Patients with first-episode psychosis in northern Taiwan: neurocognitive performance and niacin response profile in comparison with schizophrenia patients of different familial loadings and relationship with clinical features.

BACKGROUND: Examining patients with first-episode psychosis (FEP) provides opportunities to better understand the mechanism underlying these illnesses. By incorporating quantitative measures in FEP patients, we aimed to (1) determine the baseline distribution of clinical features; (2) examine the impairment magnitude of the quantitative measures by comparing with external controls and then the counterparts of schizophrenia patients of different familial loadings; and (3) evaluate whether these quantitative measures were associated with the baseline clinical features. METHODS: Patients with FEP were recruited from one medical center, two regional psychiatric centers, and two private clinics in northern Taiwan with clinical features rated using the Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale. Quantitative measurements included the Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), niacin response abnormality (NRA), and minor physical anomalies and craniofacial features (MPAs). To evaluate the relative performance of the quantitative measures in our FEP patients, four external comparison groups from previous studies were used, including three independent healthy controls for the CPT, WCST, and NRA, respectively, and one group of treatment-resistant schizophrenia patients for the MPAs. Additionally, patients from simplex families and patients from multiplex families were used to assess the magnitude of FEP patients' impairment on the CPT, WCST, and NRA. RESULTS: Among the 80 patients with FEP recruited in this study (58% female, mean age = 25.6 years, mean duration of untreated psychosis = 132 days), the clinical severity was mild to moderate (mean PANSS score = 67.3; mean PSP score = 61.8). Patients exhibited both neurocognitive and niacin response impairments (mean Z-scores: -1.24 for NRA, - 1.06 for undegraded d', - 0.70 for degraded d', - 0.32 for categories achieved, and 0.44 for perseverative errors) but did not show MPAs indicative of treatment resistance. Among these quantitative measures, three of the four neurocognitive indices were correlated with the baseline clinical features, whereas NRA did not show such correlation. CONCLUSIONS: This FEP study of Taiwanese patients revealed the presence of neurocognitive performance and niacin response and their different relationships with clinical features, rendering this sample useful for future follow-up and incorporation of multiomics investigation.

pubmedKB: an interactive web server for exploring biomedical entity relations in the biomedical literature.

With the proliferation of genomic sequence data for biomedical research, the exploration of human genetic information by domain experts requires a comprehensive interrogation of large numbers of scientific publications in PubMed. However, a query in PubMed essentially provides search results sorted only by the date of publication. A search engine for retrieving and interpreting complex relations between biomedical concepts in scientific publications remains lacking. Here, we present pubmedKB, a web server designed to extract and visualize semantic relationships between four biomedical entity types: variants, genes, diseases, and chemicals. pubmedKB uses state-of-the-art natural language processing techniques to extract semantic relations from the large number of PubMed abstracts. Currently, over 2 million semantic relations between biomedical entity pairs are extracted from over 33 million PubMed abstracts in pubmedKB. pubmedKB has a user-friendly interface with an interactive semantic graph, enabling the user to easily query entities and explore entity relations. Supporting sentences with the highlighted snippets allow to easily navigate the publications. Combined with a new explorative approach to literature mining and an interactive interface for researchers, pubmedKB thus enables rapid, intelligent searching of the large biomedical literature to provide useful knowledge and insights. pubmedKB is available at https://www.pubmedkb.cc/.

Naringin Induces ROS-Stimulated G1 Cell-Cycle Arrest and Apoptosis in Nasopharyngeal Carcinoma Cells.

Naringin, a bioflavonoid compound from grapefruit or citrus, exerts anticancer activities on cervical, thyroid, colon, brain, liver, lung, thyroid, and breast cancers. The present investigation addressed exploring the anticancer effects of naringin on nasopharyngeal carcinoma (NPC) cells. Naringin exhibits a cytotoxic effect on NPC-TW 039 and NPC-TW 076 cells with IC50 372/328 and 394/307 µM for 24 or 48 h, respectively, while causing little toxicity toward normal gingival epithelial (SG) cells (>500/500 µM). We established that naringin triggered G1 arrest is achieved by suppressing cyclin D1, cyclin A, and CDK2, and upregulating p21 protein in NPC cells. Exposure of NPC cells to naringin caused a series of events leading to apoptosis including morphology change (cell shrinkage and membrane blebbing) and chromatin condensation. Annexin V and PI staining indicated that naringin treatment promotes necrosis and late apoptosis in NPC cells. DiOC6 staining showed a decline in the mitochondrial membrane potential by naringin treatment, which was followed with cytochrome c release, Apaf-1/caspase-9/-3 activation, PARP cleavage, and EndoG expression in NPC cells. Naringin upregulated proapoptotic Bax and decreased antiapoptotic Bcl-xL expression, and dysregulated Bax/Bcl-xL ratio in NPC cells. Notably, naringin enhanced death receptor-related t-Bid expression. Furthermore, an increased Ca2+ release by naringin treatment which instigated endoplasmic reticulum stress-associated apoptosis through increased IRE1, ATF-6, GRP78, GADD153, and caspase-12 expression in NPC cells. In addition, naringin triggers ROS production, and inhibition of naringin-induced ROS generation by antioxidant N-acetylcysteine resulted in the prevention of G1 arrest and apoptosis in NPC cells. Naringin-induced ROS-mediated G1 arrest and mitochondrial-, death receptor-, and endoplasmic reticulum stress-mediated apoptosis may be a promising strategy for treating NPC.

Prescribing patterns for older-age bipolar disorder patients discharged from two public mental hospitals in Taiwan, 2006-2019.

BACKGROUND: Older-age bipolar disorder (OABD) is commonly defined as bipolar disorder in individuals aged 60 or more. There have been no studies to examine temporal trends in the pharmacological treatment of OABD. We aimed to investigate prescription changes among OABD patients discharged from two public mental hospitals in Taiwan from 2006 to 2019. METHODS: OABD patients discharged from the two study hospitals, from 1 January 2006 to 31 December 2019 (n = 1072), entered the analysis. Prescribed drugs at discharge, including mood stabilisers (i.e., lithium, valproate, carbamazepine, and lamotrigine), antipsychotics (i.e., second- and first-generation antipsychotics (SGAs and FGAs)), and antidepressants, were investigated. Complex polypharmacy was defined as the use of three or more agents among the prescribed drugs. Temporal trends of each prescribing pattern were analyzed using the Cochran-Armitage Trend test. RESULTS: The most commonly prescribed drugs were SGAs (72.0%), followed by valproate (48.4%) and antidepressants (21.7%). The prescription rates of SGAs, antidepressants, antidepressants without mood stabilisers, and complex polypharmacy significantly increased over time, whereas the prescription rates of mood stabilisers, lithium, FGAs, and antidepressants plus mood stabilisers significantly decreased. CONCLUSIONS: Prescribing patterns changed remarkably for OABD patients over a 14-year period. The decreased use of lithium and increased use of antidepressants did not reflect bipolar treatment guidelines. Future research should examine whether such prescribing patterns are associated with adverse clinical outcomes.

Multi-omic analysis suggests tumor suppressor genes evolved specific promoter features to optimize cancer resistance.

Tumor suppressor genes (TSGs) exhibit distinct evolutionary features. We speculated that TSG promoters could have evolved specific features that facilitate their tumor-suppressing functions. We found that the promoter CpG dinucleotide frequencies of TSGs are significantly higher than that of non-cancer genes across vertebrate genomes, and positively correlated with gene expression across tissue types. The promoter CpG dinucleotide frequencies of all genes gradually increase with gene age, for which young TSGs have been subject to a stronger evolutionary pressure. Transcription-related features, namely chromatin accessibility, methylation and ZNF263-, SP1-, E2F4- and SP2-binding elements, are associated with gene expression. Moreover, higher promoter CpG dinucleotide frequencies and chromatin accessibility are positively associated with the ability of TSGs to resist downregulation during tumorigenesis. These results were successfully validated with independent datasets. In conclusion, TSGs evolved specific promoter features that optimized cancer resistance through achieving high expression in normal tissues and resistance to downregulation during tumorigenesis.

Autophagy in intracellular bacterial infection.

Autophagy is a conserved intracellular degradation process enclosing the bulk of cytosolic components for lysosomal degradation to maintain cellular homeostasis. Accumulating evidences showed that a specialized form of autophagy, known as xenophagy, could serve as an innate immune response to defend against pathogens invading inside the host cells. Correspondingly, infectious pathogens have developed a variety of strategies to disarm xenophagy, leading to a prolonged and persistent intracellular colonization. In this review, we first summarize the current knowledge about the general mechanisms of intracellular bacterial infections and xenophagy. We then focus on the ongoing battle between these two processes.

Streptococcus thermophilus Inhibits Colorectal Tumorigenesis Through Secreting ß-Galactosidase.

BACKGROUND & AIMS: Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples. Here, we aim to investigate whether this bacterium could act as a prophylactic for CRC prevention. METHODS: The antitumor effects of S thermophilus were assessed in cultured colonic epithelial cells and in 2 murine models of intestinal tumorigenesis. The tumor-suppressive protein produced by S thermophilus was identified by mass spectrometry and followed by ß-galactosidase activity assay. The mutant strain of S thermophilus was constructed by homologous recombination. The effect of S thermophilus on the gut microbiota composition was assessed by shotgun metagenomic sequencing. RESULTS: Oral gavage of S thermophilus significantly reduced tumor formation in both Apcmin/+ and azoxymethane-injected mice. Coincubation with S thermophilus or its conditioned medium decreased the proliferation of cultured CRC cells. ß-Galactosidase was identified as the critical protein produced by S thermophilus by mass spectrometry screening and ß-galactosidase activity assay. ß-Galactosidase secreted by S thermophilus inhibited cell proliferation, lowered colony formation, induced cell cycle arrest, and promoted apoptosis of cultured CRC cells and retarded the growth of CRC xenograft. The mutant S thermophilus without functional ß-galactosidase lost its tumor-suppressive effect. Also, S thermophilus increased the gut abundance of known probiotics, including Bifidobacterium and Lactobacillus via ß-galactosidase. ß-Galactosidase-dependent production of galactose interfered with energy homeostasis to activate oxidative phosphorylation and downregulate the Hippo pathway kinases, which partially mediated the anticancer effects of S thermophilus. CONCLUSION: S thermophilus is a novel prophylactic for CRC prevention in mice. The tumor-suppressive effect of S thermophilus is mediated at least by the secretion of ß-galactosidase.

Time to Rehospitalization for Different Oral Risperidone Dosing Frequencies in Patients With Schizophrenia: A 17-Year Retrospective Cohort Study.

PURPOSE: This retrospective cohort study aimed at determining whether the daily administration pattern of risperidone influences time to rehospitalization in patients with schizophrenia. Previous studies have related more frequent dosing to poor medication adherence. This causes suboptimal disease control, which entails shorter times between hospital admissions. METHODS: We investigated admission records from 1 tertiary psychiatric hospital in Taiwan. Patients were included if they had a main diagnosis of schizophrenia or schizoaffective disorder and were receiving oral risperidone. The enrollment period was July 2001 to December 2016; we observed whether rehospitalization would occur in subsequent periods of 3-month, 6-month, and 1-year follow-ups. RESULTS: There were 1504 patients grouped by daily dosing frequency of oral risperidone. Most patients (95.9%) received 6 mg or less of risperidone per day. After adjustment for covariates, including daily total dosages of risperidone, it showed an independent association that more frequent dosing frequency of risperidone had higher hazard ratios (HRs) of rehospitalizations (in 1-year follow-up: 2 vs 1 dosing a day: HR, 1.566; 3 vs 1 dosing a day: HR, 3.010; 4 vs 1 dosing a day: HR, 4.305) and a significant trend of more possible rehospitalizations (Cochran-Armitage test for trend: P < 0.001) in 3-month, 6-month, and 1-year follow-up. CONCLUSIONS: Patients receiving more doses of risperidone per day are more likely to be readmitted within 1 year following last discharge, indicating poorer treatment outcomes for patients who receive more frequent doses.

Hydrogels: Properties and Applications in Biomedicine.

Hydrogels are crosslinked polymer chains with three-dimensional (3D) network structures, which can absorb relatively large amounts of fluid. Because of the high water content, soft structure, and porosity of hydrogels, they closely resemble living tissues. Research in recent years shows that hydrogels have been applied in various fields, such as agriculture, biomaterials, the food industry, drug delivery, tissue engineering, and regenerative medicine. Along with the underlying technology improvements of hydrogel development, hydrogels can be expected to be applied in more fields. Although not all hydrogels have good biodegradability and biocompatibility, such as synthetic hydrogels (polyvinyl alcohol, polyacrylamide, polyethylene glycol hydrogels, etc.), their biodegradability and biocompatibility can be adjusted by modification of their functional group or incorporation of natural polymers. Hence, scientists are still interested in the biomedical applications of hydrogels due to their creative adjustability for different uses. In this review, we first introduce the basic information of hydrogels, such as structure, classification, and synthesis. Then, we further describe the recent applications of hydrogels in 3D cell cultures, drug delivery, wound dressing, and tissue engineering.

The relation between second-generation antipsychotics and laxative use in elderly patients with schizophrenia.

BACKGROUND: We aimed to investigate factors associated with concomitant laxative use among elderly patients with schizophrenia, discharged on second-generation antipsychotics (SGAs), from two large public psychiatric hospitals in Taiwan. METHODS: Elderly patients with schizophrenia who were discharged between 2006 and 2019 and received SGA monotherapy at discharge were included in the analysis. Multivariate logistic regression was used to identify factors associated with regular laxative use at discharge. The Cochrane-Armitage trend test was used to evaluate whether significant time trends existed for rates of laxative use at discharge. RESULTS: A total of 2591 elderly patients with schizophrenia were discharged during the study period, and 1727 of 2591 patients who met the inclusion criteria were included for analysis. Of these 1727 patients, 732 (42.4%) also received concomitant laxatives. Female gender, mood stabiliser use and concomitant diabetes mellitus were found to be associated with increased laxative use. Among SGAs, clozapine was associated with the highest rate of laxative use, followed by zotepine, quetiapine, olanzapine and risperidone. Additionally, risperidone, amisulpride, aripiprazole, paliperidone and sulpiride were associated with comparable rates of laxative use. Laxative use rates grew over time from 30.8% in 2006 to 46.6% in 2019 (z = 4.83, P < 0.001). CONCLUSIONS: Laxative use is common in elderly schizophrenia patients treated with SGAs. In cases of clinically significant constipation, switching to an SGA with a lower risk for constipation, or discontinuing the use of mood stabilisers should be considered, if clinically feasible.

Relationship between choice of opioid agonist therapy and distance from patients' residences in Taiwan, 2012-2014.

BACKGROUND: Choice of opioid agonist therapy (OAT) for opioid use disorder (OUD) can be impacted by variables such as age, sex, and socioeconomic status. However, it remains unknown whether accessibility of treatment affects patient choice of OAT. OBJECTIVES: To investigate the association between distance to the treatment site and choice of OAT. METHODS: Electronic records were collected for the last outpatient visits of individuals with OUD between January 1, 2012 and December 31, 2014. The address of each patient was processed using the Geographic Information System to obtain the distance between place of residence and the hospital. Multivariate logistic regression was used to assess the correlation between individual drug selection and distance of residence. Among the study population of 2804 patients (81.5% male), 74.1% were receiving methadone while 25.8% were receiving buprenorphine. The vast majority (95%) of all patients lived within 50 km of the hospital, so regression analysis was limited to this distance. Sensitivity analysis was estimated using robust Poisson regression. RESULTS: Logistic regression revealed that every 1-km increase in distance from home to hospital increased the odds ratio of choosing sublingual buprenorphine tablets over methadone by 1.05 (p = .02, 95% confidence interval (CI) = 1.02-1.08). CONCLUSIONS: Patients living closer to the treatment center were more likely to choose methadone as treatment, while patients living farther away were more likely to choose sublingual buprenorphine tablets. To mitigate the influence of travel distance on therapy choice, we recommend that more medical institutions participate in OAT services.

Comparison of irregular flux viewer system with BONENAVI version for identification of Tc-99m MDP whole body bone scan metastasis images.

The Tc-99m methylene diphosphonate (MDP) whole body bone scan (WBBS) has been widely accepted as a method of choice for the initial diagnosis of bone and joint changes in patients with oncologic diseases. The WBBS has shown high sensitivity but relatively low specificity due to bone variation. This study aims to use the self-developing irregular flux viewer (IFV) system to predict possible bone lesions in planar WBBS. The study uses gradient vector flow (GVF) and self-organizing map (SOM) methods to analyze the blood fluid-dynamics and evaluate hot points. The evaluation includes a selection of 368 patients with bone metastasis from prostate cancer, lung cancer and breast cancer. Finally, we compare IFV values with BONENAVI version data. BONENAVI is a computer-assisted diagnosis system that analyzes bone scintigraphy automatically. The analysis shows that the IFV system achieves sensitivities of 93% for prostate cancer, 91% for breast cancer, and 83% for lung cancer, respectively. On the other hand, our proposed approach achieves a higher sensitivity than the results of BONEVAVI version 2.0.5 for prostate cancer (88%), breast cancer (86%) and lung cancer (82%), respectively. The study results demonstrate that the high sensitivity and specificity of the IFV system can provide assistance for image interpretation and generate prediction values for WBBS.

Translational genomics in pancreatic ductal adenocarcinoma: A review with re-analysis of TCGA dataset.

Malignancy of the pancreas is a leading cause of cancer-related mortality, with the highest case-fatality of all cancers. Nevertheless, the lack of sensitive biomarkers and presence of biological heterogeneity precludes its early detection and effective treatment. The recent introduction of next-generation sequencing allows characterization of multiple driver mutations at genome- and exome-wide levels. Sequencing of DNA and RNA from circulating tumour cells has also opened an exciting era of non-invasive procedures for tumour detection and prognostication. This massively-parallel sequencing technology has uncovered the previously obscure molecular mechanisms, providing clues for better stratification of patients and identification of druggable targets for the disease. Identification of active oncogenic pathways and gene-gene interactions may reveal oncogene addiction and synthetic lethality. Relevant findings can be extrapolated to develop targeted and personalized therapeutic interventions. In addition to known mutational events, the role of chromosomal rearrangements in pancreatic neoplasms is gradually uncovered. Coupled with bioinformatics pipelines and epidemiological analyses, a better framework for risk stratification and prognostication of pancreatic cancer will be possible in the near future. In this review, we discuss how translational genomic studies facilitate our understanding of pathobiology, and development of novel diagnostics and therapeutics for pancreatic ductal adenocarcinoma with emphases on whole genome sequencing, whole exome sequencing, and liquid biopsies. We have also re-analyzed The Cancer Genome Atlas (TCGA) dataset to look for genetic features associated with altered survival in patients with pancreatic ductal adenocarcinoma.

Nicotine Replacement Therapy and Healthy Lifestyle Psychoeducation for Smoking Reduction in Acute Psychiatric Inpatients: A Cluster-Randomized Parallel Study.

BACKGROUND: Effectiveness of nicotine replacement therapies in acute psychiatric inpatient settings remains under-researched. The aim of this study was to compare effectiveness and acceptability of 3 different forms of nicotine replacement therapy in achieving smoking reduction among acute psychiatric inpatients. METHODS: This cluster-randomized, parallel study compared effectiveness and acceptability of nicotine inhalers, nicotine gum, and nicotine patches for smoking reduction in the acute psychiatric inpatient setting. The primary outcome was the exhaled breath carbon monoxide (CO) level change from baseline at weeks 4 and 8. Secondary outcomes included changes in nicotine withdrawal symptoms and psychiatric symptom severity. RESULTS: Three hundred ten inpatients on the acute care wards were randomly assigned to nicotine inhalers (n = 184), gum (n = 71), and patches (n = 55). Only the nicotine inhaler group showed statistically significant reduction in CO level from baseline at both weeks 4 and 8 (P < 0.001 and P = 0.032, respectively). The nicotine inhaler and the patch group showed significant decrease in nicotine withdrawal symptoms from baseline at both weeks 4 and 8. Meanwhile, the nicotine inhaler and the gum group showed significant decrease in psychiatric symptom severity from baseline at both weeks 4 and 8. Post hoc comparisons revealed that the inhaler group had a greater decrease in psychiatric symptom severity compared with the patch group. CONCLUSIONS: Nicotine inhalers may be an effective choice for smoking reduction in acute psychiatric inpatient settings given its significant effects on CO level, withdrawal symptoms, and psychiatric symptom severity, particularly during the first 4 weeks of treatment.

Mangrove-diazotroph relationships at the root, tree and forest scales: diazotrophic communities create high soil nitrogenase activities in Rhizophora stylosa rhizospheres.

BACKGROUND AND AIMS: The tidal flats on which mangrove plants grow tend to have low soil nitrogen contents because nitrogen-containing litter is repeatedly washed offshore by ebb tides. Under such circumstances, it is unclear how mangrove plants acquire the nitrogen required to support their vigorous growth. In the present work, chemical and biological characteristics of diazotrophy around mangrove plant roots were surveyed under natural conditions to elucidate mangrove-diazotroph relationships. METHODS: Soil nitrogenase activity of a representative mangrove plant, Rhizophora stylosa, which has a broad geographical distribution, was measured using the acetylene reduction assay at forest, tree and prop root scales. In addition, diazotrophic community composition was compared between rhizosphere and bulk soil based on sequencing of nifH genes. KEY RESULTS: Soil nitrogenase activity was high near prop roots, and this pattern was enhanced as soil live root content increased. At the forest scale, we observed high soil nitrogenase activity (acetylene-reducing activity) inside the forest (the highest value was 90.9 µmol C2H2 min-1 cm-3, average 46.8 ± 18.2 µmol C2H2 min-1 cm-3). Rates decreased sharply from the forest to the tidal flat (range 1.2-22.2 µmol C2H2 min-1 cm-3, average 7.9 ± 4.5 µmol C2H2 min-1 cm-3). The nifH operational taxonomic unit composition differed significantly among forest and tree rhizospheres and the bulk soil (P < 0.0001). CONCLUSIONS: Our results suggest that the accumulation of diazotrophs around R. stylosa mangrove trees enhances the supply of biologically fixed nitrogen to the mangrove roots. This supply is especially important when the soil naturally contains little nitrogen. This nitrogen acquisition system may be a key process that explains the high productivity of mangrove ecosystems.

A Comparison of Long-Acting Injectable Antipsychotics With Oral Antipsychotics on Time to Rehospitalization Within 1 Year of Discharge in Elderly Patients With Schizophrenia.

OBJECTIVE: The effectiveness of long-acting injectable antipsychotics (LAIs) in elderly patients with schizophrenia remains unclear. This study aimed to compare the effect of LAIs with oral antipsychotics (OAPs) on time to rehospitalization within 1 year of discharge in this population. Other factors potentially associated with time to rehospitalization and trends in LAI prescription rates during the study period were also investigated. METHODS: Patients over 60 years of age with schizophrenia discharged between 2006 and 2017 were followed for 1 year under naturalistic conditions. Survival analysis was used in the comparison between LAIs and OAPs regarding time to rehospitalization. Covariates thought to affect time to rehospitalization were also analyzed. The Cochran-Armitage trend test was used to evaluate whether a time trend existed for LAI prescription rates. RESULTS: The LAIs group had a significantly lower rehospitalization rate and a significantly longer time to rehospitalization within 1 year of discharge than the OAPs group. Other factors that were associated with a longer time to rehospitalization included a shorter index hospitalization during the time of the study and fewer previous hospitalizations. No significant time trend was found for LAI prescription rates during the study period. However, the prescription rate of second-generation LAIs grew significantly. CONCLUSION: LAIs were found superior to OAPs in preventing rehospitalization. A continuous increase in second-generation LAI prescription rate may be due to the better side-effect profile of second-generation LAIs compared to first-generation LAIs. More studies investigating the effectiveness of LAIs in elderly patients with schizophrenia are needed in the future.

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis.

OBJECTIVES: The intestinal epithelium compartmentalizes the sterile bloodstream and the commensal bacteria in the gut. Accumulating evidence suggests that this barrier is impaired in sepsis, aggravating systemic inflammation. Previous studies reported that cathelicidin is differentially expressed in various tissues in sepsis. However, its role in sepsis-induced intestinal barrier dysfunction has not been investigated. DESIGN: To examine the role of cathelicidin in polymicrobial sepsis, cathelicidin wild-(Cnlp+/+) and knockout (Cnlp-/-) mice underwent cecal-ligation and puncture (CLP) followed by the assessment of septic mortality and morbidity as well as histological, biochemical, immunological, and transcriptomic analyses in the ileal tissues. We also evaluated the prophylactic and therapeutic efficacies of vitamin D3 (an inducer of endogenous cathelicidin) in the CLP-induced murine polymicrobial sepsis model. RESULTS: The ileal expression of cathelicidin was increased by three-fold after CLP, peaking at 4 h. Knockout of Cnlp significantly increased 7-day mortality and was associated with a higher murine sepsis score. Alcian-blue staining revealed a reduced number of mucin-positive goblet cells, accompanied by reduced mucin expression. Increased number of apoptotic cells and cleavage of caspase-3 were observed. Cnlp deletion increased intestinal permeability to 4kD fluorescein-labeled dextran and reduced the expression of tight junction proteins claudin-1 and occludin. Notably, circulating bacterial DNA load increased more than two-fold. Transcriptome analysis revealed upregulation of cytokine/inflammatory pathway. Depletion of Cnlp induced more M1 macrophages and neutrophils compared with the wild-type mice after CLP. Mice pre-treated with cholecalciferol (an inactive form of vitamin D3) or treated with 1alpha, 25-dihydroxyvitamin D3 (an active form of VD3) had decreased 7-day mortality and significantly less severe symptoms. Intriguingly, the administration of cholecalciferol after CLP led to worsened 7-day mortality and the associated symptoms. CONCLUSIONS: Endogenous cathelicidin promotes intestinal barrier integrity accompanied by modulating the infiltration of neutrophils and macrophages in polymicrobial sepsis. Our data suggested that 1alpha, 25-dihydroxyvitamin D3 but not cholecalciferol is a potential therapeutic agent for treating sepsis.

Abnormally low prolactin levels in schizophrenia patients after switching to aripiprazole in a randomized trial: a biomarker for rebound in psychotic symptoms?

BACKGROUND: Switching to aripiprazole from other antipsychotics can avoid antipsychotic-induced hyperprolactinemia but may result in an abnormally low prolactin level. This study aimed to assess whether the aripiprazole-induced abnormally low prolactin level was a biomarker for subsequent rebound of positive symptoms in schizophrenia patients. METHODS: Participants were 63 patients in an 8-week trial of switching to aripiprazole, in which preswitching antipsychotics were maintained for the first 2 weeks and aripiprazole was fixed at 15 mg orally throughout the trial. A prolactin level of < 3.7 ng/ml was defined as abnormally low, and an increase of two or more points in the positive subscore of the Positive and Negative Syndrome Scale at two adjacent ratings was defined as a psychotic rebound. RESULTS: Among 63 patients, 25 (39.7%) had an abnormally low prolactin level and 21 (33.3%) had a psychotic rebound after switching to aripiprazole. In patients with abnormally low prolactin levels, 48.0% of them had a rebound in psychotic symptoms, whereas in those without abnormally low prolactin levels 23.7% did so. Multivariable logistic regression analysis with adjustment for sex, early age at onset, and preswitching medications revealed that abnormally low prolactin levels were associated with psychotic rebound (adjusted odds ratio = 3.55, 95% confidence interval = 1.02, 12.5). Furthermore, there was concurrency between the trend of the cumulative proportion of patients having an abnormally low prolactin level and that of the cumulative proportion of patients having a rebound in psychotic symptoms. CONCLUSIONS: An abnormally low prolactin level after switching to aripiprazole in schizophrenia patients was a potential warning sign of a psychotic rebound. Hence, monitoring of prolactin levels after switching to aripiprazole may help avoid such rebound in schizophrenia. TRIAL REGISTRATION: NCT00545467 ; Date of registration: 17/10/2007.

The factors associated with inappropriate prescription patterns of benzodiazepines and related drugs among patients with dementia.

BACKGROUND: It has been emphasised that benzodiazepines and related drugs (BZDRs) should be used cautiously in people with dementia. The aim of this study was to identify factors associated with inappropriate prescription patterns of BZDRs including polypharmacy, long-term treatment and high doses among patients with dementia taking BZDRs. METHODS: This was a retrospective chart review study of patients with dementia who were treated at the study hospital. The date that the patient was issued a catastrophic illness certificate from the National Health Insurance Administration was used as the index date. Medical records of the 2-year period after the index date were reviewed. RESULTS: A total of 308 patients with dementia were included in this study. Among them, 151 (49.0%) received at least one prescription of BZDRs. After adjusting for covariates, psychiatric comorbidities (adjusted odds ratio (aOR) = 4.74, 95% CI = 1.75-12.81), history of past suicidal behaviour (aOR = 4.25, 95% CI = 1.40-12.88) and long-term treatment with BZDRs (aOR = 3.38, 95% CI = 1.11-10.27) were associated with polypharmacy of BZDRs. Age (aOR = 1.05, 95% CI = 1.0-1.11) and polypharmacy (aOR = 3.57, 95% CI = 1.23-10.32) were associated with long-term treatment. Living with family (aOR = 3.33, 95% CI = 1.32-9.79) and fewer psychiatric admissions to the study hospital (aOR = 0.56, 95% CI = 0.36-0.86) were associated with treatment with high doses of BZDRs. CONCLUSIONS: Treatment with BZDRs is prevalent in patients with dementia. Inappropriate prescription patterns of BZDRs are not uncommon in these patients and may be interlinked.

The phytochemical polydatin ameliorates non-alcoholic steatohepatitis by restoring lysosomal function and autophagic flux.

Impaired autophagic degradation of intracellular lipids is causally linked to the development of non-alcoholic steatohepatitis (NASH). Pharmacological agents that can restore hepatic autophagic flux could therefore have therapeutic potentials for this increasingly prevalent disease. Herein, we investigated the effects of polydatin, a natural precursor of resveratrol, in a murine nutritional model of NASH and a cell line model of steatosis. Results showed that oral administration of polydatin protected against hepatic lipid accumulation and alleviated inflammation and hepatocyte damage in db/db mice fed methionine-choline deficient diet. Polydatin also alleviated palmitic acid-induced lipid accumulation in cultured hepatocytes. In both models, polydatin restored lysosomal function and autophagic flux that were impaired by NASH or steatosis. Mechanistically, polydatin inhibited mTOR signalling and up-regulated the expression and activity of TFEB, a known master regulator of lysosomal function. In conclusion, polydatin ameliorated NASH through restoring autophagic flux. The polydatin-regulated autophagy was associated with inhibition of mTOR pathway and restoration of lysosomal function by TFEB. Our study provided affirmative preclinical evidence to inform future clinical trials for examining the potential anti-NASH effect of polydatin in humans.