Objective  By summarizing the clinical characteristics and follow-up outcomes of 5 patients with immune checkpoint inhibitor induced diabetes mellitus (ICI-DM) and reviewing the relevant literatures, the article aims at providing reference to clinicians in the diagnosis and treatment of the ICI-DM.  Methods  Clinical data of 5 patients with ICI-DM who were admitted to Peking Union Medical College Hospital from December 2018 to February 2023 and did retrospectively analyzed.  Results  Five patients with a mean age of (65±7)years received treatment by the programmed cell death 1 (PD-1) or its ligand inhibitor (PD-L1). The median time from the first immunotherapy to the discovery of elevated plasma glucose was 100 (43, 210)days, and the median cycle of immunotherapy was 7 (2.5, 10.5). The onset of the illness of all the 5 patients started with diabetic ketosis or ketoacidosis. At the onset, urine ketone bodies were positive, random plasma glucose was (36.36±15.89)mmol/L, glycosylated hemoglobin A1c (HbA1c)was (8.6%±0.66%), arterial blood pH was (7.28±0.16), and the median fasting C-peptide level was 0.09 (0.05, 0.32)μg/L. Five patients had an onset plasma glucose level of grade 3 or 4.Then, ICI treatment was discontinued in all patients and insulin therapy started. The daily dosage of insulin was (56±20)IU, supplemented with hypoglycemic drugs. After treatment, urine ketone body turned negative, pH value increased to normal range, and random plasma glucose decreased significantly (the median difference of random blood glucose before and after treatment was 21.30 mmol/L, P=0.043) showing that the treatment was effective. During the follow-up, all patients continued to use insulin. The PD-1 or PD-L1 inhibitors were restarted after hyperglycemia remission. The tumor condition was under control.  Conclusions  ICI-DM mainly occurs in patients who receive treatment with PD-1 or PD-L1 inhibitors usually with acute hyperglycemia whose laboratory tests indicate insulin secretion defects. Some patients had positive islet cell antibodies, glutamic acid decarboxylase antibodies and autoantibodies.Patients with positive autoantibodies needed early diagnosis and continuous insulin treatment. ICI treatment can be restarted after endocrinologists brought the blood glucose under control.

ObjectiveTo characterize the efficacy components of Guizhi Jia Gegentang（GGT） in intervening influenza virus pneumonia by ultra-performance liquid chromatography-quadrupole-electrostatic field orbitrap high resolution mass spectrometry（UPLC-Q-Exactive Orbitrap MS）. MethodBALB/c mice were randomly divided into normal group and GGT group（36 g·kg^-1·d^-1） with six mice in each group. GGT group was continuously administered GGT extract for 5 d， while the normal group was administered an equal amount of ultrapure water. Serum and lung tissue were collected after administration， and UPLC-Q-Exactive Orbitrap MS was used to characterize the prototypical and metabolic components of GGT in serum and lung tissue of mice. The components existed simultaneously in the serum and lung tissue of mice from the GGT group were defined as its functional components， and the targets of efficacy components were searched by SwissTargetPrediction database， and GeneCards database was used to query the target of influenza virus pneumonia， and then the intersection was taken to obtain potential targets of GGT for intervening in the disease. Protein-protein interaction（PPI） network analysis of potential targets was performed by STRING database， and Kyoto Encyclopedia of Genes and Genomes（KEGG） pathway enrichment analysis on potential targets was performed by Metascape. ResultA total of 29 prototypical components and 28 metabolic components of GGT were detected in the drug-containing serum of mice， of which 11 prototypical components and 4 metabolic components were detected in the lung tissue of mice. The main metabolic pathways included reduction， hydroxylation， methylation， glucuronidation and sulfation. The results of PPI network and KEGG analysis showed that these functional components may act through their effects on targets such as albumin（ALB）， epidermal growth factor receptor（EGFR）， steroid receptor coactivator（SRC）， Toll-like receptor 4（TLR4）， nuclear transcription factor（NF）-κB and adhesion junction. ConclusionThe 11 prototypical components and 4 metabolites present simultaneously in the drug-containing serum and lung tissue of mice may be the potential therapeutic components of GGT in interfering with influenza viral pneumonia， and act through interfering with inflammatory metabolic pathways. This study can provide a reference for the mechanism study of GGT in the treatment of influenza viral pneumonia.

Objective To study the mechanism of Chaihu Guizhi Decoction(CGD)in the treatment of influenza and staphylococcus aureus co-infection.Methods The co-infection model of influenza and staphylococcus aureus was established and CGD was used to intervene.The chemical components of CGD were qualitatively analyzed by UPLC-Q-Exactive/MS technology.The potential action targets of chemical components in CGD and the related targets of influenza Staphylococcus aureus co-infection were mined by network pharmacology method.The"component target disease"network was constructed.Core targets were selected according to degree ranking.Core action pathways were enriched by KEGG analysis and GO annotation analysis.The core target was verified by RT-qPCR,and the interaction between the core component and the key target was verified by molecular docking.Results CGD could significantly improve the decrease of body weight and thymus index(P<0.05)caused by co-infection.The lung index(P<0.05),relative amount of MmRNA expression(P<0.05)and bacterial load(P<0.05)were decreased,and the survival rate was improved.51 chemical constituents were identified from CGD.Through network pharmacological analysis,107 related targets corresponding to CGD treatment of bacterial pneumonia secondary to influenza were excavated.TNF,AKT1,ALB,VEGFA,MAPK3,PTGS2,STAT3,EGFR and other targets with strong correlation,mainly involved Fc epsilon RI signal pathway,GnRH signal pathway,NF-κB signal path,etc.Molecular docking study showed that the main active component of CGD,including oroxyloside,baicalein and wogonin have strong affinity with TNF,PTGS2 and EGFR targets.Compared with co-infection model group,in CGD group TNF-α、EGFR and PTGS2 increased significantly(P<0.05).Conclusion The main active ingredient of CGD is oroxyloside,baicalein and wogonin.TNF-α,PTGS2,EGFR and other targets to played a role in the treatment of influenza staphylococcus aureus co-infection.

Objective To explore the structure changes of white matter in the first-episode schizo-phrenic patients with never-medicated(FESZ)and the relationship between facial emotion perception and white matter(WM)integrity.Methods Sixty-three schizophrenic patients and thirty health control subjects underwent diffusion tensor imaging(DTI)scans.Voxel-based analysis was used to compared fractional ani-sotropy(FA)map between the two groups.Correlations were analyzed with pearson relative analysis between impaired facial emotion perception tested by facial emotion categorization(FEC)and severity of symptoms measured by the Positive and Negative Syndrome Scale(PANSS).Results (1)Compared with controls, FESZ patients showed overall decreased FA in WM of the body of left ventral frontal lobe((MNI(x,y,z):-18,26,-4;t=4.43)),right supramarginal gyrus((MNI(x,y,z):32,-50,26;t=4.27)),left middle oc-cipital gyral((MNI(x,y,z):-26,-60,0;t=4.89)),right middle occipital gyral((MNI(x,y,z):28,-70, 14;t=4.18)),left fusiform gyrus((MNI(x,y,z):-40,-50,0;t=3.92)),left cerebellum anterior lobe ((MNI(x,y,z):-32,-56,-28;t=4.57)),right parahippocampa gyrus1((MNI(x,y,z):32,-10,-14;t=4.16)),right parahippocampa gyrus2((MNI(x,y,z):16,-6,-14;t=4.56)),left anterior cingulate ((MNI(x,y,z):-2,4,-6;t=4.41)),left extra-nuclear((MNI(x,y,z):-2,-10,-6;t=4.44)),right thalamus((MNI(x,y,z):10,-10,2;t=4.20)),left thalamus((MNI(x,y,z):-22,-28,12;t=4.01)), and right caudate((MNI(x,y,z):14,12,8;t=4.87)).(2)Compared with controls,the patients with schizo-phrenia showed a higher shift point and a steeper slope than control subjects in FEC.Correlational analysis re-vealed that the negative correlations were found between the slope and negative factor(r=-0.298,P=0.036),between positive factor and the FA value in WM of the right middle occipital gyral(r=-0.322,P=0.023)and the left middle occipital gyral(r=-0.288,P=0.043),and between the FA value in the left cere-bellum anterior lobe and shift point(r=-0.393,P=0.005),but the positive correlation was found between disorganized/concrete factor and the FA value in the right parahippocampal gyrus(r=0.429,P=0.002).Con-clusions There are extensive microstructural abnormalities in WM of patients with FESZ.Disrupted WM in-tegrity in these regions may constitute a potential neural pathological basis for the facial emotion perception impairments in schizophrenia.

Contactin 5 (CNTN5) belongs to a subgroup of the immunoglobulin superfamily.It is highly expressed in the amygdala and occipital lobe of the human brain as well as in the presynaptic terminal of glutamatergic neurons in the auditory system.In recent years,researchers have used animal experiments to identify the biological functions of CNTN5.They have also investigated the relationship between CNTN5 and menial disorders including autism,Alzheimer's disease,and anorexia nervosa among others.Furthermore,immunofluorescence assays have shown that CNTN5 is expressed in glutamatergic neurons in the hypothalamus.A reduction in the number of glutamatergic neurons can cause the long-term potentiation of synapses.Long-term potentiation is an important mechanism in post-traumatic stress disorder (PTSD).It suggests that mutation of CNTN5 may be one of the mechanisms underlying PTSD.We reviewed the research concerning CNTN5 to identify future research directions.

Monoamine oxidase A (MAOA) can catalyze the degradation of a variety of amine neurotransmitter,including serotonin.The abnormalities of these neurotransmitter are closely associated with many psychiatric disorders.Studies have found that MAOA is polymorphic,with a low activity variant (MAOA-L),and a high activity variant (MAOA-H).In this review,through the studies of early stress on human and animal models,the effects of early stress and MAOA polymorphism on the behavior and emotional loop of individuals are analyzed.Analysis shows that,MAOA-L,versus MAOA-H,is more plastic.In early adverse environment,MAOA-L will increase the risk of adult violence,and in the early of energetically favorable environment will reduce the incidence of violence.Abnormality is more likely to occur in the emotional processing and cognitive function in the neural affective loop of individuals with MAOA-L,which makes them more environmentally susceptible than those with MAOA-H.

Objective To observe changes of apoptosis and Caspase-12 expression in hippocampus of the rat model of posttraumatic stress disorder ( PTSD ) .Methods Single prolonged stress ( SPS ) was used to duplicate a rat model of PTSD.Male Wistar rats were randomly divided into 1, 4, 7 days groups after exposure to SPS and a normal control group.Transmission electron microscopy was used to observe morphologic changes of the hippocampus neurons .The expression of Caspase-12 was detected by immunohistochemistry , Western blotting and RT-PCR.Results After SPS, the hippocampus neurons had characteristic morphologic changes of apoptosis , and the expression of Caspase-12 reached the peak at SPS 4d.Conclusion PTSD activates the ERS-mediated apoptosis in hippocampus via Caspase-12, which may be a pathophysiology base of the atrophy of the hippocampus in PTSD .

Objective To investigate the clinical efficacy of adefovir dipivoxil in antiviral treatment of chronic hepatitis B and its effect on peripheral blood T lymphocyte subsets.Methods 40 cases of patients with chronic hepatitis B were selected from The Fourth People’s Hospital of Qinghai in October 2009 to June 2012,the patients were given the antiviral treatment of adefovir dipivoxil.Before treatment,3 months,6 months and 12 months after treatment,the changes of liver function indicators of alanine transaminase(ALT),aspartate transaminase(AST)and total bilirubin(TBiL),and hepatitis B virus-DNA(HBV-DNA)were recorded;the total effective rate was observed;the peripheral blood T lymphocyte subsets changes was tested and analyzed by flow cytometry.Results The ALT,AST and TBiL of the patients all improved good,and the indicators of ALT,AST and TBiL after 12 months decreased significantly than before treatment,the HBV-DNA testing of the patients recovered negative,the difference was statistically significant (P<0.05 );the total effective rate of hepatitis B patients is 92.5%;the peripheral blood T lymphocyte subsets has no significant improvement in patients after antiviral treatment for 3 months.After the treatment for 6 months and 12 months,the CD4 +T and CD4 +/CD8 +T were significantly higher than those before treatment,there was no significant changes in CD3 +T and CD8 +T before and after treatment.Conclusion Adefovir dipivoxil has a good clinical efficacy in antiviral treatment of chronic hepatitis B,and can significantly improve the patients’liver function,improve peripheral blood T lymphocyte subsets imbalance.

Objective To observe the prevalence of anionic trypsinogen (PRSS2) gene G191R mutation in patients with acute pancreatitis (AP) and chronic pancreatitis (CP),and to investigate the effect of PRSS2 gene G191R mutation on susceptibility to pancreatitis.Methods The blood samples of 82 patients with acute pancreatitis,73 patients with chronic pancreatitis and 138 healthy subjects were collected,and genomic DNA was extracted.Nest PCR were performed to amplify PRSS2 gene and restriction fragment length polymorphism (RFLP) was followed by using Hpy188Ⅲ to distinguish the G191R mutation.DNA sequencing analysis was performed to confirm the mutation status.Results The size of nest PCR products was 436 bp.RFLP2 produced 309 bp and 127 bp fragments,which were resulted from PRSS2 gene G191R mutation (GGA →AGA).DNA sequencing analysis of the PCR products further confirmed the PRSS2 gene G191R mutation.Five of eighty-two(6.1％) patients with acute pancreatitis had PRSS2 gene G191R mutation (OR=0.682,95％ CI 0.231 ～ 2.010); one of seventy-three (1.4％) patients with chronic pancreatitis had the mutation (OR =0.145,95％ CI 0.019 ～ 1.145),and the corresponding value in healthy group was 8.7％ (12/138).The G191R mutation rate in patients with chronic pancreatitis was significantly lower than that in healthy group (x2 =0.432,P =0.035),but the G191R mutation rates were not significantly different between AP group and healthy group (x2 =0.487,P =0.485).Conclusions PRSS2 gene G191R mutation facilitates the degradation of anionic trypsin,and may reduce the incidence of chronic pancreatitis.

ObjectiveTo observe the expressions of Caspase-9,Caspase-3, cytochrome C and their relationships, and investigate apoptotic mechanisms in hippocampus of post-traumatic stress disorder(PTSD) rats. Methods Sixty male Wistar rats were used in the present study. The single-prolonged stress (SPS)-method was used to set up the rat PTSD models. There were six groups:after SPS 1 day,4 days,7 days,14 days,28 days groups and control group. The expressions of caspase-9, Caspase-3 and Cytochrome C proteins were detected with immunohistochemistry, immunofluorescence and Western blotting. Results Immunohistochemical and immunofluorescent results showed that the expression of cytochrome C peaked at 4 days and maintained higher level at 7days after SPS. Expressions of Caspase-9 and Caspase-3 were increased and peaked at 7days after SPS. Western blotting results showed that compared with control group, cytochrome C protein was up-regulated and peaked at 4 days after SPS in the cytosol. Compared with the control group, cytochrome C tended to decrease in mitochondrial fractions. The activated form of Caspase-9 and caspase-3 were not detected in control group. They were present in model groups. Cleaved- caspase-9 and cleaved-caspase-3 peaked at 7 days after SPS, and then gradually decreased at 14 days. Conclusion The neuronal apoptosis in hippocampus of PTSD rats may be one of the causes inducing hippocampus atrophy. Mitochondrial apoptotic pathway is involved in apoptosis in the hippocampus of PTSD rats.