Functional connectivity of cerebellar dentate nucleus and cognitive impairments in patients with drug-naive and first-episode schizophrenia.

Cognitive impairments are the hallmark of schizophrenia and prominent in the early episode stage. However, the underlying pathological mechanisms of cognitive impairments are not fully understood. This study aimed to investigate the abnormal functional connectivity (FC) of the cerebellar dentate nucleus (DN) and its correlation with cognitive impairments in patients with drug-naive and first-episode schizophrenia. Resting-state functional magnetic resonance imaging data were acquired in 47 patients and 43 healthy controls. Cognitive functions were assessed by number sequence span, verbal category fluency, digit-symbol coding tests. The results showed that the patients had deficits in all three cognitive tests compared to the controls. Furthermore, the increased FC of DN with the bilateral postcentral gyrus and decreased FC of DN with the right inferior temporal gyrus and regional cerebellum (e.g., Vermis 4-5 and Crus I) were observed in the patient group compared to the control group. Importantly, these abnormal DN FC significantly correlated with cognitive tests (e.g., number sequence span and digit-symbol coding) and clinical symptoms (e.g., negative symptom) in the patient group. The results suggested that abnormal FC of DN with cortical and subcortical regions was associated with cognitive impairments and symptom severity and might be an underlying neural mechanism in schizophrenia.

The neural basis of complex audiovisual objects maintenances in working memory.

Working memory research has primarily concentrated on studying our senses separately; the neural basis of maintaining information from multiple sensory modalities in working memory has been not well elucidated. It is debated whether multisensory information is maintained in the form of modality-specific representations or amodal representations. The present study investigated what brain regions were engaged in both types of complex audiovisual objects maintenances (semantically congruent and incongruent) using functional magnetic resonance imaging and conjunction analysis, and examined in which form to maintain multisensory objects information in working memory. The conjunction analysis showed that there was common brain regions activation involving left parietal cortex (e.g., left angular gyrus, supramarginal gyrus, and precuneus) while maintaining semantically congruent audiovisual object, whereas the common brain regions activation including the bilateral angular, left superior parietal lobule, and left middle temporal gyrus was found during maintaining semantically incongruent audiovisual objects. Importantly, the shared conjoint brain regions activation consists of bilateral angular gyrus and left middle frontal gyrus was observed while maintaining both types of semantically congruent and incongruent complex audiovisual objects. These brain regions may play different role while maintaining these complex multisensory objects, such as supramodel storage per se and intentional attention. The findings of the present studymight support the amodal view that working memory has a central storage system to maintain multisensory information from different sensory inputs.

Frontal Alpha EEG Asymmetry Before and After Positive Psychological Interventions for Medical Students.

Subjective well-being (SWB) refers to traits concerned with happiness, fulfillment and enrichment and is a substantial predictor of a flourishing life. Interest in the promotion of well-being has blossomed in recent years, and it is widely reported that positive psychological interventions (PPIs) can effectively improve SWB. However, to date, the neural correlates of PPIs remain elusive. Since previous research has suggested that emotion regulation might be the theoretical foundation for potential working mechanisms, here we used electroencephalography (EEG) techniques to identify whether the intentional increase of subjective well-being through PPIs was associated with greater tonic left frontal activation. Fifty-five students met the inclusion criteria and were allocated to a randomized controlled trial that was single blinded. The intervention group received PPIs once a week for 10 weeks (n = 28). Meanwhile, students in a placebo control group (CG, n = 27) were asked to write down early memories every day for 10 weeks and were invited to share voluntarily at the weekly meeting. Measures of subjective well-being, depression and anxiety were assessed at pre-test and post-test. Forty-eight students completed the post-test, and the collected data were analyzed across time (PPIs, n = 25; CG, n = 23). It was found that students undergoing the 10-week PPIs reported larger improvement in SWB, and greater relief in self-rated depression and anxiety from pre-intervention to post-intervention than did those in the control group. As expected, in conjunction with the promotion of subjective well-being and the amelioration of emotional distress from pre- to post-treatment in the intervention group, a significantly increased coefficient of frontal alpha EEG asymmetry was found. In summary, these findings suggest that adaptive emotion regulation, which is characteristic of greater tonic left frontal activation, reflects the efficiency of PPIs and highlights the frontal alpha EEG asymmetry as a neural substrate linking PPIs and mental health. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-ROC-17012636.

Tenofovir disoproxil fumarate is superior to lamivudine plus adefovir in lamivudine-resistant chronic hepatitis B patients.

AIM: To assess the efficacy of tenofovir disoproxil fumarate (TDF) in lamivudine (LAM)-resistant patients with a suboptimal response to LAM plus adefovir (ADV). METHODS: We retrospectively analyzed the efficacy of switching to tenofovir disoproxil fumarate in suboptimal responders to lamivudine plus adefovir. Charts were reviewed for LAM-resistant chronic hepatitis B (CHB) patients who visited the Zhejiang Province People's Hospital and The First Affiliated Hospital, College of Medicine, Zhejiang University, from June 2009 to May 2013. Patients whose serum hepatitis B virus (HBV) DNA remained detectable despite at least 6 mo of LAM plus ADV combination therapy were included. Patients with a suboptimal response to LAM plus ADV were randomized to switch to TDF monotherapy (300 mg/d orally; TDF group) or to continuation with LAM (100 mg/d orally) plus ADV (10 mg/d orally; LAM plus ADV group) and were followed for 48 wk. Serum HBV DNA was determined at baseline and weeks 4, 12, 24, 36, and 48. HBV serological markers and biochemistry were assessed at baseline and weeks 12, 24, and 48. Resistance surveillance and side effects were monitored during therapy. RESULTS: Fifty-nine patient were randomized to switch to TDF (n = 28) or continuation with LAM plus ADV (n = 31). No significant differences were found between the groups at baseline. Prior to TDF therapy, all patients had been exposed to LAM plus ADV for a median of 11 mo (range: 6-24 mo). No difference was seen in baseline serum HBV DNA between the two groups [5.13 ± 1.08 log10 copies/mL (TDF) vs 5.04 ± 31.16 log10 copies/mL (LAM + ADV), P = 0.639]. There was no significant difference in the rates of achieving complete virological response (CVR) at week 4 between the TDF and LAM + ADV groups (17.86% vs 6.45%, P = 0.24). The rate of achieving CVR in the TDF and LAM plus ADV groups was 75% vs 16.13% at week 12, 82.14% vs 22.58% at week 24, 89.29% vs 25.81% at week 36, and 96.43% vs 29.03% at week 48, respectively (P < 0.001). The rate of alanine aminotransferase normalization was significantly higher in the TDF than in the LAM plus ADV group at week 12 (75% vs 17.86%, P < 0.001), but not at week 24 (78.57% vs 54.84%, P = 0.097) or 48 (89.26% vs 67.74%, P = 0.062). Patients were hepatitis B e antigen (HBeAg) positive at baseline. There was no significant difference in HBeAg negativity between the TDF and LAM plus ADV groups at week 48 (4% vs 0%, P = 0.481). There were no drug-related adverse effects at week 48 in either group. CONCLUSION: Switching to TDF monotherapy was superior to continuous add-on therapy in patients with LAM-resistant CHB with a suboptimal response to LAM plus ADV.

PCR restriction fragment length polymorphism in detection of YMDD variants of viral polymerase in hepatitis B virus patients treated with lamivudine.

OBJECTIVE: To analyse the emergence of YMDD motif (tyrosine-methionine-aspartate-aspartate) variants in patients with hepatitis B treated with lamivudine. METHODS: The amino acid substitution from methionine or isoleucine at the YMDD motif at the HBV polymerase gene is a main mutation resistant to lamivudine treatment. Generated from a fragment of domain C of the polymerase gene, patients' HBV DNA, which had been positive previously became positive again ever since it had been negative during lamivudine therapy. Variants were detected by cleavage of the products of the three PCRs with following enzymes: FokI, SspI, Alw441. The results of PCR-RELP were analysed by 8.4% polypropylene acidemide gel electrophoresis. PCR-RFLP assay was compared to direct sequencing. RESULTS: HBV DNA was positive again in 33 patients and positive for one year in 2 patients. YMDD variants were detected in serum 14 of 35 patients, YIDD variants in 4, YVDD variants in 6, and YI/MDD variants in 1; all were in concordance with the results of direct sequencing. The samples of other 3 patients showed YI/VDD mutations, as shown by direct sequencing. The results of PCR-RFLP assay of the mixed sera of YIDD and YVDD variants were similar to those sera of YI/VDD variants. CONCLUSION: PCR-RFLP is suitable for rapid detection of YMDD variants of viral polymerase in hepatitis B virus patients treated with lamivudine.

[Types and emergence time of YMDD motif mutation in hepatitis B virus polymerase gene during lamivudine treatment].

OBJECTIVE: To study the types and emergence time of YMDD motif mutation in hepatitis B virus (HBV) polymerase gene during lamivudine treatment. METHODS: The serum samples were collected from 33 patients with HBV DNA rebounding and 2 non-responders after at least one year lamivudine treatment. HBV polymerase gene was amplificated by PCR, then the products were detected by restriction fragment length polymorphism (RFLP) and by direct sequence analysis. RESULTS: The variants with YMDD mutation were 14 out of the 35 patients. Mutation patterns detected in these patients included four YIDD, six YVDD, three YI/VDD and one YI/MDD. The mean emergence time of YMDD variants was 11.07+/-3.65 months after the treatment, and the earliest one and the latest one occurred 5 months and 17 months after the treatment respectively. The emergence times of YIDD, YVDD, YI/VDD were (10.00 +/- 1.41) months, (11.67 +/- 4.41) months and (13.33 +/- 3.31) months respectively, which had no statistical significance (F = 0.543, P < 0.05). Three patients treated with lamivudine 200 mg every day after the mutation were followed up for 6 months, whose HBV variants had not vanished. CONCLUSIONS: There are many kinds of HBV variants after lamivudine treatment, including YIDD, YVDD, YI/VDD and YI/MDD. The emergence time of variants is quite variable between different types and the mean time is (11.07 +/- 3.65) months after treatment, and there is no relationship between the type of YMDD mutation and the time of lamivudine administration.

Effect of salvianolate on intestinal epithelium tight junction protein zonula occludens protein 1 in cirrhotic rats.

AIM: To study the effect of salvianolate on tight junctions (TJs) and zonula occludens protein 1 (ZO-1) in small intestinal mucosa of cirrhotic rats. METHODS: Cirrhosis was induced using carbon tetrachloride. Rats were randomly divided into the untreated group, low-dose salvianolate (12 mg/kg) treatment group, medium-dose salvianolate (24 mg/kg) treatment group, and high-dose salvianolate (48 mg/kg) treatment group, and were treated for 2 wk. Another 10 healthy rats served as the normal control group. Histological changes in liver tissue samples were observed under a light microscope. We evaluated morphologic indices of ileal mucosa including intestinal villi width and thickness of mucosa and intestinal wall using a pathological image analysis system. Ultrastructural changes in small intestinal mucosa were investigated in the five groups using transmission electron microscopy. The changes in ZO-1 expression, a tight junction protein, were analyzed by immunocytochemistry. The staining index was calculated as the product of the staining intensity score and the proportion of positive cells. RESULTS: In the untreated group, hepatocytes showed a disordered arrangement, fatty degeneration was extensive, swelling was obvious, and disorganized lobules were divided by collagen fibers in hepatic tissue, which were partly improved in the salvianolate treated groups. In the untreated group, abundant lymphocytes infiltrated the fibrous tissue with proliferation of bile ducts, and collagen fibers gradually decreased and damaged hepatic lobules were partly repaired following salvianolate treatment. Compared with the untreated group, no differences in intestinal villi width between the five groups were observed. The villi height as well as mucosa and intestinal wall thickness gradually thickened with salvianolate treatment and were significantly shorter in the untreated group compared with those in the salvianolate treatment groups and normal group (P < 0.01). The number of microvilli decreased and showed irregular lengths and arrangements in the untreated group. The intercellular space between epithelial cells was wider. The TJs were discontinuous, which indicated disruption in TJ morphology in the untreated group. In the treated groups, the microvilli in the intestinal epithelium were regular and the TJs were gradually integrated and distinct. The expression of ZO-1 decreased in the small intestine of the untreated cirrhotic rats. The high expression rate of ZO-1 in ileal mucosa in the untreated group was significantly lower than that in the medium-dose salvianolate group (21.43% vs 64.29%, χ(2) = 5.25, P < 0.05), high-dose salvianolate group (21.43% vs 76.92%, χ(2) = 8.315, P < 0.01) and normal group (21.43% vs 90%, χ(2) = 10.98, P < 0.01). CONCLUSION: Salvianolate improves liver histopathological changes, repairs intestinal mucosa and TJ structure, and enhances ZO-1 expression in the small intestinal mucosa in cirrhotic rats.