SUMMARY While the abuse of opiate drugs continues to rise, the neuroadaptations that occur with long-term drug exposure remain poorly understood. We describe here a series of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons, which are mediated via downregulation of AKT-mTORC2 (mammalian target of rapamycin complex-2). Chronic opiates decrease the size of VTA dopamine neurons in rodents, an effect seen in humans as well, and concomitantly increase the excitability of the cells but decrease dopamine output to target regions. Chronic morphine decreases mTORC2 activity, and overexpression of Rictor, a component of mTORC2, prevents morphine-induced changes in cell morphology and activity. Further, local knock-out of Rictor in VTA decreases DA soma size and reduces rewarding responses to morphine, consistent with the hypothesis that these adaptations represent a mechanism of reward tolerance. Together, these findings demonstrate a novel role for AKT-mTORC2 signaling in mediating neuroadaptations to opiate drugs of abuse.

Opioid receptors are critical for heroin dependence, and A118G SNP of the opioid receptor gene (OPRM1) has been linked with heroin abuse. In our population of European Caucasians (n ‫؍‬ 118), Ϸ90% of 118G allelic carriers were heroin users. Postmortem brain analyses showed the OPRM1 genotype associated with transcription, translation, and processing of the human striatal opioid neuropeptide system. Whereas down-regulation of preproenkephalin and preprodynorphin genes was evident in all heroin users, the effects were exaggerated in 118G subjects and were most prominent for preproenkephalin in the nucleus accumbens shell. Reduced opioid neuropeptide transcription was accompanied by increased dynorphin and enkephalin peptide concentrations exclusively in 118G heroin subjects, suggesting that the peptide processing is associated with the OPRM1 genotype. Abnormal gene expression related to peptide convertase and ubiquitin͞proteosome regulation was also evident in heroin users. Taken together, alterations in opioid neuropeptide systems might underlie enhanced opiate abuse vulnerability apparent in 118G individuals.drug abuse ͉ dynorphin ͉ enkephalin ͉ mRNA

These results suggest that one bout of whole body vibration can transiently increase voluntary force and muscle activation of the quadriceps muscle affected by a stroke.

Objective: to investigate the clinical usefulness of the rEharoB therapeutic System, which provides passive robot-mediated physiotherapy for patients with spastic hemiparesis. Design: Controlled, randomized, preliminary study. Patients and methods: thirty patients with hemiparesis as a consequence of upper motor neurone lesion were divided randomly into 2 groups: robotic and control. Subjects from both groups received 30 minutes of Bobath therapy sessions on 20 consecutive work days. members of the robotic group received an additional 30 minutes of robot-mediated therapy on the same days. the clinical status of each patient was assessed before the first session and at the end of the programme. the difference in the scores was statistically evaluated by t-test for dependent variables in case of parametric data and Friedman's test in case of non-parametric data. Results: the majority of the parameters measured improved in both groups, but modified Ashworth score of shoulder adductors and elbow flexors showed a statistically significant change only in the robotic group. Conclusion: the results suggest that it could be useful to supplement traditional physiotherapy with this form of robotmediated therapy. Clinical investigation of a higher number of patients is planned in the near future.

Striatal enkephalin and dynorphin opioid systems mediate reward and negative affect, respectively, relevant to addiction disorders. We examined polymorphisms of proenkephalin (PENK) and prodynorphin (PDYN) genes in relation to heroin abuse and gene expression in the human striatum and the relevance of genetic dopaminergic tone, critical for drug reward and striatal function. Heroin abuse was significantly associated with PENK polymorphic 3 UTR dinucleotide (CA) repeats; 79% of subjects homozygous for the 79-bp allele were heroin abusers. Such individuals tended to express higher PENK mRNA than the 81-bp homozygotes, but PENK levels within the nucleus accumbens (NAc) shell were most strongly correlated to catecholamine-O-methyltransferase (COMT) genotype. Control Met/ Met individuals expressed lower PENK mRNA than Val carriers, a pattern reversed in heroin users. Up-regulation of NAc PENK in Met/Met heroin abusers was accompanied by impaired tyrosine hydroxylase (TH) mRNA expression in mesolimbic dopamine neurons. In contrast to PENK, no association was detected between PDYN genotype (68-bp repeat element containing one to four copies of AP-1 binding sites in the promoter region) and heroin abuse, although there was a clear functional association with striatal PDYN mRNA expression: an increased number of inducible repeats (three and four) correlated with higher PDYN levels than adult or fetal subjects with noninducible (one and two) alleles. Moreover, PDYN expression was not related to COMT genotype. Altogether, the data suggest that dysfunction of the opioid reward system is significantly linked to opiate abuse vulnerability and that heroin use alters the apparent influence of heritable dopamine tone on mesolimbic PENK and TH function.catecholamine-O-methyltransferase ͉ drug abuse ͉ mu opioid receptor ͉ nucleus accumbens ͉ prodynorphin

The objective of the study was to investigate the chronic effect of low frequency whole body vibration (WBV) on isometric and eccentric strength of knee extensors with different force exertion capacity. It was hypothesized that (1) four-week WBV intervention with the low frequency domain would enhance muscle strength and (2) the improvement would be more pronounced in the weaker muscle. To test our hypothesis twenty patients with acute stroke were recruited. Ten patients were randomly assigned to vibration and the remaining ten patients served for control.The patients in the vibration group received WBV with 20 Hz frequency three times per week standing on a vibration platform in half squat position meanwhile flexing and extending the joints and placing the weight from one leg to the other. Knee extensor strength was determined under isometric and eccentric contraction before and after WBV intervention. Myoelectrical activity (EMG) of the vastus lateralis muscle was also measured.Significant improvement was revealed in the vibration group only. The maximum isometric torque and EMG activity increased significantly for both paretic and non-paretic leg, but the improvement was threefold greater in the vibration group. No significant alteration was found in rate of torque development. Maximum eccentric torque and EMG increased significantly for the paretic leg only. Mechanical work enhanced significantly in the paretic side only.The results of our study indicate that the selection of the effective vibration frequency depends upon the physical condition of neuromuscular system. Low vibration frequency intervention can increase the strength in weak muscles due to neuromuscular impairment and restricted physical activity.

Oral squamous cell carcinoma (OSCC) is a serious health issue worldwide that accounts for 2% to 4% of all cancer cases. Previous studies have revealed a higher yeast carriage and diversity in oral cancer patients than in healthy individuals.

The observation of increased hyperphosphorylated tau levels correlating with microglial activation in opiate abusers has been interpreted as predisposition to accelerated Alzheimer disease (AD)-related changes. The present study focused on evaluating additional neurodegeneration-related proteins, including α-synuclein and TDP-43, and p62-positive deposits. We performed a systematic mapping of protein deposits in the brains of 27 individuals with documented heroin addiction (age: 19-40) and compared with 11 controls (age: 15-40). We confirm previous findings that heroin addiction associates with tau hyperphosphorylation in predilection brain areas for aging and AD. Furthermore, we show that this occurs also in areas implicated in the molecular disturbances and in vivo neuronal networks related to heroin abuse. There was, however, no presence of Amyloid-beta deposits. We extend previous findings by showing the lack of TDP-43 or α-synuclein pathology and emphasize the independent effect of the duration of drug use on the appearance of age-related p62-positive neuritic profiles. These observations provide unique insights about neuropathological alterations in the brains of young heroin addicts and have implications about brain aging and the influences of environmental and toxic factors.