Effect of a Faith-Based Education Program on Self-Assessed Physical, Mental and Spiritual (Religious) Health Parameters.

The aim of the study was to determine the effect of attending a faith-based education program (FBEP) on self-assessed physical, mental and spiritual health parameters. The study was designed as a prospective, observational, cohort study of individuals attending a 5-day FBEP. Out of 2650 sequential online registrants, those previously unexposed to the FBEP received automated invitations to complete 5 sequential Self-Assessment Questionnaire's (SAQ's) containing: (1) Duke University Religion Index (DUREL); (2) Negative Religious Coping (N-RCOPE); (3) Perceived Stress Scale (PSS); (4) Center for Epidemiology and Statistics-Depression Scale (CES-D); (5) Brief Illness Perception Questionnaire (BIPQ); and the (6) State Trait Anxiety Inventory (STAI). Pre-attendance SAQ (S1) was repeated immediately post-FBEP (S2), at 30 days (S3), 90 days (S4) and after 1 year (S5). Of 655 invited, 274 (42 %) succeeded, 242 (37 %) failed and 139 (21 %) declined to complete S1. Of the 274, 37 (14 %) were excluded at on-site interview; 26 (9 %) never attended the FBEP (i.e., controls: 5♂; 21♀; 27-76 years); and 211 (77 %) participated (i.e., cases: 105♂; 106♀; 18-84 years) and were analyzed over time: 211 (S1); 192 (S2); 99 (S3); 52 (S4); 51 (S5). IRB approval was via the Human Research Ethics Committee of Stellenbosch University. DUREL showed significant, sustained changes in Intrinsic Religiosity. N-RCOPE showed significant, lasting improvement. In others, median values dropped significantly immediately after the FBEP (S1:S2) for STAI-State p < 0.0001; PSS p < 0.0001; BIPQ p < 0.0001; and CES-D p < 0.0001; and at 1 month (S1:S3) for STAI-Trait p < 0.001; all changes were sustained (S3 through S5). This FBEP produced statistically and clinically significant changes; these lasted in those followed up >1 year.

Neurogenetic and epigenetic correlates of adolescent predisposition to and risk for addictive behaviors as a function of prefrontal cortex dysregulation.

As addiction professionals, we are becoming increasingly concerned about preteenagers and young adults' involvement with substance abuse as a way of relieving stress and anger. The turbulent underdeveloped central nervous system, especially in the prefrontal cortex (PFC), provides impetus to not only continue important neuroimaging studies in both human and animal models, but also to encourage preventive measures and cautions embraced by governmental and social media outlets. It is well known that before people reach their 20s, PFC development is undergoing significant changes and, as such, hijacks appropriate decision making in this population. We are further proposing that early genetic testing for addiction risk alleles will offer important information that could potentially be utilized by their parents and caregivers prior to use of psychoactive drugs by these youth. Understandably, family history, parenting styles, and attachment may be modified by various reward genes, including the known bonding substances oxytocin/vasopressin, which effect dopaminergic function. Well-characterized neuroimaging studies continue to reflect region-specific differential responses to drugs and food (including other non-substance-addictive behaviors) via either "surfeit" or "deficit." With this in mind, we hereby propose a "reward deficiency solution system" that combines early genetic risk diagnosis, medical monitoring, and nutrigenomic dopamine agonist modalities to combat this significant global dilemma that is preventing our youth from leading normal productive lives, which will in turn make them happier.

Genomic medicine and risk prediction across the disease spectrum.

Genomic medicine is based on the knowledge that virtually every medical condition, disease susceptibility or response to treatment is caused, regulated or influenced by genes. Genetic testing may therefore add value across the disease spectrum, ranging from single-gene disorders with a Mendelian inheritance pattern to complex multi-factorial diseases. The critical factors for genomic risk prediction are to determine: (1) where the genomic footprint of a particular susceptibility or dysfunction resides within this continuum, and (2) to what extent the genetic determinants are modified by environmental exposures. Regarding the small subset of highly penetrant monogenic disorders, a positive family history and early disease onset are mostly sufficient to determine the appropriateness of genetic testing in the index case and to inform pre-symptomatic diagnosis in at-risk family members. In more prevalent polygenic non-communicable diseases (NCDs), the use of appropriate eligibility criteria is required to ensure a balance between benefit and risk. An additional screening step may therefore be necessary to identify individuals most likely to benefit from genetic testing. This need provided the stimulus for the development of a pathology-supported genetic testing (PSGT) service as a new model for the translational implementation of genomic medicine in clinical practice. PSGT is linked to the establishment of a research database proven to be an invaluable resource for the validation of novel and previously described gene-disease associations replicated in the South African population for a broad range of NCDs associated with increased cardio-metabolic risk. The clinical importance of inquiry concerning family history in determining eligibility for personalized genotyping was supported beyond its current limited role in diagnosing or screening for monogenic subtypes of NCDs. With the recent introduction of advanced microarray-based breast cancer subtyping, genetic testing has extended beyond the genome of the host to also include tumor gene expression profiling for chemotherapy selection. The decreasing cost of next generation sequencing over recent years, together with improvement of both laboratory and computational protocols, enables the mapping of rare genetic disorders and discovery of shared genetic risk factors as novel therapeutic targets across diagnostic boundaries. This article reviews the challenges, successes, increasing inter-disciplinary integration and evolving strategies for extending PSGT towards exome and whole genome sequencing (WGS) within a dynamic framework. Specific points of overlap are highlighted between the application of PSGT and exome or WGS, as the next logical step in genetically uncharacterized patients for whom a particular disease pattern and/or therapeutic failure are not adequately accounted for during the PSGT pre-screen. Discrepancies between different next generation sequencing platforms and low concordance among variant-calling pipelines caution against offering exome or WGS as a stand-alone diagnostic approach. The public reference human genome sequence (hg19) contains minor alleles at more than 1 million loci and variant calling using an advanced major allele reference genome sequence is crucial to ensure data integrity. Understanding that genomic risk prediction is not deterministic but rather probabilistic provides the opportunity for disease prevention and targeted treatment in a way that is unique to each individual patient.

rsfMRI effects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts.

Recently, Willuhn et al. reported that cocaine use and even non-substance-related addictive behavior increases as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors and was also associated with lower activation of cues in occipital cortex and cerebellum, in a recent PET study by Volkow's et al. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220Z™ on reward circuitry of 10 heroin addicts undergoing protracted abstinence (average 16.9 months). In a randomized placebo-controlled crossover study of KB220Z, five subjects completed a triple-blinded experiment in which the subject, the person administering the treatment, and the person evaluating the response to treatment were blinded to the treatment that any particular subject was receiving. In addition, nine subjects were genotyped utilizing the GARSDX™ test. We preliminarily report that KB220Z induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following 1-hour acute administration. Furthermore, KB220Z also reduced resting-state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all 10 abstinent heroin-dependent subjects, we observed that three brain regions of interest were significantly activated from resting state by KB220Z compared to placebo (p < 0.05). Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. These results and other quantitative electroencephalogy (qEEG) study results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results, and confirmation with additional research and ongoing rodent and human studies of KB220Z is required.

Hatching the behavioral addiction egg: Reward Deficiency Solution System (RDSS)™ as a function of dopaminergic neurogenetics and brain functional connectivity linking all addictions under a common rubric.

BACKGROUND: Following the first association between the dopamine D2 receptor gene polymorphism and severe alcoholism, there has been an explosion of research reports in the psychiatric and behavioral addiction literature and neurogenetics. With this increased knowledge, the field has been rife with controversy. Moreover, with the advent of Whole Genome-Wide Studies (GWAS) and Whole Exome Sequencing (WES), along with Functional Genome Convergence, the multiple-candidate gene approach still has merit and is considered by many as the most prudent approach. However, it is the combination of these two approaches that will ultimately define real, genetic allelic relationships, in terms of both risk and etiology. Since 1996, our laboratory has coined the umbrella term Reward Deficiency Syndrome (RDS) to explain the common neurochemical and genetic mechanisms involved with both substance and non-substance, addictive behaviors. METHODS: This is a selective review of peer-reviewed papers primary listed in Pubmed and Medline. RESULTS: A review of the available evidence indicates the importance of dopaminergic pathways and resting-state, functional connectivity of brain reward circuits. DISCUSSION: Importantly, the proposal is that the real phenotype is RDS and impairments in the brain's reward cascade, either genetically or environmentally (epigenetically) induced, influence both substance and non-substance, addictive behaviors. Understanding shared common mechanisms will ultimately lead to better diagnosis, treatment and prevention of relapse. While, at this juncture, we cannot as yet state that we have "hatched the behavioral addiction egg", we are beginning to ask the correct questions and through an intense global effort will hopefully find a way of "redeeming joy" and permitting homo sapiens live a life, free of addiction and pain.

The fat mass and obesity-associated FTO rs9939609 polymorphism is associated with elevated homocysteine levels in patients with multiple sclerosis screened for vascular risk factors.

UNLABELLED: The previously reported link between homocysteine and obesity, both identified as established risk factors for multiple sclerosis (MS), has not previously been studied in relation to the fat mass and obesity-associated (FTO) gene. AIM: To investigate the mechanism underlying homocysteine accumulation in MS patients. A total of 114 patients and 195 population-matched controls were analysed for the FTO rs9939609 polymorphism. Homocysteine levels were measured in a subgroup of 60 patients and 87 controls screened for multiple vascular risk factors. After adjustment for potential confounders, the risk-associated FTO rs9939609 A-allele was associated with raised homocysteine levels (p = 0.003) in patients diagnosed with MS, but not in controls. Homocysteine levels correlated positively with body mass index (BMI) (p = 0.045) and total cholesterol levels (p = 0.048). Both homocysteine (p = 0.011) and BMI (p = 0.017) were significantly reduced with higher intake of folate in the diet. Higher BMI also correlated with increased intake of saturated/trans fat (p < 0.01) and low physical activity (p < 0.006). Daily intake of at least five fruits and vegetables had a favourable lowering effect on the Expanded Disability Status Scale (EDSS) (p = 0.035), while smoking increased MS disability (p < 0.001). This study has shown for the first time that having a diagnosis of MS moderates the effect of the FTO rs9939609 polymorphism on homocysteine levels. This is consistent with the role of FTO in demethylation and epigenetic changes. Identification of FTO rs9939609 reinforces the importance of adequate fruit, vegetable and folate and restriction of saturated/trans fat intake in the diet.

Pathology-supported genetic testing directed at shared disease pathways for optimized health in later life.

Several chronic, noncommunicable diseases share common genetic risk factors. These include cardiovascular disease and several neurological and psychiatric disorders, as well as some forms of cancer. Clinical compartmentalization and the challenges of translational research have delayed the implementation of personalized medicine. To overcome these limitations, a pathology-supported genetic testing service has been established to enable the incorporation of genomics into a universally accepted body of knowledge. An online questionnaire is used to obtain information on personal and family medical conditions, medication use/side effects, lifestyle factors and pathology test results relevant to the genetic analysis performed. Validation studies from multidisciplinary sources and the expanding Gknowmix™ database are applied to determine whether the clinical characteristics of the patient match the test results. With this approach, a set of common functional polymorphisms at critical control points within key biological pathways can be studied to determine current or future clinical relevance across diagnostic boundaries.

Analysis of clinical outcomes of linear vs. deep stop decompression from 3.5 to 6 atmospheres absolute (350 - 600 kpa) in awake rats.

UNLABELLED: Recreational divers are introducing "deep stops" at half the depth (HD-DS) to reduce the risk of spinal DCS with only Doppler evidence to support it. Therefore this research was designed to show the effect of an HD-DS on spinal DCS manifestations by evaluating whether: (1) air diving-induced spinal DCS could be produced in awake, freely moving rats at 3.5-6.0 atm abs (350-600 kPa); and (2) whether the introduction of an HD-DS reduced spinal DCS in such a model. Fifty-one female, Wistar rats (221 to 450 g) underwent one-hour compression at 350 to 600 kPa with seven minutes of decompression with/without a five-minute DS (HD-DS / No-DS). Animals were observed for three hours. Outcomes were classified as: (1) asymptomatic; (2) breathing difficulties; (3) paralysis/weakness; (4) immobility; or (5) death. Eight animals, exposed to 385 kPa air breathing for 60 minutes followed by a three-staged decompression of 7.5 minutes, remained asymptomatic. The profile is known to produce spinal DCS in anesthetized rats. Eleven animals were then used to determine the threshold for DCS: 500 kPa. A total of 14 animals were compressed to 550 kPa (Group 1). Group 1-A (n = 8) No-DS; Group 1-B (n = 6) HD-DS; 18 were compressed to 600 kPa (Group 2). Group 2-A (n = 8) No-DS; Group 2-B (n = 10) HD-DS. RESULTS: (1) 385 kPa protocol did not produce visible DCS manifestations in awake rats. The binomial probability of no DCS in this sample size is 0.002818 for the proportion expected from a published report. The binomial probability of no fatalities is 0.005346). (2) No animals developed spinal DCS when assessed by visible paralysis/weakness or immobility, so no difference could be shown. Group 1-A: two deaths; two breathing abnormalities; four asymptomatic. Group 1-B: all asymptomatic. Difference recorded for breathing difficulties (p = 0.0483); none for fatalities (p = 0.2024). Group 2 mortality was 55% (n = 10). Group 2-A and 2-B: no difference for death (p = 0.6063) or breathing problems (p = 0.2084). CONCLUSIONS: This model could not evaluate HD-DS for the prevention of spinal DCS in rats.

Fatal respiratory failure during a "technical" rebreather dive at extreme pressure.

A diving fatality at the extreme depth of 264 m fresh water is described. The diver was equipped with an underwater video camera which recorded events leading to his death. These events corroborated predictions about respiratory complications at extreme pressure made by early researchers. Review of the video and relevant literature resulted in the following physiological interpretation: an increase in respired gas density during descent caused a progressive increase in resistance to flow in both the airways and the breathing circuit. Initially, this was associated with a shift to ventilation at higher lung volumes, a relative degree of hypoventilation, and mild permissive hypercapnia. The promotion of turbulent airway flow by increasing gas density resulted in effort-independent expiratory flow at lower flow rates than usual. The consequent inability to match ventilation to the demands of physical work at the bottom precipitated a spiraling crisis of dyspnea, increasing PaCO2, and wasted respiratory effort, thus producing more CO2. Extreme hypercapnia eventually led to unconsciousness. This tragic case provides a timely and salient lesson to a growing population of deep "technical" divers that there are physiological limitations that must be understood and considered when planning extreme dives.

Carbon monoxide actuates O(2)-limited heme degradation in the rat brain.

The biochemical paradigm for carbon monoxide (CO) is driven by the century-old Warburg hypothesis: CO alters O(2)-dependent functions by binding heme proteins in competitive relation to 1/oxygen partial pressure (PO(2)). High PO(2) thus hastens CO elimination and toxicity resolution, but with more O(2), CO-exposed tissues paradoxically experience less oxidative stress. To help resolve this paradox we tested the Warburg hypothesis using a highly sensitive gas-reduction method to track CO uptake and elimination in brain, heart, and skeletal muscle in situ during and after exogenous CO administration. We found that CO administration does increase tissue CO concentration, but not in strict relation to 1/PO(2). Tissue gas uptake and elimination lag behind blood CO as predicted, but 1/PO(2) vs. [CO] fails even at hyperbaric PO(2). Mechanistically, we established in the brain that cytosol heme concentration increases 10-fold after CO exposure, which sustains intracellular CO content by providing substrate for heme oxygenase (HO) activated after hypoxia when O(2) is resupplied to cells rich in reduced pyridine nucleotides. We further demonstrate by analysis of CO production rates that this heme stress is not due to HO inhibition and that heme accumulation is facilitated by low brain PO(2). The latter becomes rate limiting for HO activity even at physiological PO(2), and the heme stress leads to doubling of brain HO-1 protein. We thus reveal novel biochemical actions of both CO and O(2) that must be accounted for when evaluating oxidative stress and biological signaling by these gases.