Objective To investigate the effect of bromine domain protein 4(BRD4)inhibitor JQ1 and/or endurance exercise on glucose and lipid metabolism disorder in insulin resistant mice,and its mechanism.Methods Sixty C57BL/6 J mice were ran-domly divided into normal diet group(Con,n=10)and high fat diet group(HFD,n=50).HFD group was fed with high-fat diet for 12 weeks to establish insulin resistance model,and then randomly divided into high-fat diet group(HFD),JQ1 group(HFD+J),endurance exercise group(HFD+E)and J Q1+endurance exercise group(HFD+JE),with 10 mice in each group.The JQ1 group received intraperitoneal injection of JQ1(10 mg/kg,6 d/week,6 weeks),and the exercise group performed treadmill exer-cise(13 m/min,60 min/d,6 d/week,6 weeks).IPGTT and IPITT tests were performed after 6 weeks of intervention.Serum T-CHO,TG,HDL-C,LDL-C and NEFA were measured by microplate method.Myocardial BRD4,GLUT4,AMPK,autophagy in-dexes P62 and LC3,as well as the expressions of ER stress index GRP78,ATF4,IRE1,eIF2α and CHOP were detected by Western blotting.Results After 12 weeks of high fat feeding,body weight,fasting blood glucose and IPGTT-AUC in HFD group were significantly increased compared with Con group.After 6 weeks of intervention,serum NEFA in HFD+J group was significantly lower than that in HFD group.Serum TG,T-CHO and NEFA were significantly decreased in HFD+E group.IPITT-AUC,serum T-CHO,LDL-C and NEFA were significantly decreased,and HDL-C was significantly increased in HFD+JE group.Compared with HFD group,the expressions of p-AMPK/AMPK and GLUT4 in HFD+JE group were signifi-cantly increased.Compared with HFD group,BRD4 expression was significantly downregulated,and LAMP1 expression was significantly upregulated in HFD+J group.In HFD+E group,the expressions of BRD4 and P62 were significantly downregu-lated,and the ratio of LC3 Ⅱ/LC3 Ⅰ was significantly upregulated.The expressions of BRD4 and P62 in HFD+JE group were significantly downregulated,and the ratios of LAMP1 and LC3 Ⅱ/LC3 Ⅰ were significantly upregulated.Compared with HFD group,the expressions of GRP78,p-IRE1/IRE1 and CHOP in HFD+J group were significantly downregulated.The expressions of GRP78,p-IRE1/IRE1,p-eIF2α/eIF2α and CHOP were significantly downregulated in HFD+E group.The expressions of GRP78,p-eIF2α/eIF2α and CHOP were significantly downregulated in HFD+JE group.Conclusion JQ1 can antagonize myo-cardial BRD4 in insulin-resistant mice,improving autophagy and ERS.Yet it only contributes to a partial effect on glycolipid me-tabolism.Both endurance exercise and combined intervention can inhibit myocardial BRD4-mediated autophagy and ERS,impro-ving glucose and lipid metabolic disorder.The combination of these two interventions has a more significant effect,which may be related to BRD4 inhibition and autophagy function improvement.

Objective To investigate the effect of bromine domain protein 4(BRD4)inhibitor JQ1 and/or endurance exercise on glucose and lipid metabolism disorder in insulin resistant mice,and its mechanism.Methods Sixty C57BL/6 J mice were ran-domly divided into normal diet group(Con,n=10)and high fat diet group(HFD,n=50).HFD group was fed with high-fat diet for 12 weeks to establish insulin resistance model,and then randomly divided into high-fat diet group(HFD),JQ1 group(HFD+J),endurance exercise group(HFD+E)and J Q1+endurance exercise group(HFD+JE),with 10 mice in each group.The JQ1 group received intraperitoneal injection of JQ1(10 mg/kg,6 d/week,6 weeks),and the exercise group performed treadmill exer-cise(13 m/min,60 min/d,6 d/week,6 weeks).IPGTT and IPITT tests were performed after 6 weeks of intervention.Serum T-CHO,TG,HDL-C,LDL-C and NEFA were measured by microplate method.Myocardial BRD4,GLUT4,AMPK,autophagy in-dexes P62 and LC3,as well as the expressions of ER stress index GRP78,ATF4,IRE1,eIF2α and CHOP were detected by Western blotting.Results After 12 weeks of high fat feeding,body weight,fasting blood glucose and IPGTT-AUC in HFD group were significantly increased compared with Con group.After 6 weeks of intervention,serum NEFA in HFD+J group was significantly lower than that in HFD group.Serum TG,T-CHO and NEFA were significantly decreased in HFD+E group.IPITT-AUC,serum T-CHO,LDL-C and NEFA were significantly decreased,and HDL-C was significantly increased in HFD+JE group.Compared with HFD group,the expressions of p-AMPK/AMPK and GLUT4 in HFD+JE group were signifi-cantly increased.Compared with HFD group,BRD4 expression was significantly downregulated,and LAMP1 expression was significantly upregulated in HFD+J group.In HFD+E group,the expressions of BRD4 and P62 were significantly downregu-lated,and the ratio of LC3 Ⅱ/LC3 Ⅰ was significantly upregulated.The expressions of BRD4 and P62 in HFD+JE group were significantly downregulated,and the ratios of LAMP1 and LC3 Ⅱ/LC3 Ⅰ were significantly upregulated.Compared with HFD group,the expressions of GRP78,p-IRE1/IRE1 and CHOP in HFD+J group were significantly downregulated.The expressions of GRP78,p-IRE1/IRE1,p-eIF2α/eIF2α and CHOP were significantly downregulated in HFD+E group.The expressions of GRP78,p-eIF2α/eIF2α and CHOP were significantly downregulated in HFD+JE group.Conclusion JQ1 can antagonize myo-cardial BRD4 in insulin-resistant mice,improving autophagy and ERS.Yet it only contributes to a partial effect on glycolipid me-tabolism.Both endurance exercise and combined intervention can inhibit myocardial BRD4-mediated autophagy and ERS,impro-ving glucose and lipid metabolic disorder.The combination of these two interventions has a more significant effect,which may be related to BRD4 inhibition and autophagy function improvement.

The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been recently identified as a neurotrophic factor, but its role in hepatic fibrosis is unknown. Here, we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl₄. MANF deficiency in either hepatocytes or hepatic mono-macrophages, particularly in hepatic mono-macrophages, clearly exacerbated hepatic fibrosis. Myeloid-specific MANF knockout increased the population of hepatic Ly6C^high macrophages and promoted HSCs activation. Furthermore, MANF-sufficient macrophages (from WT mice) transfusion ameliorated CCl₄-induced hepatic fibrosis in myeloid cells-specific MANF knockout (MKO) mice. Mechanistically, MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation. Pharmacologically, systemic administration of recombinant human MANF significantly alleviated CCl₄-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout (HKO) mice. This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a "brake" on the upstream of NF-κB pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.

Intermittent fasting,as a dietary nutrition program of fasting and eating alternately,mainly includes alternate-day fasting,time-restricted fasting,periodic fasting and Ramadan fasting.Positive effects of intermittent fasting on metabolic disea-ses such as obesity,diabetes and cardiovascular disease has been confirmed,but its effect on exercise performance is yet to be re-vealed.This paper summarizes the effects of intermittent fasting on anaerobic exercise,aerobic endurance exercise and strength alternation as well as related mechanism.It can provide theoretical reference for diet optimization,intermittent fasting selection and scientific exercise amony athletes,sports enthusiasts and patients with chronic diseases.

Objective To evaluate the development, hot spots and trends of the fields of neurogenic bladder.Methods The relevant articles of neurogenic bladder from January, 2000 to June, 2021 in CNKI and Web of Science were retrieved.The countries, authors, institutions, cited reference and keywords were extracted with CiteSpace to draw knowledge mapping. Results and Conclusion A total of 5 064 articles were enrolled. At present, the research on the field of neurogenic bladder is in a stable period of development, and this field has been widely concerned by scholars at home and abroad. The cooperation between domestic authors and institutions is not close enough compared with foreign countries, and domestic cooperation is more between medical schools and their respective affiliated hospitals. In the future, China can further strengthen cross-regional and cross-agency cooperation. Low-frequency electrical stimulation and sacral nerve regulation are seem to be research hotspots, and children's neurogenic bladder and robot-assisted technologies are also needed more attention.

A 72-year-old female patient was admitted to our hospital due to chronic cough, expectoration and dyspnea for 10 years,aggravated with intermittent fever for 1 month. She was diagnosed as acute exacerbation of chronic bronchitis,chronic pulmonary heart disease,cardiac function class IV,bilateral lower extremity venous thrombosis and thrombocytopenia. The application of antico-agulant drugs and coagulant drugs in the patient needed to be well weighed with the methods of the bleeding score system combined with clinical assessment of actual risk of bleeding. The interactions of drugs harmful to the patient should be considered and the prognosis of the patient should also be evaluated with careful clinical thought to reduce the patient's risk.

Objective: To compare the application of Sofren injection in respiratory department before and after the intervention to provide reference for clinical application and pharmacy management.Methods: A retrospective study was conducted on the medical records of inpatients treated with Sofren injection, and then intervene the found problems.Comparative study of Sofren injection in respiratory department before and after the intervention was performed.Results: Among the 584 cases in the retrospective study, those with off-indications were 438 ones (75%), those with inappropriate solvents were 555 ones (95.03%), and those with improper course were 196 ones (33.56%).After the intervention in the clinical practice, the improvement rate of improper solvents was 98.70%, that of off-indications was 29.85%, and that of unsuitable course was 77.71%.Conclusion: Through comparative study on the main problems before the intervention and the effective performance of specific solutions, the application of Sofren injection in respiratory department is greatly improved, which provides reference for the special management of other drugs.

OBJCETIVE:To investigate the role of clinical pharmacists in medication reconciliation. METHODS:Totally 200 inpatients admitted or transferred to nephrology department of our hospital during Aug.-Oct. 2015 were selected. Within 48 h after admission,1-year medication history were collected by reviewing electronic medical records,consultation,querying self-prepared drugs and medical history;and then medication reconciliation was conducted by clinical pharmacists. RESULTS:Among drug lists collected by clinical pharmacists,there were 987 kinds of drugs,but only 9.63%(95 kinds) drugs were recorded in the medical records. There were 5 cases of ADR in total,and only 40.00% of them (2 cases) were recorded in the medical records. Among 200 patients,medication reconciliation was needed in 45 cases with reconciliation rate of 22.50%. Among 492 medical orders of 200 patients,medication errors were found in 103 medical orders;the number of medication errors per case was (2.3 ± 1.8), mainly including wrong dose,repeated medication,wrong solvent,drug interactions;the potential risk degree was mainly degree 1 (53 orders,51.46%). Among 103 medication reconciliation orders,main plans were drug withdrawal (78 cases,75.73%), followed by drug change(17 cases,16.50%)and drug supplement(8 cases,7.77%). A total of 90 reconciled medical orders were adopted by physicians,with success rate of 87.38%. CONCLUSIONS:Compared with physicians,clinical pharmacists can obtain more detailed and accurate drug list. It can reduce medication error and guarantee the safety of drug use to maximum extent that clinical pharmacists conduct medication reconciliation.

Objective To investigate the characteristics of cognitive impairment and psychotic symptoms in general paresis of insane (GPI) before and after penicillin therapy, and explore factors that may predict the clinical outcomes. Methods Thirty patients with GPI were recruited. All GPI patients underwent a comprehensive neuropsychological assessment before receiving penicillin therapy, and returned for follow-up visits after 7 months. The severity of dementia was determined by Clinical Dementia Rating Scale (CDR), cognitive functions were assessed by Mini Mental State Examination (MMSE) and Alzheimer 's Disease Assessment Scale-cognitive subscale (ADAS-Cog), ability of daily living was assessed by Instrumental Activities of Daily Living Scale (IALD) and Physical Self maintenance Scale(PSMS), behavioral and psychological symptoms were assessed by Neuropsychiatric Inventory (NPI). Aqueous crystalline penicillin G 24 million units per day was administered as continuous infusion for 14 days, followed by benzathine penicillin 2.4 million units IM once per week for 3 weeks. Patients returned for follow-up visits after 7 months. Clinical outcomes were determined by the improvement of neuropsychological test scores at the end of the treatment. Grouped by CDR scores, changes in neuropsychological tests scores among different GPI groups were used to explore the correlation between severity of dementia and clinical outcomes. Univariate analysis and multivariate linear regression analysis were used to identify factors that may predict the clinical outcomes. Results (1)After penicillin therapy, GPI patients' MMSE scores(14.4± 6.9 vs.17.1 ± 9.1)and IADL scores(4.0(2.0, 5.0)vs.6.0(2.0, 7.3))both improved significantly(t=5.820, Z=3.710, P<0.01),while in ADAS-Cog, only factor scores of attention(1.5(0.7, 3.0)vs.1.5(0, 2.3))reduced significantly(Z=- 2.680, P<0.01). NPI's total scores(46.0 ± 27.1 vs.17.6 ± 15.4)and subscores of hallucination, delusion, agitation, depression, euphoria, disinhibition and irritability reduced significantly (Z=-4.940,-2.381,-2.504,-3.095,-2.492,-3.097,-2.527,-3.715, all P<0.05).(2) Grouped by the CDR scores, MMSE scores and IADL scores in very mild GPI group with CDR=0.5 improved significantly. In mild GPI group with CDR=1, significant changes were also found in all neuropsychological tests scores(MMSE,t=5.409, P<0.01), total scores of ADAS-Cog (Z=-2.366,P<0.05), IADL (Z=2.546, P<0.05), total scores of NPI (Z=-3.558,P<0.01), but except for PSMS. In moderate to severe GPI group with CDR>1,significant change was found only in total scores of NPI (t=-3.772,P<0.05). (3) Univariate analysis and multivariate linear regression analysis showed that improvement of MMSE scores after the treatment was significantly correlated with IADL scores and MMSE scores at baseline(β=0.541,P=0.004;β=0.364,P=0.044). Conclusions After penicillin treatment, GPI patients may improve in both cognitive function and psychotic symptoms but not in all the domains. Symptoms of anxiety, sleep/nigh-time behavior change, and apathy, as well as moderate to severe GPI patients may not benefit much from the treatment.

Objective To investigate the characteristics of cognitive impairment and psychotic symptoms in general paresis of insane (GPI) before and after penicillin therapy, and explore factors that may predict the clinical outcomes. Methods Thirty patients with GPI were recruited. All GPI patients underwent a comprehensive neuropsychological assessment before receiving penicillin therapy, and returned for follow-up visits after 7 months. The severity of dementia was determined by Clinical Dementia Rating Scale (CDR), cognitive functions were assessed by Mini Mental State Examination (MMSE) and Alzheimer 's Disease Assessment Scale-cognitive subscale (ADAS-Cog), ability of daily living was assessed by Instrumental Activities of Daily Living Scale (IALD) and Physical Self maintenance Scale(PSMS), behavioral and psychological symptoms were assessed by Neuropsychiatric Inventory (NPI). Aqueous crystalline penicillin G 24 million units per day was administered as continuous infusion for 14 days, followed by benzathine penicillin 2.4 million units IM once per week for 3 weeks. Patients returned for follow-up visits after 7 months. Clinical outcomes were determined by the improvement of neuropsychological test scores at the end of the treatment. Grouped by CDR scores, changes in neuropsychological tests scores among different GPI groups were used to explore the correlation between severity of dementia and clinical outcomes. Univariate analysis and multivariate linear regression analysis were used to identify factors that may predict the clinical outcomes. Results (1)After penicillin therapy, GPI patients' MMSE scores(14.4± 6.9 vs.17.1 ± 9.1)and IADL scores(4.0(2.0, 5.0)vs.6.0(2.0, 7.3))both improved significantly(t=5.820, Z=3.710, P<0.01),while in ADAS-Cog, only factor scores of attention(1.5(0.7, 3.0)vs.1.5(0, 2.3))reduced significantly(Z=- 2.680, P<0.01). NPI's total scores(46.0 ± 27.1 vs.17.6 ± 15.4)and subscores of hallucination, delusion, agitation, depression, euphoria, disinhibition and irritability reduced significantly (Z=-4.940,-2.381,-2.504,-3.095,-2.492,-3.097,-2.527,-3.715, all P<0.05).(2) Grouped by the CDR scores, MMSE scores and IADL scores in very mild GPI group with CDR=0.5 improved significantly. In mild GPI group with CDR=1, significant changes were also found in all neuropsychological tests scores(MMSE,t=5.409, P<0.01), total scores of ADAS-Cog (Z=-2.366,P<0.05), IADL (Z=2.546, P<0.05), total scores of NPI (Z=-3.558,P<0.01), but except for PSMS. In moderate to severe GPI group with CDR>1,significant change was found only in total scores of NPI (t=-3.772,P<0.05). (3) Univariate analysis and multivariate linear regression analysis showed that improvement of MMSE scores after the treatment was significantly correlated with IADL scores and MMSE scores at baseline(β=0.541,P=0.004;β=0.364,P=0.044). Conclusions After penicillin treatment, GPI patients may improve in both cognitive function and psychotic symptoms but not in all the domains. Symptoms of anxiety, sleep/nigh-time behavior change, and apathy, as well as moderate to severe GPI patients may not benefit much from the treatment.