BACKGROUND Following cesarean section,a significant number of women encounter moderate to severe pain.Inadequate management of acute pain post-cesarean section can have far-reaching implications,adversely impacting ma...BACKGROUND Following cesarean section,a significant number of women encounter moderate to severe pain.Inadequate management of acute pain post-cesarean section can have far-reaching implications,adversely impacting maternal emotional wellbeing,daily activities,breastfeeding,and neonatal care.It may also impede maternal organ function recovery,leading to escalated opioid usage,heightened risk of postpartum depression,and the development of chronic postoperative pain.Both the Chinese Enhanced Recovery After Surgery(ERAS)guidelines and the American ERAS Society guidelines consistently advocate for the adoption of multimodal analgesia protocols in post-cesarean section pain management.Esketamine,functioning as an antagonist of the N-Methyl-D-Aspartate receptor,has been validated for pain management in surgical patients and has exhibited effectiveness in depression treatment.Research has suggested that incorporating esketamine into postoperative pain management via pain pumps can lead to improvements in short-term depression and pain outcomes.This study aims to assess the efficacy and safety of administering a single dose of esketamine during cesarean section.AIM To investigate the effect of intraoperative injection of esketamine on postoperative analgesia and postoperative rehabilitation after cesarean section.METHODS A total of 315 women undergoing elective cesarean section under combined spinal-epidural anesthesia were randomized into three groups:low-dose esketamine(0.15 mg/kg),high-dose esketamine(0.25 mg/kg),and control(saline).Postoperative Visual Analog Scale(VAS)scores were recorded at 6 hours,12 hours,24 hours,and 48 hours.Edinburgh Postnatal Depression Scale(EPDS)scores were noted on 2 days,7 days and 42 days.Ramsay sedation scores were assessed at specified intervals post-injection.Postoperative adverse reactions were also recorded.RESULTS Low-dose group and high-dose group compared to control group,had significantly lower postoperative VAS pain scores at 6 hours 12 hours,and 24 hours(P<0.05),with reduced analgesic usage(P<0.05).EPDS scores and postpartum depression rates were significantly lower on 2 days and 7 days(P<0.05).No significant differences in first exhaust and defecation times were observed(P>0.05),but ambulation times were shorter(P<0.05).Ramsay scores were higher at 5 minutes,15 minutes,and upon room exit(P<0.05).Low-dose group and high-dose group had higher incidences of hallucination,lethargy,and diplopia within 2 hours(P<0.05),and with low-dose group had lower incidences of hallucination,lethargy,and diplopia than high-dose group(P<0.05).CONCLUSION Esketamine enhances analgesia and postpartum recovery;a 0.15 mg/kg dose is optimal for cesarean sections,balancing efficacy with minimized adverse effects.展开更多
This paper proposes an improved exponential curvature-compensated bandgap reference circuit to exploit the exponential relationship between the current gainβof the bipolar junction transistor(BJT)and the temperature ...This paper proposes an improved exponential curvature-compensated bandgap reference circuit to exploit the exponential relationship between the current gainβof the bipolar junction transistor(BJT)and the temperature as well as reduce the influence of resistance-temperature dependency.Considering the degraded circuit performance caused by the process deviation,the trimmable module of the temperature coefficient(TC)is introduced to improve the circuit stability.The circuit has the advantages of simple structure,high linear stability,high TC accuracy,and trimmable TC.It consumes an area of 0.09 mm^(2)when fabricated by using the 0.25-μm complementary metal-oxide-semiconductor(CMOS)process.The proposed circuit achieves the simulated power supply rejection(PSR)of about-78.7 dB@1 kHz,the measured TC of~4.7 ppm/℃over a wide temperature range from-55℃to 125℃with the 2.5-V single-supply voltage,and the tested line regulation of 0.10 mV/V.Such a high-performance bandgap reference circuit can be widely applied in high-precision and high-reliability electronic systems.展开更多
When injected into the fourth ventricle, the proinflammagen lipopolysaccharide (LPS) induces acute neuroinflammation in the whole brain of rats. The new compound PMS777 is a novel platelet-activating factor receptor (...When injected into the fourth ventricle, the proinflammagen lipopolysaccharide (LPS) induces acute neuroinflammation in the whole brain of rats. The new compound PMS777 is a novel platelet-activating factor receptor (PAFR) antagonist and acetylcholinesterase (AChE) inhibitor. The current study determined whether PMS777 could provide neuroprotection from the cytotoxic effects associated with LPS-induced neuroinflammation. Acute LPS infusions impaired recognition in rats as measured by the Morris water maze. In addition, LPS infusions decreased the number of AChE positive cells, and increased the number of OX-42 immunoreactive microglia and GFAP immunoreactive astrocytes in the hippocampus, the cortex and the basal nuclei. Furthermore, acute infusions of LPS also impaired organelles associated with protein synthesis. Peripheral administration of PMS777 (i.e., intraperitoneal injection) protected against the impairment in recognition, and attenuated the cytotoxic effects of the acute inflammatory processes upon cholinergic cells, microglia, astrocytes and ultrastructure of hippocampal cells. Here, we propose that the cytotoxic effects of acute neuroinflammation may involve the release of PAF and loss of cholinergic neurons, and this mechanism leads to neuronal dysfunction and spatial memory impairment. The PAFR antagonist inhibitor and AChE inhibitor PMS777 could provide neuroprotection from the cytotoxic effects induced by LPS.展开更多
Background Ribosomal protein S6 kinase 1(S6K1)is a serine-threonine kinase that has two main isoforms:p70S6K(70-kDa isoform)and p85S6K(85-kDa isoform).p70S6K,with its upstream mammalian target of rapamycin(mTOR),has b...Background Ribosomal protein S6 kinase 1(S6K1)is a serine-threonine kinase that has two main isoforms:p70S6K(70-kDa isoform)and p85S6K(85-kDa isoform).p70S6K,with its upstream mammalian target of rapamycin(mTOR),has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer’s dis-ease(AD).However,the function of p85S6K has long been neglected due to its high similarity to p70S6k.The role of p85S6K in learning and memory is still largely unknown.Methods We fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K.Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor.The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence,Western blot,in situ proximity ligation assay,morphological staining and behavioral examination.Further,the expression level of p85S6K was measured in brains from AD patients and AD model mice.Results p85S6K,but not p70S6K,was enriched in the postsynaptic densities.Moreover,knockdown of p85S6K resulted in defective spatial and recognition memory.In addition,p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150.Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in syn-apses,thus sustaining synaptic function and spine densities.Moreover,p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice.Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice.Conclusions These results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1.The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.展开更多
Background:Currently,there is no cure for Alzheimer's disease(AD).Therapeutics that can modify the early stage of AD are urgently needed.Recent studies have shown that the pathogenesis of AD is closely regulated b...Background:Currently,there is no cure for Alzheimer's disease(AD).Therapeutics that can modify the early stage of AD are urgently needed.Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase(AEP).Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD.However,more than 90% of AD cases are age-related sporadic AD rather than hereditary AD.The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown.Methods:The senescence-accelerated mouse prone 8(SAMP8)was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,δ-secretase inhibitor 11.Activation of AEP was determined by enzymatic activity assay.Concentration of soluble amyloid β(Aβ)in the brain was determined by ELISA.Morris water maze test was performed to assess the learning and memory-related cognitive ability.Pathological changes in the brain were explored by morphological and western blot analyses.Results:The enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the agematched SAMR1 mice.The half maximal inhibitory concentration(IC_(50))for δ-secretase inhibitor 11 to inhibit AEP in vitro was around 150 nM.Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity,reduced the generation of Aβ_(1-40/42) and ameliorated memory loss.The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation,but also attenuated neuroinflammation in the form of microglial activation.Moreover,treatment with 6-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain.Conclusions:Pharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD.The up-regulated AEP in the brain could be a promising target for early treatment of AD.The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment.展开更多
Pharmacology is a discipline bridging basic medicine and clinical medicine. Under the disciplinebased structure,derived from the characteristics of drugs,students study pharmacology for the rational use of the drugs t...Pharmacology is a discipline bridging basic medicine and clinical medicine. Under the disciplinebased structure,derived from the characteristics of drugs,students study pharmacology for the rational use of the drugs targeting pathophysiological status according to the diseases and the symptoms. Under the organsystem-based teaching systems,the part of the principle of pharmacology is put into the basic medicine integrated module system and the other parts are divided into the according organ-system integrated courses,respectively. It is important for clinical teaching that the domestic and international status,the role and mutual relationship in and between the integrated course system,the designation and practice of the course,the problems to be addressed of the course can be understood.展开更多
基金the Project of Science and Technology Bureau of Shijiazhuang,Hebei Province,No.201460823.
文摘BACKGROUND Following cesarean section,a significant number of women encounter moderate to severe pain.Inadequate management of acute pain post-cesarean section can have far-reaching implications,adversely impacting maternal emotional wellbeing,daily activities,breastfeeding,and neonatal care.It may also impede maternal organ function recovery,leading to escalated opioid usage,heightened risk of postpartum depression,and the development of chronic postoperative pain.Both the Chinese Enhanced Recovery After Surgery(ERAS)guidelines and the American ERAS Society guidelines consistently advocate for the adoption of multimodal analgesia protocols in post-cesarean section pain management.Esketamine,functioning as an antagonist of the N-Methyl-D-Aspartate receptor,has been validated for pain management in surgical patients and has exhibited effectiveness in depression treatment.Research has suggested that incorporating esketamine into postoperative pain management via pain pumps can lead to improvements in short-term depression and pain outcomes.This study aims to assess the efficacy and safety of administering a single dose of esketamine during cesarean section.AIM To investigate the effect of intraoperative injection of esketamine on postoperative analgesia and postoperative rehabilitation after cesarean section.METHODS A total of 315 women undergoing elective cesarean section under combined spinal-epidural anesthesia were randomized into three groups:low-dose esketamine(0.15 mg/kg),high-dose esketamine(0.25 mg/kg),and control(saline).Postoperative Visual Analog Scale(VAS)scores were recorded at 6 hours,12 hours,24 hours,and 48 hours.Edinburgh Postnatal Depression Scale(EPDS)scores were noted on 2 days,7 days and 42 days.Ramsay sedation scores were assessed at specified intervals post-injection.Postoperative adverse reactions were also recorded.RESULTS Low-dose group and high-dose group compared to control group,had significantly lower postoperative VAS pain scores at 6 hours 12 hours,and 24 hours(P<0.05),with reduced analgesic usage(P<0.05).EPDS scores and postpartum depression rates were significantly lower on 2 days and 7 days(P<0.05).No significant differences in first exhaust and defecation times were observed(P>0.05),but ambulation times were shorter(P<0.05).Ramsay scores were higher at 5 minutes,15 minutes,and upon room exit(P<0.05).Low-dose group and high-dose group had higher incidences of hallucination,lethargy,and diplopia within 2 hours(P<0.05),and with low-dose group had lower incidences of hallucination,lethargy,and diplopia than high-dose group(P<0.05).CONCLUSION Esketamine enhances analgesia and postpartum recovery;a 0.15 mg/kg dose is optimal for cesarean sections,balancing efficacy with minimized adverse effects.
文摘This paper proposes an improved exponential curvature-compensated bandgap reference circuit to exploit the exponential relationship between the current gainβof the bipolar junction transistor(BJT)and the temperature as well as reduce the influence of resistance-temperature dependency.Considering the degraded circuit performance caused by the process deviation,the trimmable module of the temperature coefficient(TC)is introduced to improve the circuit stability.The circuit has the advantages of simple structure,high linear stability,high TC accuracy,and trimmable TC.It consumes an area of 0.09 mm^(2)when fabricated by using the 0.25-μm complementary metal-oxide-semiconductor(CMOS)process.The proposed circuit achieves the simulated power supply rejection(PSR)of about-78.7 dB@1 kHz,the measured TC of~4.7 ppm/℃over a wide temperature range from-55℃to 125℃with the 2.5-V single-supply voltage,and the tested line regulation of 0.10 mV/V.Such a high-performance bandgap reference circuit can be widely applied in high-precision and high-reliability electronic systems.
文摘When injected into the fourth ventricle, the proinflammagen lipopolysaccharide (LPS) induces acute neuroinflammation in the whole brain of rats. The new compound PMS777 is a novel platelet-activating factor receptor (PAFR) antagonist and acetylcholinesterase (AChE) inhibitor. The current study determined whether PMS777 could provide neuroprotection from the cytotoxic effects associated with LPS-induced neuroinflammation. Acute LPS infusions impaired recognition in rats as measured by the Morris water maze. In addition, LPS infusions decreased the number of AChE positive cells, and increased the number of OX-42 immunoreactive microglia and GFAP immunoreactive astrocytes in the hippocampus, the cortex and the basal nuclei. Furthermore, acute infusions of LPS also impaired organelles associated with protein synthesis. Peripheral administration of PMS777 (i.e., intraperitoneal injection) protected against the impairment in recognition, and attenuated the cytotoxic effects of the acute inflammatory processes upon cholinergic cells, microglia, astrocytes and ultrastructure of hippocampal cells. Here, we propose that the cytotoxic effects of acute neuroinflammation may involve the release of PAF and loss of cholinergic neurons, and this mechanism leads to neuronal dysfunction and spatial memory impairment. The PAFR antagonist inhibitor and AChE inhibitor PMS777 could provide neuroprotection from the cytotoxic effects induced by LPS.
基金supported by the National Natural Science Foundation of China(81802840,81473217)Shanghai Natural Science Foundation(20ZR1430100)Shanghai High Level Local University Construction Project(PT21002).
文摘Background Ribosomal protein S6 kinase 1(S6K1)is a serine-threonine kinase that has two main isoforms:p70S6K(70-kDa isoform)and p85S6K(85-kDa isoform).p70S6K,with its upstream mammalian target of rapamycin(mTOR),has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer’s dis-ease(AD).However,the function of p85S6K has long been neglected due to its high similarity to p70S6k.The role of p85S6K in learning and memory is still largely unknown.Methods We fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K.Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor.The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence,Western blot,in situ proximity ligation assay,morphological staining and behavioral examination.Further,the expression level of p85S6K was measured in brains from AD patients and AD model mice.Results p85S6K,but not p70S6K,was enriched in the postsynaptic densities.Moreover,knockdown of p85S6K resulted in defective spatial and recognition memory.In addition,p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150.Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in syn-apses,thus sustaining synaptic function and spine densities.Moreover,p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice.Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice.Conclusions These results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1.The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.
基金supported by the National Natural Science Foundation of China(81671375,91949116 and 81873807)Innovative Research Team of High-level Local Universities in Shanghai,China.
文摘Background:Currently,there is no cure for Alzheimer's disease(AD).Therapeutics that can modify the early stage of AD are urgently needed.Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase(AEP).Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD.However,more than 90% of AD cases are age-related sporadic AD rather than hereditary AD.The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown.Methods:The senescence-accelerated mouse prone 8(SAMP8)was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,δ-secretase inhibitor 11.Activation of AEP was determined by enzymatic activity assay.Concentration of soluble amyloid β(Aβ)in the brain was determined by ELISA.Morris water maze test was performed to assess the learning and memory-related cognitive ability.Pathological changes in the brain were explored by morphological and western blot analyses.Results:The enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the agematched SAMR1 mice.The half maximal inhibitory concentration(IC_(50))for δ-secretase inhibitor 11 to inhibit AEP in vitro was around 150 nM.Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity,reduced the generation of Aβ_(1-40/42) and ameliorated memory loss.The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation,but also attenuated neuroinflammation in the form of microglial activation.Moreover,treatment with 6-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain.Conclusions:Pharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD.The up-regulated AEP in the brain could be a promising target for early treatment of AD.The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment.
基金financially supported by Shanghai Key Course Construction Project(2015-37-59)
文摘Pharmacology is a discipline bridging basic medicine and clinical medicine. Under the disciplinebased structure,derived from the characteristics of drugs,students study pharmacology for the rational use of the drugs targeting pathophysiological status according to the diseases and the symptoms. Under the organsystem-based teaching systems,the part of the principle of pharmacology is put into the basic medicine integrated module system and the other parts are divided into the according organ-system integrated courses,respectively. It is important for clinical teaching that the domestic and international status,the role and mutual relationship in and between the integrated course system,the designation and practice of the course,the problems to be addressed of the course can be understood.
