Repetitive transcranial magnetic stimulation modulates coupling among large-scale brain networks in heroin-dependent individuals: A randomized resting-state functional magnetic resonance imaging study.

The abnormal interactions of three key large-scale brain networks (default mode [DMN], salience and executive control [ECN]) were showed underlie dysfunctions in heroin addiction. Repetitive transcranial magnetic stimulation (rTMS) targeting the left dorsolateral prefrontal cortex (DLPFC) is a potential treatment for heroin addiction. It is unclear whether impaired coupling among the large-scale brain networks would be improved by rTMS in treated heroin-dependent individuals. Thirty-five heroin-dependent individuals were included in this sham-controlled, randomized study. The patients received either active or sham rTMS for 1 week. The craving for heroin and resting-state functional magnetic resonance imaging data were collected before and after 1-week rTMS. Twenty-two healthy subjects were included as controls not receiving rTMS. After 1-week rTMS, only the active rTMS group showed a significant decrease in spontaneous and heroin cue-induced craving. The coupling between left DLPFC (a key node of left ECN) and left parahippocampal gyrus (PHG, included in DMN) significantly increased for the active group with a tendency towards that of controls. The coupling between the right precentral gyrus and three key regions included in DMN (posterior cingulate cortex/precuneus and bilateral inferior parietal cortex) significantly decreased for the active group with a tendency towards that of healthy controls. For the active rTMS individuals, the left DLPFC-PHG coupling negatively correlated with the spontaneous craving and the drug cue-induced craving. It suggested that the rTMS could reduce heroin craving, which might be related to the modulation of ECN-DMN coupling. This finding might shed light on the mechanism of rTMS for heroin addiction treatment.

MicroRNA-101 inhibits rat cardiac hypertrophy by targeting Rab1a.

Cardiac hypertrophy is a primary pathological change associated with cardiovascular diseases. Dysregulated microRNAs are frequent in cardiovascular diseases and contribute to cardiac hypertrophy by regulating a series of targeted genes. In this study, a rat model of cardiac hypertrophy was created by transverse abdominal aortic constriction, and cardiomyocyte hypertrophy in cultured neonatal rat cardiomyocytes was induced using angiotensin II (AngII) to investigate the role of miR-101 in myocardial hypertrophy. We demonstrated that miR-101 was downregulated in both the transverse abdominal aortic constriction rat model and hypertrophic cardiac myocytes. The overexpression of miR-101 in neonatal rat cardiomyocytes, which was accompanied by a reduced Rab1a level, inhibits 3 cardinal features of cardiomyocyte hypertrophy: fetal gene expression, protein synthesis, and cell enlargement. Conversely, the downregulation of miR-101 reverses these effects. Furthermore, the luciferase reporter system demonstrated that Rab1a is a target gene of miR-101, and the ectopic expression of Rab1a can reverse the cardiomyocyte hypertrophy inhibitory activity of miR-101. Taken together, our findings identify miR-101 as an important regulator in cardiac hypertrophy and implicate the potential application of miR-101 in the therapy of cardiac hypertrophy.

Regional cerebral metabolism alterations and functional connectivity in individuals with opioid use disorder: An integrated resting-state PET/fMRI study.

Individuals with opioid use disorder (OUD) have been reported to show abnormal brain metabolism and impaired coupling among brain networks such as the default mode network (DMN), salience network (SN), and executive control network (ECN). However, the characteristics of brain glucose metabolism and its related functions in the brain networks in individuals with OUD remain unknown. Thirty-six individuals with OUD and thirty matched healthy controls (HCs) were recruited in this integrated positron emission tomography/magnetic resonance imaging (PET/MRI) study. Differences in glucose metabolism were analyzed by using 18F-fluorodeoxyglucose (18F-FDG), and the corresponding coupling characteristics of the individuals with OUD were also analyzed. The individuals with OUD showed widespread bilateral hypometabolism in the middle temporal gyrus (MTG), superior temporal gyrus, angular gyrus, supramarginal gyrus, inferior parietal lobe, Rolandic operculum, and left insula, but obvious hypermetabolism in the brainstem and left cerebellum. Meanwhile, in individuals with OUD, the hypometabolism of right MTG which is included in the DMN was accompanied by decreased coupling with the left superior frontal gyrus and right superior parietal gyrus which are included in the ECN. Furthermore, individuals with OUD showed a positive correlation between the duration of heroin use and glucose metabolism of the left MTG. The individuals with OUD were characterized by widespread bilateral hypometabolism in the temporal and parietal regions but obvious hypermetabolism in the brainstem and left cerebellum. The results suggest that the hypometabolism in the temporal and parietal regions might be related to DMN dysfunction and the hypermetabolism in the brainstem and left cerebellum may be compensate for other brain regions showing hypometabolism. In particular, hypometabolism in the self-referential-related DMN regions in OUD might attenuate their relationships with the inhibitory-control-related ECN regions. These findings highlight the importance of evaluating the metabolic and functional profiles of the right MTG in future studies on the treatment of OUD.

Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: An open-label pilot study.

BACKGROUND: Deep brain stimulation (DBS) is currently used to treat addiction, with the nucleus accumbens (NAc) as one promising target. The anterior limb of the internal capsule (ALIC) is also a potential target, as it carries fiber tracts connecting the mesocorticolimbic circuits that are crucially involved in several psychiatric disorders, including addiction. Stimulating the NAc and ALIC simultaneously may have a synergistic effect against addiction. METHODS: Eight patients with a long history of heroin use and multiple relapses, despite optimal conventional treatments, were enrolled. Customized electrodes were implanted through the ALIC into the NAc, and deep brain stimulation (DBS) treatment began two weeks after surgery. The patients were followed for at least 24 months. The duration of drug-free time, severity of drug cravings, psychometric evaluations, and PET studies of glucose metabolism before and after DBS were conducted. All adverse events were recorded. RESULTS: With DBS, five patients were abstinent for more than three years, two relapsed after abstaining for six months, and one was lost of follow-up at three months. The degree of cravings for drug use after DBS was reduced if the patients remained abstinent (p < 0.001). Simultaneous DBS of the NAc and ALIC also improved the quality of life, alleviated psychiatric symptoms, and increased glucose metabolism in addiction-related brain regions. Moreover, stimulation-related adverse events were few and reversible. CONCLUSIONS: Simultaneous DBS of the NAc and ALIC appears to be safe, with few side effects, and may prevent long-term heroin relapse after detoxification in certain patients. (This trial was registered at ClinicalTrials.gov, NCT01274988).

Therapeutic effects of adenovirus-mediated CD and NIS expression combined with Na131I/5-FC on human thyroid cancer.

Thyroid cancer is the most common type of malignant endocrine tumor diagnosed. Previous studies have indicated that gene therapy is the most promising and effective therapeutic method for thyroid cancer. Therefore, in the present study, Na131I/5-fluorocytosine (5-FC) treatment was combined with cytosine deaminase (CD, encoded by the CDA gene) and sodium iodide symporter (NIS, encoded by the SLC5A5 gene) to act together as a therapeutic tool for thyroid cancer. The present study explored the combined cytotoxic effects of adenovirus-mediated CD and NIS under the control of the progression elevated gene-3 (PEG-3) promoter (Ad-PEG-3-CD-NIS) with Na131I/5-FC against the human thyroid cancer TT cell line in vitro. The PEG-3 fragment was obtained by polymerase chain reaction (PCR) using rat genomic DNA as the template, and then Ad-PEG-3-CDA-SLC5A5 was constructed using XbaI. TT cells were transfected by recombinant adenovirus. The method of reverse transcription-quantitative PCR was performed to test the expression of CD and NIS at the level of transcription. The morphological change was assessed by fluorescence microscopy and investigated by western blot analysis. An MTT assay was used to determine the number of living cells inhibited by single or combination therapies on TT cells. The results indicated that the PEG-3 was successfully cloned, and was also positively regulated in 293 cells. CDA and SLC5A5 genes were highly expressed in TT cells. Na131I combined with 5-FC significantly decreased the human thyroid cancer cells. In conclusion, combination therapy of Ad-PEG3-CDA-SLC5A5 and Na131I/5-FC induces significantly more apoptotic characteristics than either single treatment with Ad-PEG-3-CDA-SLC5A5 or Na131I/5-FC, and low doses of Ad-PEG-3-CDA-SLC5A5 enhanced the cytotoxic effects.

Four FCRL3 Gene Polymorphisms (FCRL3_3, _5, _6, _8) Confer Susceptibility to Multiple Sclerosis: Results from a Case-Control Study.

Multiple sclerosis (MS) is an autoimmune/inflammatory neurodegenerative disease which mainly affects the central nervous system in young adults. Fc-receptor-like-3 (FCRL3) gene, which involved in immune cell regulation, has drawn lots of attentions. This study aims to investigate the association between common polymorphisms of FCRL3 gene and MS risk in a Chinese Han population. Nine single nucleotide polymorphisms (SNPs) were genotyped in 120 patients and 240 healthy controls through PCR assay. t test and chi-square test was conducted to find a possible association between FCRL3 genetic mutations and risk of MS. This analysis results performed that four SNPs, rs7528684 (FCRL3_3), rs945635 (FCRL3_5), rs3761959 (FCRL3_6), and rs2282284 (FCRL3_8), were significantly associated with the risk of MS. Further haplotype analysis showed two haplotypes of FCRL3_3, 5, 6, 8, CCAG and CGAG, presented the significant associations with the susceptibility to MS. Four SNPs in FCRL3 gene could possibly associate with the susceptibility of MS in a Chinese Han population. Moreover, the haplotype analysis confirmed that the linkage disequilibrium exists in polymorphisms in FCRL3. Based on the supporting evidence, we deduced that FCRL3_3C, FCRL3_5C, FCRL3_6A, and FCRL3_8G caused increased risk of MS. Nevertheless, large cohort studies are required in the future to validate the autoimmune function.