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: Acupuncture is widely used in modulating brain excitability and motor function, as a form of complementary and alternative medicine. However, there is no existing meta-analysis evaluating the effectiveness and safety of acupuncture on corticospinal excitability (CSE), and the credibility of the evidence has yet to be quantified. OBJECTIVE: This study was designed to assess the efficacy and safety of electroacupuncture (EA) and manual acupuncture (MA) in enhancing brain excitability, specifically focusing on CSE as measured by transcranial magnetic stimulation (TMS). SEARCH STRATEGY: This study followed a systematic approach, searching 9 databases up to August 2024 and examining grey literature, in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. INCLUSION CRITERIA: Studies were included if they compared the clinical efficacy of EA or MA with sham acupuncture, no treatment or usual training. DATA EXTRACTION AND ANALYSIS: Three investigators independently conducted literature screening, data extraction, and risk of bias assessment. The primary outcome focused on motor-evoked potentials as measured by TMS, with treatment effects quantified using mean differences or standardized mean differences between pre- and post-treatment. Subgroup analyses were conducted using mixed-effects models, while random-effects or fixed-effects models were used to estimate average treatment differences across studies. RESULTS: Based on 34 studies involving 1031 adults, acupuncture techniques significantly enhanced CSE. EA had a greater impact than MA, with effect sizes of 0.53 mV vs 0.43 mV (95% confidence interval [CI]: [0.30, 0.76], P < 0.00001 vs 95% CI: [0.28, 0.59], P < 0.00001). The 5 most frequently used acupoints were LI4 (Hegu, 32 times), ST36 (Zusanli, 10 times), LI11 (Quchi, 7 times), TE5 (Waiguan, 6 times), and GB34 (Yanglingquan, 5 times). CONCLUSION This systematic review indicates that both EA and MA could effectively and safely enhance CSE, bringing the corticospinal pathway closer to the threshold for firing, which may ultimately improve motor function. LI4, ST36, LI11, TE5 and GB34 are the most commonly used acupoints. Please cite this article as: Liu R, Moe AAK, Liu W, Zoghi M, Jaberzadeh S. Does acupuncture at motor-related acupoints affect corticospinal excitability? A systematic review and meta-analysis. J Integr Med. 2025; 23(2): 113-125.
Humans ; Evoked Potentials, Motor/physiology* ; Acupuncture Points ; Acupuncture Therapy/methods* ; Transcranial Magnetic Stimulation ; Electroacupuncture ; Pyramidal Tracts/physiology*

Objective:To explore the diagnosis and treatment strategy of emphysematous pyelonephritis (EPN).Methods:The clinical data of 11 cases patients with EPN admitted to 3 hospitals from March 2016 to June 2022 were retrospectively analyzed, among them, 4 cases from Qianhai Shekou Free Trade Zone Hospital, 5 cases from the Second Hospital Affiliated to Kunming Medical University, 2 cases from the Second Affiliated Hospital of Hubei University of Scinece and Technology. Among the 11 patients, 2 were males and 9 were females, aged 50-82 years; the lesions were located on the left side in 6 cases, right side in 4 cases and bilateral in 1 case; all patients had type 2 diabetes and poor glycemic control. The clinical manifestations at admission including back pain in 8 cases, fever in 11 cases, nausea and vomiting in 5 cases, disturbance of consciousness in 3 cases, septic shock in 3 cases, accompanied with ureteral or kidney stones in 5 cases. The pathogenic bacteria were Escherichia coli in 8 cases, Klebsiella pneumoniae in 2 cases and Proteus mirabilis in 1 case. All patients received minimally invasive surgery, anti-infection, subcutaneous injection of insulin, fluid rehydration and nutritional support after admission. 2 cases had a combination of an initial ureteral stenting and second stage percutaneous drainage, 3 patients underwent ureteral stent implantation, 6 patients underwent percutaneous drainage. According to the CT classification of EPN, there were 1 case of type Ⅰ, 3 cases of type Ⅱ, 2 cases of type ⅢA, 4 cases of type ⅢB, and 1 case of type Ⅳ. Results:All 11 cases were cured, 4 cases were admitted to intensive care unit for 2-7 days, 1 case underwent nephrectomy during hospitalization, and 1 case underwent nephrectomy due to renal atrophy during follow-up. After 12 to 18 months of follow-up with urinary CT or B-ultrasound, there were no recurrence cases.Conclusions:EPN is a rare and serious renal parenchymal necrotic infection. Early urinary CT examination is necessary for the diagnosis, and positive minimally invasive surgery combined with comprehensive medical treatment is the preferred treatment strategy. If those above treatment does not work, nephrectomy should be performed.

ObjectiveTo review the effect of response interruption and redirection intervention on vocal stereotypy in children with autism spectrum disorder (ASD). MethodsLiteratures on response interruption and redirection intervention for vocal stereotypy in children with ASD were retrieved from databases of EBSCO, PubMed, Web of Science, CNKI, and Wanfang data. The information of the literatures was extracted to conduct a scoping review. ResultsA total of 16 English literatures were included. All researches employed a single-subject time series study design. A total of 41 children with ASD were involved. Significant differences were found in levels of basic verbal functioning of children with ASD. Vocal stereotypy was characterized by both verbal and nonverbal forms. Most of the reviewed researches used experimental functional assessment to analyze the function of vocal stereotypy. In most cases, the function of vocal stereotypy was automatic reinforcement. Iwata et al.'s paradigm was dominantly adopted in performing experimental functional assessment across researches. Other related paradigms developed based on Iwata et al.'s paradigm to make operating process more concise were also used for experimental functional assessment in reviewed researches. Response disruption and redirection was often conducted in individualized setting, with a few researches conducted in special education classes. The time and frequency of interventions varied widely across subjects due to the levels of impairment in vocal stereotypy and other behaviors. According to a comparison of the effects of traditional response interruption and redirection and its morphing procedures, it was found that changing the content of the redirection task, reducing the number of redirection tasks, and varying the duration of execution did not impact the improvement of vocal stereotypy. Based on the comparisons of response interruption and redirection with matched stimuli, response cost, verbal manipulation training, and medication, it was found that both response interruption and redirection and other methods (except for medication) could reduce vocal stereotypy and promote the emergence of appropriate behaviors in children with ASD. Combining response interruption and redirection with other techniques, such as stimulus matching and response costs, yielded more favorable improvement of vocal stereotypy in children with ASD. ConclusionASD children with vocal stereotypy show different levels of functional language, and vocal stereotypy is generally characterized by both verbal and nonverbal formats. The function of vocal stereotypy is mostly automatic reinforcement. Response interruption and redirection as a behavioral intervention is mostly conducted in individualized setting, and the time and frequency of interventions depend on the levels of vocal stereotypy and other behaviors problems. Changing the content and number of redirection instructions does not significantly influence the improvement of vocal stereotypy in children with ASD. Other intervention methods such as matching stimulus and response cost are able to reduce vocal stereotypy in children with ASD, but response interruption and redirection used in conjunction with these methods show more favorable improvements. Response interruption and redirection interventions can not only reduce vocal stereotypy in children with ASD, but also increase appropriate vocalizations, task engagement and command obedience.

Objective:To effectively quantify and evaluate the quality of different deformation registration algorithms, in order to enhance the possibility of implementing deformation registration in clinical practice.Methods:The Jacobian determinant mean (JDM) is proposed based on the Jacobian determinant (JD) of displacement vector field (DVF), and the Jacobian determinant error (DJDE) is introduced by incorporating the JD of the inverse DVF. The optical flow method (OF-DIR) and fast demons method with elastic regularization (FD-DIR) were tested on nasopharyngeal and lung cancer datasets. Finally, JDM and DJDE with the Jacobian determinant negative percentage (JDNP), inverse consistency error (ICE) and normalized mean square error (NMSE) were used to evaluate the registration algorithms and compare the differences evaluation indicators in different tumor images and different algorithms, and the receiver operating curve (ROC) was analyzed in evaluation.Results:In lung cancer, OF-DIR outperformed FD-DIR in terms of JDM, NMSE, DJDE and ICE, and the difference was statistically significant( z = -2.24, -4.84, t = 4.01, 6.54, P<0.05). In nasopharyngeal carcinoma, DJDE, ICE and NMSE of OF-DIR were superior to FD-DIR, and the difference was statistically significant ( t = 4.46, -7.49, z = -2.22, P<0.05), but there was no significant difference in JDM ( P>0.05). In lung cancer and nasopharyngeal carcinoma, JDNP of OF-DIR was worse than that of FD-DIR, and the difference was statistically significant ( z = -4.29, -4.02, P<0.01). In addition, DJDE is more specific and sensitive on ROC curve (AUC=0.77), and has different performance result for tumor images at different sites. Conclusions:The JDM and DJDE evaluation metrics proposed are effective for deformation registration algorithms. OF-DIR is suitable for both lung cancer and nasopharyngeal carcinoma, while the influence of organ motion on the registration effect should be considered when using FD-DIR.

Objective To systematically review and synthesize the psychological experience of kinesiophobia in patients with cardiac rehabilitation.Methods PubMed,Web of science,Journals@Ovid,Embase,CINAHL,PsycINFO,Cochrane Library,CNKI,SinoMed,WanFang Database,Vip Database,American Heart Association,European Society of Cardiology and American Association of Cardiovascular and Pulmonary Rehabilitation were searched to collect qualitative research on the psychological experience of cardiac rehabilitation patients with kinesiophobia.The retrieval time was from the establishment of the databases to Jun 2023.The literature was evaluated using the Australian JBI Quality Evaluation Criteria for Qualitative Research in Evidence-based Health Care Centres(2016),and the results were consolidated using an aggregative integration approach.Results A total of 45 results were extracted from 14 studies.Similar results were summarized into 10 groups,and 3 integrated results were synthesized as followed.Kinesiophobia was influenced by many factors;kinesiophobia affects the life experience of patients;strategies to reduce the level of kinesiophobia.Conclusion Nurses should pay more attention to psychological experience of kinesiophobia,and take the corresponding intervention measures to help patients overcome the psychological barriers of kinesiophobia,perfect personalized exercise programs,and improve the level of physical activity.

Objective:To establish the pig model of cardiac arrest and resuscitation, and then investigate the protective role of sivelestat (SV) on the heart after resuscitation and its relation with β-catenin signaling pathway.Methods:Twenty-five healthy male white pigs were purchased. The animals were randomly divided into the Sham group ( n=6), cardiopulmonary resuscitation group (CPR, n=10), and CPR+SV group ( n=9). The experimental animal model was established by 9 min of cardiac arrest induced by the method of ventricular fibrillation and then 6 min of CPR in the CPR and CPR+SV groups. At 5 min after successful resuscitation, a dose of 10 mg/kg of SV was infused in a duration of 1h via the femoral vein with a micro-infusion pump in the CPR+SV group. Myocardial function evaluated by the values of stroke volume (SV) and global ejection fraction (GEF) was measured by PiCCO at baseline, and at 0.5, 1, 2, 4 h after resuscitation. The serum concentrations of cardiac injury biomarkers including cardiac troponin I (cTnI) and creatine kinase isoenzymes (CK-MB) were measured by ELISA using blood samples drawn from the femoral vein at baseline, and at 1, 2, 4, and 24 h after resuscitation. The animals were euthanized at 24 h after resuscitation, and then cardiac tissue samples were harvested to measure the protein expression levels of β-catenin, Cyclin D1, c-Myc, cleaved caspase-9, and cleaved caspase-3 by Western blot and the degree of cell apoptosis by TUNEL. Results:Prior to cardiac arrest, myocardial function and cardiac injury biomarkers were maintained at the same levels, and no differences were observed among the three groups (all P> 0.05). After resuscitation, myocardial dysfunction and cardiac injury were observed in the CPR and CPR+SV groups, in which the values of SV and GEF were significantly decreased and meanwhile the serum concentrations of cTnI and CKMB were significantly increased when compared with the Sham group (all P< 0.05). However, myocardial dysfunction and cardiac injury were significantly milder in the CPR+SV group, in which the value of SV at 4h post-resuscitation and the values of GEF starting 1h post-resuscitation were significantly increased, and the serum concentrations of cTnI and CKMB were significantly decreased at 4 and 24 h post-resuscitation when compared to the CPR group (all P< 0.05). Tissue measurements indicated that the change of β-catenin signaling pathway and the occurrence of cell apoptosis were observed in the heart at 24 h post-resuscitation in the CPR and CPR+SV groups, which were indicated by significant increases in the protein expression levels of β-catenin, Cyclin D1, c-Myc, cleaved caspase-9, and cleaved caspase-3, and marked elevation in the index of cell apoptosis when compared with the Sham groups (all P< 0.05). However, the expression levels of proteins mentioned above were significantly decreased in the heart at 24 h post-resuscitation and the index of cell apoptosis was significantly reduced in the CPR+SV group when compared to the CPR group (all P< 0.05). Conclusion:SV has the protective role in alleviating post-resuscitation myocardial dysfunction and cardiac injury, in which the protective mechanism is possibly related to the alleviation of cell apoptosis through the inhibition of β-catenin signaling pathway activation.

ObjectiveTo clarify the scientific validity of in vivo pharmacokinetic determination of the whole drug composition in Shenbai nanosuspension in rats， and to provide methodological guidance and theoretical basis for the in vivo study of multi-component complex system of traditional Chinese medicine（TCM） preparations. MethodThe concentration of the overall components， mainly total saponins and total polysaccharides in Shenbai decoction and Shenbai nanosuspension， was determined in rat plasma at different times by area under the absorbance-wavelength curve method（AUAWC）， and the concentration of individual ginsenoside Rg₁ was determined by high performance liquid chromatography（HPLC）， and the methodology was verified. The pharmacokinetic parameters of the whole component were compared with those of ginsenoside Rg₁ to evaluate the in vivo operational characteristics of the two preparations. ResultThe methodological investigations of AUAWC and HPLC were in accordance with the requirements. AUAWC analysis showed that the overall components in both the decoction group and the nanosuspension group showed a one-compartment model， with half-life（t_1/2） of 2.43 h and 2.04 h， respectively. The relative bioavailability of Shenbai nanosuspension was 138.99%. HPLC assay showed that ginsenoside Rg₁ in the decoction group and the nanosuspension group showed a two-compartment model， with distribution half-life（t_1/2α） of 0.13 h and 2.55 h， and elimination half-life（t_1/2β） were 14.28 h and 3.85 h， respectively. The relative bioavailability of Shenbai nanosuspension was 127.49%. Compared with Shenbai decoction， the time to peak（t_max）， peak concentration（C_max） and area under the drug-time curve（AUC） of the overall components and ginsenoside Rg₁ in Shenbai nanosuspension were increased. ConclusionThe established AUAWC can be used for the pharmacokinetic study of the overall components of TCM preparations， which is complementary to the results of individual components measured by HPLC， and can provide useful reference for the in vivo study of new dosage forms of TCM.

BACKGROUND:Sodium alginate,a natural polysaccharide,has become one of the ideal materials for preparing injectable hydrogels because it is an abundant and cheap resource,and has good biocompatibility and biodegradability.It has been widely used in the production of injectable hydrogels. OBJECTIVE:To review the properties of sodium alginate,the preparation of injectable sodium alginate hydrogel,and its application progress in tissue engineering. METHODS:Web of Science,PubMed,and CNKI were searched by computer.Chinese search terms were"sodium alginate;hydrogel;injectable",and English search terms were"alginate;hydrogel;inject".The time range of searching literature was mainly from June 2017 to June 2022. RESULTS AND CONCLUSION:Alginic acid comes from a wide range of sources,and there are many modifiable groups in its molecular structure,so many injectable hydrogels with excellent properties can be produced by various chemical crosslinking or physical crosslinking methods.Introducing other bioactive molecules or drugs into sodium alginate gel can adjust its properties and broaden its application fields.In addition,injectable sodium alginate hydrogels have great application prospects in biomedicine because of their good biocompatibility,biodegradability and other physical and chemical properties.Sodium alginate hydrogels are evenly mixed with various drugs,cells,factors or other biological molecules in vitro,and can form gels in the human body,which plays a pivotal role in gene carrier,cell scaffold and wound repair.