-LCNet模型替换YOLOv8网络结构的骨干网络,并在骨干网络层引入深度可分离卷积(depthwise separable conv...为提高小麦病害检测精度,实现将模型方便快速部署到移动端,该研究提出了一种基于改进YOLOv8的轻量化小麦病害检测方法。首先,使用PP-LCNet模型替换YOLOv8网络结构的骨干网络,并在骨干网络层引入深度可分离卷积(depthwise separable convolution, DepthSepConv)结构,减少模型参数量,提升模型检测性能;其次,在颈部网络部分添加全局注意力机制(global attention mechanism, GAM)模块,强化特征中语义信息和位置信息,提高模型特征融合能力;然后,引入轻量级通用上采样内容感知重组(content-aware reassembly of features,CARAFE)模块,提高模型对重要特征的提取能力;最后,使用Wise-IoU(weighted interpolation of sequential evidence for intersection over union)边界损失函数代替原损失函数,提升网络边界框回归性能和对小目标病害的检测效果。试验结果表明,对于大田环境下所采集的小麦病害数据集,改进后模型的参数量及模型大小相比原YOLOv8n基线模型分别降低了12.5%和11.3%,同时精确度(precision)及平均精度均值(mean average precision,m AP)相较于原模型分别提高了4.5和1.9个百分点,优于其他对比目标检测算法,可为小麦病害检测无人机等移动端检测装备的部署和应用提供参考。展开更多
To the Editor: Hailey-Hailey disease (HHD), first discovered by the brothers Howard and Hugh Hailey,[1]is a genodermatosis at intertriginous sites. Mutation of ATP2C1 on chromosome 3q21-2 coding a calciumdependent ATP...To the Editor: Hailey-Hailey disease (HHD), first discovered by the brothers Howard and Hugh Hailey,[1]is a genodermatosis at intertriginous sites. Mutation of ATP2C1 on chromosome 3q21-2 coding a calciumdependent ATPase gives rise to calcium dysfunction within keratinocytes, resulting in acantholysis due to a signal transduction disorder.[2] It has been suggested that this gene mutation combined with irritation such as frequent friction, cold, and ultraviolet exposure leads to the development of HHD.[3]展开更多
文摘The Object of the Study: The author of the given paper describes an unusual combination of two diseases: extramammary Paget’s disease manifested by intraepithelial adenocarcinoma of the vulva and anus combined with invasive adenocarcinoma of the ampullary part of the rectum and describes the atypical manifestations of these diseases. The Content: The content of this research paper includes a description of the patient, an analysis of the clinical picture, diagnostic methods and therapeutic interventions used, a report of the following disease, and the result of the presented case. The Result of the Research Work: The result of the research work is the analysis of a clinical case with two different tumors, where such a combination of tumors is rarely described in the literature. Moreover, no large specific sample with this combination of diseases is available. Patient Characteristics: The given case report describes a patient of the Palliative Care Unit of the Gerontology Clinic with a primary diagnosis of C20-rectal adenocarcinoma in the background of the anal canal, perineal skin Paget’s disease, stage IV. The presented complications of the patient’s primary diagnosis are multiple metastases in the liver;status post palliative chemotherapy;hepatomegaly;metastases to abdominal lymph nodes, inguinal lymph nodes;metastases at Th12, L4 level;pain syndrome. The presented above combination of diagnosed diseases is very rare. Applied Diagnostics: In October 2021, it was performed diagnostic manipulation: biopsy and the pathologist have provided a microscopic description. The first tissue fragment had a pronounced electrothermal lesion and the epithelial structures were not valuable. The second skin tissue fragment was covered with hyperplastic and acanthotic epithelium;its basal and middle layers contained multiple large cells proliferates extending into the medial epidermis, and the cytoplasm of these cells reacted positively with PAS (Periodic Acid Schiff reaction). It needs to be noted that the patient had previously had several years of biopsies from the perineal and anal epidermis, where Paget’s disease had also been diagnosed. The performed immunohistochemistry showed these cells to be CK20 positive, CK7 rare positive and p16 negative. The following pathohistological findings were made: morphological and immunohistochemical picture is consistent with Paget’s disease. According to the ICD-10, the patient was diagnosed with C51 malignant neoplasm of the female external genitalia. Using imaging diagnostics, it became clear that the patient’s rectal adenocarcinoma had progressed to metastatic stage with distant liver metastases in the background of anal canal, perineal skin Paget’s disease. Therapeutic Plan of the Patient: Based on the patient’s main diagnoses, the complications of the principal diagnosis, the patient’s overall severe condition, pain syndrome, age and comorbidities, palliative chemotherapy was approved as a therapeutic option in council of doctors. Monitoring and Outcome of the Patient: The patient’s general condition was becoming worse over time, and she was diagnosed with exitus latalis in December 2022. At that time, the patient was discharged from hospital and was on palliative care at home under the control of her family physician.
文摘The perianal disease affects up to one-third of individuals with Crohn's disease(CD),causing disabling symptoms and significant impairment in quality of life,particularly for those with perianal fistulising CD(PFCD).The collaborative effort between gastroenterologists and surgeons is essential for addressing PFCD to achieve fistula closure and promote luminal healing.Limited fistula healing rates with conventional therapies have prompted the emergence of new biological agents,endoscopic procedures and surgical techniques that show promising results.Among these,mesenchymal stem cells injection is a particularly hopeful therapy.In addition to the burden of fistulas,individuals with perianal CD may face an increased risk of developing anal cancer.This underscores the importance of surveillance programmes and timely interventions to prevent late diagnoses and poor outcomes.Currently,there is no established formal anal screening programme.In this review,we provide an overview of the current state of the art in managing PFCD,including novel medical,endoscopic and surgical approaches.The discussion also focuses on the relevance of establishing an anal cancer screening programme in CD,intending to propose a risk-based surveillance algorithm.The validation of this surveillance programme would be a significant step forward in improving patient care and outcomes.
基金Supported by the grants from the Asan Institute for Life Sciences,Asan Medical Center,Seoul,Korea,No.2019IF0593 and No.2020IP0039.
文摘BACKGROUND Stem cell transplantation is a promising therapeutic option for curing perianal fistula in Crohn’s disease(CD).Anti-tumor necrotic factor(TNF)therapy combined with drainage procedure is effective as well.However,previous studies are limited to proving whether the combination treatment of biologics and stem cell transplantation improves the effect of fistula closure.AIM This study aimed to evaluate the long-term outcomes of stem cell transplantation and compare Crohn’s perianal fistula(CPF)closure rates after stem cell transplantation with and without anti-TNF therapy,and to identify the factors affecting CPF closure and recurrence.METHODS The patients with CD who underwent stem cell transplantation for treating perianal fistula in our institution between Jun 2014 and December 2022 were enrolled.Clinical data were compared according to anti-TNF therapy and CPF closure.RESULTS A total of 65 patients were included.The median age of females was 26 years(range:21-31)and that of males was 29(44.6%).The mean follow-up duration was 65.88±32.65 months,and complete closure was observed in 50(76.9%)patients.The closure rates were similar after stem cell transplantation with and without anti-TNF therapy(66.7%vs 81.6%at 3 year,P=0.098).The patients with fistula closure had short fistulous tract and infrequent proctitis and anorectal stricture(P=0.027,0.002,and 0.008,respectively).Clinical factors such as complexity,number of fistulas,presence of concurrent abscess,and medication were not significant for closure.The cumulative 1-,2-,and 3-year closure rates were 66.2%,73.8%,and 75.4%,respectively.CONCLUSION Anti-TNF therapy does not increase CPF closure rates in patients with stem cell transplantation.However,both refractory and non-refractory CPF have similar closure rates after additional anti-TNF therapy.Fistulous tract length,proctitis,and anal stricture are risk factors for non-closure in patients with CPF after stem cell transplantation.
基金supported by the Spanish Ministerio de Ciencia y Tecnología(FIS:PI07/0593 and PI10/00587,ISCIII-RETIC RED HERACLES RD06/0009/002-FEDER).
文摘Alzheimer’s disease (AD) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ?-peptide (A?) produced by the cleavage of a transmembrane protein termed Amyloid Precursor Protein (APP). The amyloidogenic cleavage of APP is performed by γ-secretase complex and ?-site APP cleaving enzyme 1 (BACE1), a key enzyme in AD that can be activated by different noxious stimuli. Interestingly, some viruses could activate double-stranded RNA-activated protein kinase (PKR), which phosphorylates Eukaryotic Initiation Factor 2 alpha (eIF2α). This phosphorylation stops global translation to avoid any synthesis of viral infective proteins, but paradoxically up-regulates BACE1 translation. One of the viral mechanisms to circumvent eIF2α phosphorylation is the recruitment of protein phosphatase 1 (PP1), to fully dephosphorylate eIF2α and allow viral protein synthesis. Due to the functional relationship between BACE1, PKR, PP1 and AD we have performed a large (1122 cases and 1191 control individuals) case-control genetic analysis using two biallelic polymorphisms rs2254958 and rs7480390, located within the genes coding for PKR and the catalytic unit A of PP1, respectively. Although a trend to association of the rs2254958 TT genotype with AD risk was found, our results show that neither rs7480390 nor rs2254958 are associated with AD susceptibility.
文摘AIM:Pelvic magnetic resonance imaging(MRI)and endoanal ultrasound which are established imaging methods for perianal inflammatory lesions in patients with Crohn's disease require expensive specialized equipments and expertise.We investigated the feasibility and sensitivity of transcutaneous perianal ultrasound(PAUS)using regular ultrasound probes in the imaging of perianal inflammatory lesions.The sonographic findings were correlated to pelvic MR]-scans. METHODS:We performed PAUS in 25 patients with Crohn's disease and clinical signs of perianal inflammatory disease. Wibhin a median of 10 d(range 0-75)these patients underwent MRI of the pelvis.Regular convex and linear high resolution probes were used for PAUS.The sonographic findings were correlated to the MRI findings by blinded investigators. RESULTS:The sonographic investigations were well tolerated by all patients.Fistulae typically presented as hypoechoic tracks.Twenty-nine fistulae were detected in 22 patients.Abscesses were detected in 7 patients and presented as hypo-or anechoic formations.Twenty-six of 29 fistulae and 6 of 7 abscesses could be confirmed by MRI.Kappa statistics showed an excellent agreement (kappa>0.83)between the two imaging methods. CONCLUSION:PAUS is a simple,painless,feasible,real- time method that can be performed without specific patient preparation which is comparable in its sensitivity to pelvic MRI in the detection of perianal fistulae and/or abscesses. PAUS can especially be recommended as a screening tool in acute perianal disorders such as perianal abscess and for follow-up studies of perianal inflammatory disease.
文摘To evaluate the imaging course of Crohn’s disease (CD) patients with perianal fistulas on long-term maintenance anti-tumor necrosis factor (TNF)-α therapy and identify predictors of deep remission.METHODSAll patients with perianal CD treated with anti-TNF-α therapy at our tertiary care center were evaluated by magnetic resonance imaging (MRI) and clinical assessment. Two MR examinations were performed: at initiation of anti-TNF-α treatment and then at least 2 years after. Clinical assessment (remission, response and non-response) was based on Present’s criteria. Rectoscopic patterns, MRI Van Assche score, and MRI fistula activity signs (T2 signal and contrast enhancement) were collected for the two MR examinations. Fistula healing was defined as the absence of T2 hyperintensity and contrast enhancement on MRI. Deep remission was defined as the association of both clinical remission, absence of anal canal ulcers and healing on MRI. Characteristics and imaging patterns of patients with and without deep remission were compared by univariate and multivariate analyses.RESULTSForty-nine consecutive patients (31 females and 18 males) were included. They ranged in age from 14-70 years (mean, 33 years). MRI and clinical assessment were performed after a mean period of exposure to anti-TNF-α therapy of 40 ± 3.7 mo. Clinical remission, response and non-response were observed in 53.1%, 20.4%, and 26.5% of patients, respectively. Deep remission was observed in 32.7% of patients. Among the 26 patients in clinical remission, 10 had persisting inflammation of fistulas on MRI (T2 hyperintensity, n = 7; contrast enhancement, n = 10). Univariate analysis showed that deep remission was associated with the absence of rectal involvement and the absence of switch of anti-TNF-α treatment or surgery requirement. Multivariate analysis demonstrated that only the absence of rectal involvement (OR = 4.6; 95%CI: 1.03-20.5) was associated with deep remission.CONCLUSIONDeep remission is achieved in approximately one third of patients on maintenance anti-TNF-α therapy. Absence of rectal involvement is predictive of deep remission.
文摘Decreased expression of brain-derived neurotrophic factor(BDNF) plays an important role in the pathogenesis of Alzheimer's disease, and a typical pathological change in Alzheimer's disease is neurofibrillary tangles caused by hyperphosphorylation of tau. An in vivo model of Alzheimer's disease was developed by injecting okadaic acid(2 μL) and exogenous BDNF(2 μL) into the hippocampi of adult male Wister rats. Spatial learning and memory abilities were assessed using the Morris water maze. The expression levels of protein phosphatase 2 A(PP2 A), PP2 Ac-Yp307, p-tau(Thr231), and p-tau(Ser396/404) were detected by western blot assay. The expression levels of BDNF, TrkB, and synaptophysin mRNA were measured by quantitative real-time polymerase chain reaction. Our results indicated that BDNF expression was suppressed in the hippocampus of OA-treated rats, which resulted in learning and memory deficits. Intra-hippocampal injection of BDNF attenuated this OA-induced cognitive impairment. Finally, our findings indicated an involvement of the PI3 K/GSK-3β/AKT pathway in the mechanism of BDNF in regulating cognitive function. These results indicate that BDNF has beneficial effect on Alzheimer's disease, and highlight the potential of BDNF as a drug target for treatment of Alzheimer's disease.
基金Supported by Hebei Province Colleges Hundred Outstanding Innovative Talent Support Program(First Session)Key Science and Technology Project of Hebei Provincial Education Department(ZD20131022)+1 种基金Project for Key Disciplines of Traditional Chinese Medicine in Colleges and Universities of Hebei Province(Ji Jiao Gao[2013]No.4)Program of Key Development Discipline of Pharmacology of Traditional Chinese Medicine in Chengde Medical College(Cheng Yi Fa[2016]No.140)
文摘[Objectives] To explore the inhibitory effects of flavonoids from Scutellaria baicalensis Georgi stems and leaves against abnormal formation of PHF and regulation mechanism of protein phosphatase(PP) in okadaic acid(OA) induced brain injury in rats.[Methods]Male Sprague-Dawley rats were treated with OA(200 ng/kg) in the lateral ventricle to establish a memory impairment model,and Morris water maze was used to screen the memory impairment model.Rats were intragastrically administered with 25,50 and 100 mg/kg SSF daily for 36 d.The protein expressions of PHF,PP1,PP2A-Cα,PP2A-Cβ,PP2 CA and PP2 CB in rat cortex and hippocampus were determined by Western blot.Ginkgo biloba leaf flavonoids were used as positive control drugs.[Results]Compared with the sham-operated rats,the expression of PHF protein in the cortex and hippocampus of the model group was significantly increased(P < 0.01);protein expression of PP2A-Cα and PP2A-Cβin the cortex and hippocampus,and PP2 CB in the hippocampus were significantly decreased(P < 0.05);protein expression of PP2 CA and PP2 CB in the cortex was significantly increased(P < 0.01);protein expression of PP1 in the cortex was significantly decreased(P < 0.01).Compared with the model rats,25,50 and 100 mg/kg SSF 36 d reversed the protein expression of PHF,PP2A-Cα and PP2ACβ in rat cortex and hippocampus and expression of PP1 in rat cortex induced by OA,but had no significant effect on the protein expression of PP2 CA and PP2 CB,G.biloba flavonoids also showed similar results to SSF.[Conclusions] SSF can significantly inhibit the abnormal formation of PHF in rat brain induced by OA.The inhibitory effect may be related to the regulation of PP1,PP2A-Cα and PP2A-Cβ protein expression in cerebral cortex and hippocampus by SSF,but less related to the regulation of PP2 CA and PP2 CB.
文摘OBJECTIVE PP2Ac demethyl⁃ation is regulated by LCMT(a specific leucine carboxyl methyltransferase catalyzing methyla⁃tion of PP2A)and PME(a specific methylester⁃ase catalyzing demethylation of PP2A.This study was to investigate the mechanism of Cor⁃nel iridoid glycoside(CIG)on PP2A catalytic sub⁃unit C(PP2Ac).METHODS Recombined lentivi⁃rus vector was used to deliver PME-1 genetic materials into N2a cells or transfected LCMT-1 siRNA into N2a cells to block the expression of LCMT-1.Twenty-four hours later,cells were rinsed twice with cold PBS(pH 7.4)and CIG at different concentrations(50,100 and 200 g·L^(-1),respectively)were added for 24 h.Western blotting was used to PP2Ac,demethylaion/methylation PP2Ac,LCMT-1 and PME-1.The ac⁃tivity of PP2A was detected by a biochemical as⁃say.RESULTS①Lentivirus transferred PME-1 was expressed at high level in the N2a cells after transduction.Correspondingly,the demethylation of PP2Ac was increasing and PP2A activity was decreasing after transduction.Treatment with CIG for 24 h reversed the increase of PME-1 and demethylation of PP2Ac without influencing LCMT-1 expression.PP2A activity was also sig⁃nificantly enhanced in CIG treatment group,compared with the cells after PME-1 transduc⁃tion.②LCMT-1 siRNA significantly decreased LCMT-1 expression.CIG did not affect LCMT-1expression.however,demethylation of PP2Ac is increased in siRNA-transfected cells and CIG could reversed the high demethylation of PP2Ac and PP2A activity.CONLUSION CIG increases methylation of PP2A subunit C by inhibiting PME-1.
文摘为提高小麦病害检测精度,实现将模型方便快速部署到移动端,该研究提出了一种基于改进YOLOv8的轻量化小麦病害检测方法。首先,使用PP-LCNet模型替换YOLOv8网络结构的骨干网络,并在骨干网络层引入深度可分离卷积(depthwise separable convolution, DepthSepConv)结构,减少模型参数量,提升模型检测性能;其次,在颈部网络部分添加全局注意力机制(global attention mechanism, GAM)模块,强化特征中语义信息和位置信息,提高模型特征融合能力;然后,引入轻量级通用上采样内容感知重组(content-aware reassembly of features,CARAFE)模块,提高模型对重要特征的提取能力;最后,使用Wise-IoU(weighted interpolation of sequential evidence for intersection over union)边界损失函数代替原损失函数,提升网络边界框回归性能和对小目标病害的检测效果。试验结果表明,对于大田环境下所采集的小麦病害数据集,改进后模型的参数量及模型大小相比原YOLOv8n基线模型分别降低了12.5%和11.3%,同时精确度(precision)及平均精度均值(mean average precision,m AP)相较于原模型分别提高了4.5和1.9个百分点,优于其他对比目标检测算法,可为小麦病害检测无人机等移动端检测装备的部署和应用提供参考。
基金National Natural Science Foundation of China (81371731)Milstein Medical Asian American Partnership foundation (2017, dermatology)Education Reform Projects of Peking Union Medical College (No. 2016zlgc0106).
文摘To the Editor: Hailey-Hailey disease (HHD), first discovered by the brothers Howard and Hugh Hailey,[1]is a genodermatosis at intertriginous sites. Mutation of ATP2C1 on chromosome 3q21-2 coding a calciumdependent ATPase gives rise to calcium dysfunction within keratinocytes, resulting in acantholysis due to a signal transduction disorder.[2] It has been suggested that this gene mutation combined with irritation such as frequent friction, cold, and ultraviolet exposure leads to the development of HHD.[3]