OBJECTIVE To investigate the effects of potassium channel Kv1.3knockout(Kv1.3 KO)on neurological dysfunction and neuroinflammation in C57BL/6 mice following traumatic brain injury(TBI).METHODS C57BL/6 mice and homozygous Kv1.3 KO C57BL/6 mice were subjected to the classic controlled cortical impact model to establish a TBI model.The experimental groups included the sham surgery group,C57BL/6 TBI model group(TBI group),and a Kv1.3 KO C57BL/6 TBI model group(TBI+Kv1.3 KO group).At 1,2,and 3 weeks post-modeling,real-time quantitative PCR was used to measure the mRNA expression levels of Kv1.3,interleukin-1β(IL-1β),IL-6,tumor necrosis factor-α(TNF-α),and IL-10 in hippocampal tissues.At 1 and 3 weeks post-modeling,Western blotting was performed to detect Kv1.3 protein expressions in the hippocampus.At 3 weeks post-modeling,Western blotting was used to assess the protein levels of IL-1β,IL-6,TNF-α,and IL-10 in hippocampal tissues.Additionally,immunofluorescence was employed to quantify cells co-labeled with the microglial marker ionized calcium-binding adapter molecule 1(IBA1)and Kv1.3,IL-1β,or TNF-α in the hippocampus.Patch-clamp recordings were conducted to measure Kv1.3 channel currents in primary microglia at 3 weeks post-modeling.Neurological function was evaluated at 1 and 3 weeks post-modeling using the neurological severity score(NSS),pole climbing,and rotarod tests.Cognitive function was assessed at 3 weeks post-modeling via open field,Morris water maze,and Y-maze tests.RESULTS Compared with the sham group,the TBI group exhibited significantly elevated mRNA expression levels of Kv1.3 and IL-1β in the hippocampus at 1,2 and 3 weeks post-modeling,while IL-6 and IL-10 mRNA levels showed no significant changes.Notably,TNF-α mRNA expressions demonstrated a significant increase only at 2 and 3 weeks post-modeling.At 1 and 3 weeks post-modeling,Kv1.3 protein expres-sions in the hippocampus were significantly higher in the TBI group.At 3 weeks post-modeling,hippo-campal IL-1β and TNF-α protein levels were markedly increased in the TBI group,whereas IL-6 and IL-10 protein levels did not change significantly.Moreover,Kv1.3 current density in primary microglia was signifi-cantly enhanced in the TBI group at 3 weeks post-modeling.Immunofluorescence analysis revealed that the number of IBA1-positive microglia co-labeled with Kv1.3,IL-1β,or TNF-α in the hippocampus was significantly larger in the TBI group than in the sham group at 3 weeks post-modeling.Behaviorally,the TBI group exhibited significantly higher NSS scores,lower success rates in full turn attempts,and longer times taken to descend the pole at 1 and 3 weeks post-modeling compared with the sham group.At 3 weeks post-modeling,TBI mice also demonstrated reduced total movement distance in the open field,decreased time spent in the central zone,fewer platform crossings,less time in the target quadrant,and lower spontaneous alternation rates.In contrast,the TBI+Kv1.3 KO group showed signifi-cantly improved outcomes compared with the TBI group:lower NSS scores,higher success rates in full turns,and shorter time taken to descend the pole at 1 and 3 weeks post-modeling.At 3 weeks post-modeling,the TBI+Kv1.3 KO group displayed longer rotarod endurance,increased total movement dis-tance in the open field,more time spent in the central zone,higher platform crossings,greater target quadrant exploration time,and improved spontaneous alternation rates.Furthermore,at 1 and 3 weeks post-modeling,the TBI+Kv1.3 KO group exhibited significantly reduced mRNA expression levels of the inflammatory cytokines IL-1β and TNF-α in the hippocampus compared with the TBI group.CONCLU-SION Potassium channel Kv1.3 knockout mitigates neurological dysfunction and neuroinflammation in C57BL/6 mice following TBI.

OBJECTIVE To investigate the effects of potassium channel Kv1.3knockout(Kv1.3 KO)on neurological dysfunction and neuroinflammation in C57BL/6 mice following traumatic brain injury(TBI).METHODS C57BL/6 mice and homozygous Kv1.3 KO C57BL/6 mice were subjected to the classic controlled cortical impact model to establish a TBI model.The experimental groups included the sham surgery group,C57BL/6 TBI model group(TBI group),and a Kv1.3 KO C57BL/6 TBI model group(TBI+Kv1.3 KO group).At 1,2,and 3 weeks post-modeling,real-time quantitative PCR was used to measure the mRNA expression levels of Kv1.3,interleukin-1β(IL-1β),IL-6,tumor necrosis factor-α(TNF-α),and IL-10 in hippocampal tissues.At 1 and 3 weeks post-modeling,Western blotting was performed to detect Kv1.3 protein expressions in the hippocampus.At 3 weeks post-modeling,Western blotting was used to assess the protein levels of IL-1β,IL-6,TNF-α,and IL-10 in hippocampal tissues.Additionally,immunofluorescence was employed to quantify cells co-labeled with the microglial marker ionized calcium-binding adapter molecule 1(IBA1)and Kv1.3,IL-1β,or TNF-α in the hippocampus.Patch-clamp recordings were conducted to measure Kv1.3 channel currents in primary microglia at 3 weeks post-modeling.Neurological function was evaluated at 1 and 3 weeks post-modeling using the neurological severity score(NSS),pole climbing,and rotarod tests.Cognitive function was assessed at 3 weeks post-modeling via open field,Morris water maze,and Y-maze tests.RESULTS Compared with the sham group,the TBI group exhibited significantly elevated mRNA expression levels of Kv1.3 and IL-1β in the hippocampus at 1,2 and 3 weeks post-modeling,while IL-6 and IL-10 mRNA levels showed no significant changes.Notably,TNF-α mRNA expressions demonstrated a significant increase only at 2 and 3 weeks post-modeling.At 1 and 3 weeks post-modeling,Kv1.3 protein expres-sions in the hippocampus were significantly higher in the TBI group.At 3 weeks post-modeling,hippo-campal IL-1β and TNF-α protein levels were markedly increased in the TBI group,whereas IL-6 and IL-10 protein levels did not change significantly.Moreover,Kv1.3 current density in primary microglia was signifi-cantly enhanced in the TBI group at 3 weeks post-modeling.Immunofluorescence analysis revealed that the number of IBA1-positive microglia co-labeled with Kv1.3,IL-1β,or TNF-α in the hippocampus was significantly larger in the TBI group than in the sham group at 3 weeks post-modeling.Behaviorally,the TBI group exhibited significantly higher NSS scores,lower success rates in full turn attempts,and longer times taken to descend the pole at 1 and 3 weeks post-modeling compared with the sham group.At 3 weeks post-modeling,TBI mice also demonstrated reduced total movement distance in the open field,decreased time spent in the central zone,fewer platform crossings,less time in the target quadrant,and lower spontaneous alternation rates.In contrast,the TBI+Kv1.3 KO group showed signifi-cantly improved outcomes compared with the TBI group:lower NSS scores,higher success rates in full turns,and shorter time taken to descend the pole at 1 and 3 weeks post-modeling.At 3 weeks post-modeling,the TBI+Kv1.3 KO group displayed longer rotarod endurance,increased total movement dis-tance in the open field,more time spent in the central zone,higher platform crossings,greater target quadrant exploration time,and improved spontaneous alternation rates.Furthermore,at 1 and 3 weeks post-modeling,the TBI+Kv1.3 KO group exhibited significantly reduced mRNA expression levels of the inflammatory cytokines IL-1β and TNF-α in the hippocampus compared with the TBI group.CONCLU-SION Potassium channel Kv1.3 knockout mitigates neurological dysfunction and neuroinflammation in C57BL/6 mice following TBI.

Objective:To compare the results of operative versus interventional treatments in patients presenting with sentinel hemorrhage after hepatobiliary and pancreatic surgery.Methods:The clinical data of patients presenting with sentinel hemorrhage after hepatobiliary and pancreatic surgery at the Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Guangzhou Medical University from August 2017 to July 2022 were retrospectively analyzed. Of 82 patients who were enrolled in this study, there were 50 males and 32 females, aged (59.0±7.7) years. The patients were divided into the interventional group ( n=42) and the surgical group ( n=40) based on the treatment they received for sentinel hemorrhage. The vascular injury rate, the first operation time for sentinel bleeding, the rate of successful hemostasis in a single operation, the number of deaths and other indicators were compared between groups. Results:In both the two groups of patients who underwent percutaneous transhepatic cholangial drainage, hepatectomy, endoscopic retrograde cholangiopancreatography, hilar cholangiocarcinoma resection and cholecystectomy were mainly performed hepatic artery injury, pancreaticoduodenectomy with gastroduodenal artery injury, and splenectomy with splenic artery injury. In the intervention group, 36 patients (85.7%) were successfully hemostasis after single treatment, and 32 patients (80.0%) in the operation group, and there was no significant difference between the two groups (χ 2=0.47, P=0.492). The first operation time for the intervention group was (40.5±8.5) min and the mortality rate was 2.4% (1/42), which were significantly better than that of the operation group (90.6±20.8) min and 15.0% (6/40) (all P<0.05). Conclusion:Interventional therapy can be used as the first-line diagnosis and treatment for sentinel bleeding after hepatobiliary and pancreatic surgery. It has the advantages of a lower mortality rate in treating these patients.

Humans ; SARS-CoV-2 ; COVID-19 ; Antibodies ; Antibodies, Viral/therapeutic use* ; Antibodies, Neutralizing/therapeutic use*

Blocking the biological functions of scaffold proteins and aggregated proteins is a challenging goal. PROTAC proteolysis-targeting chimaera (PROTAC) technology may be the solution, considering its ability to selectively degrade target proteins. Recent progress in the PROTAC strategy include identification of the structure of the first ternary eutectic complex, extra-terminal domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), and PROTAC ARV-110 has entered clinical trials for the treatment of prostate cancer in 2019. These discoveries strongly proved the value of the PROTAC strategy. In this perspective, we summarized recent meaningful research of PROTAC, including the types of degradation proteins, preliminary biological data in vitro and in vivo, and new E3 ubiquitin ligases. Importantly, the molecular design, optimization strategy and clinical application of candidate molecules are highlighted in detail. Future perspectives for development of advanced PROTAC in medical fields have also been discussed systematically.

Objective To evaluate the capability of Turbo inversion recovery magnitude (TIRM) magnetic resonance neurography (MRN) in the diagnosie of sacral plexus injury by comparing MRN findings with surgical results.Methods Ten patients with sacral plexus injury confirmed surgically underwent conventional T1WI,T2WI,TIRM and coronal TIRM MRN before operations from June,2011 to December,2012.The MRI data and surgical data were analyzed retrospectively to observe nerve injury.Results The coronal TIRM MRN images displayed 93 trunks of sacral plexus,of which 37 were confirmed injury by operation.The MRI findings were as follows:6 trunks involved continuous nerves,but with thickening and blurred margin,as well as abnormal high signal intensity;22 trunks were continuous,but with distortion,stiffness and adhesion accompanied by heterogeneous signal intensity and structural disorder;3 trunks showed complete loss of continuity,absence of normal signal,accompanied by retraction;and 3 trunks involved formation of traumatic neurofibroma.The coincidence of injured nerve trunks diagnosed by MRN with surgical findings amounts to 81.08％ (30/37).Conclusion MR with coronal TIRM imaging is effective in the diagnosis and depiction of sacral plexus injury,therefore it can be used as conventional sequence in sacral plexus examination to detect sacral plexus avulsion.

Objective To investigate the clinical results and related key points of surgical treatment for Hawkins Ⅲ talus neck fractures.Methods Forty-one patients with Hawkins Ⅲ talus neck fracture were treated.The fractures occurred on the left side in 21 patients and on the right side in 20 patients.All patients were performed internal fixation by internal and lateral approaches.The weight bearing should be adjusted with follow-up.The functional results were evaluated by American Orthopaedic Foot and Ankle Society (AOFAS).Results The average duration of follow-up was (37.7 ± 8.2) months.All fractures gained union and the average union time was (4.1 ±0.5) months.The average AOFAS score after treatment was (79.3 ± 2.6) scores which was higher than that before treatment [(35.1 ± 8.0) scores],and there was significant difference (P =0.026).There were 11 cases in excellent,17 cases in good,11 cases in fair and 2 cases in poor.The excellent and good rate was 68.3％ (28/41).Traumatic arthritis occurred in 18 cases (43.9％,18/41),involved tibial astragaloid joint in 4 cases,involved subtalar joint in 6 cases,involved tibial astragaloid joint and subtalar joint in 8 cases.Avascular necrosis occurred in 7 cases (17.1％,7/41).Conclusions The effect of surgical treatment for Hawkins Ⅲ talus neck fracture via a bilateral approaches is satisfactory.Pay more attention to protect blood circulation intraoperative and perform anatomic reduction according to the characteristic of body of talus displacement.After operation,functional rehabilitation should be directed by the principle of early movement,later weighted.