Effects of high-dose baclofen on cue reactivity in alcohol dependence: A randomized,placebo-controlled pharmaco-fMRI study

Increased functional brain response towards alcohol-associated stimuli is a neural hallmark of alcohol dependence and a promising target for pharmacotherapy. For the first time, we assessed the effects of individually titrated high-dose baclofen on cue reactivity and functional connectivity in alcohol-dependent (AD) patients in a randomized controlled trial (RCT).We investigated 23 recently detoxified AD patients and 23 matched healthy controls (HC) with a cue reactivity functional magnetic resonance imaging task. Patients were further scanned at baseline without medication and during treatment with high-dose baclofen/placebo (30–270 mg/d). Analyses were conducted for alcohol cue-elicited brain response, alcohol cue-modulated and stimulus-independent functional connectivity with left ventral tegmental area (VTA) as seed region.At baseline, AD patients (N?=?23) showed increased cue-elicited brain activation in the ventral striatum (VS) compared to HC (N?=?23), which was decreased at the second scanning session compared to baseline. Patients receiving baclofen (N?=?10) showed a significant stronger decrease in cue-elicited brain activation in left orbitofrontal cortex (OFC), bilateral amygdala and left VTA than patients receiving placebo (N?=?13). Treatment with baclofen further led to a decrease in alcohol cue-modulated functional connectivity between left VTA and left anterior cingulate cortex (ACC) as well as left medial prefrontal cortex (MPFC). Regarding clinical outcome, significantly more patients of the baclofen group remained abstinent during the high-dose period.Baclofen specifically decreased cue-elicited brain responses in areas known to be involved in the processing of salient (appetitive and aversive) stimuli. Treatment with high-dose baclofen seems to provide a pharmacological relief of this neural “warning signal” evoked by alcohol-related cues, thereby possibly supporting patients in remaining abstinent.Trial Registration Identifier of the main trial [BACLAD study] at clinicaltrials.gov: NCT01266655.     

Effects of squalene on expression of LDLR in HepG2 cells and its mechanism北大核心CSCD

Aim To investigate the effect of squalene on LDLR expression in HepG2 cells and its mechanism of down-regulated cholesterol. Methods The proliferation of HepG2 cells exposed to squalene at different concentrations was measured by MTT assay. The effect of squalene on the expression of LDLR in HepG2 cells was measured by flow cytometry and fluorescence mi-croscopy. The effect of different concentrations of squalene on the interaction between SCAP and Insig2, two key protein molecules of SREBP pathway, was assayed by FRET technology. Results MTT results showed that squalene had inhibitory effect on the proliferation of HepG2 cells in a dose-dependent manner. Flow cytometry and fluorescence microscopy results showed that squalene enhanced LDLR expression in HepG2 cells compared with the control group. The results of FRET technology revealed that compared with model control group, the YFP fluorescence value in Squalene group dramatically declined, and the YFP fluorescence value of each drug group decreased with the range of 5-25 |xmol L1 squalene concentration. Conclusions Squalene may promote the expression of LDLR in HepG2 cells through inhibiting the interaction between SCAP and Insig2 proteins in SREBP pathway, which may confirm that squalene is a potential novel drug for the down-regulation of cholesterol level. © 2018 Publication Centre of Anhui Medical University. All rights reserved.     

Modified translationally controlled tumor protein-derived protein transduction domain enhances nasal delivery of exendin-4 as shown with insulin

Protein transduction domains (PTDs) have been shown to promote the delivery of therapeutic proteins or peptides into the living cells. In a previous study, we showed that the double mutant of TCTP-PTD 13, TCTP-PTD 13M2, was more effective in the delivery of insulin than the wild-type TCTP-PTD 13. In this study, we applied this approach to the nasal delivery of a different peptide, exendin-4, using as carriers, several modified TCTP-PTDs, such as TCTP-PTD 13M1, 13M2, and 13M3. Nasal co-administration of TCTP-PTD 13M2 with exendin-4 showed the highest exendin-4 uptake among the three analogs in normal rats, and also decreased blood glucose levels by 43.3% compared with that of exendin-4 alone and by 18.6% compared with that of exendin-4 plus TCTP-PTD 13 in diabetic mice. We also designed an additional covalently linked conjugate of TCTP-PTD 13M2 and exendin-4 and evaluated its hypoglycemic effect after subcutaneous or intranasal delivery. Subcutaneous administration of exendin-4 that its C-terminus is covalently linked to TCTP-PTD 13M2 showed hypoglycemic effect of 42.2% compared to that in untreated group, whereas intranasal delivery was not successful in diabetic mice. We conclude that a simple mixing TCTP-PTD 13M2 with peptide/protein drugs can be potentially a generally applicable approach for intranasal delivery into animals.     

Psychometric validation of the SF-36<Superscript>®</Superscript> Health Survey in ulcerative colitis: results from a systematic literature review

Purpose

To conduct a systematic literature review of the reliability, construct validity, and responsiveness of the SF-36^® Health Survey (SF-36) in patients with ulcerative colitis (UC).

Methods

We performed a systematic search of electronic medical databases to identify published peer-reviewed studies which reported scores from the eight scales and/or two summary measures of the SF-36 collected from adult patients with UC. Study findings relevant to reliability, construct validity, and responsiveness were reviewed.

Results

Data were extracted and summarized from 43 articles meeting inclusion criteria. Convergent validity was supported by findings that 83% (197/236) of correlations between SF-36 scales and measures of disease symptoms, disease activity, and functioning exceeded the prespecified threshold (r ≥ |0.40|). Known-groups validity was supported by findings of clinically meaningful differences in SF-36 scores between subgroups of patients when classified by disease activity (i.e., active versus inactive), symptom status, and comorbidity status. Responsiveness was supported by findings of clinically meaningful changes in SF-36 scores following treatment in non-comparative trials, and by meaningfully larger improvements in SF-36 scores in treatment arms relative to controls in randomized controlled trials. The sole study of SF-36 reliability found evidence supporting internal consistency (Cronbach’s α ≥ 0.70) for all SF-36 scales and test–retest reliability (intraclass correlation coefficient ≥0.70) for six of eight scales.

Conclusions

Evidence from this systematic literature review indicates that the SF-36 is reliable, valid, and responsive when used with UC patients, supporting the inclusion of the SF-36 as an endpoint in clinical trials for this patient population.