OBJECTIVE To analyze the correlation of the peak blood concentration （cmax） of compound sulfamethoxazole （TMP/SMZ） and its metabolite N-acetyl sulfamethoxazole （NSMZ） with clinical efficacy and adverse reactions in critically ill patients. METHODS The data of critically ill patients treated with TMP/SMZ in various ICU of Hainan General Hospital from December 2023 to January 2025 were retrospectively collected. The patients were divided into success group and failure group based on the treatment outcome. Simple linear regression and Spearman correlation analysis were used to analyze the correlation of TMP cmax， SMZ cmax， and NSMZ cmax with clinical efficacy and adverse reactions. The receiver operating characteristic curve （ROC） was used to determine the cutoff values of cmax for predicting the occurrence of adverse reactions. RESULTS Among critically ill patients with an acute physiology and chronic health evaluation Ⅱ （APACHE-Ⅱ） ≥15 points 24 h of check-in at ICU， SMZ cmax of success group was significantly higher than failure group （P＜0.05）. The daily total dose of TMP/SMZ was positively correlated with TMP cmax and SMZ cmax（ P＜0.05）. TMP cmax was significantly correlated with hepatotoxicity and nephrotoxicity， SMZ cmax with hepatotoxicity， and NSMZ cmax with nephrotoxicity （P＜0.05）. The cutoff values of TMP cmax for predicting nephrotoxicity and hepatotoxicity were 7.25 μg/mL and 6.63 μg/mL， respectively. The cutoff value of SMZ cmax for predicting hepatotoxicity was 138.00 μg/mL， and that of NSMZ cmax for predicting nephrotoxicity was 60.76 μg/mL. CONCLUSIONS Among critically ill patients with an APACHE-Ⅱ ≥15 points 24 h of check-in at ICU， SMZ cmax is associated with treatment success. Hepatotoxicity risk significantly increases when TMP cmax ≥6.63 μg/mL or SMZ cmax ≥138.00 μg/mL； nephrotoxicity risk significantly increases when TMP cmax ≥7.25 μg/mL or NSMZ cmax ≥60.76 μg/mL.

Objective:To discuss the effects of bone marrow-derived mesenchymal stem cells(BMSCs)transplantation on mitophagy in the vascular dementia(VaD)rats through reactive oxygen species(ROS)/nuclear factor erythroid 2-related factor 2(Nrf2)signaling,and to clarify its mechanism.Methods:Forty-five male adult SD rats were randomly divided into sham operation group,model group,unloaded group,BMSCs group,and MSCs+ML385(Nrf2 inhibitor)group(combination group),and there were 9 rats in each group.After intraperitoneal anesthesia,the VaD models were established in all groups except sham operation group.Morris water maze test was used to detect the learning and memory abilities of the rats in various groups;HE staining was used to observe the histopathological morphology of brain tissue of the rats in various groups;Nissl staining was used to observe the changes of Nissl bodies in hippocampus region of brain tissue of the rats in various groups;transmission electron microscope was used to observe the ultrastructure of hippocampus region of the rats in various groups;fluorescence probe method was used to detect the ROS levels in hippocampus neurons in various groups;Western blotting method was used to detect the expression levels of Nrf2,heme oxygenase-1(HO-1),PTEN-induced putative kinase 1(PINK1),parkin RBR E3 ubiquitin protein ligase(Parkin),Beclin-1,ubiquitin-binding protein p62(P62),and microtubule-associated protein 1A/1B-light chain 3(LC3-Ⅱ/LC3-Ⅰ)ratio in brain tissue of the rats in various groups.Results:The Morris water maze results showed that compared with sham operation group,the escape latency of the rats in model group was significantly increased(P<0.01),while the number of crossing time and residence time were significantly decreased(P<0.01).Compared with model group,the escape latency of the rats in BMSCs group was significantly decreased(P<0.01),while the number of crossing time and residence time were significantly increased(P<0.01).Compared with BMSCs group,the escape latency of the rats in combination group was significantly increased(P<0.01),while the number of crossing time and residence time were significantly decreased(P<0.01).The HE staining results showed that hippocampus neurons of the rats in sham operation group were normal in quantity and morphology,with uniform staining and clear structure.Compared with sham operation group,the hippocampus tissue of the rats in model group showed sparse arrangement,disordered structure,reduced neuronal quantity,varied morphology,uneven staining,nuclear pyknosis,and partial neuronal necrosis.Compared with model group,the neuronal damage of the rats in hippocampus regio in BMSCs group was alleviated,with restored morphology and improved neuronal loss.Compared with BMSCs group,the neurons of the rats in hippocampus region in combination group showed irregular morphology,disordered structure,unclear cell boundaries,uneven staining,and nuclear pyknosis.The Nissl staining results showed that the hippocampal neurons in sham operation group were tightly arranged with intact morphology,obvious nucleoli,and abundant darkly stained Nissl bodies.Compared with sham operation group,the neurons in hippocampus region of the rats in model group showed pyknosis,vacuolization,and sparse Nissl bodies.Compared with model group,the BMSCs group showed reduced neuronal pyknosis,relatively intact morphology,and increased Nissl bodies.Compared with BMSCs group,the combination group showed neuronal pyknosis,loss of morphological integrity,and fragmented Nissl bodies.The transmission electron microscope results showed that mitochondria in sham operation group exhibited oval shape with intact double-membrane structure and cristae.Compared with sham operation group,the mitochondria in model group showed swelling,disrupted membranes,broken cristae,and numerous autophagosomes.Compared with model group,the BMSCs group showed improved mitochondrial structure and reduced autophagosomes.Compared with BMSCs group,the combination group showed swollen mitochondria,disrupted membranes,broken cristae,and visible autophagosomes.The fluorescence probe results showed that compared with sham operation group,the ROS levels in the hippocampus neurons in brain tissue of the rats in model group were significantly increased(P<0.01);compared with model group,the ROS levels in hippocampus neurons in brain tissue of the rats in BMSCs group were significantly decreased(P<0.01);compared with BMSCs group,the ROS levels in hippocampus neurons in brain tissue of the rats in combination group were significantly increased(P<0.01).The Western blotting results showed that compared with sham operation group,the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in model group were significantly decreased(P<0.01);compared with model group,the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in BMSCs group were significantly increased(P<0.01);compared with BMSCs group,the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in combination group were significantly decreased(P<0.01);compared with sham operation group,the expression levels of Parkin,PINK1,and Beclin-1 proteins,and LC3-Ⅱ/LC3-Ⅰ ratio of the rats in model group were significantly increased(P<0.01),while the expression level of P62 protein was significantly decreased(P<0.01);compared with model group,the expression levels of Parkin,PINK1,and Beclin-1 proteins,as well as the LC3-Ⅱ/LC3-Ⅰ ratio,of the rats in BMSCs group were significantly decreased(P<0.01),while the expression level of P62 protein was significantly increased(P<0.01);compared with BMSCs group,the expression levels of Parkin,PINK1,and Beclin-1 proteins,as well as the LC3-Ⅱ/LC3-Ⅰ ratio,of the rats in combination group were significantly increased(P<0.01),while the expression level of P62 protein was significantly decreased(P<0.01).Conclusion:BMSCs can alleviate the hippocampal neuronal pathological changes and improve cognitive function in the VaD rats,and its mechanism may be related to the regulation of ROS/Nrf2 signaling pathway to inhibit mitophagy.

Objective To observe the effects of Ditan Yizhi Decoction on learning and memory ability,structure of hippocampal tissue,neuronal morphology of hippocampus,and the expression of endoplasmic reticulum autophagy-related protein FAM134B in hippocampal tissue;To explore the mechanism of its therapeutic effect on vascular dementia.Methods Totally 32 SD rats were randomly divided into sham-operation group,model group,donepezil group and Ditan Yizhi Decoction group,with 8 rats in each group.The model group,donepezil group and Ditan Yizhi Decoction group were prepared with a modified permanent ligation method of bilateral common carotid arteries to create a rat model of vascular dementia,the common carotid artery was separated in the sham-operation group,but not ligated.After modeling,the donepezil group was given donepezil hydrochloride,Ditan Yizhi Decoction group was given Ditan Yizhi Decoction,and the sham-operation group and model group were given equal volume of distilled water for gavage for 4 consecutive weeks.Morris water maze experiment was used to evaluate the learning and memory ability,HE staining and Nissl staining were used to observe the morphological changes of hippocampus,ultrastructure of hippocampal neurons was observed using transmission electron microscopy,Western blot was used to detect the protein expression of FAM134B and p-FAM134B in hippocampal tissue.Results Compared with the sham-operation group,the escape latency period was prolonged of the rats in model group,and the number of crossing the original platform and the duration of stay in the target quadrant was reduced(P<0.01),the gap between neurons in CA1 region of the hippocampus increased,the cell morphology was irregular,the boundaries were blurred,the neurons shrinked,the Nissl bodies dissolved and broke,the number decreased,the endoplasmic reticulum arrangement was scattered,mitochondria swelled and deformed,and the expressions of FAM134B and p-FAM134B protein in hippocampal tissue increased(P<0.01).Compared with the model group,the escape latency period of rats in donepezil group and Ditan Yizhi Decoction group were significantly shortened,and the number of crossing the original platform and the duration of stay in the target quadrant were increased(P<0.01),the morphology and quantity of neurons in CA1 region of the hippocampus were more regular,with a decrease in neuronal pyknosis,an increase in the number of Nissl bodies,and a reduction in dissolution and fragmentation,the swelling and deformation of the endoplasmic reticulum were restored,and the expression of FAM134B and p-FAM134B protein in hippocampal tissue increased(P<0.01).Moreover,the effects of Ditan Yizhi Decoction group were better than those of the donepezil group(P<0.01).Conclusion Ditan Yizhi Decoction can improve the learning and memory ability and the morphology of neurons in vascular dementia rats.The mechanism may related to increasing the expression and phosphorylation of FAM134B protein,thereby promoting endoplasmic reticulum autophagy.

Objective:To explore the metabolic outcomes of type 2 diabetes patients with different durations after 1 year treatment under the standardized metabolic disease management model.Methods:(1)From September 2017 to September 2018, 345 type 2 diabetes patients in the Standardized Metabolic Management Center(MMC) of Shanghai General Hospital were recruited and included in this research. They were divided into newly-diagnosed type 2 diabetes(duration≤1 year) and long-term groups(duration>1 year). The general characteristics, blood pressures, glycemic levels, lipids levels, control rates and comprehensive compliance rates(blood glucose, pressure and lipids all reached targets) were compared at baseline between 2 groups.(2)All patients underwent one year standardized management, and metabolic indicators mentioned above and control rates at the time were compared as well.Results:(1) At baseline, compared with long-term group, patients in newly-diagnosed type 2 diabetes group were younger ( P<0.01), and 2 h blood glucose level after glucose loading were higher [(15.20±5.26 vs 13.68±4.94) mmol/L, P<0.01]. (2) After one year standardized management, body weight, blood pressure, glucose and lipids metabolism in all patients were significantly improved. Compared with patients in long-term group, newly-diagnosed type 2 diabetes patients achieved better glycemic level [fasting blood glucose(6.27±1.56 vs 7.63±2.08) mmol/L, P<0.01; glycated hemoglobin(6.33±0.96 vs 7.23±1.37) %, P<0.01] , and had higher HOMA-β [(74.01±56.45 vs 40.17±37.07) %, P<0.01]. The glycemic control, blood pressure and blood lipids control rates in both groups increased significantly in one year. Comprehensive compliance rate of the whole patients increased from 5.80% to 24.06%. The metabolism indexes of the newly-diagnosed type 2 diabetes group were better than those of the long-term group[comprehensive compliance rate: (24.73% vs 17.18%, P=0.087, glycemic control rate(84.62% vs 53.37%, P<0.01)]. Conclusion:Standardized metabolic disease management promoted the overall improvement in blood glucose, blood pressure, and lipids levels in type 2 diabetes patients, especially in terms of blood glucose and those of the newly-diagnosed type 2 diabetes. In the future, we should focus on the early diagnosis and treatment of type 2 diabetes, actively promote the MMC model and stress the integrated management of blood glucose, blood pressure, and blood lipid levels. We should pay more attention to the long-term patients, to improve their awareness and treatment compliance.

Objective: To explore the glycemic control of newly-diagnosed type 2 diabetes with different levels of baseline body mass index (BMI) after 6 months treatment under the standardized metabolic disease management model. Methods: (1) 163 patients of newly-diagnosed type 2 diabetes were divided into normal weight (BMI 18.5-23.9 kg/m²), overweight (BMI 24.0-27.9 kg/m²), and obese (BMI≥28 kg/m²) groups according to baseline BMI, the blood glucose and lipids levels were compared among 3 groups. (2) The blood glucose levels were compared among 3 groups after 6 months of standardized management. (3) The overweight and obese patients were divided into group weight loss≥5% and group weight loss<5% or weight gain in 6 months. The blood glucose levels were compared. Results: (1) At baseline, overweight and obese groups had higher homeostasis model assessment for insulin resistance and lower high density lipoprotein-cholesterol compared with normal weight group. (2) After 6 months of treatment, HbA_1C and HbA_1C reduction showed no difference among 3 groups (normal, overweight and obese) after adjusted by baseline HbA_1C. The rate of HbA_1C<7% among 3 groups were 77.78%, 83.95%, and 80.43% (P>0.05). (3) After 6 months of treatment, 32.28% overweight and obese patients lost weight by ≥ 5%, while HbA_1Cand HbA_1Creduction showed no difference between 2 groups (weight loss≥5% and weight gain or weight loss<5%) after adjusted by baseline HbA_1C. Both groups achieved good glycemic control [(6.27±1.38 vs 6.43±0.66)%], but have no significantly(P>0.05). Group weight loss≥5% had better glucose control (92.68% vs 77.91%, P<0.05). Conclusions As BMI increased, insulin resistance and lipid disorders were more serious in newly-diagnosed type 2 diabetes. After 6 months of standardized metabolic management, newly-diagnosed type 2 diabetes with different baseline BMI and weight changes both achieved good glycemic control. In addition, patients losing weight equal to or more than 5% achieved higher attainment of HbA_1C targets.

Objective The aim of this study is to investigate the cerebral cortical thickness changes in type 2 diabetes mellitus (T2DM) using a whole brain cortical thickness mapping system based on brain magnetic resonance imaging (MRI).Methods High resolution three-dimensional T1-weighted fast spoiled gradient recalled echo MR images were obtained from 16 patients with T2DM, as well as from 16 normal controls. The whole brain cortical thickness maps were generated, and the cortical thickness of each brain region was calculated according to gyral based regions of interest (ROI) using an automated labeling system by the Freesurfer software. We compared mean cortical thickness at each brain region by the analysis of covariance with age and sex as covariates. The regional difference of the cortical thickness over the whole brain was compared by the analysis of surface-based cortical thickness.Results Mean cortical thicknesses analysis showed bilateral cerebrum in the patients with T2DM (left: 2.52±0.07 mm; right: 2.51±0.08 mm) were significant thinner than those in the normal controls (left: 2.56±0.09 mm; right: 2.56±0.09 mm) (both P<0.05). Regional cortical thinning in T2DM was demonstrated in the paracentral lobule, postcentral gyrus, lateral occipital gyrus, lingual gyrus, precuneus, superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus and posterior cingulate gyrus, compared to the normal controls. The cortical thickness of left middle cingulate and right inferior temporal gyrus were negatively correlated with the disease course.Conclusion A widespread cortical thinning was revealed in patients with T2DM by the analysis of brain cortical thickness on MR. Our finding supports the idea that T2DM could lead to subtle diabetic brain structural changes.
Aged ; Cerebral Cortex ; pathology ; Diabetes Mellitus, Type 2 ; diagnostic imaging ; pathology ; Female ; Humans ; Magnetic Resonance Imaging ; methods ; Male ; Middle Aged ; Pilot Projects