Compared with conventional transdermal drug delivery systems, dissolving microneedles significantly enhance drug bioavailability by penetrating the stratum corneum barrier and achieving intradermal drug delivery. In order to improve the transdermal bioavailability of dexmedetomidine hydrochloride, in this study, a novel microneedle delivery system was developed for dexmedetomidine hydrochloride based on 3D printing combined with micro-molding. By systematically optimizing the microneedle geometrical parameters, array arrangement, and preparation process parameters, we determined the optimal ratio of drug-carrying matrix as 15% PVP (polyvinyl pyrrolidone) K90. The microneedles exhibited significant drug loading gradients, with mean content of (209.99±27.56) μg/patch, (405.31±30.31) μg/patch, and (621.61±34.43) μg/patch. They showed a regular pyramidal structure under SEM and handheld electron microscopy, and their mechanical strength allowed effective penetration into the stratum corneum. The surface contact angles were all < 90°, indicating excellent hydrophilicity. The microneedles dissolved completely within 10 min after skin insertion, achieving a cumulative release rate of 90% (Higuchi model, r=0.996) during 2 hours of in vitro transdermal permeation. The cytotoxicity test and hemolysis test verified good biocompatibility. Pharmacodynamic evaluation showed that the microneedle group demonstrated pain-relieving effect within 15 min, with the pain threshold at the time point of 60 min being 3 times that in the transdermal cream group. The microneedle system developed in this study not only offers an efficient drug delivery option for patients but also establishes an innovative platform for rapid percutaneous delivery of hydrophilic drugs, demonstrating significant potential in perioperative pain management.
Dexmedetomidine/pharmacokinetics* ; Printing, Three-Dimensional ; Needles ; Drug Delivery Systems/methods* ; Administration, Cutaneous ; Animals ; Microinjections/instrumentation* ; Skin Absorption ; Skin/metabolism*

Breast clustered microcalcification (BCM) is one of the most critical X-ray signs of early breast cancer. However, due to the fact that BCM is very tiny and hidden, and manual interpretation is susceptible to subjective factors such as visual fatigue, manual diagnosis of dense BCM based on X-images suffers from a low detection rate, high false-negative rate, and high recall rate. In recent years, with the continuous optimization innovation of deep learning algorithms, and advancements of computer hardware technology, new hope has been brought to accurate diagnosis of BCM, which is expected to realize the accurate assessment of individual breast cancer risk. In this review, the research progress of deep learning for accurate diagnosis of BCM was summarized, such as full-field digital mammography (FFDM), digital breast tomosynthesis (DBT) and contrast-enhanced mammography (CEM), as well as the future developments in this field were discussed.

Multimodal analgesia is the gold standard for postoperative pain management,and ultra-sound-guided nerve block as the cornerstone supplemented with fewer opioids and a sufficient amount of non-steroidal anti-inflammatory drugs(NSAIDs)throughout the entire course of the procedure is the most main-stream multimodal analgesic regimen at present.However,ultrasound-guided nerve blocks are limited by the duration of action of local anesthetics and often provide effective analgesia for surgical patients for no more than 8 hours,resulting in a low satisfaction rate of postoperative analgesia in surgical patients.With the con-tinuous research on the concept of rapid rehabilitation,how to extend the duration of action of local anesthet-ics is the focus and hotspot of research.Ultra-long-acting local anesthetics include liposomal bupivacaine and HTX-011,which have been applied in clinical practice,and quaternary ammonium derivatives,which are still in the research stage.In this paper,we will review the existing ultra-long-acting local anesthetics in terms of ultra-long-acting local anesthetics with extended-release systems,new pathways and targets of ultra-long-acting local anesthetics,and the development of ultra-long-acting local anesthetics in the form of brand-new compounds,so as to provide new ideas for the subsequent research and clinical application of ultra-long-acting local anesthetics.

Objective To observe the effect of Jinshui Liujun decoction on airway lesions in mice with COPD and explore its possible mechanism.Methods 48 C57BL/6 mice were randomly divided into blank group,model group,Jinshui Liujun decoction group and NAC group,with 12 in each group.The COPD mouse model was established by intranasal drip of LPS and smoking,and the corresponding drugs were given intragastric administration for 14 days after the model was established.Observe the general condition of the mice,measure the MV,PEF and PIF of the mice with the small animal lung function instrument,semi quantitatively evaluate the inflammation of the lung tissue,the thickness of the alveolar septum and the thickness of the airway wall with HE staining,and observe the airway mucus secretion and goblet cell proliferation with PAS staining.The content of MPO,SA and Urea in BALF was detected by the kit,and the ratio of SA and Urea was calculated.The content of MUC5AC in BALF was detected by ELISA.The levels of ROS,GSH,GSSG and GR in lung tissue were detected with the kit,and the ratio of GSH and GSSG was calculated.The expression level of CFTR mRNA in lung tissue was detected by qRT-PCR.Western blot was used to detect the expression level of CFTR protein in lung tissue.Results Compared with the control group,the growth of mice in the model group was poor.The body weight at each time point during the modeling period decreased(P<0.01),and the indexes of MV,PEF and PIF decreased(P<0.01).The lung tissue pathological score,alveolar septal thickness,airway wall thickness,airway mucus and goblet cell increased(P<0.01).The levels of SA,SA/Urea,MUC5AC and MPO in BALF increased(P<0.01),and the level of Urea decreased(P<0.01),The levels of ROS and GSSG in lung tissue increased(P<0.01),and the levels of GSH,GSH/GSSG,and GR decreased(P<0.01).The expression levels of CFTR mRNA and protein in lung tissue decreased(P<0.01).Compared with the model group,the growth condition of COPD mice improved,the body weight increased at each time point during the modeling period(P<0.05,P<0.01),the indexes of MV,PEF and PIF improved significantly(P<0.01),the pathological score of lung tissue,the thickness of alveolar septa,the thickness of airway wall,airway mucus and goblet cell decreased(P<0.01,P<0.05),and the levels of SA,SA/Urea,MUC5AC and MPO in BALF decreased(P<0.01),And an increase in Urea levels(P<0.01),a decrease in ROS and GSSG levels in lung tissue(P<0.01),and an increase in GSH,GSH/GSSG,and GR levels(P<0.01).The expression levels of CFTR mRNA and protein in lung tissue increased(P<0.01).Conclusion Jinshui Liujun decoction can correct CFTR acquired defects through antioxidant effects to improve airway lesions in COPD.

Objective:To explore the effects of workshops combined with problem-based learning (PBL) in clinical teaching of joint surgery.Methods:A total of 60 students who would participate in standardized residency training from September 2019 to June 2021 were randomly divided into traditional lecture-based learning (LBL) group, PBL group, and workshops combined with PBL group, with 20 students in each group. The effects were evaluated by theoretical knowledge and clinical skill assessment and anonymous teaching quality questionnaire surveys. SPSS 25.0 was used to perform the t test and chi-squared test. Results:The workshop+PBL group showed the highest theoretical knowledge score (86.40±9.76), clinical skill score (92.15±4.49), and total score (88.70±5.75), compared with the PBL group (78.45±10.40, 85.80±10.00, and 81.39±7.27, respectively) and the LBL group (80.10±6.77, 85.20±8.12, and 82.14±6.14, respectively). According to the teaching quality questionnaire surveys, the workshop+PBL group was significantly superior to the PBL and LBL groups in self-ability evaluation and the degree of satisfaction with teaching ( P<0.05). Conclusions:Workshops combined with PBL can effectively improve students' scores of theoretical knowledge and clinical skills, with better self-ability evaluation results and higher satisfaction with teaching, which is worthy of application and promotion in clinical teaching of joint surgery.

Objective To investigate the effect of Lumbricus protein on the phenotypic transformation of corporal cavernosum smooth muscle cells(CCSMC)and erectile function in diabetic erectile dysfunction(DMED)rats.Methods Sixty male SD rats with normal erectile function were randomly divided into a blank group,a model group,a Sildelafil group(5 mg·kg-1),and a Lumbricus protein low-,medium-,and high-dose group(45,90,and 180 mg·kg-1),with 10 rats in each group.The diabetic rat model was established by intraperitoneal injection of Streptozotocin(STZ,50 mg·kg-1)combined with high-fat feed feeding;after 8 weeks,the DMED rat model was prepared by neck injection of Apomorphine(APO,100 μg·kg-1).After successful modeling,the rats were administered with a dose of Apomorphine by gavage once a day for 4 weeks.The blood glucose levels and body mass of rats in each group were measured before modeling,on the third day of modeling,and after 4 weeks of drug administration.The intracavernous pressure(ICP)and carotid artery pressure(MAP)were measured by multi-channel physiological recorder,and the ICP/MAP ratio was calculated.The expressions of contractile markers α-smooth muscle actin(α-SMA),smooth muscle myosin heavy chain(SMMHC)and synthetic markers Collagen I and osteopontin(OPN)in corpus cavernosum were detected by immunohistochemistry.The mRNA expression levels of α-SMA,SMMHC and Collagen I in corpus cavernosum were detected by RT-PCR.The protein expression levels of α-SMA,Desmin,Collagen I and OPN in corpus cavernosum were detected by Western Blot.Results Compared with the blank group,the blood glucose levels of the rats in the model group were significantly increased on the third day of modeling and after 4 weeks of administration(P＜0.01),and the body mass was significantly decreased after 4 weeks of administration(P＜0.01).ICP and ICP/MAP ratio were significantly decreased(P＜0.01).The protein expression levels of α-SMA,SMMHC and Desmin in penile corpus cavernosum were significantly decreased(P＜0.01),and the protein expression levels of Collagen I and OPN were significantly increased(P＜0.01).The mRNA expression levels of α-SMA and SMMHC in corpus cavernosum were significantly decreased(P＜0.01),and the mRNA expression level of Collagen I was significantly increased(P＜0.01).Compared with the model group,there was no significant change in blood glucose and body mass of rats in the administration group(P＞0.05).ICP and ICP/MAP ratio were significantly increased(P＜0.01).The expression levels of α-SMA,SMMHC and Desmin in corpus cavernosum were significantly increased(P＜0.01),while the expression levels of Collagen I and OPN were significantly decreased(P＜0.01).The mRNA expression levels of α-SMA and SMMHC in corpus cavernosum were significantly increased(P＜0.01),and the mRNA expression level of Collagen I was significantly decreased(P＜0.01).Conclusion Lumbricus protein can improve the erectile function of DMED rats,and its mechanism may be related to the inhibition of CCSMC from'contractile'to'synthetic(proliferative)'transformation.

OBJECTIVE To study the pharmacokinetics of Esketamine hydrochloride nasal spray in rats and ciliary toxicity to maxillary mucosa of bullfrog. METHODS The plasma concentration of esketamine hydrochloride in rats was determined by LC-MS/ MS after intravenous injection of esketamine hydrochloride solution and nasal administration of esketamine hydrochloride； the pharmacokinetic parameters were calculated by using Phoenix WinNonlin 8.1.0 software. Using the maxillary mucosa of isolated bullfrog as a model， the morphological changes of maxillary mucosa were investigated， and the duration and recovery of ciliary oscillation were recorded after nasal administration of esketamine hydrochloride. RESULTS The peak of blood concentration occurred 2 min after nasal administration of esketamine hydrochloride； cmax was （814.58±418.80） ng/mL， AUC0－∞ was （203.75± 92.76） ng·h/mL， and the absolute bioavailability was 60.68%. After nasal administration of esketamine hydrochloride， it was observed that the cilia of bullfrog were arranged neatly， the edges were clear， the cilia tissue structure was complete and the cilia moved actively. The cilia movement time was （178.17±13.30） min for the first time， and after the cilia moved again， the ciliary movement time measured again was （24.50±9.19）min with a relative movement percentage of 53.56%. CONCLUSIONS Esketamine hydrochloride nasal spray has a rapid onset of action， high bioavailability， and low ciliary toxicity.

Objective To investigate testicular damage in traumatic brain injury(TBI)rats and to analyze the in-terventional effects of cannabidiol(CBD)on TBI-induced testicular damage.Methods 18 Sprague Dawley(SD)rats were randomly divided into three groups:the sham operation group(Sham group),model group(TBI group)and treatment group(TBI+CBD group).HE staining was used to observe the testicular histopathological changes in the rat testis.ELISA was used to detect testosterone level in rat serum.TUNEL staining was utilized to observe apoptosis,while immunofluorescence staining,Western blot and RT-qPCR were employed to evaluate Bax,Bcl-2,Cleaved Caspase-3 and TNF-α protein and mRNA expression.Results HE staining showed pathological changes in the testes of TBI rats compared with those in the Sham group.ELISA assay showed a decrease in testosterone levels in the TBI group compared to the Sham group,but there was no significant difference(P＞0.05).Immunofluores-cence results showed that the intensity of Bax fluorescence expression increased in the TBI group compared with the Sham group(P＜0.01),whereas the intensity of Bax fluorescence decreased and the intensity of Bcl-2 fluorescence increased in the rats after the CBD intervention(P＜0.01).Western Blot results showed that CBD treatment in rats decreased the protein levels of testicular apoptosis-related proteins(Bax and Cleaved Caspase-3,all P＜0.05)and inflammation-related proteins(TNF-α,P＜0.01),and increased the protein level of the anti-apoptotic protein,Bcl-2(P＜0.05).The trend of RT-qPCR results was similar,with mRNA expression of Bax(P＜0.05)and TNF-α(P＜0.01)decreased and mRNA expression of Bcl-2 increased after CBD intervention compared with the TBI group(P＜0.05).Conclusion TBI induces testis injury,and CBD treatment effectively repairs apoptosis and in-flammatory in testicular tissue of TBI rats.