The Reduced Gray Matter Volume and Functional Connectivity of the Cerebellum in Type 2 Diabetes Mellitus with High Insulin Resistance.

INTRODUCTION: Insulin resistance is widely thought to be a critical feature in type 2 diabetes mellitus (T2DM), and there is significant evidence indicating a higher abundance of insulin receptors in the human cerebellum than cerebrum. However, the specific structural or functional changes in the cerebellum related to T2DM remain unclear, and the association between cerebellar alterations, insulin resistance, cognition, and emotion is yet to be determined. METHODS: We investigated neuropsychological performance, and structural and functional changes in specific cerebellar subregions in 43 T2DM patients with high insulin resistance (T2DM-highIR), 72 T2DM patients with low insulin resistance (T2DM-lowIR), and 50 controls. Furthermore, the correlation and stepwise multiple linear regression analysis were performed. RESULTS: Compared to the controls, T2DM exhibited lower cognitive scores and higher depressive/anxious scores. Furthermore, T2DM-highIR patients showed reduced gray matter volume (GMV) in the right cerebellar lobules VIIb, Crus I/II, and T2DM showed reduced GMV in left lobules I-IV compared to controls. Additionally, functional connectivity decrease was observed between the right lobules I-V and orbital part of the superior frontal gyrus in T2DM-highIR compared to both T2DM-lowIR and controls. Notably, there were negative correlations between the GMV of the lobules VIIb, Crus I/II, and updated homeostatic model assessment of insulin resistance, and positive correlation with executive/visuospatial performance in T2DM patients. CONCLUSIONS: These results suggest that the cerebellar lobules VIIb, Crus I/II, represent vulnerable brain regions in the context of insulin resistance. Overall, this study offers new insights into the neuropathophysiological mechanisms of brain impairment in patients with T2DM.

Synthesis, Renal Clearance, and Photothermal Therapy Based on the Self-Assembly of a Nanomedicine Consisting of Quaterrylene Bisimide and Glycocluster Conjugates.

Renal-clearable nanomedicines are considered the next generation of nanomedicines, and show potential application for future clinical translations. However, it is important to determine whether self-assembly can form large aggregates that accrue in tumors and then tailor the size of these assemblies to be excreted renally. In this paper, a renal-clearable nanomedicine based on quanterrylene bisimide-mannose conjugates (QDI-Man) was developed. QDI-Man showed a high renal clearance efficiency of 80.31 ± 2.85% in mice. We confirmed that the self-assembly of QDI-Man exhibited a dynamic adjustment process through the renal filtration thresholds, that is, "aggregation → self-regulating the aggregate size through the renal filtration thresholds → reaggregating into aggregates". Benefiting from the modification of mannose-based glycoclusters, QDI-Man showed selective photothermal therapy because of the mannose receptors overexpressed in breast cancer cells, and showed good photothermal therapy in mice. This paper developed a dynamic adjustment theory for effective renal clearance based on organic self-assembly.

Positional Isomeric Effects on the Optical Properties, Multivalent Glycosidase Inhibition Effect, and Hypoglycemic Effect of Perylene Bisimide-deoxynojirimycin Conjugates.

Although multivalent glycosidase inhibitors have shown enhanced glycosidase inhibition activities, further applications and research directions need to be developed in the future. In this paper, two positional isomeric perylene bisimide derivatives (PBI-4DNJ-1 and PBI-4DNJ-2) with 1-deoxynojirimycin conjugated were synthesized. Furthermore, PBI-4DNJ-1 and PBI-4DNJ-2 showed positional isomeric effects on the optical properties, self-assembly behaviors, glycosidase inhibition activities, and hypoglycemic effects. Importantly, PBI-4DNJ-1 exhibited potent hypoglycemic effects in mice with 41.33 ± 2.84 and 37.45 ± 3.94% decreases in blood glucose at 15 and 30 min, respectively. The molecular docking results showed that the active fragment of PBI-4DNJ-1 has the highest binding energy (9.649 kcal/mol) and the highest total hydrogen bond energy (62.83 kJ/mol), which were related to the positional isomeric effect on the hypoglycemic effect in mice. This work introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.

Evaluation of the efficacy of steroid therapy on acute liver failure.

The effects of corticosteroids in the treatment of patients with acute or subacute liver failure (ALF or SALF) are controversial. The aims of the present study were to evaluate the efficacy of corticosteroids in improving spontaneous survival (SS) rate in patients with ALF and SALF, and to determine the groups with the highest rates of response to, and the most effective timing of, corticosteroid administration. A retrospective analysis was performed of all patients with ALF and SALF who were hospitalized in the Department of Infectious Diseases, Southwest Hospital, Chongqing, China from 2000-2012. The most common result of this was SS. A total of 238 patients were studied, including 73 patients with ALF (n=34 steroids, n=39 no steroids) and 165 patients with SALF (n=21 steroids, n=144 no steroids). Corticosteroids improved rates of SS in patients with liver failure (steroids vs. no steroids, 38.2 vs. 20.2%; P=0.011), including patients with ALF (steroids vs. no steroids, 29.4 vs. 5.1%; P=0.013) and with SALF (steroids vs. no steroids, 52.4 vs. 24.3%; P=0.013), patients with viruses (steroids vs. no steroids, 32.4 vs. 14.1%; P=0.042) and patients without viruses (steroids vs. no steroids, 50.0 vs. 24.1%; P=0.043). SS rates were extremely low for patients with coma grade 4 or Model for End-stage Liver Disease (MELD) scores ≥35 (2.2 vs. 11.8%; P=0.180). A significantly improved rate of SS associated with steroid use was observed among patients who had alanine aminotransferase (ALT) levels ≥30 × the upper limit of normal and coma grade <4 and MELD scores <35 (65.0 vs. 17.4%; P=0.002). SS associated with steroid use was significantly higher in patients with an illness duration ≤2 weeks compared with patients with an illness duration >2 weeks (51.4 vs. 15.0%; P=0.010). Corticosteroids improved the prognosis of patients with ALF and SALF. The highest rates of response were observed in patients with a lower MELD score and coma grade but who had extremely high ALT levels. The most effective treatment time was within 2 weeks of the onset of symptoms.

Changing etiologies and outcome of liver failure in Southwest China.

BACKGROUND: The prognosis of liver failure depends greatly on the underlying cause, and there were few data about the prognosis, etiologies or trigger factors of liver failure in China based on long-term and large samples cohorts. METHODS: We screened out 3171 liver failure cases from 25467 patients hospitalized in our department between 2000 and 2012 according to Chinese criteria, and determined their etiologies and prognosis. RESULTS: 97.3 % cases were associated with at least one of 25 identified factors. The 3 leading etiologies were HBV (91.6 %), alcohol (18.1 %) and antiviral therapy (AVT) related hepatitis B flares (6.7 %). Acute-on-chronic liver failure (ACLF) accounted for 92.1 % of all cases. 96.5 % ACLF cases were associated with HBV, in which the percentage of AVT related flares increased from 0 % in 2000 up to 11.5 % in 2012, and hepatitis virus superinfection declined from peak 19.3 % in 2002 down to 2.5 % in 2012. Three-month spontaneous survival (SS) rate of 3171 cases was 31.4 %, but improved from 17.4 % in 2000 up to 40.4 % in 2012. SS was significantly different among various etiological groups (P = 0.000). In HBV related liver failure aged 25 to 54 years, males accounted for 87.6 %, and had a progressively decreased SS with increasing age. From 25 to 54 years, SS was lower in male than in female HBV related liver failure, and having significant difference in cases of ages 40 to 44 years (27.6 % versus 50.9 %, P = 0.001). CONCLUSION: Etiologies of liver failure were numerous and varied in southwest China. HBV was the most leading cause of liver failure, especially in ACLF. AVT related flares had become the third leading cause of ACLF. The prognosis of liver failure remained poor, but had markedly improved in recently 3 years. Middle-aged male HBsAg carriers had an extremely higher risk for liver failure and worse prognosis compared to female. 1. Etiologies of liver failure were numerous and varied in southwest China. HBV infection is the main cause of liver failure in southwest China, especially the major cause of ACLF. Antiviral related liver failure, especially the NUCs withdrawal induced ACLF were extremely increased, which has replaced the superinfection as the third important cause of HBV-ACLF. 2. The prognosis of liver failure is still poor, but the spontaneous survival rate showed a trend of steady rise in recent years. The prognosis of patients with liver failure caused by different causes also exists certain difference, the more damage factors bulls the worse prognosis. 3. The prognosis of the HBV and HCV reactivation induced by the steroids was poor.Interferon treatment of CHB in ACLF although rare, but should be taken into consideration seriously. 4. Patients with liver failure caused by different etiologies showed larger differences of gender and age distribution. Gender and age are the important factors with the occurrence and prognosis of HBV-ACLF.

[Distribution of pathogenic microorganisms and its relationship with clinical features in children with community-acquired pneumonia].

OBJECTIVE: To study the distribution of pathogenic microorganisms in different genders, age groups and seasons in children with community-acquired pneumonia (CAP) and the relationship between the distribution of pathogenic microorganisms and clinical features. METHODS: A total of 1,155 children with CAP were enrolled, among whom there were 670 boys and 485 girls, with a mean age of 3.1±2.8 years (range: one month to 14 years). Indirect immunofluorescence assay, particle agglutination test, enzyme-linked immunosorbent assay, colloidal gold method. and bacterial culture were applied to determine common respiratory pathogenic microorganisms in sputum, throat swabs, blood samples, bronchoalveolar lavage fluid, and urine. RESULTS: A total of 758 specimens (65.63%) were tested positive by pathogen detection. The top three dominant pathogens were Mycoplasma pneumoniae (MP, 43.64%), bacteria (15.12%), and respiratory syncytial virus (RSV, 9.26%), and the rate of mixed infection was 16.02%. The rates of MP infection between boys and girls with CAP were different (40.8% vs 47.6%; P<0.05). The MP detection rate was the highest in the age group of 6-14 years (77.4%) and the lowest in children younger than 1 year (11.2%), while the detection rates of bacteria and RSV were the highest in children younger than 1 year (21.2% and 17.2%, respectively). The MP detection rate was significantly higher in summer and autumn than in winter and spring, while the detection rates of bacteria and RSV in summer and autumn were significantly lower than those in winter and spring. Among children who were MP positive, fever, chills, cough, crackles were more likely to appear; children with RSV infection were more likely to have wheezes; children with bacterial infection were less likely to have cough. Serum levels of C-reactive protein and procalcitonin were associated with bacterial infection (OR=1.747 and 1.418, respectively; both P<0.05). CONCLUSIONS: MP plays a more and more important role in the pathogenic microorganisms of CAP in children. Prevalence and outbreaks of MP infection among children should be alerted in summer and autumn. There are differences in the detection rate of various pathogenic microorganisms in CAP children with various age groups. The clinical features of children with CAP caused by different pathogenic microorganisms are different.

Epigallocatechin-3-gallate attenuates lipopolysaccharide-induced inflammation in human retinal endothelial cells.

AIM: To investigate the mechanism underlying the anti-inflammatory effects of epigallocatechin-3-gallate (EGCG) in lipopolysaccharide (LPS)-stimulated human retinal endothelial cells (HRECs). METHODS: HRECs pre-treated with EGCG (0-100 µmol/L) were stimulated with LPS (250 ng/mL). Levels of tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1) and nitric oxide (NO) in the supernatants were determined by enzyme-linked immunosorbent assay (ELISA) and Griess assay. The protein expression of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinases (p38) were determined by Western blot analysis. RESULTS: EGCG pre-treatment significantly inhibited the secretion of TNF-α, VEGF, MCP-1 and NO in LPS-stimulated HRECs. Moreover, EGCG effectively attenuated LPS-induced activation and phosphorylation of ERK1/2 and p38 in HRECs in a dose-dependent manner. CONCLUSION: EGCG exhibited inhibitory effects on LPS-induced pro-inflammatory cytokines production by modulating ERK1/2 and p38 pathways in HRECs, suggesting EGCG as a potential candidate for anti-inflammatory intervention.

[Epigallocatechin gallate attenuates the expression of regulated upon activation normal T cell expressed and secreted induced by lipopolysaccharide in human retinal endothelial cells].

The present study was undertaken to determine the effect of epigallocatechin gallate (EGCG) on lipopolysaccharide (LPS)-induced production of inflammatory chemokine regulated upon activation normal T cell expressed and secreted (RANTES) in human retinal endothelial cells (HRECs) and to explore the underlying regulatory mechanism. HRECs were stimulated with LPS in the presence or absence of EGCG at various concentrations (100, 50, 25, 12.5, 6.25 µmol/L). The optimum concentration of drug was determined by a real-time cell-electronic sensing (RT-CES) system, and MTS chromatometry was used to detect the toxicity of LPS and EGCG on HRECs. RANTES production in the culture supernatant was measured by ELISA. The expression levels of Akt and phosphorylated Akt were examined by Western blot assay. The result showed that LPS markedly stimulated RANTES secretion from HRECs. EGCG treatment significantly suppressed LPS-induced RANTES secretion in a dose-dependent manner. Furthermore, EGCG exhibited a dose-dependent inhibitory effect on LPS-induced phosphorylation of Akt. Taken together, our data suggest that EGCG suppresses LPS-induced RANTES secretion, possibly via inhibiting Akt phosphorylation in HRECs.

[Program optimization in the stage treatment of periarthritis of shoulder with acupuncture, moxibustion and positive functional exercise].

OBJECTIVE: To optimize the therapeutic programs for periarthritis of shoulder treated with acupuncture, moxibustion and kinetohterapy with orthogonal design method adopted. METHODS: The orthogonal design table of L8 (2(7)) hierarchical principle was used to randomly divide 192 patients of periarthritis of shoulder into 8 groups, 24 cases in each one. Separately, 4 factors and each different 2 levels were adopted in treatment, named acupuncture timing (factor A: A, acute stage, A2 adhesion stage), acupoint combination (factor B: B, local acupoints, B2 local acupoints and distal acupoints along meridians), filiform needling and warm needling therapy (factor C: C1 acupuncture with filiform needle, CZ acupuncture with filiform needle and warm needling therapy) and positive functional exercise (factor D: D1 without positive functional exercise, D2 with positive functional exercise). The treatment was given once a day, 10 treatments made one session and 2 sessions were required totally. The time points of observation were the point after 1 session of treatment and after 2 sessions of treatment. The short-form McGill pain questionnaire (MPQ) and shoulder joint motor disturbance score were adopted for evaluation. RESULTS: In the orthogonal design analysis, taking the hierarchical factors into consideration, the age was considered as the main factor in the evaluation of shoulder pain and shoulder motor disturbance (P<0.01), and the shoulder function grade apparently impacted pain evaluation and the efficacy on shoulder motor disturbance (P<0.01). The best combination of 4 factors and 2 levels were A1B1CzD2 and A2BC2D2. SAS statistical analysis showed that at acute stage and adhesion stage, CZ Dz , meaning acupuncture with fifiform needling and warm needling therapy combined with positive functional exercise, is the main factor of the improvements of shoulder motor function (P<0.05). CONCLUSION: For periarthritis of shoulder at acute stage, the combined therapy of acupuncture at local acupoints, warm needling and positive functional exercise is adopted. At chronic stage, the combined therapy of acupuncture at local acupoints and distal acupoints, acupuncture with filiform needle and warm needling and positive functional exercise is the best program. Additionally, in clinical treatment, the patients' age, sex, shoulder joint function and duration of treatment should be considered comprehensively for the impacts on the efficacy.

Serum lipids and other risk factors for diabetic retinopathy in Chinese type 2 diabetic patients.

OBJECTIVE: To investigate the association of serum lipids and other risk factors with diabetic retinopathy (DR) in Chinese type 2 diabetic patients. METHODS: Five hundred and twenty-three type 2 diabetic patients underwent ophthalmic examination by experienced retinal specialists to assess their DR. Serum lipids, including triglycerides, total cholesterol, high density lipoprotein cholesterol (HDLC), and low density lipoprotein cholesterol (LDLC), were measured using Roche automated clinical chemistry analyzers. The concentration of very low density lipoprotein cholesterol (VLDLC) was calculated based on total cholesterol, HDLC and LDLC. Hyperlipidemia was defined as a total cholesterol concentration of 6.2 mmol/L or higher or the use of lipid-lowering medications. The association of risk factors with any DR or proliferative diabetic retinopathy (PDR) was assessed using the odds ratio (OR) and its 95% confidence interval (CI), calculated from logistic regression models. RESULTS: In multivariate logistic regression models, hyperlipidemia (OR=2.39, 95% CI: 1.02-5.66), higher VLDLC (OR=1.59, 95% CI: 1.14-2.23), and higher triglyceride (OR=1.18, 95% CI: 1.03-1.37) were associated with increased risk of DR. A longer diabetic duration was associated with increased risk of DR (P<0.0001) and PDR (P=0.002) in a dose-response manner. Higher systolic blood pressure (P=0.02) and higher serum creatinine (P=0.01) were independently associated with increased risk of DR, and female gender was associated with increased risk of PDR (P=0.03). CONCLUSIONS: Among Chinese type 2 diabetic patients, hyperlipidemia, higher VLDLC, and higher triglyceride were independently associated with increased risk of DR, suggesting control of serum lipids may decrease the risk of DR.

Efficacy of pegylated interferon α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy.

BACKGROUND: Improving the HBe seroconversion rate of patients without HBeAg loss after long-term lamivudine therapy has become an urgent clinical problem that we have to face. Unfortunately, there is no consensus on the mananement of these patients. The aim of this study was to evaluate the efficacy of pegylated interferon (PEG-IFN) α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy. METHODS: Fifty patients with chronic hepatitis B without the loss of HBeAg after ≥96 weeks of lamivudine treatment were enrolled to withdraw from treatment to induce a biochemical breakthrough. Patients who achieved a biochemical breakthrough within 24 weeks received 48-weeks of PEG-IFN α2a therapy, and were then assessed during a subsequent 24-week follow-up period. RESULTS: Forty-three (86.0%) patients achieved a biochemical breakthrough within 24 weeks of lamivudine withdrawal. The rates of combined response (both undetectable HBV DNA and HBeAg loss) and HBsAg loss were alone 51.2% and 20.9%, respectively after 48 weeks of PEG-IFN α2a therapy, and 44.2% and 18.6%, respectively, at 24 weeks after treatment cessation. The end-of-treatment combined response rate was 65.4% among patients with a baseline HBsAg <20,000 IU/mL, which was significantly higher than 29.4% of patients with HBsAg ≥20,000 IU/mL (P=0.031). For patients with HBsAg levels <1,500 IU/mL at 12 and 24 weeks therapy, the end-of-treatment combined response rate was 68.2% and 69.0%, which were both significantly higher than patients with HBsAg ≥1,500 IU/mL (33.3% and 14.3%; P=0.048 and 0.001). The end-of-treatment combined response rate was significantly higher among patients with HBV DNA<105 copies/mL (76.2%) compared to patients with HBV DNA ≥105 copies/mL (27.3%) after 24 weeks of therapy (P=0.004). CONCLUSION: Retreatment with PEG-IFN α2a was effective and safe for patients without HBeAg loss after the withdrawal of long-term lamivudine therapy. HBsAg levels at the baseline, 12 and 24 weeks of therapy, and HBV DNA levels at 24 weeks of therapy, can predict the effect of PEG-IFN α2a after 48 weeks of therapy.

Severe acute exacerbation of chronic hepatitis B during pegylated interferon treatment and early intervention with corticosteroid.

Severe acute exacerbation or liver failure induced by standard interferon-α(IFN-α) therapy had been reported to occur in few patients with chronic hepatitis B. However, no report showed that pegylated interferon-α therapy was able to induce severe acute exacerbation of chronic hepatitis B. Here, we describe three patients with severe acute exacerbation of chronic hepatitis B during pegylated interferon-α2a (Pegasys) treatment. One patient progressed into acute-on-chronic liver failure (ACLF) at the second week of Pegasys treatment. Two patients progressed into acute-on-chronic pre-liver failure (pre-ACLF) at the second and eighth week of Pegasys treatment, respectively. Three patients recovered after early combined intervention with corticosteroid and lamivudine. Our data indicated that there was a risk of severe acute exacerbation among patients with chronic hepatitis B during receiving Pegasys treatment. Importantly, early combined intervention with corticosteroid and lamivudine should be introduced to prevent the disease progression and improve their prognosis once severe acute exacerbation was diagnosed.

Efficacy of short-term dexamethasone therapy in acute-on-chronic pre-liver failure.

AIM: Acute-on-chronic pre-liver failure (pre-ACLF) is defined as a severe acute episode of chronic hepatitis B characterized by serum bilirubin of 171 µmol/L or more, alanine aminotransferase of five times or more the upper limit of normal and prothrombin activity of more than 40%, having a potential for progression to acute-on-chronic liver failure (ACLF). This study is to evaluate the efficacy of short-term dexamethasone in pre-ACLF. METHODS: One hundred and seventy patients were assigned to dexamethasone therapy and control group at a ratio of 1:2. For the two groups, we compared biochemical indicators, the incidence of ACLF and mortality. The influential factors on the mortality of patients with pre-ACLF were studied by Cox proportional hazards models. RESULTS: The significantly lower incidence of ACLF and higher survival rate were observed in patients on dexamethasone therapy (8.9%, 96.4%, respectively) than in control patients (70.2%, 52.6%, respectively; P < 0.001). Dexamethasone treatment was an independent factor influencing the survival rate (P < 0.001, odds ratio = 0.055, 95% confidence interval = 0.013-0.225). During 4 weeks of treatment, serum bilirubin levels of survival patients were significantly lower in the dexamethasone group than control group. CONCLUSION: Five-day dexamethasone therapy is effective in improving the liver function and survival rate of patients with pre-ACLF.

[The changes of TSP-1 expression in the retina of STZ-induced rat diabetic mellitus model with pioglitazone].

To observe the changes of TSP-1 expression in the retina of STZ-induced rat diabetic mellitus model with pioglitazone and to elucidate the possible mechanism involved and the effects of thiazolidinediones compound pioglitazone on the early stages of diabetic retinopathy. 30 Male SD rats were randomly divided into 3 groups: control group, DM group and pioglitazone treated DM group (DP group). DM group and pioglitazone treated DM group were injected with STZ intraperitoneally. 8 weeks after the onset of diabetes, the expression of TSPI mRNA was quantified in retinal tissue by quantitative reverse transcription-polymerase chain reaction (RT-PCR) respectively. The locations of TSP-1 in three groups were also established by immunohistochemistry. 8 weeks after the onset of diabetes, every layer of the retina tissue had significant TSP-1 positive staining and when compared with the control group and DM group, the pioglitazone treated DM group had higher TSP-1 positive cell number per unit area; There were significant differences among the DM group, pioglitazone treated DM group and control group in TSP-1 mRNA level, DM group and pioglitazone treated DM group had significantly higher TSP-1 mRNA level than the control group. Our results showed that pioglitazone treatment can alleviate the pathological changes of DR and the expression level of TSP-1 was increased in pioglitazone treated DM rats compared with other DM rats. Our study suggests pioglitazone may have a role on early stage of DR by increased TSP-1 expression.

[The study of thrombospondin-I (TSP1) expression in the early stages of diabetic retinopathy induced by streptozotocin].

Thrombospondin1 (TSP1) is a known antiangiogenic factor, but its possible alteration during the early stages of diabetic retinopathy has not been explored yet. The present study sought to investigate the expression of TSP1 using a model of streptozotocin (STZ) induced diabetes in the rat. Diabetes was induced in male SD rats by an intraperitoneal injection of STZ. Age matched animals served as control. 2 months after the onset of diabetes, the expression of TSP1 mRNA was quantified in retinal tissue by quantitative real time reverse transcription-polymerase chain reaction (RT-PCR) respectively. The locations of TSP1 normal and diabetic retinas were also established by immunohistochemistry. 2 months after the onset of diabetes, retinal TSP1 concentrations were significantly increased in the diabetic rats compared with control rats. Diabetes caused the upregulation of TSP1 expression in the layers of the retina 2 months after the induction of diabetes. The upregulation of TSP1 in retinas of diabetic rats suggests a role in experimental diabetic retinopathy. Further studies should address the possible involvement of the TSP1 in the pathophysiology of diabetic retinopathy.