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*

Objective:To investigate the repair effect of bone marrow mesenchymal stem cells(BMSCs)on interferon gamma(IFN-γ)induced ovarian granulosa cell immune injury.Methods:A model of IFN-γ-induced ovarian granulosa cell immune injury was estab-lished.KGN cells after modeling were co-cultured with human BMSCs(hBMSCs)and divided into three groups:negative control(NC)group,IFN-γ group,and BMSC group.After co-culture,cell proliferation was determined by a cell counting kit 8 assay for 3 consecu-tive days.Cell apoptosis was determined using an Annexin V-FITC apoptosis detection kit and a CytoFLEX flow cytometer.The estra-diol level and the mRNA expression levels of aromatase CYP19A1 and FSHR were measured to evaluate the hormone synthesis ability.The level of lactate dehydrogenase(LDH),mRNA expression levels of NLRP3,caspase-1(CASP1),and interleukin-1β,and protein expression levels of NLRP3,CASP1,and gasdermin-D were determined to evaluate cell pyroptosis.Results:The proliferation rate of granulosa cells in the IFN-γ group and the BMSC group was lower than that in the NC group at 24 h,48 h and 72 h,and that in the IFN-γ group was lower than that in the BMSC group(P<0.001).The number of apoptotic granulosa cells in the INF-γ group and the BMSC group was higher than that in the NC group,and that in the INF-γ group was higher than that in the BMSC group(P<0.001).The estradiol level in the INF-γ group and the BMSC group was lower than that in the NC group,and that in the INF-γ group was lower than that in the BMSC group(P<0.001).Compared with the IFN-γ group,the mRNA expression of CYP19A1 and FSHR in the BMSC group decreased(P<0.001).Compared with the IFN-γ group,the BMSC group had significantly decreased LDH level,mRNA expression levels of NLRP3 and CASP1,and protein expres-sion level of CASP1.Conclusion:hBMSCs repair the immune in-jury of KGN cells induced by IFN-γ by restoring cell proliferation,inhibiting cell apoptosis,repairing endocrine function,and reducing pyroptosis.

Objective To analyze the status quo and high-risk factors of hemorrhagic transformation(HT)in patients with acute cerebral infarction(ACI)treated with alteplase(rt-PA).Methods A total of 462 patients with ACI who were admitted to Hai'an People's Hospital and treated with rt-PA from June 2019 to June 2023 were retrospectively emrolled.According to the occurrence of HT,the patients were assigned to HT group(n=31)or non-HT group(n=431).The clinical data of the two groups were compared,and high-risk factors of HT in ACI patients treated with rt-PA were analyzed.Results The incidence of HT was 6.71%(31/462).Multivariate logistic analysis showed that increased systolic blood pressure(SBP),severe cerebral small vessel disease(CSVD),and increased neutrophil-to-lymphocyte ratio(NLR)were the high-risk factors of HT in patients with ACI after treatment with rt-PA(P＜0.05).Conclusion There is a high incidence of HT in patients with ACI after treatment with rt-PA,the levels of SBP,CSVD and NLR are the influencing factors,and they can provide a basis for prediction and clinical intervention.

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.

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.

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.

Objective To explore the clinical effect of personalized pars plana vitrectomy(PPV)for proliferative di-abetic retinopathy(PDR).Methods In this retrospective case study,76 patients(86 eyes)diagnosed with PDR and re-ceiving PPV in the Department of Ophthalmology of Songjiang Hospital affiliated to Shanghai Jiao Tong University School of Medicine,from October 2019 to November 2022,were divided into the observation group(40 patients,46 eyes)and the control group(36 patients,40 eyes).Patients in the obseration group were treated with personalized PPV,while patients in the control group were treated with conventional PPV,After treatment,all patients were followed up for 12 months.The operation time,intraoperative use of heavy water and silicone oil,incidence of iatrogenic retinal tears and heavy water resi-dues,proportion of scleral buckling,preoperative and postoperative best corrected visual acuity(BCVA)and intraocular pressure(IOP),retinal reattachment rate at 12 months after surgery,and the incidence of post-vitrectomy vitreous hemor-rhage(PVH),diabetic macular edema(DME)and neovascular glaucoma(NVG)were compared between the two groups.Results The operation time of patients in the observation group was shorter than that in the control group(P＜0.05).Intraoperative use of heavy water and silicone oil in the observation group was lower than that in the control group(both P＜0.05).The incidence of iatrogenic retinal tears and heavy water residues and the proportion of scleral buckling showed no statistically significant difference between the two groups(all P＞0.05).There was no statistically significant difference between the two groups in BCVA preoperatively,3,6 and 12 months postoperatively(all P＞0.05).BCVA in the observa-tion group was better than that in the control group at 1 day,1 week and 1 month after surgery(all P＜0.05).Compared with the preoperative value,BCVA increased in the observation group at 1 day,1 week,1 month,3 months,6 months,and 12 months after surgery(all P＜0.05);in the control group,BCVA increased slightly at 1 day and 1 week(both P＞0.05)and then increased significantly at 1 month,3 months,6 months,and 12 months after surgery(all P＜0.05).The two groups showed no statistically significant difference in IOP at 1 day,1 week,1 month,3 months,6 months,and 12 months postoperatively(all P＞0.05).There was no statistically significant difference in the retinal reattachment rate and the inci-dence of complications such as PVH,DME,and NVG between the two groups at 12 months postoperatively(all P＞0.05).Conclusion Personalized PPV can shorten the operation time,reduce the intraoperative use of heavy water and silicone oil,enhance the efficiency of the operation,and rapidly improve the visual acuity of PDR patients.