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Adolescents are susceptible to exhibiting internalizing and externalizing symptoms following natural disasters. However, little is known regarding factors that may influence these symptoms from the perspective of positive psychology. The current study examined whether and how social support and resilience mediated the association between gratitude and adolescents' internalizing and externalizing symptoms.The participants were 765 Chinese adolescents exposed to the Wenchuan earthquake (41.8% male, mean age 17.46 years), who were enrolled in a three-wave longitudinal study with data spanning 1 year. All adolescents completed self-report questionnaires on gratitude at 18 months postearthquake (TThe results showed that social support (TBy highlighting the mechanisms by which gratitude longitudinally attenuates adolescents' internalizing, externalizing, and total symptoms, our findings may provide clinical practitioners with important information regarding intervention design.

Background Extraskeletal myxoid chondrosarcomas (EMCs) are solid tumors that have been genetically and biologically characterized. Only a few studies have discussed the role of the KIT gene or CD117 expression in EMCs, identified by immunohistochemical (IHC) staining. Herein, we present a novel case of cellular EMC exhibiting an EWSR1-NR4A3 fusion, KIT exon 13 mutations and strong diffuse expression of CD117. Case presentation A 69-year-old man presented with a fist-sized tumor on his left shoulder. CT revealed a tumor in the left thoracic and dorsal muscle space. The tumor was completely resected. Histologically, the tumor cells had a nodular structure and infiltrated the peripheral fat and muscle tissues. The tumor cells were uniform in size with round nuclei, well-defined nucleoli and eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for CD117, vimentin, CD56 and NSE and focally expressed desmin; the cells were negative for myogenin, S-100, SYN, INSM1, CD34, STAT6, INI-1, Brachyury, ERG, TLE1, AE1/AE3, WT-1, CD99 and SMA. NGS revealed an EWSR1-NR4A3 fusion and KIT exon 13 mutations. The patient had no further treatment after surgery, and no recurrence or metastasis occurred during the ~ 10 month follow-up period. Conclusions Molecular detection is an indispensable technique for diagnosing cellular EMCs. The KIT mutations noted in this case report may offer fresh insights into EMCs treatment options.

This 10-year cohort study explored whether individual differences in resilience during early stages post-earthquake could have diverse impacts on future PTG and whether the impacts varied by sex. 1357 Chinese adolescent survivors of the Wenchuan earthquake were assessed on their resilience at 6-, 12-, 18-, and 24-months post-earthquake. 799 participants responded to an online survey 10 years later, and 744 of which provided useable data for subsequent analysis. Resilience trajectories were modeled using the latent class growth analysis. Linear regressions were used to test the predictive effects of different resilience trajectories on subsequent PTG. Of 744 samples (M

To observe the effect of electroacupuncture (EA) at "Zusanli" (ST 36) combined with mosapride on gastric emptying rate and gastric motility in the rats with diabetic gastroparesis.Using random number table method, 68 male SD rats were divided into a blank group (12 rats) and a model establishment group (56 rats). In the model establishment group, the models of diabetic gastroparesis were established with intraperitoneal injection of streptozotocin combined with high-fat and high-sugar diet. Six weeks later, the successful rat models in the model establishment group were randomized into a model group, an EA group, a mosapride group and a combined treatment group, 12 rats in each one. In the EA group, EA was exerted at "Zusanli" (ST 36) (disperse-dense wave, 2 Hz/15 Hz in frequency, 2 mA in intensity) for 20 min. In the mosapride group, mosapride was intervened with intragastric administration (2 mg/kg). In the combined treatment group, electroacupuncture at "Zusanli" (ST 36) was combined with intragastric administration of mosapride. The intervention was given once daily in each group. There was 1 day at interval after 6-day intervention, consecutively for 5 weeks. At the end of intervention, the random blood glucose, gastric emptying rate and the data of gastric motility (average intra-gastric pressure, amplitude and frequency of gastric motility) were detected.Compared with the blank group, blood glucose was increased in the model group (Electroacupuncture at "Zusanli" (ST 36) combined with intragastric administration of mosapride could regulate blood glucose and improve the gastric motility in the rats with diabetic gastroparesis. The effect is better than either simple electroacupuncture or mosapride.

This study retrospectively analyzed the clinical outcome of 172 children with newly diagnosed severe aplastic anemia (SAA) between January 2008 and April 2018, who received rabbit antithymocyte globulin (ATG) and cyclosporine (CsA) as first-line treatment. The median age at diagnosis was 5 years (range, 1–14). The overall response rates were 22.7%, 45.3%, and 61% at 40 days, 3 months, and 6 months, respectively, after rabbit ATG. In multivariate analysis, mild disease severity was the only predictor of favorable response at 6 months (P = 0.006). In the present study, median follow-up period was 63 months (range, 1–135). The 5-year overall survival (OS) and failure-free survival (FFS) rates were 90.5% and 70.4%. Multivariate analysis showed that erythroid burst-forming units (BFU-E) > 2/105 bone marrow mononuclear cell (BMMNC) (P = 0.037) and time interval before IST ≤ 30 days (P = 0.017) were independent positive predictors for OS, meanwhile BFU-E > 2/105BMMNC (P = 0.029) was the only favorable prognostic factor for FFS.

Context As a major active iridoid glycoside from Gardenia jasminoides J. Ellis (Rubiaceae), geniposide possesses various pharmacological activities, including anti-platelet aggregation and anti-inflammatory action. Objectives This study explores the effect of geniposide in diabetic wound model by anti-inflammatory action. Materials and methods Diabetic rodent model in Wistar rats was induced by streptozotocin combined with high-fat feed. The selected rats were divided into control group, the diabetic model group and geniposide subgroups (200, 400 and 500 mg/kg), and orally administrated once daily with saline or geniposide. Wound area and histochemical indicators were measured on day 7 after continuous administration, to assess lesion retraction, inflammatory cells and fibroblasts. Results Geniposide notably enhanced lesion retraction by 1.06–1.84 times on day 7 after surgical onset in diabetic rats (p

BACKGROUND Interleukin 10 receptor alpha subunit (IL10RA) dysfunction is the main cause of very early-onset inflammatory bowel disease (VEO-IBD) in East Asians. AIM To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations. METHODS From May 2016 to September 2020, four young patients with clinically diagnosed VEO-IBD were recruited. Before hospitalization, using targeted gene panel sequencing and trio-whole-exome sequencing (WES), three patients were found to harbor a IL10RA mutation (c.301C>T, p.R101W in one patient; c.537G>A, p.T179T in two patients), but WES results of the fourth patient were not conclusive. We performed whole-genome sequencing (WGS) on patients A and B and reanalyzed the data from patients C and D. Peripheral blood mononuclear cells (PBMCs) from patient D were isolated and stimulated with lipopolysaccharide (LPS), interleukin 10 (IL-10), and LPS + IL-10. Serum IL-10 levels in four patients and tumor necrosis factor-α (TNF-α) in the cell supernatant were determined by enzyme-linked immunosorbent assay. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and Ser727 in PBMCs was determined by western blot analysis. RESULTS The four children in our study consisted of two males and two females. The age at disease onset ranged from 18 d to 9 mo. After hospitalization, a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data. Patient D was homozygous for the 333 bp deletion. All four patients had elevated serum IL-10 levels. In vitro, IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-α production induced by LPS. Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS + IL-10 in both healthy subjects and in patient D. CONCLUSION WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD, whereas the WES results were inconclusive.

Variation in normal blood cells during chemotherapy has not been recognised as a risk factor guiding chemotherapy in childhood acute lymphoblastic leukaemia (ALL). This study aims to explore whether variations in normal haematopoiesis determine prognosis as well as to improve risk-stratified treatment in childhood ALL. A retrospective study of 279 cases of ALL treated with the CCCG-ALL-2015 regimen in the Division of Pediatric Blood Diseases Center, Institute of HematologyBlood Diseases Hospital, Chinese Academy of Medical SciencesPeking Union Medical College, from May 2015 to January 2017 was performed to analyse the prognostic impact of blood cell levels on day 19 of induction therapy by Kaplan-Meier method. Patients with childhood ALL with absolute neutrophil count (ANC) ≤ 90 cells/μl, absolute monocyte count (AMC) ≤ 10 cells/μl or absolute lymphocyte count (ALC) ≤ 1000 cells/μl on day 19 of induction therapy had a lower event-free survival (EFS) rate than those with higher values (all P0.05). Multivariate analysis confirmed that ANC ≤ 90 cells/μl and ALC ≤ 1000 cells/μl were independent adverse prognostic factors (HR = 1.981 and 2.162, respectively, both P0.05). Among patients with minimal residual disease (MRD)1% on day 19 of induction therapy, those with ANC ≤ 90 cells/μl had lower EFS than those with ANC90 cells/μl (70.8 ± 6.1% vs 86.4 ± 3.1%, P = 0.001). In the subgroup with the BCR/ABL1 fusion gene, patients with ANC ≤ 90 cells/μl on day 19 of induction therapy also had lower EFS than those with ANC90 cells/μl (34.4 ± 25.2% vs 25.0 ± 21.7%, P = 0.041). ANC and ALC during induction therapy are independent prognostic factors for childhood ALL. ANC contributes to guiding the prognosis of patients with low-level MRD or the BCR/ABL1 fusion gene.

Nucleic acid testing and antibody testing data from 143 recovered COVID-19 patients during the convalescent phase were retrospectively analyzed. A total of 23 (16.1%) recovered patients re-tested positive for SARS-CoV-2 RNA by RT-PCR. Three months after symptom onset, 100% and 99.3% of the patients remained positive for total and IgG antibodies, and the antibody levels remained high. IgM antibodies declined rapidly, with a median time to seroconversion of 67 (95% CI: 59, 75) days after onset. Approximately 25% of patients were seronegative for IgA antibodies at three months after onset. There was no statistically significant difference in antibody kinetics between patients with and without re-positive RT-PCR results during the convalescent phase. Supplementary Information The online version contains supplementary material available at 10.1007/s00705-021-05132-9.

Aims Previous studies regarding associations between depressive symptoms and suicidality (suicidal ideation, plans and attempts) have usually employed a variable-centred approach, without considering the individual variance in time-varying changes of depressive symptoms. Through 10-year follow-up of a large cohort of Chinese adolescents exposed to the 2008 Wenchuan earthquake, this study examined whether individual variance in depressive symptoms during the early phases post-earthquake could generate different suicidality outcomes in young adulthood. Methods A total of 1357 Chinese adolescents exposed to the Wenchuan earthquake were surveyed on depressive symptoms and other variables at 6, 18 and 30 months post-earthquake. In total, 799 participants responded to the 10-year follow-up and completed an online survey covering suicidality and other variables. The analytic sample was 744 participants who had valid data on depressive symptoms and suicidality. Data were analysed using logistic regressions. Results Prevalence estimates of past-year suicidal ideation, suicide plans and suicide attempts measured at 10 years post-earthquake were found to be 10.8%, 7.3% and 3.0%, respectively. Five trajectories of depressive symptoms were classified: resistance (54.4%), chronicity (13.3%), recovery (10.4%), delayed dysfunction (12.0%) and relapsing/remitting (10.0%). After controlling for covariates, whole-sample regressions revealed only the relapsing/remitting depressive trajectory remained significantly predictive of suicidality. Moreover, males not females in the chronic group were more likely to have suicide plans. Conclusions The findings highlight the importance of detecting disaster survivors with different trajectories of mental status and providing with them individualised and effective mental health services, to decrease their risk of suicidality in the future.

Pathogenic mutations in 3-keto-dihydrosphingosine reductase (KDSR) gene are associated with keratinization disorders and impaired platelet function. However, no case with both homozygotic mutation of

Objective To examine the prevalence of sleep disturbances 10 years after Wenchuan earthquake, and to explore whether comorbid post-traumatic stress disorder (PTSD) and depressive symptoms could predict sleep disturbances and whether such effects were modified by gender. Methods Participants were 1357 adolescents in the Wenchuan Earthquake Adolescent Health Cohort Study (WEAHC). 799 of the participants completed the followed-up survey 10 years after the earthquake. At 12-month post-earthquake (T12m), a battery of standardized measures were used to assess individual earthquake exposure, sleep disturbances (insomnia symptoms and poor sleep quality), PTSD, and depressive symptoms. At 10 years post-earthquake (T10y), those survivors reported their sleep disturbances via an online survey. Data were analyzed using binary logistic regression. Results The prevalence of insomnia (14.3%) and of poor sleep quality (19.8%) at T10y decreased when compared with it at T12m. After controlling for covariates, it is revealed that depression-only and comorbidity groups at T12m predicted sleep disturbances at T10y among the whole sample and males. As for females, who have depression-only and comorbidity were more likely to develop insomnia symptoms but not poor sleep quality. Conclusions Sleep disturbances remained highly prevalent among survivors even 10 years after the earthquake. Depression-only and comorbidity groups were related to higher risks of sleep disturbances, especially for males. Assessments and interventions targeting both depressive symptoms and comorbid PTSD to reduce sleep disturbances after a deadly disaster are warranted.

To investigate the application value of dynamic intracavitary three-dimensional contrast-enhanced tomographic transrectal ultrasound imaging (3D-CETRUS TUI) in transperineal prostate biopsy for patients with different levels of PSA.This prospective study included 180 patients with escalated levels of PSA (≥4 μg/L) or abnormal results of digital rectal examination. According to the level of PSA, the patients were divided into groups A (PSA ≤10 μg/L, n = 104) and B (PSA10 μg/L, n = 76), and all underwent intracavitary 3D-CETRUS TUI followed by transperineal prostate biopsy under the guidance of two-dimensional gray-scale ultrasound, which involved a standard 12-core transperineal systematic prostate puncture by intracavitary biplane probe and then a 2-core puncture in the abnormal region displayed by 3D-CETRUS TUI. With the pathological results as the gold standard, comparisons were made between the diagnostic value of 3D-CETRUS TUI-guided biopsy and that of 12-core systematic biopsy.Prostate cancer was diagnosed in 69 (38.33%) of the 180 cases and in the specimens from 631 (25.03%) of the 2 520 punctures. The positive rates of prostate cancer were 37.5% (39/104) and 57.9% (44/76) in groups A and B, respectively. 3D-CETRUS TUI-guided prostate biopsy achieved a higher positive rate than 12-core systematic biopsy in both of the groups, with statistically significant difference in group A (P0.05), but not in B (P0.05).For patients with a PSA level ≤10 μg/L, dynamic intracavitary 3D-CETRUS TUI-guided transperineal prostate biopsy is more efficient than 12-core systematic biopsy in detecting the positive lesion, while for those with a PSA level10 μg/L, it effectively reduces the number of punctures.

Purpose: We assessed the performance of metagenomic next-generation sequencing (mNGS) in the diagnosis of infectious encephalitis and meningitis. Methods: This was a prospective multicenter study. Cerebrospinal fluid samples from patients with viral encephalitis and/or meningitis, tuberculous meningitis, bacterial meningitis, fungal meningitis, and non-central nervous system (CNS) infections were subjected to mNGS. Results: In total, 213 patients with infectious and non-infectious CNS diseases were finally enrolled from November 2016 to May 2019; the mNGS-positive detection rate of definite CNS infections was 57.0%. At a species-specific read number (SSRN) ≥2, mNGS performance in the diagnosis of definite viral encephalitis and/or meningitis was optimal (area under the curve [AUC] = 0.659, 95% confidence interval [CI] = 0.566-0.751); the positivity rate was 42.6%. At a genus-specific read number ≥1, mNGS performance in the diagnosis of tuberculous meningitis (definite or probable) was optimal (AUC=0.619, 95% CI=0.516-0.721); the positivity rate was 27.3%. At SSRNs ≥5 or 10, the diagnostic performance was optimal for definite bacterial meningitis (AUC=0.846, 95% CI = 0.711-0.981); the sensitivity was 73.3%. The sensitivities of mNGS (at SSRN ≥2) in the diagnosis of cryptococcal meningitis and cerebral aspergillosis were 76.92 and 80%, respectively. Conclusion: mNGS of cerebrospinal fluid effectively identifies pathogens causing infectious CNS diseases. mNGS should be used in conjunction with conventional microbiological testing. Trial Registration: Chinese Clinical Trial Registry, ChiCTR1800020442.

Typical halogenated persistent organic pollutants (Hal-POPs), including polybrominated diphenyl ethers (PBDEs), polybrominated biphenyls (PBBs), polychlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (DDT), are a group of ubiquitous organic pollutants with an endocrine disrupting effect. This study evaluated the accumulation and congener profiles of Hal-POPs in the bodies of men who live/work in areas of South China where electronic wastes are collected and managed, especially in their semen samples. The results show that the detection frequency and serum concentrations of Hal-POP congeners within the high-exposure group (HEG) were higher than those of the low-exposure group (LEG). Furthermore, an identical trend was observed for the seminal plasma concentrations of Hal-POPs. The distribution characteristics, such as their mean, median, and discrete values, of PBDE congeners in serum and semen samples from the same subjects were consistent with each other. However, the distribution characteristics of PCB congeners in serum samples were different from those in semen samples. BDE153 was one of the most abundant congeners found in the serum and semen samples; hence, it can be identified as an indicator PBDE congener. Further research is needed to explore the mechanism of Hal-POPs distribution in human semen and serum samples. Keywords: Halogenated persistent organic pollutants (Hal-POPs), Polybrominated diphenyl ethers (PBDEs), Polychlorinated biphenyls (PCBs), Semen, Congener profiles

Vascular dysfunction is a common pathological basis for complications in individuals affected by diabetes. Previous studies have established that endothelial dysfunction is the primary contributor to vascular complications in type 2 diabetes (T2DM). However, the role of vascular smooth muscle cells (VSMCs) in vascular complications associated with T2DM is still not completely understood. The aim of this study is to explore the potential mechanisms associated with Ca

Background This study was aimed to explore the METTL3 and METTL14 expressions in children with ETV6/RUNX1(E/R)‐positive acute lymphoblastic leukemia (ALL) and investigate the relation between the METTL3 and METTL14 expressions with clinical features. Methods Thirty‐seven newly diagnosed E/R‐positive ALL children and six controls were included in this study. Real‐time quantitative polymerase chain reaction (RT‐PCR) was used to detect the mRNA expression level of METTL3 and METTL14. Results Among the 37 cases, 51.35% (n = 19) were boys and 48.65% (n = 18) were girls and the median age was 4.72 (1.72–11.99) years. Among the six controls, 50% (n = 3) were boys and 50% (n = 3) were girls and the median age was 5.24 (1.53–13.17) years. The expression level of METTL3 and METTL14 in E/R‐positive ALL patients were lower than in controls (p

Background: There are sparse and limited studies on small sample size reporting the application of next-generation sequencing (NGS) in the detection of central nervous system (CNS) viral infections. We assessed the diagnostic performance of NGS of cerebrospinal fluid (CSF) for predicting viral infections of the CNS caused by the neurotropic herpes viruses in a pilot population. Materials and Methods: We prospectively collected CSF samples from 24 patients with CNS viral infection from April 2017 to October 2018. Of the 24 patients, 19 patients were infected with herpes simplex virus 1 (HSV-1), 1 patient with HSV-2, and 4 patients with varicella-zoster virus (VZV). All CSF samples were screened for viral DNA using NGS technologies to detect viral CNS infections. Results: Of the 24 patients with confirmed viral CNS infection caused by the neurotropic herpes viruses, 10 (10/24, 41.67%) patients exhibited positive NGS results. With the help of NGS, HSV-1 DNA was detected in the CSF of 6 patients (6/19; 31.58%). HSV-2 DNA was detected in 1 patient (1/1; 100%) and VZV DNA was detected in 3 patients (3/4; 75%). The positive rate of virus detected by NGS decreased with time. The positive rates of NGS of CSF in the first, second, and third weeks were 54.5% (6/11), 44.4% (4/9), and 0% (0/4), respectively. Conclusions: NGS method is a promising pathogen detection tool for identifying viral CNS infections. It should be recommended to sequence viral DNA of CSF in the early stage of CNS viral infections.

Although posttraumatic stress disorder (PTSD) is highly comorbid with psychiatric disorders, little longitudinal research has been conducted to determine the potentially causal links. This study aimed to investigate the prevalence and comorbidity patterns of posttraumatic stress disorder symptoms and psychiatric symptoms among adolescents exposed to the 2008 Wenchuan earthquake in China and to examine the bidirectional prospective associations between PTSD symptoms and other psychiatric symptoms. A sample of 1573 adolescent survivors (45.8% male; mean age at initial survey was 15.0 years, SD = 1.3) completed a battery of standardized measures assessing symptoms of PTSD, depression, panic disorder, generalized anxiety disorder (GAD), separation anxiety disorder (SAD), social phobia, conduct disorder, and attention deficit hyperactivity disorder at 6 and 18 months post-earthquake. Among participants with PTSD symptoms, 91.9 and 94.0% had at least one comorbid psychiatric disorder at 6 and 18 months post-earthquake, respectively; however, among those without PTSD symptoms, 54.3 and 50.4% had at least one psychiatric disorder. PTSD symptoms were more likely to co-occur with subtypes of anxiety or depression symptoms than with behavior problems. Participants who were screened as having PTSD comorbid with depression or SAD at 6 months were less likely to recover from PTSD over time. Longitudinal analyses showed that symptoms of depression, GAD and SAD predicted increases in PTSD symptoms. In turn, PTSD symptoms predicted increases in GAD and panic disorder symptoms. Overall, our results support causal hypotheses of PTSD comorbidity. Specific multi-modal assessments and treatments targeting to both PTSD and its comorbidity disorders are warranted.

To explore the HER22 expression in children with ETV6/RUNX1 (E/R)-positive acute lymphoblastic leukemia(ALL) and to investigate the relationship between the HER2 expression and clinical features.Thirty-seven newly diagnosed E/R-positive ALL children and 6 controls (4 cases of ITP and 2 healthy children) were selected in Institute of hematology and blood disease hospital. The 37 patients were divided into standard risk (SR), intermediate risk(IR), high risk(HR) groups according to risk stratification; and they were divided into relapse and non-relapse groups according to follow-up result. The CD10Among the 37 cases, 51.35% (n=19) were boys and 48.65% (n=18) were girls and their median age was 4.72 (1.72-11.99) years old. Among the 6 controls, 50% (n=3) were boys and 50% (n=3) were girls and the median age was 5.24 (1.53-13.17) years old. The expression level of HER2 in E/R-positive ALL patients were lower than that in controls (P0.05). Although the difference of HER2 expression level between the 2 groups failed to achieve statistical significance, the expression level of HER2 in relapse patients were significantly lower than that in non-relapse patients, and the HER2 expression in HR group patients were lower than that in SR and IR groups. In addition, there was no significant correlation between the expression level of HER2 and the sex, age, initial white blood cell count, blast cell percentage and the level of LDH (P0.05).The expression level of HER2 in E/R

Objective The aim of this study was to investigate the prospective association of circulating adipocyte fatty acid-binding protein (A-FABP) levels with the development of subclinical atherosclerosis in patients with type 2 diabetes in an 8-year prospective study. Methods A total of 170 patients with newly diagnosed type 2 diabetes were recruited in the study and 133 patients completed the follow-up of 8 years. Baseline plasma A-FABP levels were measured with enzyme-linked immunosorbent assays. The role of A-FABP in predicting the development of subclinical atherosclerosis over 8 years was analyzed using multiple logistic regression. Results Of the 133 patients without subclinical atherosclerosis at baseline, a total of 100 had progressed to subclinical atherosclerosis over 8 years. Baseline A-FABP level was significantly higher in patients who had progressed to subclinical atherosclerosis at year 8 compared with ones who had not developed subclinical atherosclerosis after adjustment for sex (15.3 [12.1–23.2] versus 13.3 [10.0–18.9] ng/ml, P = 0.021). High baseline A-FABP level was an independent predictor for the development of subclinical atherosclerosis in patients with type 2 diabetes (odds ratio: 16.24, P = 0.022). Conclusions Circulating A-FABP levels predict the development of subclinical atherosclerosis in type 2 diabetes patients.

Hetrombopag olamine (hetrombopag) is a novel small-molecule, orally bioavailable, non-peptide thrombopoietin (TPO) receptor agonist that is being developed as the treatment for thrombocytopenia. Two randomized, placebo-controlled phase I studies were conducted in 72 healthy subjects to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of hetrombopag. Hetrombopag was orally administered with a single dose in 5 dose cohorts (5 mg, 10 mg, 20 mg, 30 mg or 40 mg) in the first study, and given once daily for 10 days in 3 dose cohorts (2.5 mg, 5.0 mg or 7.5 mg) in the second study, respectively. Hetrombopag was well tolerated, and the majority of adverse events associated with medicine were platelet elevations significantly above the normal range in healthy subjects. The single dose escalation study revealed a Tmax of approximate 8 hr, and a t1/2 of 11.9 hr to 40.1 hr in a dose-prolonged manner. A dose-proportional increase in maximum concentration (Cmax) of hetrombopag was observed, with area under the curve (AUC) increasing in a greater-than-dose-proportional manner. The plasma concentration of hetrombopag reached the steady state after 7 days. The steady-state AUC0-24hr and Cmax were dose-proportionally elevated from the 5.0 mg to 7.5 mg dose level. The potent pharmacological effect of the hetrombopag-induced platelet elevation was observed in a time- and dose-dependent manner. Furthermore, the thrombopoietic response was significantly (p

Background Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is an obviously heterogeneous and highly invasive malignancy without definite phenotype. MicroRNAs (miRNAs) are powerful gene regulators and have been reported as biomarkers in many malignancies. Objective To discover potential signaling miRNAs in PTCL-NOS distinguished from reactive lymphoid hyperplasia (RLH) and to explore the molecular characteristics based on the discovery. Methods We measured the expression profile of miRNAs in PTCL-NOS and RLH from our patients using a panel PCR array. We used GO-Analysis to evaluate the function of the targets regulated by the detected miRNAs. Then using pathway enrichment analysis, we defined potential pathways connected with the selected miRNAs. Results We found 20 miRNAs which were remarkably up/down-regulated in PTCL-NOS. GO-Analysis and pathway analysis indicated 61 GOs and 34 signaling pathways that were significantly increased or decreased regarding tumorigenesis, tumor progression, invasion, metastasis, and drug resistance. Conclusions Briefly, our results suggest that 20 miRNAs have the potential to be used as biomarker for identification of patients with PTCL-NOS.

Background Previous research has examined the association between parents’ and children’s posttraumatic stress disorder symptoms (PTSS) after a variety of traumatic events. However, longitudinal parent-child dyadic studies are scarce. Methods Independent self-reports were collected from parent-adolescent dyads (n = 688) after the 2008 Wenchuan earthquake. Adolescents (Mean = 15.22 years; 61.63% female) and one of their parents (Mean = 41.04 years; 58.14% female) each reported on their PTSS at 12 (T12m) and 18 months (T18m) following the earthquake. Longitudinal actor-partner interdependence models (APIMs) were used to examine PTSS within dyads. Results The prevalence rates of probable PTSD at T12m and T18m were 18.90% and 11.92% in adolescents; as well as 22.09% and 15.12% in parents, showing a significant decline over time. After adjusted for earthquake exposure, both maternal and paternal PTSS at T12m prospectively predicted adolescent girls’ and boys’ PTSS at T18m (mother to daughter: β = 0.13; mother to son: β = 0.17; father to daughter: β = 0.17; father to son: β = 0.33), while adolescent girls’ and boys’ PTSS at T12m only predicted maternal PTSS at T18m (daughter to mother: β = 0.20; son to mother: β = 0.20), but not paternal PTSS at T18m. Limitations Self-reported measures other than clinical reviews were used to collect data. Conclusions This study highlights the mutual impacts of adolescent and parental (especially maternal) PTSS after a disaster. Psychological prevention and intervention for adolescent disaster survivors should adopt a whole family approach.

Depression is a frequent mood disorder that affects around a third of stroke patients and has been associated with poorer outcome. Our aim was to determine whether there is a relationship between serum Brain-derived neurotrophic factor (BDNF) levels and post-stroke depression (PSD).Two hundred and sixteen ischemic stroke patients admitted to the hospital within the first 24h after stroke onset were consecutively recruited and followed up for 3 months. Based on the symptoms, diagnoses of depression were made in accordance with DSM-IV criteria for post-stroke depression at day 90. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of BDNF at admission. Multivariate analyses were performed using logistic regression models.In our study, 59 patients (27.3%) were diagnosed as having major depression at 3 months. Patients with major depression showed lower levels of serum BDNF [8.1 (5.6-9.4) vs. 13.7 (10.4-16.5)ng/ml, P0.0001] at admission. In multivariate analyses, serum BDNF was an independent predictor of PSD at 3 months [odds ratio (OR): 0.79(0.72-0.87), P=0.003]. Serum levels of BDNF≤10.2ng/ml were independently associated with post-stroke (OR, 11.5; 95% CI, 5.6-23.4, P0.0001), after adjustment for possible variables.The present study demonstrates a strong relationship between serum BDNF levels at admission and the development of PSD within 3 months. Further studies are necessary to confirm this association, which may open the way to the proposal of new therapeutic options.

To further elucidate the correlation of resveratrol sensitivities with biotransformation activities of human and rat glioblastoma cells for personalized anti-glioblastoma therapy. Resveratrol sensitivity of human U251 and rat RG2 and C6 glioblastoma cells was evaluated by 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide/MTT, flow cytometry, and TUNEL assays. The metabolic patterns of those cell lines were analyzed by high-performance liquid chromatography/HPLC coupled with tandem mass spectrum/MS/MS, and high-resolution mass spectrometry/HRMS. Immunocytochemical staining and Western blotting were employed to check resveratrol metabolic enzyme expression. Both rat RG2 and C6 and human U251 glioblastoma cells are sensitive to 100 μM resveratrol in terms of growth arrest and increased apoptotic fraction. The main resveratrol metabolite in U251 cells is monosulfate biotransformed by sulfotransferases/SULTs and in RG2 and C6 cells is monoglucuronide generated by UDP-glucuronosyltransferase/UGT. Both metabolites show lesser therapeutic efficacy. Although brain-associated UGTs (UGT1A6, 2B7, and 8) and SULTs (SULT1A1, 1C2, and 4A1) are expressed in rat and human glioma cells, the overall level of UGTs is predominant in the rat and SULTs in human glioblastoma cells. In similar to SULT expression pattern, UGT1A6, 2B7, and 8 are frequently downregulated (84.6 %, 82/97; 90.7 %, 88/97; 80.4 %, 78/97) in human glioblastoma tissues. Our results suggest (1) the decreased resveratrol biotransforming activity in rat and human resveratrol-sensitive glioblastoma cells; (2) the discrepant resveratrol metabolic patterns between human and rat glioblastoma cells; (3) the more powerful anti-glioblastoma efficacy of trans-resveratrol rather than resveratrol monoglucuronide or monosulfate; and (4) the value of RG2 and C6 cells in establishing resveratrol-based rat in vivo therapeutic model.

Crocin is a pharmacologically active component of Crocus sativus L. (saffron) and has been reported to be useful in the treatment of neuronal damage. In the present study, we investigated the neuroprotective effect of crocin on retinal ganglion cells (RGCs) after retinal ischaemia/reperfusion (IR) injury, and our results show that crocin acts through the PI3K/AKT signalling pathway. Retinal IR injury was induced by raising the intraocular pressure of Sprague-Dawley rats to 110 mmHg for 60 min. The neuroprotective effect of crocin was determined by quantifying the surviving RGCs and apoptotic RGCs following IR injury by means of retrograde labelling and TUNEL staining, respectively. The phosphorylated AKT protein level was determined by western blot and immunohistochemical analysis. To determine the extent to which the PI3K/AKT pathway contributes to the neuroprotective effect of crocin, experiments were also performed using the PI3K inhibitor LY294002. Compared with the IR + vehicle group, crocin (50 mg/kg) treatment enhanced RGC survival by approximately 36% and decreased RGC apoptosis by 44% after retinal IR injury. Western blot and immunohistochemical analysis demonstrated that the PI3K/AKT pathway was activated by crocin in the ganglion cell layer after retinal IR injury. Intravitreal injection of LY294002 blocked the neuroprotective effect of crocin on IR-induced RGC death. In conclusion, crocin prevents retinal IR-induced apoptosis of RGCs by activating the PI3K/AKT signalling pathway.

Connexin 43 (Cx43) plays an important role in the pathogenesis of atrial fibrillation (AF). The present study sought to investigate the effect of macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, on Cx43 expression and activity and determine the intracellular signalling pathways. Cx43 protein and mRNA levels were assayed using immunofluorescence, real-time polymerase chain reaction (PCR), and western blot. We found that increased MIF and extracellular regulated protein kinases (ERK) expression was accompanied by a significant reduction in Cx43 protein expression in atrial tissues from patients with AF compared with those with sinus rhythm. In cultured atrium-derived myocytes (HL-1 cells), mouse recombinant-MIF (rMIF, 20 or 40 nmol/L, 24 hours) down-regulated gene and protein expression of Cx43 in a concentration-dependent manner. U0126, a specific inhibitor of mitogen-activated protein kinase kinase (MAPKK) could reverse the decrease in expression of Cx43 protein induced by rMIF. Further studies revealed that rMIF (40 nmol/L, 15, 30, and 45 minutes) was able to stimulate phospho-Erk1/2 (Thr202/Tyr204) production in a time-dependent manner. These results suggest that MIF is involved in the pathogenesis of AF, probably by down-regulating the protein and gene expression of Cx43 via ERK1/2 kinase activation. Our findings represent a potential pathogenic mechanism in AF.

Thromboxane A

A chiral LC-MS/MS method for the simultaneous analysis of desvenlafaxine (DVS) enantiomers in human plasma was developed and applied to a pharmacokinetic study on 12 Chinese healthy volunteers. d6-Desvenlafaxine was used as internal standard (IS). Chromatographic separation was performed on the Astec Chirobiotic V chiral column (150 mm x 4.6 mm, 5 μm). The assay was linear over the concentration range of 0.500-150 ng x mL(-1) for both enantiomers (r20.99). The method was successfully applied to a stereoselective pharmacokinetic study of 100 mg desvenlafaxine sustained release tablets on 12 Chinese healthy volunteers under fasting conditions. The results showed that the pharmacokinetic parameters were similar to both enantiomers in Chinese healthy volunteers. The AUC(0-t), and C(max) of the two enantiomers were about 1.5 times higher than those of blacks and whites reported in the literature.

Resveratrol possesses anti-tumor activities against central nervous system (CNS) tumors in vitro but has not yet been used clinically due to its low bioavailability, particularly in the CNS. This study thus aimed to elucidate brain bioavailability of trans-resveratrol by monitoring brain concentrations and dwell times following administration of resveratrol through intragastric, intraperitoneal, external carotid artery/ECA and intrathecal routes. In parallel, we evaluated the biological responses of rat RG2 glioblastoma cells as well as RG2-formed rat intracranial glioblastomas treated with resveratrol via intrathecal administration. The results revealed that resveratrol was detected in rat brains except when administered systemically. Intrathecal administration of reseveratrol led to abundant apoptotic foci and increased staining of the autophagy proteins, LC-3 and Beclin-1 and shrinkage of the intracranial tumors. In conclusion, the BBB penetrability of resveratrol is remarkably increased by intracthecal administration. Regular short-term resveratrol treatments suppress growth and enhance autophagic and apoptotic activities of rat RG2 glioblastoma cells in vitro and in vivo. Therefore, intrathecal administration of resveratrol could be an optimal intervention approach in the adjuvant management of brain malignancies.

The oriental fruit fly, Bactrocera dorsalis, is a serious pest of fruits and vegetables. Methyl eugenol (ME), a male attractant, is used to against this fly by mass trapping. Control effect may be influenced by learning, which could modify the olfactory response of the fly to this attractant. To collect the behavioral evidence, studies on the capability of this fly for olfactory learning are necessary. We investigated olfactory learning in male flies with a classical olfactory conditioning procedure using restrained individuals under laboratory conditions. The acquisition of the proboscis extension reflex was used as the criterion for conditioning. A high conditioned response level was found in oriental fruit flies when an odor was presented in paired association with a sucrose reward but not when the odor and sucrose were presented unpaired. We also found that the conditioning performance was influenced by the odor concentration, intertrial interval, and starvation time. A slight sensitization elicited by imbibing sucrose was observed. These results indicate that oriental fruit flies have a high capacity to form an olfactory memory as a result of classical conditioning.

A marked difference in the dissolution rate between two brands of nimodipine tablets was observed using a newly developed dissolution medium of pH 4.5 acetate buffer containing 0.05% sodium dodecyl sulfate (SDS). However, when pH 4.5 acetate buffer containing 0.3% SDS was used as dissolution medium, which was specified in the edition, the dissolution results of the both brands conformed to the BP requirements and no significant difference in dissolution was observed. The dissolution data obtained for two commercial brands of nimodipine tablets indicate the superiority of the proposed system as a discriminatory dissolution medium for nimodipine tablets. The relative bioavailability of the two brands of nimodipine tablets was determined in healthy adult volunteers after a single dose in a randomized crossover study. Plasma concentrations were determined by a liquid chromatography-tandem mass spectrometry method. Statistical comparison of the AUC(0-T), AUC(0- infinity), C(max), and T(max) indicated a significant difference in the two brands of nimodipine tablets.

The study aims to evaluate the bioequivalence of valsartan hydrochlorothiazide tablets, and to investigate the potential cause of bioinequivalence. This was a single-center study with an open, randomized double-way crossover design. Test and reference preparations containing 160 mg of valsartan and 25 mg of hydrochlorothiazide were given to 36 healthy male volunteers. Plasma concentrations of valsartan and hydrochlorothiazide were determined simultaneously by LC-MS/MS. The pharmacokinetic parameters and relative bioavailability were calculated, while the bioequivalence between test and reference preparations were evaluated. The dissolution profiles of test and reference preparations in four different mediums were determined via dissolution test and HPLC. The similarity was investigated according to the similarity factors (f2). The F(o-t) and F(0-infinity) were (139.4 +/- 65.2)% and (137.5 +/- 61.2)% for valsartan of test preparations. It led to get the conclusion that test and reference preparations were not bioequivalent for valsartan. A significant difference was observed between test and reference tablets in the valsartan dissolution test of pH 1.2 hydrochloric acid solution. The key factor of the bioinequivalence might be that dissolution of valsartan in acid medium has marked difference between two preparations.

Depression is a frequent mood disorder that affects around 33% of stroke patient. Our aim was to test the possible association between plasma glutamate and the development of post-stroke depression (PSD) in Chinese patients.The subjects were first-ever acute ischemic stroke (AIS) patients who were hospitalized during the period from November 2011 to September 2013. Clinical information and stroke severity was collected at admission. Neurological and neuropsychological evaluations were conducted at the 3-month follow-up. Plasma glutamate levels were analyzed at baseline using liquid chromatography followed by tandem mass spectrometry. Glutamate oxaloacetate transaminase (GOT), glutamate-pyruvate transaminase (GPT) and blood markers were also tested. Multivariate analyses were performed using logistic regression models.During the study period, 209 patients were included in the analysis. Seventy patients (33.5%) were diagnosed as having major depression at 3 month. Patients with major depression showed higher levels of plasma glutamate [299 (235-353) vs. 157 (108-206) μM, P0.0001] and lower GOT [14 (11-20) vs. 21 (15-32)U/L, P0.0001] at admission. In multivariate analyses, plasma glutamate and GOT were independent predictors of PSD at 3 months [odds ratio (OR): 1.03 (1.02-1.04), P0.0001; 0.84 (0.75-0.97), P=0.003]. Plasma levels of glutamate205 μM were independently associated with PSD (OR, 21.3; 95% CI, 8.28-67.36, P0.0001), after adjustment for possible variables.The present study demonstrates a strong relationship between plasma glutamate and GOT levels at admission and the development of PSD within 3 months. Further studies are necessary to confirm this association, which may open the way to the proposal of new therapeutic options.

A total of 22 (14F/8M) patients with a mean age of 50.3 years (range, 33 to 64 y) and a mean body mass index of 28.4 kg/m (range, 21.8 to 38.3 kg/m) underwent loop duodenojejunal bypass with sleeve gastrectomy from October 2011 to March 2012. The mean duration of onset of type 2 diabetes mellitus was 8 years (range, 1 to 20 y). All patients were on oral hypoglycemic agents; 3 (14%) patients were also using insulin. The mean preoperative glycosylated hemoglobin (HbA1c), fasting plasma sugar, and C-peptide levels dropped from 8.6% (range, 7% to 13.2%), 147 mg/dL (range, 108 to 241 mg/dL), and 2.4 ng/mL (range, 0.7 to 4.1 ng/mL) to 6.2% (range, 5.1% to 9.1%), 110 mg/dL (range, 72 to 234 mg/dL), and 1.3 ng/mL (range, 0.6 to 2.8 ng/mL) at 6 months, respectively. At 6 months, 11 (50%) patients showed type 2 diabetes mellitus remission (HbA1c6.0%), and 20 (91%) patients achieved HbA1c7.0% without medicine. There were no intraoperative or early postoperative complications. Loop duodenojejunal bypass with sleeve gastrectomy is safe, feasible, and shows good efficacy in terms of glycemic control in this preliminary report with short follow-up.

A simple, sensitive, selective, and reproducible liquid chromatography-tandem mass spectrometric method was developed for the simultaneous determination of repaglinide and metformin in human plasma using d5-repaglinide and d6-metformin as internal standards (ISs). After a simple protein precipitation using acetonitrile as the precipitation solvent, both analytes and ISs were separated on a Venusil ASB C 18 (150 mm x 4.6 mm, 5 microm) via gradient elution using acetonitrile--10 mmol x L(-1) ammonium acetate as the mobile phase. A chromatographic total run time of 7.5 min was achieved. Mass spectrometric detection was conducted with atmospheric pressure chemical ionization under positive-ion and multiple-reaction monitoring modes. The method was linear over the 0.2 to 60.0 ng x mL(-1) concentration range for repaglinide and over the 4 to 1 000 ng x mL(-1) range for metformin. For both analytes, the intra- and inter-accuracies and precisions were within the +/- 15% acceptable limit across all concentrations. The validated method was successfully applied to a clinical bioequivalence study.

A sensitive, rapid and accurate liquid chromatography-tandem mass spectrometric (LC-MS/MS) method with pre-column derivatization was developed for the simultaneous determination of erdosteine and its thiol-containing active metabolite in human plasma. Paracetamol and captopril were chosen as the internal standard of erdosteine and its active metabolite, respectively. Aliquots of 100 microL plasma sample were derivatized by 2-bromine-3'-methoxy acetophenone, then separated on an Agilent XDB-C18 (50 mm x 4.6 mm ID, 1.8 microm) column using 0.1% formic acid methanol--0.1% formic acid 5 mmol x L(-1) ammonium acetate as mobile phase, in a gradient mode. Detection of erdosteine and its active metabolite were achieved by ESI MS/MS in the positive ion mode. The linear calibration curves for erdosteine and its active metabolite were obtained in the concentration ranges of 5-3 000 ng x mL(-1) and 5-10 000 ng x mL(-1), respectively. The lower limit of quantification of erdosteine and its active metabolite were both 5.00 ng x mL(-1). The pharmacokinetic results of erdosteine and its thiol-containing active metabolite showed that the area under curve (AUC) of the thiol-containing active metabolite was 6.2 times of that of erdosteine after a single oral dose of 600 mg erdosteine tables in 32 healthy volunteers, The mean residence time (MRT) of the thiol-containing active metabolite was (7.51 +/- 0.788) h, which provided a pharmacokinetic basis for the rational dosage regimen.

In the present paper, lyophilized sera from 31 patients with colorectal cancer, 8 patients with enteritis and 10 healthy controls were measured using Nicolet Nexus-670 Fourier Transform Infrared (FTIR) spectrometer, and the spectral features were investigated and comparison among three groups was made. The result showed that (1) there are 11 peaks of absorption in the spectrum of lyophilized sera, the wavenumber of the ninth peak moved to 1 249 cm(-1) in the colorectal cancer group and significant difference was observed with the control group (Z = -2.051, P0.05); Five ratios of absorbance were calculated and no significant difference was observed among three groups; (2) spectrum in the region of 1 700-1 000 cm(-1) was analysed with the method of hierarchical cluster analysis and showed only partial success in distinguishing the three groups; (2) spectrum of amide I peptide (1 700-1 600 cm(-1)) was deconvolved to get the percentage composition of protein secondary structures, and no significant difference was observed among three groups. The results provide a preliminary theoretical basic for using FTIR spectrum of lyophilized serum for the early diagnosis of colorectal cancer.

To compare the bioequivalence and pharmacokinetics of national made and imported atorvastatin in healthy male Chinese volunteers after single oral administration.This randomized sequence, open-label, two-period crossover study with a one-week washout period between doses was performed in 24 fasting healthy Chinese males. They were randomly assigned to receive 20 mg of either the test (national made) or reference (imported) formulation orally. The blood samples were collected over a 72-hour period. Plasma concentrations of parent atorvastatin (AT), ortho-hydroxy-atorvastatin (o-OAT) and para-hydroxy-atorvastatin (p-OAT) were simultaneously determined using the validated liquid chromatography-tandem mass spectrometry method, the bioequivalence was also evaluated throughout the study.The main pharmacokinetic parameters of test and reference formulations were as follows: the values of C(max) for AT were (10.6 ± 11.9) µg/L and (10.6 ± 9.8) µg/L, t(1/2z) were (11.4 ± 3.9) h and (11.4 ± 5.3) h, AUC(0-t) were (54.2 ± 37.4) µg×h(-1)×L(-1) and (51.7 ± 34.1) µg×h(-1)×L(-1), respectively. The values of C(max) for o-OAT were (7.8 ± 4.5) µg/L and (7.6 ± 4.3) µg/L, t(1/2z) were (12.3 ± 4.2) h and (11.9 ± 3.4) h, AUC(0-t) were (96.8 ± 48.2) µg×h(-1)×L(-1) and (92.3 ± 44.4) µg×h(-1)×L(-1), respectively. The values of C(max) for p-OAT were (0.5 ± 0.4) µg/L and (0.4 ± 0.3) µg/L, t(1/2z) were (18.4 ± 12.4) h and (23.3 ± 17.8) h, AUC(0-t) were (15.9 ± 12.3) µg×h(-1)×L(-1) and (13.8 ± 8.11) µg×h(-1)×L(-1), respectively. The relative bioavailability of AT and o-OAT in test formulation were (105.3 ± 20.7)% and (107.8 ± 23.2)%, respectively. The 90% confidence interval of the test/reference geometric mean ratios of AUC(0-t) for AT and o-OAT were (97.7 - 110.5)% and (98.3 - 111.3)%, C(max) for AT and o-OAT were (75.8 - 114.0)% and (90.6 - 122.9)%, they were all located within the bioequivalence criteria range (80% - 125% for AUC, and 70% - 143% for C(max)).The result demonstrated that two formulations were bioequivalent.

Yong-yan Bei1, Xiao-yan Chen1, Yang Liu1, Jing-yu Xu1, Wen-juan Wang1, Zong-lin Gu1, Kong-lang Xing1, Ai-jun Zhu1, Wei-liang Chen1, Lin-seng Shi1, Qin Wang1, Xue-nong Zhang1, Qiang Zhang21College of Pharmaceutical Science, Soochow University, Suzhou, 2Department of Pharmaceutics, School of Pharmaceutical Science, Peking University, Beijing, People's Republic of ChinaAbstract: In this paper, two novel liver-targeting nanoparticles, norcantharidin-loaded chitosan nanoparticles (NCTD-CS-NPs) and norcantharidin-associated galactosylated chitosan nanoparticles (NCTD-GC-NPs), were prepared using ionic cross-linkage. The physical properties, particle size, encapsulation efficiency, and drug release characteristics of the nanoparticles were investigated in vitro. To investigate the intestinal absorption mechanisms of the two preparations, a series of experiments was carried out, including in situ circulation method, in vitro everted gut sacs, and Ussing chamber perfusion technique. The absorption rate constants (Ka) of NCTD at different segments were found to be duodenum > jejunum > ileum > colon. The concentration had no distinctive effect on absorption kinetics, suggesting that drug absorption is not dose-dependent. The transport of NCTD was found to be inhibited by P-glycoprotein (P-gp) inhibitor, indicating that NCTD might be the substrate of P-gp. The order of the absorption enhancer effects were as follows: low molecular weight chitosan (CS-8kDa) . high molecular weight chitosan (CS-30kDa) > Poloxamer > sodium dodecyl sulfate (SDS) > sodium deoxycholate (SDCh). The results indicate that the chitosan nanoparticles can improve intestinal absorption of NCTD.Keywords: P-glycoprotein, absorption enhancers

Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic properties. The aim of this study was to investigate whether low adiponectin levels predict the impairment of endothelial function in newly diagnosed type 2 diabetic patients in an 8-year prospective study.In the prospective study, we enrolled 133 newly diagnosed type 2 diabetic patients without subclinical atherosclerosis and gave them intensive therapy; the mean treatment period was 8 years. Intensive treatment was a stepwise implementation of behavior modification and pharmacological therapy targeting hyperglycaemia, hypertension, dyslipidaemia and obesity. We measured baseline circulating adiponectin with an enzyme-linked immunosorbent assay, endothelium-dependent and -independent vasodilation by high-resolution vascular ultrasound. At year 8, 102 patients were reexamined for endothelium-dependent and -independent vasodilation.Sex-adjusted adiponectin level was positively correlated with endothelium-independent vasodilation both at baseline (r = 0.150, P = 0.043) and at year 8 (r = 0.339, P = 0.001), whereas no association was found between adiponectin and endothelium-dependent vasodilation. In a stepwise multivariate linear regression model, adiponectin was an independent predictor for impaired endothelium-independent vasodilation at year 8 (P = 0.001).Plasma adiponectin concentration was associated with endothelium-independent vasodilation and hypoadiponectinemia predicted the impairment of endothelium-independent vasodilation in newly diagnosed type 2 diabetic patients under multifactorial intervention. These data support the causative link of impairment of endothelium-independent vasodilation with hypoadiponectinemia.

Chlorogenic acid (5-CQA) is one of the major components in some Chinese herbal injections. However, the metabolism of 5-CQA in rats after intravenous injection has not been determined. An ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) method was applied to identify the metabolites in bile, urine, feces and plasma after a single intravenous administration of 10 mg x kg(-1) 5-CQA to rats. Using MSE and mass defect filter techniques, a total of 35 metabolites were detected in bile, urine, feces and plasma. The predominant metabolites in bile were glutathione conjugates of O-methyl-5-CQA, accounting for approximately 80% of the metabolites excreted in bile. The major components in urine were parent drug, O-methyl-5-CQA, hydrolyzed metabolites and glucuronide conjugates. The major components in feces were O-methyl-5-CQA and its cysteine conjugates. The major component in plasma was the parent drug. The urinary and fecal excretion pathways were equally important to 5-CQA in rats. These results demonstrate that 5-CQA undergoes extensively metabolism in rats and are highly reactive to nucleophiles such as GSH. This finding indicates that attention should be paid on the injections containing 5-CQA, which may covalently bind to proteins, leading to allergenic drug reactions.

To investigate the signal patterns of dual color dual fusion (DCDF) probe and extra signal (ES) probe in the detection of BCR/ABL fusion gene, and illustrate the relation between the fluorescence in situ hybridization (FISH) pattern and the karyotype.Sixty-five cases of chronic myelocytic leukemia (CML) and 50 cases of acute lymphoblastic leukemia (ALL) were detected by FISH with DCDF probe, the BCR/ABL positive samples were detected by FISH with ES probe. Among these cases, 47 cases of CML and 40 cases of ALL perform conventional cytogenetics simultaneously.All 65 cases of CML were all BCR/ABL positive by FISH. 17 cases showed the atypical pattern by DCDF-FISH, and 12 cases showed the atypical pattern by ES-FISH. There were 7 cases of BCR/ABL positive in 50 cases of ALL by FISH. By ES-FISH, there were 5 cases in which the break-point of BCR gene was located in m-bcr, 2 cases in which the break-point of BCR gene was located in M-bcr. Conventional cytogenetics demonstrated that 43/44(98%) cases of CML and 7/32(22%) cases of ALL were Ph positive.The features of DCDF-FISH, ES-FISH and conventional cytogenetic are different from each other. According to the features of these method, it can increase the precision of the adjustment of genetic feature to analyze these results comprehensively.

To explore the in vivo inhibitory effect of Livin gene silencing by RNA interference on xenograft of lung adenocarcinoma SPC-A-1 cells in BALB/C nude mice.Three different BALB/C nude mice models were established by subcutaneously inoculating differently treated SPC-A-1 cells into 3 nude mice groups: the blank control group was inoculated with blank SPC-A-1 cells, while the negative group was inoculated with cells transfected with lentivirus-delivered negative shRNA, the experimental group was inoculated with cells with lentivirus-delivered Livin shRNA. Then the growth of tumors was observed, and the volume and weight of the tumors were measured at different time points. The curve of tumor growth was then described, and the inhibition rate was calculated. Livin gene expression in the tumor tissues was determined by RT-PCR and Immunohistochemistry. Cell apoptosis of tumor tissues was detected by TUNEL.Slower tumor growth, smaller tumor volume and lighter tumor weight were observed in the experimental group as compared to the blank and negative groups (F = 70.509, P0.01; F = 12.821, P0.01). The inhibition rate of tumor volume was (59.5 ± 3.4)%, and the inhibition rate of tumor weight was (71.1 ± 5.6)%. Livinα mRNA and Livinβ mRNA expressions in the experimental group were significantly lower than the 2 control groups [(37.2 ± 1.6)% versus (63.3 ± 3.8)%, (66.1 ± 2.6)%; (29.4 ± 1.1)% versus (53.2 ± 3.4)%, (52.3 ± 3.1)% (F(α) = 45.309, P0.01; F(β) = 30.076, P0.01)]. Livin protein expression level was also significantly lower than the blank and the negative groups [(15.3 ± 2.8)% versus (51.3 ± 2.1)%, (52.5 ± 2.5)%, F = 78.92, P0.01]. The apoptosis rate in the experimental group was significantly higher than that in the 2 control groups [(35.4 ± 3.2)% versus (5.4 ± 1.3)%, (8.6 ± 1.5)%, F = 14.509, P0.01].The lentivirus-delivered Livin shRNA was shown to inhibit the proliferation of transplantation tumor of lung carcinoma effectively, and Livin may be a target for gene therapy in lung cancer.

To investigate the pathogenetic mechanism of beta-arrestin1 in the rat's experimental colitis, whether the delta opioid receptor-beta-arrestin1 -Bcl-2 signal transduction pathway involves the pathological process of experimental colitis in rats, and whether oxymatrine could attenuate colitis through this pathway.Twenty-six SD rats were randomly divided into four groups, the normal control group, the model group, the mesalazine treated group and the oxymatrine treated group (8 rats in the last group and 6 each in the others). The colitis model was established with trinitrobenzene sulfonic acid (TNBS), and rats in the latter two groups were treated by oxymatrine (intramuscular injection) and mesalazine (3 mL solution gavaged) for 15 days, respectively, while rats in the former two groups were fed with equal volume of distilled water. Symptoms of diarrhea and bloody stool as well as colonic patho-histologic changes were observed, and changes in expressions of delta opioid receptor, beta-arrestin1 and Bcl-2 in rat's colon tissue and spleen T lymphocytes were detected with immuno-histochemistry and Western immune-blotting techniques, respectively.In contrast to the normal control group, expressions of delta opioid receptor, beta-arrestin1 and Bcl-2 were significantly higher in the model group (P0.01); compared with the model group, they were significantly lower in the two treated groups (P0.01).Delta opioid receptor-beta-arrestin1 -Bcl-2 signal transduction pathway participates in the pathogenesis of TNBS-induced experimental colitis in rats. Oxymatrine can intervene the signal transduction, which may be one of the mechanisms of oxymatrine in attenuating colitis in rats.

To investigate the β2-adrenoceptor (β2AR)-β-arrestin2-nuclear factor-κB (NF-κB) signal transduction pathway and the intervention effects of oxymatrine in a rat model of ulcerative colitis.Forty SD rats were randomly divided into four groups, which included the normal control group, the model group, the mesalazine group and the oxymatrine treatment group, with 10 rats per group. Experimental colitis induced with trinitrobenzene sulfonic acid (TNBS) was established in each group except the normal control group. The rats in the oxymatrine treatment group were treated with intramuscular injection of oxymatrine 63 mg/(kg·d) for 15 days and the rats in the mesalazine group were treated with mesalazine solution 0.5 g/(kg·d) by gastric lavage for 15 days. The rats in the normal control group and model group were treated with 3 mL water by gastric lavage for 15 days. Diarrhea and bloody stool were carefully observed. Histological changes in colonic tissue were examined on day 7 in 2 rats per group that were randomly selected. The expression of β2AR, β-arrestin2 and NF-κB p65 in colon tissue and spleen lymphocytes were detected with immunohistochemistry and Western immunoblotting techniques on day 16 after fasting for 24 h. Six rats died of lavage with 2 each in the normal control, the model group and the mesalazine group; and were not included in the analysis.The rats in the model group suffered from looser stool and bloody purulent stool after modeling. But in the oxymatrine and mesalazine groups, looser stool and bloody purulent stool reduced after treatment. And the colonic wall in the model group was thickened and the colon length shortened. The colon mucosa was congested in multiple areas with edema, erosion, superficial or linear ulcer and scar formation, while the intestinal mucosa injury reduced in the mesalazine and oxymatrine groups (P0.01). In colonic mucosa and in spleen lymphocytes, compared with the normal control group, the expression of NF-κBp65 were significantly increased (P0.01) in the model group while the expressions of β 2AR and β-arrestin2 were significantly decreased (P0.01). Compared with the model group, the expression of NF-κ Bp65 was significantly decreased in the mesalazine group (P0.01) and oxymatrine treatment group (P0.01) while the expressions of β2AR and β-arrestin2 were significantly increased (P0.01). There were no statistically significant differences in the expression of β2AR, β-arrestin2 and NF-κBp65 between the mesalazine group and oxymatrine group (P0.05).The β2AR-β-arrestin2-NF-κB signal transduction pathway participated in the pathologic course of ulcerative colitis. Oxymatrine attenuated ulcerative colitis through regulating the β2AR-β-arrestin2-NF-κB signal transduction pathway.

Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatment-induced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20–100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A1receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-α/β activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.

To explore the relationship between plasma adipocyte fatty acid-binding protein (A-FABP), adiponectin (APN) levels and A-FABP/APN ratio with femoral intima-media thickness (FA-IMT) and endothelium-dependent vasodilation in patients with newly diagnosed type 2 diabetes mellitus (T2DM).Plasma A-FABP and APN in 133 patients with newly diagnosed T2DM were measured by enzyme-linked immunosorbent assays. FA-IMT, endothelium-dependent and independent vasodilation of brachial artery was measured by high-resolution vascular ultrasound. Upper quartile of FA-IMT was regarded as a criterion of elevated FA-IMT, defined as early atherosclerosis (AS). The patients were subdivided into low FA-IMT group (FA-IMT0.60 mm, n = 34), middle FA-IMT group (0.60 mm/= FA-IMT0.73 mm, n = 33), high FA-IMT group (0.73 mm/= FA-IMT0.80 mm, n = 33) and early AS group (FA-IMT/= 0.80 mm, n = 33).Plasma A-FABP/APN ratio was higher in early AS group than in low IMT control group [A-FABP/APN x 1000, 3.9(2.8 approximately 6.1) vs 2.9(1.8 approximately 5.7), P0.05]. FA-IMT correlated positively with plasma A-FABP/APN ratio (r = 0.216, P = 0.006) and negatively with APN (r = -0.179, P = 0.020). After adjusted for age, gender and BMI, FA-IMT still correlated positively with plasma A-FABP/APN ratio (r = 0.217, P = 0.007) and negatively with APN (r = -0.172, P = 0.026). Endothelium-dependent vasodilation correlated negatively with plasma A-FABP/APN ratio (r = -0.166, P = 0.028). After adjusted for age, gender and BMI, endothelium-dependent vasodilation still correlated negatively with plasma A-FABP/APN ratio (r = -0.153, P = 0.042).Plasma A-FABP/APN ratio is closely associated with FA-IMT and endothelium-dependent vasodilation. Plasma A-FABP/APN ratio may be a better clinical marker of AS and endothelial dysfunction than A-FABP or APN alone in patients with newly diagnosed T2DM.

This study was aimed to investigate the relationship between immunophenotype of the background lymphocytes and histological subtype of Hodgkin's lymphoma (HL), and its significance. The relative protein expressions of background lymphocytes were detected in 37 HL specimens on the basis of instant-rapid MaxVision(TM) immunohistochemical method and assessed quantitatively with image analysis software IPP6.0. The adoptive antibody included anti-CD3/CD45RO, anti-CD20/CD79a, anti-CD4, anti-CD8, anti-GrB, anti-TIA-1. The results indicated that out of 37 cases 4 were NLPHL, 33 were CHL including 6 of MCHL, 14 of NSHL, 13 of LRHL. In addition, 10 cases (1 was NLPHL, 4 were NSHL, 5 were LRHL) were involved in the analysis of T/B ratios. The ratio of T/B in NLPHL was 0.28 +/- 0.07, in CHL 4.34 +/- 2.45 (p = 0.001), in CHL the ratio was LRHLNSHLMCHL (p = 0.649); CD4(+)/CD8(+) ratio in NLPHL was 4.55 +/- 1.28, in CHL 4.10 +/- 1.50 (p = 0.574), in CHL it was MCHLNSHLLRHL (p = 0.037); GrB(+)/TIA-1(+) ratio in NLPHL was 0.71 +/- 0.57, in CHL 0.74 +/- 0.39, it was MCHLNSHLLRHL (p0.05). It is conduced that immune cell composition of the diagnostic HL lymph node represents the immune microenvironment. It is different between NLPHL and CHL in terms of the T- and B-lymphocyte distribution. NLPHL is of unique feature. The subtypes of CHL are of peculiar. The T/B ratio is in order as LRHLNSHLMCHL, but CD4(+)/CD8(+) and GrB(+)/TIA-1(+) ratios are in the opposite order. Combining with prognosis of subtypes of CHL i.e, LRHLNSHLMCHL, these data suggest that low ratio of T/B with high ratios of CD4(+)/CD8(+) and GrB(+)/TIA-1(+) may represent biological markers predicting an unfavorable outcome of CHL subtypes.