The inherent complexity of Alzheimer's disease (AD) and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology. Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action. Pseudo-irreversible inhibition of the first therapeutic target, human butyrylcholinesterase (hBChE), enhances cholinergic transmission, and thereby provides symptomatic treatment, same as the standard therapeutics in use for AD. Simultaneously, this step also functions as a metabolic activation that liberates a nanomolar selective α ₂-adrenergic antagonist atipamezole, which blocks pathological amyloid β (Aβ)-induced and noradrenaline-dependent activation of GSK3β that ultimately leads to hyperphosphorylation of tau, thus achieving a disease-modifying effect. Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition, metabolic activation in human plasma, blood-brain barrier permeability, and p.o. bioavailability in mice. Multi-day in vivo treatment with 8 in an Aβ-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine, the current drug of choice for AD therapy. Furthermore, decreased GSK3β activation and lowered tau phosphorylation were observed in APP/PS1 mice. This surpasses the symptomatic-only treatment with cholinesterase inhibitors, as it directly blocks an essential pathological cascade in AD. Therefore, these multifunctional α ₂-adrenergic antagonists-butyrylcholinesterase inhibitors, exemplified by lead compound 8, present an innovative, small molecule-based, disease-modifying approach to treatment of AD.

BACKGROUND:The objective of this retrospective hospital-based study was to describe the epidemiological features of traumatic spinal cord injury(TSCI)in the intensive care unit(ICU)and assess the incidence and possible risk factors for venous thromboembolism(VTE)following TSCI. METHODS:We retrospectively reviewed the medical records of 370 patients with TSCI who were admitted between January 2018 and March 2023.The following parameters were collected:age,sex,body mass index,occupation,underlying diseases,smoking history,education level,etiology of injury,injury segments,American Spinal Injury Association(ASIA)Impairment Scale score,severity of injury,injury severity score(ISS),VTE risk score(Caprini score),treatment,VTE prophylaxis,ICU length of stay,length of hospital stay,concomitant injuries,and complications.Descriptive statistics were used to summarize the demographic and clinical characteristics of the study participants.Logistic regression analysis was used to determine the risk factors for VTE. RESULTS:The mean age of patients with TSCI was 55.5±13.4 years,with a male-to-female ratio of 6.5:1.The leading cause of TSCI was falls from height(46.5%),followed by traffic accidents(36.5%).The cervical spinal cord was the most affected segment,followed by the thoracolumbar region.Among all the patients,362(97.8%)had concomitant injuries.Complications were observed in 255 patients(68.9%)during hospitalization.The incidence rate of VTE was 25.1%.Logistic regression analysis revealed that age(OR=1.721,95%CI:1.207-2.454,P=0.003),mechanical ventilation(OR=3.427,95%CI:1.873-6.271,P<0.001),and non-use of chemical prophylaxis(OR=2.986,95%CI:1.749-5.099,P<0.001)were risk factors for VTE. CONCLUSION:Falls from height and traffic accidents were the main causes of TSCIs in the ICU,especially for male patients with cervical spinal cord injuries.VTE is a frequent complication in patients with TSCI in the ICU.Age,mechanical ventilation,and non-use of chemical prophylaxis were found to be independent risk factors for VTE following TSCI.

BACKGROUND:The objective of this retrospective hospital-based study was to describe the epidemiological features of traumatic spinal cord injury(TSCI)in the intensive care unit(ICU)and assess the incidence and possible risk factors for venous thromboembolism(VTE)following TSCI. METHODS:We retrospectively reviewed the medical records of 370 patients with TSCI who were admitted between January 2018 and March 2023.The following parameters were collected:age,sex,body mass index,occupation,underlying diseases,smoking history,education level,etiology of injury,injury segments,American Spinal Injury Association(ASIA)Impairment Scale score,severity of injury,injury severity score(ISS),VTE risk score(Caprini score),treatment,VTE prophylaxis,ICU length of stay,length of hospital stay,concomitant injuries,and complications.Descriptive statistics were used to summarize the demographic and clinical characteristics of the study participants.Logistic regression analysis was used to determine the risk factors for VTE. RESULTS:The mean age of patients with TSCI was 55.5±13.4 years,with a male-to-female ratio of 6.5:1.The leading cause of TSCI was falls from height(46.5%),followed by traffic accidents(36.5%).The cervical spinal cord was the most affected segment,followed by the thoracolumbar region.Among all the patients,362(97.8%)had concomitant injuries.Complications were observed in 255 patients(68.9%)during hospitalization.The incidence rate of VTE was 25.1%.Logistic regression analysis revealed that age(OR=1.721,95%CI:1.207-2.454,P=0.003),mechanical ventilation(OR=3.427,95%CI:1.873-6.271,P<0.001),and non-use of chemical prophylaxis(OR=2.986,95%CI:1.749-5.099,P<0.001)were risk factors for VTE. CONCLUSION:Falls from height and traffic accidents were the main causes of TSCIs in the ICU,especially for male patients with cervical spinal cord injuries.VTE is a frequent complication in patients with TSCI in the ICU.Age,mechanical ventilation,and non-use of chemical prophylaxis were found to be independent risk factors for VTE following TSCI.

Objective To explore the mechanism by which soybean isoflavone(SI)reduces calcium overload induced by cerebral ischemia-reperfusion(I/R).Methods Forty-eight SD rats were randomized into 4 groups to receive sham operation,cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion(I/R model group),or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+signaling pathway.Calcium levels and pathological changes in the ischemic penumbra(IP)were measured using calcium chromogenic assay and HE staining,respectively.Another 72 SD randomly allocated for sham operation,I/R modeling,or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter,and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining,and ROS level,Ca2+level,cell apoptosis,and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry;the protein expressions of Wnt5a,Frizzled-2,and P-CaMK II in the IP were detected with Western blotting and immunohistochemistry.Results In rats with cerebral I/R,Frizzled-2 knockdown significantly lowered calcium concentration(P<0.001)and the expression levels of Wnt5a,Frizzled-2,and P-CaMK II in the IP area.In soy isoflavones-pretreated rats,calcium concentration,ROS and MDA levels,cell apoptosis rate,cerebral infarct volume,and expression levels of Wnt/Ca2+signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group.Conclusion Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+signaling pathway.

BACKGROUND:The objective of this retrospective hospital-based study was to describe the epidemiological features of traumatic spinal cord injury(TSCI)in the intensive care unit(ICU)and assess the incidence and possible risk factors for venous thromboembolism(VTE)following TSCI. METHODS:We retrospectively reviewed the medical records of 370 patients with TSCI who were admitted between January 2018 and March 2023.The following parameters were collected:age,sex,body mass index,occupation,underlying diseases,smoking history,education level,etiology of injury,injury segments,American Spinal Injury Association(ASIA)Impairment Scale score,severity of injury,injury severity score(ISS),VTE risk score(Caprini score),treatment,VTE prophylaxis,ICU length of stay,length of hospital stay,concomitant injuries,and complications.Descriptive statistics were used to summarize the demographic and clinical characteristics of the study participants.Logistic regression analysis was used to determine the risk factors for VTE. RESULTS:The mean age of patients with TSCI was 55.5±13.4 years,with a male-to-female ratio of 6.5:1.The leading cause of TSCI was falls from height(46.5%),followed by traffic accidents(36.5%).The cervical spinal cord was the most affected segment,followed by the thoracolumbar region.Among all the patients,362(97.8%)had concomitant injuries.Complications were observed in 255 patients(68.9%)during hospitalization.The incidence rate of VTE was 25.1%.Logistic regression analysis revealed that age(OR=1.721,95%CI:1.207-2.454,P=0.003),mechanical ventilation(OR=3.427,95%CI:1.873-6.271,P<0.001),and non-use of chemical prophylaxis(OR=2.986,95%CI:1.749-5.099,P<0.001)were risk factors for VTE. CONCLUSION:Falls from height and traffic accidents were the main causes of TSCIs in the ICU,especially for male patients with cervical spinal cord injuries.VTE is a frequent complication in patients with TSCI in the ICU.Age,mechanical ventilation,and non-use of chemical prophylaxis were found to be independent risk factors for VTE following TSCI.

BACKGROUND:The objective of this retrospective hospital-based study was to describe the epidemiological features of traumatic spinal cord injury(TSCI)in the intensive care unit(ICU)and assess the incidence and possible risk factors for venous thromboembolism(VTE)following TSCI. METHODS:We retrospectively reviewed the medical records of 370 patients with TSCI who were admitted between January 2018 and March 2023.The following parameters were collected:age,sex,body mass index,occupation,underlying diseases,smoking history,education level,etiology of injury,injury segments,American Spinal Injury Association(ASIA)Impairment Scale score,severity of injury,injury severity score(ISS),VTE risk score(Caprini score),treatment,VTE prophylaxis,ICU length of stay,length of hospital stay,concomitant injuries,and complications.Descriptive statistics were used to summarize the demographic and clinical characteristics of the study participants.Logistic regression analysis was used to determine the risk factors for VTE. RESULTS:The mean age of patients with TSCI was 55.5±13.4 years,with a male-to-female ratio of 6.5:1.The leading cause of TSCI was falls from height(46.5%),followed by traffic accidents(36.5%).The cervical spinal cord was the most affected segment,followed by the thoracolumbar region.Among all the patients,362(97.8%)had concomitant injuries.Complications were observed in 255 patients(68.9%)during hospitalization.The incidence rate of VTE was 25.1%.Logistic regression analysis revealed that age(OR=1.721,95%CI:1.207-2.454,P=0.003),mechanical ventilation(OR=3.427,95%CI:1.873-6.271,P<0.001),and non-use of chemical prophylaxis(OR=2.986,95%CI:1.749-5.099,P<0.001)were risk factors for VTE. CONCLUSION:Falls from height and traffic accidents were the main causes of TSCIs in the ICU,especially for male patients with cervical spinal cord injuries.VTE is a frequent complication in patients with TSCI in the ICU.Age,mechanical ventilation,and non-use of chemical prophylaxis were found to be independent risk factors for VTE following TSCI.

BACKGROUND:The objective of this retrospective hospital-based study was to describe the epidemiological features of traumatic spinal cord injury(TSCI)in the intensive care unit(ICU)and assess the incidence and possible risk factors for venous thromboembolism(VTE)following TSCI. METHODS:We retrospectively reviewed the medical records of 370 patients with TSCI who were admitted between January 2018 and March 2023.The following parameters were collected:age,sex,body mass index,occupation,underlying diseases,smoking history,education level,etiology of injury,injury segments,American Spinal Injury Association(ASIA)Impairment Scale score,severity of injury,injury severity score(ISS),VTE risk score(Caprini score),treatment,VTE prophylaxis,ICU length of stay,length of hospital stay,concomitant injuries,and complications.Descriptive statistics were used to summarize the demographic and clinical characteristics of the study participants.Logistic regression analysis was used to determine the risk factors for VTE. RESULTS:The mean age of patients with TSCI was 55.5±13.4 years,with a male-to-female ratio of 6.5:1.The leading cause of TSCI was falls from height(46.5%),followed by traffic accidents(36.5%).The cervical spinal cord was the most affected segment,followed by the thoracolumbar region.Among all the patients,362(97.8%)had concomitant injuries.Complications were observed in 255 patients(68.9%)during hospitalization.The incidence rate of VTE was 25.1%.Logistic regression analysis revealed that age(OR=1.721,95%CI:1.207-2.454,P=0.003),mechanical ventilation(OR=3.427,95%CI:1.873-6.271,P<0.001),and non-use of chemical prophylaxis(OR=2.986,95%CI:1.749-5.099,P<0.001)were risk factors for VTE. CONCLUSION:Falls from height and traffic accidents were the main causes of TSCIs in the ICU,especially for male patients with cervical spinal cord injuries.VTE is a frequent complication in patients with TSCI in the ICU.Age,mechanical ventilation,and non-use of chemical prophylaxis were found to be independent risk factors for VTE following TSCI.

BACKGROUND:The objective of this retrospective hospital-based study was to describe the epidemiological features of traumatic spinal cord injury(TSCI)in the intensive care unit(ICU)and assess the incidence and possible risk factors for venous thromboembolism(VTE)following TSCI. METHODS:We retrospectively reviewed the medical records of 370 patients with TSCI who were admitted between January 2018 and March 2023.The following parameters were collected:age,sex,body mass index,occupation,underlying diseases,smoking history,education level,etiology of injury,injury segments,American Spinal Injury Association(ASIA)Impairment Scale score,severity of injury,injury severity score(ISS),VTE risk score(Caprini score),treatment,VTE prophylaxis,ICU length of stay,length of hospital stay,concomitant injuries,and complications.Descriptive statistics were used to summarize the demographic and clinical characteristics of the study participants.Logistic regression analysis was used to determine the risk factors for VTE. RESULTS:The mean age of patients with TSCI was 55.5±13.4 years,with a male-to-female ratio of 6.5:1.The leading cause of TSCI was falls from height(46.5%),followed by traffic accidents(36.5%).The cervical spinal cord was the most affected segment,followed by the thoracolumbar region.Among all the patients,362(97.8%)had concomitant injuries.Complications were observed in 255 patients(68.9%)during hospitalization.The incidence rate of VTE was 25.1%.Logistic regression analysis revealed that age(OR=1.721,95%CI:1.207-2.454,P=0.003),mechanical ventilation(OR=3.427,95%CI:1.873-6.271,P<0.001),and non-use of chemical prophylaxis(OR=2.986,95%CI:1.749-5.099,P<0.001)were risk factors for VTE. CONCLUSION:Falls from height and traffic accidents were the main causes of TSCIs in the ICU,especially for male patients with cervical spinal cord injuries.VTE is a frequent complication in patients with TSCI in the ICU.Age,mechanical ventilation,and non-use of chemical prophylaxis were found to be independent risk factors for VTE following TSCI.

BACKGROUND:The objective of this retrospective hospital-based study was to describe the epidemiological features of traumatic spinal cord injury(TSCI)in the intensive care unit(ICU)and assess the incidence and possible risk factors for venous thromboembolism(VTE)following TSCI. METHODS:We retrospectively reviewed the medical records of 370 patients with TSCI who were admitted between January 2018 and March 2023.The following parameters were collected:age,sex,body mass index,occupation,underlying diseases,smoking history,education level,etiology of injury,injury segments,American Spinal Injury Association(ASIA)Impairment Scale score,severity of injury,injury severity score(ISS),VTE risk score(Caprini score),treatment,VTE prophylaxis,ICU length of stay,length of hospital stay,concomitant injuries,and complications.Descriptive statistics were used to summarize the demographic and clinical characteristics of the study participants.Logistic regression analysis was used to determine the risk factors for VTE. RESULTS:The mean age of patients with TSCI was 55.5±13.4 years,with a male-to-female ratio of 6.5:1.The leading cause of TSCI was falls from height(46.5%),followed by traffic accidents(36.5%).The cervical spinal cord was the most affected segment,followed by the thoracolumbar region.Among all the patients,362(97.8%)had concomitant injuries.Complications were observed in 255 patients(68.9%)during hospitalization.The incidence rate of VTE was 25.1%.Logistic regression analysis revealed that age(OR=1.721,95%CI:1.207-2.454,P=0.003),mechanical ventilation(OR=3.427,95%CI:1.873-6.271,P<0.001),and non-use of chemical prophylaxis(OR=2.986,95%CI:1.749-5.099,P<0.001)were risk factors for VTE. CONCLUSION:Falls from height and traffic accidents were the main causes of TSCIs in the ICU,especially for male patients with cervical spinal cord injuries.VTE is a frequent complication in patients with TSCI in the ICU.Age,mechanical ventilation,and non-use of chemical prophylaxis were found to be independent risk factors for VTE following TSCI.

BACKGROUND:The objective of this retrospective hospital-based study was to describe the epidemiological features of traumatic spinal cord injury(TSCI)in the intensive care unit(ICU)and assess the incidence and possible risk factors for venous thromboembolism(VTE)following TSCI. METHODS:We retrospectively reviewed the medical records of 370 patients with TSCI who were admitted between January 2018 and March 2023.The following parameters were collected:age,sex,body mass index,occupation,underlying diseases,smoking history,education level,etiology of injury,injury segments,American Spinal Injury Association(ASIA)Impairment Scale score,severity of injury,injury severity score(ISS),VTE risk score(Caprini score),treatment,VTE prophylaxis,ICU length of stay,length of hospital stay,concomitant injuries,and complications.Descriptive statistics were used to summarize the demographic and clinical characteristics of the study participants.Logistic regression analysis was used to determine the risk factors for VTE. RESULTS:The mean age of patients with TSCI was 55.5±13.4 years,with a male-to-female ratio of 6.5:1.The leading cause of TSCI was falls from height(46.5%),followed by traffic accidents(36.5%).The cervical spinal cord was the most affected segment,followed by the thoracolumbar region.Among all the patients,362(97.8%)had concomitant injuries.Complications were observed in 255 patients(68.9%)during hospitalization.The incidence rate of VTE was 25.1%.Logistic regression analysis revealed that age(OR=1.721,95%CI:1.207-2.454,P=0.003),mechanical ventilation(OR=3.427,95%CI:1.873-6.271,P<0.001),and non-use of chemical prophylaxis(OR=2.986,95%CI:1.749-5.099,P<0.001)were risk factors for VTE. CONCLUSION:Falls from height and traffic accidents were the main causes of TSCIs in the ICU,especially for male patients with cervical spinal cord injuries.VTE is a frequent complication in patients with TSCI in the ICU.Age,mechanical ventilation,and non-use of chemical prophylaxis were found to be independent risk factors for VTE following TSCI.