Neurogenetics and Clinical Evidence for the Putative Activation of the Brain Reward Circuitry by a Neuroadaptagen: Proposing an Addiction Candidate Gene Panel Map

Abstract

This document presents evidence supporting the role of the KB220/KB220Z neuroadaptagens consisting of amino-acid neurotransmitter precursors and enkephalinase-catecholamine–methyl-transferase (COMT) inhibition therapy called Neuroadaptagen Amino Acid Therapy (NAAT) in brain reward function. It is becoming increasingly clear that this novel formulation is the first neuroadaptagen known to activate the brain reward circuitry. Ongoing research repeatedly confirms the numerous clinical effects that ultimately result in significant benefits for victims having genetic antecedents for all addictive, compulsive and impulsive behaviors. These behaviors are correctly classified under the rubric of “Reward Deficiency Syndrome” (RDS). We are proposing a novel addiction candidate gene map. We present preliminary findings in the United States using qEGG and in China using Functional Magnetic Resonance Imaging (fMRI) regarding the effects of oral NAAT on the activation of brain reward circuitry in victims of SUD. In unpublished data utilizing an fMRI 2X2 design at resting state, NAAT in comparison to placebo shows activation of the caudate brain region and potentially a smoothing out of heroin-induced putamen (a site for emotionality) abnormal connectivity. Although awaiting final analysis, if confirmed by ongoing studies in China coupled with published qEEG results in America, showing an increase in alpha and low beta, NAAT may be shown to impact treatment outcomes.     

The Akt inhibitor,triciribine, ameliorates chronic hypoxia-induced vascular pruning and TGFβ-induced pulmonary fibrosis

Background and Purpose

Interstitial lung disease accounts for a group of chronic and progressive disorders associated with severe pulmonary vascular remodelling, peripheral vascular rarefaction and fibrosis, thus limiting lung function. We have previously shown that Akt is necessary for myofibroblast differentiation, a critical event in organ fibrosis. However, the contributory role of the Akt-mTOR pathway in interstitial lung disease and the therapeutic benefits of targeting Akt and mTOR remain unclear.

Experimental Approach

We investigated the role of the Akt-mTOR pathway and its downstream molecular mechanisms in chronic hypoxia- and TGFβ-induced pulmonary vascular pruning and fibrosis in mice. We also determined the therapeutic benefits of the Akt inhibitor triciribine and the mTOR inhibitor rapamycin for the treatment of pulmonary fibrosis in mice.

Key Results

Akt1^−/− mice were protected from chronic hypoxia-induced peripheral vascular pruning. In contrast, hyperactivation of Akt1 induced focal fibrosis similar to TGFβ-induced fibrosis. Pharmacological inhibition of Akt, but not the Akt substrate mTOR, inhibited hypoxia- and TGFβ-induced pulmonary vascular rarefaction and fibrosis. Mechanistically, we found that Akt1 modulates pulmonary remodelling via regulation of thrombospondin1 (TSP1) expression. Hypoxic Akt1^−/− mice lungs expressed less TSP1. Moreover, TSP1^−/− mice were resistant to adMyrAkt1-induced pulmonary fibrosis.

Conclusions and Implications

Our study identified Akt1 as a novel target for the treatment of interstitial lung disease and provides preclinical data on the potential benefits of the Akt inhibitor triciribine for the treatment of interstitial lung disease.     

The novel combination of fat clearance and immunohistochemistry improves prediction of the outcome of patients with colorectal carcinomas: a preliminary study

To evaluate the significance of micrometastases in relation to survival rate, specimens from 48 colorectal carcinoma patients were analysed after fat clearance. The number and size of the lymph nodes harbouring metastases and the significance of micrometastases for patients' survival were assessed. We found that although the majority of metastatic lymph nodes (71.8%) were 5 mm or less in diameter, their size had no effect on survival. Immunohistochemical staining of lymph nodes revealed that 15 of 25 patients with Dukes' stage B diagnosed by routine staining had micrometastases, 86% of these lymph nodes being less than 5 mm in diameter. The survival rate of this subgroup was found to be considerably poorer than that of Dukes' stage B patients with no micrometastases. None of the three patients with Dukes' stage A carcinoma had micrometastases. Since most of the metastases and micrometastases occur in lymph nodes of 5 mm and less and can be easily missed by routine examination, we suggest that fat clearance and routine immunohistochemical analysis of Dukes' stage B improve the prediction of outcome of colorectal cancer patients. Accepted: 10 February 1998     

Anti-arrhythmia effect of prolecophen in patients with extrasystole in comparison with other anti-arrhythmia drugs

Oral prolecohen (LEK, Yugoslavia) was given in a single dose of 300 mg to 15 patients with extrasystole of various genesis. The drug produced an antiarrhythmic effect in 50% of patients with ventricular extrasystole, but in those with supraventricular extrasystole. Prolecophenum showed a good tolerance. In 20% of the patients the adverse reactions appeared as mild headache, dizziness, dry mouth, malaise in the epigastric region. There is also evidence for efficacy of other antiarrhythmic agents used in this group of patients.     

Imaging techniques for muscle injury in sports medicine and clinical relevance

Magnetic resonance imaging (MRI) and ultrasound are the imaging modalities of choice to assess muscle injuries in athletes. Most authors consider MRI as the reference standard for evaluation of muscle injuries, since it superiorly depicts the extent of injuries independently of its temporal evolution, and due to the fact that MRI seems to be more sensitive for the detection of minimal injuries. Furthermore, MRI may potentially allow sports medicine physicians to more accurately estimate recovery times of athletes sustaining muscle injuries in the lower limbs, as well as the risk of re-injury. However, based on data available, the specific utility of imaging (including MRI) regarding its prognostic value remains limited and controversial. Although high-quality imaging is systematically performed in professional athletes and data extracted from it may potentially help to plan and guide management of muscle injuries, clinical (and functional) assessment is still the most valuable tool to guide return to competition decisions.     

Prevalence and behavioural risks for HIV and HCV infections in a population of drug users of Dakar,Senegal: the ANRS 12243 UDSEN study

Objectives

Data on the extent of drug use and associated HIV, hepatitis C and hepatitis B infection in West Africa are lacking. The objectives of ANRS12244 UDSEN study were to estimate the size of the heroin and/or cocaine drug user (DU) population living in the Dakar area (Senegal), and assess the prevalence and risk factors of HIV, hepatitis C virus (HCV) and hepatitis B virus (HBV), including behavioural determinants in this population, in order to set up an integrated prevention and treatment programme for DUs.

Design and methods

A capture-recapture method was applied for population size estimation, whereas the respondent-driven sampling (RDS) method was used to recruit a sample of DUs living in the Dakar area and determine HIV, HBV and HCV prevalence. Behavioural data were gathered during face-to-face interviews, and blood samples were collected on dried blood spots for analysis in a central laboratory. Data analysis was performed using the RDS analysis tool, and risk factors were determined by logistic regression. Access to laboratory results was organized for the participants.

Results

The size of the DU population in the Dakar area was estimated to reach 1324 (95% confidence interval (95% CI: 1281–1367)). Based on the 506 DUs included in the study, the HIV, HCV and HBV prevalence were 5.2% (95% CI: 3.8–6.3), 23.3% (95% CI: 21.2–25.2) and 7.9% (95% CI: 5.2–11.1), respectively. In people who inject drugs (PWID), prevalence levels increased to 9.4% for HIV and 38.9% for HCV (p=0.001 when compared to those who never injected). Women were more at risk of being HIV infected (prevalence: 13.04% versus 2.97% in males, p=0.001). Being PWID was a risk factor for HCV and HIV infection (odds ratio, OR: 2.7, 95% CI: 1.7–4.3, and OR: 4.3, 95% CI: 1.7–10.7, respectively), whereas older age and female sex were additional risk factors for HIV infection (10% increase per year of age, p=0.03 and OR: 4.9, 95% CI: 1.6–156, respectively). No specific determinant was associated with the risk of HBV infection.

Conclusions

High HIV and HCV prevalence were estimated in this population of DUs (including non-injectors) living in the Dakar area, Senegal, whereas HBV prevalence was close to that of the global Senegalese population, reflecting a risk of infection independent of drug use. Women seem to be highly vulnerable and deserve targeted interventions for decreasing exposure to HIV, while behavioural risk factors for HIV and HCV include the use of unsafe injections, reflecting the urgent need for developing harm reduction interventions and access to opioid substitution therapy services.