Genotrim, a DNA-customized nutrigenomic product, targets genetic factors of obesity: hypothesizing a dopamine-glucose correlation demonstrating reward deficiency syndrome (RDS)

Obesity is the second largest cause of preventable death in the United States. Historically, obesity was considered a behavioral problem that could be simply addressed with behavioral modifications in diet and exercise. As scientific advancements have demonstrated in other neurological healthcare conditions such as alcoholism, there are important biological and genetic components that limit the efficacy of behavioral adjustments alone. In light of data suggesting frequent co-morbidities to obesity, including diabetes mellitus, atherosclerosis, osteoporosis, and potentially others, we hypothesize that the biologic and genetic factors, synergistically with behavioral modifications, must be addressed to adequately treat this disease. We hypothesize that one such genetic factor that influences behavior and thus obesity is a predisposition to glucose craving and the overall effect of dopaminergic activity in the reward center of the brain. This defect drives individuals to engage in activities of behavioral excess, which will increase brain dopamine function, for which we have created the term reward deficiency syndrome (RDS) to categorize such biological influences on behavior. Consuming large quantities of alcohol or carbohydrates (carbohydrate bingeing) stimulates the brain's production of and utilization of dopamine. So too does the intake of crack/cocaine and the abuse of nicotine. We are proposing that a novel approach to nutritional supplementation may be required to target the RDS role in obesity. In this regard, Genotrim, a DNA based customized nutraceutical has been designed and is currently under investigation in several clinical studies. This is the first hypothesis paper whereby this new paradigm shift in thinking about obesity is presented.     

Manipulation of catechol-O-methyl-transferase (COMT) activity to influence the attenuation of substance seeking behavior, a subtype of Reward Deficiency Syndrome (RDS), is dependent upon gene polymorphisms: a hypothesis

There are common genetic mechanisms responsible for both drug effects and subsequent seeking behavior. In 1996, we coined the term Reward Deficiency Syndrome (RDS). Past and current treatment of substance seeking behavior, a subtype of Reward Deficiency Syndrome (RDS), is considered by most to be inadequate. Recently, we evaluated a complex named Synaptamine [Haveos (SG8839R)]. The main difference with an older studied variant and the latest variant is the inclusion of a proprietary form of Rhodiola rosea, a known catechol-O-methyl-transferase inhibitor (COMT) to potentially enhance the activity of presynaptic released dopamine. In this regard, based on the current literature we hypothesize that manipulation of catechol-O-methyl-transferase (COMT) activity to influence the attenuation of substance seeking behavior, is dependent upon gene polymorphisms. In this regard we hypothesize that carrying the LL genotype with low COMT activity should as theorized, increase the reward induced by substance-induced dopamine release and may indeed increase the propensity to type 1 alcoholism and possibly other drugs that activate the dopaminergic system. Thus when alcohol is present in low COMT LL genotype, increasing COMT activity, not inhibiting it should assist in the reduction of social consumption or abuse. Alternatively, under physiological conditions (no psychoactive substances present (e.g. alcohol) carrying the DRD2 A1 allele with associated low D2 receptors should, as theorized, increase craving behavior because of a low or hypodopaminergic state causing the individual to seek out substances that increase the release of dopamine for subsequent activation of unbound D2 sites in the nucleus accumbens. Thus, in the absence of alcohol or other psychoactive drugs (dopamine releasers), especially during recovery or rehabilitation, decreasing, not increasing COMT activity, should result in enhanced synaptic dopamine as physiologically released, thereby proliferating D2 receptors while reducing stress, increasing well-being, reducing craving behavior and preventing relapse. Based on this hypothesis, we believe that adding the COMT inhibitor R. rosea (as Rhodimin) to our amino-acid and chromium combination in DUI offenders and other illegal drug-related crimes, increases the potential for more targeted neurochemical rebalancing and enhanced relapse prevention. Finally, we hypothesize that these data coupled together provide evidence that the combination of enkephalinase inhibition, neurotransmitter precursor loading, brain tryptophan enhancing and COMT inhibition as well as DNA analysis of the individual's genome, may be useful as an adjunct to therapy when used in outpatient recovery, specifically to assist in reducing craving behavior and preventing relapse.     

Citicoline is not protective in experimental models of Huntington's disease

We have evaluated the neuroprotective effects of citicoline in relevant phenotypic models of Huntington's disease induced by either the mitochondrial inhibitor 3-nitropropionic acid or the N-methyl-d-aspartate agonist quinolinic acid, which, respectively, reproduce the metabolic defect or the excitotoxicity seen in the disease. We found that citicoline failed to reverse behavioural and histological alterations induced by both neurotoxins. In addition, citicoline did not reduce PC12 cell death induced by the expression of an N-terminal fragment of mutated Huntingtin. Altogether, our results suggest that citicoline is not a potential therapeutic agent for the treatment of Huntington's disease.     

Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease

The aim of this review is to summarize and critically discuss the complex role played by adenosine A_2A receptors (A_2ARs) in Huntington's disease (HD). Since A_2ARs are mainly localized on the neurons, which degenerate early in HD, and given their ability to stimulate glutamate outflow and inflammatory gliosis, it was hypothesized that they could be involved in the pathogenesis of HD, and that A_2AR antagonists could be neuroprotective. This was further sustained by the demonstration that A_2ARs and underlying signaling systems undergo profound changes in cellular and animal models of HD. More recently, however, the equation A_2A receptor blockade = neuroprotection has appeared too simplistic. First, it is now definitely clear that, besides mediating ‘bad’ responses (for example, stimulation of glutamate outflow and excessive glial activation), A_2ARs also promote ‘good’ responses (such as trophic and antinflammatory effects). This implies that A_2AR blockade results either in pro-toxic or neuroprotective effects according to the mechanisms involved in a given experimental model. Second, since HD is a chronically progressive disease, the multiple mechanisms involving A_2ARs may play different relative roles along the degenerative process. Such different mechanisms can be influenced by A_2AR activation or blockade in different ways, even leading to opposite outcomes depending on the time of agonist/antagonist administration. The number, and the complexity, of the possible scenarios is further increased by the influence of mutant Huntingtin on both the expression and functions of A_2ARs, and by the strikingly different effects mediated by A_2ARs expressed by different cell populations within the brain.     

An evaluation of the role of tumor load in cytoreductive nephrectomy

IntroductionNew radiological tools can accurately provide preoperative three-dimensional spatial assessment of metastatic renal cell carcinoma (RCC). We aimed to determine whether the distribution, volume, shape, and fraction of RCC resected in a cytoreductive nephrectomy associates with survival.MethodsWe retrospectively reviewed 560 patients undergoing cytoreductive nephrectomy, performing a comprehensive volumetric analysis in eligible patients of all detectable primary and metastatic RCC prior to surgery. We used Cox regression analysis to determine the association between the volume, shape, fraction resected, and distribution of RCC and overall survival (OS).ResultsThere were 62 patients eligible for volumetric analysis, with similar baseline characteristics to the entire cohort, and median survivor followup was 34 months. Larger primary tumors were less spherical, but not associated with different metastatic patterns. Increased primary tumor volume and tumor size, but not the fraction of tumor resected, were associated with inferior survival. The rank of tumors based on unidimensional size did not completely correspond to the rank by primary tumor volume, however, both measurements yielded similar concordance for predicted OS. Larger tumor volume was not associated with a longer postoperative time off treatment.ConclusionsPrimary tumor volume was significant for predicting OS, while the fraction of disease resected did not appear to impact patient outcomes. Although rich in detail, our study is potentially limited by selection bias. Future temporal studies may help elucidate whether the primary tumor shape is associated with tumor growth kinetics.     

Serum amyloid type a may be a predictor of restenosis

Background: Elevation of acute phase proteins [C-reactive protein (CRP) and serum amyloid type A (SAA)] has been demonstrated in unstable angina with an adverse clinical prognosis. Hypothesis: The study was undertaken to determine the effect of angioplasty on the levels of SAA and the correlation with postangioplasty restenosis. Methods: In a university-affiliated tertiary medical center, a prospective case study was undertaken in 55 patients who underwent successful percutaneous transluminal coronary angioplasty (PTCA) of a single coronary lesion for angina pectoris. Three groups of patients were clinically characterized according to Braunwald's classification of anginal syndrome: Group A: class III; Group B: class I; Group C: stable angina. Serum amyloid type A was measured by an ELISA method before PICA and after 24 h, 1, and 3 months. Patients were followed clinically for 12 months. A thallium stress perfusion scan was performed 3 months after PTCA and coronary angiography was repeated in patients with an abnormal thallium perfusion scan. Results: Serum amyloid type A levels >100 m?/ml could identify Group A patients with a high sensitivity and specificity (r = 0.85 and 0.86, respectively). Of the patients studied. 75% increased their SAA level 24 h after angioplasty. An increase of SAA by >100% was associated with an increased risk of restenosis, with a relative risk of 6.4 (p < 0.05). Conclusion: Increased levels of SAA characterize patients with unstable angina pectoris with a high specificity and sensitivity. Levels of SAA that increase > 100% 24 h after angioplasty may serve as a marker of restenosis.