Axon initial segment (AIS) is the most excitable subcellular domain of a neuron for action potential initiation. AISs of cortical projection neurons (PNs) receive GABAergic synaptic inputs primarily from chandelier cells (ChCs), which are believed to regulate action potential generation and modulate neuronal excitability. As individual ChCs often innervate hundreds of PNs, they may alter the activity of PN ensembles and even impact the entire neural network. During postnatal development or in response to changes in network activity, the AISs and axo-axonic synapses undergo dynamic structural and functional changes that underlie the wiring, refinement, and adaptation of cortical microcircuits. Here we briefly introduce the history of ChCs and review recent research advances employing modern genetic and molecular tools. Special attention will be attributed to the plasticity of the AIS and the ChC-PN connections, which play a pivotal role in shaping the dynamic network under both physiological and pathological conditions.
Animals ; Neuronal Plasticity/physiology* ; Cerebral Cortex/cytology* ; Axons/physiology* ; Nerve Net/physiology* ; Humans ; Synapses/physiology* ; GABAergic Neurons/physiology*

Purpose: In non-metastatic prostate cancer (nmPCa) setting, it is important to early identify the patients at risk of biochemical recurrence (BCR) for immediate postoperative intervention. Our study aimed to evaluate the potential clinical utility of circulating tumor DNA (ctDNA) for predicting disease recurrence. Materials and Methods: This real-world observational study evaluated 161 cases of nmPCa undergoing next-generation sequencing at our institution. A total of 139 ctDNA samples and 31 biopsied tumor tissue underwent genomic profiling. The study endpoint was BCR after radical prostatectomy. Relationships between the ctDNA status and the biochemical progression-free survival (bPFS) were analyzed by log-rank test and multivariate Cox regression. Results: Of 161 enrolled patients, 19 (11.8%) harbored deleterious alterations in NCOR2, followed by BRCA2 (3.7%), ATR (2.5%), and CDK12 (2.5%). Of available pre-operative blood samples (n=139), ctDNA was detectable in 91 (65.5%). Until last follow-up, 56 of 68 patients (85.3%) with detectable ctDNA had achieved BCR, whereas only eight of 39 patients (20.5%) with undetectable ctDNA had achieved BCR. Patients who had undetectable ctDNA experienced significantly longer bPFS compared with those who had detectable ctDNA (not available vs. 8.2 months; hazard ratio, 0.14; p < 0.01). Pre-operative ctDNA status was a significant prognostic factor of disease recurrence. Conclusion Pre-operative ctDNA detection could identify patients at high risk of recurrence and has the potential to inform immediate postoperative interventions, but these approaches remain to be validated in prospective studies. ctDNA studies can provide insights into accurate monitoring and precise treatment rather than simply following routine clinical care.

Objective To investigate effects of human postures on flow characteristics of iliac vein compression syndrome. Methods The numerical model of iliac vein was reconstructed from CT images of a typical patient with pelvic-type iliac vein compression syndrome with collateral veins. Based on the computational fluid dynamics method, the non-Newtonian model and the porous media model were adopted to describe effects of abnormal structures on blood flow and acquire the wall shear stress and pressure of iliac vein. The discrete phase model was used to study the residence conditions of erythrocytes under three human postures. Results The pressure gradient at two ends of the compressive region was lowest under lying state, while the iliac vein showed a high pressure under sitting and walking states. The local maximum wall shear stresses under three postures were found at narrow segment of the collateral vein and convergence region of two flows of right iliac vein. The maximum shear stress was largest under lying state and smallest under sitting state. The blood residence time of 52.2 s in the left iliac vein was the longest under sitting state. The residence time of 14.8 s was shortest under lying state. The blood residence time was 23.8 s under walking state. Conclusions Porous media model used to simulate the effect of abnormal structures was highly consistent with the angiography data. The venous hypertension under sitting and walking states was consistent with the clinical results, and the lying state could relieve the hypertensive condition. In terms of wall shear stress and blood residence time in iliac vein, the continual change between three human postures would cause endothelial damage and blood flow stasis alternately, thus increase the risk of thrombosis.

BACKGROUND: Red-cell transfusion is critical for surgery during the peri-operative period; however, the transfusion threshold remains controversial mainly owing to the diversity among patients. The patient's medical status should be evaluated before making a transfusion decision. Herein, we developed an individualized transfusion strategy using the West-China-Liu's Score based on the physiology of oxygen delivery/consumption balance and designed an open-label, multicenter, randomized clinical trial to verify whether it reduced red cell requirement as compared with that associated with restrictive and liberal strategies safely and effectively, providing valid evidence for peri-operative transfusion. METHODS: Patients aged >14 years undergoing elective non-cardiac surgery with estimated blood loss > 1000 mL or 20% blood volume and hemoglobin concentration <10 g/dL were randomly assigned to an individualized strategy, a restrictive strategy following China's guideline or a liberal strategy with a transfusion threshold of hemoglobin concentration <9.5 g/dL. We evaluated two primary outcomes: the proportion of patients who received red blood cells (superiority test) and a composite of in-hospital complications and all-cause mortality by day 30 (non-inferiority test). RESULTS: We enrolled 1182 patients: 379, 419, and 384 received individualized, restrictive, and liberal strategies, respectively. Approximately 30.6% (116/379) of patients in the individualized strategy received a red-cell transfusion, less than 62.5% (262/419) in the restrictive strategy (absolute risk difference, 31.92%; 97.5% confidence interval [CI]: 24.42-39.42%; odds ratio, 3.78%; 97.5% CI: 2.70-5.30%; P <0.001), and 89.8% (345/384) in the liberal strategy (absolute risk difference, 59.24%; 97.5% CI: 52.91-65.57%; odds ratio, 20.06; 97.5% CI: 12.74-31.57; P <0.001). No statistically significant differences were found in the composite of in-hospital complications and mortality by day 30 among the three strategies. CONCLUSION: The individualized red-cell transfusion strategy using the West-China-Liu's Score reduced red-cell transfusion without increasing in-hospital complications and mortality by day 30 when compared with restrictive and liberal strategies in elective non-cardiac surgeries. TRIAL REGISTRATION ClinicalTrials.gov, NCT01597232.
Humans ; Adult ; Postoperative Complications ; Erythrocyte Transfusion/adverse effects* ; Blood Transfusion ; Hospitals ; Hemoglobins/analysis*

Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, has been shown to accelerate the progression of atherosclerosis (AS). However, the definite mechanisms remain elusive. Emerging evidence supports an association between mitochondrial dysfunction and AS. In our study, the impact of P. gingivalis on mitochondrial dysfunction and the potential mechanism were investigated. The mitochondrial morphology of EA.hy926 cells infected with P. gingivalis was assessed by transmission electron microscopy, mitochondrial staining, and quantitative analysis of the mitochondrial network. Fluorescence staining and flow cytometry analysis were performed to determine mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP) levels. Cellular ATP production was examined by a luminescence assay kit. The expression of key fusion and fission proteins was evaluated by western blot and immunofluorescence. Mdivi-1, a specific Drp1 inhibitor, was used to elucidate the role of Drp1 in mitochondrial dysfunction. Our findings showed that P. gingivalis infection induced mitochondrial fragmentation, increased the mtROS levels, and decreased the MMP and ATP concentration in vascular endothelial cells. We observed upregulation of Drp1 (Ser616) phosphorylation and translocation of Drp1 to mitochondria. Mdivi-1 blocked the mitochondrial fragmentation and dysfunction induced by P. gingivalis. Collectively, these results revealed that P. gingivalis infection promoted mitochondrial fragmentation and dysfunction, which was dependent on Drp1. Mitochondrial dysfunction may represent the mechanism by which P. gingivalis exacerbates atherosclerotic lesions.
Endothelial Cells ; Mitochondria ; Mitochondrial Dynamics ; Porphyromonas gingivalis

Objective To explore the expression of Bcl-6 mRNA in the Tfh cells of HIV/AIDS patients and the relationship between Bcl-6 mRNA and the progression of HIV/AIDS.Methods This experiment chose 60 patients who were confirmed by HIV antibody test positive,during May 2014 to November from AIDS Research Institute in the First Affiliated Hospi-tal,Henan College of Traditional Chinese Medicine.According to the amount of CD4+T cells,the patients with HIV/AIDS were divided into A(CD4<200 cells/μl),B(200 cells/μl500 cells/μl)three groups.The Tfh cells expressed CD4+ CXCR5 + ICOS+ and lymphocyte subpopulation including T,B and NK cells were detected by flow cytometry (FCM).The expression of Bcl-6 mRNA levels were detected by reverse transcription-polymerase chain reaction (RT-PCR).The association between Tfh cells and Bcl-6 mRNA,B cells were analyzed.Results The expression of Bcl-6 mRNA from patients of A,B and C three groups was increased than in healthy individuals (2.94±0.91,2.27±0.62,2.15± 0.351,P <0.05).The percent of Tfh cells from group A patients was higher than group C patients (5.88±3.01 vs 1.26± 0.87,P =0.032)and also the healthy control group (5.88±3.01 vs 0.78±0.42,P =0.004).The percentage of NK cells and B cells in HIV/AIDS patients was no statistically significant.Correlation analysis showed that there was positive corre-lation between the proportion of Tfh cells and Bcl-6 mRNA (r=0.799,P =0.000).And Tfh cells were observed no relation-ship with B cells (r=-0.083,P =0.657).Conclusion The changes of Bcl-6 mRNA and Tfh cells may be related to the progression of HIV/AIDS.

Objective To analyse the suspected hereditary non-polyposis colorectal cancer (HNPCC) in mismatch repair protein (MMR) expression of hMLH1 and hMSH2. Methods Immunohistochemical staining method was used for the detection of hMLH1 and hMSH2 protein expression in 193 cases suspected HNPCC patients, the deletion of MMR proteins was identified as highly suspected HNPCC cases. Results Of the 193 patients with suspected HNPCC hMLH1/hMSH2 abnormal expression rate was 29.02%; ≤30 years old was 40%, 31 ~ 40 years old was 28.05%, 41 ~ 50 years old was 28.71%,3 suspected HNPCC showed the deletion of hMLH1/hMSH2 protein expression at the same time ,; In the right colon , the left half colon and rectal anomaly detection rates were 40.74%, 32.65%and 18.89%; hMLH1/hMSH2 deletion was 46.15%with family history. Conclusions The deletion of MMR protein is closely related to age,site and family history in suspected HNPCC, and the deletion of hMLH1 is an important factor to induce early-set colorectal cancer. The deletion of hMLH1/hMSH2 at the same time indicates that hMLH1/hMSH2 genes may play important role in the incidence of HNPCC.

BACKGROUNDLow molecular weight heparin (LMWH), as one of anticoagulant drugs, has been used for the treatment of chronic obstructive pulmonary disease (COPD) with prethrombotic state, but the specific use time is unclear. The aim of the study is to observe the effect of LMWH at two different periods of prethrombotic state in COPD in rats and to find the optimal time to use LMWH.

METHODSForty Wistar rats were randomly divided into 4 groups: normal control, raised for 55 days without any treatment; COPD control without LMWH, cigarette inhalation plus intratracheal instillation of lipopolysaccharide and hypodermic injection of normal saline once a day for 10 days; COPD control given LMWH 150 U/kg subcutaneous injection, once a day for 10 days starting day 15 (LMWH-d15); COPD control given LMWH 150 U/kg subcutaneous injection, once a day for 10 days starting day 29 (LMWH-d29).

RESULTSComparing LMWH-d15 with LMWH-d29, plasma viscosity, whole blood viscosity, von Willebrand factor, serum fibrinogen, plasminogen activator inhibitor-1 and fibrin D-dimer were each significantly reduced; but thrombin plasminogen activator increased significantly whilst arterial PO2 and PCO2 improved significantly.

CONCLUSIONThe better time to use LMWH is the time when coagulation and fibrinolytic indices begin to change in COPD.

Animals ; Anticoagulants ; therapeutic use ; Heparin, Low-Molecular-Weight ; therapeutic use ; Male ; Pulmonary Disease, Chronic Obstructive ; drug therapy ; Random Allocation ; Rats ; Rats, Wistar ; Time Factors

Objective To investigate the relationship between glutathione S-transferases P1(GSTP1)Ile105Val and glutathione S-transferases M1(GSTM1)single nucleotide polymorphisms(SNP) and the sensitivity to chemotherapy among patients with ad-vanced non-small cell lung cancer(NSCLC) .Methods We used gene sequencing analysis to determine the SNP of GSTP1 Ile105Val and PCR analysis to GSTM1 in DNA from peripheral lymphocytes of NSCLC patients .Totally 89 patients with NSCLC were trea-ted with platinum-based chemotherapy ,and clinical response was evaluated after 2 cycles .The association between GSTP1 Ile105Val and GSTM1 SNP and chemosensitivity were analyzed .Results The overall response rate was 29 .2% .Chemotherapy re-sponse did not show statistically significant differences between the wild genotypes and the variant genotypes for the GSTP1 Ile105Val and GSTM1 gene(P>0 .05) .Conclusion The polymorphisms of GSTP1 Ile105Val and GSTM1 may be not associated with sensitivity to chemotherapy in NSCLC patients .